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.
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