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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.
