Goldman: Cecil Textbook of Medicine, 22nd ed., Copyright © 2004 W. B. Saunders Company


Barry M. Massie

Heart failure is a heterogeneous syndrome in which an abnormality of cardiac function is responsible for the inability of the heart to pump blood at an output sufficient to meet the requirements of metabolizing tissues or to do so only at abnormally elevated diastolic pressures or volumes. The heart failure syndrome is characterized by signs and symptoms of intravascular and interstitial volume overload, including shortness of breath, rales, and edema, and/or manifestations of

inadequate tissue perfusion, such as impaired exercise tolerance, fatigue, and renal dysfunction. Heart failure may occur as a result of impaired myocardial contractility (systolic dysfunction, characterized as reduced left ventricular ejection fraction); increased ventricular stiffness or impaired myocardial relaxation (diastolic dysfunction, which often is associated with a preserved left ventricular ejection fraction); a variety of other cardiac abnormalities (including obstructive or regurgitant valvular disease, intracardiac shunting, or disorders of heart rate or rhythm); or states in which the heart is unable to compensate for increased peripheral blood flow or metabolic requirements. In adults, left ventricular involvement is almost always present even if the manifestations are primarily those of right ventricular dysfunction (fluid retention without dyspnea or rales). Heart failure may result from an acute insult to cardiac function, such as a large myocardial infarction (MI), or, more commonly, from a chronic process. The focus in this chapter is on the syndrome of chronic heart failure; the most common causes of de novo acute heart failure, such as MI ( Chapter 69 ), valvular disease ( Chapter 72 ), myocarditis ( Chapter 73 ), and cardiogenic shock ( Chapter 103 ), are discussed elsewhere.
Heart failure is growing in incidence and prevalence and is associated with rising mortality rates. Although these trends primarily reflect the strong association between heart failure and advancing age, they also are influenced by the rising prevalence of precursors such as hypertension, dyslipidemia, and diabetes in industrialized societies and the improved long-term survival of patients with ischemic and other forms of heart disease. The annual incidence of new cases of heart failure rises from less than 1/1000 patient-years younger than age 45, to 10/1000 patient-years older than age 65, to 30/1000 (3%) patient-years older than age 85. Prevalence figures follow a similar exponential pattern, increasing from 0.1% younger than age 50 to 55 to nearly 10% older than age 80. In the United States, there are an estimated 4.8 million heart failure patients, of whom approximately 75% are age 65 or older. Although the relative incidence and prevalence of heart failure are lower in women than men, women constitute at least half of the cases because of their longer life expectancy.
The prognosis of patients with heart failure is poor despite advances in therapy. Of patients who survive the acute onset of heart failure, only 35% of men and 50% of women are alive after 5 years. Although it is difficult to predict prognosis in individual patients, patients with symptoms at rest (class IV) have a 30 to 70% annual mortality rate, patients symptomatic with mild activity (class III) have mortality rates of 10 to 20% annually, and patients with symptoms only with moderate activity (class II) have a 5 to 10% annual mortality rate. Mortality rates are higher in older patients, men, and patients with reduced ejection fractions and underlying coronary heart disease. In the United States, nearly 1 million hospitalizations each year with a primary diagnosis of heart failure account for 6 million hospital days. The estimated cost of heart failure management ranges from $15 to $40 billion annually, depending on the formula used.
Etiology and Prevention
Any condition that causes myocardial necrosis or produces chronic pressure or volume overload can induce myocardial dysfunction and heart failure. In developed countries, the causes of heart failure have changed greatly over several decades. Valvular heart disease, with the exception of calcific aortic stenosis, has declined markedly, whereas coronary heart disease has become the predominant cause in men and women, being responsible for 60 to 75% of cases. Hypertension, although less frequently the primary cause of heart failure than in the past, continues to be a factor in 75%, including most patients with coronary disease.
Treatment of hypertension, with a focus on the systolic pressure, reduces the incidence of heart failure by 50%. This intervention remains effective even in patients older than 75 years of age ( Chapter 63 ). Any intervention that reduces the risk of a first or recurrent MI also reduces the incidence of heart failure ( Chapter 47 ). In post-MI patients, ß-blockers, antihyperlipidemic agents, antithrombotic therapy, and coronary revascularization can prevent the development of heart failure. In patients with reduced ejection fractions, angiotensin-converting enzyme (ACE) inhibitors and ß-blockers prevent or delay progressive left ventricular dysfunction and dilation and the onset or worsening of heart failure.
Heart failure is a syndrome that may result from many cardiac and systemic disorders ( Table 55-1 ). Some of these disorders, at least initially, do not involve the heart, and the term heart failure may be confusing. Even high-output states may present, however, with the classic findings of exertional dyspnea and edema—high-output heart failure—that resolve if the underlying disorder is eliminated. If persistent, these conditions may impair myocardial performance secondarily as a result of chronic volume overload or direct deleterious effects on the myocardium. Other conditions, including mechanical abnormalities, disorders of rate and rhythm, and pulmonary abnormalities, do not primarily affect myocardial function but are frequent causes of heart failure.
Ischemic damage or dysfunction
Myocardial infarction
Persistent or intermittent myocardial ischemia
Hypoperfusion (shock)
Chronic pressure overloading
Obstructive valvular disease
Chronic volume overload
Regurgitant valvular disease
Intracardiac left-to-right shunting
Extracardiac shunting
Nonischemic dilated cardiomyopathy
Familial/genetic disorders
Toxic/drug-induced damage
Immunologically mediated necrosis
Infectious agents
Metabolic disorders
Infiltrative processes
Idiopathic conditions
Pathologic myocardial hypertrophy
Primary (hypertrophic cardiomyopathies)
Secondary (hypertension)
Ischemic fibrosis
Restrictive cardiomyopathy
Infiltrative disorders (amyloidosis, sarcoidosis)
Storage diseases (hemochromatosis, genetic abnormalities)
Endomyocardial disorders
Obstructive valvular disease
Regurgitant valvular disease
Intracardiac shunts
Other congenital abnormalities
Obstructive (coarctation, supravalvular aortic stenosis)
Left-to-right shunting (patent ductus)
Bradyarrhythmias (sinus node dysfunction, conduction abnormalities)
Tachyarrhythmias (ineffective rhythms, chronic tachycardia)
Cor pulmonale
Pulmonary vascular disorders
Metabolic disorders
Nutritional disorders (beriberi)
Excessive blood flow requirements
Chronic anemia
Systemic arteriovenous shunting

Ventricular systolic function (contractility)
Ventricular diastolic function
Ventricular preload
Ventricular afterload
Cardiac rate and conduction
Myocardial blood flow
In the normal ventricle, stroke volume increases over a wide range of end-diastolic volumes (the Frank-Starling effect). If contractility (or the inotropic state of the myocardium) is enhanced, such as during exercise or catecholamine stimulation, this increase is correspondingly greater ( Table 55-2 ). In the failing heart with depressed contractility, there is relatively little increment in systolic function with further increases in left ventricular volume, and the ventricular function curve is shifted downward and flattened ( Chapter 48 ). In the clinical setting, systolic dysfunction is characterized by depressed stroke volume despite elevated ventricular filling pressures. The resulting symptoms are those of pulmonary or systemic congestion, activity intolerance, and organ dysfunction.
Assessment of systolic function clinically is more problematic. The most useful measure is the left ventricular ejection fraction (stroke volume/end-diastolic volume, usually expressed as a percent), which reflects a single point on the ventricular function curve. The ejection fraction is “load dependent,” however, meaning that alterations in afterload (see later) can affect it independent of contractility. In addition, mitral regurgitation, which facilitates ejection into the low-pressure left atrium, may lead to an overestimation of systolic function by the ejection fraction. Nonetheless, with the exceptions indicated earlier, when the ejection fraction is normal (>50% in most laboratories), systolic function is usually adequate. Ejection fractions that are mildly (40 to 50%), moderately (30 to 40%), and severely (<30%) depressed are associated with reduced survival and, in the severe range, with reduced functional reserve if not overt symptoms of heart failure. Cardiac output, in contrast, is a poor measure of systolic function because it can be affected markedly by heart rate, systemic vascular resistance, and the degree of left ventricular dilation.
Diastole is the portion of the cardiac cycle between aortic valve closure and mitral valve closure. Diastole consists of three phases: (1) active relaxation, (2) the conduit phase, and (3) atrial contraction. If relaxation is delayed or if the myocardium is abnormally stiff (e.g., a steeper relationship between change in pressure to change in volume; ?P/?V is excessively steep), passive filling may be impaired and atrial pressures are abnormally elevated. In this setting of a noncompliant ventricle (compliance is the inverse of stiffness, e.g., the change in volume for a given change in pressure), atrial contraction is responsible for a disproportionately large amount of diastolic filling.
The importance of abnormalities of diastolic function in the pathogenesis of heart failure is increasingly appreciated. Because relaxation is energy dependent, it frequently is impaired in the presence of ischemia or hypoxemia. Recurring myocardial ischemia, pathologic myocardial hypertrophy, chronic volume overload, and aging all are associated with increased interstitial fibrosis and poor relaxation.
In the left ventricle with diastolic dysfunction, left ventricular filling pressures rise because of the compliance changes, with resulting left atrial hypertension and pulmonary congestion. Cardiac output may be reduced if ventricular filling is sufficiently impaired. With activity, these abnormalities are exaggerated, with resulting exertional dyspnea and exercise intolerance.
In the intact heart, preload is characterized best by the end-diastolic volume or pressure, which are indirect indicators of end-diastolic fiber length ( Chapter 48 ). The performance of the normal ventricle is highly preload dependent, but the failing heart operates at high preloads and on the flat part of the ventricular function curve (see Fig. 48-3 ). In contrast to the normal ventricle, a modest decrease in preload has little effect on left ventricular filling pressures, whereas an increase in preload does not improve systolic function but worsens pulmonary congestion further. Preload reduction by diuresis or by reducing venous return with venodilating agents generally has a beneficial clinical effect in heart failure.
Left ventricular afterload frequently is equated with arterial pressure or systemic vascular resistance, but a more accurate measurement of afterload is systolic wall stress ( Chapter 48 ), defined as: [Pressure × the radius of the left ventricle] ÷ [2 × the thickness of the left ventricle]. At any given arterial pressure, afterload is increased in a dilated thin ventricle and decreased with a smaller or thicker ventricle. Increased afterload has an effect similar to that of depressed contractility, so afterload reduction can improve cardiac performance.
Heart rate affects cardiac performance by two mechanisms. First, increasing heart rate enhances the inotropic state by upregulating cytosolic calcium concentrations. Second, heart rate is an important determinant of cardiac output and is the primary mechanism by which cardiac output is matched to demand in situations such as exercise. Because stroke volume is relatively fixed in the failing heart, heart rate becomes the major determinant of cardiac output. Chronic tachycardia impairs ventricular performance, however, and cardiac function often improves with control of tachyarrhythmias such as atrial fibrillation.
Optimal cardiac performance depends on a well-coordinated sequence of contraction. Normal atrioventricular conduction times (0.16 to 0.20 second) enhance the contribution of atrial contraction to left ventricular filling, which is particularly important in the noncompliant ventricle. Patients with heart failure frequently have intraventricular conduction abnormalities, which result in dyssynchronous contractions, such that the septum and parts of the anterior wall begin contracting only after systole has ended in other regions.
In the normal heart, myocardial blood flow is closely coupled to oxygen requirements, and it is not ordinarily considered a determinant of cardiac performance. Myocardial ischemia is associated, however, with a rapid decline in contractile function that may persist long beyond the episode (myocardial stunning). Chronically inadequate blood flow may lead to a reduction in contractility, which re-establishes the balance between oxygen delivery and demands (hibernation). Low arterial diastolic pressures may interfere with the autoregulatory reserve of the coronary circulation, which is limited at diastolic pressures less than 60 mm Hg. Endothelial dysfunction, which is common in heart failure patients, also may limit blood flow. At the same time, tachycardia, increased afterload, and substantial left ventricular hypertrophy increase myocardial oxygen requirements. Inadequate myocardial blood flow plays an important role in the pathogenesis of cardiac dysfunction, sometimes even in patients without obstructive coronary disease.
Although much less is known about the genetics of dilated cardiomyopathy than hypertrophic cardiomyopathy, several forms of familial cardiomyopathy have been recognized, most of which are inherited in an autosomal dominant pattern. Mutations of genes encoding for nuclear membrane proteins (emerin, lamin) or for contractile or cytoskeletal proteins (desmin, a cardiac myosin, vinculin) have been identified. Cardiomyopathy also is associated with muscular dystrophies (Duchenne’s, Becker’s, and limb-girdle dystrophies; Chapter 463 ) and other forms of myopathy. As research in this area burgeons, it is estimated that genetic abnormalities may be involved in 20 to 30% of patients with idiopathic dilated cardiomyopathy.
Goldman: Cecil Textbook of Medicine, 22nd ed., Copyright © 2004 W. B. Saunders Company

Chronic heart failure is a multifaceted syndrome with diverse presentations ( Fig. 55-1 ). The initial manifestations of hemodynamic dysfunction are a reduction in stroke volume and a rise in ventricular filling pressures, perhaps in the basal state but consistently under conditions of increased systemic demand for blood flow. These changes have downstream effects on cardiovascular reflexes and systemic organ perfusion and function, which in turn stimulate a variety of interdependent compensatory responses involving the cardiovascular system,

Figure 55-1 Pathophysiology of heart failure, illustrated by Venn diagram.
neurohormonal systems, and alterations in renal physiology. It is this constellation of responses that leads to the characteristic pathophysiology of the heart failure syndrome. Recognition of the role of neurohormonal activation in heart failure has grown with the increasing understanding of its pathophysiology and with evidence that blockade of some of these responses can have a profound effect on the natural history of the disease ( Table 55-3 ). The number of hormonal systems that are known to be activated in heart failure continues to grow.
Neurohumoral Responses
Initial activation of the sympathetic nervous system probably results from reduced pulse pressures, which stimulate arterial baroreceptors, and renal hypoperfusion. Evidence for its activation comes from elevated levels of circulating norepinephrine, direct sympathetic nerve recordings showing increased activity, and increased norepinephrine release by several organs, including the heart. As cardiac function deteriorates, responsivity to norepinephrine diminishes, as evidenced by baroreceptor desensitization and downregulation of cardiac adrenergic receptors and signal transduction. This densensitization may stimulate sympathetic responses further.
The adaptive role of norepinephrine is to stimulate heart rate and myocardial contractility and to produce vasoconstriction. All of these actions reverse the depression of cardiac output and blood pressure. Elevated levels of plasma norepinephrine are associated with a worse

Plasma and tissue renin activity
Angiotensin II
Neuropeptide Y
Vasoactive intestinal peptides
Natriuretic peptides
Calcitonin gene-related peptide
Growth hormone
Proinflammatory cytokines
Neurokinin A
Substance P
prognosis, although it is unclear whether this is a cause-and-effect relationship. There is also convincing, albeit circumstantial, evidence that norepinephrine has adverse effects on the myocardium. In this regard, ß-adrenoceptor blockade, which for many years has been considered dangerous in heart failure because it deprives the heart of important compensatory stimulation, consistently improves left ventricular function and prognosis. The role of other catecholamines in heart failure remains undefined.
Elements of the renin-angiotensin-aldosterone system are activated relatively early in heart failure. The presumptive mechanisms of induction include renal hypoperfusion, ß-adrenergic system stimulation, and hyponatremia. All may be activated further by diuretic therapy. Angiotensin II increases blood pressure by vasoconstriction and enhances glomerular filtration by increasing renal pressure and maintaining glomerular flow by its intrarenal hemodynamic effects. Aldosterone causes sodium retention, which restores normal cardiac output by enhancing intravascular volume. These adaptations have deleterious consequences, however. Excessive vasoconstriction can depress left ventricular function, and sodium retention worsens the already elevated ventricular filling pressures. There also is experimental evidence indicating that angiotensin II may have pathologic effects on the myocardium and induce vascular hypertrophy, whereas aldosterone induces myocardial fibrosis. The striking success of ACE inhibitors and, more recently, spironolactone in improving the natural history of heart failure suggests that the adverse effects of renin-angiotensin-aldosterone activation may outweigh their benefit.
Levels of several natriuretic peptides are elevated consistently in heart failure, and they may counterbalance the vasoconstricting and sodium-retaining actions of the renin-angiotensin-aldosterone and sympathetic nervous systems. It does seem, however, that responses to these natriuretic hormones are downregulated so that they do not have the same diuretic effects in chronic heart failure that they manifest in normal individuals. Elevated circulating and tissue levels of vasodilating prostaglandins may improve glomerular hemodynamics, and inhibitors of prostaglandin synthesis (including aspirin and other nonsteroidal anti-inflammatory agents) interfere with the hemodynamic and renal actions of ACE inhibitors.
Endothelin and arginine vasopressin are elevated in many heart failure patients, and interference with their actions may promote vasodilation and diuresis. Arginine vasopressin induces vasoconstriction through a vascular (V-1) receptor and reduces free water clearance through a renal tubular (V-2) receptor. The endothelins cause prolonged vasoconstriction, reductions in glomerular filtration, mesangial hypertrophy, bronchoconstriction, and pulmonary arteriolar constriction. The endothelins are particularly attractive targets for therapy.
Circulating levels of many proinflammatory cytokines, including tumor necrosis factor-a, interleukin-1ß, and interleukin-6, are elevated in patients with relatively severe heart failure and may be involved in the syndrome of cardiac cachexia. These cytokines also may induce contractile dysfunction, myocardial fibrosis, and myocyte necrosis, perhaps by mediating some of the deleterious responses to catecholamines and angiotensin II.
Altered Renal Physiology
In most patients with chronic heart failure, the kidneys are anatomically and structurally normal. Reduced blood pressure, diminished stroke volume, and reduced renal perfusion pressure and flow are sensed as reduced blood volume by the high-pressure baroreceptors and the juxtaglomerular apparatus that maintain cardiovascular homeostasis. In chronic heart failure, these receptors become desensitized, generating reduced afferent responses. The low-pressure intracardiac pressure and volume receptors also are desensitized. Thirst and fluid

intake may be increased as a result of activation of the cerebral thirst center. Although heart failure usually is associated with a normal or increased blood volume, it paradoxically is characterized by activation of the same homeostatic responses as those to hemorrhage and shock; the result is abnormal retention of sodium and water. In advanced heart failure, usually characterized by low cardiac output and/or hypotension (or with coexisting renal vascular disease), the glomerular filtration rate may become so severely reduced that sodium and fluid retention becomes refractory to diuretic therapy.
Left Ventricular Remodeling and Progression of Heart Failure
After an initial insult precipitates heart failure, progressive alterations occur in myocardial structure and function owing to continuing damage by the underlying process and responses to hemodynamic stresses and neurohormonal activation. The left ventricle progressively dilates and changes from the normal ellipsoid shape to a more spherical geometry. This “remodeling” is accompanied by changes in the cardiac interstitium, leading to altered orientation of the myofibrils and progressive fibrosis. The result is more discoordinate and less effective contraction. ACE inhibitors and ß-blockers slow, halt, or reverse this remodeling process, preventing left ventricular dilation, geometric distortion, and deterioration in contractile function.
Goldman: Cecil Textbook of Medicine, 22nd ed., Copyright © 2004 W. B. Saunders Company

Heart failure may present acutely in a de novo manner, chronically, or as an acute exacerbation of chronic heart failure.
Acute Heart Failure
Acute heart failure usually presents as shortness of breath, culminating, sometimes in a matter of minutes, with pulmonary edema. A more subacute presentation is of progressive dyspnea associated with systemic fluid retention over days to a few weeks. The precipitous form usually suggests extensive acute damage, most commonly as an ongoing or recent MI. Other insults include the acute development of valvular regurgitation from ruptured chordae tendineae, bacterial endocarditis, or aortic dissection or of rapidly progressive myocarditis or toxic damage. The syndrome may progress to cardiogenic shock ( Chapter 103 ).
Rapid diagnosis by noninvasive testing, early cardiac catheterization, and, in some cases, endomyocardial biopsy is crucial. Treatment is cause specific and may include early coronary revascularization, valve repair or replacement, or supportive care (e.g., inotropic support, intra-aortic balloon pumping, ventricular assist devices). If not reversed, cardiac transplantation ( Chapter 80 ) may be the best option for appropriate candidates.
Chronic Heart Failure
Most adult patients with heart failure have abnormalities of the left ventricle as the underlying cause. Nonetheless, the clinical presentation may be variable, sometimes suggesting predominantly or even exclusively right ventricular dysfunction. The manifestations of left ventricular dysfunction are related to elevated filling (diastolic) pressures, which are transmitted backward to the left atrium and pulmonary veins, or inadequate cardiac output. The former results in dyspnea, sometimes at rest but usually with activity, and, when severe, pulmonary edema, classically associated with rales and possibly pleural effusions. The cardiac output may be insufficient to support peripheral organ function, causing exertional muscle fatigue, impaired renal function and salt excretion, or depressed mentation.
Right-sided heart failure results from either chronic right ventricular pressure overload (e.g., pulmonary hypertension resulting from cor pulmonale or pulmonary vascular disease) or intrinsic dysfunction of the right ventricle or its valves. The most common cause of right ventricular pressure overload is left-sided heart dysfunction, however, resulting in pulmonary hypertension. When the symptoms and signs of left-sided heart failure are absent or difficult to elicit, the physician inappropriately may seek a primarily right-sided pathology. The primary manifestations of right-sided failure are related to chronically elevated right atrial and systemic venous pressures: jugular venous distention, peripheral edema, ascites, hepatic and bowel edema, and varied gastrointestinal complaints.
Myocardial mechanisms that lead to the syndrome of heart failure can be differentiated into conditions that depress left ventricular systolic function and conditions that occur despite preserved contractility. Although arbitrary, a left ventricular ejection fraction threshold of 45 to 50% often is employed for this distinction.
Until the widespread use of noninvasive assessments of left ventricular function, heart failure with preserved systolic function was considered unusual in the absence of valvular abnormalities or other specific and uncommon causes. It is now recognized, however, that 20 to 40% of heart failure patients have normal ejection fractions. In the ongoing Cardiovascular Health Study, a population-based study of more than 5000 patients age 65 and older, more than 70% of patients developing heart failure had normal or only mildly impaired systolic function. It is likely that more elderly heart failure patients have diastolic dysfunction as the primary cause of their symptoms.
Although there are many potential causes of heart failure with preserved systolic function, most patients have current hypertension or a history of treated hypertension; the resulting left ventricular hypertrophy and increased fibrosis are probably responsible for increased chamber stiffness. Ischemic heart disease also may contribute to heart failure with preserved systolic function, probably by virtue of subendocardial fibrosis or as a result of acute, intermittent ischemic dysfunction. Diabetes mellitus is often present, especially in women. Age itself is a crucial predisposing factor because it causes loss of myocytes (apoptosis), increased fibrosis with shifts to more rigid forms of collagen, and loss of vascular compliance.
The mortality rates of patients with preserved systolic function are lower than those with low ejection fractions but remain higher than the general population, even in comparison with similarly older aged individuals. Hospitalization and rehospitalization rates for these patients are comparable to rates for patients with reduced ejection fractions, and there are few data on treatment to guide physicians in the management of these patients.
Although heart failure patients with preserved systolic function often are considered to have diastolic dysfunction, there are many other explanations for this presentation, some of which are reversible or warrant specific therapy ( Table 55-4 ). The first two questions are whether the patient’s symptoms are due to heart failure of any type

Inaccurate diagnosis of heart failure (e.g., pulmonary diseases, obesity)
Inaccurate measurements of ejection fraction
Systolic function overestimated by ejection fraction (e.g., mitral regurgitation)
Episodic, unrecognized systolic dysfunction
Intermittent ischemia
Severe hypertension
Diastolic dysfunction
Abnormalities of myocardial relaxation
Abnormalities of myocardial compliance
Infiltrative diseases (amyloidosis, sarcoidosis)
Storage diseases (hemachromatosis)
Endomyocardial diseases (endomyocardial fibrosis, radiation, anthracyclines)
Pericardial diseases (constriction, tamponade)

and whether important valvular abnormalities were missed. Ejection fraction measurements may be inaccurate, particularly when their technical quality is suboptimal. Regurgitant valve diseases may lead to a dissociation between the ejection fraction and underlying myocardial dysfunction because in this setting the afterload may be low. There also are many conditions in which left ventricular function is impaired transiently, but subsequently measured ejection fractions may be normal; intermittent ischemia, presenting as episodic heart failure (“flash pulmonary edema”) is the most important because revascularization may be indicated. Severe hypertension with subsequent treatment and transient arrhythmias also may have temporary effects on ejection fraction. Some patients with alcoholic cardiomyopathy may exhibit rapid recovery in ejection fraction when they cease drinking.
The remaining patients most likely have diastolic dysfunction as the underlying disorder. The noninvasive measurement of diastolic function remains problematic. The most common test used, Doppler echocardiography, is neither sensitive nor specific for diastolic dysfunction. Particularly in the elderly, Doppler mitral valve filling patterns show impaired early diastolic filling in most subjects, whether or not they have evidence of heart failure. Diastolic dysfunction is basically a diagnosis of exclusion based on accompanying conditions and circumstantial evidence.
Many patients with chronic heart failure maintain a stable course, then abruptly present with acutely or subacutely worsening symptoms. Although this decompensation may reflect unrecognized gradual progression of the underlying disorder, many precipitating events must be considered and, if present, addressed ( Table 55-5 ). An important focus is on changes in medications (by patient or physician), diet, or activity. Superimposed new or altered cardiovascular conditions, such as arrhythmias, ischemic events, hypertension, or valvular abnormalities, should be considered. Systemic processes, such as fever, infection, or anemia, also may cause cardiac decompensation.
Goldman: Cecil Textbook of Medicine, 22nd ed., Copyright © 2004 W. B. Saunders Company

Symptoms of Heart Failure
The common symptoms of heart failure are well known but are frequently absent and variably specific for this condition. The symptoms generally reflect, but may be dissociated from, the hemodynamic derangements of elevated left-sided and right-sided pressures and impaired cardiac output or cardiac output reserve.
Dyspnea, or perceived shortness of breath, is the most common symptom of patients with heart failure. In most patients, dyspnea is

Discontinuation of therapy (patient noncompliance or physician initiated)
Initiation of medications that worsen heart failure (calcium antagonists, ß-blockers, nonsteroidal anti-inflammatory drugs, antiarrhythmic agents)
Iatrogenic volume overload (transfusion, fluid administration)
Dietary indiscretion
Alcohol consumption
Increased activity
Exposure to high altitude
Myocardial ischemia or infarction
Worsening hypertension
Worsening mitral or tricuspid regurgitation
Fever or infection
present only with activity or exertion. The underlying mechanisms are multifactorial. The most important is pulmonary congestion with increased interstitial or intra-alveolar fluid, which activates juxtacapillary J receptors, which stimulate a rapid and shallow pattern of breathing. Increased lung stiffness may enhance the work of breathing, leading to a perception of dyspnea. Central regulation of respiration may be disturbed in more severe heart failure, resulting in disordered sleep patterns and sleep apnea. Cheyne-Stokes respiration, or periodic breathing, is common in advanced heart failure, is usually associated with low output states, and may be perceived by the patient (and the patient’s family) as either severe dyspnea or transient cessation of breathing. Hypoxia, which is uncommon in heart failure patients unless there is accompanying pulmonary disease, suggests the presence of pulmonary edema. Dyspnea is a relatively sensitive symptom of heart failure, provided that a careful history is taken of the patient’s level of activity, but dyspnea may become less prominent with the onset of right ventricular failure and tricuspid regurgitation, which may lead to lower pulmonary venous pressures. Dyspnea is a common symptom of patients with pulmonary disease, obesity, and anemia and of sedentary individuals.
Orthopnea is dyspnea that is positional, occurring in the recumbent or semirecumbent position. It occurs as a result of the increase in venous return from the extremities and splanchnic circulation to central circulation with changes in posture, with resultant increases in pulmonary venous pressures and pulmonary capillary hydrostatic pressure. Nocturnal cough may be a manifestation of this process and is an underrecognized symptom of heart failure. Orthopnea is a relatively specific symptom of heart failure, although it may occur in patients with pulmonary disease who breathe more effectively in an upright posture and in individuals with significant abdominal obesity or ascites. Most patients with mild or moderate heart failure do not experience orthopnea, however, when they are treated adequately.
Paroxysmal nocturnal dyspnea is an attack of acute, severe shortness of breath awakening the patient from sleep, usually 1 to 3 hours after the patient retires. Symptoms usually resolve over 10 to 30 minutes after the patient arises, often gasping for fresh air from an open window. Paroxysmal nocturnal dyspnea results from increased venous return and mobilization of interstitial fluid from the extremities and elsewhere, with accumulation of alveolar edema. Paroxysmal nocturnal dyspnea almost always represents heart failure, but it is a relatively uncommon finding.
Pulmonary edema results from transudation of fluid into the alveolar spaces as a result of acute rises in capillary hydrostatic pressures owing to an acute depression of cardiac function or to an acute rise in intravascular volume. The initial symptoms may be cough or progressive dyspnea. Because alveolar edema may precipitate bronchospasm, wheezing is common. If the edema is not treated, the patient may begin coughing up pink (or blood-tinged), frothy fluid and become cyanotic and acidotic.
Activity or exercise intolerance is, together with dyspnea, the most characteristic symptom of chronic heart failure. Intuitively, it might be assumed that exercise would be limited by shortness of breath because of rising pulmonary venous pressures and pulmonary congestion. Although this mechanism may contribute, it is only one of many operating. Blood flow to exercising muscles is impaired, as a result of reduced cardiac output reserve and impaired peripheral vasodilation; oxygen delivery is limited, and early fatigue ensues. Heart failure is associated with additional abnormalities of skeletal muscle itself, including biochemical changes and alterations in fiber types, which increase muscle fatigue and impair muscle function. Finally, heart failure may affect adversely respiratory muscle function and ventilatory control.
Fatigue is a common, if nonspecific, complaint of patients with heart failure. Perhaps the most common origin of this complaint is

muscle fatigue. Fatigue also may be a nonspecific response to the systemic manifestations of heart failure, such as chronic increases in catecholamines and circulating levels of cytokines, sleep disorders, and anxiety.
Elevated right atrial pressures increase the capillary hydrostatic pressures in the systemic circulation, with resultant transudation. The location of edema fluid is determined by position (e.g., dependent) and accompanying pathology. Most commonly, edema accumulates in the extremities and resolves at night when the legs are not dependent. Edema may occur only in the feet and ankles, but if it is more severe, it may accumulate in the thighs, scrotum, and abdominal wall. Edema is more likely and more severe in patients with accompanying venous disease (or who have had veins harvested for coronary bypass surgery) and patients on calcium channel blockers, which themselves cause edema.
Fluid also may accumulate in the peritoneal cavity and in the pleural or pericardial space. Ascites occurs as a result of elevated pressures in the hepatic, portal, and systemic veins draining the peritoneum. Ascites is unusual in heart failure and almost always is associated with peripheral edema. Most commonly, there is severe tricuspid regurgitation, with potential damage to the liver. Otherwise, significant primary liver disease should be suspected as an exacerbating factor or cause of ascites. Pleural effusions are fairly common in chronic heart failure, especially when they are accompanied by left-sided and right-sided manifestations. The effusions result from an increase in transudation of fluid into the pleural space and impaired lymphatic drainage owing to elevated systemic venous pressures. Pericardial effusions are far less frequent but may occur.
Passive congestion of the liver may lead to right upper quadrant pain and tenderness and mild jaundice. Usually only mild elevations of transaminase levels and modest increases in bilirubin levels are observed. With severe, acute rises in central venous pressures, especially when associated with systemic hypotension, a severe congestive and ischemic hepatopathy may occur with striking elevations in liver function tests and hypoglycemia. Recovery is usually rapid and complete if the hemodynamic abnormalities are corrected.
Bowel wall edema may lead to early satiety (a common symptom in heart failure), nausea, diffuse abdominal discomfort, malabsorption, and a rare form of protein-losing enteropathy. The potential role of heart failure in producing these nonspecific gastrointestinal symptoms is often overlooked, leading to extensive diagnostic testing or unnecessary discontinuation of medications.
Periods of nocturnal oxygen desaturation to less than 80 to 85% are relatively common in patients with heart failure, coincide with episodes of apnea, and often are preceded or followed by episodes of hyperventilation. These are similar to, and may represent truncated forms of, Cheyne-Stokes respiration. These episodes reflect altered central nervous system ventilatory control and have been associated with diminished heart rate variability. Supplemental oxygen seems to reverse some of the ventilatory disorders, and the apneic spells respond to nasal positive-pressure ventilation. In some patients, these interventions may have a striking beneficial effect on fatigue and other symptoms of heart failure.
Aside from the common complaint of fatigue, which may be in part central nervous system in origin, brain function is not affected in most patients with heart failure. In advanced heart failure, cerebral hypoperfusion may cause impairment of memory, irritability, limited attention span, and altered mentation.
In chronic, severe heart failure, unintentional chronic weight loss may occur, leading to a syndrome of cardiac cachexia. The cause of this syndrome is unclear, but it may result from many factors, including elevated levels of proinflammatory cytokines (e.g., tumor necrosis factor), elevated metabolic rates, loss of appetite, and malabsorption. Cardiac cachexia carries a poor prognosis.
Physical Findings
The physical findings associated with heart failure generally reflect elevated ventricular filling pressures and, to a lesser extent, reduced cardiac output. In chronic heart failure, many of these findings are absent, often obscuring the correct diagnosis.
Compensated patients may be comfortable, but patients with more severe symptoms are often restless, dyspneic, and pale or diaphoretic. Although the heart rate is usually at the high end of the normal range or above (>80 beats per minute), it may be lower in chronic, stable patients. Premature beats or arrhythmias are common. Pulsus alternans (alternating amplitude of successive beats) is a sign of advanced heart failure (or a large pericardial effusion). The blood pressure may be normal or high, but in advanced heart failure it is usually on the low end of normal or below.
Examination of the jugular veins is one of the most useful aspects of the evaluation of heart failure patients. The jugular venous pressure should be quantified in centimeters of water (normal =8 cm) estimating the level of pulsations above the sternal angle (and arbitrarily adding 5 cm in any posture). The presence of abdominal-jugular reflux should be assessed by putting pressure on the right upper quadrant of the abdomen for 30 seconds and avoiding an induced Valsalva maneuver; a positive finding is a rise in the jugular pressure of at least 1 cm. Either an elevated jugular venous pressure or an abnormal abdominal-jugular reflux has been reported in 80% of patients with advanced heart failure. No other simple sign is nearly as sensitive.
An additional important finding in the neck is evidence of tricuspid regurgitation—a large cv wave, usually associated with a high jugular venous pressure. This finding is confirmed by hepatic pulsations, which can be detected during the abdominal-jugular reflux determination. The carotid pulses should be evaluated for evidence of aortic stenosis, and thyroid abnormalities should be sought.
Although dyspnea is the most common symptom of patients with heart failure, the pulmonary examination is usually unremarkable. Rales, representing alveolar fluid, are a hallmark of heart failure; when present in patients without accompanying pulmonary disease, they are highly specific for the diagnosis. In chronic heart failure, they are usually absent, however, even in patients known to have pulmonary capillary wedge pressures greater than 20 mm Hg (normal (<12 mm Hg). Left ventricular failure cannot be excluded by the absence of rales. Pleural effusions, which are indicative of bilateral heart failure in patients with appropriate symptoms, are relatively rare.
The cardiac examination is a crucial part of the evaluation of the patient with heart failure, but more for identification of associated cardiac abnormalities than the assessment of its severity ( Chapter 46 ). Assessment of the point of maximal impulse may provide information concerning the size of the heart (enlarged if displaced below the fifth intercostal space or lateral to the midclavicular line) and its function (if sustained beyond one third of systole or palpable over two interspaces). Additional precordial pulsations may indicate a left ventricular aneurysm. A parasternal lift is valuable evidence of pulmonary hypertension.
The first heart sound (S1 ) may be diminished in amplitude when left ventricular function is poor, and the pulmonic component of the second heart sound (P2 ) may be accentuated when pulmonary hypertension is present. An apical third heart sound (S3 ) is a strong indicator of significant left ventricular dysfunction but is present only in a few patients with low ejection fractions and elevated left ventricular filling pressures. A fourth heart sound (S4 ) is not a specific

indicator of heart failure, but it is usually present in patients with diastolic dysfunction. An S3 at the lower left or right sternal border or below the xiphoid indicates right ventricular dysfunction. Murmurs may indicate the presence of significant valvular disease as the cause of heart failure, but mitral and tricuspid regurgitation also are common secondary manifestations of severe ventricular dilation and dysfunction.
The size, pulsatility, and tenderness of the liver should be evaluated as evidence of passive congestion and tricuspid regurgitation. Ascites and edema should be sought and quantified.
The diagnosis of heart failure is straightforward when a patient presents with classic symptoms and accompanying physical findings. In patients with chronic heart failure, however, the diagnosis is often delayed or missed entirely because no single sign or symptom is diagnostic ( Table 55-6 ).
The most frequent symptoms, dyspnea and fatigue, are not specific for heart failure, especially in the older population, although their presence always should lead to a more complete evaluation. The more specific symptoms of orthopnea, paroxysmal nocturnal dyspnea, and edema are much less common. Although the physical examination may be helpful, characteristic physical findings may be absent. The chest radiograph, on which many physicians rely, adds relatively little to the clinical evaluation.
The key to making the timely diagnosis of chronic heart failure is to maintain a high degree of suspicion, particularly in high-risk patients (patients with coronary artery disease, chronic hypertension, diabetes, histories of heavy alcohol use, and advanced age). When these patients present with any of the symptoms or physical findings suggestive of heart failure, additional testing (see later) should be undertaken, generally beginning with echocardiography.
Although the standard posteroanterior and lateral chest radiograph provides limited information about chamber size, the presence of overall cardiomegaly (a cardiothoracic ratio >0.50 and especially >0.60) is a strong indicator of heart failure or another cause of cardiomegaly (especially valvular insufficiency) ( Chapter 49 ). Nearly

Exertional dyspnea
Paroxysmal nocturnal dyspnea
History of edema
Resting heart rate >100 beats/min
Third heart sound
Jugular venous distention†
Edema (on examination)
Adapted from Harlan WR, et al: Chronic congestive heart failure in coronary artery disease: Clinical criteria. Ann Intern Med 1977;86:133–138.

*See Chapter 6 for definitions.
†Reported to have much higher sensitivity (57%) and predictive accuracy (67%) at rest and better sensitivity (81%) and predictive accuracy (81%) with abdominal jugular reflux in another series (Butman SM, et al: Bedside cardiovascular examination in patients with severe chronic heart failure: Importance of direct or inducible jugular venous distention. J Am Coll Cardiol 1993;22:968–974).
50% of heart failure patients do not have this high a cardiothoracic ratio, however.
Most patients with acute heart failure, but only a few with chronic heart failure, have evidence of pulmonary venous hypertension (upper lobe redistribution, enlarged pulmonary veins) or interstitial (haziness of the central vascular shadows or increased central interstitial lung markings) or pulmonary (perihilar or patchy peripheral infiltrates) edema. The absence of these findings reflects the subjectivity of interpretation and the increased capacity of the lymphatics to remove interstitial and alveolar fluid in chronic heart failure. This absence of radiographic findings is consistent with the absence of rales in most patients with chronic heart failure despite markedly elevated pulmonary venous pressures. Pleural effusions are important adjunctive evidence of heart failure. Characteristically these are more common and larger on the right than left side, reflecting the greater pleural surface area of the right lung.
The major importance of the electrocardiogram is to evaluate cardiac rhythm, identify prior MI, and detect evidence of left ventricular hypertrophy ( Chapter 50 ). Prior MIs suggest that the cause is ischemic cardiomyopathy with systolic dysfunction. Left ventricular hypertrophy is a nonspecific finding but may point toward left ventricular diastolic dysfunction if the ejection fraction is not depressed.
Noninvasive cardiac imaging is a crucial part of the diagnosis and evaluation of heart failure. The most useful procedure is the transthoracic echocardiogram ( Chapter 51 ), which provides a quantitative assessment of left ventricular function and can confirm, in the presence of appropriate symptoms and signs, the presence of heart failure owing to systolic dysfunction or indicate whether the patient has heart failure with preserved systolic function. The echocardiogram also provides a wealth of additional valuable information, including assessment of left and right ventricular size, regional wall motion (as an indicator of prior MI), evaluation of the heart valves, and diagnosis of left ventricular hypertrophy. The echocardiogram generally has replaced the chest radiograph in the diagnostic assessment of heart failure.
Serum levels of natriuretic peptides can be measured quickly and accurately, including point-of-care testing at the bedside. B-type natriuretic peptide and N-terminal pro-B natriuretic peptide are relatively sensitive and specific markers of clinically confirmed heart failure, whether secondary to left ventricular systolic or diastolic dysfunction. These peptides also seem to be useful adjuncts in the diagnosis of patients presenting with possible heart failure, although further experience is required to define their appropriate use. Levels also increase with age, especially in women, and may be elevated slightly in patients with chronic obstructive pulmonary disease. These elevations may reflect diastolic dysfunction or right ventricular dysfunction but nonetheless may lead to a false-positive clinical diagnosis of heart failure. Serial natriuretic peptide measurements seem to be helpful in assessing the response to therapy, in guiding the management of individual patients, and in assessing prognosis.
Although it is not difficult to make the definitive diagnosis of heart failure in a patient presenting with the classic symptoms and signs, several alternative diagnoses need to be considered in less clear-cut situations, such as in the patient with normal left ventricular function and less definitive clinical evidence. The most important differentiation is between heart failure and pulmonary disease. In this setting, pulmonary function testing or additional tests to characterize lung pathology may be helpful. When left ventricular systolic function is normal, it sometimes may be difficult to make a conclusive determination of the relative role of heart failure compared with other concomitant conditions, such as severe obesity, chronic anemia, or other systemic illnesses; in some patients, a therapeutic trial ( Chapter 56 ) may be diagnostic.
Goldman: Cecil Textbook of Medicine, 22nd ed., Copyright © 2004 W. B. Saunders Company

When the diagnosis of heart failure is made, the goal of additional testing is to identify potentially correctable or specifically treatable cases and to obtain further information necessary for future management.
Routine Diagnostic Assessment

An extensive battery of laboratory tests is not required for most patients with heart failure. Routine testing should include a complete blood cell count (to detect anemia and systemic diseases with hematologic manifestations), measurement of renal function and electrolytes including magnesium (to exclude renal failure and to provide a baseline for subsequent therapy), liver function tests (to exclude accompanying liver pathology and provide a baseline), and blood glucose and lipid testing (to diagnose diabetes and dyslipidemia, both of which should be managed aggressively in heart failure patients).
A few additional tests may be indicated. Thyrotoxicosis, and to a lesser extent hypothyroidism, may cause heart failure and may be difficult to diagnose clinically, especially in older patients ( Chapter 239 ). Many guidelines recommend thyroid function tests in all patients, or at least in elderly patients and patients with atrial fibrillation. Hemochromatosis ( Chapter 225 ) is a potentially treatable cause of heart failure; particularly if there is accompanying diabetes or hepatic disease, serum ferritin levels are indicated. Sarcoidosis ( Chapter 91 ) is another potentially treatable cause, although it would be unusual not to have evidence of accompanying lung disease. Amyloidosis ( Chapter 290 ) should be considered in patients with other manifestations, but treatment of the cardiac manifestations is rarely successful except with heart transplantation.
Although heart failure is a syndrome with many pathogenic mechanisms, the most common are left ventricular systolic dysfunction and left ventricular diastolic dysfunction. In some patients, it may be nearly impossible to distinguish between these two forms of heart failure by clinical evaluation because both may present with the same symptoms and with only subtle differences on physical examination. It is essential to distinguish between these two entities, however, because they may require different diagnostic evaluations and different therapeutic approaches ( Chapter 56 ). The most useful and practical test is the echocardiogram ( Chapter 51 ); alternative approaches include radionuclide measurements of ejection fraction ( Chapter 52 ) and left ventriculography if cardiac catheterization ( Chapter 54 ) is being performed. All these tests allow the detection of significant systolic dysfunction; diastolic dysfunction sometimes can be documented ( Chapter 51 ) but often is identified primarily as a process of exclusion in patients with preserved systolic function.
Additional Diagnostic Evaluation
Coronary artery disease is the most common cause of heart failure in industrialized societies. Although it often is known whether a patient has coronary disease based on a prior history of MI or positive results in an angiogram or noninvasive test, in some patients it may be silent. There are two reasons to identify the coexistence of heart failure and coronary disease: first, to treat symptoms that may be due to ischemia and, second, to improve prognosis ( Chapter 67 , Chapter 68 , and Chapter 69 ). A prudent approach is to subdivide heart failure patients into three groups: (1) patients with clinical evidence of ongoing ischemia (active angina or a possible ischemic equivalent), (2) patients who have had a prior MI but do not currently have angina, and (3) patients who may or may not have underlying coronary disease. The first group of patients may be evaluated most expeditiously by coronary angiography because they stand to benefit in terms of symptoms and probably have more extensive ischemia. In the second group are patients with heart failure and prior MI who by other criteria (age, absence of other major comorbid conditions) are otherwise good candidates for coronary revascularization; they generally should undergo noninvasive stress testing in conjunction with nuclear myocardial perfusion imaging or echocardiography. These procedures identify individuals with extensive ischemic but viable myocardium, whose prognosis and symptoms also may be improved with revascularization. The third group, patients without either angina or prior MI, are much less likely to benefit from an evaluation for asymptomatic coronary disease.
There is no rationale for routine myocardial biopsy in patients with heart failure, even in the subgroup without apparent coronary disease. Few entities that might be detected are amenable to specific therapy, and those that are (hemochromatosis, sarcoidosis) usually can be detected by their other manifestations or other procedures. A possible exception is acute fulminant myocarditis ( Chapter 73 ), particularly eosinophilic and giant cell myocarditis, which may respond to immunosuppressive therapy. Another potential exception is the patient being evaluated for cardiac transplantation ( Chapter 80 ) because the presence of some entities may preclude this procedure.
Quantitative assessment of exercise capacity provides additional insight into prognosis over the clinical evaluation and measurements of cardiac function, particularly when a detailed history of activity tolerance cannot be obtained. Exercise testing with measurements of peak oxygen uptake by respiratory gas exchange has become a routine part of the transplant evaluation ( Chapter 80 ) because it provides an indication of need for early intervention and an additional method for follow-up. In most patients, testing is not necessary, however. Emphasis should be placed on eliciting each patient’s maximum tolerated activity and the minimum activity associated with symptoms; both can be followed from visit to visit, as a guide to management.
Ventricular arrhythmias are extremely common in patients with chronic heart failure, with 50 to 80% of patients exhibiting nonsustained ventricular tachycardia during 24-hour monitoring. Because approximately 50% of cardiac deaths in these patients are sudden, these arrhythmias have been viewed with concern. In multivariate analyses, asymptomatic ventricular arrhythmias carry little independent prognostic significance when the severity of symptoms, ejection fraction, and presence of concurrent coronary disease are taken into account. Arrhythmias are no more predictive of sudden death than of total mortality. Further evaluation of asymptomatic arrhythmias is not warranted. In contrast, ventricular arrhythmias associated with syncope or hemodynamic compromise must be taken seriously and require further evaluation and treatment ( Chapter 52 ).
Follow-Up Evaluation
After the diagnosis of heart failure is confirmed and the initial evaluation is complete, there is little need for further testing beyond the laboratory tests (primarily renal function and electrolytes) necessary to monitor therapy. When the status of ventricular function is known, there are few indications for retesting. Exceptions are monitoring for transplantation and important changes in clinical status (e.g., marked deterioration in a patient previously known to have preserved left ventricular function, occurrence of new murmurs in conjunction with declining status).
Instead the key to successful follow-up is the careful tracking of clinical symptoms and patient weights, which often involves interviewing not only the patient, but also family members, who may be more aware of changes in status than the patient. Continuity of care and seamless transitions from the inpatient to outpatient setting are crucial aspects of optimal management. Patients with advanced heart failure and patients requiring frequent hospitalization require special handling. Programs that provide telephone-based tracking of daily weights and symptoms can detect deterioration in time to intervene before the need for hospitalization. Although these programs may be costly, several evaluations have found them to be cost-effective. Because the management of these patients requires considerable experience and expertise, specialized heart failure programs and clinics have been developed and may provide additional benefit compared with traditional care.
Goldman: Cecil Textbook of Medicine, 22nd ed., Copyright © 2004 W. B. Saunders Company

Milton Packer
The cardinal manifestations of heart failure ( Chapter 55 ) are (1) dyspnea and fatigue, which may limit exercise tolerance, and (2) fluid retention, which may lead to pulmonary and peripheral edema. Both abnormalities can impair the functional capacity and quality of life of affected individuals. In addition, by its very nature, heart failure is a progressive disorder. With time, the functional limitations imposed by the disease become increasingly apparent, and eventually patients experience symptoms at rest or on minimal exertion. This progression is directly related to the inexorable deterioration of cardiac structure and function, which can occur without any recurrence of the initial injury to the heart. Once initiated, heart failure advances (often silently) and leads inevitably to a recurrent need for medical care and hospitalization and, finally, to the death of the patient.
Goldman: Cecil Textbook of Medicine, 22nd ed., Copyright © 2004 W. B. Saunders Company

Approach to the Patient with Heart Failure
The primary step in the management of heart failure is to identify and characterize the nature of the underlying cardiac disorder. A careful history may reveal the past occurrence of a myocardial infarction (MI) ( Chapter 69 ), valvular disease ( Chapter 72 ), hypertension ( Chapter 63 ), myocarditis ( Chapter 73 ), thyroid disease ( Chapter 239 ), or the ingestion of cardiotoxic substances. Direct inquiry may also identify any associated disorders (e.g., anemia, arrhythmias, ischemia, or renal dysfunction) or concomitant medications (e.g., calcium channel blockers, antiarrhythmic drugs, and nonsteroidal anti-inflammatory drugs) that can exacerbate the syndrome of heart failure or complicate its management. The physical examination may indicate the presence of cardiac enlargement, valvular disorders, or congenital heart disease ( Chapter 65 ) or evidence of a systemic disease that may lead to or contribute to heart failure.
Although the history and physical examination may provide important clues about the nature of the underlying cardiac abnormality, such information may occasionally be misleading, because patients with risk factors for one specific cause of heart failure may prove to have an unrelated cardiac disorder. Hence, regardless of the clinical impressions formed during the initial evaluation, the physician should define the precise nature of the underlying disorder by performing an invasive or a noninvasive imaging test of the cardiac chambers. The most useful diagnostic test is the two-dimensional Doppler flow echocardiogram. This test allows the physician to determine if the primary abnormality is pericardial, myocardial, valvular, or vascular and, if it is myocardial, whether the dysfunction is primarily systolic or diastolic ( Chapter 55 ). This distinction is critical, because surgery is the primary approach to the management of most pericardial, valvular, or vascular disorders, whereas pharmacologic strategies are the primary approaches to the management of myocardial disorders.
The focus in this chapter is on the management of patients with left ventricular systolic dysfunction, which is the cause of heart failure in 70% of patients presenting with the syndrome. The management of patients with a hypertrophic cardiomyopathy ( Chapter 73 ) or with disorders of the pericardium ( Chapter 74 ), valves ( Chapter 72 ), or great vessels ( Chapter 75 ) is discussed in the chapters specifically devoted to these topics.
There are four distinct phases in the evolution of heart failure ( Fig. 56-1 ): (1) the initial cardiac injury, (2) neurohormonal activation and cardiac remodeling, (3) fluid retention and peripheral vasoconstriction, and (4) contractile failure.
A variety of disorders can injure the myocardium and lead to systolic dysfunction. About two thirds of patients with systolic dysfunction have coronary artery disease; in these patients, the occurrence of an acute MI is usually the injurious event that triggers the decline in ejection fraction. These patients characteristically show regional abnormalities of wall motion in the myocardial segments that are perfused by the obstructed coronary arteries,
Figure 56-1 Mechanisms contributing to the development of heart failure at each stage of the disease. This diagram should be used in conjunction with Figure 56-2 ; see text for details. The classes designated at the top of the page refer to the functional classification developed by the New York Heart Association. According to this classification system, patients may have symptoms at rest (class IV), on less than ordinary exertion (class III), on ordinary exertion (class II), or only at levels that would cause symptoms in normal individuals (class I).
and the left ventricle is typically more severely affected than the right. In the remaining third of patients, the coronary vessels appear normal; the ventricle is globally (rather than regionally) hypokinetic; and the right and left ventricles are generally affected to a similar degree. The source of myocardial injury in patients with a nonischemic cardiomyopathy may be a prior infection (e.g., myocarditis), exposure to a cardiac toxin (e.g., alcohol, cocaine, or cancer chemotherapeutic agent), or a systemic disorder (e.g., hypothyroidism or hyperthyroidism). However, no cause of myocardial injury may be found; such patients are considered to have idiopathic dilated cardiomyopathy.
Is it important to identify the cause of myocardial injury in a patient with systolic dysfunction due to a cardiomyopathy? Coronary arteriography and noninvasive imaging studies can indicate the presence and functional consequences of coronary artery disease, and myocardial biopsy may identify the presence of inflammatory or infiltrative disorders of the heart. Yet, it remains unclear how the information generated by these tests should be used. There is little evidence that anti-ischemic interventions can improve clinical outcomes in patients who have heart failure due to advanced systolic dysfunction but who do not have angina, and most infiltrative or inflammatory disorders are not reversible. Indeed, most treatable causes of myocardial injury can be identified by history or by simple blood tests (e.g., thyroid function tests).
Regardless of the source of myocardial injury, once a critical mass of the left ventricle is injured, heart failure becomes a progressive, self-reinforcing process, regardless of whether the initial insult recurs or is adequately treated. The principal manifestation of such progression is a change in the geometry of the left ventricle such that the chamber enlarges and becomes more spherical; this process is termed cardiac remodeling. This change in chamber size not only increases the hemodynamic stresses on the walls of the failing heart and depresses its performance but also increases the magnitude of regurgitant flow through the mitral and tricuspid valves. These effects in turn serve to sustain and exacerbate the remodeling process, leading to a progressive decline in the left ventricular ejection fraction. Remodeling is an essential step in the transition from the initial cardiac injury to asymptomatic ventricular dysfunction to symptomatic heart failure.
What factors are responsible for, or accelerate, the process of left ventricular remodeling? Although many mechanisms may be involved, there is substantial evidence that the activation of endogenous neurohormonal systems ( Chapter 55 ) plays a critical role in cardiac remodeling and thereby in the progression of heart failure. These systems are activated early after an acute myocardial injury, and their activity is progressively enhanced as the disorder advances. Elevated circulating or tissue levels of norepinephrine and angiotensin II can act, alone or in concert, to affect adversely the structure and function of

the failing heart. These neurohormonal factors not only increase the hemodynamic stresses on the heart by causing peripheral vasoconstriction but also may exert a direct toxic effect on the heart by causing myocytes to undergo a process of programmed cell death (apoptosis). Neurohormonal factors can also stimulate the process of myocardial fibrosis, which can further alter the architecture and impair the performance of the failing heart. Interestingly, the initial activation of neurohormonal systems and cardiac remodeling that follows a myocardial injury is commonly asymptomatic. Although the ejection fraction is depressed and may further deteriorate, the patient commonly shows no evidence of symptoms or fluid retention for long periods of time. This is the phase referred to as asymptomatic left ventricular dysfunction.
As the process of physiologic deterioration continues, the activation of neurohormonal systems not only adversely affects the heart but also begins to exert a deleterious effect on the kidneys and peripheral blood vessels. The sympathetic nervous system and renin-angiotensin system act on the kidneys to retain sodium and water and act on peripheral blood vessels to cause vasoconstriction. Both of these mechanisms increase the loading conditions in the failing heart, which can in turn lead to symptoms of pulmonary congestion and exercise intolerance—a phase termed chronic heart failure. As cardiac function deteriorates, hemodynamic factors can exacerbate the functional derangements of the kidneys and peripheral vessels produced by neurohormonal systems. A decline in renal blood flow impairs the ability of the kidneys to excrete salt and water, and an increase in the sodium content of peripheral vessels can impair their dilatory capacity. Similarly, a decline in regional blood flow can attenuate the physiologic actions of endogenous natriuretic peptides that normally counteract vasoconstrictor mechanisms. Over time, the interplay of hemodynamic and neurohormonal factors leads to worsening of symptoms and a deterioration of clinical status, often with little additional decrease in the left ventricular ejection fraction.
As the process that causes heart failure progresses, the myocardium eventually loses a critical mass of functioning myocytes and no longer can sustain forward flow and peripheral perfusion. Despite the decline in cardiac performance, the patient survives because the inotropic and vasoconstrictor effects of the sympathetic nervous system and the renin-angiotensin system act to support cardiac contractility and systemic pressures, at least in the short term. The renal retention of salt and water is intense, but the resulting expansion of intravascular volume fails to support the circulation and acts only to exacerbate pulmonary and peripheral congestion. This precarious state cannot be sustained; the threat to the circulation is so immediate that the patient can be stabilized only by intensive medical care in a hospital. The phase of contractile failure frequently characterizes the terminal stages of the disorder.
The evolution through these four stages of heart failure may occur slowly or rapidly, with the rate of progression being determined by the severity of the initial cardiac injury and the intensity of neurohormonal activation. Death may occur during any of the four phases, although it is commonly sudden in patients with minimal or mild symptoms and is usually related to pump failure in patients with advanced symptoms.
Each of the four phases of heart failure requires a specific therapeutic approach ( Fig. 56-2 ). For patients who have not yet experienced an initial cardiac insult, every effort should be made to minimize the occurrence and impact of diseases that can injure the heart. For patients who have developed left ventricular dysfunction but remain asymptomatic, physicians should interfere with the neurohormonal systems that can cause cardiac remodeling and lead to the development of clinical heart failure. For patients who have developed symptoms, the primary goals are to alleviate fluid retention, lessen disability, and reduce the risk of further progression and death. These goals generally require a strategy that combines diuretics (to control salt and water retention) with neurohormonal interventions (to minimize the deleterious effects of the sympathetic nervous system and renin-angiotensin system) and that frequently adds hemodynamic interventions (to enhance cardiac performance and reduce peripheral vasoconstriction). Finally, for patients hospitalized with immediately life-threatening heart failure, the principal objectives are to stabilize the precarious state of the circulation and to maintain end-organ
Figure 56-2 Treatment strategies appropriate to each stage of heart failure. This diagram should be used in conjunction with Figure 56-1 ; see text for details. The classes designated at the top of the page refer to the functional classification developed by the New York Heart Association (see legend to Fig. 56-1 ). ACE = angiotensin-converting enzyme.
function until precipitating factors have resolved or until a definitive solution can be formulated to treat the underlying disease. Such patients generally require intensive hemodynamic or mechanical support ( Chapter 103 ). These observations suggest that neurohormonal mechanisms are dominant in the early phases of heart failure, whereas hemodynamic mechanisms play an increasingly critical role as the disease advances to its terminal phase.
Both neurohormonal and hemodynamic interventions can improve the performance of the failing heart, but they do so in distinct ways. On the one hand, drugs can increase ejection fraction by directly stimulating the contractility of individual myocyte cells. This approach (used by positive inotropic agents) can produce immediate hemodynamic benefits but may exacerbate the deleterious actions of neurohormonal systems and thereby the process of cardiac remodeling. As a result, positive inotropic agents may be useful in the short-term management of patients hospitalized with immediately life-threatening disease, but long-term treatment with these agents may increase morbidity and mortality. On the other hand, drugs can increase ejection fraction by antagonizing the neurohormonal activation that can impair the function and viability of cardiac cells. This approach (used by angiotensin-converting enzyme [ACE] inhibitors and ß-adrenergic receptor blockers) can slow the progression of heart failure and reduce the risk of major cardiac events in patients with asymptomatic left ventricular dysfunction or established symptoms of heart failure. However, in patients with end-stage disease, neurohormonal antagonists can undermine the homeostatic mechanisms that are critical for the support of cardiac contractility and systemic pressures. These observations indicate that the treatment of heart failure should be targeted to the mechanisms that drive the disease process during each phase of the disorder.
Prevention of Heart Failure
Heart failure can be prevented by decreasing the risk of the initial cardiac injury or, if the injury has already occurred, by decreasing the early and continuing loss of myocardium. Specific interventions can alter the development and progression of heart failure during each phase of the disease ( Fig. 56-3 ).
The treatment of hyperlipidemia and hypertension in high-risk patients can reduce the risk of MI and, as a result, the likelihood of developing heart failure. In patients with hypercholesterolemia and a history of angina or MI, treatment with a lipid-lowering agent has been shown to decrease the risk of heart failure and of death ( Chapter 67 and Chapter 69 ). In patients with systolic or diastolic hypertension, antihypertensive therapy

Figure 56-3 Sequence of steps in the evolution and progression of heart failure. Also identified are interventions that have been shown to inhibit each step in the process and thus can favorably affect the natural history of the disease. ACE = angiotensin-converting enzyme.
decreases the risk of stroke and of heart failure ( Chapter 63 ); these benefits are particularly marked in patients with a previous MI.
The aggressive treatment of patients during an acute MI can reduce the extent of the initial myocardial injury. In patients who are experiencing an acute MI, reperfusion with percutaneous transluminal coronary angioplasty and thrombolytic agents can minimize the loss of myocardium and can thereby reduce the risk of developing subsequent heart failure in patients with an uncomplicated MI and decrease the risk of death in patients whose MI is complicated by heart failure ( Chapter 69 ).
Furthermore, the aggressive treatment of patients after an acute MI can reduce the extension of the initial injury to other segments of the myocardium. In patients with a recent MI, treatment with a ß-blocker reduces the risk of reinfarction and of death, especially in those with left ventricular dysfunction or heart failure at the start of treatment ( Chapter 69 ). Similarly, use of an ACE inhibitor in patients with a recent MI reduces the risk of reinfarction, heart failure, and death, especially in those with left ventricular dysfunction at the start of treatment. Combined neurohormonal blockade (ACE inhibitors and ß-blockers) may produce complementary benefits. Finally, in patients with established ischemic or nonischemic left ventricular systolic dysfunction (ejection fraction, <35 to 40%) with no or minimal symptoms of heart failure, treatment with an ACE inhibitor can reduce the risk of developing heart failure.
Outpatient Treatment of Heart Failure
The goals of outpatient management of patients with symptoms of heart failure due to systolic dysfunction of the left ventricle are (1) the control of fluid retention, (2) the control of neurohormonal activation (to reduce morbidity and mortality), and (3) the control of symptoms and disability.
Several general measures are advisable for most patients with chronic heart failure. Obese patients should lose weight, smokers should stop using tobacco products, and those concomitant cardiac conditions and risk factors (e.g., hyperlipidemia) should have their conditions actively managed. Moderate sodium restriction is usually indicated to permit the use of lower doses of diuretic drugs, but water restriction is generally unnecessary unless patients have moderate or severe hyponatremia. Although most patients should not participate in heavy labor or exhaustive sports, exercise should be encouraged, and bed rest should be avoided (except during periods of acute decompensation), because the restriction of activity promotes physical deconditioning and increases disability.
Specific interventions are indicated and contraindicated in patients with heart failure. Hypertension ( Chapter 63 ) should be treated aggressively, because a reduction in cardiac load can improve both systolic and diastolic function. In patients with chronic atrial fibrillation, every effort should be made to control the ventricular response, both at rest and during exercise. Anticoagulants are indicated in patients with atrial fibrillation ( Chapter 59 ) or a history of an embolic event. Asymptomatic ventricular arrhythmias ( Chapter 60 ) require no therapy, but electrophysiologic devices may reduce the risk of death in patients who have sustained ventricular tachycardia or ventricular fibrillation or who have been resuscitated from or at high risk of sudden death. Patients with heart failure are predisposed to the proarrhythmic effects of antiarrhythmic drugs and the cardiodepressant effects of calcium channel blockers, and such agents should be avoided. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the effects of diuretics and ACE inhibitors and can worsen both cardiac and renal function.
The first step in the treatment of patients with chronic heart failure is the control of fluid retention. This step is generally not necessary in patients with asymptomatic left ventricular systolic dysfunction.
Diuretics interfere with the sodium retention of heart failure by inhibiting the reabsorption of sodium and chloride at specific sites in the renal tubules. Of the commonly used agents, furosemide, torsemide, and bumetanide act at the loop of Henle (i.e., loop diuretics); thiazides and metolazone act in the distal tubule; and potassium-sparing diuretics act at the level of the collecting duct.
All diuretics increase urine volume and sodium excretion, but these agents differ in their pharmacologic properties. The loop diuretics increase the fractional excretion of sodium up to 20% to 25% of the filtered load, enhance the clearance of free water, and maintain efficacy even when renal perfusion and function are impaired. In contrast, the thiazide diuretics increase the fractional excretion of sodium to only 5% to 10% of the filtered load, tend to decrease free water clearance, and lose their effectiveness in patients with only moderately impaired renal perfusion and function. Consequently, the loop diuretics are the preferred diuretic agents for patients with heart failure.
Controlled trials have shown that diuretic drugs can decrease signs and symptoms of fluid retention, but diuretics alone cannot maintain the clinical stability of patients with heart failure for long periods of time. However, the risk of clinical decompensation can be reduced if diuretics are combined with a neurohormonal antagonist (e.g., an ACE inhibitor). These observations indicate that diuretics are a necessary, but not sufficient, component of any successful therapeutic strategy for heart failure.
Diuretics play a pivotal role in the treatment of heart failure for three reasons. First, diuretics are the only drugs that can adequately control the fluid retention of heart failure. Few patients with heart failure can maintain sodium balance without the use of diuretic drugs, and attempts to substitute ACE inhibitors for diuretics can lead to pulmonary and peripheral congestion. Second, diuretics produce symptomatic benefits more rapidly than any other drug for heart failure, because they can relieve pulmonary and peripheral edema within hours or days, whereas the effects of digitalis, ACE inhibitors, or ß-blockers may require weeks or months to become apparent. Third, diuretics modulate the responses to other drugs used for the treatment of heart failure, because the effects of neurohormonal antagonists are highly dependent on sodium balance. If diuretics are prescribed in doses that are too low, the expansion of intravascular volume inhibits the response to ACE inhibitors and enhances the risks of treatment with ß-blockers.
Diuretics are generally initiated in low doses ( Table 56-1 ), and the dose is increased until signs and symptoms of fluid retention are alleviated. Once this goal has been achieved, treatment with the diuretic is continued on a long-term basis to prevent the recurrence of salt and water retention. Although diuretics are commonly prescribed at a constant daily dose, the doses of these drugs should ideally be adjusted based on changes in the patient’s body weight. As heart failure advances and renal function declines, patients become resistant to the effects of low doses of these drugs and respond only when high doses are used or when diuretics with different renal tubular sites of action are used in combination. NSAIDs can decrease the efficacy and increase the risk of diuretics and should be avoided.


20–40 mg qd or bid
Titrate to achieve dry weight (up to 400 mg/day)
10–20 mg qd or bid
Titrate to achieve dry weight (up to 200 mg/day)
0.5–1.0 mg qd or bid
Titrate to achieve dry weight (up to 10 mg/day)
2.5–5.0 mg qd or bid
Titrate to achieve dry weight (up to 20 mg/day)
6.25 mg tid
Titrate to target dose (50 mg tid)
2.5 mg bid
Titrate to target dose (10–20 mg bid)
2.5–5.0 mg qd
Titrate to target dose (20–35 mg qd)
1.25–2.5 mg bid
Titrate to target dose (5 mg bid)
10 mg bid
Target dose not established (not >40 mg bid)
5–10 mg qd
Target dose not established (not >40 mg qd)
3.125 mg bid
Titrate to target dose (25 mg bid)
1.25 mg qd
Titrate to target dose (10 mg qd)
Metoprolol tartrate*
6.25 mg bid
Titrate to target dose (50 mg bid)
Metoprolol succinate (extended-release)
12.5–25 mg qd
Titrate to target dose (200 mg qd)
12.5–25 mg qd
Titrate to target dose (25 mg qd)
0.125–0.25 mg qd
Target dose not established (=0.375 mg/day)

*Drugs not approved by the U.S. Food and Drug Administration for use in the management of chronic heart failure, July 2002.
The principal adverse effects of diuretics include (1) electrolyte depletion, (2) neurohormonal activation, and (3) hypotension and azotemia. Other types of side effects may occur (e.g., rash, hearing difficulties), but these are generally idiosyncratic reactions or occur with the use of very large doses.
Electrolyte Depletion.
Diuretics can cause the depletion of potassium and magnesium, which can predispose patients to serious cardiac arrhythmias, particularly in the presence of digitalis therapy. The loss of electrolytes is related to enhanced delivery of sodium to distal sites in the renal tubules and the exchange of sodium for other cations, a process that is potentiated by activation of the renin-angiotensin-aldosterone system. Concomitant administration of ACE inhibitors, angiotensin II receptor blockers, or aldosterone antagonists can prevent the loss of electrolytes caused by diuretics.
Neurohormonal Activation.
Diuretic drugs may increase the activation of endogenous neurohormonal systems in patients with heart failure. Such activation may increase the risk of disease progression, unless patients are receiving concomitant treatment with a neurohormonal antagonist (ACE inhibitor or sympathetic antagonist).
Hypotension and Azotemia.
Although the use of diuretics can lower blood pressure or cause azotemia, these changes are generally asymptomatic and require no specific treatment. The dose of diuretic should not be reduced for asymptomatic changes in blood pressure or renal function if the patient has signs of fluid overload.
Drugs that interfere with the actions of endogenous neurohormonal systems (e.g., the renin-angiotensin system and the sympathetic nervous system) can relieve the symptoms of heart failure by antagonizing the vasoconstriction caused by an increase in neurohormonal activity. However, their major advantage over traditional treatments is their ability to inhibit the cardiotoxic effects of the neurohormonal system and thereby retard the progression of heart failure. As a result, neurohormonal interventions have emerged as essential agents in the management of heart failure. Several types of neurohormonal antagonists have been approved for the treatment of heart failure by the U.S. Food and Drug Administration (FDA): (1) ACE inhibitors, (2) ß-adrenergic receptor blockers, and (3) angiotensin receptor blockers.
Angiotensin-Converting Enzyme Inhibitors
ACE inhibitors interfere with the renin-angiotensin system by inhibiting the enzyme responsible for the conversion of angiotensin I to angiotensin II. However, the benefits of these drugs may not be entirely explained by their actions on the renin-angiotensin system. Because the ACE is identical to kininase II, ACE inhibition not only interferes with the formation of angiotensin II but also enhances the action of kinins; kinin potentiation may add importantly to angiotensin suppression in mediating the effects of ACE inhibitors. The favorable effects of ACE inhibitors on cardiac remodeling may be greater than those of angiotensin II receptor antagonists, and this advantage of ACE inhibitors is abolished by the coadministration of kinin antagonists. Moreover, the hemodynamic and prognostic benefits of ACE inhibitors may be attenuated by the coadministration of aspirin, which blocks kinin-mediated prostaglandin synthesis.
Five ACE inhibitors have been approved for the treatment of chronic heart failure by the FDA: captopril, enalapril, lisinopril, quinapril, and fosinopril (see Table 56-1 ). Ramipril is approved for the treatment of heart failure after an acute MI.
All ACE inhibitors approved for the treatment of heart failure have been shown in double-blind, placebo-controlled trials to produce hemodynamic and clinical benefits. Treatment with these drugs improves left ventricular ejection fraction and decreases left ventricular chamber size; both actions suggest a favorable effect on the process of cardiac remodeling. ACE inhibitors relieve dyspnea, prolong exercise tolerance, and reduce the need for emergency care for worsening heart failure. These benefits are seen in patients with mild, moderate, and severe symptoms, regardless of whether they are treated with digitalis. However, ACE inhibitors should not be used before (or instead of) diuretics in patients with a history of fluid retention, because diuretics are needed to maintain sodium balance and prevent the development of peripheral and pulmonary edema. Nevertheless, ACE inhibitors may reduce the need for large doses of diuretics and potassium supplements and may attenuate many of the adverse metabolic effects of aggressive diuretic therapy (e.g., hypokalemia and hyponatremia).
In addition, several long-term trials have shown that ACE inhibitors can reduce the risk of death and retard the progression of heart failure in patients with an ischemic or a nonischemic cardiomyopathy who are already receiving digitalis and diuretics.[1] [2] In the Studies of Left Ventricular Dysfunction (SOLVD) Treatment Trial, the use of enalapril in patients with mild-to-moderate symptoms was associated with a 16% reduction in all-cause mortality (P = .004) and a 26% decrease in the risk of death or hospitalization for heart failure (P < .001). In the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS), the use of enalapril in patients with severe symptoms was associated with a 27% reduction in the risk of death (P = .003). When the results of all studies are combined, ACE inhibitors appear to reduce both the risk of death and the risk of hospitalization for heart failure by 20% to 30%. Furthermore, ACE inhibitors produce greater effects on survival than a combination of direct-acting vasodilators (e.g., hydralazine and isosorbide dinitrate). ACE inhibitors have also been shown to reduce mortality rates in patients with impaired left ventricular function or heart failure after an acute MI ( Chapter 60 ).
Because of their ability to improve the natural history of heart failure, all patients with heart failure due to left ventricular systolic dysfunction should receive an ACE inhibitor unless they are unable to tolerate the drug or have a contraindication to it. Physicians

should not withhold treatment with an ACE inhibitor until the patient becomes resistant to treatment with other drugs, because such patients might die during the period of delay and such deaths might have been prevented if treatment with the ACE inhibitor had been initiated earlier. The available data do not justify withholding ACE inhibitors from any specific subset of patients, even patients with low blood pressures or impaired renal function. Treatment is generally maintained even in patients who do not experience symptomatic benefits.
Treatment with an ACE inhibitor is generally initiated in low doses followed by gradual increments in dose if lower doses have been well tolerated. In general, the dose of ACE inhibitor is increased until the doses are similar to those used in the clinical trials that established the ability of these drugs to reduce morbidity and mortality. Examples of starting dosages of ACE inhibitors include captopril 6.25 mg three times a day, enalapril 2.5 mg twice daily, or lisinopril 2.5 to 5.0 mg once daily (see Table 56-1 ). Examples of target dosages of ACE inhibitors include captopril 50 mg three times a day, enalapril 10 to 20 mg twice daily, and lisinopril 20 to 35 mg once daily. High doses are more effective than low doses in reducing the risk of hospitalization. The clinical effects of therapy may take weeks or months to become apparent.
Because fluid retention can attenuate the effects of ACE inhibitors, physicians should ensure that the dose of diuretics is optimized before initiating treatment. Close monitoring of diuretic therapy is also needed after initiation of treatment, because the dose of diuretic may need to be reduced if the patient experiences symptomatic decreases in blood pressure or clinically important declines in renal function. NSAIDs can decrease the efficacy and increase the risks of ACE inhibitors and should be avoided.
The adverse effects of ACE inhibitors can be attributed to the two principal pharmacologic actions of these drugs: (1) those related to the effects of angiotensin suppression and (2) those related to the effects of kinin potentiation.
Adverse Effects Related to Angiotensin Suppression.
Decreases in blood pressure or increases in blood urea nitrogen may be seen early in treatment but are generally asymptomatic and require no specific therapy. However, if hypotension is accompanied by dizziness or blurred vision or if renal function deteriorates significantly, the physician should reduce the dose of the diuretic, unless fluid retention is present. Potassium retention may be seen if the patient is receiving potassium supplements or potassium-sparing diuretics but usually resolves after a change in these background medications. Most patients with hypotension, azotemia, or hyperkalemia can be managed without the withdrawal of the ACE inhibitor; thus, most patients (about 90%) who experience these early reactions remain excellent candidates for, and tolerate, long-term ACE inhibition.
Adverse Effects Related to Kinin Potentiation.
Angioedema occurs in less than 1% of patients, but because it may be life threatening, its occurrence justifies avoidance of all ACE inhibitors for the lifetime of the patient. A nonproductive cough is observed in 5% to 15% of patients receiving ACE inhibitors; it usually appears within the first several months of therapy, disappears within 1 to 2 weeks of discontinuation of treatment, and recurs within days of rechallenge. When a patient receiving an ACE inhibitor complains of cough, other causes should be considered (especially pulmonary congestion), and the ACE inhibitor should be implicated only after the physician confirms that the cough disappears after withdrawal of the drug and recurs after rechallenge. Because the cough is related to a common action of all ACE inhibitors, its occurrence frequently requires the withdrawal of the ACE inhibitor and the use of alternative approaches to interfering with the renin-angiotensin system (e.g., angiotensin II receptor antagonists; see Drugs Used in Patients Intolerant of Angiotensin-Converting Enzyme Inhibitors).
ß-Adrenergic Receptor Blockers
Although most physicians were formerly taught to avoid the use of ß-blockers in patients with heart failure, these drugs can produce important clinical benefits in this disorder. Like ACE inhibitors, ß-blockers interfere with the deleterious actions of an endogenous neurohormonal system, which can adversely affect the failing heart by promoting cell death, hypertrophy, ischemia, and arrhythmias. Although these deleterious effects are mediated through three distinct adrenergic receptors (a1 , ß1 , and ß2 ), evidence suggests that agents that block multiple receptors may provide greater protection against catecholamine-induced cardiomyopathy than drugs that block only one receptor. Of available ß-blockers, only carvedilol and metoprolol have been approved by the FDA for the treatment of heart failure.
Several ß-blockers have been shown in double-blind, placebo-controlled trials to produce hemodynamic and clinical benefits. Treatment with these drugs improves left ventricular ejection fraction and decreases left ventricular chamber size; both actions suggest a favorable effect on the process of cardiac remodeling. ß-Blockers relieve symptoms and improve clinical status; these benefits have been seen in patients with mild, moderate, and severe symptoms, regardless of whether they are treated with digitalis. ß-Blockers are generally used together with ACE inhibitors in clinical practice; combined use of both neurohormonal antagonists can be expected to produce additive benefits.
In addition, several long-term trials have shown that ß-blockers can reduce the risk of death and retard the progression of heart failure in patients with an ischemic or nonischemic cardiomyopathy who are already receiving digitalis, diuretics, and ACE inhibitors.[3] [4] In the U.S. Carvedilol Program, the use of carvedilol in patients with mild-to-moderate symptoms was associated with a 65% reduction in all-cause mortality (P < .001) and a 36% decrease in the risk of death or hospitalization for a cardiovascular reason (P < .001). In the Metoprolol CR/XL Randomized Trial in Heart Failure (MERIT-HF) study, the use of metoprolol in mild-to-moderate heart failure was associated with an approximately 35% reduction in the risk of death (P < .001) and a 31% lower risk of death or hospitalization for heart failure (P < .001). In the Second Cardiac Insufficiency Bisoprolol Study (CIBIS II), the use of bisoprolol in moderate-to-severe heart failure was associated with a 32% reduction in the risk of death (P < .001) and a 32% decrease in the frequency of being hospitalized for heart failure (P < .0001). In the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study, the use of carvedilol in patients with severe symptoms was associated with a 35% reduction in all-cause mortality (P < .001) and a 31% lower risk of death or hospitalization for heart failure (P < .001). When the results of all studies are combined, ß-blockers appear to reduce both the risk of death and the risk of hospitalization for heart failure by 30% to 40% in patients already receiving ACE inhibitors. The magnitude of the effects is similar regardless of the cause or severity of heart failure. ß-Blockers have also been shown to reduce mortality rates in patients with impaired left ventricular function or heart failure after an acute MI ( Chapter 69 ). Recent data suggest that carvedilol is significantly more efficacious than metoprolol in reducing mortality, presumably because it provides more comprehensive sympathetic antagonism.[5]
Because ß-blockers can favorably modify the natural history of heart failure, all patients with heart failure due to left ventricular systolic dysfunction should receive a ß-blocker unless they have a contraindication to its use or are unable to tolerate treatment with the drug. ß-Blockers should not be withheld until the patient is shown to be resistant to treatment with other drugs, because such patients might die or experience worsening of their disease during the period of delay and such progression might have been prevented if treatment with the ß-blocker had been initiated earlier. Treatment is generally maintained even in patients who do not experience symptomatic benefits. However, there are insufficient data on the efficacy and safety of ß-blocker use in patients in an intensive care unit or receiving intravenous positive inotropic drugs for heart failure to recommend the use of ß-blockers in those with clinical instability or end-stage disease. In addition, patients with bronchospastic disease or advanced heart block should not receive treatment with these drugs.
Treatment with a ß-blocker is generally initiated in very low doses followed by gradual increments in dose if lower doses have been well tolerated (see Table 56-1 ). In general, the dose of these drugs is increased until doses are achieved similar to those used in the clinical trials that established the ability of these drugs to reduce morbidity and mortality. Examples of starting dosages of ß-blockers include carvedilol 3.125 mg twice daily, bisoprolol 1.25 mg/day, and metoprolol (sustained-release) 12.5 mg/day. Examples of long-term dosages of ß-blockers include carvedilol 25 mg twice daily, bisoprolol 10 mg/day, and metoprolol (sustained-release) 200 mg/day. As in the case of ACE inhibitors, the clinical effects of therapy may take weeks or months to become apparent.
Because fluid retention can increase the risks of ß-blockade, physicians should ensure that the dose of diuretics is optimized before initiating treatment. Close monitoring of diuretic therapy is also needed after initiation of treatment, because an increase in the dose of diuretic

may be required if the patient experiences a significant increase in body weight or worsening symptoms of heart failure.
Like ACE inhibitors, ß-blockers can produce unwanted side effects that result directly from changes in neurohormonal activity. These adverse reactions occur during initiation of therapy but are generally mild in severity, can be managed by changes in concomitant therapy, usually subside after several days or weeks of treatment, and, thus, infrequently lead to the withdrawal of treatment. In clinical trials, most patients (>85%) with heart failure were able to tolerate short- and long-term therapy with these drugs.
Vasodilatory side effects may be seen within 24 to 48 hours of initiation of therapy or after increments in dose but usually subside with repeated dosing without any change in the dose of the ß-blocker or background medications. Physicians can minimize the risk of hypotension by administering the ß-blocker and the ACE inhibitor at different times of the day.
Fluid Retention.
Initiation of therapy with a ß-blocker can produce fluid retention, which is usually manifested as an asymptomatic increase in body weight but may be severe enough to cause worsening symptoms of heart failure. Increases in body weight are generally seen within 3 to 5 days of initiation of therapy or after increments in dose. Physicians should ask patients to weigh themselves daily, and asymptomatic increases in weight should be treated promptly by increasing the dose of concomitantly administered diuretics until the patient’s weight is restored to pretreatment levels.
Bradycardia and Heart Block.
Therapy with a ß-blocker can decrease heart rate and alter cardiac conduction, thereby leading to bradycardia or heart block. These changes are usually asymptomatic but may be severe enough to cause symptomatic hypotension. If the heart rate declines to less than 50 beats per minute or second or third heart block is observed, the dose of ß-blocker should be decreased. Cardiac pacing might be considered to allow the use of ß-blockade in selected patients.
Aldosterone Antagonists
Although generally classified in the category of potassium-sparing diuretics, drugs that block the actions of aldosterone (e.g., spironolactone) act to antagonize an endogenous neurohormonal mechanism that may adversely affect the heart independent of its effects on sodium balance. In the Randomized Aldactone Evaluation Study (RALES) trial, the addition of low dosages of spironolactone (12.5 to 25 mg/day) to patients with current or recent class IV symptoms receiving ACE inhibitors decreased the risk of death by 25% to 30% and the risk of hospitalization for heart failure by approximately 35% (P < .001). [6] This principle has been reinforced by a recent study in which another aldosterone antagonist, eplerenone (50 mg per day) reduced the risk of death by 15% in patients with left ventricular dysfunction after myocardial infarction.[7] Therefore, the use of low doses of spironolactone merits consideration in patients with advanced heart failure. Such use, however, is not approved by the FDA.
The digitalis glycosides exert their effects in patients with heart failure by virtue of their ability to inhibit sodium-potassium adenosine triphosphatase (Na+ , K+ -ATPase). Inhibition of this enzyme in the heart results in an increase in cardiac contractility, and for many decades, the benefits of digitalis in heart failure were ascribed to this positive inotropic action. However, by inhibiting Na+ , K+ -ATPase in vagal afferents, digitalis acts to sensitize cardiac baroreceptors, which, in turn, reduce the outflow of sympathetic impulses from the central nervous system. In addition, by inhibiting Na+ , K+ -ATPase in the kidney, digitalis reduces the renal tubular reabsorption of sodium; the resulting increase in the delivery of sodium to the distal tubules leads to the suppression of renin secretion. These observations have led to the hypothesis that, in addition to increasing contractile force, digitalis may produce important vasodilatory effects by attenuating the activation of neurohormonal systems.
Although a variety of digitalis glycosides have been used in the treatment of heart failure for the past 200 years, the most commonly used preparation in the United States is digoxin. Digoxin is the principal glycoside that has been evaluated in placebo-controlled trials.
Controlled studies have shown that digoxin can improve symptoms, quality of life, and exercise tolerance in patients with mild-to-moderate heart failure. These benefits are seen regardless of the underlying rhythm (sinus rhythm or atrial fibrillation), cause of heart failure (ischemic or nonischemic cardiomyopathy), or concomitant therapy (with or without ACE inhibitors). The addition of digoxin produces favorable effects on clinical status and ejection fraction, and the withdrawal of digoxin is followed by hemodynamic and clinical deterioration. However, in a long-term controlled clinical trial, digoxin did not reduce the risk of death and was associated with only a modest reduction in the combined risk of death and hospitalization.[8] These results indicate that the primary benefit of digoxin in heart failure is to alleviate symptoms and improve clinical status.
Digoxin provides a convenient, inexpensive, and well-tolerated means of improving the clinical status of patients with heart failure. However, the finding that the drug has little effect on the progression of heart failure has minimized any mandate for its early use; thus, it can be prescribed at any time if symptoms persist after the use of other drugs. Digoxin is a preferred agent in patients with heart failure who have atrial fibrillation and a rapid ventricular response ( Chapter 59 ). The drug is not recommended for use in patients who have no symptoms or for the stabilization of patients with acutely decompensated heart failure.
Digoxin is usually initiated and maintained at a dosage of 0.25 mg/day (see Table 56-1 ). Lower doses are indicated in patients who are elderly (>70 years old) or in those with impaired renal function (serum creatinine > 1.5 mg/dL). Higher doses may be needed to control the ventricular response in patients with atrial fibrillation. Although serum digoxin levels are commonly used to guide the administration of digoxin, there is little evidence to support this approach. There is no relation between drug levels and efficacy in patients in sinus rhythm, and patients with atrial fibrillation are better monitored by their heart rate response than by drug levels.
The principal adverse effects of digoxin include (1) cardiac arrhythmias (e.g., ectopic and reentrant cardiac rhythms and heart block), (2) gastrointestinal symptoms (e.g., anorexia, nausea and vomiting), and (3) neurologic complaints (e.g., visual disturbances, disorientation, and confusion). These side effects are commonly associated with serum digoxin levels greater than 2 ng/mL, but digitalis toxicity may occur with lower digoxin levels, particularly if hypokalemia or hypomagnesemia coexist. The concomitant use of quinidine, verapamil, spironolactone, flecainide, propafenone, and amiodarone can increase serum digoxin levels and may increase the risk of adverse reactions. Patients with advanced heart block should not receive the drug unless a pacemaker is in place.
Low doses of digoxin are well tolerated by most patients with heart failure. Adverse effects occur primarily when the drug is administered in large doses, but large doses are generally not needed to produce clinical benefits. Nevertheless, there is persistent concern that digitalis may exert deleterious cardiovascular effects in the long term at doses that appear to be well tolerated in the short term. In a largescale trial, the use of digoxin in doses that produced serum levels below the toxic range appeared to increase the frequency of hospitalizations and deaths related to cardiovascular events other than heart failure. These observations raise the possibility that even low doses of digoxin can adversely affect the heart.
The evidence summarized in this section can be synthesized into an algorithm that can guide the management of patients with symptoms of heart failure ( Fig. 56-4 ).
Step 1: Establish the Diagnosis of Heart Failure
Patients who are limited in their ability to exercise or perform activities of daily living because of dyspnea or fatigue should be evaluated for the presence of heart failure. During the initial evaluation, the clinician should obtain a two-dimensional echocardiogram, which can identify disorders of the valves, pericardium, or great vessels that may be corrected surgically and can quantify the type and magnitude of ventricular dysfunction. Patients with systolic dysfunction (ejection fraction <40%) should be distinguished from patients with preserved left ventricular function (>40%).
Every effort should be made to identify and treat concomitant conditions (e.g., anemia, thyroid disorders) or withdraw concomitant

Figure 56-4 Algorithm for the management of chronic heart failure. Step 1: Establish the diagnosis. A two-dimensional echocardiogram can quantify the type and magnitude of ventricular dysfunction and can identify disorders of the valves, pericardium, or great vessels that may be corrected surgically. Step 2: Control volume with the use of diuretics. The dose of diuretic should be adjusted until there is no evidence of fluid retention, as reflected either by resolution of peripheral edema or normalization of jugular venous pressure. Step 3: Slow disease progression with the use of ACE inhibitors, ß-blockers, and an aldosterone antagonist. Even if symptoms are controlled with a diuretic, ACE inhibitors, ß-blockers, and usually an aldosterone antagonist should be used together to reduce the risk of death and hospitalization. Step 4: Treat any residual symptoms with digoxin. Some physicians prescribe digoxin to all symptomatic patients with systolic dysfunction receiving a diuretic, whereas others reserve digoxin for patients who remain symptomatic despite the use of a diuretic, ACE inhibitor, ß-blocker, and aldosterone antagonist. Resynchronization therapy may be considered in patients with a widened QRS who have persistent symptoms despite other therapies. ACE = angiotensin-converting enzyme.
medications (e.g., calcium channel blockers, antiarrhythmic drugs, and NSAIDs) that may exacerbate the syndrome of heart failure. Patients who are in respiratory distress, have evidence of poor end-organ perfusion or fluid overload, or have a serious complicating illness should be hospitalized for treatment with intravenous agents (e.g., diuretics, vasodilators and/or positive inotropic agents) to achieve rapid stabilization of their clinical condition.
Step 2: Initiate Therapy with a Diuretic to Stabilize the Symptoms
Because of the critical importance of fluid retention, the use of diuretics is warranted in most patients with symptoms of heart failure, together with a moderate degree of sodium restriction. The dose of diuretic should be adjusted until there is no evidence of fluid retention, as reflected either by resolution of peripheral edema or by normalization of jugular venous pressure. After these early goals are achieved, treatment with the diuretic should be continued in the long term to prevent the recurrence of fluid retention, and the doses of diuretics should be continually reevaluated to maintain patients free of edema and at dry weight. If this approach is not followed, the resulting underuse of diuretics not only undermines the ability of these drugs to relieve symptoms but also adversely affects the patient’s ability to respond favorably and safely to ACE inhibitors and ß-blockers. As heart failure advances and renal function declines, patients may become resistant to the effects of low doses and respond only when high doses are used or a second diuretic (e.g., metolazone) is added.
Step 3: Use Angiotensin-Converting Enzyme Inhibitors and ß-Blockers to Stabilize the Disease
Because diuretics do not prevent disease progression, patients with heart failure due to systolic dysfunction should not be treated with a diuretic alone, even if their symptoms are alleviated with the use of diuretic drugs. Patients who respond favorably to diuretics should receive additional therapy with agents that block the actions of neurohormonal systems (ACE inhibitors and ß-blockers). The use of neurohormonal inhibitors should not be reserved for patients who are refractory to diuretics, because patients might die during the period of delay and patients with end-stage heart failure and persistent fluid retention often respond poorly to ACE inhibitors and ß-blockers. In patients with mild, moderate, or severe heart failure, treatment with the ACE inhibitor should be started first, initially in low doses, and every effort should be made to maintain treatment if patients experience early intolerance. Changes in diuretics may be needed to minimize the risk of adverse reactions. In stable patients with mild, moderate, or severe heart failure, treatment with a ß-blocker should be added to the ACE inhibitor, regardless of the degree of clinical improvement with the ACE inhibitor. Therapy should be initiated in low doses followed by appropriate increments in dose, and every effort should be made to maintain treatment if patients experience early intolerance. As with ACE inhibitors, changes in diuretics may be needed to minimize the risk of adverse reactions. In patients with recent or current class IV symptoms, the addition of spironolactone to the ACE inhibitor merits consideration.
Optimal effects on disease progression can be achieved only by using both an ACE inhibitor and a ß-blocker in combination. ACE inhibition appears to reduce the risk of death and of hospitalization by 20 to 30%, and the addition of a ß-blocker to the ACE inhibitor produces a further 30 to 40% reduction in the risk of a major clinical event. However, treatment with ACE inhibitors and a ß-blocker should not be initiated at the same time. Therapy with a ß-blocker should be started after the patient has been stabilized on appropriate doses of the ACE inhibitor.
Step 4: Add Therapy with Digoxin in Patients with Persistent Symptoms
Because the benefits of digoxin are largely related to its ability to improve symptoms and clinical status, the drug may be used at any time to alleviate symptoms. Some physicians prescribe digoxin to all symptomatic patients with systolic dysfunction receiving a diuretic, whereas others reserve digoxin for patients who remain symptomatic despite the use of diuretics, ACE inhibitors, and ß-blockers. Digoxin should be a preferred agent in patients whose heart failure is associated with atrial arrhythmias (e.g., atrial fibrillation).
Drugs Used in Patients Intolerant of ACE Inhibitors
Two types of drugs are available for patients who cannot tolerate treatment with an ACE inhibitor. Neither approach is recommended in patients who can tolerate an ACE inhibitor without difficulty.
Angiotensin II receptor antagonists (e.g., losartan, valsartan, irbesartan, eprosartan, candesartan) interfere with the actions of the renin-angiotensin system by blocking the interaction of angiotensin II with its receptor. This mechanism, distinct from that of ACE inhibitors, is not associated with the accumulation of kinins; thus, the effects of these drugs in heart failure may differ from those reported for ACE inhibitors. In the Losartan Heart Failure Survival Study (ELITE II), the angiotensin II antagonist losartan was somewhat less effective than the ACE inhibitor captopril in modifying survival, especially in patients receiving a ß-blocker. In the Valsartan Heart Failure Trial (Val-HeFT), the angiotensin II antagonist valsartan was shown to reduce the risk of death or hospitalization for heart failure in patients not receiving an ACE inhibitor, but had little effect when added to patients already receiving an ACE inhibitor and may have exerted an adverse effect in patients receiving both an ACE inhibitor and ß-blocker. Accordingly, angiotensin II receptor antagonists should not be used for the treatment of heart failure in patients who have no prior exposure to an ACE inhibitor, and these drugs should not be substituted for ACE inhibitors in patients who are tolerating ACE inhibitors without difficulty. Furthermore, these agents cause hypotension and renal insufficiency as frequently as ACE inhibitors. Angiotensin II antagonists may be used in patients who cannot tolerate an ACE inhibitor because of cough or angioedema.[9] [10]
Although direct-acting vasodilators can produce favorable short-term hemodynamic effects in patients with heart failure, their long-term use has not improved symptoms and has increased the risk of heart failure and death in

controlled clinical trials. Of the agents evaluated, only a combination of isosorbide dinitrate and hydralazine has produced some encouraging results. The combination of these two direct-acting vasodilators reduces the risk of death in patients with heart failure receiving digitalis and diuretics. However, this vasodilator combination has no effect on the frequency of hospitalizations, and many patients fail to tolerate long-term treatment with these drugs. Furthermore, when compared with ACE inhibitors, the nitrate-hydralazine combination is associated with a higher risk of death, despite greater benefits on exercise fraction and exercise tolerance. Finally, there is little experience with the use of hydralazine and isosorbide dinitrate in patients receiving an ACE inhibitor or a ß-blocker. For all of these reasons, neither hydralazine nor isosorbide dinitrate (alone or in combination) is approved by the FDA for the treatment of heart failure.
Therefore, the combination of hydralazine and isosorbide dinitrate is not used for the treatment of heart failure in patients who have no prior exposure to an ACE inhibitor, and these drugs should not be substituted for ACE inhibitors in patients who are tolerating ACE inhibitors. The combined use of hydralazine and isosorbide dinitrate may be used in patients who cannot tolerate an ACE inhibitor because of hypotension or renal insufficiency. There is no good evidence to support the use of nitrates alone or hydralazine alone in the management of chronic heart failure.
Drugs and Devices Used for the Treatment of Coexistent Cardiac Disorders
Many patients with heart failure have coexistent cardiac disorders that require active management. Revascularization should be strongly considered in patients with heart failure who have angina, because it may reduce the risk of major cardiac events ( Chapter 67 ). Nitrates and ß-blockers may be used if revascularization cannot be performed or is unsuccessful. Diuretics, ACE inhibitors, and ß-blockers are excellent choices for the treatment of patients who have heart failure and hypertension ( Chapter 63 ).
Atrial arrhythmias are common in patients with heart failure, and if accompanied by a rapid ventricular response, they can exacerbate the severity of symptoms and possibly accelerate progression of the underlying disease. Although the prevention of atrial arrhythmias would be highly desirable, this goal cannot be effectively or safely achieved with most antiarrhythmic drugs. The agent most likely to suppress atrial arrhythmias in patients with heart failure is amiodarone, but the substantial toxicity of the drug has justifiably discouraged its widespread use. As a result, many physicians do not attempt to restore sinus rhythm in patients with an established atrial arrhythmia but instead focus on controlling the rate of the ventricular response with digitalis and ß-blockers and reducing the risk of embolic events with anticoagulants. If a slow ventricular response cannot be achieved in this manner, amiodarone or radiofrequency ablative procedures ( Chapter 59 ) should be considered.
Most patients with heart failure have frequent and complex ventricular arrhythmias, but when asymptomatic, these do not presage or contribute to the occurrence of sudden death and thus do not require therapy. The appearance of ventricular arrhythmias in these patients is likely to reflect the severity of the underlying cardiac disease and thus may respond to interventions that reduce the risk of disease progression. In addition, every effort should be made to correct electrolyte imbalances if these are found. In patients who have an immediate life-threatening ventricular arrhythmia (sustained ventricular tachycardia or ventricular fibrillation) or who have been resuscitated from or are at high risk of sudden death, use of an implantable cardioverter-defibrillator may reduce the risk of a lethal recurrence ( Chapter 60 ). In addition, implantation of a cardioverter-defibrillator may decrease the risk of death in survivors of an acute MI who have a depressed ejection fraction with or without symptoms of heart failure.[11] In the second Multicenter Automatic Defibrillator Implantation Trial (MADIT-II), prophylactic use of a cardioverter-defibrillator reduced the risk of death by 31% (P = .016) in post-MI patients who had no or mild symptoms of heart failure and who were not selected based on the findings of electrophysiological testing. However, questions remain about the applicability of these results to patients with more severe symptoms or without coronary artery disease, and concerns remain about the potential of these devices to increase the risk of hospitalization for heart failure. Additional studies are in progress to address these issues.
About one third of patients with moderate-to-severe heart failure have a widened QRS complex on the surface electrocardiogram owing to asynchronous activation of the right and left ventricles. Such asynchrony may contribute to the hemodynamic abnormalities and symptoms experienced by some patients. Asynchronous contraction can be ameliorated by electrically activating the right and left ventricles in a synchronized manner with a pacemaker to enhance ventricular contraction and to reduce the degree of secondary mitral regurgitation that results from delayed septal activation. Patients randomized to cardiac resynchronization have improvement in their symptoms and a significant reduction in mortality.[12] Resynchronization therapy can be combined with an implantable cardiovertor defibrillator in appropriate patients.
Because of stasis of blood in dilated hypokinetic cardiac chambers, patients with a dilated cardiomyopathy are at increased risk of cardiac thrombi and embolic events. However, it is unclear whether all patients with a depressed ejection fraction should receive treatment with anticoagulant drugs, even if they are known to harbor a cardiac thrombus. Most cardiac thrombi detected by echocardiography do not embolize, and most embolic events are related to thrombi that were not visualized. Anticoagulation is recommended primarily for patients with a previous embolic event or atrial fibrillation.
Drugs to be Avoided in Patients with Heart Failure
Patients with heart failure can improve dramatically after the withdrawal of drugs that are known to affect cardiac function adversely or that interact unfavorably with drugs of established benefit.
Prostaglandins play an important role in circulatory homeostasis and in the action of many drugs used to treat heart failure. These substances are endogenous vasodilators that act to unload the heart when peripheral vessels are constricted and can support glomerular filtration when renal perfusion is compromised. The natriuretic actions of diuretics and the vasodilatory effects of ACE inhibitors are mediated in part by the release of endogenous prostaglandins. For all of these reasons, the administration of agents that block prostaglandin synthesis can produce worsening cardiac and renal function and can lead to clinical deterioration, particularly in patients with compromised renal perfusion who are receiving diuretics and ACE inhibitors. As a result, most patients with heart failure should not receive NSAIDs.
Whether the recommendation to avoid inhibitors of prostaglandin synthesis applies to aspirin remains controversial. Aspirin is widely prescribed to patients with heart failure, either to reduce the risk of recurrent myocardial ischemic events in patients with coronary artery disease or to decrease the frequency of systemic embolic events in patients with normal coronary arteries. However, by interfering with kinin-mediated prostaglandin synthesis, aspirin can attenuate the hemodynamic actions of ACE inhibitors in patients with heart failure. In large multicenter trials, the use of aspirin was associated with a loss of the effects of ACE inhibitors on survival and an attenuation of the effects of these drugs on cardiovascular morbidity. As a result, some physicians prefer to use a nonaspirin platelet inhibitor (e.g., clopidogrel) ( Chapter 33 ) in patients with heart failure who are receiving ACE inhibitors.
Antagonists of the actions of tumor necrosis factor are approved for use in the treatment of several chronic inflammatory diseases, including rheumatoid arthritis and Crohn’s disease. Two types of antagonists are commercially available: a soluble receptor (etanercept) and a chimeric antibody (infliximab). Both agents have been shown to exacerbate the course of patients with chronic heart failure in controlled clinical trials. As a result, both etanercept and infliximab should be avoided in patients with heart failure, even if they are being used for a noncardiovascular indication.
Drugs that interfere with the interaction between endothelin and its receptors produce notable vasodilatory effects, in both the systemic and pulmonary circulations. Only one endothelin receptor antagonist is approved by the FDA for clinical use, specifically for the treatment of patients with pulmonary arterial hypertension ( Chapter 64 ). However, most patients with pulmonary hypertension have elevated pulmonary artery pressures as a result of left heart failure, a condition in which long-term treatment has been associated with an early risk of worsening heart failure. As a result, physicians contemplating the use of bosentan for pulmonary hypertension should confirm that systolic function is preserved before the drug is initiated.

Although calcium channel blockers are peripheral vasodilators, these agents have not improved the symptoms of heart failure or enhanced exercise tolerance. Instead, the short- and long-term administration of these drugs has caused serious adverse cardiovascular reactions, including profound hypotension, worsening heart failure, pulmonary edema, and cardiogenic shock. These deleterious responses have been observed with short- or long-acting formulations of the same drug (e.g., nifedipine) as well as with the older and newer members of this class (e.g., felodipine and mibefradil). As a result, clinicians should not use calcium channel blockers for the treatment of heart failure, and most calcium channel blockers should be avoided for the treatment of angina, atrial fibrillation, or hypertension in patients with heart failure.
Antiarrhythmic agents can suppress ventricular arrhythmias in patients with heart failure, but these agents have not been shown to reduce the risk of sudden death. Instead, the short- and long-term administration of these drugs has caused serious adverse cardiovascular reactions, including worsening heart failure, life-threatening proarrhythmia, and death. These deleterious responses have been observed with most types of antiarrhythmic agents, including class I (encainide, flecainide, and mexiletine) and class III (D-sotalol) drugs ( Chapter 62 ). Mixed results have been reported with amiodarone. As a result, antiarrhythmic therapy should not be used to treat patients with heart failure who have asymptomatic ventricular arrhythmias, regardless of their frequency or complexity. Antiarrhythmic drugs may be useful for patients with rapid atrial fibrillation or for those with hemodynamically destabilizing ventricular tachycardia or ventricular fibrillation.
Although positive inotropic agents (e.g., dobutamine and milrinone) can produce striking hemodynamic benefits when given intravenously for short periods of time, long-term use of these drugs has not been shown to produce symptomatic benefits and has been associated with an increase in the risk of death. Such toxicity has been reported with all types of agents of this class (except for digitalis), whether these have been prescribed orally or intravenously or administered continuously or intermittently. Because of the lack of data demonstrating efficacy and important concerns about toxicity, the use of intermittent intravenous positive inotropic therapy cannot be recommended as a long-term treatment strategy, even in patients with end-stage heart failure.
Treatment of Patients Hospitalized for Heart Failure
Most patients with heart failure can be managed as outpatients, but nearly one third of patients with heart failure require hospitalization each year. The major syndromes requiring hospitalization include (1) fluid overload resistant to orally administered diuretics (e.g., refractory peripheral edema), (2) severe respiratory distress with or without hypoxemia (e.g., acute pulmonary edema), and (3) refractory symptoms with poor end-organ perfusion requiring intravenous therapy. Each syndrome represents an exaggerated expression of each of the pathophysiologic mechanisms that play a role in the evolution of heart failure. Refractory edema reflects excessive sodium and water retention, acute pulmonary edema is the result of extreme vasoconstriction, and refractory symptoms associated with systemic hypoperfusion are the ultimate consequences of contractile failure. Aspects of these syndromes frequently coexist in the same patient.
These syndromes share a common therapeutic approach: because of their immediate life-threatening nature, physicians must rely on short-term hemodynamic interventions to achieve clinical stability as rapidly as possible. If the syndromes are the result of changes in diet or medications or the advent of a treatable complicating illness (e.g., arrhythmia, pneumonia, or renal failure), the hemodynamic support can be gradually withdrawn, and a long-term outpatient strategy can be implemented. However, if these syndromes represent the end stage of a terminal disease that is refractory to medical therapy, hemodynamic support must be continued until a definitive mechanical solution can be devised (e.g., cardiac transplantation; Chapter 80 ). In either case, neurohormonal activation is not a therapeutic target in patients who are hospitalized for the treatment of decompensated heart failure. Indeed, by supporting cardiac contractility and systemic blood pressure, the activation of the sympathetic nervous system and renin-angiotensin system may help to maintain circulatory homeostasis in acutely ill patients. The administration of neurohormonal antagonists (ACE inhibitors and ß-blockers) in this setting is frequently ineffective and may be deleterious.
Patients with heart failure are frequently hospitalized for the treatment of edema that persists despite the use of diuretics. These patients typically present with a marked increase in body weight, associated with pleural effusions, ascites, and massive peripheral edema. The degree of fluid retention can become so severe that the edema itself becomes incapacitating and may require mechanical removal of fluid for relief of symptoms. A frequent cause of this syndrome is non-compliance with diet or medications; when such is the case, clinical stability can usually be achieved rapidly by restoring the patient’s earlier therapeutic regimen. However, in some patients, the occurrence of refractory edema is indicative of advancing right and left ventricular failure. By causing mesenteric congestion, right ventricular failure can impair the rate of absorption of diuretics; by causing renal hypoperfusion, left ventricular failure can impede the delivery of diuretics to active sites in the renal tubules. As a result, as heart failure advances, patients become increasingly resistant to the effects of diuretic drugs and require increasingly larger doses to achieve a therapeutic response.
Management of Refractory Peripheral Edema
Several strategies should be considered in the management of patients with refractory edema. NSAIDs, which can decrease the efficacy and increase the risk of diuretics, should be withdrawn. Vasodilators (especially ACE inhibitors) may reduce renal perfusion pressure and attenuate the effects of furosemide; they should be used cautiously. Diuretics acting on the loop of Henle (e.g., furosemide) should be selected and administered intravenously to ensure their rapid entry into the bloodstream in high concentrations. If the patient fails to respond to the intravenous administration of large dosages of furosemide (e.g., 160 to 200 mg/day), the physician may add a second diuretic with a different renal tubular site of action (e.g., metolazone). A combination of two diuretics can produce a dramatic increase in urine output, but such a regimen is commonly accompanied by striking (and occasionally life-threatening) degrees of hypokalemia. If a combination of intravenous furosemide and oral metolazone proves ineffective, these diuretics should be coadministered with drugs that increase renal blood flow (e.g., dopamine alone or combined with dobutamine). Finally, if the edema becomes refractory to all pharmacologic interventions, hemofiltration or peritoneal dialysis may be useful in restoring fluid balance in selected patients.
Regardless of the severity of fluid retention, every effort should be made to achieve dry weight, even if achievement of this goal requires a prolonged hospitalization. Patients discharged prematurely with residual edema due to an inadequate diuresis are commonly readmitted to the hospital for refractory edema within several weeks. In contrast, patients who achieve dry weight frequently become responsive to conventional treatments for heart failure and have a lower risk of recurrent hospitalization.
One of the most common clinical presentations of advanced left ventricular failure is the syndrome of pulmonary congestion. These patients complain of dyspnea at rest and have pulmonary rales on physical examination. Pulmonary congestion may be the first evidence of heart failure in patients without a history of cardiac disease; it may appear in patients who are already hospitalized for an acute cardiac disorder (e.g., MI); or it may complicate the course of a patient with long-standing heart failure. If severe, abrupt, and accompanied by clinical evidence of sympathetic overactivity (tachycardia, diaphoresis, and vasoconstriction), the syndrome is designated as acute pulmonary edema. Acute pulmonary edema may also be triggered by noncardiac disorders, including direct injury to the alveolar-capillary membrane, high-altitude stress, catastrophes of the central nervous system, narcotic overdose, or pulmonary embolism.
Regardless of its cause, pulmonary edema reflects the transudation of fluid into the alveolar space and arises from an imbalance in the factors that regulate the transport of fluid from the pulmonary microcirculation to the interstitial space of the lung. When the cause of the syndrome is cardiac, pulmonary edema results from the rapid onset of intense peripheral vasoconstriction that leads to a marked increase in pulmonary venous pressures. The profound constriction

of systemic arteries and veins causes a sudden and dramatic redistribution of blood from peripheral reservoirs to the pulmonary circuit, causing the pulmonary capillary hydrostatic pressure in the lung to exceed the capillary colloid osmotic pressure. However, the transudation of fluid into the alveoli cannot occur if pulmonary blood flow is impaired; thus, patients with an elevated pulmonary vascular resistance or depressed right ventricular function rarely develop acute pulmonary edema.
Management of Pulmonary Edema
Several general measures are advisable for most patients with pulmonary congestion. Every effort should be made to identify an underlying precipitating factor, because its correction is often critical to the success of treatment. Patients usually feel most comfortable resting in bed in the upright position with the legs dependent. Special attention should be devoted to maintaining adequate oxygenation, which can be achieved by increasing the concentration of inspired oxygen or (if necessary) by endotracheal intubation and mechanical ventilation.
Given the importance of peripheral vasoconstriction in the pathogenesis of pulmonary edema, pharmacologic dilation of peripheral vessels represents the critical element in any successful approach to management. This goal can be achieved with the use of (1) morphine, (2) loop diuretic drugs (e.g., furosemide), and (3) direct-acting vasodilators (e.g., nitroglycerin, nitroprusside, and nesiritide). Because of the need for rapid and reliable treatment, these interventions are generally administered intravenously.
Morphine remains the most effective single agent for the treatment of acute cardiogenic pulmonary edema. The drug acts specifically to antagonize the peripheral vasoconstrictor effects of the sympathetic nervous system; the resultant vasodilatation leads to an immediate and dramatic decline in pulmonary arterial and venous pressures, leading directly to symptomatic improvement. The precise site of the vasodilation produced by morphine is uncertain. The magnitude of venodilation produced by the drug in the limbs is insufficient to explain its effects on pulmonary flow and pressures; instead, morphine appears to act primarily to increase the pooling of blood in the splanchnic circulation. In addition, morphine blunts the chemoreceptor-mediated ventilatory reflexes that trigger the severe tachypnea that accompanies pulmonary edema; by doing so, the drug reduces the work of breathing and thereby oxygen demand.
Morphine is administered in intermittent dosages of 2 to 4 mg IV (up to 10 to 15 mg) until dyspnea is relieved and diaphoresis subsides. The former reflects the acute decline in pulmonary blood flow and pulmonary venous pressures; the latter indicates a decline in the activity of the sympathetic nervous system. Patients should be monitored for respiratory depression, which an be reversed by narcotic antagonists.
All diuretics increase urine output in patients with pulmonary edema, but loop diuretics can produce dramatic clinical benefits even before a diuresis has materialized. These immediate benefits are related to the peripheral arterial and venous dilatation produced by these drugs, which results from their ability to enhance the release of prostaglandins from the kidney. Nonloop diuretics do not exert this direct vasodilator action. Although loop diuretics act quickly to increase sodium excretion, the rapidity of diuresis does not determine the clinical response to treatment, because vasodilation (not diuresis) is the principal mechanism of symptom relief. Indeed, an increase in urine output in general is not seen until peripheral signs of vasoconstriction have resolved.
Furosemide is the loop diuretic most commonly used in the treatment of pulmonary edema. The dose of the drug is determined by the prior exposure of the patient to diuretic therapy. In patients who have not received loop diuretics, treatment is usually begun with low dosages (40 to 80 mg IV), whereas patients who have received long-term therapy may require large dosages of the drug (120 to 200 mg IV). Furosemide is usually well tolerated, but hypotension may occur when the drug is administered to patients with acute heart failure after an acute MI. In such patients, pulmonary congestion may be primarily related to diastolic dysfunction rather than volume overload.
By stimulating guanylate cyclase within the vascular smooth muscle cell, nitroprusside, nitroglycerin, and nesiritide exert dilating effects on arterial resistance and venous capacitance vessels and thereby lower pulmonary blood flow and pulmonary venous pressures. Of the three, nitroprusside has the greatest effects and nitroglycerin has the least effects on arterial resistance vessels, and thus nitroprusside is most likely and nitroglycerin is the least likely to produce hypotension. Prolonged infusion of nitroglycerin (but not nitroprusside or nesiritide) may be accompanied by a loss of the drug’s hemodynamic effects (pharmacologic tolerance). Although nesiritide has natriuretic properties in normal subjects, it does not increase sodium excretion in heart failure and has not been shown to replicate or potentiate the effects of diuretics.
Therapy with nitroprusside, nitroglycerin, and nesiritide is usually initiated as a continuous low-dose intravenous infusion, the rate of which is increased to achieve specific hemodynamic or clinical goals. Nitroglycerin (1 to 50 µg/kg/min) is a reasonable first choice for most patients and may have advantages in patients with underlying ischemic heart disease. Nesiritide (2 µg/kg bolus followed by 0.01 to 0.03 µg/kg/min) or nitroprusside (0.2 to 5.0 µg/kg/min) may be used in patients who have not responded well to nitroglycerin, but nitroprusside is preferred for patients who have severe hypertension or valvular regurgitation. Hypotension is the most common side effect of all three vasodilators; thus, infusions of the drugs require close continuous monitoring of vital signs. Symptomatic hypotension is frequently associated with bradycardia (not tachycardia), particularly when nitroglycerin is used. All three drugs can cause pulmonary vasodilatation, which can aggravate arterial hypoxemia in patients with ventilation-perfusion abnormalities. Long-term (>48-hour) infusions of all three drugs is fraught with difficulties (i.e., the development of hemodynamic tolerance with nitroglycerin, the risk of cyanide and thiocyanate toxicity with nitroprusside, and renal impairment and possibly increased mortality with nesiritide). Hence, these drugs should be used generally only for brief periods.
If dyspnea, diaphoresis, and peripheral vasoconstriction persist or if the syndrome becomes immediately life threatening, mechanical ventilation can improve oxygenation and reduce the redistribution of blood into the pulmonary circuit. If this approach fails to stabilize the course of the patient, the removal of 250 to 500 mL of blood by phlebotomy can produce a rapid reduction in pulmonary blood volume and dramatic clinical improvement.
The most serious presentation of heart failure in the hospitalized patient is the syndrome of refractory heart failure, which is characterized by hemodynamic instability and systemic hypotension. Patients complain of dyspnea and fatigue at rest and have objective evidence of poor peripheral perfusion, as reflected by low systemic blood pressure, diminished mental alertness, cool extremities, and decreased urine output. Laboratory evaluation frequently reveals hyponatremia and azotemia. Refractory heart failure may represent the first evidence of heart disease; it may appear in patients who are already hospitalized for an acute cardiac disorder (e.g., MI), or it may complicate the course of a patient with long-standing heart failure. If severe, abrupt, and accompanied by clinical evidence of sympathetic overactivity, the syndrome is designated as cardiogenic shock ( Chapter 103 ).
The central feature of refractory heart failure is a deterioration of cardiac performance to a level incompatible with adequate perfusion of peripheral organs. Although patients characteristically present with very low blood pressures, the level of systemic pressure may not accurately reflect the adequacy of perfusion. Some patients have very low blood pressures but maintain excellent end-organ perfusion and function (e.g., patients with heart failure receiving ACE inhibitors). In others, blood pressure is preserved by intense peripheral vasoconstriction even though cerebral and renal function is severely compromised. In either case, the degree of circulatory compromise is so profound and the state of the circulation is so precarious that small changes in physiologic variables can readily provoke end-organ failure or death. The primary goal of treatment is the restoration of clinical stability and adequate perfusion to all organs of the body.
Management of Refractory Heart Failure
Several general measures are indicated in all patients with refractory heart failure. Immediate hospitalization (usually in a critical care

unit) is essential. Noninvasive assessment of ventricular function may be useful to quantify the magnitude of ventricular dysfunction and to allow the diagnosis of surgically correctable lesions (e.g., papillary muscle rupture, ventricular septal defect, prosthetic valve thrombosis). Invasive hemodynamic monitoring may be helpful in characterizing the hemodynamic derangement and guiding the use of pharmacologic agents. Daily measurements of urine output and body weight are useful in monitoring fluid balance.
The most important therapeutic measures in the treatment of refractory heart failure are (1) fluid management, (2) the use of intravenous positive inotropic agents, (3) the use of intravenous vasoconstrictor agents, and (4) mechanical and surgical interventions.
In general, patients should be maintained at dry weight as long as this goal can be achieved without compromising peripheral perfusion. Although fluids are commonly administered with the goal of maintaining the pulmonary capillary wedge pressure at a specific level, there is little evidence that this approach improves the outcome of patients. Similarly, although pulmonary artery balloon flotation catheters are frequently used to perform hemodynamic measurements, physicians should recognize that the level of cardiac output does not assess the adequacy of peripheral perfusion and that the level of pulmonary capillary wedge pressure is influenced not only by intravascular volume but also by changes in cardiac contractility, diastolic function, mitral valve function, and the peripheral circulation. Hence, the clinical response to fluid administration may provide more useful information than isolated measurements of cardiac output or ventricular filling pressures.
Positive inotropic drugs can produce hemodynamic and clinical benefits not only by stimulating cardiac contractility but also by exerting dilatory effects on peripheral blood vessels. Cardiac output is increased and pulmonary wedge pressures are decreased, usually with little change in systemic blood pressure. All positive inotropic agents used in the treatment of refractory heart failure act by increasing myocardial levels of cyclic adenosine monophosphate, either by increasing its synthesis (e.g., dobutamine) or by decreasing its degradation (e.g., milrinone). However, milrinone differs from dobutamine in several ways: (1) because it is a more effective vasodilator, milrinone produces greater decreases in pulmonary wedge pressure and greater decreases in blood pressure than dobutamine; (2) because it is a long-acting agent, adverse effects persist for longer periods with milrinone than dobutamine; and (3) pharmacologic tolerance may occur with dobutamine, but this is less of a problem with milrinone. A combination of dobutamine and milrinone may be particularly useful in selected patients with nonischemic cardiomyopathy, but such a regimen should be used cautiously because both drugs can produce tachycardia, myocardial ischemia, and serious arrhythmias.
Dobutamine is administered as a continuous intravenous infusion, initially at a rate of 3 to 6 µg/kg/min (without a bolus), and the rate may be increased up to 10 to 15 µg/kg/min. Milrinone is generally initiated with a bolus dose of 0.5 µg/kg, followed by a continuous infusion at a rate of 0.375 to 0.75 µg/kg/min. Short-term infusions of both drugs (alone or in combination) can be effective in the treatment of refractory heart failure, especially when systemic blood pressures are relatively preserved. However, long-term continuous or intermittent infusions can increase the risk of cardiac events (including death) and should be avoided.
Two vasoconstrictor agents are commonly used to support systemic blood pressure in patients with refractory heart failure: dopamine and levarterenol. Dopamine is an endogenous catecholamine that interacts with dopamine receptors (both DA1 and DA2 subtypes), ß1 (but not ß2 ) adrenergic receptors, and a-adrenergic receptors in the heart and peripheral circulation. As a result of these interactions, the drug causes vasodilation (owing to its agonist effects on DA1 receptors), stimulates cardiac contractility (owing to its agonist effects on ß1 receptors), and causes constriction of peripheral arterial and venous vessels (owing to its agonist effects on a1 -receptors). The hemodynamic effects of dopamine depend largely on the dose of the drug administered. Low dosages (<2 µg/kg/min), which stimulate DA1 and DA2 receptors, act to dilate the renal and splanchnic circulations. Moderate dosages (2 to 5 µg/kg/min), which activate ß1 -receptors, increase cardiac output but produce little change in pulmonary wedge pressure, heart rate, or systemic vascular resistance. High dosages (>5 µg/kg/min), which stimulate a1 -receptors, increase pulmonary wedge pressure, blood pressure, and heart rate and may reduce renal blood flow. Dopamine may be useful in the treatment of both pulmonary congestion and peripheral hypoperfusion. In normotensive patients with pulmonary congestion, low doses of dopamine increase renal blood flow and are used alone (or in combination with dobutamine) to potentiate the diuretic actions of furosemide. In hypotensive patients with peripheral hypoperfusion, large doses of dopamine are used to support systemic blood pressure ( Chapter 103 ).
Levarterenol is the commercial preparation of the endogenous catecholamine norepinephrine, which stimulates both a1 – and ß1 -receptors when administered in therapeutic doses. Because of its lack of DA1 -receptor effects, levarterenol increases systemic vascular resistance and blood pressure more than does dopamine, and the degree of systemic vasoconstriction may be sufficient to reduce renal blood flow even though cardiac output is increased as a result of ß1 -receptor stimulation. Consequently, levarterenol is used only in patients with shock whose blood pressure cannot be supported adequately with dopamine ( Chapter 103 ). Levarterenol is generally infused in dosages ranging from 0.03 to 0.12 µg/kg/min.
Both dopamine and levarterenol can cause serious adverse effects. Stimulation of a-receptors can cause intense peripheral vasoconstriction, which may reduce peripheral perfusion and (if extravasated during infusion) can cause local tissue necrosis. Stimulation of ß-receptors can lead to serious atrial and ventricular arrhythmias and myocardial ischemia. Stimulation of DA1 -receptors may cause nausea and vomiting.
If pharmacologic interventions fail to stabilize the patient with refractory heart failure, mechanical and surgical interventions may provide effective circulatory support ( Chapter 71 ). These include intra-aortic balloon counterpulsation, left ventricular assist device, and cardiac transplantation ( Chapter 80 ). A number of experimental surgical procedures have also been developed to support the failing heart (cardiomyoplasty and partial resection of the left ventricle), but despite a high level of initial enthusiasm, the results to date have been variable, unpredictable, and largely disappointing.
Intra-aortic balloon counterpulsation has been useful in the management of cardiogenic shock that is caused by acute myocardial ischemia or infarction ( Chapter 103 ), particularly when there is a coexisting mechanical defect (e.g., ventricular septal defect or papillary muscle rupture). Short-term use of ventricular assist devices has produced dramatic hemodynamic and clinical benefits, but long-term use of these devices has been associated with a high risk of infection and thromboembolic events. Ventricular assist devices have been primarily used to provide temporary circulatory support for patients awaiting transplantation, but they may have a limited role as a long-term treatment strategy. In the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH), patients with end-stage heart failure who were randomized to a permanent left ventricular assist device had a 48% lower risk of death than a control group. However, treatment was frequently complicated by infection, bleeding, and device malfunction, and the mortality advantage at 2 years was marginal. Cardiac transplantation ( Chapter 80 ) is an effective treatment for refractory heart failure, with a survival rate of 80% to 90% at 1 year and 60% to 70% at 5 years, usually with a markedly improved quality of life, despite the risks of organ rejection, immunosuppression, and allograft vasculopathy. These outcomes exceed the results with any medical or surgical intervention available for the management of patients with advanced heart failure, but such outcomes are comparable (and perhaps somewhat inferior) to the results with medical therapy in patients with mild or moderate heart failure. Hence, cardiac transplantation should be considered only for patients with refractory symptoms. The usefulness of transplantation is limited by the small number of donor hearts.
Goldman: Cecil Textbook of Medicine, 22nd ed., Copyright © 2004 W. B. Saunders Company

Grade A

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2. The SOLVD Investigators: Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293–302.

3. Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF): Effect of metoprolol CR/XL in chronic heart failure. Lancet 1999;353:2001–2007.

4. Packer M, Coats AJ, Fowler MB, et al, for the Carvedilol Prospective Randomized Cumulative Survival Study Group: Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651–1658.

5. Poole-Wilson PA, Swedberg K, Cleland JG, et al: Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003;362:7–13.

6. Pitt B, Zannad F, Remme WJ, et al, for the Randomized Aldactone Evaluation Study Investigators: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709–717.

7. Pitt B, Remme W, Zannad F, et al: Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309–1321.

8. The Digitalis Investigation Group: The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525–533.

9. Pitt B, Poole-Wilson PA, Segal R, et al: Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: Randomised trial—the Losartan Heart Failure Survival Study ELITE II. Lancet 2000;355:1582–1587.

10. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators: A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667–1675.

11. Moss AJ, Zareba W, Hall WJ, et al: Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877–883.

12. Bradley DJ, Bradley EA, Baughman KL, et al: Cardiac resynchronization and death from progressive heart failure: A meta-analysis of randomized controlled trials. JAMA 2003;289:730–740.
Goldman: Cecil Textbook of Medicine, 22nd ed., Copyright © 2004 W. B. Saunders Company


Anker SD, Negassa A, Coats AJ, et al: Prognostic importance of weight loss in chronic heart failure and the effect of treatment with angiotensin-converting enzyme inhibitors: an observational study. Lancet 2003;361:1077–1083. Weight loss is independently linked to impaired survival.

Jong P, Demers C, McKelvie RS, et al: Angiotensin receptor blockers in heart failure: meta-analysis of randomized controlled trials. J Am Coll Cardiol 2002;39:463–470. ARBs are promising as monotherapy and may add to ACE inhibitors but are not better alone than ACE inhibitors alone.

McMurray J, Pfeffer MA: New therapeutic options in congestive heart failure. Circulation 2002;105:2099–1106 and 2223–2228. A two-part overview.

Rose EA, Gelijns AC, Moskowitz AJ, et al: Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group. Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med 2001;345:1435–1443. These devices provided a marginal improvement in outcome.


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