Goldman: Cecil Medicine, 23rd ed.
Barry M. Massie
Definition
Heart failure is a heterogeneous syndrome in which abnormalities of cardiac function are responsible for the inability of the heart to pump blood at an output sufficient to meet the requirements of metabolizing tissues or the ability 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 (shortness of breath, rales, elevated jugular venous pressure, and edema) and/or manifestations of inadequate tissue perfusion (impaired exercise tolerance, fatigue, signs of hypoperfusion, renal dysfunction). Heart failure may occur as a result of (1) impaired myocardial contractility (systolic dysfunction, commonly characterized as reduced left ventricular [LV] ejection fraction [EF]); (2) increased ventricular stiffness or impaired myocardial relaxation (diastolic dysfunction, which is commonly associated with a relatively normal LVEF); (3) a variety of other cardiac abnormalities, including obstructive or regurgitant valvular disease, intracardiac shunting, or disorders of heart rate or rhythm; or (4) states in which the heart is unable to compensate for increased peripheral blood flow or metabolic requirements. In adults, LV involvement is almost always present even if the manifestations are primarily those of right ventricular (RV) 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, including its presentation in an acutely decompensated state. The most common causes of de novo acute heart failure, such as MI ( Chapter 72 ), valvular disease ( Chapter 75 ), myocarditis ( Chapter 59 ), and cardiogenic shock ( Chapter 108 ), are discussed elsewhere.
Epidemiology
Both the incidence and the prevalence of heart failure are growing, as is the resulting burden of deaths and hospitalizations. 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, diabetes, dyslipidemia, and obesity 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 per 1000 patient-years among those younger than 45 years of age, to 10 per 1000 patient-years for those older than 65 years, to 30 per 1000 patient-years (3%) for those older than 85 years. Prevalence figures follow a similar exponential pattern, increasing from 0.1% before 50 to 55 years of age to almost 10% after age 80 years. In the United States, there are an estimated 5.1 million patients with heart failure, of whom approximately 75% are 65 years of age 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.
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 major factor in 75%, including most of the patients with coronary disease.
Prevention of Heart Failure
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 66 ). Any intervention that reduces the risk of a first or recurrent MI (e.g., treatment of hypertension or dyslipidemia, antiplatelet therapy in high-risk individuals, and aggressive management of diabetes) will also reduce the incidence of heart failure ( Chapter 49 ). In post-MI patients ( Chapter 72 ), these measures plus β-blockers and angiotensin-converting enzyme (ACE) inhibitors, with coronary revascularization in selected individuals, can still prevent the development of heart failure. In patients with reduced LVEF, ACE inhibitors and β-blockers prevent or delay progressive LV dysfunction and dilation and the onset or worsening of heart failure. Well-timed intervention for progressive valvular disease affords another opportunity to prevent eventual heart failure ( Chapter 75 ).
Stages of Heart Failure
The recognition that most patients who develop heart failure have underlying risk factors or predisposing clinical conditions that precede its development, usually by many years, has led to a greater emphasis on early detection and treatment of predisposing factors, on the staging of heart failure ( Fig. 57-1 ), and on early intervention. Stage A heart failure includes patients who are at risk for development of heart failure but do not as yet have either symptoms or apparent structural abnormalities of the heart; this includes patients with hypertension, atherosclerotic disease, diabetes, obesity, or the metabolic syndrome and individuals with ongoing excessive alcohol intake, use of cardiotoxic drugs, a familial history of cardiomyopathy, or a known genetic abnormality associated with cardiomyopathy ( Chapter 59 ). Stage B encompasses asymptomatic patients who have demonstrable structural abnormalities that predispose to heart failure, such as prior MI, LV hypertrophy by electrocardiography or echocardiography, reduced LVEF or LV dilatation, or asymptomatic but hemodynamically significant valvular heart disease. Stage C heart failure includes patients who have exhibited symptoms or signs of heart failure. These patients may have improved to the point of being relatively asymptomatic, but they still are classified as Stage C and usually continue to receive treatment with agents that are known to improve their natural history, such as β-blockers and inhibitors of the renin-angiotensin-aldosterone system.
FIGURE 57-1 Stages of heart failure. EF = ejection fraction; FHx CM = family history of cardiomyopathy; HF = heart failure; LV = left ventricle; LVH = left ventricular hypertrophy; MI = myocardial infarction. (Modified from Hunt SA: ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure]. J Am Coll Cardiol 2005;46:e1–e82.) |
Pathobiology
Differing Mechanisms of Heart Failure
Heart failure is a syndrome that may result from many cardiac and systemic disorders ( Table 57-1 ). Some of these disorders, at least initially, do not involve the heart, and the term “heart failure” may be confusing. Even in high-output states, however, the patient may present with the classic findings of exertional dyspnea and edema (high-output heart failure) that resolve if the underlying disorder is eliminated. If they persist, 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.
TABLE 57-1 -- PATHOGENESIS OF HEART FAILURE
IMPAIRED SYSTOLIC (CONTRACTILE) FUNCTION | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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IMPAIRED DIASTOLIC FUNCTION (RESTRICTED FILLING, INCREASED STIFFNESS) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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MECHANICAL ABNORMALITIES | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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DISORDERS OF RATE AND RHYTHM | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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PULMONARY HEART DISEASE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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HIGH-OUTPUT STATES | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Abnormalities of Cardiac Function
Systolic Function
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 57-2 ). In the failing heart with depressed contractility, there is relatively little increment in systolic function with further increases in LV volume, and the ventricular function curve is shifted downward and flattened ( Chapter 50 ). 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.
TABLE 57-2 -- MAJOR DETERMINANTS OF CARDIAC PERFORMANCE
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Assessment of systolic function clinically is more problematic. The most useful measure is the LVEF (stroke volume/end-diastolic volume, usually expressed as a percentage), which reflects a single point on the ventricular function curve. The EF is “load dependent,” however, meaning that alterations in afterload (see later discussion) can affect it independently 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 EF. Nonetheless, with the exceptions indicated earlier, when the EF is normal (>50 to 55% in most laboratories), systolic function is usually adequate. LVEFs that are mildly (40 to 50%), moderately (30 to 40%), or 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 LV dilation.
Diastolic Function
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., an excessively steep relationship between change in pressure and change in volume [ΔP/ΔV]), passive filling may be impaired and atrial pressures are abnormally elevated. In this setting of a noncompliant ventricle (compliance is the inverse of stiffness—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, LV 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, resulting in exertional dyspnea and exercise intolerance.
Ventricular Preload
In the intact heart, preload is best characterized by the end-diastolic volume or pressure, which are indirect indicators of end-diastolic fiber length ( Chapter 50 ). The performance of the normal left ventricle is highly preload dependent, but the failing heart operates at high preloads and on the flat part of the LV function curve (see Fig. 50-3 in Chapter 50 ). In contrast to the normal ventricle, a modest decrease in preload has little effect on LV filling pressures, whereas an increase in preload does not improve systolic function but worsens pulmonary congestion further. Preload reduction by diuresis or by reduction of venous return with venodilating agents generally has a beneficial effect on symptoms of heart failure.
Ventricular Afterload
LV afterload frequently is equated with arterial pressure or systemic vascular resistance, but a more accurate measurement of afterload is systolic wall stress ( Chapter 50 ), defined as follows:
At any given arterial pressure, afterload is increased with a dilated, thin-walled 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 and Rhythm
Heart rate affects cardiac performance by two mechanisms. First, increasing the 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 LV 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.
Myocardial Blood Flow and Oxygen Requirements
In the normal heart, myocardial blood flow is closely coupled to oxygen requirements, and it is not ordinarily considered a determinant of cardiac performance. However, myocardial ischemia is associated 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 reestablishes 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 of less than 60 mm Hg. Endothelial dysfunction, which is common in patients with heart failure, also may limit blood flow. At the same time, tachycardia, increased afterload, and substantial LV 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.
Genetic Causes of Dilated Cardiomyopathy
Although much less is known about the genetics of dilated cardiomyopathy than that of hypertrophic cardiomyopathy ( Chapter 59 ), 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 447 ) 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 cases of idiopathic dilated cardiomyopathy.
Heart Failure Syndrome
Chronic heart failure is a multifaceted syndrome with diverse presentations ( Fig. 57-2 ). 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, 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 57-3 ). The number of hormonal systems that are known to be activated in heart failure continues to grow.
FIGURE 57-2 Pathophysiology of heart failure, illustrated by Venn diagram. |
TABLE 57-3 -- NEUROHORMONES THAT MAY BE INCREASED IN CHRONIC HEART FAILURE
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Neurohormonal Responses
Sympathetic Nervous System
Initial activation of the sympathetic nervous system probably results from reduced pulse pressures, which activate 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 release of norepinephrine 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 further stimulate sympathetic responses.
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. Increased levels of plasma norepinephrine are associated with a worse 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, β-adrenoceptor blockade, which once was considered dangerous in heart failure because it would interfere with important compensatory mechanisms, consistently improves LV function and prognosis. The roles of other catecholamines in heart failure remain undefined.
Renin-Angiotensin-Aldosterone System
Elements of the renin-angiotensin-aldosterone system are activated relatively early in heart failure. The presumptive mechanisms of induction include renal hypoperfusion, β-adrenergic system stimulation, and hyponatremia. All may be activated further by diuretic therapy. Angiotensin II increases blood pressure by vasoconstriction; it enhances glomerular filtration by increasing renal pressure and maintaining glomerular flow through 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 LV 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 may induce vascular hypertrophy, whereas aldosterone induces myocardial fibrosis. The striking success of ACE inhibitors and, more recently, of spironolactone in improving the natural history of heart failure suggests that the adverse effects of renin-angiotensin-aldosterone activation may outweigh their benefit.
Other Neurohormonal Systems
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. However, the renal responses to these natriuretic hormones are downregulated, so that they do not have the same natriuretic effects in patients with 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 patients with heart failure, and interference with their actions may promote vasodilation and aquaresis. Arginine vasopressin induces vasoconstriction through a vascular (V-1) receptor and reduces free water clearance through a renal tubular (V-2) receptor. Endothelin causes prolonged vasoconstriction, reductions in glomerular filtration, mesangial hypertrophy, bronchoconstriction, and pulmonary arteriolar constriction. Although endothelin is a theoretically attractive target for therapy, clinical trials with endothelin antagonists have yielded unimpressive results, indicating that interdiction of neurohormonal activation is not uniformly beneficial.
Cytokine Activation
Circulating levels of many proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β, 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. Nonetheless, trials using antagonists of TNF-α have not shown clinical benefit.
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, which 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 that act in hemorrhage and shock; the result is abnormal retention of sodium and water. In advanced heart failure, which is usually characterized by low cardiac output and/or hypotension (or 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 that lead to altered orientation of the myofibrils and progressive fibrosis. The result is more discoordinate and less effective contraction. ACE inhibitors and β-blockers slow, halt, or reverse this remodeling process, preventing LV dilation, geometric distortion, and deterioration in contractile function.
Clinical Manifestations
Heart failure may manifest acutely in a de novo manner, chronically, or as an acute exacerbation of chronic heart failure.
Acute Decompensation of Heart Failure
Most episodes of acute worsening of heart failure occur in patients with previously recognized symptoms of chronic heart failure. Patients with such decompensations usually present with shortness of breath, generally after a period of fluid retention or signs of congestion, as manifested by worsening edema and some degree of worsening dyspnea ( Fig. 57-3 ). Occasionally, the presentation may be more acute, with rapid progression to resting dyspnea and/or pulmonary edema. The latter presentation is often associated with hypertension and is particularly characteristic of patients who have diastolic dysfunction and whose stiff left ventricle tolerates fluid retention poorly. In patients without a preceding history of heart failure, other precipitating factors, such as acute MI ( Chapter 72 ), tachyarrhythmias ( Chapters 63 and 64 ), previously unrecognized or new valvular abnormalities ( Chapter 75 ), toxic damage (including alcohol excess), or acute myocarditis ( Chapter 59 ), should be considered. Rapid diagnosis by noninvasive testing, early cardiac catheterization, and, in selected cases, endomyocardial biopsy is essential. 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 the condition is not reversed, cardiac transplantation ( Chapter 82 ) may be the best option for appropriate candidates.
FIGURE 57-3 Number of days from onset of worsening of selected symptoms of heart failure to admission to hospital: cumulative percentage of patients. (Reprinted with permission from Schiff GD, Fung S, Speroff T, et al: Decompensated heart failure: Symptoms, patterns of onset, and contributing factors. Am J Med 2003;114:625-630.) |
Chronic Heart Failure
Left-Sided and Right-Sided 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 RV dysfunction. The manifestations of LV 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 RV puressure overload (e.g., pulmonary hypertension resulting from cor pulmonale or pulmonary vascular disease) or intrinsic dysfunction of the right ventricle or its valves. However, the most common cause of RV pressure overload is left-sided heart dysfunction, which results in pulmonary hypertension. If 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.
Heart Failure with Preserved Systolic Function
Myocardial mechanisms that lead to the syndrome of heart failure can be differentiated into conditions that depress LV systolic function and conditions that occur despite preserved contractility. Although it is arbitrary, a LVEF threshold of 45 to 50% often is used for this distinction.
Until the widespread use of noninvasive assessments of LV 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 that at least 40% of patients with heart failure have normal EFs. In the ongoing Cardiovascular Health Study, a population-based study of more than 5000 patients aged 65 years and older, more than 70% of the patients developing heart failure had normal or only mildly impaired systolic function. It is likely that more elderly patients with heart failure 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 LV hypertrophy and 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 rate of patients with preserved systolic function is lower than the rate for those with low EFs but remains higher than in the general population, even among similarly older-aged individuals. Hospitalization and rehospitalization rates for these patients are comparable to the rates for patients with reduced EFs, and there are few data on treatment to guide physicians.
Although patients who have heart failure with preserved systolic function often are considered to have diastolic dysfunction, other explanations for this presentation must be considered, some of which are reversible or warrant specific therapy ( Table 57-4 ). The first two questions to consider are whether the patient's symptoms are caused by heart failure of any type and whether important valvular abnormalities are present. LVEF measurements may be inaccurate, particularly if their technical quality is suboptimal. Regurgitant valve disease may lead to a dissociation between the LVEF and underlying myocardial dysfunction, because afterload may be low in this setting. There also are many conditions in which LV function is impaired transiently, but subsequently measured EFs may be normal. Intermittent ischemia, presenting as episodic heart failure (“flash pulmonary edema”), is the most important of these conditions, because revascularization may be indicated. Severe hypertension with subsequent treatment and transient arrhythmias also may have temporary effects on EF. Some patients with alcoholic cardiomyopathy exhibit rapid recovery in EF when they cease drinking.
TABLE 57-4 -- CAUSES OF (AND ALTERNATIVE EXPLANATIONS FOR) HEART FAILURE WITH PRESERVED SYSTOLIC FUNCTION (LEFT VENTRICULAR EJECTION FRACTION >45–50%)
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The remaining patients most likely have diastolic dysfunction as the underlying disorder. The noninvasive measurement of diastolic function remains problematic. The most commonly used test, 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.
Factors Precipitating Acute Decompensation of Chronic Heart Failure
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 57-5 ). 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 can cause cardiac decompensation.
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Diagnosis
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.
The most frequent symptoms, dyspnea and fatigue, are not specific for heart failure, especially in the older population, but 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 ( Chapter 51 ), 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 with coronary artery disease, chronic hypertension, diabetes, a history of heavy alcohol use, and/or advanced age. If such patients present with any of the symptoms or physical findings suggestive of heart failure, additional testing (see later discussion) should be undertaken, typically beginning with echocardiography ( Chapter 53 ).
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
Dyspnea ( Chapter 83 ), or perceived shortness of breath, is the most common symptom of heart failure. In most patients, dyspnea is 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, stimulating 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 those with 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 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 RV failure and tricuspid regurgitation, which may lead to lower pulmonary venous pressures. Dyspnea is a common symptom of patients with pulmonary disease ( Chapter 83 ), obesity, or anemia and of sedentary individuals.
Orthopnea and Paroxysmal Nocturnal Dyspnea
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 the 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 under-recognized 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 if they are treated adequately.
Paroxysmal nocturnal dyspnea is an attack of acute, severe shortness of breath that awakens 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.
Acute Pulmonary Edema
Pulmonary edema results from transudation of fluid into the alveolar spaces due to acute rises in capillary hydrostatic pressures caused by an acute depression of cardiac function or 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.
Exercise Intolerance
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
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.
Edema and Fluid Retention (Ascites, Pleural Effusion, Pericardial Effusion)
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 by the 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, in those who have had veins harvested for coronary bypass surgery, and in patients taking calcium channel blockers, which themselves cause edema. Fluid retention precipitated by the thiazolidinediones ( Chapter 248 ) may precipitate heart failure or mimic it.
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 from impaired lymphatic drainage caused by elevated systemic venous pressures. Pericardial effusions are far less frequent but may occur.
Abdominal and Gastrointestinal Symptoms
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 if associated with systemic hypotension, a severe congestive and ischemic hepatopathy may occur, with striking elevations in liver function markers 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.
Sleep Disorders and Central Nervous System Manifestations
Periods of nocturnal oxygen desaturation to less than 80 to 85% are relatively common in patients with heart failure; they coincide with episodes of apnea ( Chapter 101 ), 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 have a striking beneficial effect on fatigue and other symptoms of heart failure.
Aside from the common complaint of fatigue, which originates in part in the central nervous system, brain function is not affected in most patients with heart failure. In advanced heart failure, cerebral hypoperfusion can 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 increased levels of pro-inflammatory cytokines (e.g., TNF), elevated metabolic rates, loss of appetite, and malabsorption. Cardiac cachexia carries a poor prognosis.
Physical Examination
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.
Appearance and Vital Signs
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 higher (>80 beats per minute), it may be lower in patients with chronic, stable heart failure. Premature beats and arrhythmias are common. Pulsus alternans (alternating amplitude of successive beats) is a sign of advanced heart failure (or of 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 lower.
Jugular Veins and Neck Examination
Examination of the jugular veins is one of the most useful aspects of the evaluation of patients with heart failure. The jugular venous pressure should be quantified in centimeters of water (normal = 8 cm H2O) ( Chapter 48 ), estimating the level of pulsations above the sternal angle (and arbitrarily adding 5 cm H2O 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.
Pulmonary Examination
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 they are 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 mmHg). LV 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.
Cardiac Examination
The cardiac examination is a crucial part of the evaluation of the patient with heart failure, but it is more useful for identification of associated cardiac abnormalities than for assessment of the severity of the heart failure ( Chapter 48 ). 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 an LV aneurysm. A parasternal lift is valuable evidence of pulmonary hypertension.
The first heart sound (S1) may be diminished in amplitude when LV 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 LV dysfunction, but it is present only in a few patients with low EFs and elevated LV 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 RV 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.
Examination of the Abdomen and Extremities
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.
Characterization: Essential and Contingent Tests
Essential Tests
Chest Radiography
Although the standard posteroanterior and lateral chest radiographs provide limited information about chamber size, the presence of overall cardiomegaly (a cardiothoracic ratio >0.50, especially if >0.60) is a strong indicator of heart failure or another cause of cardiomegaly (especially valvular insufficiency) ( Chapter 51 ). However, almost 50% of patients with heart failure do not have this high a cardiothoracic ratio.
Most patients with acute heart failure, but only a few of those with chronic heart failure, have evidence of pulmonary venous hypertension (upper lobe redistribution, enlarged pulmonary veins), interstitial edema (haziness of the central vascular shadows or increased central interstitial lung markings), or pulmonary edema (perihilar or patchy peripheral infiltrates). 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 on the left side, reflecting the greater pleural surface area of the right lung.
Electrocardiography
The major importance of the electrocardiogram is to evaluate cardiac rhythm, identify prior MI, and detect evidence of LV hypertrophy ( Chapter 52 ). Prior MI suggests that the cause is ischemic cardiomyopathy with systolic dysfunction. LV hypertrophy is a nonspecific finding but may point toward LV diastolic dysfunction if the EF is not depressed.
Echocardiography
Noninvasive cardiac imaging is a crucial part of the diagnosis and evaluation of heart failure. The most useful procedure is the transthoracic echocardiogram ( Chapter 53 ), which provides a quantitative assessment of LV function; in the presence of appropriate symptoms and signs, it can confirm the presence of heart failure resulting from 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 LV and RV size and regional wall motion (as an indicator of prior MI), evaluation of the heart valves, and diagnosis of LV hypertrophy. The echocardiogram generally has replaced the chest radiograph in the diagnostic assessment of heart failure.
Measurements of Natriuretic Peptides
Serum levels of natriuretic peptides can be measured quickly and accurately, including point-of-care testing at the bedside. B-type natriuretic peptide (BNP) and amino (N)-terminal pro-BNP are relatively sensitive and specific markers for clinically confirmed heart failure These peptides have been found to be useful adjuncts in the diagnosis of patients presenting in the acute care setting with possible heart failure, particularly when the diagnosis remains uncertain.[1] However, levels of both BNP and N-terminal pro-BNP increase with age in the absence of clinical heart failure, especially in women, probably reflecting increased ventricular stiffness associated with aging and hypertension. BNP levels may also be increased slightly in patients with chronic obstructive pulmonary disease, in whom elevations may reflect diastolic dysfunction or RV dysfunction but nonetheless may lead to a false-positive clinical diagnosis of heart failure. Elevated natriuretic peptide measurements are associated with a worse prognosis and may be helpful in assessing the response to therapy. However, the clinical value of serial measurements in guiding therapy, and whether they can facilitate improved outcomes, have not been assessed.
Contingent Tests
After the diagnosis of heart failure is made, the goal of additional testing is to identify potentially correctable or specifically treatable causes and to obtain further information that is necessary for future management.
Laboratory Testing
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 patients with heart failure).
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 244 ). Many guidelines recommend thyroid function tests for all patients, or at least all elderly patients and those with atrial fibrillation. Hemochromatosis ( Chapter 231 ) is a potentially treatable cause of heart failure; particularly if there is accompanying diabetes or hepatic disease, measurement of serum ferritin levels is indicated. Sarcoidosis ( Chapter 95 ) is another potentially treatable cause, although it would be unusual not to have evidence of accompanying lung disease. Amyloidosis ( Chapter 296 ) should be considered in patients with other manifestations, but treatment of the cardiac manifestations is rarely successful except with heart transplantation.
Assessment of Left Ventricular Function
Although heart failure is a syndrome with many pathogenic mechanisms, the most common are LV systolic dysfunction and LV diastolic dysfunction. In some patients, it is almost 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. However, it is essential to distinguish between these two entities, because they may require different diagnostic evaluations and different therapeutic approaches ( Chapter 58 ). The most useful and practical test is the echocardiogram ( Chapter 53 ); alternative approaches include radionuclide measurements of LVEF ( Chapter 54 ) and left ventriculography if cardiac catheterization ( Chapter 56 ) is being performed. All of these tests allow the detection of significant systolic dysfunction; diastolic dysfunction sometimes can be documented ( Chapter 53 ) but often is identified primarily as a process of exclusion in patients with preserved systolic function. Randomized trials have found no benefit, in terms of days alive and out of hospital or in a number of other relevant end points, among patients who were monitored with pulmonary artery catheterization compared with those who were not.[2]
Diagnostic Evaluation
Assessment for Coronary Artery Disease
Coronary artery disease is the most common cause of heart failure in industrialized societies. Often it is known that a patient has coronary disease based on a prior history of MI or positive results on an angiogram or noninvasive test, but in some patients MI can be silent. There are two reasons to identify the coexistence of heart failure and coronary disease: first, to treat symptoms that may be caused by ischemia and, second, to improve prognosis ( Chapters 70 , 71 , and 72 ). A prudent approach is to divide patients with heart failure into three groups: (1) those with clinical evidence of ongoing ischemia (active angina or a possible ischemic equivalent), (2) those who have had a prior MI but do not currently have angina, and (3) those 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 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.
Myocardial Biopsy
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 82 ), particularly eosinophilic and giant cell myocarditis, which may respond to immunosuppressive therapy. Another potential exception is in the patient being evaluated for cardiac transplantation ( Chapter 82 ), because the presence of some entities may preclude this procedure.
Assessment of Exercise Capacity
Quantitative assessment of exercise capacity provides additional insight into prognosis beyond 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 evaluation for transplantation ( Chapter 82 ) 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 monitored from visit to visit as a guide to management.
Assessment of Arrhythmias
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, EF, 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 64 ).
Differential Diagnosis
Although it is not difficult to make the definitive diagnosis of heart failure in a patient who presents 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 LV function and less definitive clinical evidence. The most important alternative is possible pulmonary disease, for which pulmonary function testing is usually helpful ( Chapter 85 ). If LV systolic function is normal, it may be difficult to make a conclusive determination of the relative role of diastolic heart failure compared with other concomitant conditions, such as severe obesity, chronic anemia, or other systemic illnesses; in some patients, a therapeutic trial of treatment for heart failure ( Chapter 58 ) may be diagnostic.
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 necessary to monitor therapy (primarily renal function and electrolytes). If the status of ventricular function is known, there are few indications for retesting. Exceptions are monitoring for transplantation and important changes in clinical status, such as marked deterioration in a patient previously known to have preserved LV function or the occurrence of new murmurs in conjunction with declining status.
Chapter 58 – HEART FAILURE: MANAGEMENT AND PROGNOSIS
John J.V. McMurray Marc A. Pfeffer
Heart failure is an overarching term for a syndrome (i.e., a constellation of signs and symptoms) that encompasses a vast spectrum of cardiovascular disorders and is associated with a greatly heightened risk of death and nonfatal adverse cardiovascular events ( Chapter 57 ). Treatment is initially directed toward prevention of cardiac injury (e.g., due to hypertension or myocardial infarction) or toward limiting structural progression if cardiac damage has already occurred (e.g., left ventricular remodeling with declining left ventricular ejection fraction) and delaying the development of symptomatic heart failure. Once symptoms develop, treatments are also directed at improving functional status as well as prognosis.
Approximately one in five adults will develop heart failure. In the United States, the nearly 1 million annual hospitalizations with a primary diagnosis of heart failure account for 5 million hospital days. The estimated cost of heart failure management ranges from $15 billion to $40 billion annually, depending on the formula used.
Randomized controlled clinical trials (RCTs) supply the framework for quantifying what different therapeutic approaches can offer. Even when they are definitive, RCTs only generate data about average risks and benefits of the tested therapeutic option in a selected cohort. Because an individual patient's responses can only be implied from the overall estimated group responses, RCTs cannot definitively direct the approach of every patient or answer the myriad questions that confront the practitioner regarding the specific circumstances of the patient. Another major limitation of RCTs is the relatively narrow time frame of observation, generally only months to several years, compared with epidemiologic experiences during decades. Despite these limitations, RCTs are the premier tool of evidence-based medicine, and the field of heart failure has fortunately been the focus of relatively high quality RCTs that have provided robust evidence to improve clinical care and prognosis ( Table 58-1 ). Indeed, the implementation of evidence from RCTs into clinical practice has resulted in impressive temporal improvements in survival after discharge from a first hospital admission for heart failure. Moreover, the age at which symptomatic heart failure first becomes evident has increased. Despite these tangible advances, heart failure continues to be a leading cause of morbidity and mortality in the elderly.
Trial, Treatment, and Year Published | N | Severity of Heart Failure | Estimated First-Year Placebo/Control Group Mortality | Background Treatment[†] | Treatment Added | Trial Duration (years) | Primary End Point | Relative Risk Reduction (%)[‡] | Events Prevented per 1000 Patients Treated[¶¶] | ||
DEATH | HF HOSP. | DEATH OR HF HOSP. | |||||||||
ACE INHIBITORS | |||||||||||
CONSENSUS, 1987[a] | 253 | End stage | 52 | Spironolactone | Enalapril, 20 mg bid | 0.54[‡] | Death | 40 | 146 | — | — |
SOLVD-T, 1991[b] | 2569 | Mild-severe | 15.7 | — | Enalapril, 20 mg bid | 3.5 | Death | 16 | 45 | 96 | 108 |
β-BLOCKERS | |||||||||||
CIBIS-2, 1999[c] | 2647 | Moderate-severe | 13.2 | ACE-I | Bisoprolol, 10 mg qd | 1.3[‡] | Death | 34 | 55 | 56 | — |
MERIT-HF, 1999[d] | 3991 | Mild-severe | 11.0 | ACE-I | Metoprolol CR/XL, 200 mg qd | 1.0[‡] | Death | 34 | 36 | 46 | 63 |
COPERNICUS, 2001[e] | 2289 | Severe | 19.7 | ACE-I | Carvedilol, 25 mg bid | 0.87[‡] | Death | 35 | 55 | 65 | 81 |
ANGIOTENSIN RECEPTOR BLOCKERS | |||||||||||
Val-HeFT, 2001[8] | 5010 | Mild-severe | ∼8.0 | ACE-I | Valsartan, 160 mg bid | 1.9 | CV death or morbidity | 13 | 0 | 35 | 33[¶] |
CHARM-Alternative, 2003[7] | 2028 | Mild-severe | 12.6 | BB | Candesartan, 32 mg qd | 2.8 | CV death or HF hosp. | 23 | 30 | 31 | 60 |
CHARM-Added, 2003[9] | 2548 | Moderate-severe | 10.6 | ACE-I + BB | Candesartan, 32 mg qd | 3.4 | CV death or HF hosp. | 15 | 28 | 47 | 39 |
ALDOSTERONE BLOCKADE | |||||||||||
RALES, 1999[11] | 1663 | Severe | ∼25 | ACE-I | Spirolactone, 25–50 mg qd | 2.0[‡] | Death | 30 | 113 | 95 | — |
HYDRALAZINE-ISDN | |||||||||||
V-HeFT-1, 1986[f] | 459 | Mild-severe | 26.4 | — | Hydralazine, 75 mg tid-qid | 2.3 | Death | 34 | 52 | 0 | — |
ISDN, 40 mg qid | |||||||||||
A-HeFT, 2004[14] | 1050 | Moderate-severe | ∼9.0 | ACE-I + BB + spironolactone | Hydralazine, 75 mg tid | 0.83[‡] | Composite | — | 40 | 80 | — |
ISDN, 40 mg tid | |||||||||||
DIGITALIS GLYCOSIDES | |||||||||||
DIG, 1997[13] | 6800 | Mild-severe | ∼11.0 | ACE-I | Digoxin | 3.1 | Death | 0 | 0 | 79 | 73 |
CRT | |||||||||||
COMPANION, 2004[17] | 925 | Moderate-severe | 19.0 | ACE-I + BB + spironolactone | CRT | 1.35[‡] | Death or any hospital admission | 19 | 38 | — | 87 |
CARE-HF, 2005[g] | 813 | Moderate-severe | 12.6 | ACE-I + BB + spironolactone | CRT | 2.45 | Death or CV hospital admission | 37 | 97 | 151 | 184 |
CRT-D | |||||||||||
COMPANION, 2004[17] | 903 | Moderate-severe | 19.0 | ACE-I + BB + spironolactone | CRT-ICD | 1.35[‡] | Death or any hospital admission | 20 | 74 | — | 114 |
IMPLANTABLE CARDIOVERTER DEFIBRILLATOR | |||||||||||
SCD-HeFT, 2005[16] | 1676 | Mild-severe | ∼7.0 | ACE-I + BB | ICD | 3.8 | Death | 23 | — | — | — |
VENTRICULAR ASSIST DEVICE | |||||||||||
REMATCH, 2001[h] | 129 | End stage | 75 | ACE-I + spironolactone | LVAD | 1.8 | Death | 48 | 282 | — | — |
Modified from McMurray JJ, Pfeffer MA: Heart failure. Lancet 2005;365:1877–1889.
ACE-I = ACE inhibitor; BB = β-blocker; CRT = cardiac resynchronization therapy (biventricular pacing); CRT-D = CRT device that also defibrillates; CV = cardiovascular; HF hosp. = patients with at least one hospital admission for worsening heart failure—some patients had multiple admissions; ICD = implantable cardioverter defibrillator; ISDN = isosorbide dinitrate; LVAD = left ventricular assist device. |
