Heart failure (HF) is a clinical syndrome that occurs in patients who, because of an inherited or acquired abnormality of cardiac structure and/or function, develop a constellation of clinical symptoms (dyspnea and fatigue) and signs (edema and rales) that lead to frequent hospitalizations, a poor quality of life, and a shortened life expectancy.
HF is a burgeoning problem worldwide, with more than 20 million people affected. The overall prevalence of HF in the adult population in developed countries is 2%. HF prevalence follows an exponential pattern, rising with age, and affects 6–10% of people over the age of 65. Although the relative incidence of HF is lower in women than in men, women constitute at least half of the cases of HF because of their longer life expectancy. In North America and Europe, the lifetime risk of developing HF is approximately one in five for a 40-year-old. The overall prevalence of HF is thought to be increasing, in part because current therapies of cardiac disorders, such as myocardial infarction (MI), valvular heart disease, and arrhythmias, are allowing patients to survive longer. Very little is known with respect to the prevalence or risk of developing HF in emerging nations because of the lack of population-based studies in these countries. Although HF was once thought to arise primarily in the setting of a depressed left ventricular (LV) ejection fraction (EF), epidemiological studies have shown that approximately one-half of patients who develop HF have a normal or preserved EF (EF 40–50%). Accordingly, HF patients are now broadly categorized into one of two groups: (1) HF with a depressed EF (commonly referred to as systolic failure) or (2) HF with a preserved EF (commonly referred to as diastolic failure).
As shown in Table 227-1, any condition that leads to an alteration in LV structure or function can predispose a patient to developing HF. Although the etiology of HF in patients with a preserved EF differs from that of those with depressed EF, there is considerable overlap between the etiologies of these two conditions. In industrialized countries, coronary artery disease (CAD) has become the predominant cause in men and women and is responsible for 60–75% of cases of HF. Hypertension contributes to the development of HF in 75% of patients, including most patients with CAD. Both CAD and hypertension interact to augment the risk of HF, as does diabetes mellitus.
Table 227-1 Etiologies of Heart Failure
Depressed Ejection Fraction (<40%)
Coronary artery disease
Nonischemic dilated cardiomyopathy
Chronic pressure overload
Obstructive valvular diseasea
Chronic volume overload
Regurgitant valvular disease
Disorders of rate and rhythm
Intracardiac (left-to-right) shunting
Preserved Ejection Fraction (>40–50%)
Primary (hypertrophic cardiomyopathies)
Infiltrative disorders (amyloidosis, sarcoidosis)
Storage diseases (hemochromatosis)
Pulmonary Heart Disease
Pulmonary vascular disorders
Excessive blood-flow requirements
Systemic arteriovenous shunting
Nutritional disorders (beriberi)
aNote: Indicates conditions that can also lead to heart failure with a preserved injection fraction.
In 20–30% of the cases of HF with a depressed EF, the exact etiologic basis is not known. These patients are referred to as having nonischemic, dilated, or idiopathic cardiomyopathy if the cause is unknown (Chap. 231). Prior viral infection or toxin exposure (e.g., alcoholic or chemotherapeutic) may also lead to a dilated cardiomyopathy. Moreover, it is becoming increasingly clear that a large number of the cases of dilated cardiomyopathy are secondary to specific genetic defects, most notably those in the cytoskeleton. Most of the forms of familial dilated cardiomyopathy are inherited in an autosomal dominant fashion. Mutations of genes encoding cytoskeletal proteins (desmin, cardiac myosin, vinculin) and nuclear membrane proteins (lamin) have been identified thus far. Dilated cardiomyopathy is also associated with Duchenne's, Becker's, and limb girdle muscular dystrophies. Conditions that lead to a high cardiac output (e.g., arteriovenous fistula, anemia) are seldom responsible for the development of HF in a normal heart. However, in the presence of underlying structural heart disease, these conditions can lead to overt HF.
Rheumatic heart disease remains a major cause of HF in Africa and Asia, especially in the young. Hypertension is an important cause of HF in the African and African-American populations. Chagas' disease is still a major cause of HF in South America. Not surprisingly, anemia is a frequent concomitant factor in HF in many developing nations. As developing nations undergo socioeconomic development, the epidemiology of HF is becoming similar to that of Western Europe and North America, with CAD emerging as the single most common cause of HF. Although the contribution of diabetes mellitus to HF is not well understood, diabetes accelerates atherosclerosis and is often associated with hypertension.
Despite many recent advances in the evaluation and management of HF, the development of symptomatic HF still carries a poor prognosis. Community based studies indicate that 30–40% of patients die within 1 year of diagnosis and 60–70% die within 5 years, mainly from worsening HF or as a sudden event (probably because of a ventricular arrhythmia). Although it is difficult to predict prognosis in an individual, patients with symptoms at rest [New York Heart Association (NYHA) class IV] have a 30–70% annual mortality rate, whereas patients with symptoms with moderate activity (NYHA class II) have an annual mortality rate of 5–10%. Thus, functional status is an important predictor of patient outcome (see Table 227-2).
Figure 227-1 provides a general conceptual framework for considering the development and progression of HF with a depressed EF. As shown, HF may be viewed as a progressive disorder that is initiated after an index event either damages the heart muscle, with a resultant loss of functioning cardiac myocytes, or alternatively disrupts the ability of the myocardium to generate force, thereby preventing the heart from contracting normally. This index event may have an abrupt onset, as in the case of a MI; it may have a gradual or insidious onset, as in the case of hemodynamic pressure or volume overloading; or it may be hereditary, as in the case of many of the genetic cardiomyopathies. Regardless of the nature of the inciting event, the feature that is common to each of these index events is that they all, in some manner, produce a decline in the pumping capacity of the heart. In most instances patients remain asymptomatic or minimally symptomatic following the initial decline in pumping capacity of the heart, or develop symptoms only after the dysfunction has been present for some time. Thus, when viewed within this conceptual framework, LV dysfunction is necessary, but not sufficient, for the development of the syndrome of HF.
Pathogenesis of heart failure with a depressed ejection fraction. Heart failure begins after an index event produces an initial decline in the heart's pumping capacity. Following this initial decline in pumping capacity, a variety of compensatory mechanisms are activated, including the adrenergic nervous system, the renin-angiotensin-aldosterone system and the cytokine system. In the short term, these systems are able to restore cardiovascular function to a normal homeostatic range with the result that the patient remains asymptomatic. However, with time the sustained activation of these systems can lead to secondary end-organ damage within the ventricle, with worsening left-ventricular remodeling and subsequent cardiac decompensation. (From D Mann: Circulation 100:999, 1999.)
Although the precise reasons why patients with LV dysfunction may remain asymptomatic is not certain, one potential explanation is that a number of compensatory mechanisms become activated in the presence of cardiac injury and/or LV dysfunction, and they appear to be able to sustain and modulate LV function for a period of months to years. The list of compensatory mechanisms that have been described thus far include (1) activation of the renin-angiotensin-aldosterone (RAA) and adrenergic nervous systems, which are responsible for maintaining cardiac output through increased retention of salt and water (Fig. 227-2), and (2) increased myocardial contractility. In addition, there is activation of a family of countervailing vasodilatory molecules, including the atrial and brain natriuretic peptides (ANP and BNP), prostaglandins (PGE2 and PGI2), and nitric oxide (NO), that offset the excessive peripheral vascular vasoconstriction. Genetic background, gender, age, or environment may influence these compensatory mechanisms, which are able to modulate LV function within a physiologic/homeostatic range, such that the functional capacity of the patient is preserved or is depressed only minimally. Thus, patients may remain asymptomatic or minimally symptomatic for a period of years. However, at some point patients become overtly symptomatic, with a resultant striking increase in morbidity and mortality. Although the exact mechanisms that are responsible for this transition are not known, as will be discussed below, the transition to symptomatic HF is accompanied by increasing activation of neurohormonal, adrenergic, and cytokine systems that lead to a series of adaptive changes within the myocardium, collectively referred to as LV remodeling.
Activation of neurohormonal systems in heart failure. The decreased cardiac output in HF patients results in an "unloading" of high-pressure baroceptors (circles) in the left ventricle, carotid sinus, and aortic arch. This unloading leads to the generation of afferent signals to the central nervous system (CNS) that stimulate cardioregulatory centers in the brain which stimulate the release of arginine vasopression (AVP) from the posterior pituitary. AVP [or antidiuretic hormone (ADH)] is a powerful vasoconstrictor that increases the permeability of the renal collecting ducts, leading to the reabsorption of free water. These afferent signals to the CNS also activate efferent sympathetic nervous system pathways that innervate the heart, kidney, peripheral vasculature, and skeletal muscles.
Sympathetic stimulation of the kidney leads to the release of renin, with a resultant increase in the circulating levels of angiotensin II and aldosterone. The activation of the renin-angiotensin-aldosterone system promotes salt and water retention and leads to vasoconstriction of the peripheral vasculature, myocyte hypertrophy, myocyte cell death, and myocardial fibrosis. While these neurohormonal mechanisms facilitate short-term adaptation by maintaining blood pressure, and hence perfusion to vital organs, these same neurohormonal mechanisms are believed to contribute to end-organ changes in the heart and the circulation, and to the excessive salt and water retention in advanced HF. [From E Braunwald: Pathophysiology of heart failure, in Braunwald's Heart Disease, 7th ed, D Zipes et al (eds). Philadelphia, Elsevier Saunders, pp 509–538, 2005; and adapted from Schrier RW, Abraham WT: N Engl J Med 341:577, 1999.]
In contrast to our understanding of the pathogenesis of HF with a depressed EF, our understanding of the mechanisms that contribute to the development of HF with a preserved EF is still evolving. That is, although diastolic dysfunction (see below) was thought to be the only mechanism responsible for the development of HF with a preserved EF, community-based studies suggest that additional mechanisms, such as increased vascular and ventricular (ventricular-vascular) stiffness, may also be important.
Basic Mechanisms of Heart Failure
LV remodeling develops in response to a series of complex events that occur at the cellular and molecular levels. These changes include: (1) myocyte hypertrophy; (2) alterations in the contractile properties of the myocyte; (3) progressive loss of myocytes through necrosis, apoptosis, and autophagic cell death; (4) -adrenergic desensitization; (5) abnormal myocardial energetics and metabolism; and (6) reorganization of the extracellular matrix with dissolution of the organized structural collagen weave surrounding myocytes and subsequent replacement by an interstitial collagen matrix that does not provide structural support to the myocytes. The biological stimuli for these profound changes include mechanical stretch of the myocyte, circulating neurohormones (e.g., norepinephrine, angiotensin II), inflammatory cytokines [e.g., tumor necrosis factor (TNF)], other peptides and growth factors (e.g., endothelin), and reactive oxygen species (e.g., superoxide, NO). Although these molecules are collectively referred to as neurohormones, this historical terminology is somewhat misleading insofar as the classical neurohormones, such as norepinephrine and angiotensin II, may also be synthesized directly within the myocardium and thus may also act in an autocrine and paracrine manner. Nonetheless, the overarching concept is that the sustained overexpression of these biologically active molecules contributes to the progression of HF by virtue of the deleterious effects that they exert on the heart and the circulation. Indeed, this insight forms the clinical rationale for using pharmacologic agents that antagonize these systems [e.g., angiotensin-converting enzyme (ACE) inhibitors and beta blockers] in treating patients with HF.
In order to understand how the changes that occur in the failing cardiac myocyte contribute to depressed LV systolic function in HF, it is instructive first to review the biology of the cardiac muscle cell (Chap. 217). Sustained neurohormonal activation results in transcriptional and posttranscriptional changes in the genes and proteins that regulate excitation-contraction coupling and cross-bridge interaction (see Fig. 217-7). Collectively, these changes impair the ability of the myocyte to contract and, therefore, contribute to the depressed LV systolic function observed in patients with HF.
Myocardial relaxation is an ATP-dependent process that is regulated by uptake of cytoplasmic calcium into the sarcoplasmic reticulum (SR) by sarcoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA2A) and extrusion of calcium by sarcolemmal pumps (see Fig. 217-7). Accordingly, reductions in ATP concentration, as occurs in ischemia, may interfere with these processes and lead to slowed myocardial relaxation. Alternatively, if LV filling is delayed because LV compliance is reduced (e.g., from hypertrophy or fibrosis), LV filling pressures will similarly remain elevated at end diastole (see Fig. 217-11). An increase in heart rate disproportionately shortens the time for diastolic filling, which may lead to elevated LV filling pressures, particularly in noncompliant ventricles. Elevated LV end-diastolic filling pressures result in increases in pulmonary capillary pressures, which can contribute to the dyspnea experienced by patients with diastolic dysfunction. Importantly, diastolic dysfunction can occur alone or in combination with systolic dysfunction in patients with HF.
Left Ventricular Remodeling
Ventricular remodeling refers to the changes in LV mass, volume, shape, and composition of the heart that occur following cardiac injury and/or abnormal hemodynamic loading conditions. LV remodeling may contribute independently to the progression of HF by virtue of the mechanical burdens that are engendered by the changes in the geometry of the remodeled LV. For example, the change in LV shape from a prolate ellipsoid of revolution to a more spherical shape during LV remodeling results in an increase in meridional wall stress of the LV, which creates a de novo mechanical burden for the failing heart. In addition to the increase in LV end-diastolic volume, LV wall thinning also occurs as the left ventricle begins to dilate. The increase in wall thinning along with the increase in afterload created by LV dilation leads to a functional afterload mismatch that may contribute further to a decrease in stroke volume. Moreover, the high end-diastolic wall stress might be expected to lead to: (1) hypoperfusion of the subendocardium, with resultant worsening of LV function; (2) increased oxidative stress, with the resultant activation of families of genes that are sensitive to free radical generation (e.g., TNF and interleukin 1); and (3) sustained expression of stretch-activated genes (angiotensin II, endothelin, and TNF) and/or stretch activation of hypertrophic signaling pathways.
A second important problem that results from increased sphericity of the ventricle is that the papillary muscles are pulled apart, resulting in incompetence of the mitral valve and the development of functional mitral regurgitation. In addition to the loss of forward blood flow, mitral regurgitation also results in further hemodynamic overloading of the ventricle. Taken together, the mechanical burdens that are engendered by LV remodeling can be expected to lead to decreased forward cardiac output, increased LV dilation (stretch), and increased hemodynamic overloading, all of which are sufficient to contribute to the progression of HF.
The cardinal symptoms of HF are fatigue and shortness of breath. Although fatigue has been traditionally ascribed to the low cardiac output in HF, it is likely that skeletal-muscle abnormalities and other noncardiac comorbidities (e.g., anemia) also contribute to this symptom. In the early stages of HF, dyspnea is observed only during exertion; however, as the disease progresses, dyspnea occurs with less strenuous activity, and ultimately may occur even at rest. The origin of dyspnea in HF is likely multifactorial (Chap. 33). The most important mechanism is pulmonary congestion with accumulation of interstitial or intra-alveolar fluid, which activates juxtacapillary J receptors, which in turn stimulate rapid, shallow breathing characteristic of cardiac dyspnea. Other factors that contribute to dyspnea on exertion include reductions in pulmonary compliance, increased airway resistance, respiratory muscle and/or diaphragm fatigue, and anemia. Dyspnea may become less frequent with the onset of right ventricular (RV) failure and tricuspid regurgitation.
Orthopnea, which is defined as dyspnea occurring in the recumbent position, is usually a later manifestation of HF than is exertional dyspnea. It results from the redistribution of fluid from the splanchnic circulation and lower extremities into the central circulation during recumbency, with a resultant increase in pulmonary capillary pressure. Nocturnal cough is a frequent manifestation of this process and a frequently overlooked symptom of HF. Orthopnea is generally relieved by sitting upright or by sleeping with additional pillows. Although orthopnea is a relatively specific symptom of HF, it may occur in patients with abdominal obesity or ascites and in patients with pulmonary disease whose lung mechanics favor an upright posture.
Paroxysmal Nocturnal Dyspnea (PND)
This term refers to acute episodes of severe shortness of breath and coughing that generally occur at night and awaken the patient from sleep, usually 1–3 h after the patient retires. PND may be manifest by coughing or wheezing, possibly because of increased pressure in the bronchial arteries leading to airway compression, along with interstitial pulmonary edema leading to increased airway resistance. Whereas orthopnea may be relieved by sitting upright at the side of the bed with the legs in a dependent position, patients with PND often have persistent coughing and wheezing even after they have assumed the upright position. Cardiac asthma is closely related to PND, is characterized by wheezing secondary to bronchospasm, and must be differentiated from primary asthma and pulmonary causes of wheezing.
Also referred to as periodic respiration or cyclic respiration, Cheyne-Stokes respiration is common in advanced HF and is usually associated with low cardiac output. Cheyne-Stokes respiration is caused by a diminished sensitivity of the respiratory center to arterial PCO2. There is an apneic phase, during which the arterial PO2 falls and the arterial PCO2 rises. These changes in the arterial blood gas content stimulate the depressed respiratory center, resulting in hyperventilation and hypocapnia, followed in turn by recurrence of apnea. Cheyne-Stokes respirations may be perceived by the patient or the patient's family as severe dyspnea or as a transient cessation of breathing.
Acute Pulmonary Edema
See Chap. 266.
Patients with HF may also present with gastrointestinal symptoms. Anorexia, nausea, and early satiety associated with abdominal pain and fullness are frequent complaints and may be related to edema of the bowel wall and/or a congested liver. Congestion of the liver and stretching of its capsule may lead to right-upper-quadrant pain. Cerebral symptoms, such as confusion, disorientation, and sleep and mood disturbances, may be observed in patients with severe HF, particularly elderly patients with cerebral arteriosclerosis and reduced cerebral perfusion. Nocturia is common in HF and may contribute to insomnia.
A careful physical examination is always warranted in the evaluation of patients with HF. The purpose of the examination is to help determine the cause of HF, as well as to assess the severity of the syndrome. Obtaining additional information about the hemodynamic profile and the response to therapy and determining the prognosis are important additional goals of the physical examination.
General Appearance and Vital Signs
In mild or moderately severe HF, the patient appears in no distress at rest, except for feeling uncomfortable when lying flat for more than a few minutes. In more severe HF, the patient must sit upright, may have labored breathing, and may not be able to finish a sentence because of shortness of breath. Systolic blood pressure may be normal or high in early HF, but it is generally reduced in advanced HF because of severe LV dysfunction. The pulse pressure may be diminished, reflecting a reduction in stroke volume. Sinus tachycardia is a nonspecific sign caused by increased adrenergic activity. Peripheral vasoconstriction leading to cool peripheral extremities and cyanosis of the lips and nail beds is also caused by excessive adrenergic activity.
(See also Chap. 220) Examination of the jugular veins provides an estimation of right atrial pressure. The jugular venous pressure is best appreciated with the patient lying recumbent, with the head tilted at 45°. The jugular venous pressure should be quantified in centimeters of water (normal 8 cm) by estimating the height of the venous column of blood above the sternal angle in cm and then adding 5 cm. In the early stages of HF, the venous pressure may be normal at rest but may become abnormally elevated with sustained (~1 min) pressure on the abdomen (positive abdominojugular reflux). Giant v waves indicate the presence of tricuspid regurgitation.
Pulmonary crackles (rales or crepitations) result from the transudation of fluid from the intravascular space into the alveoli. In patients with pulmonary edema, rales may be heard widely over both lung fields and may be accompanied by expiratory wheezing (cardiac asthma). When present in patients without concomitant lung disease, rales are specific for HF. Importantly, rales are frequently absent in patients with chronic HF, even when LV filling pressures are elevated, because of increased lymphatic drainage of alveolar fluid. Pleural effusions result from the elevation of pleural capillary pressure and the resulting transudation of fluid into the pleural cavities. Since the pleural veins drain into both the systemic and pulmonary veins, pleural effusions occur most commonly with biventricular failure. Although pleural effusions are often bilateral in HF, when unilateral they occur more frequently in the right pleural space.
Examination of the heart, although essential, frequently does not provide useful information about the severity of HF. If cardiomegaly is present, the point of maximal impulse (PMI) is usually displaced below the fifth intercostal space and/or lateral to the midclavicular line, and the impulse is palpable over two interspaces. Severe LV hypertrophy leads to a sustained PMI. In some patients, a third heart sound (S3) is audible and palpable at the apex. Patients with enlarged or hypertrophied right ventricles may have a sustained and prolonged left parasternal impulse extending throughout systole. An S3 (or protodiastolic gallop) is most commonly present in patients with volume overload who have tachycardia and tachypnea, and it often signifies severe hemodynamic compromise. A fourth heart sound (S4) is not a specific indicator of HF but is usually present in patients with diastolic dysfunction. The murmurs of mitral and tricuspid regurgitation are frequently present in patients with advanced HF.
Abdomen and Extremities
Hepatomegaly is an important sign in patients with HF. When present, the enlarged liver is frequently tender and may pulsate during systole if tricuspid regurgitation is present. Ascites, a late sign, occurs as a consequence of increased pressure in the hepatic veins and the veins draining the peritoneum. Jaundice, also a late finding in HF, results from impairment of hepatic function secondary to hepatic congestion and hepatocellular hypoxia, and is associated with elevations of both direct and indirect bilirubin.
Peripheral edema is a cardinal manifestation of HF, but it is nonspecific and usually absent in patients who have been treated adequately with diuretics. Peripheral edema is usually symmetric and dependent in HF and occurs predominantly in the ankles and pretibial region in ambulatory patients. In bedridden patients, edema may be found in the sacral area (presacral edema) and the scrotum. Long-standing edema may be associated with indurated and pigmented skin.
With severe chronic HF, there may be marked weight loss and cachexia. Although the mechanism of cachexia is not entirely understood, it is likely multifactorial and includes elevation of the resting metabolic rate; anorexia, nausea, and vomiting due to congestive hepatomegaly and abdominal fullness; elevation of circulating concentrations of cytokines such as TNF; and impairment of intestinal absorption due to congestion of the intestinal veins. When present, cachexia augers a poor overall prognosis.
The diagnosis of HF is relatively straightforward when the patient presents with classic signs and symptoms of HF; however, the signs and symptoms of HF are neither specific nor sensitive. Accordingly, the key to making the diagnosis is to have a high index of suspicion, particularly for high-risk patients. When these patients present with signs or symptoms of HF, additional laboratory testing should be performed.
Routine Laboratory Testing
Patients with new-onset HF and those with chronic HF and acute decompensation should have a complete blood count, a panel of electrolytes, blood urea nitrogen, serum creatinine, hepatic enzymes, and a urinalysis. Selected patients should have assessment for diabetes mellitus (fasting serum glucose or oral glucose tolerance test), dyslipidemia (fasting lipid panel), and thyroid abnormalities (thyroid-stimulating hormone level).
A routine 12-lead ECG is recommended. The major importance of the ECG is to assess cardiac rhythm, determine the presence of LV hypertrophy or a prior MI (presence or absence of Q waves), as well as to determine QRS width to ascertain whether the patient may benefit from resychronization therapy (see below). A normal ECG virtually excludes LV systolic dysfunction.
This provides useful information about cardiac size and shape, as well as the state of the pulmonary vasculature, and may identify noncardiac causes of the patient's symptoms. Although patients with acute HF have evidence of pulmonary hypertension, interstitial edema, and/or pulmonary edema, the majority of patients with chronic HF do not. The absence of these findings in patients with chronic HF reflects the increased capacity of the lymphatics to remove interstitial and/or pulmonary fluid.
Assessment of Lv Function
Noninvasive cardiac imaging (Chap. 222) is essential for the diagnosis, evaluation, and management of HF. The most useful test is the 2-D echocardiogram/Doppler, which can provide a semiquantitative assessment of LV size and function as well as the presence or absence of valvular and/or regional wall motion abnormalities (indicative of a prior MI). The presence of left atrial dilation and LV hypertrophy, together with abnormalities of LV diastolic filling provided by pulse-wave and tissue Doppler, are useful for the assessment of HF with a preserved EF. The 2-D echocardiogram/Doppler is also invaluable in assessing RV size and pulmonary pressures, which are critical in the evaluation and management of cor pulmonale (see below). MRI also provides a comprehensive analysis of cardiac anatomy and function and is now the gold standard for assessing LV mass and volumes.
The most useful index of LV function is the EF (stroke volume divided by end-diastolic volume). Because the EF is easy to measure by noninvasive testing and easy to conceptualize, it has gained wide acceptance among clinicians. Unfortunately, the EF has a number of limitations as a true measure of contractility, since it is influenced by alterations in afterload and/or preload. For example, the LV EF is increased in mitral regurgitation as a result of ejection of the blood into the low-pressure left atrium. Nonetheless, with the exceptions indicated above, when the EF is normal (50%), systolic function is usually adequate, and when the EF is significantly depressed (<30–40%), contractility is usually also depressed.
Circulating levels of natriuretic peptides are useful adjunctive tools in the diagnosis of patients with HF. Both B-type natriuretic peptide (BNP) and N-terminal pro-BNP, which are released from the failing heart, are relatively sensitive markers for the presence of HF with depressed EF; they are also elevated in HF patients with a preserved HF, albeit to a lesser degree. However, it is important to recognize that natriuretic peptide levels increase with age and renal impairment, are more elevated in women, and can be elevated in right HF from any cause. Levels can be falsely low in obese patients and may normalize in some patients following appropriate treatment. A normal concentration of natriuretic peptides in an untreated patient is extremely useful for excluding the diagnosis of HF. Other biomarkers, such as troponin T and I, C-reactive protein, TNF receptors, and uric acid, may be elevated in HF and provide important prognostic information. Serial measurements of one or more biomarkers may ultimately help to guide therapy in HF, but they are not currently recommended for this purpose.
Treadmill or bicycle exercise testing is not routinely advocated for patients with HF, but either is useful for assessing the need for cardiac transplantation in patients with advanced HF (Chap. 228). A peak oxygen uptake (VO2) <14 mL/kg per min is associated with a relatively poor prognosis. Patients with a VO2 <14 mL/kg per min have been shown, in general, to have better survival when transplanted than when treated medically.
HF resembles but should be distinguished from (1) conditions in which there is circulatory congestion secondary to abnormal salt and water retention but in which there is no disturbance of cardiac structure or function (e.g., renal failure) and (2) noncardiac causes of pulmonary edema (e.g., acute respiratory distress syndrome). In most patients who present with classic signs and symptoms of HF, the diagnosis is relatively straightforward. However, even experienced clinicians have difficulty in differentiating the dyspnea that arises from cardiac and pulmonary causes (Chap. 33). In this regard, noninvasive cardiac imaging, biomarkers, pulmonary function testing, and chest x-ray may be useful. A very low BNP or N-terminal pro-BNP may be helpful in excluding a cardiac cause of dyspnea in this setting. Ankle edema may arise secondary to varicose veins, obesity, renal disease, or gravitational effects. When HF develops in patients with a preserved EF, it may be difficult to determine the relative contribution of HF to the dyspnea that occurs in chronic lung disease and/or obesity.
Heart Failure: Treatment
HF should be viewed as a continuum that is comprised of four interrelated stages. Stage A includes patients who are at high risk for developing HF but without structural heart disease or symptoms of HF (e.g., patients with diabetes mellitus or hypertension). Stage B includes patients who have structural heart disease but without symptoms of HF (e.g., patients with a previous MI and asymptomatic LV dysfunction). Stage C includes patients who have structural heart disease and have developed symptoms of HF (e.g., patients with a previous MI with dyspnea and fatigue). Stage D includes patients with refractory HF requiring special interventions (e.g., patients with refractory HF who are awaiting cardiac transplantation). In this continuum, every effort should be made to prevent HF, not only by treating the preventable causes of HF (e.g., hypertension) but by treating the patient in Stages B and C with drugs that prevent disease progression (e.g., ACE inhibitors and beta blockers) and by symptomatic management of patients in stage D.
Defining an Appropriate Therapeutic Strategy for Chronic HF
Once patients have developed structural heart disease, their therapy depends on their NYHA functional classification (Table 227-2). Although this classification system is notoriously subjective and has large interobserver variability, it has withstood the test of time and continues to be widely applied to patients with HF. For patients who have developed LV systolic dysfunction but remain asymptomatic (class I), the goal should be to slow disease progression by blocking neurohormonal systems that lead to cardiac remodeling (see below). For patients who have developed symptoms (class II–IV), the primary goal should be to alleviate fluid retention, lessen disability, and reduce the risk of further disease progression and death. These goals generally require a strategy that combines diuretics (to control salt and water retention) with neurohormonal interventions (to minimize cardiac remodeling).
Table 227-2 New York Heart Association Classification
Patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitations, dyspnea, or anginal pain.
Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.
Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain.
Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.
Source: Adapted from New York Heart Association, Inc., Diseases of the Heart and Blood Vessels: Nomenclature and Criteria for Diagnosis, 6th ed. Boston, Little Brown, 1964, p. 114.
Management of HF with Depressed Ejection Fraction (<40%)
Clinicians should aim to screen for and treat comorbidities such as hypertension, CAD, diabetes mellitus, anemia, and sleep-disordered breathing, as these conditions tend to exacerbate HF. HF patients should be advised to stop smoking and to limit alcohol consumption to two standard drinks per day in men or one per day in women. Patients suspected of having an alcohol induced cardiomyopathy should be urged to abstain from alcohol consumption indefinitely. Extremes of temperature and heavy physical exertion should be avoided. Certain drugs are known to make HF worse and should also be avoided (Table 227-3). For example, nonsteroidal anti inflammatory drugs, including cyclooxygenase 2 inhibitors, are not recommended in patients with chronic HF because the risk of renal failure and fluid retention is markedly increased in the presence of reduced renal function or ACE inhibitor therapy. Patients should receive immunization with influenza and pneumococcal vaccines to prevent respiratory infections. It is equally important to educate the patient and family about HF, the importance of proper diet, as well the importance of compliance with the medical regimen. Supervision of outpatient care by a specially trained nurse or physician assistant and/or in specialized HF clinics have all been found to be helpful, particularly in patients with advanced disease.
Table 227-3 Factors that May Precipitate Acute Decompensation in Patients with Chronic Heart Failure
Arrhythmias (tachycardia or bradycardia)
Discontinuation of HF therapy
Initiation of medications that worsen HF
Calcium antagonists (verapamil, diltiazem)
Nonsteroidal anti-inflammatory drugs
Antiarrhythmic agents [all class I agents, sotalol (class III)]
Although heavy physical labor is not recommended in HF, routine modest exercise has been shown to be beneficial in patients with NYHA class I–III HF. For euvolemic patients, regular isotonic exercise such as walking or riding a stationary bicycle ergometer, as tolerated, should be encouraged. Some trials of exercise training have led to encouraging results with reduced symptoms, increased exercise capacity, and improved quality and duration of life. The benefits of weight loss by restriction of caloric intake have not been clearly established.
Dietary restriction of sodium (2–3 g daily) is recommended in all patients with HF and preserved or depressed EF. Further restriction (<2 g daily) may be considered in moderate to severe HF. Fluid restriction is generally unnecessary unless the patient develops hyponatremia (<130 meq/L), which may develop because of activation of the renin-angiotensin system, excessive secretion of antidiuretic hormone, or loss of salt in excess of water from diuretic use. Fluid restriction (<2 L/day) should be considered in hyponatremic patients or for those whose fluid retention is difficult to control despite high doses of diuretics and sodium restriction. Caloric supplementation is recommended for patients with advanced HF and unintentional weight loss or muscle wasting (cardiac cachexia); however, anabolic steroids are not recommended for these patients because of the potential problems with volume retention. The use of dietary supplements ("nutriceuticals") should be avoided in the management of symptomatic HF because of the lack of proven benefit and the potential for significant (adverse) interactions with proven HF therapies.
Many of the clinical manifestations of moderate to severe HF result from excessive salt and water retention that leads to volume expansion and congestive symptoms. Diuretics (Table 227-4) are the only pharmacologic agents that can adequately control fluid retention in advanced HF, and they should be used to restore and maintain normal volume status in patients with congestive symptoms (dyspnea, orthopnea, edema) or signs of elevated filling pressures (rales, jugular venous distention, or peripheral edema). Furosemide, torsemide, and bumetanide act at the loop of Henle (loop diuretics) by reversibly inhibiting the reabsorption of Na+, K+, and Cl– in the thick ascending limb of Henle's loop; thiazides and metolazone reduce the reabsorption of Na+ and Cl– in the first half of the distal convoluted tubule; and potassium-sparing diuretics such as spironolactone act at the level of the collecting duct.
Table 227-4 Drugs for the Treatment of Chronic Heart Failure (EF <40%)
20–40 mg qd or bid
10–20 mg qd bid
0.5–1.0 mg qd or bid
25 mg qd
2.5–5.0 mg qd or bid
Angiotensin-Converting Enzyme Inhibitors
6.25 mg tid
50 mg tid
2.5 mg bid
10 mg bid
2.5–5.0 mg qd
20–35 mg qd
1.25–2.5 mg bid
2.5–5 mg bid
0.5 mg qd
4 mg qd
Angiotensin Receptor Blockers
40 mg bid
160 mg bid
4 mg qd
32 mg qd
75 mg qd
300 mg qdb
12.5 mg qd
50 mg qd
3.125 mg bid
25–50 mg bid
1.25 mg qd
10 mg qd
Metoprolol succinate CR
12.5–25 mg qd
Target dose 200 mg qd
12.5–25 mg qd
25–50 mg qd
25 mg qd
50 mg qd
Combination of hydralazine/isosorbide dinitrate
10–25 mg/10 mg tid
75 mg/40 mg tid
Fixed dose of hydralazine/isosorbide dinitrate
37.5 mg/20 mg (one tablet) tid
75 mg/40 mg (two tablets) tid
0.125 mg qd
aDose must be titrated to reduce the patient's congestive symptoms.
bTarget dose not established.
Although all diuretics increase sodium excretion and urinary volume, they differ in their potency and pharmacologic properties. Whereas loop diuretics increase the fractional excretion of sodium by 20–25%, thiazide diuretics increase it by only 5–10% and tend to lose their effectiveness in patients with moderate or severe renal insufficiency (creatinine >2.5 mg/dL). Hence, loop diuretics are generally required to restore normal volume status in patients with HF. Diuretics should be initiated in low doses (Table 227-4) and then carefully titrated upward to relieve signs and symptoms of fluid overload in an attempt to obtain the patient's "dry weight." This typically requires multiple dose adjustments over many days and occasionally weeks in patients with severe fluid overload. Intravenous administration of diuretics may be necessary to relieve congestion acutely and can be done safely in the outpatient setting. Once the congestion has been relieved, treatment with diuretics should be continued to prevent the recurrence of salt and water retention.
Refractoriness to diuretic therapy may represent patient noncompliance, a direct effect of chronic diuretic use on the kidney or progression of underlying HF. The addition of thiazides or metolazone, once or twice daily, to loop diuretics may be considered in patients with persistent fluid retention despite high dose loop diuretic therapy. Metolazone is generally more potent and much longer-acting than the thiazides in this setting as well as in patients with chronic renal insufficiency. However, chronic daily use, especially of metolazone, should be avoided if possible because of the potential for electrolyte shifts and volume depletion. Ultrafiltration and dialysis may be used in cases of refractory fluid retention that are unresponsive to high doses of diuretics and have been shown to be helpful in the short term.
Diuretics have the potential to produce electrolyte and volume depletion, as well as worsening azotemia. In addition, they may lead to worsening neurohormonal activation and disease progression. One of the most important adverse consequences of diuresis is alterations in potassium homeostasis (hypokalemia or hyperkalemia), which increases the risk of life-threatening arrhythmias. In general, both loop- and thiazide-type diuretics lead to hypokalemia, whereas spironolactone, eplerenone, and triamterene lead to hyperkalemia.
Preventing Disease Progression
Drugs that interfere with the excessive activation of the RAA system and the adrenergic nervous system can relieve the symptoms of HF with a depressed EF by stabilizing and/or reversing cardiac remodeling. In this regard, ACE inhibitors and beta blockers have emerged as the cornerstones of modern therapy for HF with a depressed EF.
There is overwhelming evidence that ACE inhibitors should be used in symptomatic and asymptomatic patients (Figs. 227-3 and 227-4) with a depressed EF (<40%). ACE inhibitors interfere with the renin-angiotensin system by inhibiting the enzyme that is responsible for the conversion of angiotensin I to angiotensin II. However, because ACE inhibitors also inhibit kininase II, they may lead to the upregulation of bradykinin, which may further enhance the beneficial effects of angiotensin suppression. ACE inhibitors stabilize LV remodeling, improve symptoms, reduce hospitalization, and prolong life. Because fluid retention can attenuate the effects of ACE inhibitors, it is preferable to optimize the dose of diuretic before starting the ACE inhibitor. However, it may be necessary to reduce the dose of diuretic during the initiation of ACE inhibition in order to prevent symptomatic hypotension. ACE inhibitors should be initiated in low doses, followed by gradual increments if the lower doses have been well tolerated. The doses of ACE inhibitors should be increased until they are similar to those that have been shown to be effective in clinical trials (Table 227-4). Higher doses are more effective than lower doses in preventing hospitalization.
Meta-analysis of angiotensin-converting enzyme (ACE) inhibitors in heart failure patients with a depressed ejection fraction.A. The Kaplan-Meier curves for mortality for 5966 HF patients with a depressed EF treated with an ACE inhibitor following acute myocardial infarction (three trials). B. The Kaplan-Meier curves for mortality for 12,763 HF patients with a depressed EF treated with an ACE inhibitor in five clinical trials, including postinfarction trials. The benefits of ACE inhibitors were observed early and persisted long-term. (Modified from Flather et al: Lancet 355:1575, 2000.)
Treatment algorithm for chronic heart failure patients with a depressed ejection fraction. After the clinical diagnosis of HF is made, it is important to treat the patient's fluid retention before starting an ACE inhibitor (or an ARB if the patient is ACE-intolerant). Beta blockers should be started after the fluid retention has been treated and/or the ACE inhibitor has been uptitrated. If the patient remains symptomatic, an ARB, aldosterone antagonist, or digoxin can be added as "triple therapy." The fixed-dose combination of hydralazine/isosorbide dinitrate should be added to an ACE inhibitor and beta blocker in African-American patients with NYHA class II–IV HF. Device therapy should be considered in addition to pharmacological therapy in appropriate patients. HF, heart failure; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; NYHA, New York Heart Association; CRT, cardiac resynchronization therapy; ICD, implantable cardiac defibrillator.
The majority of adverse effects are related to suppression of the renin-angiotensin system. The decreases in blood pressure and mild azotemia that may occur during the initiation of therapy are generally well tolerated and do not require a decrease in the dose of the ACE inhibitor. However, if hypotension is accompanied by dizziness or if the renal dysfunction becomes severe, it may be necessary to reduce the dose of the inhibitor. Potassium retention may also become problematic if the patient is receiving potassium supplements or a potassium-sparing diuretic. Potassium retention that is not responsive to these measures may require a reduction in the dose of ACE inhibitor.
The side effects of ACE inhibitors related to kinin potentiation include a nonproductive cough (10–15% of patients) and angioedema (1% of patients). In patients who cannot tolerate ACE inhibitors because of cough or angioedema, angiotensin receptor blockers (ARBs) are the recommended first line of therapy (see below). Patients intolerant of ACE inhibitors because of hyperkalemia or renal insufficiency are likely to experience the same side effects with ARBs. In these cases, the combination of hydralazine and an oral nitrate should be considered (Table 227-4).
Angiotensin Receptor Blockers
These drugs are well tolerated in patients who are intolerant of ACE inhibitors because of cough, skin rash, and angioedema. ARBs should be used in symptomatic and asymptomatic patients with an EF <40% who are ACE-intolerant for reasons other than hyperkalemia or renal insufficiency (Table 227-4). Although ACE inhibitors and ARBs inhibit the renin-angiotensin system, they do so by different mechanisms. Whereas ACE inhibitors block the enzyme responsible for converting angiotensin I to angiotensin II, ARBs block the effects of angiotensin II on the angiotensin type 1 receptor. Some clinical trials have demonstrated a therapeutic benefit for the addition of ARB to an ACE inhibitor in patients with chronic HF. When given in concert with beta blockers, ARBs reverse the process of LV remodeling, improve patient symptoms, prevent hospitalization, and prolong life.
Both ACE inhibitors and ARBs have similar effects on blood pressure, renal function, and potassium. Therefore the problems of symptomatic hypotension, azotemia, and hyperkalemia are similar for both of these agents.
-Adrenergic Receptor Blockers
Beta blocker therapy represents a major advance in the treatment of patients with a depressed EF (Fig. 227-5). These drugs interfere with the harmful effects of sustained activation of the adrenergic nervous system by competitively antagonizing one or more adrenergic receptors (1, 1, and 2). Although there are a number of potential benefits to blocking all three receptors, most of the deleterious effects of adrenergic activation are mediated by the 1 receptor. When given in concert with ACE inhibitors, beta blockers reverse the process of LV remodeling, improve patient symptoms, prevent hospitalization, and prolong life. Therefore beta blockers are indicated for patients with symptomatic or asymptomatic HF and a depressed EF <40%.
Meta-analysis of beta blockers on mortality in HF patients with a depressed EF. Effect of beta blockers vs. placebo in patients who were not (A) or who were (B) receiving an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) at baseline in six clinical trials. There was a similarimpact of beta-blocker therapy on the endpoints of all-cause mortalityas well as death and heart failure hospitalization in both thepresence and absence of ACE inhibitor or ARB at baseline. BEST, Beta-blocker Evaluation of Survival Trial (bucindolol); CIBIS, Cardiac Insufficiency BIsoprolol Study (bisoprol); COPERNICUS, Carvedilol prOsPEctive RaNdomIzed Cumulative Survival (carvedilol); MERIT-HF, Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (metoprolol CR/XL). (Modified from Krum et al: Eur Heart J 26:2154, 2005.)
Analogous to the use of ACE inhibitors, beta blockers should be initiated in low doses (Table 227-4), followed by gradual increments in the dose if lower doses have been well tolerated. The dose of beta blocker should be increased until the doses used are similar to those that have been reported to be effective in clinical trials (Table 227-4). However, unlike ACE inhibitors, which may be titrated upward relatively rapidly, the titration of beta blockers should proceed no more rapidly than at 2-week intervals, because the initiation and/or increased dosing of these agents may lead to worsening fluid retention consequent to the withdrawal of adrenergic support to the heart and the circulation. Thus, it is important to optimize the dose of diuretic before starting therapy with beta blockers. If worsening fluid retention does occur, it is likely to do so within 3–5 days of initiating therapy, and it will be manifest as an increase in body weight and/or symptoms of worsening HF. The increased fluid retention can usually be managed by increasing the dose of diuretics. In some patients the dose of the beta blocker may have to be reduced.
Contrary to early reports, the aggregate results of clinical trials suggest that beta-blocker therapy is well tolerated by the great majority (85%) of HF patients, including patients with comorbid conditions such as diabetes mellitus, chronic obstructive lung disease, and peripheral vascular disease. Nonetheless, there is a subset of patients (10–15%) who remain intolerant to beta blockers because of worsening fluid retention or symptomatic hypotension or bradycardia.
The adverse effects of beta-blocker use are generally related to the predictable complications that arise from interfering with the adrenergic nervous system. These reactions generally occur within several days of initiating therapy and are generally responsive to adjusting concomitant medications, as described above. Therapy with beta blockers can lead to bradycardia and/or exacerbate heart block. Accordingly, the dose of beta blocker should be reduced if the heart rate decreases to <50 beats/min and/or second or third degree heart block or symptomatic hypotension develops. Beta blockers are not recommended for patients who have asthma with active bronchospasm. Beta blockers that also block the 1 receptor can lead to vasodilatory side effects.
Although classified as potassium-sparing diuretics, drugs that block the effects of aldosterone (spironolactone or eplerenone) have beneficial effects that are independent of the effects of these agents on sodium balance. Although ACE inhibition may transiently decrease aldosterone secretion, with chronic therapy there is a rapid return of aldosterone to levels similar to those before ACE inhibition. Accordingly, the administration of an aldosterone antagonist is recommended for patients with NYHA class IV or class III (previously class IV) HF who have a depressed EF (<35%) and who are receiving standard therapy, including diuretics, ACE inhibitors, and beta blockers. The dose of aldosterone antagonist should be increased until the doses used are similar to those that have been shown to be effective in clinical trials (Table 227-4).
The major problem with the use of aldosterone antagonists is the development of life-threatening hyperkalemia, which is more prone to occur in patients who are receiving potassium supplements or who have underlying renal insufficiency. Aldosterone antagonists are not recommended when the serum creatinine is >2.5 mg/dL (or creatinine clearance is <30 mL/min) or when the serum potassium is >5.0 mmol/L. Painful gynecomastia may develop in 10–15% of patients who use spironolactone, in which case eplerenone may be substituted.
The combination of hydralazine and isosorbide dinitrate (Table 227-4) is recommended as part of standard therapy in addition to beta blockers and ACE inhibitors for African Americans with NYHA class II–IV HF. Although the exact mechanism for the effects of this combination is not known, it is believed to be secondary to the beneficial effects of NO on the peripheral circulation. Recent studies suggest that the combination of hydralazine and isosorbide dinitrate may be more effective for patients who have variant genotypic markers (polymorphisms) for the genes that encode for endothelial nitric oxide synthase (NOS3) and aldosterone synthase.
Management of Patients WHO Remain Symptomatic
As noted above, an ACE inhibitor (or an ARB) plus a beta blocker should be standard background therapy for HF patients with a depressed LV EF. Additional pharmacologic therapy should be considered in patients who have persistent symptoms or progressive worsening despite optimized therapy with an ACE inhibitor and beta blocker. Agents that may be considered as part of additional therapy include an ARB, spironolactone, the combination of hydralazine and isosorbide dinitrate, or digitalis. The optimal choice of additional drug therapy to further improve outcome has not been firmly established. Thus, the choice of specific agent will be influenced by clinical considerations, including renal function, serum potassium concentration, blood pressure, and race. The triple combination of an ACE inhibitor, an ARB, and an aldosterone antagonist should not be used because of the high risk of hyperkalemia.
Digoxin is recommended for patients with symptomatic LV systolic dysfunction who have concomitant atrial fibrillation, and it should be considered for patients who have signs or symptoms of HF while receiving standard therapy, including ACE inhibitors and beta blockers. Therapy with digoxin is commonly initiated and maintained at a dose of 0.125–0.25 mg daily. For the great majority of patients, the dose should be 0.125 mg daily, and the serum digoxin level should be <1.0 ng/mL, especially in elderly patients, patients with impaired renal function, and a low lean body mass. Higher doses (and serum concentrations) appear to be less beneficial. There is no indication for using loading doses of digoxin to initiate therapy in patients with HF.
Anticoagulation and Antiplatelet Therapy
Patients with HF have an increased risk for arterial or venous thromboembolic events. In clinical HF trials, the rate of stroke ranges from 1.3 to 2.4% per year. Depressed LV function is believed to promote relative stasis of blood in dilated cardiac chambers with increased risk of thrombus formation. Treatment with warfarin [goal international normalized ratio (INR) 2.0–3.0] is recommended for patients with HF and chronic or paroxysmal atrial fibrillation, or with a history of systemic or pulmonary emboli, including stroke or transient ischemic attack. Patients with symptomatic or asymptomatic ischemic cardiomyopathy and documented recent large anterior MI or recent MI with documented LV thrombus should be treated with warfarin (goal INR 2.0–3.0) for the initial 3 months after MI, unless there are contraindications to its use.
Aspirin is recommended in HF patients with ischemic heart disease for the prevention of MI and death. However, lower doses of aspirin (75 or 81 mg) may be preferable because of the concern of worsening of HF at higher doses.
Management of Cardiac Arrhythmias
(See also Chap. 226) Atrial fibrillation occurs in 15–30% of patients with HF and is a frequent cause of cardiac decompensation. Most antiarrhythmic agents, with the exception of amiodarone and dofetilide, have negative inotropic effects and are proarrhythmic. Amiodarone is a class III antiarrhythmic that has little or no negative inotropic and/or proarrhythmic effects and is effective against most supraventricular arrhythmias. Amiodarone is the preferred drug for restoring and maintaining sinus rhythm, and it may improve the success of electrical cardioversion in patients with HF. Amiodarone increases the level of phenytoin and digoxin and prolongs the INR in patients taking warfarin. Therefore it is often necessary to reduce the dose of these drugs by as much as 50% when initiating therapy with amiodarone. The risk of adverse events, such as hyperthyroidism, hypothyroidism, pulmonary fibrosis, and hepatitis, are relatively low, particularly when lower doses of amiodarone are used (100–200 mg/d).
Implantable cardiac defibrillators (ICDs; see below) are highly effective in treating recurrences of sustained ventricular tachycardia and/or ventricular fibrillation in HF patients with recurrent arrhythmias and/or cardiac syncope, and they may be used as stand-alone therapy or in combination with amiodarone and/or a beta blocker (Chap. 226). There is no role for treating ventricular arrhythmias with an antiarrhythmic agent without an ICD.
Approximately one-third of patients with a depressed EF and symptomatic HF (NYHA class III–IV) manifest a QRS duration >120 ms. This ECG finding of abnormal inter- or intraventricular conduction has been used to identify patients with dyssynchronous ventricular contraction. The mechanical consequences of ventricular dyssynchrony include suboptimal ventricular filling, a reduction in LV contractility, prolonged duration (and therefore greater severity) of mitral regurgitation, and paradoxical septal wall motion. Biventricular pacing, also termed cardiac resynchronization therapy (CRT), stimulates both ventricles near simultaneously, thereby improving the coordination of ventricular contraction and reducing the severity of mitral regurgitation. When CRT is added to optimal medical therapy in patients in sinus rhythm, there is a significant decrease in patient mortality and hospitalization, a reversal of LV remodeling, as well as improved quality of life and exercise capacity. Accordingly, CRT is recommended for patients in sinus rhythm with an EF <35% and a QRS >120 ms and those who remain symptomatic (NYHA III–IV) despite optimal medical therapy. The benefits of CRT in patients with atrial fibrillation have not been established.
Implantable Cardiac Defibrillators
(See also Chap. 226) The prophylactic implantation of ICDs in patients with mild to moderate HF (NYHA class II–III) has been shown to reduce the incidence of sudden cardiac death in patients with ischemic or nonischemic cardiomyopathy. Accordingly, implantation of an ICD should be considered for patients in NYHA class II–III HF with a depressed EF of <30–35% who are already on optimal background therapy, including an ACE inhibitor (or ARB), a beta blocker, and an aldosterone antagonist. An ICD may be combined with a biventricular pacemaker in appropriate patients.
Management of HF with a Preserved Ejection Fraction (>40–50%)
Despite the wealth of information with respect to the evaluation and management of HF with a depressed EF, there are no proven and/or approved pharmacologic or device therapies for the management of patients with HF and a preserved EF. Therefore, it is recommended that initial treatment efforts should be focused, wherever possible, on the underlying disease process (e.g., myocardial ischemia, hypertension) associated with HF with preserved EF. Precipitating factors, such as tachycardia or atrial fibrillation, should be treated as quickly as possible through rate control and restoration of sinus rhythm when appropriate. Dyspnea may be treated by reducing total blood volume (dietary sodium restriction and diuretics), decreasing central blood volume (nitrates), or blunting neurohormal activation with ACE inhibitors, ARBs, and/or beta blockers. Treatment with diuretics and nitrates should be initiated at low doses to avoid hypotension and fatigue.
Defining an Appropriate Therapeutic Strategy
The therapeutic goals for the management of acute HF therapy are to (1) stabilize the hemodynamic derangements that provoked the symptoms responsible for the hospitalization, (2) identify and treat the reversible factors that precipitated decompensation, and (3) reestablish an effective outpatient medical regimen that will prevent disease progression and relapse. In most instances this will require hospitalization, often in an intensive care unit (ICU) setting. Every effort should be made to identify the precipitating causes, such as infection, arrhythmias, dietary indiscretion, pulmonary embolism, infective endocarditis, occult myocardial ischemia/infarction, environmental and/or emotional or environmental stress (Table 227-3), since removal of these precipitating events is critical to the success of treatment.
The two primary hemodynamic determinants of acute HF are elevated LV filling pressures and a depressed cardiac output. Frequently the depressed cardiac output is accompanied by an increase in systemic vascular resistance (SVR) as a result of excessive neurohormonal activation. Because these hemodynamic derangements may occur singly or together, patients with acute HF generally present with one of four basic hemodynamic profiles (Fig. 227-6): normal LV filling pressure with normal perfusion (Profile A), elevated LV filling pressure with normal perfusion (Profile B), elevated LV filling pressures with decreased perfusion (Profile C), and normal or low LV filling pressure with decreased tissue perfusion (Profile L).
Hemodynamic profiles in patients with acute heart failure. Most patients can be categorized into one of the four hemodynamic profiles by performing a brief bedside examination that includes examination of the neck veins, lungs, and peripheral extremities. More definitive hemodynamic information may be obtained by performing invasive hemodynamic monitoring, particularly if the patient is gravely ill or if the clinical presentation is unclear. This hemodynamic classification provides a useful guide for selecting the initial optimal therapies for the management of acute HF. LV, left ventricular; CO, cardiac output; SVR, systemic vascular resistance. (Modified from Grady et al: Circulation 102:2443, 2000.)
Accordingly, the therapeutic approach to treating patients with acute HF should be tailored to reflect the patient's hemodynamic presentation. The goal should be, whenever possible, to restore the patient to a normal hemodynamic profile (Profile A). In many instances the patient's hemodynamic presentation can be approximated from the clinical examination. For example, patients with elevated LV filling pressures may have signs of fluid retention (rales, elevated neck veins, peripheral edema) and are referred to as being "wet," whereas patients with a depressed cardiac output and an elevated SVR generally have poor tissue perfusion manifested by cool distal extremities and are referred to as being "cold." Nonetheless, it should be emphasized that patients with chronic heart failure may not have rales or evidence of peripheral edema at the time of the initial presentation with acute decompensation, which may lead to the underrecognition of elevated filling pressures. In these patients, it may be appropriate to perform invasive hemodynamic monitoring.
Patients who are not congested and have normal tissue perfusion are referred to as being "dry" and "warm," respectively. When acute HF patients present to the hospital with profile A, their symptoms are often due to conditions other than HF (e.g., pulmonary or hepatic disease, or transient myocardial ischemia). More commonly, however, acute HF patients present with congestive symptoms ["warm and wet" (profile B)], in which case treatment of the elevated filling pressures with diuretics and vasodilators is warranted to reduce LV filling pressures. Profile B includes most patients with acute pulmonary edema. The treatment of this life-threatening condition is described in Chap. 266.
Patients may also present with congestion and a significant elevated SVR and reduction of cardiac output ["cold and wet" (Profile C)]. In these patients, cardiac output can be increased and LV filling pressures reduced using intravenous vasodilators. Intravenous inotropic agents with vasodilating action [dobutamine, low dose dopamine, milrinone (Table 227-5)] augment cardiac output by stimulating myocardial contractility as well as by functionally unloading the heart.
Table 227-5 Drugs for the Treatment for Acute Heart Failure
Bolus 2 g/kg
0.01–0.03 g/kg per mina
1–2 g/kg per min
2–10 g/kg per minb
Bolus 50 g/kg
0.1–0.75 g/kg per minb
1–2 g/kg per min
2–4 g/kg per minb
Bolus 12 g/kg
0.1–0.2 g/kg per minc
Dopamine for hypotension
5 g/kg per min
5–15 g/kg per min
0.5 g/kg per min
50 g/kg per min
0.3 g/kg per min
3 g/kg per min
aUsually <4 g/kg/min.
bInotropes will also have vasodilatory properties.
cApproved outside of the United States for the management of acute heart failure.
Patients who present with profile L ("cold and dry") should be carefully evaluated by right-heart catheterization for the presence of an occult elevation of LV filling pressures. If LV filling pressures are low [pulmonary capillary wedge pressure (PCWP) <12 mmHg] a cautious trial of fluid repletion may be considered. The goals of further therapy depend on the clinical situation. Therapy to reach the aforementioned goals may not be possible in some patients, particularly if they have disproportionate RV dysfunction or if they develop cardiorenal syndrome, in which renal function deteriorates during aggressive diuresis. Worsening renal dysfunction occurs in approximately 25% of patients hospitalized with HF and is associated with prolonged hospital stays and higher mortality after discharge.
Pharmacologic Management of Acute HF
After diuretics, intravenous vasodilators are the most useful medications for the management of acute HF. By stimulating guanylyl cyclase within smooth-muscle cells, nitroglycerin, nitroprusside, and nesiritide exert dilating effects on arterial resistance and venous capacitance vessels, which results in a lowering of LV filling pressure, a reduction in mitral regurgitation, and improved forward cardiac output, without increasing heart rate or causing arrhythmias.
Intravenous nitroglycerin is generally begun at 20 g/min and is increased in 20 g increments until patient symptoms are improved or PCWP is decreased to 16 mmHg without reducing systolic blood pressure below 80 mmHg. The most common side effect of intravenous or oral nitrates is headache, which, if mild, can be treated with analgesics and often resolves during continued therapy.
Nitroprusside is generally initiated at 10 g/min and increased by 10–20 g every 10–20 min as tolerated, with the same hemodynamic goals as described above. The rapidity of onset and offset, with a half life of approximately 2 min, facilitates early establishment of an individual patient's optimal level of vasodilation in the ICU. The major limitation of nitroprusside is side effects from cyanide, which manifests predominantly as gastrointestinal and central nervous system manifestations. Cyanide is most likely to accumulate in patients with severely reduced hepatic perfusion and decreased hepatic function from low cardiac output, and it is more likely to develop in patients receiving >250 g/min for over 48 h. Suspected cyanide toxicity is treated by decreasing or discontinuing the nitroprusside infusion. Long-term (>48 h) use of both nitroprusside and nitroglycerin is associated with hemodynamic tolerance.
Nesiritide, the newest vasodilator, is a recombinant form of brain type natriuretic peptide (BNP), which is an endogenous peptide secreted primarily from the LV in response to an increase in wall stress. Nesiritide is given as a bolus (2 g/kg) followed by a fixed-dose infusion (0.01–0.03 g/kg per min). Nesiritide effectively lowers LV filling pressures and improves symptoms during the treatment of acute HF. Headache is less common with nesiritide than with nitroglycerin. Although termed a natriuretic peptide, nesiritide has not been associated with major diuresis when used alone in clinical trials. It does, however, appear to potentiate the effect of concomitant diuretics such that the total required diuretic dose may be slightly lower.
Hypotension is the most common side effect of all three vasodilating agents, although less so with nesiritide. Hypotension is frequently associated with bradycardia, particularly when nitroglycerin is used. All three drugs can cause pulmonary artery vasodilation, which can lead to worsening hypoxia in patients with underlying ventilation-perfusion abnormalities.
Positive inotropic agents produce direct hemodynamic benefits by stimulating cardiac contractility, as well as by producing peripheral vasodilation. Collectively, these hemodynamic effects result in an improvement in cardiac output and a fall in LV filling pressures.
Dobutamine, which is the most commonly used inotropic agent for the treatment of acute HF, exerts its effects by stimulating 1 and 2 receptors, with little effect on 1 receptors. Dobutamine is given as a continuous infusion, at an initial infusion rate of 1–2 g/kg per min. Higher doses (>5 g/kg per min) are frequently necessary for severe hypoperfusion; however, there is little added benefit to increasing the dose above 10 g/kg per min. Patients maintained on chronic infusions for >72 h generally develop tachyphylaxis and require increasing doses.
Milrinone is a phosphodiesterase III inhibitor that leads to increased cAMP by inhibiting its breakdown. Milrinone may act synergistically with -adrenergic agonists to achieve further increase in cardiac output than either agent alone, and it may also be more effective than dobutamine in increasing cardiac output in the presence of beta blockers. Milrinone may be administered as a bolus dose of 0.5 g/kg per min, followed by a continuous infusion rate of 0.1–0.75 g/kg per min. Because milrinone is a more effective vasodilator than dobutamine, it produces a greater reduction in LV filling pressures, albeit with a greater risk of hypotension.
Although short-term use of inotropes provides hemodynamic benefits, these agents are more prone to cause tachyarrhythmias and ischemic events than vasodilators. Therefore inotropes are most appropriately used in clinical settings in which vasodilators and diuretics are not helpful, such as in patients with poor systemic perfusion and/or cardiogenic shock, in patients requiring short-term hemodynamic support after a MI or surgery, and in patients awaiting cardiac transplantation, or as palliative care in patients with advanced HF. If patients require sustained use of intravenous inotropes, strong consideration should be given to the use of an ICD to safeguard against the proarrhythmic effects of these agents.
Vasoconstrictors are used to support systemic blood pressure in patients with HF. Of the three agents that are commonly used (Table 227-5), dopamine is generally the first choice for therapy in situations where modest inotropy and pressor support are required. Dopamine is an endogenous catecholamine that stimulates 1, 1 receptors, and dopaminergic receptors (DA1 and DA2) in the heart and circulation. The effects of dopamine are dose-dependent. Low doses of dopamine (<2 g/kg per min) stimulate the DA1 and DA2 receptors and cause vasodilation of the splanchnic and renal vasculature. Moderate doses (2–4 g/kg per min) stimulate the 1 receptors and cause an increase in cardiac output with little or no change in heart rate or SVR. At higher doses (5 g/kg per min) the effects of dopamine on the 1 receptors overwhelm the dopaminergic receptors, and vasoconstriction ensues, leading to an increase in SVR, LV filling pressures, and heart rate.
Dopamine also causes release of norepinephrine from nerve terminals, which itself stimulates 1 and 1 receptors, thus raising blood pressure. Dopamine is most useful in the treatment of HF patients who have depressed cardiac output with poor tissue perfusion (Profile C). Significant additional inotropic and blood pressure support can be provided by epinephrine, phenylephrine, and vasopressin (Table 227-5); however, prolonged use of these agents can lead to renal and hepatic failure and can cause gangrene of the limbs. Therefore, these agents should not be administered except in true emergency situations.
Mechanical and Surgical Interventions
If pharmacologic interventions fail to stabilize the patient with refractory HF, mechanical and surgical interventions may provide effective circulatory support. These include intraaortic balloon counter pulsation, LV assist device, and cardiac transplantation (Chap. 228).
Planning for Hospital Discharge
Patient education should take place during the entire hospitalization, with a specific focus on salt and fluid status and obtaining daily weights, in addition to medication schedules. Whereas the majority of patients hospitalized with HF can be stabilized and returned to a good level of function on an oral regimen designed to maintain stability, 30–50% of patients discharged with a diagnosis of HF are rehospitalized within 3–6 months. Although there are multiple reasons for rehospitalization, failure to meet criteria for discharge is perhaps the most frequent. Criteria for discharge should include at least 24 h of stable fluid status, blood pressure, and renal function on the oral regimen planned for home. Patients should be free of dyspnea or symptomatic hypotension while at rest, washing, and walking on the ward.
Cor pulmonale, often referred to as pulmonary heart disease, is defined as dilation and hypertrophy of the right ventricle (RV) in response to diseases of the pulmonary vasculature and/or lung parenchyma. Historically, this definition has excluded congenital heart disease and those diseases in which the right heart fails secondary to dysfunction of the left side of the heart.
Etiology and Epidemiology
Cor pulmonale develops in response to acute or chronic changes in the pulmonary vasculature and/or the lung parenchyma that are sufficient to cause pulmonary hypertension. The true prevalence of cor pulmonale is difficult to ascertain for two reasons. First, not all cases of chronic lung disease will develop cor pulmonale, and second, our ability to diagnose pulmonary hypertension and cor pulmonale by routine physical examination and laboratory testing is relatively insensitive. However, recent advances in 2-D echo/Doppler imaging and biomakers (BNP) make it easier to screen for and detect cor pulmonale.
Once patients with chronic pulmonary or pulmonary vascular disease develop cor pulmonale, their prognosis worsens. Although chronic obstructive pulmonary disease (COPD) and chronic bronchitis are responsible for approximately 50% percent of the cases of cor pulmonale in North America (Chap. 254), any disease that affects the pulmonary vasculature (Chap. 244) or parenchyma can lead to cor pulmonale. Table 227-6 provides a list of common diseases that may lead to cor pulmonale. In contrast to COPD, the elevation in pulmonary artery pressure appears to be substantially higher in the interstitial lung diseases (Chap. 255), in which there is an inverse correlation between pulmonary artery pressure and the diffusion capacity for carbon monoxide, as well as patient survival. Sleep-disordered breathing, once thought to be a major mechanism for cor pulmonale, is rarely the sole cause of pulmonary hypertension and RV failure. The combination of COPD and associated daytime hypoxemia is required to cause sustained pulmonary hypertension in obstructive sleep apnea (Chap. 259).
Table 227-6 Etiology of Chronic Cor Pulmonale
Diseases Leading to Hypoxic Vasoconstriction
Chronic obstructive pulmonary disease
Chest wall dysfunction
Living at high altitudes
Diseases That Cause Occlusion of the Pulmonary Vascular Bed
Recurrent pulmonary thromboembolism
Primary pulmonary hypertension
Collagen vascular disease
Drug induced lung disease
Diseases That Lead to Parenchymal Disease
Chronic obstructive pulmonary disease
Idiopathic pulmonary fibrosis
Pathophysiology and Basic Mechanisms
Although many conditions can lead to cor pulmonale, the common pathophysiologic mechanism in each case is pulmonary hypertension that is sufficient to lead to RV dilation, with or without the development of concomitant RV hypertrophy. The systemic consequences of cor pulmonale relate to alterations in cardiac output as well as salt and water homeostasis. Anatomically, the RV is a thin walled, compliant chamber that is better suited to handle volume overload than pressure overload. Thus, the sustained pressure overload imposed by pulmonary hypertension and increased pulmonary vascular resistance eventually causes the RV to fail.
The response of the RV to pulmonary hypertension depends on the acuteness and severity of the pressure overload. Acute cor pulmonale occurs after a sudden and severe stimulus (e.g., massive pulmonary embolus), with RV dilatation and failure but no RV hypertrophy (Chap. 256). Chronic cor pulmonale, however, is associated with a more slowly evolving and slowly progressive pulmonary hypertension that leads to RV dilation and hypertrophy. The severity of the pulmonary artery hypertension and the onset of RV failure are influenced by multiple factors that occur intermittently, including hypoxia secondary to alterations in gas exchange, hypercapnia, and acidosis, as well as alterations in RV volume overload that are affected by exercise, heart rate, polycythemia, or increased salt and retention because of a fall in cardiac output (Fig. 227-2). The most common mechanisms that lead to pulmonary hypertension, including vasoconstriction, activation of the clotting cascade, and obliteration of pulmonary arterial vessels, are discussed in Chap. 244.
The symptoms of chronic cor pulmonale are generally related to the underlying pulmonary disorder. Dyspnea, the most common symptom, is usually the result of the increased work of breathing secondary to changes in elastic recoil of the lung (fibrosing lung diseases) or altered respiratory mechanics (e.g., overinflation with COPD), both of which may be aggravated by increased hypoxic respiratory drive. The hypoxia that occurs in lung disease is the result of reduced capillary membrane permeability, ventilation-perfusion mismatch, and occasionally intracardiac or intrapulmonary shunting.
Orthopnea and paroxysmal nocturnal dyspnea are rarely symptoms of isolated right HF. However, when present, these symptoms usually reflect the increased work of breathing in the supine position that results from compromised excursion of the diaphragm. Tussive or effort-related syncope may occur in patients with cor pulmonale with severe pulmonary hypertension because of the inability of the RV to deliver blood adequately to the left side of the heart. The abdominal pain and ascites that occur with cor pulmonale are similar to the right heart failure that ensues in chronic HF. Lower-extremity edema may occur secondary to neurohormonal activation, elevated RV filling pressures, or increased levels of carbon dioxide and hypoxia, which can lead to peripheral vasodilation and edema formation. The symptoms of acute cor pulmonale with pulmonary embolus are reviewed in Chap. 256.
Many of the signs that are encountered in cor pulmonale are also present in HF patients with a depressed EF, including tachypnea, elevated jugular venous pressures, hepatomegaly, and lower-extremity edema. Patients may have prominent v waves in the jugular venous pulse as a result of tricuspid regurgitation. Other cardiovascular signs include an RV heave palpable along the left sternal border or in the epigastrium. A systolic pulmonary ejection click may be audible to the left of the upper sternum. The increase in intensity of the holosystolic murmur of tricuspid regurgitation with inspiration ("Carvallo's sign") may be eventually lost as RV failure worsens. Cyanosis is a late finding in cor pulmonale and is secondary to a low cardiac output with systemic vasoconstriction and ventilation-perfusion mismatches in the lung.
The most common cause of right heart failure is not pulmonary parenchymal or vascular disease, but left heart failure. Therefore it is important to evaluate the patient for LV systolic and diastolic dysfunction. The ECG in severe pulmonary hypertension shows P pulmonale, right axis deviation, and RV hypertrophy. Radiographic examination of the chest may show enlargement of the main pulmonary artery, hilar vessels, and the descending right pulmonary artery. Spiral CT scans of the chest are useful in diagnosing acute thromboembolic disease; however, the ventilation-perfusion lung scan remains reliable in most centers for establishing the diagnosis of chronic thromboembolic disease (Chap. 256). A high-resolution CT scan of the chest is the most accurate means of diagnosing emphysema and interstitial lung disease.
Two-dimensional echocardiography is useful for measuring RV thickness and chamber dimensions as well as the anatomy of the pulmonary and tricuspid valves. The interventricular septum may move paradoxically during systole in the presence of pulmonary hypertension. As noted, Doppler echocardiography can be used to assess pulmonary artery pressures. MRI is also useful for assessing RV structure and function, particularly in patients who are difficult to image with 2-D echocardiography because of severe lung disease. Right-heart catheterization is useful for confirming the diagnosis of pulmonary hypertension and for excluding elevated left-heart pressures (measured as the PCWP) as a cause for right heart failure. BNP and N-terminal BNP levels are elevated in patients with cor pulmonale secondary to RV stretch and may be dramatically elevated in acute pulmonary embolism.
Cor Pulmonale: Treatment
The primary treatment goal of cor pulmonale is to target the underlying pulmonary disease, since this will lead to a decrease in pulmonary vascular resistance and relieve the pressure overload on the RV. Most pulmonary diseases that lead to chronic cor pulmonale are far advanced and are, therefore, less amenable to treatment. General principles of treatment include decreasing the work of breathing using noninvasive mechanical ventilation, bronchodilation, and steroids, as well as treating any underlying infection (Chaps. 254, 255). Adequate oxygenation (oxygen saturation 90–92%) will also decrease pulmonary vascular resistance and reduce the demands on the RV. Patients should be transfused if they are anemic, and a phlebotomy should be performed to reduce pulmonary artery pressure if the hematocrit exceeds 65%.
Diuretics are effective in the treatment of RV failure, and the indications for their use are similar to those for chronic HF. One caveat of chronic diuretic use is that they may lead to contraction alkalosis and worsening hypercapnea. Digoxin is of uncertain benefit in the treatment of cor pulmonale and may lead to arrhythmias in the setting of tissue hypoxia and acidosis. Therefore, if digoxin is administered, it should be given at low doses and monitored carefully. The treatment of the acute cor pulmonale that occurs with pulmonary embolus is described in Chap. 256. The treatment of pulmonary hypertension is discussed in Chap. 244.