Editor_ by dfgh4bnmu

VIEWS: 23 PAGES: 88

									        INTRODUCTION.DOC
        1
 both groups were found also to improve survival.                      Heart failure is a common medical
 In spite of these advances, heart failure mortality      problem, it is the main cause of hospital
 rate is still high. More than 30 per cent of patients    admissions in elderly individuals and represents
 with severe heart failure - functional class IV – die    the commonest diagnosis in cardiology medical
 within one year of diagnosis in spite of ACE-            awards. In many countries the prevalence of heart
 inhibitor therapy. This has stimulated research in       failure is reaching epidemic proportions and its
 three directions. First: methods to prevent              high incidence rate is expected to continue and to
 development of heart failure through better              grow because of the aging of the population
 understanding of risk factors mechanisms and             worldwide. Heart failure is mainly a disease of the
 genetic predisposition; second: newer                    elderly. Our understanding of the pathophysiology
 pharmacologic agents that address remodeling and         of heart failure has improved very much in the
 apoptosis; third: gene therapy that correct              recent years. The introduction of molecular
 molecular defects and generate healthy contractile       biology techniques, clarified many of the
 machinery.                                               mechanisms leading to initiation and propagation
                                                          of heart failure. Neurohormonal activation,
             Because of the importance of the             apoptosis and cardiac remodeling were found to
 subject of heart failure, I invited on behalf of the     play a critical role in heart failure progression.
 Egyptian Hypertension Society, a number of               Based on this information, modern pharmacologic
 leading Egyptian cardiologists with vast clinical        therapy of heart failure is directed mainly to block
 knowledge and experience in handling heart               this excessive neurohormonal activity in an effort
 failure patients to participate in writing a practical   to slow, stop and hopefully reverse the cardiac
 heart failure manual. The manual contains                remodeling processes and its harmful
 practical information required for everyday              consequences. Drug therapy of heart failure has
 practice and also covers many of the advanced and        progressed in the last two decades and became
 the state of the art knowledge that is of interest to    more complicated than the simple measures of bed
 the more specialized cardiologist.                       rest, salt restriction, digitalis and diuretics. The
                                                          introduction of angiotensin-converting enzyme
             This book represents a collaborative         (ACE) inhibitor therapy made a breakthrough in
 effort of my friends and colleagues, members of          the management of heart failure, for the first time
 the Egyptian Hypertension Society (EHS), whom I          we have a pharmacologic agent that not only
 thank for their contribution. I would like to            improves patients symptoms and hemodynamics,
 acknowledge the efforts made by Doctors Magdi            but also prolongs survival. Furthermore, ACE-
 Abdelhamid, Yasser Baghdady and Radwa Bedir,             inhibitors can delay the development of heart
 who helped me in the final editing of this book          failure in patients with poor left ventricular
 and the excellent secretarial work of Mrs. Amany         function. Beta adrenergic blocking drugs and
 Kandeel. Finally, the support and generous grant         spironolactone are now getting an established role
 of Aventis Egypt that helped in the production of        in the management of heart failure, based upon
 this manual should be recognized.                        their effect in blocking neurohormonal activity,


   Editor,
M. MOHSEN IBRAHIM, MD
Prof. of Cardiology – Cairo University
President of the Egyptian Hypertension Society Cairo – August 2000.
                        LIST OF CONTRIBUTORS
Aly Ramzy, MD                        Mahmoud El-Sherbini, MD
Prof. of Cardiology                  Prof. of Cardiology
Ain Shams University                 Ain Shams University
Diaa Dardear, MD                     Mahmoud Hassanein, MD
Prof. of Cardiology                  Prof. of Cardiology
National Heart Institute             Alexandria University
Fathy Maklady, MD                    Mohamed Sobhy, MD
Prof. of Cardiology                  Prof. of Cardiology
Suez Canal University                Alexandria University
Hassan Khalil, MD                    Moustafa El-Sayed, MD
Prof. of Cardiology                  Prof. of Cardiology
Alexandria University                Al-Azhar University
Hossam Kandil, MD                    Omar Awad, MD
Assistant Prof. of Cardiology        Prof. of Cardiology
Cairo University                     Ain Shams University
Hussein Rizk, MD                     Omar El-Khashab, MD
Prof. of Cardiology                  Prof. of Nephrology & General Medicine
Cairo University                     Cairo University
Khairy Abdel Dayem, MD               Samir Abdel Kader, MD
Prof. of Cardiology                  Prof. of Cardiology
Ain Shams University                 Assiuyt University
M. Aziz Madkour, MD                  Sherif El-Tobgy, MD
Prof. of Cardiology                  Prof. of Cardiology
Al-Azhar University                  Cairo University
M. Mohsen Ibrahim, MD                Soliman Gharieb, MD
Prof. of Cardiology                  Prof. of Cardiology
Cairo University                     Cairo University
M. Mokhtar Gomaa, MD                 Wagdy Ayad, MD
Prof. of Cardiology                  Prof. of Cardiology
Al-Azhar University                  Alexandria University
Magdy Abdelhamid, MD                 Yasser Baghdady, MD
Assistant Prof. of Cardiology        Prof. of Cardiology
Cairo University                     Cairo University
‫‪LIST OF CONTRIBUTORS‬‬
             ‫د/ ﻋﻠﻲ رﻣﺰي ﻋﺒﺪ اﻟﻤﺠﻴﺪ‬        ‫١.‬
           ‫د/ ﻣﺤﻤﺪ ﺿﻴﺎء اﻟﺪﻳﻦ دردﻳﺮ‬        ‫٢.‬
            ‫د/ ﻓﺘﺤﻲ ﻋﺒﺪ اﻟﺤﻤﻴﺪ ﻣﻘﻠﺪي‬       ‫٣.‬
                    ‫د/ ﺣﺴﻦ ﺣﺴﻦ ﺧﻠﻴﻞ‬        ‫٤.‬
                 ‫د/ ﺣﺴﺎم إﺑﺮاهﻴﻢ ﻗﻨﺪﻳﻞ‬     ‫٥.‬
                   ‫د/ ﺣﺴﻴﻦ ﺣﺴﻦ رزق‬         ‫٦.‬
             ‫د/ ﻣﺤﻤﺪ ﺧﻴﺮي ﻋﺒﺪ اﻟﺪاﻳﻢ‬       ‫٧.‬
                 ‫د/ ﻣﺤﻤﺪ ﻋﺰﻳﺰ ﻣﺪآﻮر‬        ‫٨.‬
                ‫د/ ﻣﺤﻤﺪ ﻣﺤﺴﻦ إﺑﺮاهﻴﻢ‬       ‫٩.‬
           ‫د/ ﻣﺤﻤﺪ ﻣﺨﺘﺎر ﻣﺤﻤﺪ ﺟﻤﻌﺔ‬       ‫٠١.‬
       ‫د/ ﻣﺠﺪي ﻋﺒﺪ اﻟﺤﻤﻴﺪ ﻋﺒﺪ اﻟﻌﺰﻳﺰ‬     ‫١١.‬
                    ‫د/ ﻣﺤﻤﻮد اﻟﺸﺮﺑﻴﻨﻲ‬    ‫٢١.‬
                      ‫د/ ﻣﺤﻤﻮد ﺣﺴﻨﻴﻦ‬     ‫٣١.‬
            ‫د/ ﻣﺤﻤﺪ أﺣﻤﺪ ﺻﺒﺤﻲ ﻋﻠﻲ‬        ‫٤١.‬
                      ‫د/ ﻣﺼﻄﻔﻲ اﻟﺴﻴﺪ‬     ‫٥١.‬
                   ‫د/ ﻋﻤﺮ ﺻﻼح ﻋﻮاد‬       ‫٦١.‬
           ‫د/ ﻋﻤﺮ ﻳﺤﻴﻲ ﻋﺒﺪﻩ اﻟﺨﺸﺎب‬       ‫٧١.‬
               ‫د/ ﺳﻤﻴﺮ ﺳﻴﺪ ﻋﺒﺪ اﻟﻘﺎدر‬    ‫٨١.‬
        ‫د/ ﺷﺮﻳﻒ ﻣﺤﻤﺪ ﻓﺎﺋﻖ اﻟﻄﻮﺑﺠﻲ‬        ‫٩١.‬
        ‫د/ ﺳﻠﻴﻤﺎن ﻏﺮﻳﺐ إﺑﺮاهﻴﻢ ﻣﻬﺪي‬      ‫٠٢.‬
                   ‫د/ وﺟﺪي ﻋﻴﺎد ﺣﻠﻤﻲ‬     ‫١٢.‬
           ‫د/ ﻳﺎﺳﺮ ﻣﺤﻤﺪ ﺟﺎﺑﺮ ﺑﻐﺪادي‬      ‫٢٢.‬
                                                           A-5: Heart Failure in Special Groups
         HEART FAILURE                                            63
                                                           A-5.1: Heart Failure in the Elderly
                                                           A-5.2: Heart Failure in Pregnancy
                   MANUAL                                  A-5.3: General Anesthesia and Non-Cardiac Surgery
                                                            in Patients with Heart Failure
    EGYPTIAN HYPERTENSION SOCIETY                          A-5.4: Myocarditis

                     GUIDELINES                                          SECTION B: DIAGNOSIS
                          2000                             B-1: Clinical Evaluation
                                                                    75
                       EDITED BY:                          B-1.1: Introduction and Goals
                                                           B-1.2: Establish the Presence of Heart Failure
                                                           B-1.3: Assess Severity of Heart Failure
          M. MOHSEN IBRAHIM, MD                            B-1.4: Systolic vs. Diastolic Heart Failure
                                                           B-1.5: Identify Underlying, Precipitating and Contributing
              TABLE OF CONTENTS                            Causes
                                                           B-1.6: Associated Conditions
                                                           B-1.7: Complications of Heart Failure
            SECTION A: MECHANISMS
A-1: Epidemiology of Heart Failure                         B-2: Laboratory Evaluation
         10                                                         88
A-1.1: Increasing Importance of Heart Failure              B-2.1: Routine Laboratory Tests
A-1.2: Definition of Heart Failure                         B-2.2: Special Laboratory Tests
A-1.3: Prevalence of Heart Failure
A-1.4: Methods of Detection of Heart Failure in            B-3: Heart Failure with Normal Systolic Function
Epidemiologic Studies                                      (Diastolic Heart Failure)                      101
A-1.5: Epidemiology of Heart Failure in Egyptians          B-3.1: Definition and Epidemiology
A-1.6: Spectrum of Heart Failure                           B-3.2: Pathophysiology
A-1.7: Risk Factors for Heart Failure                      B-3.3: Causes
                                                           B-3.4: Diagnosis
A-2: Pathophysiology of Heart Failure                22    B-3.5: Differential Diagnosis
A-2.1: Introduction                                        B-3.6: Treatment
A-2.2: Molecular Basis
A-2.3: Cardiac and Circulatory Adaptation                  B-4: Differential Diagnosis of Heart Failure      106
A-2.4: Neurohormonal Changes                               B-4.1: Shortness of Breath
A-2.5: Progression of Heart Failure                        B-4.2: Pulmonary Edema
A-2.6: Cardiac Remodeling                                  B-4.3: Fatigue
A-2.7: Pathophysilogical Changes                           B-4.4: Edema of Lower Limbs
A-2.8: Mechanisms of Symptoms                              B-4.5: Systemic Venous Congestion
                                                           B-4.6: Gallop Sounds
A-3: Classification and Causes of Heart Failure       40
A-3.1: Type: Systolic vs. Diastolic Heart Failure
A-3.2: Manifestations                                       SECTION C: DRUGS FOR HEART FAILURE
A-3.3: Onset: Acute vs. Chronic                            C-1.1: Digitalis
A-3.4: Degree of Heart Failure: Functional Class                        118
A-3.5: Causes of Heart Failure                             C-1.2: Diuretics
A-3.6: Potentially Reversible Causes of Heart Failure      C-1.3: ACE Inhibitors
                                                           C-1.4: Beta Blockers
A-4: Renal and Electrolyte Disturbances in Heart Failure   C-1.5: Inotropic Agents and Other Drugs
                  52                                       C-1.6: Vasodilators
A-4.1: Introduction                                        C-1.7: Anticoagulants
A-4.2: Renal Insufficiency                                 C-1.8: Antiarrhythmic Agents
A-4.3: Hyponatremia
A-4.4: Renal Failure                                        SECTION D: THERAPEUTIC STRATEGIES
A-4.5: Hypokalemia & Hypomagnesemia
A-4.7: Hyperkalemia                                        D-1: Management of Heart Failure
A-4.8: Dialytic Treatment of Heart Failure                 165
                                                           D-1.1: Goals of Heart Failure Therapy
                                                           D-1.2: Correction of the Underlying Cause
D-1.3: Recognition and Treatment of Precipitating Factors
D-1.4: General Measures for Control of Heart Failure
D-1.5: Measures Recommended in Selected Patients
D-1.6: Other Measures
D-2: Acute Heart Failure                           175
D-2.1: Definition
D-2.2: Hemodynamic Manifestations
D-2.3: Classification
D-2.4: Causes
D-2.5: Management

D-3: Refractory Heart Failure
184
D-3.1: Introduction
D-3.2: Diagnostic Criteria
D-3.3: Potentially Correctable Causes
D-3.4: General Management
D-3.5: Diuretic Therapy
D-3.6: Drugs in Refractory Heart Failure
D-3.7: Refractory Heart Failure: Integrated Approach

D-4: New Therapeutic Strategies for Treatment of Heart
Failure                                198
D-4.1: Pharmacologic Therapy
D-4.2: Non-Pharmacologic Therapy

D-5. Rehabilitation of Patients with Heart Failure
                 215
D-5.1: Introduction
D-5.2: Exercise in the Treatment of Heart Failure
D-5.3: Possible Benefit to Exercise in Heart Failure
D-5.4: Exercise Prescription in Heart Failure
D-5.5: Contraindications to Exercise in Heart Failure
D-5.6: Patient and Family Education
D-5.7: Psychosocial Intervention

SUMMARY OF GUIDELINES FOR MANAGEMENT
OF HEART FAILURE
                        221
EPIDEMIOLOGY OF HEART FAILURE.DOC                                                                    1

    2.    Thirty per cent of asymptomatic patients with        A-1: Epidemiology of Heart Failure
          low ejection fraction (< 35%), develop heart
          failure in 3 years.
    3.    In those patients with asymptomatic left             A-1.1: Increasing Importance of Heart Failure
          ventricular dysfunction the introduction of          A-1.2: Definition of Heart Failure
          angiotensin converting enzyme inhibitors             A-1.3: Prevalence of Heart Failure
          therapy helped improve morbidity and                 A-1.4: Methods of Detection of Heart Failure in
          mortality and delayed the development of heart       Epidemiologic Studies
          failure.                                             A-1.5: Epidemiology of Heart Failure in Egyptians
                                                               A-1.6: Spectrum of Heart Failure
                                                               A-1.7: Risk Factors for Heart Failure
A-1.2: DEFINITION OF HEART FAILURE
    1.    There is no uniformly accepted definition of
          heart failure. Absence of a clear definition         A-1.1: INCREASING IMPORTANCE                 OF   HEART
          makes interpretation of epidemiologic and            FAILURE
          therapeutic studies more difficult. All
          definitions proposed so far have limitations.
                                                               1. High Prevalence and Incidence Rates:
          However, the following two definitions are the
                                                                   1.   In recent decades, heart failure has gradually
          most acceptable:
                                                                        become one of the most prevalent
         1. European Committee (1991):                                  cardiovascular disorders, especially in the
Any heart disease in which, despite adequate ventricular                elderly. Heart failure is now possibly the main
filling, the heart’s output is decreased or in which the                cause of hospitalization in our cardiac
heart is unable to pump blood at a rate adequate for                    departments and is the main cause of hospital
satisfying the requirements of the tissues.                             admission in elderly individuals. It is expected
     2. European Society of Cardiology                                  that the prevalence of heart failure will almost
   (ESC) (1995):                                                        double over the next 40 years.
       Combination of:                                             2.   There are three important reasons for the
    1.    Symptoms of heart failure (at rest or during                  present high prevalence rates of heart failure
          exercise); and                                                and the increasing incidence in the past
    2.    2. Objective evidence of cardiac dysfunction at               decades and possibly in the coming years.
          rest;      and                                                First: Heart failure is generally a disease of old
    3.    Response to treatment directed towards heart                  age. In all parts of the world there is an
          failure (in cases where                                       increase in the average life expectancy and
    4.    the diagnosis is in doubt).                                   aging of the population. In Egypt, the average
                                                                        life span increased by about 15 years in the last
                                                                        three decades (average life expectancy
         We believe that the ESC definition is the most                 increased from 54 to 69 years). Second:
         useful both in clinical practice and in                        Improvement in survival of patients with
         epidemiologic studies.                                         coronary artery disease, valvular and
         We propose the following definition for heart                  hypertensive heart disease due to the
         failure, which is a modification of the ESC                    introduction of effective surgical and
         definition: Heart failure is a syndrome of clinical            pharmacologic interventions. These modern
         manifestations of inadequate tissue perfusion                  therapies, though effective in improving
         with pulmonary and/or systemic venous                          symptoms, morbidity and mortality, allow
         congestion associated with objective evidence of               patients to live longer with poor cardiac
         cardiac dysfunction.                                           function and in the majority of cases they only
                                                                        delay the development of heart failure. Third:
                                                                        The rising incidence of diabetes mellitus, an
A-1.3: PREVALENCE OF HEART FAILURE                                      important risk factor for atherosclerotic
Methods of getting information about prevalence of                      cardiovascular disease and for heart failure.
heart failure:                                                 2. Asymptomatic Left Ventricular
    • Epidemiologic cross sectional surveys                    Dysfunction:
         conducted at national or regional levels in the           1.   There is a good percentage of patients who
         general population;                                            have poor left ventricular function on
    • Hospital medical records;                                         echocardiographic studies, yet are symptom-
    • Drug prescription data analysis;                                  free.
    • General practitioner monitoring of a sample of
         the population;
    EPIDEMIOLOGY OF HEART FAILURE.DOC                                                                     2

             adequate health facilities may be responsible              •     General practitioner’s medical records.
             for increased risk of cardiovascular disorders
             and heart failure.
                                                                    CAUSES OF HEART FAILURE DIFFERED OVER
             COSTS OF HEART FAILURE                                              THE LAST FOUR DECADES

-             USA $ 8.5 Billion / Year
                                                                 • Coronary artery disease as a cause of heart
-             UK ₤ 360 Million / Year
                                                                   failure increased in the last 50 years.
                                                                       Year                   1950s               1960s
    A-1.4: METHODS         OF   DETECTION       OF   HEART                 1970s              1980s
    FAILURE IN EPIDEMIOLOGIC STUDIES                                   Coronary artery disease           22%
                                                                           36%                53%                 67%
    1. Clinical Methods:
        •    Diagnosis of heart failure depends upon                • Diabetes mellitus prevalence increased
             symptoms and signs elicited during clinical           by > 20% per decade.
             examination. The cardinal clinical
                                                                 • Valvular heart disease declined.
             manifestations of heart failure are discussed in
                                                                 • Preceding hypertension & left ventricular
             chapter B.1. These clinical methods were used
                                                                   hypertrophy became less frequent since 1965.
             in many surveys and different scoring systems
                                                                   Hypertension was the commonest cause of heart
             were developed for heart failure diagnosis (see
                                                                   failure and the only identifiable cause in 30% of men
             table for Framingham criteria for congestive
                                                                   and 20% of women.
             heart failure).
        •    Limitations of Clinical Methods:                    • In Egypt, valvular heart disease is a common
                  1. Lack of agreement on a definition of          etiology for heart failure in young and middle aged
                       heart failure.                              persons. The incidence of coronary disease is rising,
                  2. Lack of a gold standard to confirm the        a pattern similar to Western countries, it is becoming
                       diagnosis.                                  the commonest cause of heart failure in the middle
                  3. The symptoms and signs of heart               aged and elderly Egyptians.
                       failure have poor predictive value (see
                       table).                                     Factors that influence the prevalence of heart failure:
                  4. An important limitation of clinical
                                                                       • There are large differences in the reported
                       methods is their inability to identify
                                                                            prevalence rates of heart failure among
                       asymptomatic left ventricular
                                                                            different populations and in the same
                       dysfunction. These methods diagnose
                                                                            population.
                       only advanced cases.
                                                                   1) Methodology: Diagnostic criteria of heart failure
                                                                   whether solely clinical or combined with investigations.
    2. Biochemical Methods:                                            5. Age and gender of the population surveyed:
    Detection of biochemical markers for heart failure in                   Heart failure is more prevalent in the elderly
    blood samples depends upon the demonstration of                         and in males.
    elevated plasma levels of atrial and brain natriuretic
    peptide (ANP, BNP), (see chapter on Pathophysiology).               6.    Prevalence of cardiovascular risk factors in the
    They are markers of left ventricular function and are                     population, e.g. Hypertension, diabetes
    prognostic indicators.                                                    mellitus, dyslipidemia.

    3. Echocardiographic Studies:                                       7.    Prevalence of cardiac diseases in the
    Echocardiography provides a simple, non-invasive tool                     community, e.g., valvular heart disease,
    for the objective assessment of left ventricular function.                coronary artery disease.
    Two indices can be derived for assessment of left
    ventricular systolic function: fractional shortening (FS)           8.    Prevalence: Total number of events or
    and ejection fraction (EF). Doppler studies of mitral                     individuals with a disease or with a risk factor
    flow can give an idea about left ventricular diastolic                    at one point in time per 1000 individuals in a
    function by measuring the peak atrial (A) and left                        nation or community.
    ventricular early filling (E) velocities.                                 Incidence: Number of new cases or events per
    Echocardiography can differentiate systolic from                          1000 individuals over a specific period of time,
    diastolic dysfunction, assess the severity and underlying                 e.g., one year.
    etiology of heart failure, and is useful in monitoring and
    follow-up. The limitations of echocardiography include              9.    Socioeconomic status and level of medical
                                                                              services: poverty, illiteracy and lack of
 EPIDEMIOLOGY OF HEART FAILURE.DOC                                                                   3

 Hypertension Project Survey conducted in the years              its subjective nature; accuracy depends very much on
 1991-1994. A population based study of normotensive             the training and experience of the operator.
 and hypertensive Egyptians representing all regions and
 socioeconomic groups was examined clinically and
 studied by M-mode and Doppler echocardiography. The
                                                                 The best available approach for the diagnosis of
 criteria for the diagnosis of clinical heart failure were       heart failure both in clinical practice and in
 the presence of two or more of the following: Cardiac           epidemiologic surveys is a combination of clinical
 dyspnea, ankle edema, pulmonary congestion, raised              methods and an echocardiographic study of left
 jugular venous pressure and S3 gallop.                          ventricular function.
 The sample consisted of 2313 individuals, 25 to 90
 years old. The number of hypertensives was double the
 number of normotensives in the study. Left ventricular                       HEART FAILURE
 systolic dysfunction was defined by an                                    INCIDENCE RATES / 100,000
 echocardiographic fractional shortening (FS), equal or                      GENERAL POPULATION
 less than 25%. Clinical heart failure was present in
 10.9% of individuals (5.4% in males and 14.9% in            -       HF: 300
 females). A low fractional shortening was present in
 3.4% of the population (3.6% in males and 3.2% in           -       Breast Cancer: 54
 females). A low fractional shortening (≤ 25%) was           -       Cervical Cancer: 24
 present in 1.7% of normotensives and 4.2% of
 hypertensives. Clinical heart failure was diagnosed in
 5.8% of normotensives and 13.3% of hypertensives.                SCORING SYSTEMS FOR CRITERIA OF
 A combination of low fractional shortening                         DIAGNOSIS OF HEART FAILURE
 and clinical heart failure, i.e., satisfying the                              Framingham Criteria
 European Society of Cardiology criteria for                     Major criteria:
 heart failure, was present in 0.13% of                                   - Paroxysmal nocturnal dyspnea or orthopnea.
 normotensives and 0.96% of hypertensives. In                             - Neck vein distension
 patients with low fractional shortening 33% have no                      - Pulmonary rales
 symptoms, i.e., asymptomatic left ventricular                            - Acute pulmonary edema
 dysfunction was present in 1.1% of the total population.                 - S3 gallop
                                                                          - Increased venous pressure > 16 cm of water
                                                                          - Circulation time > 25 sec.
         PREVALENCE OF HEART                                              - Hepatic jugular reflux
                                                                 Minor criteria:
               FAILURE                                                    - Ankle oedema
             POPULATION SURVEYS                                           - Night cough
         BASED UPON CLINICAL CRITERIA                                     - Dyspnea on exertion
                                                                          - Hepatomegaly
                                                                          - Pleural effusion
• Framingham Study                                                        - Vital capacity decreased 1/3 from maximum.
          At entry: 0.3% of population                                    - Tachycardia (rate of > 120/min)
          At 34 y follow-up: 0.8% at ages 50-59                  Major or Minor criterion:
                               9% at ages 80 years and                    Weight loss > 4.5 Kg in 5 days in response to
 older                                                           treatment.
                            Total : 1%                           Definite diagnosis of congestive heart failure: 2 major
                                                                 or one major and 2 minor criteria are required.
• West London 1988
                                                                  20% of patients with low EF (≤ 40%) met none of
                            Below 65 years age 0.06%
                                                                             the criteria for heart failure.
                                   65 years & older
 2.8%                                                            51% of patients with normal EF (≥ 50%) met at least
                         Overall 0.4%                                                one criterion.

• Sweden: Study of Men born 1913:
           2% at age 50 years.                                   A-1.5: EPIDEMIOLOGY OF HEART FAILURE IN
          13% at age 67 years.                                   EGYPTIANS
                                                                 Information about the prevalence of heart failure among
                                                                 Egyptians was collected during the Egyptian National
EPIDEMIOLOGY OF HEART FAILURE.DOC                                                                   4

compensate for increased pressure load, volume load or
myocyte loss. There is usually a long asymptomatic
                                                             • NHANES-1:
phase of changes in shape, geometry, architecture with                 National Survey             2%
hypertrophy and dilatation before clinical symptoms
occur. Based upon the presence or absence of heart
                                                             • Germany:
failure symptoms, there are two groups of patients with
heart failure seen in clinical practice and epidemiologic              3% of the population
surveys.

1. Asymptomatic Heart Failure:                                    PREVALENCE OF HEART FAILURE
This includes a) patients with asymptomatic left
ventricular dysfunction, i.e., patients with poor ejection
                                                                     (CLINICAL + OBJECTIVE
fraction but have no symptoms; b) patients with heart
failure who were treated and their symptoms                     MEASUREMENTS OF LV FUNCTION)
disappeared because of therapy.
                                                             • Rotterdam Study (FS ≤ 25%)
2. Symptomatic Heart Failure:
This includes a) patients with clinical manifestations of              Total: 3.7%,                Men: 5.5%,
heart failure, but lack objective evidence of left                     Women: 3.2%
ventricular dysfunction; b) patients with clinical heart
failure who have echocardiographic or nuclear studies        • Glasgow Study (EF ≤ 30%)
showing poor left ventricular function, and c) patients
with transient heart failure who have potentially                      Total: 2.9%,                Men: 4%,
reversible left ventricular dysfunction.                               Women: 2.0%

Most cases of heart failure are not cured, 60-70% of         • Egyptian Study (FS ≤ 25%)
patients experience recurrence of symptoms repeatedly
within 6 years.
                                                                       NT: 0.13%,                  HT : 0.96%

         ABNORMAL CARDIAC FUNCTION                            A-1.6: SPECTRUM OF HEART FAILURE
                                                              Heart failure is a progressive disorder. The left ventricle
                                                              goes through a number of adaptations -remodeling- to


               ASYMPTOMATIC                                                                   SYMPTOMATIC


          LVD              TREATED HEART FAILURE                           CLINICAL HF        CLINICAL HF +         TRANSIENT
                                                                                              OBJECTIVE LVD            HF
          11. Valvular deformity.
                                                               (LVD: Left Ventricular Dysfunction)
                                                               A-1.7: Risk Factors for Heart Failure
                                                                   • The following factors increase the risk
                          PROGNOSIS                                    for future development of heart failure
                                                                       (Framingham data):
               Half of the patients carrying a                        1. Age: Heart failure incidence
         diagnosis of heart failure will die within                        doubles with each advancing
         4 years and in patients with severe heart                         decade of life.
           failure half will die within one year.                     2. Increased systolic blood pressure.
                                                                      3. Rapid heart rate.
                                                                      4. Electrocardiographic evidence of
                                                                           left ventricular hypertrophy.
                                                                5. Radiologic cardiac enlargement.
                                                                6. Impaired glucose tolerance.
                                                                7. Diabetes mellitus.
                                                                8. Increased ratio of total cholesterol / high
                                                                    density lipoprotein cholesterol.
                                                                9. Reduced vital capacity.
                                                                10. Coronary artery disease.
PATHOPHYSIOLOGY OF HEART FAILURE.DOC                                                              1


A-2: PATHOPHYSIOLOGY OF                               Myocardium obtained at the time of cardiac
                                                      transplantation from patients with end stage heart
                                                      failure exhibits abnormal prolongation of the
           HEART FAILURE                              action potential. This myocardium exhibits lower
                                                      developed force and impaired relaxation, due to
                                                      slower delivery of Ca++ to the contractile
                                                      apparatus (causing slower activation) and a
A-2.1: Introduction                                   slowed rate of Ca++ sequestration during
A-2.2: Molecular Basis                                repolarization (causing a slowed relaxation).
A-2.3: Cardiac and Circulatory Adaptation             These two important abnormalities contribute to
A-2.4: Neurohormonal Changes                          both systolic and diastolic dysfunction.
A-2.5: Progression of Heart Failure
A-2.6: Cardiac Remodeling                             2. Myocardial Receptor Function:
A-2.7: Pathophysilogical Changes                      Myocardial β-adrenergic receptors are down
A-2.8: Mechanisms of Symptoms                         regulated in heart failure. This may be the result
                                                      of increased circulating catecholamines. In the
                                                      failing myocardium, there is disturbance in the
A-2.1: INTRODUCTION                                   ratio of β-1 to β-2 receptors.
                                                      G-Proteins are specialized types of proteins that
This chapter will enable the practitioner to          link the cell membrane receptors to an ionic
understand the different processes leading to heart   channel or to a membrane or cytoplasmic enzyme.
failure, the mechanisms of production of              They contain a guanosine nucleus. Different
manifestations of failure and the rationale behind    isoforms have been identified based upon their
therapeutic interventions.                            ability to stimulate (Gs) or inhibit (Gi) the enzyme
Advances in biochemistry, physiology, electron        adenylate cyclase. In heart failure Gi is increased
microscopy and pharmacology made it possible to       and Gs is decreased.
understand the mechanisms of diseases and drug
actions at the molecular and cellular levels. Some
                                                      3. Myocardial Energy Production and
of the information in this chapter may not be
                                                      Utilization:
needed by the general practitioner for his
                                                      Experimental studies showed that failing heart
everyday practice. Important changes at the
                                                      muscle requires less oxygen than does normal
cellular and molecular level have been identified
                                                      muscle. These lowered energy needs of the failing
in hypertrophied and failing myocardium.
                                                      heart may serve a protective function.
Abnormalities in excitation contraction coupling,
                                                      Mitochondria obtained from failing human cardiac
contractile protein function and myocardial energy
                                                      muscle have also shown reduced oxygen
production and utilization have been identified in
                                                      consumption during active phosphorylation.
failing myocardium at the molecular level,
                                                      Myocardial failure in the setting of hemodynamic
alterations have been observed in the proteins that
                                                      overload may be related to inability of the energy
are central to normal myocardial structure and
                                                      producing system, to keep pace with the energy
function. These molecular and cellular events are
                                                      needed for the contractile apparatus.
secondary to both mechanical forces (excessive
loading of the heart) and to a variety of neuronal,
endocrine and autocrine/paracrine mediators that      4. Contractile Proteins:
act on the myocardium.                                In end-stage heart failure in the human, electron
                                                      microscopic observations show a reduction of
                                                      ventricular myofibrillar protein. Considerable data
                                                      suggest that qualitative as well as quantitative
A-2.2: MOLECULAR BASIS                                alterations of contractile proteins occur in heart
                                                      failure. Early studies showed that the activity of
1. Sarcolemmal and Sarcoplasmic Reticulum
                                                      myofibrillar ATPase is reduced in the hearts of
Functions:
                                                      patients who died of heart failure.
Calcium plays a central role in the regulation of
myocardial contraction and relaxation.
Abnormalities in the sarcolemmal and                  5. Inflammatory Cytokines:
sarcoplasmic reticular functions which regulate       These are proteins and peptides produced by
calcium uptake and release from the cytoplasm         lymphocytes, macrophages, vascular endothelial
were reported in heart failure.                       and many other cells. They mediate inflammatory
PATHOPHYSIOLOGY OF HEART FAILURE.DOC                                                                2


and immune reactions, act on their cells of origin          2.   Myocardial hypertrophy with or without
(autocrine), neighboring cells (paracrine) or are                cardiac chamber dilatation, in which the
secreted in the blood (endocrine). Examples are                  mass of contractile tissue is augmented.
interleukins, tumor necrosis factor and interferon.              Generation of new muscle units
Plasma concentrations of inflammatory cytokines                  (sarcomeres) will augment the cardiac
are increased in patients with heart failure and                 pumping function.
correlate with its severity. They can depress
myocardial function and have been implicated in             3.   Activation of Neurohormonal Systems:
pathological states as sepsis and myocarditis.                   The release of the neurotransmitter
Some of the effects of inflammatory cytokines are                norepinephrine (NE) by adrenergic
mediated via nitric oxide (NO).                                  cardiac nerves augments myocardial
                                                                 contractility. Activation of the renin-
6. Oxidative Stress:                                             angiotensin-aldosterone system acts to
As a result of the normal metabolic process in the               maintain arterial pressure and perfusion
cell a number of reactive oxygen species named                   of vital organs (see next part). In acute
oxygen-free radicles are produced. They are very                 heart failure, these adaptive mechanisms
toxic to the cell, since they bind and oxidize the               may not be adequate to maintain the
lipids in the cell membrane and intracellular                    overall pumping performance of the
structures. However, they have an important rule                 heart. In chronic heart failure, these
in defending our tissues against invading                        changes become maladaptive.
microorganisms. Under normal condition, they are
removed by a number of enzymatic and                        4.   Sodium Handling: When the volume of
antioxidative systems. They have a very short life               blood delivered into the systemic arterial
span. There is evidence that oxidative stress is                 bed is chronically reduced, a complex
increased in patients with chronic heart failure and             sequence of adjustments occurs that
has a negative inotropic effect.                                 ultimately results in the retention of
                                                                 sodium and water in the intravascular and
                                                                 interstitial compartments. Many of the
                                                                 clinical manifestations of heart failure
A-2.3: CARDIAC           AND     CIRCULATORY                     such as dyspnea and edema are
ADAPTATION                                                       secondary to this excessive retention of
                                                                 fluid. Cardiac output is often depressed
In the presence of a primary disturbance in                      and the arterial-mixed venous oxygen
myocardial contractility secondary to direct                     difference is widened in the basal state in
damage or loss of cardiac muscle, e.g. infarction,               patients with the common forms of heart
or when there is an excessive hemodynamic                        failure. In cases of mild heart failure, the
burden placed on the ventricle, or both, the heart               cardiac output may be normal at rest but
depends on a number of adaptive mechanisms for                   fails to rise normally during exercise.
maintenance of its pumping function and cardiac
output.
                                                        A-2.4: NEUROHORMONAL CHANGES
Most important among these are:
    1.   The Frank-Starling mechanism, stretch of       Myocardial injury resulting from myocyte loss or
         cardiac muscle will increase its force of      abnormal increase in loading conditions (pressure,
         contraction. An increased preload helps        volume) will activate a number of neuroendocrine
         to sustain cardiac performance. Failure of     systems in order to maintain cardiac pumping
         the heart to empty itself secondary to         function, cardiac output and tissue perfusion.
         poor pumping capacity will lead to an          Although this activation is initially useful and
         increase in the preload, chamber               helps to adapt the heart to the results of
         dilatation and an increase in muscle           myocardial injury, on long term it becomes
         stretch. With dilatation, a lesser degree of   excessive, maladaptive and counterproductive.
         muscle fiber shortening can deliver the        This excessive neurohormonal activation is the
         same stroke volume.                            main mechanism for cardiac remodeling, leading
                                                        to structural changes in cardiac muscle and
                                                        cardiac chambers ending in a vicious circle of
                                                        progressive pump failure, more neuroendocrine
     PATHOPHYSIOLOGY OF HEART FAILURE.DOC                                                                      3


     activation, additional remodeling and finally                Vasopressin (AVP): There is a trend for
     cardiac death, (Figure ). Modern pharmacologic               increase in AVP in patients with heart failure.
     interventions are directed to check or block this            Synthesis and release of AVP from the
     excessive neurohormonal activation in an effort to           posterior hypothalamus is regulated by osmotic
     delay, arrest or hopefully reverse the cardiac               and non-osmotic stimuli. The primary osmotic
     remodeling process.                                          stimulus to AVP release is hypernatremia. The
     The neurohormonal systems that are activated in              non-osmotic stimuli include excessive diuresis,
     heart failure are best classified based upon their           hypotension and A II. AVP acts on the kidneys
     effect on systemic vascular resistance.                      to decrease the clearance of free water.

         1.   Changes that Increase Systemic Vascular        2.                         Endothelin: Endothelin
              Resistance:                                         is a 21 amino acid peptide formed mainly by
              Sympathetic Nervous System (SNS):                   the vascular endothelium. It is a very potent
              There is direct evidence that increase in           vasoconstrictor and a mitogenic substance.
              central sympathetic nerve outflow occurs            Plasma endothelin is increased in heart failure.
              in patients with heart failure and is
              associated with an increase in plasma
              norepinephrine. In general, the greater        3.                   Neuropeptide Y
              the activation of SNS, the worse the                (Neuropeptide Tyrosine): 36 amino acid
              prognosis. Increased sympathetic activity           peptide which may be an important factor in
              increases peripheral vascular resistance            control of myocardial contractility and
              and results in sodium retention by the              regulation of myocardial perfusion. Its level is
              kidney. Both appear to be compensatory              increased in some patients with heart failure. It
              helping to maintain the blood pressure,             can cause direct vasoconstriction and potentiate
              but if exaggerated, they contribute to              the vasoconstrictor effect of norepinephrine
              increased stress on the failing heart.              and angiotensin II.

         2.   Renin Angiotensin System (RAS): RAS            4.                     Tumor Necrosis
              is activated in patients with heart failure.        Factor (TNF): TNF is a cytokine expressed
              There is a substantial rise in circulating          mainly by macrophages, vascular smooth
              renin, angiotensin II and aldosterone.              muscle cells and the heart. It is expressed in
              Tissue RAS plays a critical role in both            cardiac tissue in patients with heart failure.
              myocardial and vascular remodeling. A
                                                                  TNFα may have a role in left ventricular
              number of factors are responsible for the
                                                                  remodeling and heart failure and appears to
              increased release of renin:
                                                                  be associated with apoptosis.
                   • Decreased perfusion of the
                        kidney.
                   • Increased activity of SNS.              5.                       Prostaglandins
                   • Institution of a low sodium diet.            (PG): The kidneys synthesize PGF2 in the
                   • Vasodilator therapy and                      interstitium and collecting ducts of the
                        diuretics.                                medulla. Its role in heart failure and sodium
                        Angiotensin II: Angiotensin               retention is not clear.
                        II (A II) is a potent                6.                    Decreased Nitrous
                        vasoconstrictor peptide and also          Oxide (NO): NO is an endothelial derived
                        acts upon the adrenal cortex to           relaxing factor (EDRF), and is normally
                        release aldosterone                       generated and released to maintain a state of
                        (mineralocorticoid), which is a           dilatation of vasculature. In heart failure the
                        potent sodium retaining                   production and release of NO is impaired,
                        hormone. Furthermore,                     most probably secondary to abnormal
                        aldosterone stimulates                    vascular endothelial function and increased
                        myocardial fibrosis. A II                 oxidative stress.
                        stimulates the SNS, the thirst
                        center and the release of AVP.                  2. Changes that Decrease
                                                                  Systemic Vascular Resistance:
1.                          Argenine
     PATHOPHYSIOLOGY OF HEART FAILURE.DOC                                                                       4


1.                     Atrial and Brain                            have increased levels of metabolites of
     Natriuretic Peptides (ANP & BNP):                             vasodilator PGI2. PGI2 may oppose the
     ANP & BNP are synthesized in the atria and the                vasoconstrictor effect of RAS.
     ventricles, respectively. The stimulus for their
     production is distention of the respective               4.                            Bradykinin: The
     chamber. They produce natriuresis, diuresis and               vasodilator peptide bradykinin may be involved
     vasodilatation. They antagonize the renin-                    in the intrarenal distribution of blood flow and
     angiotensin system and AVP. The level of these                excretion of sodium, but its role in heart failure is
     peptides is increased in patients with heart failure          unclear. Bradykinin enhances nitric oxide
     and correlates with severity of heart failure. They           production, which is responsible for many of the
     are early markers of impaired left ventricular                actions of bradykinin.
     function. Their beneficial effect is overcome by
     the previously mentioned vasoconstrictor
     substances.

2.                            Dopamine: Dopamine
     is probably secreted by the adrenal medulla.
     Dopamine induces natriuresis, increases renal
     blood flow and glomerular filtration rate. Plasma
     dopamine increases in heart failure. Low dose
     dopamine (≤ 2 μg/Kg/min) in severe heart failure
     increases renal blood flow and results in
     natriuresis in patients refractory to furosemide.

3.                          Prostacyclin (PGI2):
     Prostacyclin is synthesized by vascular
     endothelial cells and smooth muscle cells. It may
     help maintain glomerular filtration rate in the
     presence of marked efferent arterial
     vasoconstriction. Some patients with heart failure
                             Myocyte Loss                                         Excessive Mechanical Loading

                                                            CARDIAC INJURY
                                                                                      ↓               ↓
                                                                                      LV DILATATION
                                                                                      ↓
                                                                                      ↑ WALL STRESS
                                                                      ↓
                                            NEUROHORMONAL ACTIVATION
                                                                      ↓
                                      PROGRESSIVE CARDIAC PUMP FAILURE
                                                                      ↓
                                                             TERMINAL H F
                                                                      ↓
                                                                DEATH
                                                               A-2.5: PROGRESSION OF HEART FAILURE
PATHOPHYSIOLOGY OF HEART FAILURE.DOC                                                                5


    •    Upon imposition of an excessive                      1. Irregular myocyte hypertrophy.
         mechanical load, left ventricular wall               2. Loss of myocytes by necrosis
         stress* rises, increasing the work demand
         on the ventricle. This increased wall
                                                                  and apoptosis.
         stress leads initially to ventricular                3. Regression of proteins by
         dilation, and through                                    changing into fetal phenotype.
         “Mechanotransduction”, ultimately to            Matrix Changes: Increased collagen formation and
         ventricular hypertrophy.                        increased interstitial and replacement fibrosis.
    •    As a consequence, a “compensatory
         phase” sets in as the ventricle
         hypertrophies, and the contractile              2. Chamber Level:
         function returns to approximately normal           •    Progressive left ventricular dilatation.
         levels. Mitochondria proliferate, and              •    Change in the left ventricular shape from
         myofibrils are laid down in parallel and                ellipsoid to globular form.
         sarcomeres in series so that both the              •    Segmental hypertrophy and thinning.
         length and cross-sectional diameter of
         myocytes is increased. Later, alterations          •    Factors that lead to remodeling:
         in cellular organization take place. This          •    Increase in left ventricular wall stress
         is followed by an "exhaustion" phase, in                secondary to excessive left ventricular
         which several events take place:                        loading.
              1. there is lysis of myofibrils;              •    Excessive neurohormonal activation.
              2. lysosomes increase in number
                   (presumably to digest worn-out        Details of Left Ventricular Remodeling:
                   cell constituents);
              3. the sarcoplasmic reticulum          •         Changes in cardiac Myocyte
                   becomes distorted;                    and Myocardium:
              4. the surface densities of the key           1.   Alterations in myosin heavy chain gene
                   tubular system are reduced, and               expression: decrease in α-myosin and
              5. fibrous tissue takes the place of               increase in β-myosin.
                   cardiac cells.                           2.   Progressive loss of myofilaments.
              6. In addition, capillary density             3.   Alteration in cytoskeletal proteins.
                   and coronary reserve become              4.   Desensitization of β-adrenergic
                   reduced.                                      signaling.
    •    The resulting ischemia, most severe in             5.   Progressive myocyte loss through both
         the subendocardium, may contribute                      necrotic and apoptotic cell death.
         further to the impairment of cardiac                    Myocardial stretch, norepinephrine, TNF,
         function.                                               oxidative stress and angiotensin II trigger
    •    Myocyte function then deteriorates and                  apoptosis.
         overt heart failure occurs.                        6.   Excessive deposition of collagen,
                                                                 perivascular and following death of
                                                                 myocytes. Angiotensin II, endothelin and
                                                                 aldosterone trigger excessive fibrosis in
* Wall stress: Chamber internal dimension x
                                                                 myocardial tissue.
internal pressure / wall thickness.
                                                            7.   Progressive degradation of extracellular
A-2.6: CARDIAC REMODELING                                        matrix leading to left ventricular wall
It is a process of complex molecular and cellular                thinning and dilatation. Matrix
changes that lead to important alterations in the                metalloproteinases (MMPs), are activated
structure, function and phenotype of the                         through the action of TNF and other
myocardium. It can be defined at two levels:                     cytokines expressed within the failing
      1. Cellular and molecular level.                           myocardium.
      2. Left ventricular chamber level.
                                                           • Changes in Ventricular Chamber
1. Cellular and Molecular Level:                             Geometry:
                                                            1. Increase in left ventricular end-diastolic
Myocyte Changes:                                                volume and left ventricular dilatation.
PATHOPHYSIOLOGY OF HEART FAILURE.DOC                                                                 6


     2.    Left ventricular wall thinning.                      worsening neurohormonal activation
     3.    Increase in wall stress resulting from               occurs in response to the inability of the
           both (1) and (2).                                    remodeled left ventricle to respond
     4.    Subendocardial hypoperfusion and                     appropriately to compensatory
           increased oxygen utilization secondary to            mechanisms.
           increased wall stress.
     5.    Expression of stretch-activated genes
           (angiotensin-II, endothelin and TNF)
           and/or increased oxidative stress develop        ANTIFAILURE THERAPY BASED ON
           secondary to increased wall stress and          UNDERSTANDING PATHOPHYSIOLOGIC
           subendocardial hypoperfusion.                            MECHANISMS
     6.    Increased sphericity of the ventricle
           which creates a mechanical burden on the
           failing ventricle and separation of
           papillary muscles producing mitral
           incompetence.

 •        Mechanical disadvantages of left
          ventricular remodeling result in decreased
          cardiac output, increased left ventricular
          dilatation with further hemodynamic
          overloading contributing to disease
          progression.
 •        A self-amplifying situation develops in the
          remodeled left ventricle in which
                                                                                ACEI, BB, Spirolactone,
            Digitalis, Diuretics               Diuretics   Vasodilators             Omiapatrilat
                ↓         ↓                       ↓            ↓                          ↓
           HEMODYNAMIC                             LV UNLOADING                 NEUROHORMONAL
           IMPROVEMENT                                                             BLOCKADE



     SYMPTOM RELIEF
   PATHOPHYSIOLOGY OF HEART FAILURE.DOC                                                            7




                                                  ↓ WALL STRESS



                                                 ↓↓ REMODELING


                             Improve                                        Prolong
                             Morbidity                                      Survival
                                                                                                          with severe
                                                                                                          left-sided
                                                                  failure may occasionally be associated with a
A-2.7: PATHOPHYSIOLOGICAL CHANGES                                 significant decrease in the clinical symptoms of
  1.   Right Ventricle in Heart Failure: Right                    pulmonary congestion.
       ventricular dilatation and failure, with a
       decreased ejection fraction and rate of ejection,    2.    Kidney: The sympathetic nervous system and the
       may occur secondary to the chronic pressure                renin-angiotensin system play an important role
       overload caused by left ventricular failure and            in the renal retention of sodium and water in
       perhaps secondary to biochemical changes in the            heart failure. Within hours of the onset of heart
       right ventricular myocardium. Right ventricular            failure the kidneys secrete increased amounts of
       failure may be reflected in a decreased right              renin. The secretion of renin is controlled by the
       ventricular stroke volume and ejection fraction,           following mechanisms: 1) changes in wall
       despite increased volume and pressure. Also,               tension in renal afferent arterioles, 2) a macula
       there is a rise in mean right atrial pressure and          densa receptor that detects changes in the rate of
       mean systemic venous pressure. If the failure is           sodium and/or chloride delivery to the distal
       mild, these abnormalities may be absent at rest            tubule, 3) a negative feedback effect of
       but may become apparent during exercise.                   circulating angiotensin, 4) β2 adrenergic receptor
       Failure of the right ventricle may also be                 stimulation, and 5) the central nervous system,
       associated with the development of right                   which influences renin secretion via the renal
       ventricular pulsus alternans, and a right                  nerves, adrenal medulla, and the posterior
       ventricular diastolic gallop sound. Severe right           pituitary. Carotid sinus or atrial distension may
       ventricular failure secondary to left ventricular          also influence renin secretion. Angiotensin II
       failure is frequently associated with the                  constricts renal efferent arterioles; stimulates
       development of pulmonary hypertension and                  thirst; in the adrenal gland it stimulates secretion
       tricuspid regurgitation and occasionally                   of aldosterone. Aldosterone promotes the re-
       associated with the development of functional              absorption of sodium (in exchange for potassium
       pulmonary regurgitation due to dilatation of the           or hydrogen ions) accompanied by chloride in
       pulmonary valve ring. Tricuspid regurgitation              the distal tubules and collecting ducts of the
       may produce large regurgitant cv wave during               kidney. The kidney synthesizes prostaglandins in
       systole in the right atrium and systemic veins.            the interstitial and collecting duct cells of the
       Clinically, the development of marked right                medulla. These are released into the renal
       ventricular failure in association with tricuspid          interstitial fluid and renal venous blood and
       regurgitation in a patient                                 metabolized in both the renal cortex and lung.
                                                                  Complications can result from the redistribution
                                                                  of cardiac output and the resulting regional
                                                                  reductions of blood flow. These include marked
                                                                  sodium and nitrogen retention as a consequence
                                                                  of diminished renal perfusion
PATHOPHYSIOLOGY OF HEART FAILURE.DOC                                                         8


                                                             muscles. This latter mechanism may be in
   3.   Skeletal Muscles: In heart failure as cardiac        part responsible for the dyspnea associated
        performance declines, left ventricular output is
        redistributed to maintain blood flow to vital
                                                             with cardiac lesions which are not
        organs such as the brain and the heart while         associated with pulmonary congestion, e.g.
        blood flow is reduced to the less crucial areas      pulmonic stenosis or pulmonary
        such as the skin, skeletal muscles and kidney.       hypertension.
        This underperfusion of skeletal muscle leads to
        anaerobic metabolism, lactic acidosis, an excess     2- Fatigue: Fatigue secondary to heart failure may be
        oxygen debt, weakness, and fatigue.                  produced by a variety of mechanisms.
   4.   Vascular Endothelium: Both ischemia and
                                                             1. Inadequate blood flow to skeletal
        exercise-induced vasodilatation in the                  muscles during activity.
        extremities are attenuated in patients with heart    2. Impairment in vascular endothelial
        failure. This attenuation is related, in part, to       function and impaired release of the
        endothelial dysfunction. Defective endothelial          vasodilator NO.
        function reflected in an impaired ability to
        synthesize and/or release nitric oxide contributes   3. Excessive diuresis and dilutional
        to the impaired vasodilator capacity in heart           hyponatremia.
        failure. In addition to abnormalities in             4. Increased levels of inflammatory
        endothelial vasodilator function, the release of        cytokines.
        the vasoconstrictor endothelin by the                5. Potassium depletion.
        endothelium is augmented. Abnormalities in
        vascular endothelial function in heart failure
                                                             6. Poor appetite and poor food intake.
        contribute to patients’ complaints of muscle
        fatigue and to the dissociation between cardiac       3. Edema:
        pumping functions ejection fraction and patients’     - Patients with severe, chronic heart
        symptoms.                                                failure usually gain weight because
                                                                 of abnormal retention of salt and
A-2.8: MECHANISMS OF SYMPTOMS                                    water by the kidneys.
                                                               - Peripheral edema is a late sign
1- Shortness of Breath: This is the chief                          of heart failure.
compliant in patients with heart failure. In                   - The location of edema is
many situations it occurs when ventricular                         determined by local factors.
contractile performance becomes impaired                           The erect position favors
and the Frank-Starling mechanism                                   collection of the fluid in the
maintains cardiac output at the expense of                         feet, ankles and lower portion
increased ventricular end-diastolic volume                         of the leg. The recumbent
and pressure. In turn, the left atrial,                            position favors accumulation
pulmonary venous and pulmonary capillary                           of fluid in the sacral region.
pressures are elevated. When the
hydrostatic pressure in the pulmonary
capillary bed exceeds the oncotic pressure
of plasma proteins, transudation of fluid
occurs into surrounding lung tissue. The
increased turgidity and decreased
compliance of the congested lungs increase
the work of breathing and are in part
responsible for the subjective symptom of
dyspnea. Dyspnea may also be related to an
inadequate blood flow to the respiratory
CLASSIFICATION AND CAUSES OF HEART FAILURE.DOC                                               1


A-3: CLASSIFICATION AND                                       •   Left Sided Heart Failure: The clinical picture of
                                                                  left sided heart failure is dominated by
CAUSES OF HEART FAILURE                                           manifestations of low cardiac output and
                                                                  pulmonary congestion. The commonest causes
                                                                  are coronary artery disease, hypertension, aortic
A-3.1: Type: Systolic vs. Diastolic Heart Failure                 valve disease and mitral incompetence.
A-3.2: Manifestations                                         •   Right Sided Heart Failure: Here the clinical
A-3.3: Onset: Acute vs. Chronic                                   picture is dominated by systemic venous
A-3.4: Degree of Heart Failure: Functional Class                  congestion resulting in hepatomegaly, raised
A-3.5: Causes of Heart Failure                                    jugular venous pressure and edema of the lower
A-3.6: Potentially Reversible Causes of Heart Failure             limbs. The commonest causes of right sided
                                                                  heart failure are left sided heart failure,
                                                                  pulmonary hypertension, mitral stenosis,
                                                                  pulmonary stenosis, tricuspid valve disease, and
Patients with heart failure are very heterogenous and vary        right ventricular infarction.
according to etiology, mechanisms, symptoms, prognosis        •   A combination of right and left sided heart
and severity.                                                     failure is defined as congestive heart failure.
The following classification of heart failure will
                                                              •   This classification has obvious limitations:
categorize patients with heart failure according to type,
                                                              •   The left and right sides of the heart do not
clinical manifestations, mode of onset and functional
                                                                  operate independently of each other but do so as
class.
                                                                  an integrated unit, rendering the classification
                                                                  rather meaningless in physiological terms.
A-3.1: TYPE: SYSTOLIC VS. DIASTOLIC HEART                         In heart failure, regardless of the cause, fluid
                                                                  retention and variable degrees of reduction in
FAILURE                                                           cardiac output dominate the clinical picture, thus
    •    Systolic heart failure is said to be present when        defying a classification into left or right sided
         manifestations of heart failure are secondary to         heart failure.
         reduced myocardial contractility. The
         commonest causes are coronary artery disease
         (CAD), valvular disease, hypertension and            2: Forward vs. Backward Failure:
         dilated (idiopathic) cardiomyopathy. Systolic        •   In Forward Heart Failure: The main mechanism
         heart failure with impairment of myocardial              of symptoms is reduction in cardiac output and
         contractility is the end stage of many cardiac           stroke volume with impaired peripheral tissue
         disorders and is associated with left ventricular        perfusion, e.g., pallor, oliguria, skeletal muscle
         dilatation and a low ejection fraction.                  fatigue.
    •    Systolic heart failure is commonly accompanied       •   In Backward Heart Failure: The main
         by diastolic heart failure.                              mechanism of clinical manifestations is
    •    Diastolic heart failure means that manifestations        pulmonary and systemic venous congestion, e.g.,
         of heart failure are secondary to impaired cardiac       shortness of breath, pulmonary crepitations,
         filling while myocardial contractility is intact.        edema of lower limbs, hepatomegaly.
         The commonest causes are hypertension,
         hypertrophic cardiomyopathy (HCM),
                                                              •   3: Heart Failure vs. Myocardial Failure: Heart
         myocardial ischemia, infiltrative cardiac
                                                                  failure and myocardial failure are not
         disorders and chronic constrictive pericarditis
                                                                  synonymous.
         (see chapter B-6). Diastolic heart failure is
         difficult to treat, but the prognosis is generally   •   Heart Failure may be present without myocardial
         better than systolic heart failure.                      failure and the reverse is also true (see the
                                                                  following parts in this section).
    •    Both systolic and diastolic heart failure present
         with the same clinical manifestations of heart       •   Diagnosis of heart failure entails the presence of
         failure and are difficult to differentiate in the        clinical manifestations secondary to cardiac
         majority of patients on simple clinical grounds.         pump failure; pulmonary congestion; systemic
                                                                  venous congestion; sympathetic stimulation
    •    Echocardiography is the simplest and possibly
                                                                  (tachycardia, vasoconstriction); sodium retention
         the most accurate method to differentiate
                                                                  and other manifestations of neurohormonal
         between systolic and diastolic heart failure.
                                                                  activation.
                                                              •   Diagnosis of myocardial failure depends upon
A-3.2: MANIFESTATIONS                                             the demonstration of local signs of poor
                                                                  ventricular function (systolic, diastolic or both),
   1. Left Versus Right Sided Heart Failure:                      i.e. cardiomegaly, S3 gallop and functional
                                                                  regurgitant murmurs. Echocardiography provides
CLASSIFICATION AND CAUSES OF HEART FAILURE.DOC                                               2


       objective evidence of myocardial failure whether         with their usual daily routine activities. Shortness
       systolic (dilated ventricles with poor                   of breath and muscle fatigue develop when they
       contractility) or diastolic (cardiac Doppler             exercise moderately, e.g. ascending to a second
       manifestations of impaired ventricular                   floor, walking a distance between two bus stations
       compliance and filling).                                 provided there is no other explanation for
   •   The commonest cause of heart failure is                  symptoms, e.g., obesity, cigarette smoking,
       myocardial failure. Both heart failure and               anemia, physical deconditioning (sedentary life
       myocardial failure are commonly present in the           with no exercise) and bronchopulmonary disease.
       same patient.                                         3. Patients have marked limitation of their effort
   •   Examples of heart failure with no myocardial             tolerance, e.g., short of breath or fatigue when
       failure are tamponade and constrictive                   walking for a short distance (from bedroom to
       pericarditis. Myocardial failure with no heart           WC), washing, changing clothes, praying. The
       failure is present in treated heart failure and in       patient will have to stop and interrupt his activity
       excessive systolic load on the left ventricle            for few minutes in order to rest and take his breath
       secondary to mitral regurge.                             when washing or changing his clothes.
                                                             4. Patients in this functional class are severely
                                                                disabled. They are symptomatizing (short of
                                                                breath) while resting in a chair or in bed. The mere
       A-3.3: ONSET: ACUTE VERSUS                               act of talking or a minimal exercise can bring on a
       CHRONIC                                                  severe exacerbation of symptoms.

   •   Acute Heart Failure: This syndrome is present
       when clinical manifestations of severe reduction
       in cardiac output, pulmonary and/or systemic               A-3.5: CAUSES OF HEART FAILURE
       congestion occurs suddenly (within minutes or         •    Heart failure can result from a large number of
       hours). It can present as a picture of acute               cardiovascular disorders, which include
       cardiogenic pulmonary edema, cardiogenic                   congenital defects, myocardial and pericardial
       shock (see chapter on Acute Heart Failure), or an          diseases, coronary artery disease, hypertension,
       acute exacerbation in patients with chronic heart          valvular heart disease and arrhythmias.
       failure.                                                   Hypertension and coronary artery disease are the
   •   Chronic Heart Failure: The clinical picture is of a        commonest causes of heart failure in middle and
       gradual onset and a progressive course.                    old age. Congenital and valvular diseases are the
       Manifestations of heart failure develop over               main causes in young age.
       months or years. This is the commonest form           •    In developing countries, rheumatic valvular heart
       seen in clinical practice. Clinical manifestations         diseases used to be the principal cause of heart
       may develop spontaneously or may follow a                  failure. However, in the last two decades there
       precipitating cause. The course usually consists           was an important rise in the incidence of
       of remissions and relapses with progressive                coronary artery disease. Coronary atherosclerosis
       deterioration unless the underlying cause is               will possibly be the commonest cause of heart
       corrected.                                                 failure in the coming decades, similar to the
                                                                  situation in developed industrial countries.
                                                             •    Hypertension is present in a large proportion of
       A-3.4: DEGREE OF HEART FAILURE:                            patients with heart failure and it used to be the
                                                                  main cause of heart failure until some years ago.
       FUNCTIONAL CLASS                                           However, the early and effective control of high
                                                                  blood pressure by pharmacologic therapy helped
   •   Assessment of the degree of functional disability
                                                                  to prevent or delay the development of heart
       is critical in clinical evaluation, management and
                                                                  failure secondary to hypertension.
       prognosis in patients with heart failure.
                                                             •    In tropical and some South American countries
   • Based upon New York Heart Association
                                                                  cardiomyopathies represent an important cause
       criteria, patients with heart failure can be
                                                                  of heart failure.
       classified into four functional classes:
                                                             •    There is more than one approach for classifying
      1. Patients with underlying heart disease, e.g.,
                                                                  the causes of heart failure. The following
           hypertension, coronary artery disease,
                                                                  classification is based upon Ross concept of the
           valvular heart disease, cardiomyopathies but
                                                                  dissociation between cardiac pump function and
           suffer no disability, have no symptoms and
                                                                  myocardial failure. This approach has both
           there is no limitation of their functional
                                                                  physiologic and clinical basis.
           capacity.
  2. Patients have mild limitation of their effort
     tolerance that generally does not interfere much
CLASSIFICATION AND CAUSES OF HEART FAILURE.DOC                                                     3


 A. Heart Failure without Myocardial                               3. Impaired Cardiac Filling:
      Failure:                                                      In the following conditions there is failure of
In the following conditions, the basal myocardial                   cardiac pump function producing manifestations
contractility is not depressed but there is cardiac pump            of heart failure in spite of normal contractile
failure. Heart failure develops secondary to excessive              function because of the impaired ability of the
mechanical loading, which overpowers the cardiac                    heart to fill adequately:
compensatory and adaptive mechanisms that are activated              c. Pericardial and Myocardial
to maintain cardiac output. Heart failure can also develop                Restriction: constrictive
when the heart is not able to fill.                                       pericarditis, cardiac
                                                                          temponade, endomyocardial
                                                                          fibrosis, infiltrative
    1. Acute Mechanical                                                   cardiomyopathies.
       Overload:                                                     d. Mechanical Obstruction:
    a. Acute cor pulmonale:                                               mitral stenosis, myxomas.
Acute massive pulmonary embolism can produce sudden                  e. Severe Tachycardias
cardiac pump failure. The sudden elevation of pulmonary
artery pressure will produce an excessive pressure                 4. Low cardiac output due to heart
overload on the right ventricle before allowing for
compensatory adaptive mechanisms to develop in order to
                                                                      block or bradycardia.
maintain the cardiac pumping ability. The right ventricle      Extreme degrees of cardiac slowing can compromise
cannot withstand the excessive load and fails.                 cardiac output in spite of the normal or above normal
                                                               stroke volume.
    b. Acute Volume Overload:
Sudden and severe valvular regurgitation, e.g., acute gross
mitral or aortic regurgitation following rupture chordae          B. Heart Failure with Myocardial
tendinea in a patient with myxomatous valve and mitral             Failure:
valve prolapse, or after perforation or tear of a valve cusp      The majority of patients with heart failure seen in
complicating infective endocarditis, or rupture of a              clinical practice belong to this group. Cardiac pump
papillary muscle secondary to a myocardial infarction.            failure is associated with myocardial failure and
Acute severe volume overload of the left ventricle will           depression of myocardial contractility. Myocardial
overrun the different compensatory and adaptive                   failure develops either because of a direct loss of the
mechanisms that will have little time to develop in order         contractile units (myocytes) or because of excessive
to maintain the left ventricle pumping function. The              mechanical loading. In the presence of severe
elevation of the left ventricular end diastolic pressure          mechanical problems, e.g. valvular aortic stenosis or
following massive valvular regurgitation will result in a         regurgitation, or mitral insufficiency it is important to
rise in left atrial and pulmonary capillary pressure and          identify the extent of depression of myocardial
manifestations of pulmonary congestion. In spite of the           contractility.
rapid recruitment of compensatory mechanisms which
include left ventricle dilatation and sympathetic                  1. Myocyte Loss:
stimulation, cardiac output is not maintained because of
excessive volume overload that increases left ventricular
                                                                   a. Myocardial Infarction and Ischemia:
wall stress and interferes with the left ventricle pumping     Interruption or compromise of coronary blood flow
ability.                                                       secondary to severe coronary artery disease and coronary
                                                               thrombosis can produce myocardial ischemia, necrosis
    c. Malignant Hypertension:                                 and loss of cardiac myocytes. Myocardial infarction is
Sudden occurrence of a very high arterial pressure (e.g.       followed in 15-20% of patients by heart failure within 5
220/130 mmHg), can produce acute left ventricular failure      years, while impairment of left ventricular function is
due to excessive pressure overload.                            present in about 40% of patients following infarction.
                                                               The loss of contractile units (myocytes) followed by
    2. Chronic Severe Overload:                                replacement with collagen tissue (scar formation) results
    a. High Cardiac Output:                                    in impaired myocardial contractile function and
In patients with a large arterio-venous fistula,               development of heart failure. The extent and rapidity of
thyrotoxicosis, severe anemia, heart failure with preserved    development of heart failure depends upon the extent and
myocardial contractility might develop because of an           persistence of coronary occlusion, presence of collateral
excessive and prolonged high cardiac output state.             circulation, myocardial oxygen requirements and
    b. Severe Valvular and Congenital Heart                    coronary microvasculature. Patients with large infarcts,
                                                               big scar or with cardiac aneurysms are more liable to
        Disease:                                               develop heart failure.
Excessive mechanical pressure or volume overload
secondary to a severe valvular deformity (stenosis or
                                                                   b. Myocarditis:
reguritation) or a congenital defect can overcome cardiac         Viral, autoimmune, metabolic or toxic factors
compensatory mechanisms and produce pump failure.                 can produce acute inflammatory damage to the
CLASSIFICATION AND CAUSES OF HEART FAILURE.DOC                                                4


   myocardium with edema, myocyte necrosis and                      •   Pulmonary embolism
   inflammatory cellular infiltration. Myocarditis can
   produce acute or chronic heart failure. Some forms
                                                                 3. Spontaneously Reversible Causes:
   recover spontaneously, others progress to
                                                                    •   Arrhythmias
   congestive heart failure.
                                                                    •   Myocardial ischemia
    c. Cardiomyopathies:                                            •   Pulmonary embolism
Dilated cardiomyopathy of idiopathic origin is becoming
                                                                    •   Alcohol and toxins
a common cause of congestive heart failure in clinical
practice. A viral etiology has been proposed, while in              •   Peripartal
other cases a genetic defect was identified. Alcoholic and          •   Myocarditis
peripartal cardiomyopathies are other forms of dilated
cardiomyopathy presenting with heart failure that may
recover spontaneously.
Patients present with a picture of congestive heart failure
of varying severity, markedly dilated hearts and poor
contractile function.
Hypertrophic cardiomyopathy is a different form of
cardiomyopathy characterized by gross cardiac
hypertrophy mainly of the interventricular septum with or
without dynamic obstruction of left ventricular outflow
tract. Although initially the left ventricular cavity is small
and contractility is normal or increased, some patients
progress to dilated cardiomyopathy with impaired systolic
function.
    d. Infiltrative Disorders:
In these disorders, replacement of cardiac myocytes by
fibrous tissue, amyloid or other foreign material produces
loss of contractile units, and an increase in myocardial
stiffness. These disorders generally produce impaired left
ventricular filling and diastolic heart failure.


A-3.6: Potentially Reversible Causes of Heart Failure
           Heart failure in the majority of patients is a
progressive irreversible state running a downhill course
and ending in death secondary to cardiogenic shock or
lethal arrhythmias. However, there are a number of
conditions with potentially reversible causes where
complete recovery of normal cardiac function and
systemic hemodynamics is possible. The following is a
list of these conditions:

    1.            Surgically Correctable:
         •        Constrictive pericarditis
         •        Valvular deformities
         •        Congenital defects
         •        Arterio-venous fistulae
         •        Coronary disease-myocardial ischemia
         •        Hypertrophic cardiomyopathy

    2.            Medically Correctable:
             •     Hypertension
             •     Myocardial ischemia
         •       Arrhythmias and conduction defects, e.g.
                 atrial fibrillation and heart block.
         •       Thyrotoxicosis
         •       Anemia
         •       Nutritional deficiency – vitamin B1
RENAL AND ELECTROLYTE DISTURBANCES IN HEART FAILURE.DOC                                                       1


             A-4: RENAL AND                                 clinical settings acute tubular necrosis (ATN) can
                                                            occur. The specific gravity of urine is low in
                                                            ATN, but high in prerenal azotemia.
             ELECTROLYTE
                                                            A-4.2: Renal Insufficiency
  DISTURBANCES IN HEART
                                                                  1. Introduction:
                  FAILURE                                         •   Renal insufficiency occurs in
                                                                      decompensated heart failure particularly
A-4.1: Introduction
                                                                      in the elderly and those starting ACE-I
A-4.2: Renal Insufficiency
                                                                      treatment.
A-4.3: Hyponatremia
                                                                  •   In the intensive care units, patients
A-4.4: Renal Failure
                                                                      receiving parenteral inotropic drugs for
A-4.5: Hypokalemia & Hypomagnesemia
                                                                      heart failure commonly suffer from renal
A-4.7: Hyperkalemia
                                                                      insufficiency.
A-4.8: Dialytic Treatment of Heart Failure
                                                                  •   2. Etiology and Mechanisms:
                                                                  •   Heart failure causes constriction of the
A-4.1: Introduction                                                   afferent arterioles, resulting in a
The cardiorenal interaction in congestive heart                       reduction of the glomerular plasma flow
failure is complex. Primary renal disease may lead                    rate (QA) by one third to one fifth of the
to worsening of heart failure in patients with                        normal.
compromised heart functions. Functional changes                   •   Intense efferent arteriolar
in the renal hemodynamics and tubular functions                       vasoconstriction then occurs resulting in
also occur due to cardiac failure. Understanding                      an increase in the single nephron
this complex relationship may help plan efficient                     filtration fraction.
therapeutic strategies.                                           •   These two events result in a drop in the
                                                                      peritubular capillary pressure and
Heart failure mostly leads to prerenal                                subsequent increased sodium retention in
insufficiency that is reversible when the heart                       the body.
becomes compensated, under certain severe

                        ↓ Cardiac Output
                                    ↓
                                ↓         in Renal Blood Flow
                                                    ↓
                                 ↓ in Glomerular Filtration Rate
                                                    ↓
                               ↑ Tubular Reabsorption of Sodium
                                                    ↓
                             ↑       Total Body Sodium
         ↑        Of Extracellular Volume, ↑ Intravascular Blood Volume

  Decompensated                                   Heart Failure
RENAL AND ELECTROLYTE DISTURBANCES IN HEART FAILURE.DOC                                              2


Schema of the major effects of decreased                                  kidney function. In these cases the cardiac
renal blood flow in heart failure.                                        function is still good enough to maintain
                                                                          cardiac output and blood pressure remains
   3. Manifestations:                                                     stable despite systemic vasodilatation.
   •   Extracelluar volume is increased due to excessive             4.   In severe heart failure, ACE-I may cause a
       sodium absorption and failure to excrete free                      rise in BUN and serum creatinine due to an
       water.                                                             excessive decrease in renal perfusion
   •   Serum sodium decreases in advanced heart                           pressure (decrease blood pressure and
       failure.                                                           efferent arteriolar dilatation). Chronic
   •   Serum albumin decreases slightly.                                  administration with dose adjustment can
                                                                          prevent excessive and rapid fall of
   •   Total body sodium increases and potassium
                                                                          intraglomerular pressure with consequent
       decreases.
                                                                          preservation of renal function, and later on
   •   BUN and serum creatinine increase in severe
                                                                          even improvement in renal hemodynamics
       cases.
                                                                          with increase of cardiac output.
   •   In severe heart failure there is oliguria with high
       specific gravity. Nocturia is present.
                                                              * ACEI: Angiotensin Converting Enzyme
   •   Minimal glomerular proteinuria (0.3-1 g/24             Inhibitors
       hours), and microscopic haematuria may be                     5.   ACE-I potentiates the action of low dose
       present.                                                           furosemide in the presence of a stable
   •   BUN rises more than the expected rise of serum                     perfusion pressure. In this setting ACE-I
       creatinine.                                                        increases renal plasma flow with consequent
   •   Nartriuresis occurs with the use of diuretics and                  rise of peritubular pressure allowing less
       monitoring daily Na+ excretion predicts the                        sodium absorption and increased sodium
       response to diuretics (good if > 15 mEq/day and                    delivery to the loop of Henle. The major site
       poor if < 3.5 mEq/day).                                            of action of the loop diuretics. Furthermore,
                                                                          the increased cortical flow induced by ACE-I
  4. Prevention:                                                          may result in increased delivery of
                                                                          furosemide to its site of action.
   •   Early detection and treatment of heart failure.
   •   Monitoring serum urea and creatinine.                  6. Clinical Implications of the Neurohormonal
   •   Repeated serum sodium estimation to detect
       hyponatremic cases (associated with advanced
                                                              Response:
       heart failure and neurohormonal changes).                     •    Due to the efferent arteriolar constriction,
   •   Early gradual use of ACE-I* in hyponatremic                        any further fall in the blood pressure, results
       cases.                                                             in a decrease in the perfusion pressure, with
                                                                          consequent marked drop of the GFR.
   •   Avoidance of NSAIDs.
                                                                     •    NSAIDs by blocking prostaglandin
   •   Beware of other causes of renal impairment in
                                                                          production result in failure of the
       particular patients (e.g. benign prostatic
                                                                          compensatory afferent arteriolar dilatation,
       hypertrophy in the elderly, infections in
                                                                          and result in a severe fall in the GFR.
       diabetics).
                                                                     •    Excessive diuretic administration, by
                                                                          decreasing intravascular volume and cardiac
  5. Renal Effects of ACE-I:                                              output can cause acute renal failure.
       1.   ACE-I increases glomerular plasma flow rate              •    ACE-I by dilating the efferent arterioles can
            QA, single nephron glomerular filtration rate                 result in acute renal failure (ARF). They
            (SNGFR) and reduce single nephron                             should hence be used in small, gradually
            filtration fraction (SNFF), due to marked                     increasing doses with careful monitoring of
            efferent vasodilatation.                                      the serum creatinine. Many factors may
       2.   Plasma renin activity is high in heart failure:               increase the risk of renal dysfunction when
            Hyponatremia causes higher PRA, associated                    ACE-I are used in the treatment of heart
            with a higher BUN and creatinine and a                        failure. These include: widespread
            lower RBF and GFR in comparison with                          atherosclerotic disease, renovascular disease,
            normonatremic cases.                                          impaired pre-treatment renal function,
       3.   Mild or moderate cases of heart failure                       hypertension, hyponatremia, diabetes, use of
            treated with ACE-I have a stable or improved                  other vasodilators, diuretic therapy, and
RENAL AND ELECTROLYTE DISTURBANCES IN HEART FAILURE.DOC                                                        3


              recent volume loss as hemorrhage or severe
              vomiting.                                                  Major Hormonal and other Endogenous
Vasoconstrictive- Sodium Retaining Hormones:                               Substances Affecting Renal Function in Heart
Patients with acute or poorly compensated severe heart                     Failure: (see also chapter A-2).
failure have markedly elevated plasma renin activity,
norepinephrine and vasopressin levels. In contrast, patients             They can be divided into two categories: Those that
with chronic stable heart failure have less marked                          induce vasoconstriction and promote sodium
elevations.                                                                 absorption and those that stimulate vasodilatation
Vasodilators-Natriuretic Hormones in Heart Failure:                         and induce natriuresis.
    These include dopamine, prostaglandins (E2 and I2)
        and ANF. Evidence suggests that these hormones
        are counter-regulatory forces to the
        vasoconstrictor-sodium retentive forces.
              Hormone                                                   Renal Effect
Renin                                        •    Mediated via increases in intrarenal and vascular angiotensin II
                                                  production and elevated circulating angiotensin II and aldosterone
                                                  levels.
                                             •    Converts angiotensinogen to angiotensin I which is converted to
                                                  angiotensin II by circulating and local tissue ACE.
Angiotensin II                               •    Maintains glomerular filtration rate as renal blood flow falls by
                                                  preferentially vasoconstricting efferent arterioles.
                                             •    Promotes sodium reabsorption by proximal tubule.
                                             •    Counteracts many of the renal actions of atrial natriuretic peptide.
                                             •    Promotes renal vascular remodeling.
                                             •    Possibly increases renal interstitial fibrosis.
Aldosterone                                  •    Increases sodium reabsorption by distal tubule and collecting duct.
                                             •    Evokes potassium and magnesium loss from distal tubule.
Norepinephrine                                  Increases renin production and release.
                                                Increases sodium reabsorption by proximal tubule.
                                                Evokes modest kaliuresis.
                                                Intensive SNS activation:
                                         Reduces renal blood flow by afferent arteriolar vasoconstriction.
                                         May shift corticol blood flow to the medullary region.

Arginine-Vasopressin                     Acts on V2 receptor of distal tubule and collecting duct to allow water
                                         reabsorption from tubular filtrate and antagonizes the effects of
                                         prostaglandins.
Atrial Natriuretic Peptide                        Renal vasodilatation with afferent > efferent arteriolar dilatation
                                                  causing increased RBF and GFR.
                                                  Suppression of renin and angiotensin II release.
                                                  Reduces sodium reabsorption
Renal Prostaglandins (PGE2, PGI2)                 Afferent > efferent arteriolar dilatation causing increase in RBF and
                                                  GFR.
                                                  Inhibition of NaCl reabsorption.
                                                  Inhibition of vasopressin mediated water uptake.
Endothelin                               Increases renal vascular resistance (afferent arteriolar vasoconstriction)
                                         Decreases RBF.
                                         Decreases GFR.
                                         Decreases Sodium Excretion.
                                         Decreases Urine Volume.
RENAL AND ELECTROLYTE DISTURBANCES IN HEART FAILURE.DOC                                                4


A-4.3: HYPONATREMIA                                                    2. Chronic Renal Failure:
1. Definition: Hyponitremia is defined as serum sodium            Heart failure per se is not a cause of chronic renal
<130 mEq/l.                                                       failure, but it can exacerbate renal insufficiency in
2. Prevalence: More common in severe heart failure                the chronic renal failure patient. In treating heart
associated with neurohormonal changes.                            failure with chronic renal failure cases certain
     3. Mechanisms:                                               precautions should be taken:
     Dilutional Hyponatremia may occur in                            I. Dosage regulation and adjustment of different
                                                                          medications.
     heart failure due to:                                           II. Monitor serum potassium when ACEI or
              Enhancement of proximal tubular absorption                  potassium retaining diuretics are used.
              of sodium that results in decreased distal             III. Avoid hypotension.
              delivery of sodium which impairs free water            IV. Correct other aggravating causes of renal
              clearance.                                                  failure, e.g. benign prostatic hypertrophy.
              Increased thirst and vassopressin release (due
              to non-osmotic stimuli).
     Hyponatremia is associated with severe heart              A-4.5-4.6: Hypokalemia and Hypomagnesemia
     failure, high plasma renin activity, aldosterone,            These are caused mainly by the use of diuretics in
     PGE2, dopamine and vasopressin.                              excessive dosages. Both are arrhytmogenic and
     The presence of hyponatremia is an indication to             should be monitored to prevent occurrence of lethal
     start ACE-I gradually.                                       arrhythmias or aggravation of heart failure. Serial
                                                                  estimation of their plasma levels is mandatory when
          4. Manifestations:                                      excessive diuretics are used. Hypokalemia can be
   Dilution hyponatremia develops in patients with                corrected by intravenous potassium administration in
   severe heart failure. It can be diagnosed by a serum           severe cases and oral supplementation or potassium
   sodium < 130 mEq/l. Clinically, it is recognized by:           retaining diuretics in chronic cases.
   partial failure of diuretics, increasing body weight,
   and cerebral manifestations of lethargy, confusion,         A-4.7: HYPERKALEMIA
   drowsiness, somnolease.
          5. Prevention:                                       Hyperkalemia in heart failure may be due to:
                                                                      Development of renal insufficiency with failure to
             Early detection and treatment of heart failure.          reduce potassium intake.
             Repeated serial sodium estimation.                       Use of potassium retaining diuretics in patients with
             Good fluid balance, particularly weighing the            borderline renal failure.
             patient daily.                                           Excess oral potassium intake combined with
          6. Management:                                              potassium retaining diuretics.
                                                                      Injudicious use of ACEI either in excessive doses
                  1.   Fluid restriction, as most cases are           or in combination with potassium retaining
                       dilutional. Avoid giving hypertonic            diuretics.
                       saline.
                  2.   Start ACE-I gradually.                  Treatment of Hyperkalemia:
                  3.   Dialysis in refractory cases.                   Avoid precipitating causes.
                                                                       Serial potassium measurement and monitoring for
                                                                       ECG changes.
A-4.4: RENAL FAILURE                                                   Intravenous calcium and glucose-insulin.
                                                                       Dialysis is indicated in severe cases.
          1. Acute Renal Failure:
                                                               A-4.8: Dialytic Treatment of Heart Failure
             i)  Pre-renal as a result of low cardiac          In severe refractory heart failure, peritoneal dialysis or
                 output. Urine volume decreases,               continuous hemofiltration can result in edema resolution,
                 creatinine rises and urine specific gravity   improvement of myocardial function, reduction of cardiac
                 is high.                                      filling pressure with maintenance of blood pressure. The
             ii) Acute tubular necrosis:                       neurohormonal responses are corrected with fall of
                                                               noradrenaline, aldosterone and renin levels. Diuresis
     1.    Acute volume loss in severe heart failure as        follows. These salutary effects in most patients may last
           vomiting, diarrhea or bleeding                      for several months.
     2.    ACEI: the use of large doses in decompensated
           heart failure.
HEART FAILURE IN SPECIAL GROUPS.DOC                                                                   1


       A-5: HEART FAILURE IN                                              The diagnosis of heart failure is difficult due to
                                                                          the presence of atypical symptomatology and
                                                                          co-morbid conditions.
             SPECIAL GROUPS                                               Optimal treatment is difficult due to the high
A-5.1: Heart Failure in the Elderly                                       prevalence of confounding medical,
A-5.2: Heart Failure in Pregnancy                                         behavioural, psycho-social, and economic
A-5.3: General Anesthesia and Non-Cardiac Surgery                         factors.
in Patients with Heart Failure                                            There is scanty data on the pharmacotherapy of
A-5.4: Myocarditis                                                        heart failure in the very elderly (over the age of
                                                                          80).
                                                                          Heart failure and preserved left ventricular
A-5.1: HEART FAILURE IN THE ELDERLY                                       systolic function (diastolic dysfunction) is
       1. Introduction:                                                   common in the elderly.
                                                                        3. Exacerbating Factors of Heart
In general the incidence of heart failure has been rapidly
increasing in recent years, the greatest increase has been                 Failure in the Elderly:
in the subgroup of elderly patients.
                                                                 There are many factors associated with both first
       2. What is Different about Heart
                                                                 presentation and exacerbations of heart failure in the
Failure in the Elderly?                                          elderly. They are summarized in the following table:

             Potential Exacerbating Factors in the Elderly Patient with Heart Failure:
            Non compliance with medical therapy.
            Arrhythmias.
            Atrial fibrillation
            Ventricular arrhythmias
            Bradyarrhythmias.
            Concomitant medications:
            Especially non-steroidal anti-inflammatory agents.
            Other medical conditions:
            Anemia.
            Thyrotoxicosis.
            Pneumonia and influenza.
            Pulmonary emboli.
            Myocardial infarction or ischemia.
                                                                          Complaints of weakness, anorexia and fatigue
                                                                          are common symptoms of heart failure.
                                                                          Heart failure is one of the most frequent
4. Pathophysiology of Heart Failure in the                                precipitants of confusion in the elderly.
Elderly:                                                                  Peripheral edema is common and has poor
         With development of heart failure, cardiac                       specificity for heart failure.
         output declines, systemic vascular resistance                    Because of difficulty in diagnosis, heart failure
         increases and baroreceptor responses are                         may be wrongly diagnosed or may be missed.
         impaired.                                                        Heart failure due to diastolic dysfunction is
         Elderly patients with heart failure have                         common in the elderly. Patients with heart
         relatively greater vasoconstriction and blunted                  failure and preserved left ventricular systolic
         heart rate responsiveness, with increased                        dysfunction have similar presentation,
         circulating norepinephrine.                                      symptoms and clinical signs to those patients
         Gastrointestinal blood flow is further                           with impaired systolic function.
         decreased, and may become the rate-limiting             6. Therapeutic Objectives:
         step in the absorption of drugs.
         Renal function is markedly impaired in the
                                                                 In the elderly population the therapeutic
         elderly with heart failure.                             objectives are different, where quality of life
5. Diagnosis of Heart Failure in the Elderly:                    and morbidity are more important than
                                                                 mortality:
         The classic symptoms and signs of heart failure
         have poor specificity in the elderly.                   In the acute phase of heart failure:
         Exertional dyspnea and orthopnea are                             Rapid diuresis is needed.
         relatively uncommon.                                             Treatment of the triggering cause of heart
                                                                          failure.
HEART FAILURE IN SPECIAL GROUPS.DOC                                                                        2


In the chronic phase of heart failure:                                         If heart failure persists digoxin should be added
                                                                               in a small dose with careful monitoring for
         Diet (low-sodium diet) and life-style                                 digitalis toxicity. Elderly patients are sensitive
         modification including regular exercise.                              to digitalis.
         Underlying causes of heart failure should be                          If symptoms persists isosorbide dinitrate ±
         treated when possible.                                                hydralazine should be added.
         Precipitating causes of heart failure should be                       B-blockers should also be used as indicated in
         identified and managed.                                               other patients with heart failure.
         ACE inhibitors should be given to all patients                        Calcium channel blockers may have a role only
         with impaired left ventricular systolic function.                     in diastolic heart failure.
         Diuretics are the cornerstone of treatment to                         The role of the newer antifailure drugs (e.g.
         relieve the symptoms of congestion and                                angiotensin II receptor blockers) is still under
         volume overload.                                                      investigation in the elderly.

             Principles of Drug Treatment for Heart Failure in the Elderly
The elderly are a heterogenous population; increasing age does not automatically correlate with a
decline in organ function, and distinction between biological and chronological age must be
recognized.
Prioritize the aims of treatment.
“Start low and go slow”
Care must be taken to determine the drug dosage and the dosing interval.
Calculation of creatinine clearance in elderly patients may be beneficial to allow reliable titration.
Creatinine clearance can be usefully estimated clinically using the Cockcroft formula:
                          Creatinine Clearance = (140 – age)(weight in Kg)
                                                 72 x creatinine (mg/dl)
                             Multiply by 0.85 for women.
Provide clear and simple instructions to the patient and care-giver (when appropriate).
Review the treatment regularly and check carefully for drug interactions and adverse reactions.
Monitor the use of “over-the-counter” medicines (e.g. non-steroidal anti-inflammatory drugs).
Encourage compliance.




A-5.2: HEART FAILURE IN PREGNANCY                                    with heart disease. These changes can lead to rapid
                                                                    clinical deterioration.
1. Introduction:
Pregnancy and the peripartum period are associated
                                                                    The table below summarizes the hemodynamic
with substantial cardiocirculatory changes in the woman             changes associated with pregnancy:


          PARAMETER                          1st Trimester         2nd Trimester          3rd Trimester
Blood Volume
                                                    ↑                     ↑↑                    ↑↑↑
Cardiac Output
                                                    ↑                ↑↑ to ↑↑↑               ↑↑↑ to ↑↑
Stroke Volume
                                                    ↑                    ↑↑↑                ↑, ↔, or ↓
Heart Rate
                                                    ↑                     ↑↑                ↑↑ or ↑↑↑
Systolic Blood Pressure
                                                    ↔                      ↓                      ↔
Diastolic Blood Pressure
                                                    ↓                     ↓↓                      ↓
Pulse Pressure
                                                    ↑                     ↑↑                      ↑
Systemic Vascular Resistance
                                                    ↓                    ↓↓↓                     ↓↓
HEART FAILURE IN SPECIAL GROUPS.DOC                                                                 3


                                                                 •      Inotropics:
                                                            Dopamine, dobutamine and milrinone have been used in
                                                            pregnancy when deemed necessary.
2. Etiology:                                                B- Other Therapeutic Options:
The common causes of heart failure during                        •      Mitral valve repair or replacement:
pregnancy include:                                                   Indicated in severe symptomatic mitral stenosis
        Mitral stenosis and rarely other valvular heart              despite adequate medical therapy.
        diseases. Heart failure develops in more than                The risk to the mother is similar to the non-
        70% of patients during the third trimester and               pregnant.
        early puerpurium.                                            Fetal loss is higher with open commissurotomy
        Systemic hypertension associated with pre-                   and replacement.
        eclampsia.                                                   Risk of fetal loss is minimal with closed
        Pulmonary hypertension.                                      commissurotomy (especially useful if patient has
        Peripartum cardiomyopathy.                                   repeated attacks of pulmonary edema).
3. Management:                                                   •      Balloon mitral valvotomy:
 A- Drugs:                                                           Has recently been used successfully in an
                                                                     increasing number of patients.
   •    Beta-blockers:                                               It should be performed under echocardiographic
                                                                     guidance with abdominal and pelvic shielding if
These are the cornerstone for the treatment of mitral
                                                                     fluoroscopy is used.
stenosis during pregnancy. They reduce the heart rate,
                                                                     Complications have been reported including fetal
which is usually a precipitating cause of pulmonary
                                                                     distress due to maternal arrhythmia, fetal loss due
edema.
                                                                     to initiation of uterine contractions and systemic
   •    Digoxin:                                                     embolization or cardiac tamponade.
             Digoxin is of little value in the
             management of pulmonary edema caused           A-5.3: General Anaesthesia and Non-
             by mitral stenosis, but has a small role in    Cardiac Surgery in Patients with Heart
             hypertensive heart failure and in patients
                                                            Failure
             with dilated cardiomyopathy or other
             conditions associated with poor left           1. Introduction:
             ventricular systolic function.                 Heart failure is a major determinant of perioperative
             Fetal deaths as a result of maternal           risk, irrespective of the nature of the underlying cardiac
             digitalis toxicity have been reported.         disorder. Mortality with non-cardiac surgery increases
   •    Diuretics:                                          with worsening functional class and with the presence
                                                            of pulmonary congestion, especially when a 3rd heart
             Thiazide diuretics are useful for the relief   sound is noted.
             of symptoms of heart failure along with        2. Prognosis:
             oxygen and morphine in more severe cases
             of pulmonary edema.                            Perioperative cardiogenic pulmonary edema
             Thiazides may rarely cause fetal or            develops in about:
             neonatal jaundice or thrombocytopenia.          •       2% of patients above the age of 40 undergoing
             Their benefit must be weighed against the               major non-cardiac surgery without prior heart
             possible hazards to the foetus or neonate               failure.
             exposed to short-term therapy.
                                                             •       6% of patients whose heart failure is controlled
             Furosemide is contraindicated because it
                                                                     before surgery.
             causes fetal abnormalities, but can be used
                                                             •       16% of patients whose heart failure symptoms are
             for pulmonary edema in the last weeks of
                                                                     not controlled before surgery.
             pregnancy and in the puerpurium to
             manage life-threatening pulmonary edema.        •       3. Major Elective Non-Cardiac Surgery:
                                                             •       It is imperative to treat heart failure before
   •    Vaso-dilators:                                               surgery.
ACE inhibitors are contraindicated in all stages of          •       Since management will almost always include
pregnancy. If afterload reduction is deemed necessary                diuretics, there is a potential hazard of the
for the management of heart failure, hydralazine may be              development of hypovolemia (which results in
used in the third trimester of pregnancy. This drug must             marked hypotension during the early phases of
be avoided in the first trimester of pregnancy due to                general anaesthesia) and hypokalaemia before
teratogenic effects in experimental animals.                         surgery.
HEART FAILURE IN SPECIAL GROUPS.DOC                         4


 •   Thus, it is advisable to stabilize the patient’s
     condition approximately 1 week rather than for
     only 1 or 2 days before the contemplated surgery.
 •   Digitalis may be associated with a higher risk of
     intraoperative bradyarrhythmias, thus it is not
     recommended except in those who meet the
     criteria for long-term digitalization.
A-5.4: MYOCARDITIS
Myocarditis presents with a wide variety of cardiac
manifestations including heart failure. The most
common forms appear to be postviral in origin. Ongoing
myocardial inflammation may result in dilated
cardiomyopathy, restrictive cardiomyopathy, or acute
left ventricular failure without dilatation. The clinical
features are extremely varied and range from
asymptomatic electrocardiographic abnormalities to
severe dilated cardiomyopathy with fulminant
congestive heart failure leading to death. Treatment of
myocarditis is symptomatic, routine use of
immunosuppressive therapies is not recommended for
patients with myocarditis. Prednisone was ineffective in
improving outcome. Combined prednisone and
cyclosporine-based immunosuppressive therapy
produced no clinical bebefit.
High-dose immune globulin-intravenous immune-
globulin (2g/Kg) can be tried particularly in children
with myocarditis.
CLINICAL EVALUATION.DOC                                                                              1

 B-1: CLINICAL EVALUATION                                conditions including anemia, pregnancy, obesity,
                                                         pulmonary disease and anxiety neurosis.

B-1.1: Introduction and Goals                            Orthopnea: When the patient breathes more
B-1.2: Establish the Presence of Heart Failure           comfortably with the upper part of the body
B-1.3: Assess Severity of Heart Failure                  elevated rather than recumbent, it is called
B-1.4: Systolic vs. Diastolic Heart Failure              orthopnea. In severe heart failure, patients may
B-1.5: Identify Underlying, Precipitating and            spend the entire night sleeping in a chair to
Contributing Causes                                      maintain this elevation. It is a more specific
B-1.6: Associated Conditions                             manifestation of pulmonary congestion than
B-1.7: Complications of Heart Failure                    dyspnea. However, it can occur in patients with
B-1.1: INTRODUCTION AND GOALS                            bronchial asthma, in pregnant women, in patients
                                                         with huge ascites, and in patients with marked
Heart failure is a clinical syndrome manifesting         obesity in whom elevation of the diaphragm during
with a group of characteristic symptoms and              recumbency reduces the vital capacity.
physical signs. The diagnosis cannot be made on
the basis of a single clinical finding or laboratory     Paroxysmal Nocturnal Dyspnea (PND): Refers to
test. Confirmation of the diagnosis requires             episodes of severe shortness of breath, often
documented evidence of cardiac dysfunction. The          occurring at night and awakening patient from sleep
clinical picture covers a spectrum, varying from         with a sense of suffocation or air hunger usually 1-2
early manifestations with minimal symptoms and           hours after falling asleep. In contrast to orthopnea,
signs, to the dramatic picture of florid congestive      it is frequently not relieved by sitting upright. It is
heart failure (CHF). The course is usually               one of the most specific symptoms of left-sided
progressive and often interrupted by exacerbations       heart failure. However, patients with chronic
caused by common precipitating factors.                  obstructive pulmonary disease (COPD) may have
The goals of the physician should be:                    nocturnal attacks of cough, wheezes and dyspnea
1. To establish the presence of heart failure.           relieved by expectoration of sputum.
2. To assess the severity of heart failure and degree    Other Respiratory Symptoms: Include cough,
of impairment in cardiac function.                       cardiac asthma and Cheyne-Stokes respiration.
3. To identify the underlying etiology whenever          Cough is usually dry occurring commonly at night
possible.                                                or following exertion. Hemoptysis and
4. To determine the presence of associated diseases,     expectoration of a frothy sputum are present in
which precipitate and aggravate heart failure or         patients with severe pulmonary congestion. The
requires special management.                             wheezing from cardiac asthma may result from
B-1.2: ESTABLISH THE PRESENCE OF                         bronchospasm and bronchial mucosal congestion.
HEART FAILURE                                            Patients who have bronchospasm for other reasons
                                                         appear more susceptible to cardiac asthma. The
     1. HISTORY:                                         symptoms of cardiac asthma are sometimes difficult
The most common symptoms in patients with heart          to distinguish from those arising secondary to
failure are shortness of breath: [dyspnea, orthopnea,    bronchial asthma or bronchitis. Cheyne-Stokes
and paroxysmal nocturnal dyspnea (PND)] and              respiration (also called cyclic respiration) is
muscle fatigue.                                          recognized by periods of hyperpnea followed by
                                                         periods of apnea. It occurs in patients with cerebral
Dyspnea: Dyspnea represents the most prevalent           atherosclerosis and low cardiac output.
and earliest symptom of heart failure. The sense of      The patient in acute pulmonary edema presents
shortness of breath arises from the increased effort     with frightening dyspnea, orthopnea, profuse
of breathing that accompanies pulmonary                  sweating, central cyanosis, bubbling crepitations,
congestion. It is particularly common when left          diffuse wheezes (cardiac asthma), and
ventricular failure predominates. Left atrial and        expectoration of frothy blood-tinged sputum.
ultimately pulmonary venous pressures rise and
fluid transudates into the pulmonary interstitium.       Systemic Congestion: Dyspepsia, upper abdominal
This increases lung stiffness and raises the work of     discomfort increased by effort and following meals.
breathing. A history of the activities that provoke      Ankle swelling, especially at the end of the day,
dyspnea is important. Typically, dyspnea occurs          secondary to hydrostatic edema and weight gain are
with progressively smaller amounts of exercise and       non-specific but common manifestations of heart
finally at rest. Patients often unconsciously restrict   failure.
their activity to avoid this unpleasant sensation, and
they should be questioned closely concerning daily       Precipitating Factors: In about 50% of patients
activities. However, dyspnea is a nonspecific            with recent onset of heart failure, there is a history
symptom and can be encountered in a variety of           of a precipitating cause. The most common
                                                         precipitating events leading to heart failure are
CLINICAL EVALUATION.DOC                                                                             2

detailed in section B-1.6. These events should be         output, vascular endothelial dysfunction and
considered in any patient with heart failure.             cytokine production. These complaints are common
All patients who present with heart failure should        in elderly patients with heart failure.
be questioned for a detailed cardiac history, e.g. a
history of chest pain, rheumatic fever, cardiac           Other Symptoms: Nocturia and oliguria are
surgery to uncover possible underlying cardiac            sometimes present in heart failure and maybe the
diseases. Current medications and diet should be          only symptoms. Cerebral manifestations as
discussed.                                                confusion, drowsiness, insomnia, memory and
                                                          personality changes are also common in the elderly.
Muscle Fatigue: Fatigue, muscle weakness and
easy fatigability are manifestations of low cardiac
       Symptoms Suggestive of Heart Failure:
           •    Paroxysmal nocturnal dyspnea.
           •    Orthopnea.
           •    Dyspnea on exertion.
           •    Lower extremity edema.
           •    Decreased exercise tolerance.
           •    Unexplained confusion, altered
                mental status, or fatigue in an
                elderly patient.
           •    Abdominal symptoms associated
                with ascites or hepatic engorgement.
                                                          venous pressure and emptying of the neck veins
2: Physical Examination: Physical findings                with inspiration excludes significant systemic
                                                          venous congestion. In patients with mild elevation
may be divided into two large categories:                 of JVP a positive abdominal jugular reflux (an
                                                          increase in JVP induced by gradual continuous
i) Findings within the cardiovascular system              abdominal compression while the patient maintains
itself:                                                   normal breathing) confirms the diagnosis of right-
Sinus tachycardia and gallop sounds are common in         sided heart failure. Pulsus alternans is an important
heart failure. A ventricular gallop S3 (which may         specific and common sign of severe heart failure. It
be normal in children and young adults with               consists of alternating strong and weak pulsation
hyperdynamic heart) is the result of a marked             waves felt in a peripheral artery. It can be readily
compliance change in the left ventricle. Left             appreciated when feeling the radial pulse.
ventricular gallops are best heard at the apex in the     Sometimes the difference between successive
left lateral position with the bell of the stethoscope;   strong and weak beats may not be easily detectable
right ventricular gallops are best heard in the           clinically. In these cases alternans can be detected
subxyphoid region or over the right ventricle. Atrial     while measuring the blood pressure. The number of
gallops (S4) may also be heard in heart failure,          Kortokoff sound, suddenly double as the cuff
although this finding is much less specific of heart      pressure is gradually reduced when all beats start to
failure. A sustained left ventricular lift or evidence    be audible instead of only the strong alternate beats.
of cardiac enlargement (dilatation) may be                Sinus tachycardia is an important manifestation of
discovered by palpation, depending on the                 heart failure particularly in acute and advanced
underlying cardiac pathology or severity of failure.      forms. However, tachycardia is absent in patients
Both systolic and diastolic murmurs are heard in          who are receiving effective treatment, beta-blockers
primary valvular disorders, e.g. rheumatic, calcific.     or developed heart block.
However, heart failure can cause mitral and/or
tricuspid regurgitation due to excessive dilatation of    ii) Findings in other organ systems resulting
the ventricles and the atrioventricular valve rings.      from heart failure:
Mitral incompetence may be far greater than               Pulmonary rales may be found at varying heights in
appreciated from the intensity of its murmur.             both lung fields. Initially they are heard over the
Likewise, severe aortic stenosis may cause a faint        bases. In pulmonary edema and severe pulmonary
murmur due to reduced cardiac output.                     congestion fine crepitations can reach the middle
Neck veins should be examined for evidence of             and upper lung zones. However, severe heart failure
elevated jugular venous pressure (JVP). Elevation         can be present in patients with clear lungs on
of the JVP is present in right sided and congestive       auscultation. Basal crepitations may be heard in the
heart failure. Examination of the neck veins may be       absence of heart failure in obese individuals,
difficult in the obese patient with a short neck and      cigarette smokers, chronic bronchitis and in the
in the presence of tachypnea and an abnormal              presence of a high diaphragm. Wheezing may be
breathing pattern. A clear-cut decline in jugular         present in heart failure especially over lung bases
       CLINICAL EVALUATION.DOC                                                                                3

       and can be confused with bronchial asthma. Liver                  •   Third heart sounds are too common to be
       engorgement from right-sided heart failure may                        specific for identifying major elevations of
       lead to tender, soft and pulsating hepatomegaly.                      left ventricular filling pressure.
       Liver dysfunction, particularly in acute and severe               •   A sudden elevation of pulmonary venous
       congestive heart failure, is likely to be complicated                 pressure causes crepitations (rales) due to
       by jaundice and may be confused with hepatitis.                       extravasation of fluid into the alveoli, but
       Transudation of fluid into the extracellular space                    chronic exudation of fluid is associated
       may lead to peripheral edema (particularly in                         with an increase in lymphatic drainage so
       dependent extremities) or to pleural effusions. A                     that the alveoli remain relatively dry and
       patient who has been bedridden should be checked                      rales are absent.
       for sacral edema. Ascites complicates severe right                •   The criteria used for diagnosis of heart
       sided heart failure.                                                  failure have limited reliability. Among
       iii) Therapeutic test:                                                subjects with low left ventricular ejection
       The diagnosis of heart failure can be confirmed by                    fraction (≤ 40%), 20% met none of the
       a therapeutic response to diuretic therapy which                      criteria for congestive heart failure.
       results in amelioration of dyspnea, regression of
       edema, resolution of X-ray signs of pulmonary                          HEART FAILURE
       interstitial edema and loss of 4.5 Kg of weight over           DIAGNOSIS AND SEVERITY ASSESSMENT
       5 days.
                                                                         •   Absence of Clinical Signs of Heart Failure
Physical Findings in Heart Failure:                                          is not Indicative of Normal Filling
   •      Elevated jugular venous pressure or                                Pressures.
          positive hepatojugular reflux.                                 •   Clinical Signs have Limited Value in
   •      A third heart sound.                                               Assessing Severity and Prognosis.
   •      Laterally displaced apical impulse.                       B-1.3: ASSESS THE SEVERITY OF HEART
   •      Pulmonary rales that do not clear with
          cough.
                                                                    FAILURE
   •      Peripheral edema not due to venous                        The severity of heart failure can be
          insufficiency.                                            assessed by:
       Relationship between Clinical Findings and                        •   Patients questionnaire for the evaluation of
       Hemodynamic Changes in Heart Failure                                  effort intolerance using the NYHA
                                                                             classification.
           •    Exertional dyspnea may result more from
                inadequate tissue oxygen delivery than                   •   The magnitude of fluid retention.
                from pulmonary venous congestion.                        •   The degree of impairment of peripheral
           •    History of recent orthopnea is a reliable                    perfusion.
                clinical indicator of high left ventricular              •   Echocardiographic measurements of
                filling pressure.                                            ventricular dimensions and function.
           •    Elevated jugular venous pressure and
                peripheral edema are specific but not
                sensitive for high right ventricular filling              New York Heart Association
                pressure.                                            Classification of Heart Failure (table 2)
                    Class I:            No limitation: ordinary physical exercise
                                        does not cause undue fatigue, dyspnea or
                                        palpitations.
                    Class II:           Slight limitation of physical activity:
                                        comfortable at rest but ordinary activity
                                        results in fatigue, palpitations, dyspnea
                                        or angina.
                    Class III:          Marked limitation of physical activity:
                                        comfortable at rest but less than ordinary
                                        activity results in symptoms.
                    Class IV:           Unable to carry out any physical activity
                                        without discomfort. Symptoms of heart
                                        failure are present even at rest, with
                                        increased discomfort with any physical activity.
                                                                              patients into functional classes according
           •    Despite its subjective nature, NYHA                           to the amount of effort required to provoke
                classification is widely used to categorize                   the symptoms of dyspnea or fatigue.
CLINICAL EVALUATION.DOC                                                                           4

    •    The extent and distribution of edema           Heart failure may be associated with COPD,
         (involving the ankles, legs, presacral         diabetes mellitus, chronic liver disease, chronic
         regions, scrotum or abdominal wall), the       renal disease and abnormalities in thyroid function,
         extent of jugular venous pressure elevation    which contribute to the patient's disability. The
         and hepatomegaly and serial changes in         recognition and management of these diseases
         body weight can judge the severity of fluid    improves the clinical status and prevents recurrent
         retention.                                     events and complications.
    •    Hypotension, tachycardia, a small pulse        B-1.6: ASSOCIATED CONDITIONS
         volume, oliguria and the mental status
         indicate the degree of impairment of           Several conditions are unrelated to heart failure but
         peripheral perfusion.                          can influence the way it should be managed as they
                                                        may affect the action or the choice of the drugs that
    •    The severity of cardiac dysfunction can
                                                        are used in the treatment of CHF. Senile prostatic
         also be assessed by echocardiographic
                                                        enlargement may modify diuretic therapy because
         measurements of left ventricular end-
                                                        of the danger of urinary retention associated with
         systolic and end-diastolic diameters, the
                                                        excessive distention of the bladder. Liver or kidney
         ejection fraction (EF) and right ventricular
                                                        impairment may cause accumulation of some drugs
         enlargement. Clinical studies of heart
                                                        such as digitalis, ACE inhibitors, etc. Diuretics can
         failure showed a poor correlation between
                                                        induce acute gout.
         the severity of symptoms, abnormal EF
         and hemodynamic abnormalities (e.g.
         pulmonary wedge pressure). While the           B-1.7: COMPLICATIONS OF HEART
         assessment of symptoms is important to
         ensure the short-term improvement in the       FAILURE
         patient's quality of life, long term changes   Heart failure can result in several complications
         in LVEF are more closely related to            that may cause further deterioration of the clinical
         disease progression and ultimate               condition. These include:
         prognosis.
                                                        1. Deep Leg Vein Thrombosis:
                                                        The slow circulation that characterizes heart failure
B-1.4: SYSTOLIC VS. DIASTOLIC HEART                     and the increased viscosity caused by diuretic
FAILURE (SEE CHAPTERS A-3 AND B-3).                     therapy may predispose to thrombosis in the deep
                                                        veins of the leg and thigh.
B-1.5: IDENTIFY UNDERLYING,                             2. Pulmonary Thromboembolism:
                                                        Part of the thrombi that may occur in the legs or
PRECIPITATING AND CONTRIBUTING                          right atrium may detach and obstruct one or more
                                                        of the pulmonary arteries, causing sudden
CAUSES                                                  deterioration of the clinical condition and ultimately
                                                        increasing pulmonary hypertension. Massive
The etiologic diagnosis can be obtained from the
                                                        emboli may obstruct the pulmonary circulation
history (angina pectoris), the physical examination
                                                        causing severe acute right ventricular failure and
(characteristic cardiac murmurs), or laboratory
                                                        rendering heart failure refractory to therapy.
investigations (e.g. ECG evidence of an old
myocardial infarction).                                 3. Dysarrhythmias:
                                                        Arrhythmias are very common in heart failure. This
Precipitating Causes:
                                                        is due to:
The common precipitating factors of heart failure
                                                             1. Stretch of atria
are: Infection (especially chest infection);
                                                             2. Digitalis overdoses
Rheumatic Activity; Arrhythmias (AF); Drugs
                                                             3. Hypokalemia caused by diuretic therapy
(Non-steroidal anti-inflammatory, steroids, anti-
                                                             4. Activation of sympathetic nervous system
arrhythmics); Dietary Excesses (salty food);
                                                        The most common arrhythmia is atrial fibrillation.
Anemia, Environmental (exertion in heat or
                                                        Its onset usually causes sudden deterioration of the
humidity); Severe emotional stress; Development
                                                        clinical condition due to loss of the atrial
of unrelated illness (worsening of renal function);
                                                        contribution to ventricular filling as an well as
Myocardial ischemia and infarction; Infective
                                                        increased heart rate.
endocarditis; Pulmonary embolism; Thyrotoxicosis.
Precipitating factors often induce an acute             4. Hepatic Complications:
exacerbation of heart failure manifestations and        Chronic hepatic congestion may cause progressive
their prompt recognition and management may             degeneration of liver cells with resultant
revert the deterioration in clinical status to a more   hypoalbuminemia and loss of prothrombin activity.
stable condition. For details, refer to section D-1.    Acute hepatic congestion can produce sudden
                                                        deterioration in liver function and produce a picture
Contributing Conditions:
                                                        of acute hepatitis.
CLINICAL EVALUATION.DOC                                 5

5. Cardiac Cachexia:
Caused by anorexia, increased catabolism, cytokine
and TNFα production.
6. Complication of Heart Failure Treatment:
Manifestations of digitalis toxicity, hypokalemia,
hypovolemia, muscle cramps, increasing azotemia,
deterioration of diabetic control and gout may result
from inappropriate use of antifailure therapy.
LABORATORY EVALUATION.DOC                                                                               1


 B-2: LABORATORY EVALUATION                                        c. Urine Examination:
                                                                Severe heart failure may be associated with protreinuria <
                                                                1 g/24 hours. Otherwise urine analysis is essentially
B-2.1: Routine Laboratory Tests                                 normal in the absence of concomitant renal disease. Heavy
B-2.2: Special Laboratory Tests                                 proteinuria points to nephrotic syndrome and glycosuria to
                                                                diabetes mellitus.
B-2.1: Routine Laboratory Tests
       Radiologic, electrocardiographic,
echocardiographic hematologic and biochemical                   2. BLOOD TESTS:
studies are needed for all patients, not only for                   a. Renal and electrolyte profile:
                                                                Severe congestive heart failure may be associated with
diagnosis and differential diagnosis of heart                   mild elevation of blood urea with normal serum creatinine
failure, but also for monitoring therapy.                       and high specific gravity of urine (in renal failure specific
                                                                gravity is low). The serum creatinine level is important to
1. TYPES:                                                       guide digitalis, ACE-inhibitors and diuretic therapy.
                                                                Serum electrolyte values are generally normal in untreated
   a. Chest X-ray:                                              heart failure. In severe heart failure the combination of
The combination of cardiomegaly and pulmonary                   rigid salt restriction, intensive diuretic therapy angiotensin
congestion supports the diagnosis of heart failure.             stimulation, elevated vasopressin levels with reduced
However, the chest x-ray is not a sensitive method for          water excretion may lead to dilutional hyponatremia.
accurate detection of increased cardiac dimensions. Heart       Hyponatremia is usually associated with expansion of
failure with a normal cardiothoracic ratio occurs in patients   extracelluar fluid volume despite a normal or increased
with acute myocardial infarction, acute valvular                total body sodium. Hyponatremia causes resistance to
regurgitation and diastolic heart failure. The shape of the     diuretic therapy.
cardiac silhouette and the detection of calcification in the    Hypokalemia develops as a result of diuretic therapy and
valves, pericardium or myocardium may suggest a specific        should be corrected to avoid digtalis toxicity, ventricular
etiologic diagnosis.                                            arrythmias and muscular hypotonia.
The earliest sign of pulmonary congestion is dilatation and     Hyperkalemia may occur in patients with severe heart
increased diameter of the upper lobe vessels. More              failure who have a marked reduction in glomerular
advanced pulmonary venous hypertension causes haziness          filtration rate and inadequate delivery of sodium to the
and blurring of pulmonary vascular marking, interstitial        distal tubular sodium potassium exchange sites,
opacities in the basal lung zone, thickened septal lines        particularly if they receive potassium sparing diuretics and
(Kerly B- lines) and pleural effusion. Alveolar pulomay         ACE inhibitors.
edema is characterized by lobular or confluent lung
opacities characteristically involving the central regions of      b.     Sugar and lipid profile:
the lungs, giving a butterfly appearance. Dilatation of the
                                                                         Impaired glucose tolerance, diabetes and
main pulmonary artery and its branches signifies
                                                                abnormal lipoprotein pattern are associated with risk of
pulmonary arterial hypertension. However, there is a poor
                                                                ischemic heart disease, the commonest cause of heart
correlation between the x-ray findings and hemodynamic
                                                                failure.
measurements.
   b. Electrocardiography (ECG):
The electrocardiogram is nearly always abnormal in heart           c.     Blood picture:
failure. The changes are often nonspecific [e.g. T-wave                   The ESR is normal or low except in the presence
changes, bundle branch block], in which case an                 of a complication. Anemia may aggravate the symptoms of
etiological diagnosis cannot be made. However, many             heart failure. Polycythemia may suggest chronic
patients will have pathological Q waves, confirming that        pulmonary disease or congenital cyanotic heart disease.
heart failure was the result of underlying coronary artery
disease and previous myocardial infarction. Other               3. ECHOCARDIOGRAPHY:
electrocardiographic changes that may point to the cause        Echocardiography is a routine noninvasive tool in
of heart failure include exaggerated voltage deflections,       diagnosis, management, and follow-up of patients
reflecting ventricular hypertrophy. Atrial abnormalities are    suspected of having heart failure.
common. Left atrial abnormality can help in the diagnosis       A definitive diagnosis of heart failure usually rests on
of left ventricular dysfunction when the origin of patients’    echocardiography. It is an optimal noninvasive technique
symptoms is not clear. Sinus tachycardia, atrial fibrillation   for initial and serial assessment of left ventricular function.
and ventricular arrhythmias are frequently encountered          It can assess both global and segmental left ventricular
arrhythmias in heart failure.                                   systolic function. Ejection fraction is the hallmark of left
LABORATORY EVALUATION.DOC                                                                                    2

ventricular systolic function. Resting ejection fraction of          left ventricular pressure fall which results in a prolongation
≥55% is considered normal. Ejection fraction should be               of isovolemic relaxation and a decrease in peak E velocity
obtained using appropriate formulas from 2D images                   as the peak atrial to ventricular pressure gradient and its
(apical 2 and 4 chamber views). This is particularly                 rate of decay is reduced. The reduction in early diastolic
important in patients with coronary artery disease and               filling leads to enhanced atrial preload and atrial
segmental left ventricular dysfunction. Global impairment            contraction, increased A velocity and a decrease in the E to
of contractility usually points to the diagnosis of dilated          A ratio.
cardiomyopathy, whereas segmental left ventricular                   With marked decreases in left ventricular compliance and
dysfunction with wall thinning and/or left ventricular               severe elevation of left atrial pressure, the mitral E velocity
aneurysm usually points to the presence of coronary artery           increases with marked shortening of its deceleration time
disease. Left ventricular ejection fraction dose not always          (DT). The E to A ratio is greater than two and the DT less
correlate to the severity of heart failure clinically. Left          than 150 msec. This pattern is referred to as a restrictive
ventricular systolic dysfunction might precede the onset of          filling pattern.
patient symptoms. Echocardiography is also essential in
delineating structural cardiac abnormalities that might
reflect the etiologic diagnosis of heart failure. In the
presence of the clinical syndrome of heart failure with              B-2.2: SPECIAL LABORATORY TESTS
normal ejection fraction, one should suspect the presence
of diastolic dysfunction. Echocardiography may help in          1.                 Liver function tests:
assessment of diastolic left ventricular function using              Hepatic congestion maybe associated with modest
pulsed Doppler echocardiography. Doppler techniques can              increases in liver enzymes and serum bilirubin. Cardiac
detect diastolic dysfunction, it dose not allow quantitation         cirrhosis in some cases of long standing heart failure may
of its severity, and they lack sensitivity and specificity.          cause more signficant elevation of serum bilirubin and
Echocardiography with its modalities is the leading                  liver enzymes, prolongation of prothrombin time and
method for assessment of valvular diseases that might                hypoalbuminemia. These abnormalities may regress with
result or participate in the production of heart failure. It         proper treatment of heart failure. Acute right-sided heart
can also clearly show intracardiac thrombi that can                  failure may cause a sharp rise in hepatic enzymes and
frequently form in the setting of left ventricular                   serum bilirubin, a picture simulating viral hepatitis.
dysfunction.
Myocardial ischemia and viability can be assessed by                          2. Thyroid function:
Dobutamine echocardiography. A latent ischemia can                   Assessment of thyroid functions is not routinely done in
become demonstrable in stress echocardiography.                      heart failure patients. Heart failure due to thyrotoxicosis is
                                                                     frequently associated with rapid atrial fibrillation and may
   Doppler Echocardiography:                                         be the presenting feature of thyrotoxicosis especially in the
Doppler echocardiography allows the velocity of blood                elderly. Hypothyroidism may present as heart failure.
flow to be measured. The transmitral flow velocity curves            Measurement of the serum levels of T3, T4 and TSH are
obtained by pulse wave Doppler with the sample volume                the basic screening procedures for assessment of thyroid
at the tips of the mitral valve leaflets reflects the                function.
instantaneous pressure gradient between the left atrium
and the left ventricle. The transmitral flow velocity curve                   3. Exercise stress testing:
has a biphasic contour: an early diastolic wave (mitral E)           In some patients with heart failure, exercise testing will
and a late atrial contraction wave (mitral A). The peak              provide evidence of unsuspected myocardial ischemia.
mitral E velocity is determined by left atrial pressure, the         These patients frequently might need coronary
left ventricle diastolic pressure, left atrial compliance and        angiography and heart failure improves with
the rate of left ventricle relaxation. The peak A velocity is        revascularization.
dependent on left ventricular chamber compliance, left
atrial preload and left atrial contractile function. The                  Objectives of exercise testing in heart
duration of A wave provides information regarding the
resistance to ventricular filling with atrial concentration               failure:
and thus, left ventricular-end-diastolic pressures. The                  1.   To determine physical work capacity.
transmitral flow velocity curves are sensitive both to                   2.   To rule out exercise induced myocardial ischemia
alterationsin diastolic function and to preload.                              as a reason for myocardial dysfunction.
The E to A ratio is greater than one, with increasing age                3.   To determine prognosis.
there is a reduction in peak E velocity and an increase in A             4.   To stratify patients for cardiac transplantation.
velocity. With impaired relaxation there is a slower rate of
LABORATORY EVALUATION.DOC                                                                                3

    5.    Patients evaluated for cardiac transplantation             3.   Right ventricular endomyocardial biopsy can also
          (peak oxygen consumption <14 ml/kg per                          be performed if an unusual cause of myocarditis
          minute).                                                        is suspected.
                                                                     4.   Intracardiac shunts/anomalies can be detected and
         Predictive accuracy:                                             the magnitude of secondary pulmonary
             Simple treadmill exercise test is a very                     hypertension can be assessed.
             accurate and objective test for the assessment
             of functional work capacity. When the test is                   b) Indications:
             done for assessment of myocardial ischemia, it      Coronary angiography is indicated in some patients with
             becomes limited by several factors including        new onset heart failure, even in the presence of a normal
             abnormal resting ECG (left bundle branch            exercise test. Recommendations for use of coronary
             block, resting ST-T changes, left ventricular       Angiography in patients with congestive heart failure are:
             hypertrophy) and patient’s gender (female               1. Congestive heart failure due to systolic
             patients have low specificity). In general the               dysfunction with angina or with regional wall
             sensitivity of the test is around 85% in both                motion abnormalities and /or scintigraphic
             men and women, however the specificity                       evidence of reversible myocardial ischemia when
             drops to 50% in women as compared to 85%                     revascularization is being considered.
             in men.                                                 2. Congestive heart failure secondary to
                                                                          postinfarction ventricular aneurysm or other
         Role in clinical decision making:                                mechanical complications of myocardial
             Referral for coronary angiography, cardiac                   infarction.
             transplantation, and cardiac rehabilitation             3. Normal systolic function, but episodic heart
             programs are dependent on the results of                     failure raises suspicion of ischemically mediated
             exercise stress testing.                                     left ventricular dysfunction.

Cost effectiveness:                                                          Predictive accuracy:
Stress testing is very cost effective when done in the           Coronary angiography is the gold standard for verification
proper clinical setting. The test is inexpensive, safe and its   of the coronary anatomy. No other test can provide similar
diagnostic yield is high.                                        information. When properly done it is highly sensitive and
                                                                 specific.
          4. Pulmonary function tests:
The assessment of pulmonary function may help in the                      6. Tests for myocardial viability:
evaluation of the relative importance of the cardiac versus      Several noninvasive tests are available to detect ischemic
pulmonary contribution to the symptoms in patients with          or hibernating myocardium. The “gold standard” for the
combined heart and lung disease. Primary cardiac                 identification of myocardial viability is positron emission
disorders and restrictive lung disease are characterized by      tomography, which is costly and not generally available.
decreasing vital capacity, total lung capacity with a normal
residual volume. In patient with heart failure the forced                 a) Nuclear Studies:
expiratory volume in the first second (FEV1) and peak            Quantitative thallium scintigraphy using exercise with late
expiratory flow rate may be mildly reduced.                      redistribution or reinjection at rest imaging as well as rest–
In contrast, the patient with COPD shows a decrease in           redistribution imaging also provide most of the clinically
vital capacity and an increase in total lung capacity and the    relevant information regarding viable myocardium in
residual volume. FEV1 and peak expiratory flow rate are          patients with left ventricular dysfunction. Technetium-99m
markedly reduced. The improvement of airway obstruction          sestamibi is of value in measuring ventricular function and
following inhalation of B2 stimulants indicates a                detecting ischemia but appears to be of lesser value in
significant contribution of pulmonary disease.                   assessing myocardial viability. Pharmacologic means for
5. Cardiac catheter and coronary                                 inducing “ischemia,” such as the use of dipyridamole,
angiography:                                                     dobutamine or adenosine, are useful in patients who
         a) Value:                                               cannot exercise.
    1.    Diagnosis of coronary artery disease.                  Irreversibly damaged myocardial cells cannot extract
    2.    Measurements of cardiac output, the degree of          thallium (201TI) intracellularly, even after coronary
          left ventricular dysfunction, and left ventricular     reflow. Various approaches have been used in the
          end-diastolic pressure.                                assessment of 201TI imaging. Most laboratories image 5
                                                                 minutes after administration of 201TI injected during
LABORATORY EVALUATION.DOC                                                                                  4

stress in order to assess the initial distribution of the tracer.   artery bypass surgery, whereas patients with nonviable
The images are then repeated in 2.5 to 4 hours to assess the        tissue are perhaps more suitable for heart transplantation.
presence or absence of redistribution. Occasionally, the
images repeated at 24 hours after injection or a second
reinjection dose of thallium is performed at rest to enhance
the detection of defect reversibility. If there is total               7. Tests for immune function:
redistribution 2.5 to 4 hours after 201TI injection, the            It has been suggested that heart failure may be mediated by
implications are that viability is preserved. However, we           the biological effects of cytokines.
now know that approximately 30% to 40% of persistent                Systemic immune activation and inflammation can be
201TI defects may represent myocardial viability rather             assessed on the basis of plasma levels of cytokines, such as
than scar. Defects that are dense and show more than 50%            interleukin-6 and-8 (IL-6 and –IL8), tumour necrosis
reduction in regional 201TI counts rarely show                      factor (TNF-alpha) and soluble adhesive molecules, such
improvement after coronary artery bypass surgery,                   as selectins. Assessment of immune function in heart
whereas late 201TI redistribution at 18 to 24 hours after           failure is still experimental and only in research centers.
tracer injection tends to predict a favorable response to
coronary revascularization. Occasionally reinjection of a
second dose of 201TI should be performed when
redistribution images remain unresolved. However, it is
difficult to prospectively identify those patients for whom
reinjection will enhance detection of viability.
Occasionally the clinical question is simply whether or not
there is viable myocardium in a zone of severely reduced
myocardial function. In such cases, early and delayed
201TI imaging performed in the resting state are quite
adequate. Resting 201TI imaging can accurately
distinguish viable from nonviable myocardium in patients
with left ventricular dysfunction. Segments of the heart
that have 201TI defects that later take up 201TI during
redistribution show the greatest amount of improvement in
wall motion following revascularization.
New 99mTc-labeled perfusion defects have emerged in
recent years and may be useful in assessing regional
myocardial perfusion and viability. 99mTc sestamibi
uptake is comparable to delayed 201TI uptake. The two
imaging agents appear to be comparable for predicting
enhanced regional systolic function after revascularization.
99mTc sestamibi may be superior to 201TI because of its
better physical characteristics. The images are sometimes
of higher quality than those produced by 201TI. A shorter
half-life of 99mTc allows one to administer doses that are
much higher than those for 201TI.

   b) Dobutamine stress echocardiography:
It is the preferred method of assessing myocardial viability
in patients with heart failure. However, it is relatively
nonquantitative. Evaluation of wall thickening by echo
during low-dose dobutamine infusion can also be used to
determine reversible left ventricular dysfunction in patients
with chronic coronary artery disease. Dobutamine
echocardiography has 88% sensitivity and an 87%
specificity in identifying viable but hypoperfused
dysfunctional myocardial segments before
revascularization.
Those patients with reversible severe left ventricular
dysfunction will often respond favorably to coronary
HEART FAILURE WITH NORMAL SYSTOLIC FUNCTION.DOC                              1


     B-3: HEART FAILURE WITH                               2.   Decrease compliance: occurs with
                                                                increased ventricular chamber stiffness
                                                                due to hypertrophy, fibrosis or infiltration
   NORMAL SYSTOLIC FUNCTION                                     of the wall (e.g. amyloid).
    (DIASTOLIC HEART FAILURE)
                                                       Very commonly systolic and diastolic dysfunction
                                                       co-exist and contribute to the manifestations of
                                                       heart failure. This is because several diseases
                                                       affect contractility as well as compliance and
B-3.1: Definition and Epidemiology                     relaxation.
B-3.2: Pathophysiology
B-3.3: Causes                                          B-3.3: CAUSES
B-3.4: Diagnosis
                                                           1.   The most common cause is hypertension
B-3.5: Differential Diagnosis                                   resulting in left ventricular hypertrophy
B-3.6: Treatment                                                and increased fibrosis of the
                                                                myocardium.
                                                           2.   Ischemic heart disease can cause
B-3.1: DEFINITION AND EPIDEMIOLOGY                              impaired relaxation due to ischemia.
                                                                Replacement of myocardial fibres by
Traditionally when the syndrome of heart failure                fibrosis whether due to chronic ischemia
existed, it was assumed that the cause is impaired              or infarction leads to increased chamber
ventricular systolic function. However, when                    stiffness and decreased compliance.
echocardiography was extensively used, it became           3.   Old age alone can cause diastolic
clear that 20 to 40 % of heart failure patients have            dysfunction probably by loss of
normal left ventricular systolic function. This is              myocytes due to programmed cell death
particularly common in the elderly. Above the age               (apoptosis) and by increased fibrosis.
of 65 almost 70 % of patients diagnosed as heart           4.   Cardiac hypertrophy from whatever
failure have normal ejection fraction. It is                    cause e.g., valvular disease, hypertrophic
assumed that the manifestations of heart failure in             cardiomyopathy, coarctation of aorta, etc,
these cases are due to depressed diastolic function             will reduce ventricular compliance.
of the ventricles.                                         5.   The infilterative lesions e.g., sarcoidosis,
                                                                amyloidosis cause restrictive
B-3.2: PATHOPHYSIOLOGY (SEE ALSO                                cardiomyopathy with impaired diastolic
                                                                function.
CHAPTER A-3)                                               6.   Pericardial disease such as constrictive
                                                                pericarditis and cardiac tamponade
Heart failure due to systolic dysfunction exists due            causes external compression of the heart
to poor ventricular contractility resulting in                  and impair diastolic filling.
impaired ejection and inadequate output. On the            7.   Endomyocardial fibrosis.
other hand, heart failure due to diastolic
dysfunction occurs when ventricular filling is
limited and blood is not evacuated from the atria.
The ventricle is usually thick walled with
concentric hypertrophy and a normal or small           B-3.4: DIAGNOSIS
cavity. Systemic or pulmonary congestion results,
depending on which ventricle is involved.              Basically, this condition is diagnosed when the
                                                       syndrome of heart failure exists and the ejection
                                                       fraction is found to be normal (≥ 40%).
There are two mechanisms for depressed                 Echocardiography is the essential diagnostic tool.
diastolic function:                                    Measuring the parameters of diastolic function
    1.   Impaired relaxation: because relaxation is    can be done by Doppler echocardiography the
         an active process that consumes energy,       relation between the early and late diastolic
         it can be impaired in situations of           filling, i.e. A/E ratio. However, this, and other
         ischemia.                                     Doppler indices, are not specific and occur very
HEART FAILURE WITH NORMAL SYSTOLIC FUNCTION.DOC       2

commonly in old age without manifestations of
heart failure.
Thus the diagnosis of diastolic dysfunction is
basically one of exclusion based on the
accompanying conditions, the clinical assessment,
echocardiographic evaluation of ventricular
systolic function and Doppler evaluation of
diastolic function.

B-3.5: DIFFERENTIAL DIAGNOSIS
Many conditions may simulate heart failure and if,
in these situations, the ejection fraction was
measured and found to be normal, diastolic
dysfunction will be assumed to be the cause
however, other diseases have to be excluded.
These conditions include: chronic obstructive
pulmonary disease, liver disease with edema and
ascitis, silent mitral stenosis, primary pulmonary
hypertension, Ebstein anomaly of tricuspid valve,
etc.

B-3.6: TREATMENT
There is no known therapy that improves diastolic
performance. So the treatment is that of the cause.
In addition, if systolic dysfunction co exist, it
must be given appropriate management.
Diuretics can be used with caution. They improve
the manifestations of systemic or pulmonary
congestion. However, they will reduce the
ventricular filling pressure and may lead to
reduction of forward output.
Beta adrenergic blockers and non-dihydropyridine
calcium antagonists, e.g. verapamil, may be
helpful since they decrease the heart rate and
prolong the diastolic filling period and thus allow
better filling of the ventricles in spite of its
impaired diastolic properties.
Every effort must be made to maintain sinus
rhythm in order to preserve the atrial contribution
to ventricular filling.
DIFFERENTIAL DIAGNOSIS OF HEART FAILURE.DOC OF HEART FAILURE                                           1


       B-4: DIFFERENTIAL                                   • Hyperresonant chest with diminished air
                                                             entry, diffuse wheezes and coarse rales.
      DIAGNOSIS OF HEART                                   • Absence of features of left ventricular
             FAILURE                                         failure like a sustained displaced apical
                                                             impulse, small pulse volume, pulsus
                                                             alternans apical S3 gallop and a murmur of
B-4.1: Shortness of Breath                                   mitral regurgitation. Many patients have
B-4.2: Pulmonary Edema                                       combined left ventricular dysfunction and
B-4.3: Fatigue                                               COPD. In these patients the ECG,
B-4.4: Edema of Lower Limbs                                  echocardiogram and pulmonary function
                                                             tests help to elucidate the diagnosis. The
B-4.5: Systemic Venous Congestion
                                                             ECG points to heart disease if it shows
B-4.6: Gallop Sounds                                         LVH, LBBB, left atrial abnormality or
                                                             evidence of myocardial infarction.
                                                           • The echocardiogram shows isolated
B-4.1: SHORTNESS OF BREATH                                   enlargement of right-sided cardiac
Exertional breathlessness is a frequent presenting           chambers while the left ventricle shows
symptom in heart failure, it is a common symptom             normal dimensions and function.
in the general population, particularly in patients        • The use of pulmonary function tests in
with pulmonary disease. Dyspnea is therefore                 differential diagnosis is reviewed in
moderately sensitive, but poorly specific, for the           Chapter B-2.
presence of heart failure. Orthopnea is a more
specific symptom, although it has a low sensitivity     b) Bronchial Asthma:-
and therefore has little predictive value.              Cardiac asthma and bronchial asthma may both
Paroxysmal nocturnal dyspnea (PND) results from         present with acute shortness of breath, orthopnea
increased left ventricular filling pressures (due to    and diffuse wheezes, which interfere with cardiac
nocturnal fluid redistribution and enhanced renal       auscultation.
reabsorption) and therefore has a greater                   • History of similar attacks relieved by
sensitivity and predictive value.                                bronchodilators.
                                                            • Symptoms may be largely absent
Dyspnea secondary to lung diseases:                              between the attacks.
                                                            • The chest is hyperexpanded and
a) Chronic Obstructive Pulmonary                                 hyperresonant with active accessory
                                                                 muscles of respiration.
   Disease (COPD):-
                                                            • There is prolonged expiration and diffuse
           •    Dyspnea of COPD develops more
                                                                 wheezes, but crepitations are less
                gradually over a long history                    prominent.
                characterized by recurrent cough,
                                                            • The patients improve with inhalation or
                wheezes and expectoration.
                                                                 intravenous bronchodilator therapy.
           •    Patient’s with COPD show central
                cyanosis, facial puffiness, lip
                pursing, barrel shaped chest,                   The main differentiating points
                indrawing of lower intercostal                  are summarized in the table
                muscles, warm hands, big pulse                  below.
                volume and sometimes clubbing.
           •    The neck veins may be engorged
                during expiration but they empty
                normally during inspiration.
                  Acute cardiac asthma                               Bronchial asthma
                                                        History of similar attacks relieved by
      History and clinical evidence of heart disease.
                                                        bronchondilators. Symptoms may be largely
      Symptoms usually persist after the attack.
                                                        absent between the attacks
DIFFERENTIAL DIAGNOSIS OF HEART FAILURE.DOC OF HEART FAILURE                                        2


     Left ventricular apical impulse                ⎯

     Profuse sweating , cold extremities            ⎯
     Central cyanosis                               ±

                                                    Hyperexpanded , hyperresonant chest with active
     Dullness over the lung bases
                                                    accessory muscles of respiration

     Bubbling crepitations                          Less prominent rales
     Frothy blood tinged sputum                     ⎯

     Therapeutic response to IV diuretic            To inhalation / IV bronchondilators

                                                         features of thyrotoxicosis include
c) Pulmonary Interstitial Fibrosis:                      nervousness, tremors, loss of weight, heat
  Progressive shortness of breath, cough, diffuse        intolerance, wide palpebral fissure and
  crepitations and loss of weight which maybe            sometimes a thyroid swelling. The diagnosis
  mistaken for heart failure. Characteristic             is established by estimation of T3, T4 and
  features include central cyosis, clubbing              TSH.
  polycythemia and bilateral pulmonary
  infiltrations on the chest X-ray. The ECG may
  show right axis deviation, clockwise rotation,    B-4.2: PULMONARY EDEMA
  right ventricular hypertrophy and p-pulmonale.
  The echocardiogram excludes the presence of            Non-cardiogenic pulmonary edema: Non
  left ventricular disease.                              cardiogenic pulmonary edema may occur as
                                                         a result of rapid ascent to high altitude,
                                                         central nervous system disorders, heroin
d) Bronchopneumonia,                                     overdose, septicemia, overwhelming
   Pneumothorax and Pulmonary                            pneumonia, massive pulmonary embolism,
   Atelectasis:                                          and shock lung. It can be differentiated from
   May present with acute dyspnea and cough.             pulmonary edema of cardiac origin by:
  They are differentiated by the characteristic          * Absence of an acute cardiac event or
  clinical features and X-ray findings.                  history of heart disease.
                                                         * Evidence of underlying disease e.g.
High output states:                                      pneumonia, toxin inhalation, pancreatitis
    High cardiac output states may precipitate           * Warm periphery, bounding pulses.
    heart failure in the presence of underlying          * Absence of cardiomegaly, S3 gallop. The
    cardiac disease. More often, however, they           JVP is normal.
    present with clinical features which simulate        * ECG is usually normal.
    heart failure.                                       * Chest X-ray shows a peripheral
    Thyrotoxicosis may be associated with                distribution of pulmonary opacities.
    dyspnea, easy fatigue, palpitations, sinus
    tachycardia, atrial fibrillation, systolic      Pulmonary embolism: Patients with pulmonary
    hypertension, hyperdynamic apex, S3,            embolism may present with dyspnea, tachypnea,
    ejection systolic murmur and sometimes          tachycardia, hypotension, pleuritic pain, cough,
    pretebial myxedema (non-pitting edema).         rales, and diminished breath sounds over the lung
    However in the absence of CHF, the JVP is       bases. The diagnosis is suspected by
                                                    circumstantial evidence of factors predisposing to
    normal and there is no hepatomegaly or          thromboembolism. The ECG is non-specific but
                                                    may shows subtle signs of RV overload. The chest
                                                    x-ray will reveal absence of pulmonary
    radiological signs of pulmonary congestion.     congestion. A normal chest x – ray in the setting
    Echocardiography will show normal cardiac       of severe dyspnea suggests pulmonary embolism.
    dimensions and normal EF. Characteristics       Echocardiography shows evidence of RV
     DIFFERENTIAL DIAGNOSIS OF HEART FAILURE.DOC OF HEART FAILURE                                                 3


     dilatation and dysfunction. The diagnosis is               Fatigue in chronic heart failure is in part, related
     established by lung ventillation perfusion scan.           to abnormalities in skeletal muscle, with
                                                                premature muscle lactate release, impaired muscle
     Other causes of dyspnea: Including obesity,                blood flow, deficient endothelial function and
     anemia and psychogenic dyspnea can be easily               abnormalities in skeletal muscle structure and
     differentiated by the absence of cardiomegaly and          function.
     the demonstration of normal left ventricular
                                                                B-4.4: EDEMA OF LOWER LIMBS
     function by echocardiography.
                                                                Swelling of ankles and heart is another common
                                                                presenting feature, although there are numerous
     B-4.3: FATIGUE                                             non-cardiac causes of this symptom.

                                    Common Causes of Lower Limb Edema

                        Venous insufficiency.
                        Gravitational immobility.
                        Congestive heart failure.
                        Venous thrombosis or obstruction, varicose veins.
                        Hypoproteinemia, e.g., nephrotic syndrome andliver disease.
                        Lymphatic obstruction.
                                                                 tachypnea, tachycardia, pulsus paradoxus,
                                                                 hepatomegaly and sometimes a pericardial
     B-4.5: SYSTEMIC VENOUS CONGESTION                           friction rub. The ECG may show low voltage
                                                                 and electrical alternans. Echocardiography
1.        Constrictive pericarditis: It is                       shows pericardial effusion, right atrial and
     characterized by marked elevation of the JVP                right ventricular diastolic collapse.
     with prominent x-descent and rapid steep y              4.       Liver cirrhosis: This is characterized
     descent, inspiratory increase in JVP                        by a firm shrunken non-pulsating liver,
     (Kussmaul’s sign), pulsus paradoxus,                        splenomegaly, ascites, edema, jaundice,
     precordial systolic retraction, and sharp early             palmar erythema and spider angiomas.
     S3 (pericardial knock). Other findings                      Patients with hepatocellular failure have
     simulating heart failure include enlarged                   cyanosis, hyperdynamic circulation and
     pulsating liver, oedema, ascites and pleural                ejection systolic murmurs. However, the JVP
     effusion. The x-ray shows pericardial                       is normal, there is no cardiomgealy or S3
     calcification in 50% of patients.                           gallop and no signs of pulmonary congestion.
     Echocardiography shows thickened                            Echocardiography shows normal cardiac
     pericardium, and normal LV dimensions and                   function.
     systolic function.                                      5.       Renal disease: Patients with chronic
2.        Restrictive cardiomyopathy: The                        renal failure may present with hypertension,
     clinical presentation may be very similar to                anaemia, abnormal salt and water retention
     constrictive pericarditis. However there may                associated with hypervolaemia, pulmonary
     be LV apical impulse, S3 gallop or a murmur                 congestion, SOB, elevated JVP, and edema
     of valvular regurgitation. Echocardiography,                despite a normal cardiac function .The
     CT and MRI will show absence of thickened                   disease is characterized by elevated serum
     pericardium characteristic of constrictive                  creatinine, abnormal urinary sediment and
     pericarditis.                                               bilateral small kidneys.
3.        Cardiac tamponade: Patients                        6.       Myxedema: Maybe associated with
     present with dyspnea, hypotension and chest                 dyspnea, cardiomegaly, non-pitting edema,
     pain. The JVP is markedly elevated showing                  anasarca, and pericardial effusion. ECG may
                                                                 show bradycardia, low voltage and T wave
                                                                 changes. Characteristically, the
     an x-descent and absent y descent. There is                 cardiovascular abnormalities are reversible
                                                                 upon treatment with thyroid replacement
                                                                 therapy. Diagnostic features include fatigue,
    DIFFERENTIAL DIAGNOSIS OF HEART FAILURE.DOC OF HEART FAILURE                                                4


    lethargy, gain in weight, pallor, periorbital             injection shows absent central veins opacification
    puffiness, and dry rough skin. TSH is                     and a prominent collateral circulation.
    elevated; T3 and T4 are reduced.                       7.      Other causes of edema: These
    Superior vena cava syndrome: This may present             include nutritional edema, localized edema
    with gross engorgement of the neck veins with             caused by deep vein thrombosis or chronic
    attenuated pulsations, facial swelling, headache,         lymphagaitis, pregnancy, treatment with
    edema of the arms and collateral veins over the           calcium channel blockers and periodic
    anterior chest wall. CT scan with contrast                idiopathic edema in females.
                                                              Protodiastolic sounds generally arising from the
                                                              left ventricle (but occasionally from the right), and
         DIAGNOSIS OF HEART FAILURE                           occurring 0.13 to 0.16 sec. after the second heart
-       Criteria for Diagnosis                                sound, are common findings in healthy children
                                                              and young adults. Such physiological sounds are
                   Two Thirds of Patients Wrongly             seldom heard in healthy persons after age 40, but
                                                              occur in patients of all ages with heart failure and
    Diagnosed.                                                are referred to as protodiastolic gallop or S3
-       Poor Predictive Value of Clinical Signs.              gallops. In older adults, they generally signify the
                                                              presence of heart failure. Thus, a protodiastolic
-       Problem of Overdiagnosis:                             gallop sound is an excellent sign of heart failure
                                                              when other causes such as a physiological S3
                        Only 26-41% have Left                 occurring in a healthy child or young adult,
                                                              hyperkinetic circulation (e.g., anemia,
    Ventricular Systolic Dysfunction (ECHO)                   thyrotoxicosis, pregnancy, fever), constrictive
                                                              pericarditis, mitral and tricuspid regurge or a left
-       Diagnostic Gold Standard Test?                        to right shunt can be excluded.


    B-4.7: GALLOP SOUNDS
    Clinical Features                        Sensitivity         Specificity         Positive   Predictive   Value
                                                                 (%)                 (%)
    I) History:
    History of edema                         23                  80                  22
    Shortness of breath                      66                  52                  23
    Orthopnea                                21                  81                  2
    PND                                      33                  76                  26
    II) Examination:
    Tachycardia (> 100 beats/min)            7                   99                  6
    Crepitations                             13                  91                  27
    Edema (on exam)                          10                  93                  3
    Gallop (S3)                              31                  95                  61
    Neck vein distension                     10                  97                  2
    III) Chest X-ray Exam:
    Cardiomegaly                             62                  67                  32
DRUGS FOR HEART FAILURE.DOC                                                                       1


        C-1: DRUGS FOR HEART                                •    Decreased conduction velocity in the AV
                                                                 node, producing an important reduction in
                   FAILURE                                       ventricular response in atrial fibrillation.
                                                            •    Digitalis also increases the slope of phase 4
                                                                 diastolic depolarization and therefore
                                                                 increases automaticity of ectopic
C-1.1: Digitalis
                                                                 pacemakers.
C-1.2: Diuretics
C-1.3: ACE Inhibitors
C-1.4: Beta Blockers                                     3. Hemodynamic Effects:
C-1.5: Inotropic Agents and Other Drugs                     •    Digitalis improves the cardiac index and
C-1.6: Vasodilators                                              stroke work index and decreases pulmonary
C-1.7: Anticoagulants                                            capillary wedge pressure in congestive
C-1.8: Antiarrhythmic Agents                                     heart failure patients.
                                                            •    The decrease in heart rate may be beneficial
                                                                 by decreasing myocardial oxygen
C-1.1: DIGITALIS                                                 consumption, increasing diastolic filling
                                                                 and improving overall myocardial
Digoxin (Lanoxin) is the most reliable                           efficiency.
digitalis preparation and is used by the                    •    In absence of heart failure, digitalis has a
majority of physicians.                                          direct vasoconstrictor effect which
                                                                 increases total systemic resistance. On the
                                                                 other hand, in the failing heart, it produces
Mechanism of Action:
                                                                 vasodilatation and a fall in total systemic
1. Direct Actions: Positive Inotropic                            resistance.
Effect:
    •    Digitalis produces partial inhibition of        Indications:
         Na+/K+ ATPase enzyme.                              1.   Heart failure associated with atrial
    •    This results in K+ efflux from the cell                 fibrillation and a rapid ventricular response.
         decreasing the intracellular K+.                        In patients with heart failure and atrial
    •    This is associated with Na+ influx into the             fibrillation with a rapid ventricular
         cell, increasing the intracellular Na+.                 response, the administration of high doses
    •    This inhibits passive exchange between                  of digoxin (greater than 0.25 mg) for the
         extracellular Na+ and intracellular Ca2+                purpose of rate control is not recommended.
         and will increase the Ca2+ retained inside              When necessary, additional rate control
         the cell.                                               should be achieved by the addition of B-
    •    Digitalis also directly activates the                   blockers or amiodarone.
         sarcolemmal Ca2+ channels, increasing              2.   The presence of poor left ventricular
         Ca2+ influx.                                            contractility as evidenced by the presence
                                                                 of a 3rd heart sound gallop (S3),
    •    The increased influxed Ca2+ causes the
                                                                 crepitations over the lung fields and low
         sarcoplasmic reticulum to release the bound
                                                                 ejection fraction (< 40%).
         Ca2+.
                                                            3.   As an adjunct to diuretics and vasodilators
    •    Increased free ionizable intracellular
                                                                 when there is failure of symptomatic relief
         calcium inhibition of troponin and
                                                                 produced by the two drug groups. Diogoxin
         tropomyosin positive inotropic effect.
                                                                 should be considered for patients who have
                                                                 symptoms of heart failure caused by left
2. Electrophysiologic Effects:                                   ventricular systolic dysfunction while
    Digitalis increases the vagal tone                           receiving standard therapy.
through:
    •    Sensitization of the baroreceptors in the       Recent Clinical Benefits:
         aortic arch and carotid sinus.                     •    Although digitalis did not reduce the total
    •    Direct stimulation of the vagal centre in the           mortality rate in patients with heart failure
         medulla.                                                who were treated with ACE inhibitors and
    •    Inhibition of compensatory reflexes, e.g.               diuretics, it significantly reduced the rate of
         Bainbridge reflex, due to the improved                  hospitalization for patients with worsening
         circulation results in decreased sympathetic            heart failure and slightly reduced the risk of
         tone and increased vagal tone.                          death attributed to worsening heart failure
                                                                 (Digitalis Investigation Group (DIG)).
DRUGS FOR HEART FAILURE.DOC                                                                     2

     •    Relatively low doses of digitalis are           DOSE:
          sufficient to suppress neurohumoral factors     Loading Dose: For adults and children over
          (plasma norepinephrine, renin activity,
          angiotensin II and aldosterone) in patients
                                                          10 years of age:
          with heart failure.
     •    Digitalis improves myocardial relaxation in     Orally: A dose of 0.5 to 1 mg is given as
          patients with systolic dysfunction.             follows:
     •    In the DIG study, there was a trend towards       • 0.5 mg immediately and 0.25 mg
          an increased mortality in patients with high
                                                                every 12 hours for two doses (1
          serum digoxin levels when compared to
          those with digoxin levels within the                  mg/24 hours).
          therapeutic range (1-2 ng/ml).                   •   0.25 mg twice daily for 2 days, then
                                                                maintenance depending on age and
     •    Digitalis is NOT recommended in the                   renal function.
          following subset of patients:                    •   Intravenously:
     •    Acute myocardial infarction (during the          •   0.75 mg IV slowly over 5 min, then 0.25
          first 2 days) unless the heart failure is not         mg every 2 hours for 2 doses. A total
          controlled by diuretics, ACE inhibitors and           dose of 1.25-1.5 mg is often necessary.
          inotropics (e.g. dobutamine).                    •   0.75-1.25 mg as an infusion over 2 hours
     •    In the presence of heart block (1st, 2nd or           or more, which is advised in the UK
          3rd degree) unless a pacemaker is used.               when rapid control is needed.
     •    Mitral stenosis and normal sinus rhythm.         •   Maintenance Dose: In the presence of a
     •    Hypertrophic cardiomyopathy.                          normal renal function:
     •    Sick sinus syndrome.                             •   Age < 70 years: 0.25 mg daily.
     •    Cor-pulmonale unless AF is present.              •   Age > 70 years: 0.125 mg daily.




In the presence of renal failure the dosing interval is increased according to the creatinine
clearance.

Conditions in which there is increased sensitivity to digoxin and lower dosing is
recommended:
    Elderly patients (age > 70 years).
    Renal impairment.
    Thin patients, low skeletal muscle mass.
    Hypokalaemia.
    Hyperkalaemia.
    Hypoxaemia.
    Acidosis.
    Acute myocardial infarction.
    Hypomagnesaemia.
    Hypercalcaemia.
    Hypocalcaemia.
    Myocarditis.
    Hypothyroidism.
    Amyloidosis

Serum Digoxin Levels:                                      •    Low therapeutic or subtherapeutic
 •       Therapeutic levels of digoxin are 1-2                  levels (< 0.8 ng/ml) do not exclude
         ng/ml (levels should be determined 6                   toxicity.
         hours after the last digoxin dose).               •    Patients must never be allowed to have
                                                                levels higher than 3 ng/ml.
                                                           •    Limited application in daily practice.
DRUGS FOR HEART FAILURE.DOC                                                                       3

                                                            Tachycardias:
           Digitalis Toxicity:                                 •   Potassium intravenously: 40-60 mEq/litre
  •       Gastrointestinal: anorexia, nausea,                      unless the patient has a raised serum K
           vomiting, diarrhea and weight loss.                     level or in the presence of renal
  •       CNS: visual hallucinations, mental                       insufficiency or AV block.
           confusion, psychosis, restlessness,                 •   Lidocaine: In the presence of ventricular
           insomnia, drowsiness and extreme                        tachycardia give 50-100 mg IV bolus then
           weakness. Blue-green-yellow vision,                     2-3 mg/min.
           blurring of vision and scotomas.                    •   Phenytoin: given for non-responders to the
  •       Cardiac Dysrhythmias:          Ventricular               above therapy given IV 250 mg at a rate of
           premature beats: bigeminal or                           25-50 mg/min as an infusion.
           multifocal.                                         •   Magnesium intravenously in the presence
             AV block:                                             of hypomagnesaemia.
 ⇒ 2nd degree (Wenchbach).                                     •   B-blockers may have a role in non-
 ⇒ Atrial tachycardia with AV block.                               responders of the above therapy.
 ⇒ Rarely, complete heart block.                            Bradyarrhythmias:
 ⇒ A very slow ventricular response (< 50/min).                •   Atropine (IV): 0.4, 0.5, 0.6 mg every 5 min
 ⇒ Tachycardias:                                                   to a maximum of 2.4 mg.
 ⇒ Non-paroxysmal junctional tachycardia.                      •   Temporary pacing: If there is failure to
 ⇒ Ventricular tachycardia or ventricular                          respond to atropine.
   fibrillation.                                               •   Cardioversion: If the patient develops
 ⇒ Bradyarrhythmias:                                               ventricular fibrillation.
 ⇒ Sinus bradycardia.                                          •   Digoxin-Immune Fab (Digoxin-specific
                                                                   antibody):
 ⇒ Sinus arrest and sinoatrial block.
                                                               •   Dose: Vial 40 mg, give 2-6 vials. These
                                                                   reverse most cases of toxicity.
Management of Toxicity:                                        •   Effective for life threatening arrhythmias
General Measures:                                                  especially with failure of conventional
 •        Stop the drug.                                           therapy.
 •        Measure digoxin levels and serum potassium.          •   Especially useful in the presence of
 •        Monitor the patient.                                     hyperkalaemia.
                                                               •   Skin testing to avoid allergy is
Specific Therapy:                                                  recommended.

Drug name:                Digoxin
Trade name:               Lanoxin
Supplied:                 0.25 mg tablets.
                          0.5 mg ampoules.


C-1.2: DIURETICS                                                   edema is accompanied by the use of
                                                                   vasodilators.
Introduction:                                                  •   Long-term diuretic administration leads to
The role of diuretics in heart failure is essentially              activation of the renin-angiotensin-
symptomatic relief. Their role on survival was                     aldosterone system, which has raised
totally lacking. Definite survival benefit was found               concerns over the possible adverse effects
with the use of spironolactone, in a recent                        of diuretics on left ventricular remodeling
randomized controlled trial, added to a background                 and survival. Thus, whenever possible,
treatment with an ACE inhibitor and loop diuretics.                patients requiring diuretics should also
                                                                   receive ACE inhibitors.
Guidelines:                                                    •   When cardiac compensation is achieved,
      •      Diuretics are not indicated in                        the minimum possible oral dose should be
             asymptomatic, normotensive, left                      used.
             ventricular dysfunction.                          •   Spironolactone should be added in
      •      In symptomatic heart failure (congestive), a          persistent NYHA class III or IV
             diuretic will almost always be necessary.             symptomatic heart failure.
             Their acute administration in pulmonary
DRUGS FOR HEART FAILURE.DOC                                                                    4

   •   Combination of loop and thiazide diuretics               glucose tolerance, lipid status and/or gout
       can be used in refractory edematous heart                may be required.
       failure.                                             •   Drugs that are prostaglandin inhibitors, in
   •   Monitoring of plasma potassium,                          particular indomethacin and other NSAIDs
       magnesium, sodium and creatinine is                      reduce the diuretic and antihypertensive
       necessary. Specific therapy for disturbed                actions of furosemide and thiazides.




               THE ROLE OF DIURETICS IN HEART FAILURE


                                      Left ventricular dysfunction
                                            (LV EF < 40%)                               ACE
                                                                                     INHIBITOR

                                                Symptoms


               Yes                                                       No



         Loop
                                                                Hypertension
       Diuretics



Resolution of edema?                                    Yes                       No
Control of symptoms?

                                                         Thiazide
Yes                     No                               Diuretics            No diuretic


Minimum, oral
                                           Spironolactone
maintenance dose
of loop diuretic


                                          Control


                        Yes                             No


               Continue ACE inhibitor
               Loop diuretics and                                    COMBINED DIURETICS
               Spironolactone.                                         Loop diuretics plus
                                                                      metolazone or other
                                                                            thiazide
    DRUGS FOR HEART FAILURE.DOC                                                                         5



    After Richards, Nicholls and Troughton.


    THIAZIDE DIURETICS:
    Example:
    Drug name:            Hydrochlorothiazide
    Trade name:           Esidrex
    Supplied:             25, 50, 100 mg
    Dose:                 12.5-25 mg each morning, max. 50 mg/day

    Indications:                                                    •Gastrointestinal: Anorexia, gastric
        •    Heart failure associated with hypertension.             irritation, intrahepatic cholestatic jaundice,
                                                                     pancreatitis.
        •    In combination with loop diuretics in
             refractory edematous heart failure.                  • CNS: Dizziness, vertigo, parasthesia,
                                                                     headache.
                                                                  • Haematologic: Leucopenia, rarely
    Mechanism of Action:                                             agranulocytosis, thrombocytopenia, aplastic
    The exact mechanism of action and its                            anaemia and haemolytic anaemia; increased
    antihypertensive effect is unknown, and the effect is            serum cholesterol, decreased HDL
    believed to be related to: decreased vascular volume,            cholesterol, and increased blood viscosity.
    negative Na+ balance, and arteriolar dilatation               • Cardiovascular: Orthostatic hypotension;
    causing a decrease in total peripheral resistance.               low cardiac output, arrhythmias due to
                                                                     hypokalaemia, especially if the patient is on
    Contraindications:                                               digitalis.
        •    Hypersensitivity to thiazides or                     • Hepatic coma may be precipitated due to
             sulfonamides.                                           hypokalaemia.
        •    Anuria or severe renal failure.                      • Diabetes: Insulin requirements may be
        •    Patients taking lithium.                                increased, latent diabetes may become
                                                                     manifest; rarely, hyperosmolar nonketotic
                                                                     hyperglycaemic diabetic coma may be
    Adverse effects:                                                 precipitated.
        •    Dehydration and orthostatic hypotension.
                                                                  • Hypercalcaemia.
        •    Hypokalaemia.
                                                                  • Acute allergic interstitial pneumonitis.
        •    Hyperuricaemia.
                                                                LOOP DIURETICS:

    Example:
    Drug name:            Furosemide
    Trade name:           Lasix
    Supplied:             Tablets: 40 mg
                          Ampoules: 20 or 40 mg
    Dose:                 Oral: 20, 40 or 80 mg each morning until desired effect is
                          achieved, maintenance 20-40 mg daily or every second day.
                          Intravenous: 80-160 mg daily. In refractory heart failure with renal
                          failure doses of 160-320 mg may be required to promote diuresis.

    Indications:                                                             o    Refractory heart failure with renal
                                                                                 failure.
•         Intravenous: Emergency or life-
    threatening situations, e.g.:                           •          Oral: Symptomatic relief of dyspnea,
                  o Pulmonary edema.                            relief of edema.
                  o Severe heart failure with poor oral
                       absorption.                              Mechanism of Action:
    DRUGS FOR HEART FAILURE.DOC                                                                             6

•         Loop diuretics inhibit the Na+/K+/Cl-              •           Hepatic failure.
    transport system of the luminal membrane in              •           Severe hypokalaemia.
    the thick ascending loop of Henle, and thus              •           Hypersensitivity to furosemide or
    block Cl- reabsorption at this site where                      sulfonamides.
    approximately 40% of filtered Na+ is normally            •           Drug Interactions:
    reabsorbed. Loop diuretics, through their                •           Combination with cephalosporins or
    action on Na+-Cl- co-transport, inhibits Ca2+,                 aminoglycosides may increase nephrotoxicity.
    K+ and Mg2+ reabsorption.                                •           Care is necessary with patients treated
•         Venodilatation, an action that involves                  with lithium, as it may induce toxicity.
    prostaglandins.

    Contraindications:

    Adverse Effects:
         Hypokalaemia.                                           Hypomagnesemia.
         Hyponatraemia.                                          Dyslipidemia.
         Hypochloremic                metabolic                  Glucose intolerance.
    alkalosis.                                                   Nonketotic hyperosmolar coma.
         Azotaemia.                                              Hypocalcaemia.
         Hyperuricaemia.
    K+ SPARING DIURETICS:
    Example:
    Drug name:             Spironolactone
    Trade name:            Aldactone.
    Supplied:              Tablets: 25 and 100 mg
    Dose:                  50-200 mg daily in single or two divided doses.

    Mechanism of Action:                                             •    ACE inhibitors and spironolactone both
    It is a weak diuretic acting by competitive inhibition                cause hyperkalaemia.
    of aldosterone. It handles approximately 2% of                   •    NSAIDs combined with spironolactone
    filtered Na+ at the distal tubule, so only a small                    may precipitate acute renal failure.
    diuresis is achieved.

    Indications:                                                   C-1.3: ANGIOTENSIN CONVERTING
    •     When added to thiazides or loop                          ENZYME (ACE) INHIBITORS
         diuretics, diuresis is greatly augmented.
         The serum K+ remains within the normal
         range.
                                                                   Rationale and Background:
    •     In the presence of secondary                             One of the major consequences of reduced cardiac
         aldosteronism e.g. chronic recurrent heart                performance in chronic congestive heart failure
         failure especially in the presence of liver               (CHF), is activation of the renin angiotensin system
         impairment.                                               (RAS). Angiotensin (Ang) II is believed to mediate
                                                                   the deleterious effects of RAS activation. Apart from
         Disadvantages:                                            other effects, Ang II induces vasoconstriction,
    •     Gynecomastia: Depends on dose and                        aldosterone secretion and possibly activation of the
         duration of treatment.                                    sympathetic nervous system and norepinephrine
    •     Risk of hyperkalemia in patients with                    release. Vasoconstriction and volume overload lead
         renal failure, or patients receiving ACE-                 to augmented wall stress, which increases
         inhibitors.                                               myocardial oxygen consumption. Together with
    •     Gastrointestinal side effects.                           other mechanisms, this promotes myocardial
    •     Drug Interactions:                                       dysfunction, which further stimulates the RAS as
    •     Aspirin may antagonize the diuretic                      well as the sympathetic nervous system. Ang II
         effect of spironolactone.                                 plays a central role in the initiation and progression
                                                                   of the viscous cycle of cardiac remodeling. It
DRUGS FOR HEART FAILURE.DOC                                                                           7

stimulates myocardial hypertrophy, myocyte                  •      Captopril differs from other ACE inhibitors by
apoptosis, collagen formation and degradation. One                 its short half-life.
possible intervention to interrupt this viscous cycle       •      With the exception of fosinopril ACE inhibitors
is to suppress Ang II formation by inhibition of                   are cleared predominantly by the kidney.
ACE.                                                        •      Except for Captopril, ACE inhibitors are
                                                                   administered as prodrugs that remain inactive
                                                                   until estrified in the liver.
Pharmacology:                                               •      There are differences in the tissue affinity of
                                                                   ACE inhibitors. The clinical significance of
    •    These drugs are competitive inhibitors of
                                                                   differences in the tissue binding have not been
         the angiotensin converting enzyme (ACG).
                                                                   established.
         They prevent the conversion of Angiotensin
         I to Angiotensin II.
    •    ACE inhibitors may be classified into three
                                                            Impact on Symptomatology:
         groups according to the chemical structure.
                                                            All ACE inhibitors have been shown to improve
              o Captopril is the prototype of the
                                                            symptomatology. Dyspnea was relieved, exercise
                  sulfhydryl-containing ACE
                                                            tolerance was prolonged, and the need for
                  inhibitors.
                                                            emergency care for worsening of heart failure was
              o Fosinopril is the only ACE
                                                            decreased. These benefits were seen in patients with
                  inhibitor that contains a phosphinl
                                                            mild, moderate, and severe symptoms, whether they
                  group.
                                                            were treated or not with digitalis. In addition, ACE
              o The majority of the other ACE
                                                            inhibitors may decrease the need for large doses of
                  inhibitors contain a carboxyl
                                                            diuretics and may attenuate many of the adverse
                  group.
                                                            metabolic effects of diuretic therapy (e.g.
                                                            hypokalemia).


Main Clinical Trials of ACE-Inhibitors in Congestive Heart Failure
and Left Ventricular Dysfunction

         STUDY                PATIENT POPULATION            ACE-INHIBITORS               OUTCOME

        Consensus                    NYHA IV               Enalapril Vs placebo        ↓ mort & CHF
 SOLVD-Treatment                   NYHA II & III           Enalapril Vs placebo        ↓ mort & CHF
 V HeFT                            NYHA II & III                 Enalapril Vs             ↓ mort &
                                                                 hydralazine            sudden death
 SOLVD-Prevention                Asymptomatic LV           Enalapril Vs placebo        ↓ mort & CHF
                                    dysfunction
 CONSENSUS-II                        MI (24 hrs)             Enalapril (IV) Vs            no change
                                                                   placebo
 SAVE                      MI + ↓ LV function (3-16 d) Captopril Vs placebo                ↓ mort
 AIRE                           MI + CHF (3-10 d)          Ramipril Vs placebo             ↓ mort
 TRACE                      MI + ↓ LV function (3-7 d)          Trandolapril Vs            ↓ mort
                                                                   placebo

MI= acute myocardial infarction               LV = left ventricular
Mort. = mortality                             CHF = congestive heart failure
                                                            All patients with heart failure due to left ventricular
NYHA: functional class                                      systolic function should receive an ACE inhibitors
                                                            unless they have been shown to be intolerant to or
Indications:                                                have a contraindication to the use of this class of
DRUGS FOR HEART FAILURE.DOC                                                                      8

drugs. In patients with evidence for a prior history    sudden death and myocardial ischemic events are
of fluid retention, ACE inhibitors are generally used   also deceased.
with diuretics. ACE inhibitors are also
recommended for use in patients with left ventricular   Risks and Side Effects:
systolic dysfunction who have no symptoms of heart      Hypotension: Symptomatic hypotension is not
failure.                                                uncommon in patients already treated with diuretics.
ACE inhibitors are indicated for long term              First dose hypotension may occur when starting with
management of chronic heart failure. These drugs        a large dose in a salt depleted patient, e.g., on large
generally should not be used to stabilize acutely ill   dose diuretic. Hypotension is primarily a concern if
patients, e.g. those who are in intensive care units    it is accompanied by worsening renal function,
with refractory heart failure requiring intravenous     blurred vision or syncope. Such events may occur at
pressor support.                                        any time during the course of treatment, but are seen
                                                        most frequently during the first few days of
Initiation of Therapy:                                  initiation of, or increments in therapy. The following
Treatment with an ACE inhibitor should be initiated     groups are at increased risk of hypotensive reactions:
at very small doses followed by gradual increments      elderly, marked hyponatremia (< 130 mmol/L),
in dose if lower doses have been well tolerated. For    recent rapid diuresis. Withholding diuretics for 1-2
example, therapy may be started at a dose of 6.25       days may avoid these reactions.
mg of captopril 2-3 times daily, 2.5 mg enalapril       Renal Failure: Glomerular filtration is critically
twice daily, or 2.5 or 5 mg lisinopril once daily,      dependent on angiotensin mediated efferent
followed by a doubling in dose every 3-7 days. The      arteriolar vasoconstriction in patients with severe
titration schedule may be advanced more rapidly or      heart failure and decreased renal perfusion. ACE
more slowly in individual patients if clinically        inhibitors may cause functional renal insufficiency.
appropriate. Renal function and serum potassium         Hyperkalemia: Especially with renal dysfunction or
should be assessed within 1-2 weeks of initiating       when taking oral potassium supplements or
therapy and periodically thereafter (3-6 months).       potassium sparing diuretics.
Physician should ensure that the dose of diuretics is   Cough: Dry, tickling cough occurs in up to 15-30%
optimized before treatment with these drugs.            of patients, probably due to bradykinin
                                                        accumulation. It may necessitate cessation of
                                                        therapy.
3. Impact of treatment:                                 Angioedema: Rare, but it is life threatening
A) On symptomatology and quality of                     complication. Treatment is prompt hospital transfer,
life:                                                   spray of vasoconstructors nasal drops in the throat,
                                                        adrenaline injection.
It is proved that ACE inhibitors are                    Skin Rash
associated with the following clinical                  Proteinuria
benefits:                                               Neutropenia and agranulocytosis (very rare)
       - Reduce severity and                            Pregnancy: Fetal malformation and death.
          frequency of
          symptoms.                                     Interaction with Aspirin:
       - Prevent progression of                         There is insufficient evidence concerning the
                                                        potential negative therapeutic interaction between
          symptoms.                                     Aspirin and ACE inhibitors to warrant withholding
       - Improve functional                             either of these medications in which an indication
          status.                                       exists.
       - Improve exercise
          tolerance.
ACE inhibitors can also decrease the risk of
developing heart failure in asymptomatic patients
with left ventricular systolic dysfunction.
                                                        Contraindications:
                                                        Absolute:
B) On survival:                                         •   History of allergic reactions or life threatening
Several clinical studies have demonstrated that ACE         side effects (angioedema or anuric renal
inhibitors improve survival in patients with                failure).
congestive heart failure and in asymptomatic left       •   Bilateral renal artery stenosis.
ventricular dysfunction. This reduction in mortality    •   Pregnancy.
results primarily from a reduction in progression of
congestive heart failure, although the incidence of     •   Relative:
    DRUGS FOR HEART FAILURE.DOC                                                                           9

    •      ACE inhibitors can be given if necessary, but        The sympathetic nervous system is activated early in
           with great caution and close monitoring and in       the course of heart failure even if the disease is still
           hospital.                                            asymptomatic. Since the sympathetic activation has
    •      Very low systemic blood pressures (SBP < 80          a primary role in the progression of left ventricular
           mmHg)                                                dysfunction and is associated with poor prognosis in
    •      Increased serum creatinine (> 3 mg/dL)               patients with heart failure, blockade of this effect
    •      Elevated serum potassium (> 5.5 mmol/L)              seems to be beneficial.
                                                                Sympathetic activation can increase ventricular
    •      Azotemia:                                            volumes and pressure by causing peripheral
    •      The risk of azotemia is highest in patients with     vasoconstriction and by impairing sodium excretion
           severe congestive heart failure (NYHA IV),           by the kidney. Also, it can provoke arrhythmias by
           hyponatremia and in patients receiving               increasing the automaticity of cardiac cells.
           NSAIDs.                                              Norepinephrine can induce ventricular hypertrophy
    •      An increase in serum creatinine by > 0.5 mg/dL       and can also trigger programmed cell death
           is observed in 15-30 % of patients with severe       (apoptosis) by stimulating oxidative stress. These
           heart failure.                                       deleterious effects are mediated through actions on
    •      Renal function usually improves after a              α1, β1- and β2- adrenergic receptors. Furthermore
           reduction in the dose of concomitantly               an increase in plasma norepinephrine in heart failure
           administered diuretics without the need to           will lead to downregulation of beta receptors in
           discontinue ACE-inhibitor.                           cardiac myocytes and a decrease in beta receptor
    •      Mild-to-moderate degree of azotemia can be           density in myocardium.
           tolerated in order to maintain therapy with ACE
           inhibitor.
                                                                Pharmacology:
                                                                Three types of beta blockers have been developed:
                                                                (1) Those that selectively inhibit β1 receptors, e.g.
                                                                metoprolol, atenolol and bisoprolol; (2) those that
                                                                inhibit both
    C-1.4: BETA BLOCKERS                                        β1 and β2 receptors, e.g. propranolol; (3) those that
                                                                inhibit β1-, β2-, and α1,-adrenergic receptors, e.g.
    Background:                                                 carvedilol.

                                  ADRENERGIC RECEPTOR BLOCKING AFFINITIES
              Generation / Class                      Compound                  β1 / β2 selectivity
              First / Nonselective                    Propranolol                       2.1
              Second / selective β1                   Metoprolol                         74
                                                      Bisoprolol                        119
    Third / β-blockers - vasodilators                 Carvedilol                        7.3
                                                      Bucindolol                        1.4
                                                       Nebivolol

Impact on Symptomatology:                                      A number of multicenter randomized placebo
•       In trials that enrolled patients with moderate to      controlled trials evaluated the effect of B-blockers in
        severe symptoms due to ischemic or non-ischemic        patients with chronic heart failure who were treated
        cardiomyopathy, B-blockers produced significant        for at least 6 months. Metoprolol, carvedilol and
        clinical improvement with neutral effects on           bisoprolol were found to decrease the risk of death and
        exercise tolerance.                                    prolong survival.
•       In trials that enrolled patients with minimal or       Mode of Action:
        mild symptoms, B-blockers produced little              Beta blockade acts in a number of ways that
        improvement in functional status, but decreased        may benefit patients with congestive heart
        the likelihood of worsening symptoms.
•       In both types of trials, B-blockers produced
                                                               failure:
        improvement in left ventricular ejection fraction.          1.   Upregulation of beta-receptors on myocytes.
                                                                    2.   Decrease myocardial energy requirements.
                                                                    3.   Antiarrhythmic effect.
Impact on Survival:                                                 4.   Improve myocardial relaxation.
                                                                    5.   Decreased heart rate.
DRUGS FOR HEART FAILURE.DOC                                                                         10

    6.   Protection against harmful effects of                 equal to 40%) and mild to moderate heart failure
         circulating catecholamines.                           symptoms (NYHA class II-III) who are on standard
    7.   Decrease myocyte apoptosis.                           therapy.
                                                               To maximize patient safety, a period of clinical
Indications:                                                   stability on standard therapy should occur before B-
Patients who are considered suitable for receiving beta        blocker therapy is started.
blockers include all patients with NYHA class II or III
heart failure due to left ventricular systolic
dysfunction if there is no contraindication to B-              Maintenance of Therapy:
Blocker therapy. Beta blockers are indicated for the           Once a target dose or the highest tolerated dose is
long term management of heart failure together with            achieved, patients can be maintained on long-term
diuretics and ACE inhibitors.                                  therapy with a beta-blocker. Even if symptoms do not
Patients receiving beta blockers should be advised             improve, long term treatment should be maintained to
regarding:                                                     decrease the risk of major clinical events.
                                                                    •   Abrupt withdrawal of treatment with a beta
     1. Side effects may occur early in therapy, but
          do not generally prevent long-term use of the                 blocker can lead to clinical deterioration and
          drug;                                                         should be avoided, unless seriously indicated.
                                                                    •   If patients experience mild or moderate
     2. Symptomatic improvement may not be seen
          until the patients received treatment for 2-3                 degrees of worsening, beta-blockers should
          months;                                                       be continued while efforts are made to
     3. Beta blocker may reduce the risk of disease                     achieve clinical stability by optimizing the
          progression even if the symptoms of the                       use of diuretics and ACE inhibitors.
                                                                    •   If deterioration in clinical status requires
          patient have not responded favorably to
          treatment.                                                    hospitalization or the use of intravenous
Beta-blockers should not be used in acutely ill                         drugs, the dose of beta-blockers is reduced or
patients, including those who are in intensive care                     discontinued temporarily until the condition
units with refractory heart failure requiring                           of the patient stabilized.
intravenous support and those with pulmonary edema.
Beta blocker therapy in heart failure should be started        Complications and Side Effects:
in hospital.                                               •       Hypotension:
Treatment with beta-blockers should not be delayed                    •             Initiation of therapy with
until the patient is found to be resistant to treatment                    carvedilol can produce excessive
with other drugs.                                                          vasodilatation, which is usually
                                                                           asymptomatic.
Initiation of Therapy:                                                •             Vasodilatory side effects
    1.   Very small initial doses and cautious titration                   are generally seen within 48 hours
         is required. Therapy should be started at a                       of the first dose or increments in
         dose of 3.125 mg of carvedilol twice daily,                       dose, and usually subside with
         1.25 mg of bisoprolol once daily, or 12.5 mg                      repeated dosing.
         of metoprolol (sustained-release) once daily,                •             Administering B-blockers
         followed by doubling in dose every 2-4                            and ACE inhibitors at different
         weeks if the patient has tolerated each                           times of the day may minimize
         preceding dose. Low doses of beta blockers                        the risk of hypotension.
         should be maintained if high doses are not                   •             The occurrence of
         tolerated.                                                        symptomatic hypotension may
    2.   Patients should be monitored closely for                          require a temporary reduction in
         evidence of hypotension, bradycardia, fluid                       the dose of diuretic and if not
         retention, or worsening of heart failure during                   helpful decrease the dose of beta-
         uptitration period.                                               blocker.
    3.   Worsening of heart failure or severe              •          Fluid retention and worsening of
         bradyarrhythmias may require temporary
         intravenous inodilator support and
                                                               heart failure:
         discontinuation of beta-blocking agent.                      •             Increases in body weight
    4.   Clinical benefits may not be seen for 3                           may be seen after 3-5 days of
         months after therapy initiation.                                  starting treatment and may lead to
                                                                           worsening of symptoms within 1-
                                                                           2 weeks.
Beta blocker therapy should be routinely administered
                                                                      •             For this reason physician
to clinically stable patients with left ventricular
                                                                           should ask the patients to weight
systolic dysfunction (LV ejection fraction less than or
                                                                           themselves daily and manage any
DRUGS FOR HEART FAILURE.DOC                                                                                 11

               increase in weight by immediately                            •              Bradycardia and heart
               increasing the dose of                                             block are rarely seen with low
               concomitantly administered                                         doses, but the risk of these side
               diuretics.                                                         effects increases to 5-10% as the
     •    Bradycardia and heart block:                                            dose is progressively increased.
          •             B-blockers can produce                              •              If the heart rate decreases
               decrease in heart rate and                                         to <50 beats/minute, or second, or
               alteration in cardiac conduction                                   third degree heart block is
               that may lead to bradycardia or                                    observed the dose should be
               heart block.                                                       reduced.
     C-1.5: INOTROPIC AGENTS
                                                      1. DOBUTAMINE
     Generic Name                   Dobutamine
     Trade Name                     Dobutrex (vial); Dobuject (amp)
     Supply                         250 mg

     Background:                                               3.       Cardiogenic shock.
     This is a beta adrenergic stimulating agent. It mainly
     exerts a potent ionotropic effect with limited                 Side Effects:
     increase in heart rate and blood pressure. It can be
     used cautiously as an inotrope in heart failure to
                                                                       • Tachycardia.
     increase cardiac output while decreasing filling                  • Ventricular arrhythmia.
     pressure.                                                         • Tolerance to the inotropic effect
                                                                                after prolonged infusion.
     Dose:
     The standard dose is 2.5–10 μg/kg/min by IV                    Precautions:
     infusion, occasionally up to 40 μg/kg/min may be                  • Dilute in sterile water, dextrose or
     used for 72 hours. Higher doses may increase the                            saline, not in alkaline solutions.
     heart rate.                                                       •        It should not be used with extremely
                                                                                 low blood pressure below 70 mmHg
     Indications:                                                                systolic.
1.       Refractory heart failure                                      •        Close monitoring is mandatory.
2.       Severe acute myocardial failure
     (acute MI and post-cardiac surgery).

                                                        2. DOPAMINE
         Generic Name               Dopamine
         Trade Name                 Inotropin (amp)
         Supply                     200 mg

     Background:                                                                to the renal, mesenteric, coronary and
           •   A catecholamine-like agent used for the                          cerebral beds.
               treatment of severe heart failure and                    •       At high doses, it causes peripheral α
               cardiogenic shock.                                               receptor stimulation with peripheral
           •   It is a precursor of norepinephrine and                          vasoconstriction. Thus, the dose should be
               releases norepinephrine from the                                 kept as low as possible.
               sympathetic nerve endings.
           •   Dopamine stimulates the heart by both β              Dose and Indications:
               and α adrenergic responses and causes                                 1.   Refractory heart failure: 0.5 to 1
               vaso-dilatation through dopamine                                           μg/kg/min is the starting dose
               receptors. In severe congestive heart failure                              which can be raised till adequate
               or shock it specifically increases blood flow                              urine flow, blood pressure and
                                                                                          heart rate are achieved. Vaso-
DRUGS FOR HEART FAILURE.DOC                                                                           12

                   constriction begins at 10                      •     Use cautiously in aortic stenosis.
                   μg/kg/min and increases with                   •     Extravasation can cause sloughing, use a
                   higher doses. This can be                            large central vein. If extravasation occurs,
                   corrected by adding sodium                           use local infiltration with phentolamine.
                   nitroprusside.                                 •     Marked augmentation of action occurs with
              2.   Acute MI and cardiogenic shock:                      MAO inhibitors (up to 10 times).
                   5 μg/kg/min is started and may be
                   increased to 7.5 μg/kg/min.                         3. DOPAMINE AND DOBUTAMINE
                   Arrhythmias may appear at 10
                   μg/kg/min.                                                   COMBINATION:

Precautions:                                                  Indications:
                                                                  1.    Patients who remain hypotensive with
    •    Do not dilute in alkaline solutions.
                                                                        dobutamine alone.
    •    Close monitoring is mandatory.                           2.    Heart failure patients not responding to
    •    If there is oliguria, first correct                            dopamine up to 7.5 μg/kg/min.
         hypovolemia.                                             3.    Patients with a markedly increased filling
                                                                        pressure.
Side Effects and Interactions:
    •    Contraindicated in ventricular tachycardia.

                                                    4. EPINEPHRINE
 Generic Name                   Epinephrine (Adrenaline)
 Trade Name                     Epinephrine
 Supply                         0.5 ml of 1/1000 = 0.1 mg

Background:                                                   - During the early post-operative period after heart
Epinephrine stimulates β1 and β2 receptors with               surgery
some α mediated effects at higher doses. At low               Dose of 0.5 mg IV into a central vein:
doses it has a vasodilator effect and at higher doses         When combined inotropic and chronotropic
it has a combined inotropic and vasoconstrictor               stimulation is urgently desired as in cardiac arrest.
effect.
                                                              Side Effects:
Dose and Indications:                                             • Tachycardia, arrhythmias.
2-12 μg/kg/min IV infusion is reserved for the                    • Anxiety
following situations:
- Lack of response to first line inotropic agents
(Dopamine, dobutamine & milirinone).
                                                5. NOR-EPINEPHRINE
 Generic Name                   Nor-Epinephrine
 Trade Name                     Levophed

Has a prominent α & β1 effects, with less                         •     When a shock-like state is accompanied by
                                                                        peripheral vasodilatation. e.g. septic shock
β2 stimulation.
                                                                        or overdose of vasodilators.
Dose and Indications:                                             •     Combination therapy with PDE inhibitor
                                                                        helps to avoid their hypotensive effects.
8-12 μg/kg/min.                                                   •     Refractory supraventricular tachycardia
This is a rarely used drug, the main                                    with low blood pressure.
indications are:
DRUGS FOR HEART FAILURE.DOC                                                                      13



                                                6. ISOPROTERENOL
 Generic Name                   Isoproterenol
 Trade Name                     Isupril
 Supply                         0.2 mg amp

Background:                                                   • Acute heart failure with pulmonary
It has a pure beta stimulant effect (β1 > β2). It is the           embolism.
   only catecholamine inotrope, which is effective in
                             the presence of acidosis.     Adverse Effects:
                                                           Tachycardia, arrhythmia, drop of diastolic blood
Dose and Indications:                                      pressure by its β2 vasodilator stimulation.
  • Situations of poor contractility and
         slow heart rate.                                  Contraindication:
    •   Beta blocker overdose.                             Myocardial ischemia and arrhythmia.
    •   Temporary measure in complete
         heart block, IV infusion of 0.5 – 10
         (μg/kg/min).


                                    7. PHOSPHODIESTERASE INHIBITORS
 Generic Name                   Milrinone and Amrinone
 Trade name                     Primacor

Background:                                                    •   When the blood pressure is low, milirinone
They are phosphdiestrase (PDE) inhibitors that                     can be used in combination with high dose
inhibit the breakdown of cAMP, which increases                     dopamine.
intracellular Ca2+ causing improved myocardial                 •   Cardiogenic shock when dopamine and
contractility and vasodilatation in the blood vessels.             dobutamine are ineffective.

                                                                   Contraindications:
Dose:                                                          •   Acute myocardial infarction for fear of
    •    Milrinone: A slow IV injection of 50                      arrhythmias.
         μg/kg/min diluted in 100 cm3 saline or                •   Aortic or pulmonary stenosis.
         dextrose over 10 min. This is followed by             •   Hypertrophic cardiomyopathy.
         an IV infusion at a rate of 375-750
         μg/kg/min, up to 12 hours following open-                 Side Effects:
         heart surgery or 48 h to 72 h in CHF. A               •   Ventricular arrhythmia.
         reduced dose is used in renal failure.                •   Hepatotoxicity.
    •    Amrinone: is rare, if ever used.                      •   Hypotension.
                                                               •   Amrinone can cause serious
         Indications:                                              thrombocytopenia.
    •    Severe congestive heart failure not
         responsive to digoxin, diuretics and
         vasodilators.

Table: Pharmacologic Properties of Inotropic Agents
                                                                     Dopamine
DRUGS FOR HEART FAILURE.DOC                                                                             14


Pharmacologic Feature             Dobutamine             Milrinone       Low        High        Norepinephrine
                                                                         Dose       Dose
Receptor Agonism
α                                        +                  O             +         +++               ++++
β1                                     ++++                 O             +          ++                 +
β2                                      ++                  O             O          O                 O
Dopaminergic                            O                   O            +++         ++                O
Systemic Vascular                       ↓↓                 ↓↓↓            ↓         ↑↑                ↑↑↑↑
Resistance
Stroke Volume &                       ↑↑↑↑                ↑↑↑↑             ↑         ↑↑                  ↑
Cardiac Output
Ability to Increase BP                 →↑                  →↑             →         ↑↑↑               ↑↑↑↑
Ventricular Filling                    ↓↓                  ↓↓↓           ↓→         →↑↑               →↑↑
Pressure
Chronotropic                           →↑↑                 →↓↑            →        →↑↑↑                →↑




C-1.6: VASODILATORS
                                           SODIUM NITROPRUSSIDE
 Generic Name                   Sodium Nitroprusside
 Trade Name                     Nipride
 Supply                         50 mg amp

Background:                                                          •    Solution must be shielded from direct light
    •    IV sodium nitroprusside remains the                              (using the reflective silver foil supplied in
         reference vasodilator for severe low-output                      the packing).
         left-sided heart failure provided that the                  •    Solution must be discarded if colour
         arterial pressure is ≥ 90 mmHg systolic.                         changes occur or if the solution is 4 hours
    •    It acts rapidly dilating both arterioles and                     old or more.
         veins with a balanced effect.                               •    Lactic acidosis may occur in high doses due
                                                                          to accumulation of cyanide.
        Pharmacokinetics:
    •    The vasodilatation starts within minutes                        Indications:
         and stops equally quickly.                                  •    Myocardial infarction with left ventricular
    •    Given IV it is converted to                                      failure.
         cyanmethemoglobin and free cyanide in the                   •    Severe heart failure in acute regurgitant
         red cells, the free cyanide is then converted                    valve diseases.
         to thiocyanate in the liver and is cleared by               •    Hypertensive crisis with heart failure.
         the kidneys.                                                •    It may be combined with inotropics
                                                                          optimizing the hemodynamic benefit.
        Dose:
IV infusion of 10 μg/min is increased by 10 μg/ min            Contraindication:
every 10 min with a maximal dose of 300 μg/min.                 • Hypotension.
                                                                • Renal failure.
        Precautions:
    •    Titration is necessary to avoid hypotension.          Side Effects:
    •    Avoid abrupt stoppage (rebound                           • Severe hypotension.
         hypertension can occur).                                 • Myocardial ischemia.
    •    Diluted in saline (avoid alkaline solutions).
DRUGS FOR HEART FAILURE.DOC                                                                         15


   • Fatigue, nausea, vomiting and                                    due to accumulation                of
     disorientation.                                                  thiocyanate.
   • Prolonged administration in
     patients with renal failure
     may result in hypothyroidism
NITRATES
Generic & Trade         Nitrates:
Names:                  Isosorbide dinitrate (Isomack, Isordil, Dinitra).
                        Isosorbide mononitrate (Effox, Monomack).
                        Long acting mononitrates (Monomack depo).
                        Intravenous glyceryl trinitrate (Tridil, Nitirocine).
                        Transderm preparation (Nitroderm)
Supply                  Isosorbide dinitrate: range from 5 mg & 40 mg tab. or capsules
                        Isosorbide mononitrates: 20 and 40 mg tablets.
                        Long acting mononitrates: 50 and 100 mg tablets.
                        IV nitroglycerine: 50 mg ampoules.
                        Transdermal preparation (Nitroderm) 5-15 mg

Background:                                                      2.   Acute myocardial infarction with
   •     Exogenous nitrates undergo complex                           hypertension.
         metabolic changes predominantly in the                  3.   Acute myocardial infarction with heart
         intracellular space of the smooth muscle                     failure.
         leading to the formation of cGMP. This                  4.   Hypertension with severe congestive heart
         reduces the intracellular Ca2+ levels                        failure.
         leading to vasodilatation.                              5.   With hydralazine in congestive heart failure
   •     The main effect is venous > arteriolar                       in ACE inhibitor intolerant patients.
         dilatation. They are most suited for patients           6.   Patients with heart failure who continue to
         with elevated wedge pressure with clinical                   have congestive lung symptoms, e.g.
         features of pulmonary congestion. They are                   orthopnea, paroxysmal nocturnal dyspnea
         better than sodium nitroprusside for                         in spite of giving digitalis, diuretics, ACE-
         patients with pumonary edema of acute                        inhibitors in the maximal tolerable dose.
         myocardial infarction.
                                                             Precautions:
Dose:                                                            1.   Dose interruption is needed to avoid
   •     Isosorbide dinitrate: 40-120 mg TID.                         tolerance. An 8-12 hour nitrate – free
                                                                      interval is advised.
   •     Isosorbide mononitrate: 40 mg BID
                                                                 2.   Some IV nitrate preparations contain ethyl
   •     Nitroglycerine IV infusion: 10-400 μg/min
                                                                      alcohol.
         (use the provided IV set and glass
                                                                 3.   Transdermal preparations are to be applied
         containers).
                                                                      on the body surface and are to be removed
                                                                      before electric cardioversion.
Indications:
   1.    Acute myocardial infarction with
                                                             Side Effects:
         pulmoanry edema.
                                                             Headache, hypotension.
DRUGS FOR HEART FAILURE.DOC                                                                       16

Table: The hemodynamic effect of nitrates:
   BP          HR         Rt. atrial         PA         PWP         SVR           PVR             CO
                          pressure         pressure
  ↓↔            ↔            ↓↓               ↓↓         ↓↓           ↓             ↓↓             ↑

BP      : Blood pressure                              PWP : Pulmonary wedge pressure
HR      : Heart rate                                  SVR : Systemic vascular resistance
PA      : Pulmonary artery                            PVR : Pulmonary vascular resistance


C-1.7: ANTICOAGULANTS                                               of anticoagulation in CHF in sinus
                                                                    rhythm.
Background:
  • Factors that contribute to the                         Indications:
                                                               1.   AF, sustained or paroxysmal, particularly
         increased thromboembolic risk in
                                                                    with rheumatic mitral valve disease. All
         heart failure, include:
                                                                    patients with heart failure and atrial
             • Procoagulant state:                                  fibrillation should be treated with warfarin-
                   Tendency for blood to clot                       goal international normalized ratio (INR)
                   due to increased platelet                        2.0-3.0 – unless contraindicated.
                   activation, plasma and                      2.   Previous history of arterial or venous
                   blood viscosity and                              thrombo-embolism.
                   coagulation factors.                        3.   Left ventricular thrombus protruding into
             • Intracardiac thrombi.                                cardiac cavities.
             • High prevalence of atrial                       4.   Warfarin anticoagulation is considered for
                   fibrillation (4% with                            patients with left ventricular ejection
                   asymptomatic left                                fraction of 35% or less. Assessments of
                   ventricular dysfunction,                         risks and benefits of anticoagulation should
                   15% with mild-moderate                           be undertaken in individual patients.
                   heart failure, and up to 50%
                   of patients with severe                 Caution:
                   heart failure).                         Elderly patients and those exposed to trauma or falls
   •    Studies estimated an annual                        are at high risk of bleeding on anticoagulation
         incidence of stroke of 2-3% in                    therapy. The risk–benefit ratio of such treatment
         patients with heart failure, while the            should be weighed individually.
         annual risk of stroke in the general
         population aged 50-70 years is less
         than 0.5%.
                                                           C-1.8: ANTI-ARRHYTHMIC AGENTS
   •    Hemostasis is disturbed in heart
         failure. The rate of thrombo-                     Two types of arrhythmia are clearly related to heart
         embolic events is high. However,                  failure. Atrial fibrillation and serious ventricular
         there is no proven survival benefit               arrhythmia. These will be outlined here.
  DRUGS FOR HEART FAILURE.DOC                                                     17

  Flow chart for the management of atrial fibrillation with heart failure:


                                       Atrial
                                     Fibrillation


< 48 hours                                                                   > 3 months




                                      2 days to 3
                                        months



Cardiovert           Anti-coagulation               Rate control &       Maintain sinus rhythm
                         4 weeks                    anti-coagulate       (anticoagulate):
                                                                             Cardiovert
                                                                             Amiodarone



                        Cardiovert

 Anti-coagulation
     4 weeks




  Flow chart for the management of serious ventricular arrhythmias:


                                  Non-sustained
                                   Or sustained
                                   Ventricular
                                   tachycardia




                 Asymptomatic                          Symptomatic
DRUGS FOR HEART FAILURE.DOC                                                         18




                                               Syncope Dizziness:
        No current
                                                                     Resuscitated cardiac arrest:
                                                  Drugs
        convincing evidence
                                                                       ICD
                                                  ICD
        for arrhythmogenic
                                                                       Drugs:
        risk stratification
                                                                          - Amiodarone
                                                                          - Sotalol




Table: Comparison of Amiodarone and Sotalol
          AMIODARONE (CORDARONE)                               SOTALOL (BETACOR)
Tablet: 200 mg                                       Tablet: 80 mg
Amp. : 250 mg
Dose:                                                Dose:
Rapid Control [hospitalized patient (oral)]:
                                           Oral:
Loading: 1200-1600 mg in 2-4 divided doses
given for 7-14 days.                       160-640 mg/day in 2 divided doses.
Reduced loading: 400-800 mg/day for 1-3 Dose < 320 mg has less side effects.
weeks.                                     (Decrease the dose in renal impairment to
Maintenance: 100-400 mg/day.
                                           avoid pro-arrhythmic effect).
Intravenous:
Loading: 5 mg/kg over 20 minutes.
Maintenance: 500-1000 mg over 24 hours.
DRUGS FOR HEART FAILURE.DOC                                                        19


Side Effects:                             Side Effects:
Pulmonary:
                                          Side effects like beta-blockers with
Pneumonitis.
Pulmonary fibrosis (dose related – higher increased risk of long QT interval resulting
incidence in higher doses).
                                          in torsade de pointes.
Cardiac:                                        Incidence of heart failure is less than other
Inhibition of SA or AV node.
                                                beta-blockers.
Torsade de pointes
(care is needed if the patient has hypokalaemia
or digoxin toxicity).

Neurological:
Proximal muscle weakness.
Peripheral neuropathy.
Headache or ataxia.

Thyroid:
Variable hypo- or hyperthyroid states.

GIT: Increased liver enzymes.

Less serious side effects:
Corneal microdepositions.
Decrease gonadotropin levels.
Photosensitivity (grey-blue skin discoloration).
ACUTE HEART FAILURE.DOC                                                                           1


    D-2: ACUTE HEART FAILURE                                  •   Myocardial infarction with acquired ventricular
                                                                  septal defect.
                                                              •   Acute prosthetic valve malfunction.
D-2.1: Definition
D-2.2: Hemodynamic Manifestations                             D-2.5: MANAGEMENT
D-2.3: Classification
D-2.4: Causes                                                 1: General Measures:
D-2.5: Management                                                 1.   Hospital admission: Monitoring and emergency
                                                                       measures.
                                                                  2.   Diagnosis of the underlying cause.
D-2.1: DEFINITION
Heart failure is described as acute if symptoms and signs     2: Specific Measures:
develop rapidly, within minutes to hours. The clinical
presentation of acute heart failure ranges from sudden
appearance of dyspnea to frank cardiogenic shock.                    (A) ACUTE PULMONARY EDEMA
                                                              Clinical Picture:
                                                              Patients with acute pulmonary edema present in acute
D-2.2: HEMODYNAMIC MANIFESTATIONS
                                                              distress with extreme breathlessness. They may have
    1.   The earliest sign of ventricular dysfunction is an   cough with hemoptysis and pink frothy sputum. They are
         increase in pulmonary capillary wedge pressure       often diaphoretic (sweating) and demonstrate a variable
         (pcwp). The stroke volume is maintained at this      reduction in peripheral perfusion manifest as cold
         stage because the ventricle is still preload         extremities, pallor and mild cyanosis.
         responsive.                                          Pulmonary examination usually demonstrates coarse
    2.   The next stage is marked by a decrease in stroke     rales and diffuse rhonchi. The cardiac examination in this
         volume and an increase in heart rate.                setting may be difficult because of patient distress. A
    3.   The final stage is characterized by a decrease in    third sound gallop, and or a murmur may however be
         cardiac output. The point at which the cardiac       heard.
         output begins to decline marks the transition
         from compensated to decompensated heart              Initial Diagnostic Evaluation:
         failure. The decompensated phase of heart                1. Focused history / physical examination.
         failure is characterized by peripheral                   2. Secure IV line and urinary catheter.
         vasoconstriction, which initially maintains              3. Twelve-lead ECG (diagnose acute MI, rapid
         blood pressure.                                             AF, or other arrhythmias).
                                                                  4. Continuous bed side monitoring : ECG, pulse
D-2.3: CLASSIFICATION                                                oximetry, CVP, BP.
                                                                  5. Blood-serum studies:
Acute heart failure can present clinically in                            o Cardiac enzymes
three forms:                                                             o Arterial blood gases
•   acute cardiogenic pulmonary edema                                    o Complete blood count (CBC)
•   cardiogenic shock                                                    o Electrolytes
•   acute decompensation of chronic left-sided heart                     o Blood urea nitrogen (BUN)
    failure.                                                             o Creatinine
                                                                  1. Chest X-ray.
                                                                  2. Echocardiography.
D-2.4: CAUSES
                                                              Therapeutic Management:
         May be myocardial or mechanical:                         1.   Oxygen therapy: 60-100 % O2 via a face mask
•   Massive myocardial infarction.                                     or nasal prongs. If the patient is still hypoxic
•   Pulmonary embolism.                                                (PaO2 persistently < 50mmHg on room air),
•   Cardiac tamponade.                                                 endotracheal intubation should be performed .
•   Brady or tachy arrhythmias.                                   2.   Morphine sulfate: (3 to 5 mg) IV to alleviate
•   Rupture chordae.                                                   symptoms of acute pulmonary edema. NB:
•   Rupture papillary muscles.                                         morphia is contraindicated in patients with
•   Acute aortic incompetence.                                         chronic airway obstruction, marked respiratory
                                                                       depression, and liver failure.
ACUTE HEART FAILURE.DOC                                                                             2


    3.   Nitroglycerin: sublingual administration (0.4 to       of excessive sympathetic stimulation (sweating,
         0.6 mg) repeated every 5 minutes if needed. If         vasoconstriction, tachycardia).
         systolic blood pressure is adequate (>
         100mmHg) nitroglycerine is administered IV             Initial Diagnostic Evaluation:
         (20 ug/min that may be titrated up to 100                  1.  Focused History: chest pain, fever, previous
         ug/min), according to clinical response and                    disease.
         arterial blood pressure.                                   2. Physical examination: pallor, cold extremities,
    4.   Furosemide (lasix): 20 to 80mg IV; to be                       hypotension, gallop, murmur. High JVP maybe
         repeated if necessary.                                         present in cardiac tamponade, pulmonary
    5.   Sodium nitroprusside: starting dose                            embolism and right ventricular myocardial
         (0.1ug/kg/min) may be gives to patients whose                  infarction.
         pulmonary edema is due to acute mitral or                  3. Twelve-lead ECG.
         aortic valvular incompetence or marked                     4. Continuous ECG monitoring.
         systemic hypertension.                                     5. Blood-serum studies:
    6.   Positive inotropic agents: If systolic blood                   •    complete blood count(CBC)
         pressure is < 100 mmHg, Dobutamine (3-15                       •    electrolytes
         ug/kg/min) may be infused. Dopamine may be                     •    blood urea nitrogen (BUN)
         added to Dobutamine in case of hypotension                     •    creatinine
         (>5ug / kg/min to stimulate peripheral alpha                   •    cardiac enzymes
         receptors). Smaller doses of dopamine (<                   6. Arterial blood gases.
         3ug/kg/min) may be used to enhance urine flow.             7. Chest X-ray.
    7.   Thrombolytic therapy or urgent                             8. Echocardiography (transthoracic and
         revascularization for acute myocardial                         transesophageal if needed).
         infarction.                                                9. Indwelling arterial cannula for continuous
    8.   Intraaortic balloon counterpulsation is of value               monitoring of systemic blood pressure and
         if the patient does not respond to previous                    arterial blood gas sampling.
         measures and is candidate to undergo urgent                10. Tabulation of fluid volume intake, urine output,
         revacularization.                                              and other fluid volume loss.
    9.   Correction of the underlying cause when                    11. Cardiac catheterization/coronary arteriography
         feasible.                                                      if acute revascularization is anticipated.

  Recommendations for Pulmonary Artery                          Management:
                  Balloon                                       General Principles:
      Catheter in Acute Heart Failure                       ♦       Exclusion of non-cardiac causes of shock, e.g.,
                                                                blood or fluid loss.
    1. Cardiogenic shock that does not
                                                            ♦       Rapid recognition and treatment of potentially
       respond promptly to the proper                           reversible causes
       administration of fluid volume.                                        o RV infarction
    2. Acute pulmonary edema that does                                        o Cardiac tamponade.
       not respond to appropriate                                             o Pulmonary embolism.
       intervention.                                                          o Rupture chordae, papillary muscles or
                                                                                   ventricular septum.
    3. To resolve any uncertainty of                                          o Critical valvular stenosis or acute
       whether pulmonary edema is                                                  regurgitation.
       cardiogenic or non-cardiogenic in                                      o Aortic dissection with complicated
       origin.                                                                     lesion.
                                                                              o Prompt stabilization of the clinical and
                                                                                   hemodynamic status.
             (B) CARDIOGENIC SHOCK

Cardiogenic shock is a clinical syndrome characterized
                                                                Therapeutic Measures:
                                                                    1.   Oxygen therapy.
by systemic arterial hypotension (SBP less than 90
                                                                    2.   Brisk intravenous administration of fluid
mmHg), evidence of impaired perfusion to the skin,
                                                                         volume (in the absence of obvious
kidneys (urine flow < 10 ml/h), and central nervous
                                                                         intravascular volume overload), 500 cm2
system (confusion, initability, etc.), and manifestations
            ACUTE HEART FAILURE.DOC                                                                             3


                   0.9% saline should be administered at a
                   reasonably fast rate. If hypotension does not           Acute Heart Failure Treatment Algorithm:
                   improve, Swan Ganz catheter should be
                   inserted to monitor the various
                   hemodynamic parameters, PCWP, SV, CO.
                     Low                        Optimal PCWP ~ 20 mmHg                      High PCWP > 20 mmHg
                PCWP ≤ 15 mmHg
Patient
Group




                                           Low BP       Normal BP      High BP              Low CO            Normal CO


                Volume infusion to       Dopamine       Dobutamine Nitroprusside       Dobutamine           Nitroglycerine
Treatment




                optimal PCWP                            Amrinone   Nitroglycerine      Amrinone             Furosemide
                                                                                       Dopamine and or      Nitroprusside
                May add dobutamine if                                                  Norepinephrine
                infusion fails                                                         (If SBP still too
                                                                                       low)

                RV Infarction              Ischemia/     Ischemia/      Severe             Ischemia/        Severe mitral/
Situations
 Clinical




                Pulmonary embolism         Infarction    Infarction   hypertension         Infarction       aortic
                Cardiac tamponade                                                                           insufficiency
                                                                                                            Diastolic heart
                                                                                                            failure
                                                                           2. Acute heart failure accompanied by
 1.             Intravenous administration of                                 refractory ischaemia in preparation for
            cardiovascular supportive drugs if severe                         cardiac catheterization.
            hypotension persists:                                          3. Acute heart failure complicated by
                       o    Dopamine given at an increasing dose:             significant mitral regurgitation or
                            5-10 ug/kg/min. >5mg/kg/min of                    rupture of the ventricular septum.
                            dopamine has vasoconstrictive and
                            positive inotropic effect.
                                                                              - Contraindications: Aortic aneurysm;
                       o    Norepinephrine: 4-16 μg/min can be             Aortic incompetence; Aortic dissection.
                            added when BP is still low in order to
                            increase systemic blood pressure to
                            acceptable levels (> 80 mmHg).                  (C) ACUTE DECOMPENSATION OF CHRONIC
                       o    Dobutamine: 3 μg/kg/min is of value
                                                                                  CONGESTIVE HEART FAILURE
                            in patients with volume overload and
                            less systemic hypotension.
                                                                           Acute heart failure may also develop in the patient with
            4. Intraaortic balloon counterpulsation if the                 chronic heart failure who has been maintained with
                above measures fail to correct hypotension                 relative stability on a regimen of medication and life
                and the patient has a potentially reversible               style adjustments.
                condition.                                                 The clinical manifestations of this group are generally
            5.Treatment of the Cause: e.g., urgent coronary                secondary to volume overload, elevated ventricular
                                                                           filling pressures and depressed cardiac output.
            revascularization for acute myocardial
            infarction.
                                                                           Precipitating Factors: Refer to section D-1.3.
             Recommendations for Intra-Aortic Balloon
                                                                           Management:
              Counterpulsation in Acute Heart Failure                          1.    Recognition of reversible precipitating factors.
               - Indications:                                                  2.    Correction or removal of aggravating factors.
            1. Cardiogenic shock, pulmonary edema,
               and other acute heart failure conditions
               not responding to proper treatment.
    MANAGEMENT OF HEART FAILURE.DOC                                                                     1


                          D-1: MANAGEMENT OF HEART FAILURE
                                                            1.   Relief of symptoms and improving quality
                                                                 of life.
D-1.1: Goals of Heart Failure Therapy
                                                            2.   Prevention of progression of heart failure;
 D-1.2: Correction of the Underlying Cause
                                                                 decreasing need for hospitalization.
D-1.3: Recognition and Treatment of
                                                            3.   Prevention of cardiovascular events, e.g.
Precipitating Factors
                                                                 embolization.
D-1.4: General Measures for Control of Heart
                                                            4.   Prolong survival; decrease mortality rate.
Failure
D-1.5: Measures Recommended in Selected
Patients                                                 The management of heart failure has
D-1.6: Other Measures                                    three principal components:
                                                            1.   Identification and correction of the
D-1.1: GOALS OF HEART FAILURE                                    underlying cause if possible.
                                                            2.   Recognition and treatment of the
THERAPY                                                          precipitating factor if present.
                                                            3.   Control of the heart failure state.

                   QUESTIONS TO DETERMINE THERAPEUTIC STRATEGY
               • Is heart failure present?
               • Is the problem primarily systolic or diastolic
                dysfunction?
               • What caused the problem?
               • What precipitated deterioration?
               • How severe is the heart failure?
               • What is the best acute therapeutic strategy?
               • What is the best chronic therapeutic strategy?
                                                                   The most common causes of
D-1.2: CORRECTION          OF THE     UNDERLYING         decompensation in a previously compensated patient
                                                         with heart failure are interruption or reduction of
CAUSE                                                    antifailure drug treatment, excessive dietary sodium
                                                         intake, or commonly a combination of these factors.
    1.   Improvements of coronary blood flow
         through catheter-based intervention or
         coronary bypass surgery in patients with        2. Arrhythmias:
         coronary artery disease.                                 Cardiac arrhythmias are far more common
    2.   Repair of structural abnormalities such as      in patients with an underlying structural heart disease
         congenital heart defects, valvular lesions or   than in normal subjects and commonly precipitate or
         left ventricular aneurysms.                     intensify heart failure. The development of
    3.   Pharmacological management of                   arrhythmias may precipitate heart failure through
         hypertension.                                   several mechanisms:
                                                              1. Tachyarrhythmias reduce the time allowed
                                                                  for ventricular filling, and in addition
                                                                  increase myocardial O2 demands. Atrial
D-1.3: RECOGNITION          AND   TREATMENT         OF            fibrillation is the commonest arrhythmia that
                                                                  precipitates heart failure.
PRECIPITATING FACTORS                                         2. Marked bradycardia depresses cardiac
                                                                  output.
        In 50-60% of episodes of clinical                     3. Atrio-ventricular dissociation results in loss
heart failure, there is an obvious                                of the atrial booster pump mechanism and
precipitating factor.                                             lowers cardiac output.

• Factors Precipitating Heart                            3. Pulmonary embolism:
      Failure Include:                                            Patients with congestive heart failure,
                                                         particularly when confined to bed are at a high risk of
 1. Interruption of therapy or inadherence               developing pulmonary embolism.
 to dietary instructions:
MANAGEMENT OF HEART FAILURE.DOC                                                               2


                                                         the need for regular antifailure drug regimen and
4. Cardiac infections and inflammations:                 dietary instructions. Regular measurement of body
        Myocarditis due to rheumatic fever or            weight is recommended. Sudden increase in weight
secondary to viral, collagen or autoimmune disorders     i.e. 2 kg in 1-3 days, development of new symptoms
may impair myocardial function directly and              or the worsening of present symptoms should alert
exacerbate existing heart disease.                       the patient to seek advice.


5. Systemic infection:                                   b. Physical activity and employment:
         Increased total metabolism, as a                        Moderate physical activity should be
consequence of fever and the accompanying sinus          encouraged and patients should continue their daily
tachycardia, increases the hemodynamic burden on         work unless they are severely decompensated
the heart. Furthermore, systemic toxemia in bacterial    (Functional class III, IV).
infections can impair myocardial function.
                                                         c. Travel:
6. Physical, environmental and emotional                           Short periods of air travelling are preferred
                                                         over other forms of transport. Long flights may cause
stress:                                                  problems such as dehydration, excessive leg edema
         Intense and prolonged exertion, prolonged       and risk of venous thrombosis. In severe heart failure
travel, emotional crisis and severe climatic change      (NYHA class III & IV), prolonged travel should be
(hot humid environment) can precipitate cardiac          discouraged. If air travel is necessary, care of fluid
decompensation.                                          intake, use of diuretics and mobility during travel is
                                                         required.
7. Cardiac depressants or salt retaining                           All patients with heart failure should be
drugs:                                                   advised of the effect of diet changes when travelling,
         Drugs that depress cardiac function include:    particularly diet rich in salt. Precautions should be
excess alcohol, B-blockers, verapamil, the majority      taken against gastrointestinal upset and the effect of
of the antiarrhythmic drugs, adriamycin and              high temperature and humidity or fluid balance
cyclophosphamide. Salt retaining drugs such as           disturbances.
corticosteriods and non-steriodal anti-inflammatory
agents aggravate fluid retention.                        d. Vaccination:
                                                                  All heart failure patients should be advised
8. High output states:                                   to be vaccinated against influenza and pneumococal
        Pregnancy, thyrotoxicosis and severe             disease.
anemia can precipitate or aggravate heart failure.
                                                         e. Contraception:
9. Acute myocardial infarction:                                    In patients with advanced heart failure
         An acute myocardial infarction can              NHHA class III, IV, the risk of maternal mortality
precipitate heart failure. The development of heart      and morbidity is high and a successful pregnancy is
failure may be the only clinical presentation of         unlikely. In these patients pregnancy should be
infarction.                                              avoided. Counseling is required even in mild heart
                                                         failure. Current methods of hormonal contraception
                                                         are safer than in the past. Low-dose estrogen and
10. Development of unrelated illness:                    third generation progestogen derivatives are
         Excess blood or saline infusion, prostatic      associated with a low risk of thrombogenesis and
obstruction, parenchymal liver disease and renal         systemic hypertension. Intra-uterine devices remain a
failure may precipitate heart failure in patients with   suitable form of contraception, except in heart failure
underlying heart disease.                                related to valvular disease, where infections or
                                                         anticoagulant therapy may pose problems.

D-1.4: GENERAL MEASURES FOR CONTROL                      f. Sexual activity:
                                                         Difficulty with sexual performance is one of the most
OF HEART FAILURE
                                                         disturbing symptoms for patients with chronic heart
1. Advice                                                failure. The greatest problems are frequent difficulty
                                                         in achieving and maintaining an erection, problems of
a. Counseling:                                           ejaculation and lack of interest in sex. This may be
          The symptoms and signs of heart failure and    due to the effect of drugs, changes in mood and
the recommended treatment should be explained to         libido, anxiety and fear of death during sexual
patients and relatives. Emphasis should be placed on     activity. It is recommended that the sexual history be
MANAGEMENT OF HEART FAILURE.DOC                                                                        3


included in the process of patient assessment.                       2.   If a salty taste is desired, use half sodium
Reassure the frightened patient and partner. It may be                    and half potassium preparations or a pure
appropriate to advise the use of sublingual                               potassium chloride substitute.
nitroglycerine before sex and discourage major                       3.   Avoid the use of fast foods, e.g. pizza,
emotional involvement.                                                    hamburger, many of which have high
                                                                          sodium content.
                                                                     4.   Avoid preserved, canned and smoked foods
2. Diet
                                                                          because of their high salt content. All
a. Salt intake                                                            cheeses are rich in salt.
•   Limiting salt intake is needed more in advanced
    than in mild heart failure. The daily intake of salt     b. Fluids:
    is limited to less than 3 g/day. Natural foods are           •    Liquid intake should be reduced to 1-1.5
    low in sodium and high in potassium, whereas                      L/24 h. in patients with advanced heart
    most processed foods have a high sodium                           failure except in warm climates.
    content. Additional guidelines include the
    following:
    1. Add no sodium chloride to food during
         cooking or at the table.
 Measures to maintain fluid balance: Patients should restrict their daily intake of salt to a
 moderate degree (to ≤ 3 grams daily), and weight should be measured daily to detect the early
 occurrence of fluid retention.
                                                            d. Smoking: Smoking should be strongly
c. Other measures: Patients should be advised                  discouraged in all patients.
   not to fill their stomach and to take small meals        e. Alcohol: Alcohol intake should be forbidden in
   and avoid fatty, heavy foods, limit animal fat and          all patients especially when alcoholic
   sugar intake, not to exercise or go to bed                  cardiomyopathy is suspected.
   immediately after meals. It is preferable to rest in
   an armchair for 1-2 hours after meals.
 Measures to decrease the risk of a new cardiac injury: These include: (1) Cessation of
 smoking; (2) Weight reduction in obese patients; (3) Control of hypertension, hyperlipidemia
 and diabetes mellitus, and (4) Discontinuation of alcohol use.

3. Rest and Exercise                                            capacity. Formal exercise testing appears to be safe
Bedrest should not be encouraged in stable chronic              in heart failure. Regular exercise training might be
heart failure. An exercise program of daily walking             beneficial in heart failure. Several studies showed an
in suitable weather is recommended. On the other                improvement in exercise time and symptom scores
hand, in patients with acute heart failure or                   following physical training. Training seems to
exacerbations of chronic heart failure, bedrest is              benefit patients with all grades of heart failure and to
required. Training in patients with ischemic heart              have a rapid beneficial effect that persists while
disease is associated with improved exercise                    continuing training.



    Measures to improve physical conditioning: Patients with heart failure should not be
    instructed to limit their physical activity, but should be encouraged to engage in moderate
    degrees of exercise to prevent or reverse physical deconditioning. Exercise improves anxiety and
    insomnia.
                                                                D-1.5: MEASURES RECOMMENDED                          IN

                                                                SELECTED PATIENTS
These include: (1) Control of ventricular response in patients with atrial fibrillation or other supraventricular
tachycardias; (2) Anticongulation in patients with atrial fibrillation or with a history of previous embolic event; and (3)
Coronary revascularization in patients with angina (and, possibly in patients with ischemic but viable myocardium).

D-1.6: OTHER MEASURES                                               supervision can decrease the likelihood of non-
                                                                    compliance and detect changes in body weight
•     Patients are advised to visit outpatient clinic at            or clinical status early enough to institute
      regular intervals for follow-up. Close                        treatment that can prevent further deterioration.
MANAGEMENT OF HEART FAILURE.DOC                                                                      2


•      Some interventions should be avoided in
       patients with heart failure. Asymptomatic
       ventricular arrhythmias require no therapy. In
       general antiarrhythmic agents are not
       recommended since patients with heart failure
       may be particularly predisposed to their
       cardiodepressant and proarrhythmic effects.
       Amiodarone can be recommended in patients
       with recurrent ventricular arrhythmias.
•      Non steroidal anti-inflammatory drugs can
       inhibit the effect of diuretics and ACE inhibitors
       and can worsen both cardiac and renal
       functions. Sleep disorders are common in heart
       failure patients due to anxiety, dyspnea, cough
       and nocturia. Minor tranquilizers and hypnotics
       will help patients complaining from insomnia.
       A good nights sleep can improve patients’
       general condition and well being.
•      Nutritional supplements e.g. coenzyme Q10,
       carinitine, vitamins or hormonal therapy. There
       is no evidence that these agents have any value
       in the treatment of heart failure.


    Patient Education
    Daily weighing upon awakening, before breakfast, in the same clothes, and using the same scale.
    Report on weight gain over 1.5 Kg in one week (without a change in diet).
    Maintain a low-salt diet; include low sodium foods in diet and avoid those high in sodium.
    Take all medications as prescribed; know the names, dosages, side-effects and actions.
    Report any side-effects or problems with medications.
    Know the symptoms of heart failure; promptly report shortness of breath, increased fatigue, swelling of
    ankles or abdomen, a need to use the bathroom more frequently.
    Participate in regular exercise program as prescribed by your physician.
     NEW THERAPEUTIC STRATEGIES FOR TREATMENT OF HEART FAILURE.DOC                              1


     D-4: NEW THERAPEUTIC                          1.            Angiotensin II Receptor
                                                        Blockers (ARBS): Angiotensin II
     STRATEGIES FOR                                     receptor antagonists act by
                                                        blocking the AT1 receptors.
     TREATMENT OF HEART                                 Effects are similar to ACE-I, but
     FAILURE                                            without their side effects, namely,
                                                        cough and angioedema. The
     D-4.1: Pharmacologic Therapy                       actions of ACE-I are limited by
                                                        the fact that in spite of interfering
     D-4.2: Non-Pharmacologic Therapy
                                                        with A-II production, A-II can
                                                        still be generated from A-I and
     In spite of the established role of ACE-I,         angiotensinogen through other
     beta-blockers and spironolactone in                enzymatic pathways (chymase,
     improving prognosis and survival rate in           cathepsins, PAI) that are not
     patients with heart failure, still heart           blocked by ACE-I. Furthermore,
     failure particularly in its advanced state,        reduction of A-II production will
     carries a very high mortality rate of about        result in up regulation of A II-
     50% in one year in patients NYHA,                  receptors with increased
     functional class IV. New therapeutic               sensitivity to A-II. Also, A-II
     strategies, are therefore, being developed         inhibits renin production with a
     to help patients in severe heart failure.          loss of negative feed back effect,
     New pharmacological interventions are              thus, ACE-I can increase renin
     under investigation, some are in clinical          and A-I generation. For these
     trials, while many are in the experimental         reasons, some of the initial
     stage. Furthermore, established drugs are          beneficial effect of ACE-I is lost
     being studied in order to find the optimal         in some patients with heart failure
     dose and the best drug combinations in             during prolonged administration.
     order to achieve the most favorable
     results. New therapeutic strategies can be             Impact of Treatment: Short- term
     classified as follows:                                 studies comparing the effects of ACE
                                                            Inhibitors and Angiotensin II receptor
     I. Pharmacologic Therapy:                              antagonists on symptoms;
            1. Established drugs                            hemodynamics, neurohormones and
            2. New drugs                                    exercise capacity revealed that both
                                                            drugs are equally effective with
     II. Non-Pharmacologic Therapy:                         respect to these endpoints.
            1. Physical exercise                            Current use of Angiotensin II receptor
            2. Cardiac pacing                               blockers in heart failure is reserved
            3. Ultrafiltration                              for patients with intolerance to ACE
            4. LV assist devices                            inhibitors mainly due to cough.
            5. Surgery

                                                            2. Combination of ACE Inhibitors and
     D-4.1: PHARMACOLOGIC THERAPY                           Angiotensin II Receptor Blockers
                                                            (ARBS):
1.      Established Drugs:                                   It is possible that bradykinin
NEW THERAPEUTIC STRATEGIES FOR TREATMENT OF HEART FAILURE.DOC                        2


    accumulation contributes to the              for CHF and total cardiac mortality.
    beneficial effects of ACE inhibitors.        Also, spironolactone was associated
    In addition, AT1 receptors mediate           with 30 % reduction in death due to
    most of the harmful effects of AT II.        lower risk of death from progressive
    Thus, incomplete suppression of AT1          heart failure and sudden death from
    receptor-mediated effects and the            cardiac causes. Serious hyperkalemia
    accumulation of bradykinin by ACE            was rare. The commonest side effect
    inhibitors provide rationale for the         is gynecomastia (10%).
    combination of ACE inhibitors and            Spironolactone is contraindicated in
    AT1 receptor antagonist in treatment         patients with anuria, renal
    of congestive heart failure.                 insufficiency (creatinine > 2.5 mg%),
    Impact of treatment:                         or hyperkalemia.
    Remodeling of the left ventricle,
    plasma level of neuropeptides and             4. Calcium Channel Blocking
    suppression of aldosterone                    Agents (CCBA):
    production were beneficially                  The only calcium channel blocker
    influenced by the combination of an           that may be safely recommended for
    ARB (candesartan) and ACEI                    treatment of angina or hypertension
    (enalapril) as compared to either drug        in congestive heart failure is
    alone.                                        amlodipine.
    When given this combination, careful
    monitoring for symptomatic                    5. Nitrates in Large Doses: Nitrates
    hypotension and renal dysfunction is          produce vascular smooth muscle
    needed, particularly in patients              relaxation more on the venous than
    receiving large doses of diuretic             the arterial side. When given to
    therapy. Currently, this combination          patients with heart failure in large
    can be tried in patients who are              doses, (80-120 mg/day), they
    resistant to ACE-I alone.                     improve patients exercise tolerance
                                                  and symptoms. Through their
   3. Aldosterone Receptor                        vasodilator effect, nitrates decrease
Antagonists                                       the preload and left ventricular filling
   Aldosterone increases myocardial               pressure, wall stress and pulmonary
   fibrosis and collagen deposition,              congestion. They are more effective
   causes salt and water retention and            than ACEI in reducing pulmonary
   tendency to cardiac arrhythmias.               arteriolar resistance and right atrial
   Excess aldosterone production is               pressure. These agents can be tried in
   common in patients with CHF.                   patients with refractory heart failure
   Spironolactone (25 mg OD), improves            and symptoms of pulmonary
   mortality in patients with class III –IV       congestion in spite of administration
   heart failure when added to a standard         of digitalis, ACE-I, loop diuretics in
   regimen of ACE inhibitors, digoxin             the maximal tolerable doses.
   and a loop diuretic. Patients treated
   with spironolactone had improvement
   of symptoms as assessed on the basis
   of the NYHA functional class. It
   significantly reduced hospitalization
   NEW THERAPEUTIC STRATEGIES FOR TREATMENT OF HEART FAILURE.DOC                             3


   2. New Drugs:                                 3.              Any tendency for
                                                      cardiac output to fall is offset
   1. Natriuretic Peptides: The Natriuretic
                                                      by modest vasodilation.
   peptide system consists of:
   1. Atrial natriuretic peptide (ANP)
                                                      Limitations of NEPI: NEP enzyme breaks
      secreted from the atria and has
                                                      down a number of peptides (which
      natriuretic, diuretic and vasodilator
                                                      include AII), in addition to ANP and
      effects.
                                                      BNP. Interference with degradation of A
   2. Brain natriuretic peptide (BNP)
                                                      II by NEPI will increase its level.
      secreted from human left ventricle and
      it has the same effects of ANP.
                                                      3. Combined NEPI & ACEI
   Potential beneficial hemodynamic effects
                                                      (Omapatrilat):
   of ANP and BNP (decreased pulmonary
                                                      The clearance of Angiotensin II is
   capillary wedge pressure, increased
                                                      diminished by candoxatrialt (NEP
   cardiac index, decreased peripheral
                                                      inhibitor) and its vasopressor effect is
   vascular
                                                      enhanced. Therefore, a logical approach
   resistance) have been demonstrated in
                                                      is to combine ACE inhibitors with NEP
   CHF patients who received ANP and
                                                      inhibitor for complete neurohormonal
   BNP infusions. Recently, it has been
                                                      suppression.
   suggested that nesiritide (human b-type
                                                      Oral treatment with ompatrialt was
   ntriuretic peptide) is a safe and effective
                                                      associated with significant decrease in
   treatment by IV infusion for patients with
                                                      PCWP and increase in cardiac index. This
   acutely decompensated heart failure. It
                                                      drug proved useful in clinical trials and is
   improves the symptoms of heart failure in
                                                      now available in many countries for
   seriously ill patients and it does not
                                                      treatment of heart failure and
   increase ventricular arrhythmias.
                                                      hypertension.
   2. Neutral Endopeptidase Inhibitors
                                                      4. Endothelin Antagonists:
   (NEPI): candoxatrilat
                                                      Plasma endothelin levels are increased in
    ANP and BNP have a very short life
                                                      patients with heart failure. Endothelin is a
   span and they are rapidly degraded by the
                                                      very potent vasoconstrictor peptide.
   enzyme neutral endopeptidase (NEP).
                                                      Activation of the endothelin (ET)
   Neutral Endopeptidase Inhibitors (NEPI)
                                                      receptor, particularly the subtype A
   reduce the plasma clearance and prolongs
                                                      receptor (ETA), has been demonstrated to
   the half-life of ANP & BNP.
                                                      modulate a wide variety of biological
   Mode of Action:
                                                      processes including vascular tone and
   a. Renal effects: Natriuretic and Diuretic
                                                      myocardial contractile function. There are
   b. Effect on Hemodynamics:
                                                      two types of endothelin receptors:
1.               Decrease
                                                      1. ETA receptors which mediate
   pulmonary capillary wedge
                                                      vasoconstriction.
   pressure with no effect on
                                                      2. ETB receptors which predominantly
   cardiac output or change in
                                                      mediate vasodilation by release of EDRF.
   arterial blood pressures or
                                                      Treatment with Bosentan, a nonselective
   heart rate.
                                                      ETA/ATB receptor blocker resulted in
2.               Venodilation and
                                                      favorable hemodynamic effects in
   fall in left ventricular filling
                                                      patients with CHF. However, there was
   pressure.
NEW THERAPEUTIC STRATEGIES FOR TREATMENT OF HEART FAILURE.DOC                              4


no significant improvement in the                   TNF-α may also potentiate the skeletal
exercise capacity of patients treated with          muscle dysfunction that contributes to
Bosentan. Furthermore, treatment was                exercise limitation in severe heart failure.
associated with abnormalities in liver              Treatment with the monoclonal antibody
function tests, which might prevent its             against TNF-α can be cardioprotective,
clinical development. Although there are            particularly in the setting of heart failure
a number of new ETA selective blockers              in patients with AMI.
that apparently do not have the same                Patients who received intravenous
degree of hepatotoxic effects of Bosentan,          injection of Etanercept (TNF antagonist)
their clinical usefulness is still unproven.        achieved improvement of symptoms,
                                                    effort tolerance as guided by a six-minute
5. Human Growth Hormone                             walk test, and their quality of life
There is now little doubt that growth               improved.
hormone (GH) and insulin like growth                Treatment with Etanercept was associated
factor-1 (IGF-1), play a role in cardiac            with improvement of ejection fraction and
development and in cardiovascular                   significant decrease in circulating blood
physiology in the adult.                            levels of TNF.
Cardiac hypertrophy is a physiologic                Although no side effects have been
response that allows the heart to adapt to          reported with Etanercept, more studies
an excess hemodynamic load. It was                  are needed to predict the impact of
hypothesized that inducing cardiac                  treatment on survival.
hypertrophy with recombinant human
growth hormone (GH) might be an                     Inotropic Agents for Congestive Heart
effective approach to the treatment of              Failure:
dilated cardiomyopathy.
Treatment with GH (4 IU)                       1.       Agents that increase intracellular
subcutaneously every other day for 3                calcium:
months improve symptoms, quality of life                Agents which increase cytosolic
and increase exercise time.                             calcium are divided into two big
Growth hormone therapy for 3 months                     groups depending on the mechanism
was associated with an increase in left                 of their inotropic action. The first
ventricular mass and heart wall thickness,              group are agents that increase the
decreases in end- diastolic and end-                    cyclic adenosine monophosphate
systolic size with increase in ejection                 (cAMP) inside the cell. cAMP is an
fraction.                                               important secondary messanger
There is no evidence of a beneficial effect             produced through activation of the
on survival.                                            enzyme adenyl cyclase. This enzyme
                                                        is linked to beta adrenergic receptors
6. Tumor Necrosis Factor Antagonists:                   in the myocyte membrane. Some
Proinflammatory cytokines such as TNF-                  inotropes in this group stimulate
α and interleukin-1 have been implicated                directly the adrenergic receptors
in the pathogenesis of heart failure and                increasing cAMP production, other
other conditions.                                       increase intracellular cAMP level by
Elevated levels of cytokines may                        inhibiting the enzyme
contribute to the diminished myocardial                 phosphodiasterase which breaks down
contractility in congestive heart failure.              cAMP. The second group are
NEW THERAPEUTIC STRATEGIES FOR TREATMENT OF HEART FAILURE.DOC                          5


   inotropic agents that increase                inhibits PDE. The effects of two doses of
   intracellular calcium independent of          vesnarinone (60mg and 120 mg) versus
   intracellular cAMP level.                     placebo were examined. Although the
                                                 60mg showed a significant reduction in
       a) cAMP Dependent Inotropic               mortality, the 120mg was associated with
       Agents:                                   a twofold increase in mortality.
               A. Aderenrgic and                 Side Effects: Main side-effect is
               Dopaminergic Agonists:            neutropenia.
                  Established :
               Dobutamine-Dopamine               2. Calcium Sensitizers:
               .                             -                     Pim
                  New       :                    obendan
               Ibopamine                     -                     Lev
               B. Phosphodiesterase              osimendan
               (PDE) Inhibitors:
                 Established :                   Pimobendan
               Amrinone –Milirinone              Calcium sensitizers enhance cardiac
                 New          :                  contractility by increasing the sensitivity
               Enoxamine                         of myofilaments to intracellular calcium
               C. β-Agonists :                   ions. Administration of Pimobendan in
               Xamoterol (selective β1           patients with moderate heart failure was
               adrenoceptor agonist)             associated with a significant improvement
                                                 in the quality of life, an increase in
An important limitation of this group of         exercise capacity and reduction in morbid
cAMP dependant inotropic agents is their         events. Treatment with Pimobendan was
proarrhythmic potential and the                  associated with a non-significant increase
development of tolerance to their                in mortality.
inotropic effect. They produce rapid
hemodynamic improvement, increase in             Levosimendan
cardiac output and reduction in left             Levosimendan is a new inodilator drug
ventricular filling pressure when given          that sensitizes troponin C in heart muscle
acutely, but they increase mortality rate        to calcium, thus improving contractility.
when administered for a long time. They          Levosimendan has hemodynamic effects
produce ventricular arrhythmias.                 comparable in magnitude or superior to
                                                 those of dobutamine. A single dose of
       b) cAMP Independent Inotropic             2mg increased cardiac output by 40% and
Agents:                                          decreased PWP by 40-50%.
               - Inhibitors of sodium-           Levosimendan improved symptoms in
       potassium ATPase pump                     patients with advanced heart failure.
       (digoxin).                                Levosimendan was generally well
               - Opening of sodium               tolerated in severely ill patients without
       channels (vesnarinone).                   side effects.
Vesnarinone
c-AMP independent inotrope with ionic
channel action (inhibition of the voltage-
gated potassium channel) and also
NEW THERAPEUTIC STRATEGIES FOR TREATMENT OF HEART FAILURE.DOC                              6


Miscellaneous Agents in                           increased in congestive heart failure.
Treatment of Heart Failure                        Inhibition of BARK can reverse heart
                                                  failure in mouse genetic models. Also,
The following agents are in the                   recently inserting the SERCA2a gene into
experimental stage and has yet no                 cardiac cells can reverse life threatening
established role in the treatment of heart        heart failure. Over-expression of
failure.                                          SERCA2a is associated with increased
                                                  protein expression and pump activity and
ANTIOXIDANTS                                      increasing contraction and relaxation
Congestive heart failure is associated with       velocities.
increased production of oxygen free
radicles and oxidative stress. In addition,
                                                  D-4.2: NON-PHARMACOLOGIC THERAPY
there is impaired endothelial function and
                                                         1. Physical Exercise
impaired ability to generate nitric oxide.
                                                         2. Cardiac Pacing
Furthermore, increased production of free
                                                         3. Ultrafiltration
oxygen radicals in congestive heart
                                                         4. LV Assist Devices
failure, results in degradation of NO.
                                                         5. Surgery
Vitamin C is an antioxidant that may
prevent the inactivation of NO by free
                                                  1. Physical Exercise (refer to cardiac
radicals.
                                                  rehabilitation).
Vitamin C restored flow dependent
dilation in CHF patients after 4 weeks of
                                                  2. Cardiac Pacing:
oral therapy.
                                                  Wide QRS complex in patients with
                                                  dilated cardiomyopathy is associated with
L–ARGININE
                                                  longer left ventricular contraction and
Endothelial dysfunction of systemic
                                                  relaxation times and poor left ventricular
arteries in CHF may be partially reversed
                                                  systolic performance.
by administration of oral L–arginine
                                                  Rationale:
(substrate for endothelial NO).
                                                           a) Optimization of left ventricular
Intravenous L–arginine produces increase
                                                  filling.
in stroke volume, cardiac output and
                                                           b) Reduction of pre-systolic mitral
decrease in peripheral vascular resistance
                                                  regurge.
with no change in LVEF.
                                                  Programming:
                                                           DDD with short atrioventricular
IMMUNE GLOBULIN
                                                  (AV) delay.
Intravenous immune globulin has been
                                                  Impact of Treatment:
reported to improve left ventricular
                                                  Dual chamber pacing (DDD) in refractory
function in children with myocarditis and
                                                  heart failure was associated with
was also effective in peripartum
                                                  improvement of the following:
cardiomyopathy.
                                                           - NYHA functional class.
                                                           - Left ventricular function (EF).
GENE THERAPY
                                                           - Decreased need for hospital
Desensitization to beta adrenergic
                                                  admission, inotropic support and
receptor stimulation in heart failure is
                                                  transplantation.
caused by a second molecule called B–
                                                  Results:
adrenergic receptor kinase (BARK) that is
                                              -                Benefits appear to
    NEW THERAPEUTIC STRATEGIES FOR TREATMENT OF HEART FAILURE.DOC                            7


    be more significant in patients                   solutions are usually not necessary unless
    with longer PR interval (>250                     removal of intravascular volume has been
    m sec) and or wider QRS                           excessive, or a specific electrolyte deficit
    complex (intraventricular                         is being corrected (e.g., hyponatremia or
    conduction block).                                hypokalemia). An improved response to
-              Benefits of temporary pacing           diuretics has been reported following
    are not predictive of hemodynamic                 ultrafiltration, an effect that might be due
    improvement.                                      to an improved cardiac output and
                                                      reduced intracardiac filling pressures with
    Current Status:                                   a subsequent decline in the neurohumoral
    Recently, multi-site pacing has been              sodium–retaining signals to the kidney.
    suggested as an innovative way of
    achieving hemodynamic improvement in              4. Mechanical Circulatory Support:
    patients with end–stage heart failure. Bi-           a) Short–Term Devices:
    ventricular pacing has the ability to pace               These play a role in the treatment of
    the two ventricles simultaneously, thus                  acute onset of CHF with
    expecting to correct the activation and                  insufficient response to medical
    contraction asynchrony.                                  treatment.
    Acute Hemodynamic Effects of Bi-              -                The intraaortic
    ventricular Pacing:                               balloon pump (IABP):
            1. Increase CO                 2.         Functions by decreasing LV
    Increase arterial BP                              afterload through a reduction
            3. Decrease PASP               4.         in end systolic wall tension
    Decrease PCWP                                     and volume while decreasing
            5. Decrease SVR                           LV work. Mortality associated
    Cardiac pacing has no established role yet        with this device remains high.
    in treatment of heart failure.                       b) Long-term Devices:
                                                             Ventricular assist devices (VAD)
    3. Ultrafiltration:                                      are currently used exclusively to
    In refractory heart failure extracorporeal               bridge patients to cardiac
    ultrafiltration has a place as a useful and              transplantation. VAD are in the
    relatively safe mechanism for removing                   form of inflow conduit which is
    fluid and electrolytes in a controlled                   inserted into any one of the heart
    fashion, whether or not there is                         chambers and provide inflow into a
    underlying renal insufficiency.                          pumping machine that pump blood
    Ultrafiltration also usually avoids the                  into the ascending aorta and
    adverse hemodynamic effects of                           pulmonary artery via an outflow
    hemodialysis that can be difficult to                    conduit.Valves in the conduits
    manage in patients with heart failure and                ensure unidirectional flow .
    underlying ischemic heart disease.                       Types:
    Concurrent invasive hemodynamic                          - The heart Mate and
    monitoring is desirable, especially in                       Novacor systems
    unstable patients. Careful monitoring of                     specially assist the
    plasma electrolytes and the hematocrit,                      LV.
    which should not exceed 50 per cent is                   - Total Artificial Heart
    required. Replacement of electrolyte                         (CardioWest AZ)
   NEW THERAPEUTIC STRATEGIES FOR TREATMENT OF HEART FAILURE.DOC                           8


             replaces                               Impact on Survival:
             biventricular                          1st year: 80%           2nd year: 68%
             function.                                      Mortality: 4% per year
         - The Abiomed BVS and Thoratec             Complications and Causes of Death:
             devices assist either right, left or   1st year: - Non specific graft failure. - Acute
             both ventricles.                       rejection. - Infection.
         Complications:                             Later years: - Graft coronary artery
         - Bleeding           - Infection           disease – accelerated coronary
         - Thromboembolism                          atherosclerosis.
         Impact of Treatment:                                        - Malignancy. - Rejection.
         After successful implantation, end         93% of patients will suffer from the
         organ dysfunction due to low               following after the 3rd year:
         cardiac output is improved, and                             - Hypertension - Hyperlipidemia
         patients can receive adequate                      - Diabetes- Malignancy
         nutrition and rehabilitation with
         improvement of exercise capacity.             b) Cardiomyoplasty:
         The devices have occasionally been               Dynamic cardiomyoplasty is a
         used for longer than 500 days                    procedure in which skeletal muscle
         before transplantation.                          (latissimus dorsi) is used as a graft
                                                          wrapped around the myocardium
   5. Surgical Strategies for Advanced                    and stimulated by a pacemaker to
   Heart Failure:                                         contract in synchrony with the
      a) Cardiac Transplantation:                         heart.
         Transplantation is considered as the             Impact on Symptoms:
         most effective therapy for end stage             A small and statistically
         heart disease, but the severely                  insignificant increase in left
         limited donors supply and need for               ventricular ejection fraction and
         immunosupression have catalyzed                  some symptomatic improvement
         the development of many                          have been seen.
         alternative therapies.                           Complications:
                                                          High operative mortality has been
          Accepted Indications for                        reported in patients with more
          Transplantation:                                advanced (NYHA IV) congestive
1.             Maximal VO2 < 10                           heart failure.
   ml/kg/min with achievement
   of anaerobic metabolism.                            c) Ventricular remodeling (Batista
2.             Severe ischemia                            operation):
   consistently limiting routine                          Rationale:
   activity not amenable to                               Reducing the cavity of the left
   bypass surgery or angioplasty.                         ventricle in dilated cardiomyopathy
3.             Recurrent                                  by surgically resecting a portion of
   symptomatic ventricular                                the ventricular wall may provide
   arrhythmias refractory to all                          improved cardiac geometry and
   accepted therapeutic                                   contractility.
   modalities.                                            Efficacy and Safety:
                                                          This procedure was associated with
NEW THERAPEUTIC STRATEGIES FOR TREATMENT OF HEART FAILURE.DOC   9


     symptomatic improvement and
     increase in LV ejection fraction in
     patients with NYHA class IV.
     However, the main morbidities
     were renal insufficiency and cardiac
     arrhythmias with a 5%
     intraoperative mortality and 15%
     in-hospital mortality.
     Impact on Survival: The 2 years
     survival rate was 62%.
REFRACTORY HEART FAILURE.DOC                                                   1


D-3: REFRACTORY HEART                                      failure are discontinuation of anti-failure
                                                           drugs (ACE-inhibitors, diuretics) and
FAILURE                                                    excessive salt intake. Careful re-evaluation
                                                           may show that surgical or catheter
                                                           intervention modalities may be of value. If
D-3.1: INTRODUCTION                                        the maximum therapy cannot improve the
                                                           patients condition, then IV inotropics and
                                                           vasodilators may help. Cardiac assist
D-3.2: DIAGNOSTIC CRITERIA                                 devices and surgery to increase the
                                                           myocardial pumping action as
D-3.3: POTENTIALLY CORRECTABLE                             cardiomyoplasty and ventricular muscle
                                                           resection are further possibilities. Lastly
CAUSES                                                     cardiac transplantation may add a few
                                                           years to the patient.
D-3.4: GENERAL MANAGEMENT
                                                    D-3.2: DIAGNOSTIC CRITERIA
D-3.5: DIURETIC THERAPY
                                                       1. Major Criteria:
                                                    1. Resting LVEF < 30%.
D-3.6: DRUGS IN REFRACTORY HEART                    2. NYHA class III or IV symptoms or
                                                       achievement of < 5 METS on a
FAILURE                                                symptom limited exercise test; or
                                                       inability to walk a distance > 300
                                                       meters in 6 minutes, or peak oxygen
D-3.7: REFRACTORY HEART FAILURE:
                                                       consumption < 14 ml/Kg/min.
                                                    3. The patient on a standard heart
INTEGRATED APPROACH                                    failure therapy which includes ACE
                                                       inhibition, digoxin and diuretic for
D-3.1: INTRODUCTION                                    at least 3 months.
   Refractory and intractable heart failure are
                                                    2. Other Supportive Criteria:
     usually late stages in heart failure
                                                          1. Cardiac cachexia.
     syndrome associated with increased
                                                          2. > 1 visit to the hospital for
     mortality as high as 40-60% annually.
                                                              treatment of heart failure in the
     Refractory heart failure is present in up to
                                                              past 6 weeks.
     25% of patients of heart failure. Heart
                                                          3. Plasma norepinephrine > 900
     failure is considered to be refractory to
                                                              pg/ml.
     medical treatment when severe symptoms
                                                          4. Clinical, ECG or
     persist despite therapy with ACE inhibitors
                                                              echocardiographic evidence of
     and/or other vasodilators, as well as
                                                              pulmonary hypertension and/or
     diuretics, and digoxin. Typically, these
                                                              right ventricular hypertrophy.
     patients have manifestations of substantial
                                                          5. Hyponatremia with serum
     fluid retention and/or significantly reduced
                                                              sodium < 130 mmol/l in patients
     cardiac output. Sometimes, this condition
                                                              not treated with ACE-inhibitors.
     can be reversible, since the commonest
     causes of refractory or intractable heart
REFRACTORY HEART FAILURE.DOC                                               2


D-3.3: POTENTIALLY CORRECTABLE CAUSE            1. Hospitalization:
                                                   Patients in functional class IV are referred to
 1. Dietary causes such as excessive salt
                                                   hospital and confined to armchair or bed rest.
     intake, overweight and excessive
                                                   They can be followed up in a general medical
     alcohol consumption.
                                                   ward if the condition is easily controllable.
 2. Non-compliance and interruption of
                                                   Otherwise, they may need to be admitted to an
     anti-failure drug therapy.
                                                   intensive care unit if hemodynamically
 3. Sub-optimal medical therapy, e.g.
                                                   unstable, e.g. oliguria, hypotension (SBP < 80
     inadequate dosages.
                                                   mmHg), altered mental state, need for a Swan
 4. Infections whether systemic,
                                                   Ganz catheter. Monitoring of the ECG, blood
     pulmonary or cardiac (i.e., infective
                                                   pressure, kidney function, urine output, serum
     endocarditis).
                                                   electrolytes and blood gases should be carried
 5. Arrhythmias especially rapid atrial
                                                   out. The following are indications for
     fibrillation, but also includes other
                                                   introduction of a right sided heart catheter to
     tachy or brady arrhythmias.
                                                   measure right atrial and pulmonary capillary
 6. Anemia.
                                                   wedge pressures and cardiac output (Swan
 7. Hyperdynamic circulatory states, e.g.,
                                                   Ganz catheter):
     thyrpotoxicosis.
                                                    1. failure to identify the state of fluid
 8. Persistent rise in blood pressure.
                                                        balance and pulmonary congestion
 9. Electrolyte disturbance, such as
                                                        by clinical evaluation;
     hyponatremia, hyper or hypokalemia
                                                  2. deterioration of patient condition in
     and hypomagnesemia.
                                                      spite of empirical parenteral
 10.        Hypoalbuminemia may cause
                                                      antifailure therapy;
     refractory peripheral or pulmonary
                                                  3. acute pulmonary edema, when a trial
     edema by reducing the oncotic pressure
                                                      of diuretic and/or vasodilator therapy
     of plasma proteins and thus, favoring
                                                      has failed or is considered of high
     transudation of fluids from the vascular
                                                      risk.
     compartment to the intestinal or
     alveolar space.
                                                2. Diet: Small frequent meals free of salt.
 11. Poorly controlled diabetes mellitus.
 12. Myocardial ischemia.
                                                3. Management of Correctable Causes:
 13. Renal insufficiency.
                                                   Oxygen therapy may be needed in severely
 14. Intake of drugs that may depress
                                                   dyspneic patients. Electrolyte imbalance should
     myocardial contractility or enhance
                                                   be corrected. If anemia is present packed
     sodium and fluid retention, such as:
                                                   RBC’s should be given in small amounts
 - calcium channel blockers (verapamil
                                                   slowly. Hypoalbuminemia is a rare cause for
     and diltiazem)
                                                   the refractoriness of the failure, 50 ml albumin
 - antiarrhythmic drugs, specially class I
                                                   can be infused every other day. Protein
 - antimitotic drugs especially adriamycin
                                                   supplement in the diet can be helpful as well. If
     and trastuzumab
                                                   arrhythmia is present it should be corrected,
 - steroids
                                                   however, antiarrhythmics with negative
 - non-steroidal anti-
                                                   intropic action should be avoided (e.g.,
     inflammatory drugs.
                                                   disopyramide).
                                                4. Tailored Medical Therapy:
                                                   The patient should be evaluated clinically and
D-3.4: GENERAL MANAGEMENT
                                                   by hemodynamic measurements if necessary to
REFRACTORY HEART FAILURE.DOC                                                     3


  determine the degree of volume overload               2. Mechanisms:
  (pulmonary and systemic congestion) and               1. Failure of absorption of oral diuretics
  peripheral hypoperfusion. In patients with                due to intestinal edema and congestion
  florid congestion and excessive edema (wet),              in severe congestive heart failure.
  the first line of therapy is intensive diuretic       2. Progressive deterioration of kidney
  regimen. Some patients may appear free of                 function and failure of loop diuretics to
  excessive fluid retention (dry), yet suffer from          gain access to tubular fluid and their
  shortness of breath and manifestations of                 site of action.
  hypoperfusion due to low CO (cold                     3. Progressive deterioration of cardiac
  extremities). Those, patients will benefit more           function with excessive neurohormonal
  from initial treatment with neurohormonal                 activation.
  antagonists (ACE-inhibitors and angiotensin           4. Administration of non-steroidal anti-
  receptor blocker), and vasodilators (Nitrates,            inflammatory drugs (NSAIDs).
  nitroprusside). In practice, the presence of          5. Hypotension and decrease in renal
  marked hypotension, (systolic < 80 mmHg),                 blood flow.
  precludes the administration of vasodilator           6. Severe impairment in renal function
  therapy or aggressive diuretic therapy unless             (creatinine clearance < 5 ml/min).
  the CO and blood pressure are initially
  improved by positive inotropic infusion.           II. Strategies to Improve Diuretic Response:
  Most patients with severe refractory pump              1. Increase the dose and frequency of
  failure will require a combination of all or              administration, giving large doses of
  several available drug groups (diuretics,                 loop diuretics up to 4,000-mg
  inotropes, neurohormonal antagonists and                  frusemide/day. IV loop diuretics 2-3
  vasodilators), at one stage of the treatment.             times daily improve their bioavailability
                                                            and overcomes the “rebound
                                                            augmentation of sodium retention”,
D-3.5: DIURETIC THERAPY
                                                            which occurs as the effect of the
I. Diuretic Resistance: Two forms of diuretic               previous dose weans off.
resistance or tolerance are described:                   2. Supine position 4 hours post diuretic
    a. Early tolerance when the natriuretic                 dose, helps to increase renal blood flow.
        response diminishes after the initial            3. Limit salt intake.
        first dose of the diuretic. This is              4. Continuous IV infusion of frusemide (≥
        secondary to acute activation of the                5 mg/Kg over 24 hr), can be initiated to
        renin-angiotensin-aldosterone and                   augment diuresis.
        sympathetic nervous systems.                     5. The combination of a loop diuretic with
    b. Late or delayed diuretic resistance                  a thiazide agent has a synergistic effect.
        following long term administration of               The thiazide diuretic blocks sodium
        loop diuretic. The underlying                       reabsorption in the proximal tubule and
        mechanisms include hypertrophy of                   increase sodium delivery to the distal
        the epithelium of the distal                        tubule. They counteract hypertrophy-
        convoluted tubule with increased                    enhanced distal tubular sodium
        reabsorption of sodium.                             reabsorption.
                                                         6. The concomitant use of low-dose
  1. Definition: “The excretion of less than 90             dopamine or dobutamine (2-5
      mmol Na over 72 hr on an oral dose of                 μg/Kg/min) can improve renal blood
      Furosemide of 160 mg twice daily”.                    flow and enhance diuresis.
REFRACTORY HEART FAILURE.DOC                                                          4


                                                             The combination of positive intropic agent and
D-3.6: DRUGS IN REFRACTORY HEART FAILURE                     vasodilator proved to be better than either of
1. Furosemide and Other Diuretics:                           them alone.
   Furosemide is a drug with dose related diuretic           When the patient’s condition is stabilized
   effect and doses as high as 250 mg to 4000 mg             continue on oral ACE inhibitor. High-dose (50-
   can be used. Metolazone can be added which                100 mg) transdermal nitroglycerin or oral
   may potentiate diuresis. If furosemide and other          isorbid dinitrate (160-240 mg/day) are added if
   diuretics are used in large doses, the C.V.P and          symptoms persist.
   left atrial pressure should be monitored since
   hypovolemia and consequently lower filling             5. Intermittent Intravenous Intropic Therapy:
   pressure can aggravate the low CO state.                  Dobutamine infusion 4 hours weekly may be
   Thiazide and spironolactone may be added to               tried in intractable failure. This approach was
   potentiate the diuretic effect.                           introduced to improve the quality of life of
   NB: Very low cardiac output may result in                 patients awaiting cardiac transplantation; it is
   renal hypoperfusion and reduce the delivery of            carried out on outpatient basis to reduce the
   diuretics to the active site of the renal tubules         cost. The long-term use of intravenous positive
   as a result patient will be refractory to the effect      inotropic therapy is not recommended and may
   of diuretics.                                             increase the risk of death. No data are available
                                                             as to which patient (if any) might benefit from
2. ACE-inhibitors and Angiotensin II receptor                this therapy, which agents should be used and
blockers:                                                    at what dosage.
   ACE-inhibitors should be used in maximum
   tolerable doses, they were found to reduce             6. New and Experimental Drugs: (see chapter
   mortality in heart failure when given in large         D-4)
   doses.                                                    These include intravenous infusion of brain
   Angiotensin II receptor blockers gave the same            natriuretic peptide, combined neutral
   beneficial effect, they can replace ACE-                  endopeptidase and ACE-inhibitors
   inhibitors if side-effects (cough, allergy)               (omapatrilat), new inotropic agents (cyclic
   develop after ACE-inhibitors.                             AMP-independent inotropes).

3. Digitalis:                                             II) OTHER MODALITIES OF MEDICAL
   Digitalis toxicity can occur even with the usual       MANAGEMENT:
   doses. Monitoring of patients for early toxicity       a) Ultrafiltration:
   and sometimes the serum digoxin level is               This method is used successfully to deload the
   important.                                             patient with resistant heart failure especially when
                                                          diuretics are no longer effective. It can be repeated
4. Vasodilators:                                          every other day or twice per week until the patient
    Hydralazine 100 mg TID, plus Isosorbide               is stabilized and dry weight achieved.
   dinitrate 40-60 mg, every 4-6 hours can be used
   guided by the blood pressure. If the systolic          b) Ablation and AICD:
   blood pressure is 90 mmHg or above                     Atrial fibrillation refractory to medical
   Nitoprussied 10-300 ug/min can be used.                management and leading to aggravation of the
   However, if the systolic blood pressure is             failure can be corrected by partial ablation of the
   below 90 mmHg, dopamine and dobutamin can              AV node. Recurrent VT or VF, which can
   be used until the systolic pressure is above 90        aggravate heart failure, can be managed by AICD.
   mmHg, when nitroprusside can be installed.
REFRACTORY HEART FAILURE.DOC                                                            1


Strategies for Persistent Congestion Despite Digoxin
Diuretic and ACE-Inhibitor Therapy
  •     Insertion of pulmonary artery catheter (Swan-Ganz) capable of measuring
       pulmonary capillary wedge pressure.
   • Placement of arterial line.
   • Hemodynamically guided therapy with:
                • Parenteral vasodilator (nitroglycerin, nitroprusside).
                • Parenteral inotrope (dopamine, doputamine, milrinone).
   • Continuous parenteral frusemide infusion.
   • Infusion of dopaminergic or “renal” doses of dopamine (< 5 μg/Kg/min).
   • Hemofiltration / ultrafiltration.
   • Peritoneal dialysis.
                                                              was not indicated before, e.g. a ventricular
III. CARDIAC ASSIST DEVICES: (SEE CHAPTER D-                  aneurysm need to be removed if the patient
4)                                                            goes into frank failure, while its removal is not
a) Intraaortic balloon pump:                                  indicated if the patient’s heart was
    This is a well established methods of cardiac             compensated. Restudy of the patients may
    support in cardiogenic shock which maintains              show that the reason for aggravation of the
    adequate blood pressure, improve peripheral               failure is a new myocardial insult, however
    and coronary perfusion, as well as lower                  there may be a large area of viable myocardium
    afterload especially in systole. It can be used to        which will improve by revascularization.
    support the patient in the CCU, during the                Aggravation of the heart failure due to
    cardiac catheterization or intervention, it is also       ventricular septal defect or rupture of papillary
    valuable after surgery.                                   muscle requires surgical correction urgently.
b) External counter pulsation:
    This method can be used to improve the blood           b) Cardiomyoplasty:
    pressure and consequently improve coronary                In this operation skeletal muscle is used to
    and cerebral perfusion by synchronized                    provide contractile capacity to the left ventricle.
    compression of the lower part of the body in              Latissimus dorsi is wrapped around the heart to
    diastole, with release of pressure in systole             construct a skeletal muscle ventricle. Operative
    leading to lower afterload simulating balloon             mortality is high and the left ventricular
    counter pulsation.                                        ejection fraction does not increase significantly.
c) Left ventricular assist devices:
    Several types of assist devices are being tried        c) Surgical remodeling:
    now with more effort to overcome the problems             The idea is to reduce the cavity of the dilated
    of the early prototypes, like infection. Novacor          poorly contracting left ventricle by surgical
    and Heart Mate are examples. Both devices                 resection of a portion of the ventricle, which
    require transcutaneous energy cables that                 may improve the cardiac geometry and
    remain potential entry points for infection.              contractility. This was performed in a small
                                                              number of patients and few centers and its
IV) SURGICAL PROCEDURES: (SEE CHAPTER D-4)                    assessment remains to be seen.
a) General:
    Reconsideration of the patients condition              d) Cardiac transplant:
    should be made if the failure is aggravated and           This surgery is a standard therapy for selected
    surgical intervention may be indicated while it           end stage heart failure patients. The
     REFRACTORY HEART FAILURE.DOC                                                          2


        improvement of the technique, tissue                   pickles, cheeses, canned and smoked foods,
        preservation, immunology, treatment of                 pizza, fast foods, excess salt added at table and
        rejection and infection rendered this procedure        on cooking.
        widely used and accepted as a modality of                3. Excessive physical exertion.
        treatment for selected candidates. One year and          4. Inadequate drug therapy:
        five-year survival rate are 75-85% and 60-65%            a. Inadequate doses of diuretics or ACE-
        respectively.                                                inhibitors.
                                                                 b. Excessive diuresis resulting in
                                                                     hypokalemia, deterioration of kidney
     D-3.7: REFRACTORY HEART FAILURE:
                                                                     function due to contraction of blood
     INTEGRATED APPROACH                                             volume (hypovolemia), and reflex
                                                                     sympathetic and renin-angiotensin
     In patients referred to specialists diagnosed as
                                                                     systems activation.
     having refractory heart failure, the etiology can be
                                                                 c. Under or over digitalization.
     one or more of the following conditions:
                                                            5.     Administration of negative inotropic drugs
         1. Error in diagnosis
                                                               or agents that potentiate salt and water
         2. Error in treatment
                                                               retention.
          3. Hopelessly damaged myocardium
                                                               III. Hopelessly Damaged Myocardium:
     I. Error in Diagnosis:
                                                                    In ischemic or idiopathic dilated
     1. Patient does not have heart failure and his
                                                                    cardiomyopathy, following multiple large
         symptoms of shortness of breath, fatigue,
                                                                    infarctions, viral, toxic, autoimmune
         edema of lower limbs are secondary to non-
                                                                    myocardial damage or excessive mechanical
         cardiac causes, e.g. obesity, severe anemia,
                                                                    loading of the left ventricle in severe
         bronchopulmonary disease, disseminated
                                                                    prolonged valvular leasions.
         malignancy, nephrotic syndrome, liver
                                                               Irreversible loss of cardiac myocytes and their
         cirrhosis, anxiety states, severe nutritional
                                                               replacement by collagen tissue will changes
         deficiency. Patients with constrictive
                                                               the heart into a bag of fibrous tissue with little
         pericarditis or chronic pericardial effusion can
                                                               contractile elements.
         be misdiagnosed as having heart failure.
     2. Missing an important precipitating or
         contributing factor such as infection, silent
         myocardial infarction, myocardial ischemia,
         pulmonary embolism, severe anemia, thyroid
         dysfunction, mild elevation of blood pressure,
         uncontrolled diabetic state, severe anxiety and
         emotional conflicts, arrhythmias, renal failure,
         excessive alcohol intake, electrolyte
         disturbances
     3. Missing an underlying valvular disease, e.g.,
     silent mitral stenosis, aortic stenosis.

   II. Error in Treatment:
1.     Patient non-compliance with heart failure
   treatment. Discontinuation of diuretic, digitalis
   or ACE-inhibitor therapy.
2.     Excess salt intake, e.g., Chips, french fries,
REHABILITATION OF HEART FAILURE.DOC                                                     1


D-5: REHABILITATION OF HEART                            peripheral blood flow and an exaggerated
FAILURE PATIENTS                                        sensitivity to exercise derived metabolic signals,
                                                        lead to early and profound exercise – induced
                                                        fatigue and dyspnea, the mechanisms of which we
                                                        are only now beginning to understand. These
D-5.1: INTRODUCTION                                     observations raise the possibility of improving
                                                        exercise tolerance through peripherally acting
D-5.2: EXERCISE IN THE TREATMENT OF HEART               therapies such as exercise training of skeletal
                                                        muscles in left ventricular dysfunction and chronic
FAILURE                                                 heart failure.
                                                        Training seems to benefit patients with all grades
D-5.3: POSSIBLE BENEFIT TO EXERCISE IN HEART            of heart failure, especially if underlying ischemia is
                                                        present, and to have a beneficial effect that occurs
FAILURE                                                 rapidly and persists for up to 1 year after the
                                                        initiation of training.
D-5.4: EXERCISE PRESCRIPTION IN HEART

FAILURE                                                 D-5.2: EXERCISE IN THE TREATMENT OF HEART
                                                        FAILURE
D-5.5: CONTRAINDICATIONS TO EXERCISE IN
                                                                 Many of the peripheral abnormalities of
HEART FAILURE                                           congestive heart failure are similar to those seen in
                                                        detrained individuals; with activation in the renin-
D-5.6: PATIENT AND FAMILY EDUCATION                     angiotensin and sympathetic systems. The effects
                                                        of training for 4-6 months were examined in a
D-5.7: PSYCHOSOCIAL INTERVENTION                        group of heart failure patients (mean EF 24%).
                                                        Following training, there was a reduction in heart
                                                        rate, 23% increase in exercise capacity as measured
                                                        by peak oxygen consumption and a reduction in
D-5.1: INTRODUCTION                                     arterial and venous lactate with no effect on central
         The aim of rehabilitation is to improve        hemodynamics. Furthermore, the ventilatory
exercise capacity, effort tolerance and quality of      response to exercise was reduced with an increase
life in patients with cardiac failure.                  in the anerobic threshold.
Physical training can significantly improve the
anatomic and functional capacity of the
deconditioned skeletal and respiratory muscles.         D-5.3: POSSIBLE BENEFIT TO EXERCISE IN HEART
Physical training though, does not seem to have a       FAILURE
measurable effect on cardiac function. A 20 to 30%
gain in exercise capacity can be achieved, mainly       1. Beneficial effects of exercise in CHF:
increasing the duration of submaximal exercise                - ↓ central sympathetic tone
rather than maximum performance. Muscular                     - ↑ parasympathetic activity
fatigue is the symptom, which is improved most.               - ↓ plasma renin activity
Recent research has demonstrated that it is not only          - Improvement of
a restricted cardiac output that limits exercise, but             baroreceptor sensitivity
an abnormality in the pathway of delivery of                  - ↑ anaerobic threshold
oxygen to the exercising muscles. Deficiencies in             - ↑ leg muscle bulk
REHABILITATION OF HEART FAILURE.DOC                                                       2


    - ↓ ventillatory response                              pain, or dizziness.
 2. Training is not accompanied by any great                • Don’t exercise the patient immediately after meals,
     change in central hemodynamics.                       preferably 1-2 hours after a light meal.
 3. Other possible mediators of improvement                 • Avoid exercising in extreme heat or cold.
     include improved endothelial function, as              • Monitor pulse and perceived level of exertion.
     shown by an increase in flow-dependent
     dilatation.
The evidence accumulating from clinical trials             D-5.5: CONTRAINDICATIONS TO EXERCISE IN
suggests that even short-term training results in an
improvement of peak exercise capacity of around            HEART FAILURE
20% and a reduction in the ventilatory response to         1. Absolute: Acute myocardial infarction,
exercise. This is accompanied by an improvement               unstable angina, LVOT obstruction
in symptom score and well-being. It is not clear           2. Relative: Functional class NYHA IV
whether these benefits extend to an improvement
in prognosis. There are hints from the studies that
this may be so. Many of the adverse prognostic             D-5.6: PATIENT AND FAMILY EDUCATION
features of heart failure are improved. In addition
to the increase in exercise capacity; there is an          Hygenic Approaches:
increase in heart rate variability, a reduction in         By choosing a healthy lifestyle the patient can
noradrenaline spillover and an increase in muscle          improve the way he feels. A healthy diet and
bulk.                                                      exercise regimen will help the patient stay active
                                                           and feel his best. Check dietary guidelines and use
                                                           daily weight chart to keep track of his weight.
D-5.4: EXERCISE PRESCRIPTION IN HEART
                                                           Doctor Visits:
FAILURE                                                    A visit to the doctor need not be a stressful
Indications: Exercise training should be initiated         experience. Doctor should try to help the patient
in patients with compensated heart failure (NYHA           feel better and to monitor his progress. Patient can
II–III).                                                   help his doctor and himself out by reporting any
Most studies of exercise as a therapeutic                  symptoms he has, and being specific about when
intervention have used supervised exercise at levels       they occurred and how he felt.
of around 60% of predetermined maximal exertion.
Patients with more severe heart failure are trained        Lifestyle Modifications:
at low workloads (< 50% of maximal).                       Choosing a healthy lifestyle means avoiding
Specific recommendations include dynamic                   smoking, alcohol, maintaining a healthy weight,
aerobic exercise (walking) 3-5 times per week for          and making use of social support structures.
20-30 minutes or cycling for 20 minutes at 70-80%
of peak heart rate 5 times per week. Strenuous
isometric activities should be discouraged.                D-5.7: PSYCHOSOCIAL INTERVENTION
                                                                  Emotional health is also important in
Some Useful Exercise Tips:                                 coping with heart failure. Family and friends can
 • Warm up with stretching exercises before beginning      provide support. Communicating with others is a
exercise.                                                  good way of allaying fears and apprehensions
 • Choose exercises the patient enjoys.                    about heart failure.
 • Avoid exercises that require quick bursts of energy.
 • Avoid exercises that cause shortness of breath, chest
SUMMARY OF GUIDELINES FOR MANAGEMENT OF HEART FAILURE.DOC                       1


   1.    Careful clinical evaluation, including careful history, physical examination, chest X-ray ECG; renal and
         electrolyte profile to establish the diagnosis of heart failure and identify potentially correctable precipitating
         and contributing factors. These should be managed accordingly.
   2.    Echocardiography should be done in all patients to assess left ventricular systolic function, identify silent
         valvular disease, degree of cardiac chamber dilatation, scarring aneurysms, thrombi, pulmonary hypertension,
         diastolic function and pericardial effusion.
   3.    Detailed evaluation of patient current therapy, diet and effort tolerance.
   4.    Patients in severe heart failure, functional class IV (NYHA) with oliguria, mental deterioration, hypotension
         (SBP < 90 mmHg), orthopnea, severe edema, laboratory evidence of rising serum creatinine, hyponatremia (<
         130 mmol/l) should be hospitalized.
   5.    Patients should be instructed regarding diet, limiting salt intake, effort, physical activities, need for continued
         antifailure medications, regular weight. Mild tranquilizers to ensure adequate rest and night sleep might be
         required.
   6.    Mild exercise, e.g. walking should be encouraged in patients functional class II-III.
   7.    Loop diuretics, e.g. furosemide (Lasix) are given intravenously in patients with severe congestive symptoms
         (edema, orthopnea) 40-80 mg every 6-12 hours depending upon the condition. Once dry weight is achieved,
         oral furosemide is given 20-80 mg 1-3 times/day. It is discontinued if patient is symptom free. Diuretics have
         no place in management of patients with no congestive symptoms or without edema.
   8.    ACE inhibitors are slowly titrated starting with a small dose and increasing gradually over days to reach the
         maximal tolerable dose. Blood pressure supine and standing and kidney function should be monitored at
         initiation and after 4-8 weeks of therapy, then every 2-3 months. A rise in serum creatinine may follow
         initiation of ACE-inhibitor therapy. If less than 2.5 mg/dL, do not change ACE-therapy, diuretics are reduced
         or discontinued if possible. ACE inhibitors were given to all patients with heart failure of functional class I-
         IV.
   9.    Digoxin is given to all patients in functional class III and IV.
   10.   Spirolactone (Aldactone) is administered in a small dose 12.5-50 mg/day. Monitoring serum potassium is
         required initially, then every 3 months. It is given to all patients class III and IV.
   11.   If adequate diuresis is not achieved in spite of large doses of loop diuretics, a continuous intravenous
         frusemide infusion is given (5-10 mg/Kg/day), a thiazide diuretic is added and instructing the patient to stay
         in the supine position for 4 hours after diuretic administration. Small dose of dobutamine or dopamine 2-5
         mg/Kg/min are given in refractory cases.
   12.   Nitrates are given in large doses orally or transdermally if dyspnea persists in spite of adequate triple therapy
         (digitalis, ACE inhibitor and diuretic). It is recommended at bedtime if the patient’s sleep is interrupted by
         orthopnea or attacks of paroxysmal nocturnal dyspnea.
   13.   Intravenous inotropic agents, e.g. dobutamine and milrinone are given only in emergency conditions or to tide
         the patient over a critical period, but have no place in the long term management of heart failure. They are
         particularly effective when a correctable cause of hemodynamic deterioration is present.
   14.   Surgical correction of underlying valvular, coronary artery disease or cardiac aneurysm should be considered
         as soon as the diagnosis is established.
   15.   Beta adrenergic blockers are given to patients with heart failure, functional class II, III and possibly class IV
         after stabilization of the condition, control of dyspnea and congestion. Start with very small dose and increase
         slowly and gradually every 1-2 weeks.
   16.   When condition is stabilized, patient and his family should be educated regarding heart failure management
         and to plan follow-up visits, monitoring of treatment and progress, early recognition and treatment of
         worsening symptoms.
   17.   Heart failure with normal systolic function (diastolic heart failure) is more common in the elderly, carries a
         better prognosis but it has no specific therapy. Digitalis and ACE-inhibitors have no role, diuretics improve
         congestive symptoms but has to be given with caution. Slowing of the heart rate and treatment of myocardial
         ischemia by beta blockers and non-dihydropyridine calcium antagonists is helpful.

								
To top