Sheldon H. Gottlieb
Roy C. Ziegelstein
Definition
The amount of blood that the heart pumps per minute (the cardiac output) normally is precisely adjusted to meet the metabolic needs of the body. The cardiac output may increase twofold or threefold as a person goes from rest to exercise. An increase in cardiac output may occur within the space of one heartbeat by a decrease in vagal tone, which causes an increase in heart rate. After several seconds of exercise, sympathetic tone increases, which causes a further increase in cardiac output by increasing the heart rate and the amount of blood pumped per heartbeat (the stroke volume). Neural regulation of the peripheral circulation shunts blood flow away from the kidneys and redistributes it to the working muscle groups. The increased cardiac output soon brings about an increase in the amount of blood returning to the right side of the heart (the venous return); this leads to a further increase in cardiac output in response to the increased filling pressure and increased stretch in the heart muscle (the Frank-Starling principle).
If the heart, working at a normal filling pressure, is unable to pump enough blood to maintain tissue perfusion pressure and thereby to meet the metabolic needs of the body, compensatory neural and hormonal mechanisms that cause remodeling of the heart are brought into play. These adjustments may acutely or gradually cause symptoms and signs recognized as the syndrome of heart failure.
Most heart failure patients are either presymptomatic or undiagnosed (1). Acute heart failure, manifest usually by pulmonary edema (recognized by the abrupt onset of extreme breathlessness and evidence of alveolar edema by physical and radiologic examination), warrants immediate hospitalization for diagnosis of the underlying or precipitating cause and for treatment. Patients with advanced heart failure, who are severely symptomatic at rest despite compliance with an evidence-based heart failure regimen (see below), require urgent consultation with a cardiologist. Patients with newly diagnosed or incident heart failure and patients who have repeated episodes ofdecompensated heart failure usually require consultation with a cardiologist as well (2). All other patients with heart failure have chronic heart failure, which usually can be managed in an ambulatory setting.
Epidemiology
Almost five million Americans alive today have heart failure (3). The prevalence of heart failure increases greatly in patients older than 60 years (Fig. 66.1). The incidence of heart failure is approximately 10 per 1,000 in patients older than 65 years (3). The incidence among men is slightly higher than among women in the 45- to 84-year-old range but is higher among women in the 85- to 94-year-old range (4).
Currently there are almost one million hospital discharges for heart failure in the United States each year (3). Between 1973 and 1995, the annual hospitalization rates for congestive heart failure (CHF) among patients older than 65 years more than tripled, from approximately 60 per 10,000 people to >200 per 10,000. Mortality from heart failure rose between 1980 through 1988 but then declined between 1988 and 1995. This decrease in mortality probably reflects in part improved treatment. The percentage of hospitalized CHF patients who died decreased from 11.3%
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in 1981 to 6.1% in 1993, associated with a decrease in the average length of stay and an increase in costs and in the use of cardiac procedures (5). Population-based studies show little change in the incidence of CHF over the past 50 years, but they do suggest that survival has improved, resulting in a greater prevalence of this condition in the general population.
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FIGURE 66.1. Prevalence of heart failure reported from physicians’ offices as a function of patient age. Note the marked increase in the sixth and seventh decades. Between 10% and 20% of patients older than 60 years followed regularly by a physician have a history of heart failure. This percentage is likely to increase as preventive measures after myocardial infarction become more effective and because patients are more likely to be discharged alive from hospital after admission with a diagnosis of heart failure. (Modified from McKee P, Castelli W, McNamara P, et al. The natural history of congestive heart failure: the Framingham Study. N Engl J Med 1971;285:1441 , with permission.) |
Physiology
The Heart as a Pump
Length–Tension Relationship: Frank-Starling Principle and Preload
As heart muscle is stretched, it develops increased tension. The relationship of length to tension defines the compliance of heart muscle; the inverse of compliance is stiffness. If the ventricle is distended with blood, pressure develops within the cavity. A higher pressure is needed to distend the ventricle to a given volume in a less compliant (i.e., stiffer) ventricle. The pressure needed to stretch the ventricle to a given end-diastolic volume is called the preload, clinically measured as the left ventricular end-diastolic pressure (LVEDP). The relationship between the volume of the ventricle just before contraction and the force developed during contraction defines the Frank-Starling principle (6,7). If LVEDP is plotted against stroke work (stroke volume × mean blood pressure), a ventricular function curve is defined (Fig. 66.2). It can be seen from this relationship that the normal ventricle is compliant: It develops an adequate amount of force during contraction with a low preload. However, as the ventricle fails, it requires a higher preload to increase its stroke work (Fig. 66.2).
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FIGURE 66.2. “Ventricular function curves” showing the relationship between left ventricular filling pressures and stroke work. The position of the curve defines the inotropic state of the heart. Note that for a given curve (i.e., a given inotropic state), the function of the heart, or the amount of work the heart is capable of performing, varies with the left ventricular filling pressure. (Adapted from Weisfeldt ML. Congestive heart failure: pathophysiology and the evaluation of ventricular function. In: Harvey AM, Johns RJ, McKusick VA, et al., eds. The principles and practice of medicine. New York: Appleton-Century-Crofts, 1984; 183–191 , with permission.) |
Afterload
Afterload is the dynamic resistance against which the heart contracts. It determines the degree of stress within the myocardium. Systolic blood pressure closely approximates and is clinically the most useful indicator of afterload. Afterload determines the ease or speed of ventricular contraction; hence, stroke volume and ejection fraction (the portion of the ventricular volume that is ejected with each beat) are functions of afterload.
Contractility and Inotropic State
The relationship of preload (LVEDP) to stroke work (stroke volume × mean blood pressure) defines the functional
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state of cardiac muscle (see above). The relative position of the curve defines the inotropic state of the muscle. For example, infusing the heart with an inotropic substance such as digitalis causes the ventricular function curve to shift to the left, that is, to perform a higher stroke work at a given preload, assuming that afterload is kept constant. In other words, the contractility of the heart is increased.
Relationship between Preload, Afterload, and Inotropic State (Contractility)
If the end-diastolic pressure–volume relationship (curve) is kept constant, an increase in afterload or a decrease in inotropic state causes a decrease in the volume of the pressure–volume loop (i.e., a depression in ventricular function) as measured clinically by the ejection fraction or stroke volume. Thus, if afterload (end-systolic blood pressure) increases, ventricular function measured by the pressure–volume loop or by the ejection fraction (normally 50%–75%) decreases. A compensatory response is for LVEDP, or preload, to increase, which restores the ventricular function (pressure–volume loop) to baseline. A further increase in afterload leads to a further depression in ventricular function, which again may be restored by an increased preload (i.e., by increasing LVEDP). The preload reserve is the LVEDP above which the pulmonary capillary oncotic pressure is exceeded; fluid then passes into the alveoli, and pulmonary congestion, with symptoms of cough and dyspnea, occurs. Any increase in afterload that occurs when the preload reserve is reached causes a decrease in ventricular function and a worsening in symptoms of congestion. The preload reserve varies with the compliance of the ventricle as measured by the position of the LV pressure–volume relationship. If heart muscle is made stiffer or less compliant by a chronic disease process such as hypertension or aortic stenosis or by an acute process such as ischemia or increased heart rate, a higher filling pressure is necessary to set the level of ventricular function by means of the Frank-Starling principle, that is, the pressure–volume loop shifts upward and to the right and the preload reserve is reached at a lower level of stroke work. The only ways to improve ventricular function when the preload reserve is reached are to decrease the afterload or to change the inotropic state of the muscle. The clinical significance of these relationships is discussed at greater length under Management.
Biochemical Basis for Altered Contractility in the Failing Heart
The contractile unit of heart muscle is the sarcomere, which consists of fibers of protein called actin and myosin. Actin and myosin interact with each other by an interlocking protein, called troponin. The interlocking mechanism is facilitated by adenosine triphosphate and magnesium. An inhibitory protein, tropomyosin, is present on the myosin fibers. Tropomyosin inhibits the interaction between actin and myosin and allows the muscle to relax. Calcium inhibits the tropomyosin complex, frees the interlocking troponin, and allows actin and myosin to interact and to develop tension. Therefore, calcium is necessary for myocardial contraction to occur. Large amounts of calcium are stored within cardiac myocytes in the sarcoplasmic reticulum. Excitation–contraction coupling takes place in heart muscle when an action potential causes a release of calcium from the sarcoplasmic reticulum, thereby initiating contraction.
In classic heart failure, there appears to be decreased energy available for cardiac contraction. This leads to decreased systolic function and to slow transport of calcium back into the sarcoplasmic reticulum after contraction, which causes a delay in relaxation (lusitropy) of cardiac muscle. There is a reduction in early diastolic filling and an increased dependence on atrial pumping for ventricular filling. Abnormalities in calcium transport may predispose the failing heart to develop arrhythmias. Embryonic genes for fetal contractile proteins, natriuretic peptides, and inflammatory cytokines are induced by the heart failure state, which may cause profound changes in the structure and function of the heart (8). The pathophysiology of heart failure involves numerous changes in the structure and function of heart muscle cells, including loss of myofilaments, disturbances in calcium handling of the remaining myofilaments, changes in receptor density, and alterations in signal transduction. Processes underlying this condition include the progressive loss of cardiac muscle cells and changes in the extracellular matrix of the myocardium that produce structural changes in the heart. These changes can be produced by the unregulated process of cell necrosis, the highly regulated process of cell death called apoptosis, and by the expression of matrix metalloproteinases that have been shown to play an important role in changing the structure and function of the failing heart (9,10). The changes in ventricular size, shape, and function caused by these processes is called remodeling. A normal left ventricle has an ellipsoidal shape. A remodeled left ventricle has a spherical shape that creates mechanical disadvantages. The change in shape results in increased pressure and volume loads that can produce episodic or chronic subendocardial ischemia and in activation of compensatory mechanisms that lead to further malfunction of the heart and worsening symptoms of heart failure. Treatments that may slow or even reverse the remodeling process and thereby improve heart function and decrease symptoms of heart failure are discussed under Management.
In 30% to 50% of patients with the clinical syndrome of heart failure, systolic function as judged by the ejection fraction is normal but diastolic function (relaxation) is impaired. This leads to inadequate LV filling. Any compensatory increase in heart rate shortens diastole disproportionately more than systole, which leads to a further
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reduction in both LV filling and the time available for calcium uptake, thereby impairing ventricular relaxation (lusitropy) and adversely affecting both systolic function and diastolic compliance (11,12). Diastolic dysfunction can be detected and graded by LV filling patterns measured by Doppler echocardiography (13). Diastolic dysfunction is especially prevalent among persons older than 65 years or who have a history of hypertension, coronary heart disease, or diabetes. Both systolic dysfunction and diastolic dysfunction are highly predictive of all-cause mortality (14).
Compensatory Mechanisms
Heart Rate
The neural and hormonal responses to heart failure lead to an increase in heart rate in an attempt to maintain cardiac output. This may lead to rapid deterioration in systolic and diastolic function because of the disproportionate shortening of diastole relative to systole as heart rate increases (see above). The difference between the maximum heart rate during exercise and the resting heart rate (the heart rate reserve) is decreased, and the normal vagally mediated resting R–R interval variability is markedly blunted in heart failure. The degree of blunting is highly correlated with plasma norepinephrine levels, which may be very high in advanced heart failure (15).
Hypertrophy and Dilation
Left ventricular hypertrophy (LVH) and dilation may allow compensation of the failing heart to be maintained for many years. The stress in the wall of the heart varies with the radius of the ventricular cavity. If the heart is subjected to a volume load, it dilates to accommodate the load and to increase its ability to eject the load (the Frank-Starling principle; see above). However, ventricular dilation causes an increase in ventricular wall stress, which stimulates ventricular hypertrophy. Eventually, the heart becomes both dilated and hypertrophied, and the ratio of wall thickness to cavity size returns to normal, which normalizes wall stress. Therefore, a state of compensated ventricular dilation is achieved. The response to a pressure overload is different. An increase in wall stress in the absence of volume overload leads to cellular hypertrophy; wall stress per unit area returns to normal, but the cavity size is unchanged. Although hypertrophy and dilatation initially may be adaptive and beneficial, cardiac remodeling eventually becomes maladaptive and leads to heart failure. The increased myocyte stretch, neurohumoral activation, and myocardial hypoxia associated with cardiac remodeling activate the gene for the precursor of brain natriuretic peptide (prohormone BNP [proBNP]), which results in the synthesis and release of proBNP from ventricular myocytes. ProBNP is cleaved into biologically active BNP and the remaining N-terminal fragment pro-BNP (NT-proBNP, see below for further discussion) (16).
Activation of the Neurohormonal System
The neurohormonal activation triggered by the inability of the failing heart to maintain an effective arterial blood pressure and tissue perfusion is a major cause of the syndrome of heart failure (17). Neurohormonal activation leads to an increase in peripheral vascular resistance, a redistribution of cardiac output (maintaining flow to the heart and brain and reducing it to the kidneys, skin, splanchnic organs, and skeletal muscle), and the retention of salt and water. In less severe heart failure, when the resting cardiac output is normal, redistribution occurs only during exercise. In severe heart failure, when the resting cardiac output is significantly decreased, redistribution occurs at rest. The decrease in blood flow is functionally most important in the kidneys. Decreased renal blood flow causes a release of renin from the juxtaglomerular apparatus, which leads to increased plasma angiotensin activity. Angiotensin is a potent vasoconstrictor and acts both directly on smooth muscle and indirectly by increasing norepinephrine release from vascular nerve endings. Norepinephrine and angiotensin may directly damage myocardial cells. Prolonged increased plasma norepinephrine levels lead to a decreased density of β1-adrenergic receptors on cardiac myocytes and thereby may decrease the normal myocardial response to sympathetic stimulation. The increase in angiotensin activity leads to an increase in aldosterone production, which causes an increase in sodium resorption from the distal nephron, thereby increasing plasma volume.
Increased aldosterone levels contribute to hypokalemia and hypomagnesemia that may make the failing heart more susceptible to ventricular arrhythmias. Aldosterone also appears to stimulate myocardial fibrosis, which in turn may play a role in hypertrophy and dilation of the ventricle (18). The renal resorption of sodium is facilitated by an increased filtration fraction at a given glomerular filtration rate, which causes increased sodium reabsorption in the proximal nephron. Paradoxically, hyponatremia may result from increased thirst and consumption of free water, triggered by increased levels of circulating renin, angiotensin, aldosterone, and antidiuretic hormone and by a decreased renal responsiveness to atrial natriuretic peptide (19). The effect of angiotensin on thirst and on sodium appetite is striking (20). The importance of these compensatory responses to neurohormonal activation in the management of patients with heart failure is discussed below.
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Diagnosis
Causes of Heart Failure
When the diagnosis of heart failure is made, it is essential to determine the most likely etiology because the treatment and prognosis of heart failure vary greatly depending on its cause. Heart failure is caused by one of three basic mechanisms: an increased workload to which the heart cannot accommodate, a disorder of the myocardium so that it is unable to accommodate normal workloads, or a restriction of ventricular filling so that an adequate stroke volume cannot be achieved. Table 66.1 lists selected examples of these conditions. In the United States, the most common condition associated with both systolic and diastolic heart failure is hypertension, followed closely by ischemic heart disease (21).
The most common precipitating causes of acute heart failure are noncompliance with medication or diet in a patient with previously compensated heart failure, acute myocardial ischemia or infarction, poorly controlled hypertension, arrhythmia, valvular disease, and pneumonia. In patients for whom the precipitating cause is not obvious, it is important to consider arrhythmia (see Chapter 64), covert ischemia (see Chapter 62), and pulmonary embolism (see Chapter 59). In addition, it is important to inquire about psychosocial stress, which may lead to increased energy demands and often is associated with increased salt and water intake. Sudden, extreme levels of psychosocial stress have been shown to cause contraction band necrosis of the heart. This may lead to acute or subacute heart failure (22). Use of nonsteroidal anti-inflammatory drugs (NSAIDs; other than low-dose aspirin) is associated with a 10-fold increase in the risk of first hospital admission for heart failure in patients with a history of heart disease (23). Many other medications should be used with caution, or not at all, in patients with heart failure because the drugs may exacerbate heart failure symptoms, may be associated with an increased risk for adverse effects in patients with heart failure, or may cause conduction abnormalities (24). It is important for clinicians to consider the potential for adverse effects and drug–drug interactions in patients with heart failure, particularly because many patients with heart failure are elderly, have other medical comorbidities, and are taking multiple other medications.
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TABLE 66.1 Causes of Heart Failure |
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Right- and Left-Sided Heart Failure
Heart failure historically was classified as right sided (as evidenced by jugular venous congestion, hepatic enlargement, ascites, or peripheral edema; see below) or left sided (as evidenced by signs and symptoms of pulmonary congestion; see below) depending on which chamber(s) was compromised. Although this diagnostic scheme occasionally is encountered in clinical discourse and is enshrined in the International Classification of Diseases diagnostic codes, it now is primarily of historical interest.
Functional Classification
The amount of physical activity that a patient can perform without symptoms of heart failure determines functional class. Tables 66.2 and66.3 give several classification schemes that are useful in categorizing patients in this regard. Correctable disease may be present despite severe symptoms, so the functional classification provides useful prognostic information only within selected subsets of patients. Functional class is best determined by questioning the patient regarding performance during well-defined daily activities. For example, a patient may be asked about his or her tolerance for walking a specified number of flights of stairs, walking a specific distance, or carrying a specific load. The patient should be questioned regarding which customary interpersonal, household, or work activities have required modification (see Chapter 63 for metabolic requirements of daily activities). Several
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quality-of-life measures have been developed specifically for heart failure; these measures may be useful in evaluating the patient's impairment and response to treatment (25).
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TABLE 66.2 Assessment of Functional Capacity |
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TABLE 66.3 Goldman Specific Activity Scalea |
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TABLE 66.4 Stages of Heart Failure |
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The American College of Cardiology and the American Heart Association have taken a new approach to the classification of heart failure that emphasizes the evolution and progression of this condition (Table 66.4) (see Hunt et al., http://www.hopkinsbayview.org/PAMreferences). This classification scheme includes people who are at risk for, but who do not have, heart failure (stage A). The inclusion of patients at risk for heart failure emphasizes the need for clinicians to identify and treat conditions that are strongly associated with the development of heart failure, such as hypertension, diabetes, and coronary artery disease.
History
No symptoms, signs, or laboratory tests are pathognomonic of heart failure. The significance of symptoms and signs compatible with heart failure must be inferred based on the patient's overall condition and the stage at which the patient appears to be in the natural history of his or her disease. A normal BNP or NT-proBNP level, however, strongly suggests that heart failure is not present. Table 66.5 lists the clinical criteria for the diagnosis of heart failure.
The most common symptoms of heart failure are dyspnea and fatigue. Dyspnea in heart failure is a symptom of increased LVEDP with pulmonary venous and capillary congestion. Increased pulmonary congestion decreases lung compliance and vital capacity. The work of breathing increases and breathing becomes rapid, shallow, and forced. Fatigue, caused by low cardiac output, often is described as a general sense of weakness or “lack of ambition.” Some patients may complain of fatigue rather than dyspnea. Fatigue may be a symptom of low cardiac output with hypotension caused by overaggressive diuresis, especially when there is concomitant use of converting enzyme inhibitors and β-blockers. A complaint of dyspnea or fatigue may be difficult to interpret because effort intolerance may bear little or no relationship to objective
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measures of circulatory, ventilatory, or metabolic dysfunction during exercise. Factors other than the degree of hemodynamic dysfunction may be important; these include musculoskeletal status, muscle deconditioning, arthritis, body composition, obesity, motivation, comorbid depression, and tolerance of discomfort.
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TABLE 66.5 Diagnostic Criteria for Heart Failurea |
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Orthopnea is dyspnea in the recumbent position. It often is experienced by patients with heart failure, although it may also be a symptom of patients with obstructive lung disease or obesity. Blood normally pools in the lower extremities when a person is upright. When a person lies down, venous return to the heart increases; in a patient with heart failure, this increase in venous return may result in an increase in LVEDP that is significant enough to cause pulmonary venous congestion. The severity of orthopnea often is assessed by the number of pillows the patient must use to be able to breathe comfortably in the recumbent position. Patients should be asked if they have taken to sleeping in a recliner couch.
Patients with heart failure often have a nonproductive cough, especially when in the recumbent position; at times this is the patient's premonitory symptom of decompensated heart failure and may precede the development of dyspnea by several days. The cough is caused by pulmonary venous congestion and usually improves with diuresis.
Paroxysmal nocturnal dyspnea (PND) is characteristic of poorly compensated heart failure; it typically occurs several hours after falling asleep and is relieved by sitting up in bed or by getting out of bed and sitting in a chair. Because PND often is associated with wheezing, it must be distinguished from the nocturnal shortness of breath sometimes experienced by people with obstructive lung disease (see Chapter 60). Periodic, or Cheyne-Stokes, breathing is a symptom of severe heart failure with low cardiac output. During the hyperpneic phase, this respiratory pattern may be confused with PND and should be distinguished from obstructive sleep apnea (see Chapter 7).
A history of edema, weight gain, or abdominal bloating (from retention of salt and water) often is elicited from patients with heart failure. Many patients also give a history of having taken digitalis, diuretics, or an angiotensin-converting enzyme (ACE) inhibitor in the past for a “heart problem.” Chest pain caused by myocardial ischemia is common in patients with heart failure (see Chapter 62). Decompensated heart failure caused by salt and water overload may cause ischemic chest pain from LV dilation with increased LV oxygen demands. Heart failure caused by systolic or diastolic dysfunction (see below) may rapidly decompensate because of uncontrolled hypertension, which is often seen when patients run out of, or fail to take, antihypertensive medications or because of ischemia, especially if there is associated paroxysmal mitral regurgitation caused by acute papillary muscle dysfunction. This may occur in association with exercise in patients with stable ischemic heart disease or may occur paroxysmally and at rest in patients with unstable ischemic heart disease (see Chapter 62). The symptomatic response to nitroglycerin does not by itself differentiate between dyspnea caused by ischemia with acute LV dysfunction and dyspnea caused by chronic heart failure; sublingual nitroglycerin may relieve symptoms of congestion caused by either condition (see below).
Nocturia, a common symptom of heart failure, often occurs early in the illness. It is caused by the redistribution in cardiac output that occurs in the recumbent position, partly restoring blood flow to the kidney that, in the upright position, has been diverted to other organs.
Decreased cardiac output by itself, or in association with disturbed sleep patterns caused by orthopnea, PND, and Cheyne-Stokes respirations or with concomitant cerebrovascular disease, may lead to impairment in mental function, ranging from mild confusion to overt psychosis. However, the most common neuropsychiatric complaints are mild chronic anxiety and depression; these may be the presenting complaints, especially in elderly patients with previously undiagnosed heart failure (26).
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Symptoms of gastrointestinal congestion may be seen in patients with chronic poorly compensated heart failure. Chronically increased right heart pressure may cause passive congestion of the liver, with swelling and discomfort in the right upper quadrant of the abdomen. Chronic constipation is a common complaint and may be caused by medication, inactivity, and lack of fiber in the diet.
Physical Findings
The physical findings in heart failure depend on its cause, the degree to which neurohormonal compensatory mechanisms are invoked (see above), the degree to which cardiac remodeling has progressed, and whether the heart failure is uncompensated or compensated.
Uncompensated Heart Failure
In chronic uncompensated or poorly compensated heart failure, signs of an attempt at pulmonary and cardiac compensation (increased respiratory and heart rate), signs of cardiac remodeling (increased heart size), and signs of increased renin, angiotensin, and aldosterone activity (vascular redistribution and evidence of cardiac, pulmonary, and peripheral congestion) are seen. Congestion is manifest by a ventricular gallop sound (S3), pulmonary crackles, jugular venous distention, hepatojugular reflux, and peripheral pitting edema.
Increased heart size may be recognized by inspection, palpation, and percussion of the precordium. The precordium should be palpated with the patient in the supine and the left lateral position. The location, quality, and size of the point of maximal impulse (PMI) should be noted. The PMI of a dilated and enlarged heart is displaced laterally and caudally and is heaving and diffuse. The PMI of a concentrically enlarged heart is not displaced but may be thrusting or sustained.
Sinus tachycardia, defined as a resting heart rate >100 bpm in an adult, is a sensitive but nonspecific sign of heart failure. In patients with poorly compensated heart failure, a relative tachycardia of 85 to 95 bpm may be seen. In patients who have heart failure, tachycardia is a compensatory, but maladaptive, mechanism that attempts to increase cardiac output; the tachycardia shortens diastolic filling time and may lead to further deterioration in function (see above).
The second pulmonic sound (P2) often is accentuated in patients in LV failure because of increased pulmonary artery pressure. Paradoxical splitting of the second heart sound, an indication of prolonged LV ejection time, may be heard in patients with chronic heart failure and often is associated with a left bundle-branch block (see below).
The ventricular or S3 gallop sound is the most specific sign of heart failure (27). The sound is heard shortly after the second heart sound (S2) and is caused by sudden restriction of filling in a noncompliant left ventricle. It usually is heard using the bell of the stethoscope directly over the PMI and may be audible only when the patient is in the left lateral position. The sound is low pitched and often may be sensed by the cadence of the heart sounds rather than specifically heard. The cadence closely approximates that of the word Kentucky(pronounced kyn-TUC-ky). The middle syllable is accentuated to represent the loud second heart sound caused by increased pulmonary artery pressure in patients in heart failure. The timing of the last syllable closely approximates the timing of the third heart sound, when the word is repeated at a rate of 85 to 100 times per minute.
Crackles (formally called rales) are high-pitched sounds (similar to the sound of a clump of hair rubbed between the fingers) produced by the sudden filling with air of fluid-filled alveoli. They are a sign of moderately to severely decompensated left heart failure.
Neck vein distention and hepatojugular reflux are insensitive but specific findings of heart failure (28). In chronic heart failure, right ventricular filling pressure usually increases as LVEDP increases. With time, the right ventricle becomes less compliant. As heart size increases, the pericardium may restrain the heart and thereby limit filling. Neck vein distention is assessed while the patient is semirecumbent, with a small pillow supporting the neck and the head turned slightly away from the examiner. Ideally, the right internal jugular vein is inspected because it is directly in line with the right atrium and accurately reflects right atrial pulsations and pressure. Internal jugular venous distention is seen as a broad-based fullness in the anterior cervical triangle. An arbitrary reference point may be chosen (e.g., the sternal angle; this approximates in many the level of the right atrium), and the column of blood above this point may be measured without regard for the angle of elevation of the thorax. The value of this observation is that accurate serial assessments are possible, permitting the examiner to confirm worsening failure (increasing jugular venous pressure) or to recognize a too vigorous diuretic response (abnormally low jugular venous pressure).
Hepatojugular reflux is assessed by having the patient lie supine and semirecumbent at 45 degrees. The patient is asked to breathe normally and is warned that the examiner will apply pressure over the right upper quadrant of the abdomen. Patients so warned comply and do not hold their breath or perform the Valsalva maneuver, which distends the jugular vein and makes the sign impossible to elicit. The pressure on the vena cava causes right ventricular end-diastolic pressure and right atrial pressure to rise and to remain elevated; this is seen as jugular venous distention.
Peripheral pitting edema is a common but not specific sign of heart failure. It occurs in the dependent portions of the body, which in ambulatory patients are the feet
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and lower legs. Edema in heart failure is caused by increased resorption of salt and water by the kidney. An increase in weight may precede pitting edema as an early objective manifestation of decompensated heart failure. Patients should be encouraged to weigh themselves daily or at least three times per week, and they should record the values and bring the weight record with them at each visit.
Of note, calcium channel blockers (see below) are a common cause of pitting edema, so if a patient is taking one of these drugs, peripheral edema is not necessarily caused by heart failure. Unilateral pitting edema is also commonly seen in the vein-harvest leg after coronary artery bypass surgery.
Because of low cardiac output and vascular redistribution, patients’ extremities may be cool and their nail beds cyanotic. Delayed capillary filling in the skin of the abdomen may be apparent when the examiner's hand is removed after assessing hepatojugular reflux. In patients with decompensated heart failure, hepatic congestion may produce jaundice, hepatomegaly, and abdominal pain that mimic acute hepatitis.
Compensated Heart Failure
In contrast to the findings in patients with acute or chronic uncompensated heart failure, there may be few or no specific physical findings in patients with compensated heart failure at rest other than signs of increased heart size. A presystolic gallop or fourth heart sound (S4) can be heard in most patients with long-standing high blood pressure or ischemic heart disease who are in normal sinus rhythm. The fourth heart sound is thought to be caused by atrial contraction into a stiff ventricle (see below). A soft systolic murmur, approximately grade 1 to 2/6, is commonly heard at the PMI or along the left sternal border in patients with chronic compensated heart failure. This murmur usually represents a minor degree of mitral or tricuspid insufficiency. A paradoxically split S2 is often heard in patients who have a left bundle-branch block.
Laboratory Diagnosis
Brain Natriuretic Peptide and N-Terminal Prohormone Brain Natriuretic Peptide
BNP was discovered in porcine brain, but it is produced mainly in the cardiac ventricles. The proBNP gene is activated by myocyte stretch, neurohumoral activation, and hypoxia. These stressors lead to rapid secretion of proBNP from ventricular myocytes. As proBNP is released, it is cleaved into active BNP and inactive NT-proBNP. BNP activates peripheral receptors that cause diuresis, vasodilation, and decreased renin and aldosterone secretion (16). The kidney plays a role in the degradation and clearance of BNP and NT-proBNP, and increased plasma levels of these peptides may be difficult to interpret in the setting of renal dysfunction. However, both tests have a high sensitivity and negative predictive value for the diagnosis of heart failure, allowing their use to “rule out” this condition in the primary care setting (29,30). Thus, the test may be helpful in ambulatory patients in whom the cause of dyspnea is unclear. Diagnostic uncertainty based on routine clinical examination alone is not uncommon in elderly patients with multiple comorbidities, especially when symptoms are mild. Use of BNP and NT-proBNP in this setting may decrease the overdiagnosis of heart failure in primary care (30). BNP also may be very useful in guiding treatment. In one study in which treatment was guided either by BNP levels or by clinical signs and symptoms alone, the number of significant cardiac events in the “BNP group” was reduced by nearly 50% compared with the control group (31).
Chest X-Ray Film
The chest x-ray film is an important diagnostic procedure for evaluation of suspected heart failure. The radiologic signs of heart failure are cardiac enlargement and pulmonary congestion. In advanced or chronic heart failure, pleural effusions are frequently seen.
A number of factors influence heart size on the chest x-ray film, including body build, depth of inspiration when the film is taken, and the chambers that are enlarged. Nevertheless, determination of the ratio of the transverse diameter of the heart to the greatest diameter of the chest, the cardiothoracic ratio, is a reliable and valid measurement of heart size and should be part of the database of every patient who is thought to have, or to have had, heart failure. The normal cardiothoracic ratio is <0.5. The pulmonary vasculature should be examined, and signs of vascular redistribution, caused by pulmonary venous hypertension, and of enlarged hilar vessels, caused by acute or chronic pulmonary hypertension, should be noted.
Normally, the lower lobes of the lungs are better perfused than the upper lobes. The earliest radiologic sign of pulmonary congestion is reduction of blood flow to the lower lobes caused by compression of vessels by extravascular fluid that has gravitated to the lung bases. In early heart failure, there is simply an equalization of the size of the vessels to the upper and lower lobes. As congestion increases, the vessels to the upper lobes become more prominent, the so-called cephalization of flow. More severe failure is manifest by signs of interstitial edema and ultimately by alveolar edema and a transudative pleural effusion (see Chapter 59). The volume of pleural effusions often is underestimated by routine chest x-ray views. Decubitus films should be obtained if a pleural effusion is present.
Electrocardiogram
No changes on the electrocardiogram (ECG) are diagnostic of heart failure. However, the ECG may reflect an
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underlying disease (e.g., LVH caused by hypertension; Q waves or ST-T wave changes caused by infarction) or the presence of an unstable rhythm (e.g., atrial fibrillation with rapid ventricular response) that has caused heart failure. Changes reflecting chamber enlargement or hypertrophy (especially LVH or left atrial enlargement), conduction system disease (especially first-degree atrioventricular block and bundle-branch block), or an abnormal rhythm (especially sinus tachycardia, atrial fibrillation, or ventricular ectopy) are common. A normal ECG is unusual in patients with chronic LV dysfunction. Because of this finding, use of the ECG as a triage tool has been proposed, which could reduce by 50% the number of echocardiograms ordered for the evaluation of suspected heart failure (32).
Patients with hypertrophy of the heart may show only minor nonspecific ST-T wave changes. Grossly abnormal changes are commonly seen on the ECG of patients who have both dilation and hypertrophy of the left ventricle. The most common manifestations of LVH are left-axis deviation, increased QRS voltage and QRS duration, and ST-T wave changes. Evidence of left atrial enlargement is frequently seen (see below). Although there are numerous ECG criteria for LVH, a clinically useful criterion is the index of Lewis: net positivity in lead I plus net negativity in lead III ≥2.0 mV. Also, an R wave >11 mm in lead aVL is specific for LVH.
Conduction abnormalities are common in patients in heart failure, especially left bundle-branch block. Left bundle-branch block may be an early sign of congestive cardiomyopathy, especially when it occurs in young patients. It nearly always is a sign of organic heart disease. Left bundle-branch block or a nonspecific intraventricular conduction delay with a QRS interval >140 ms is often seen in patients with advanced heart failure. These patients may be candidates for implantation of a biventricular pacemaker resynchronization device (discussed below).
Left atrial enlargement is diagnosed by the presence of a negative P wave with an area >1 mm2 on lead V1. It commonly is seen on the ECG of a patient with acute heart failure and may disappear as the patient is treated and the volume of the left atrium decreases.
Right ventricular hypertrophy is most reliably diagnosed in adults by a shift of the QRS axis toward the right >90 degrees in combination with altered precordial R-wave progression.
Certain ECG changes suggest a decreased ejection fraction, especially in patients with heart failure caused by ischemic heart disease. These include Q waves in leads 1, aVL, and V1 through V4 with persistently upward coving of the ST segments in the precordial leads (seen in patients with extensive anterior wall infarctions with aneurysms) and deep Q waves in both inferior and precordial leads with QRS duration >0.1 second (suggesting ischemic cardiomyopathy) (32). Low QRS voltage (<10 mm in precordial leads and <5 mm in limb leads) is commonly caused by pericardial effusion, hypothyroidism, or infiltrative disease of the heart (e.g., amyloid) but also may be seen in patients with severe emphysema or marked obesity.
Echocardiography
The two-dimensional echocardiogram with Doppler is a reliable technique for determining ventricular size and thickness, the presence of valvular and structural abnormalities, the evaluation of systolic and diastolic function, and the presence or absence of pericardial effusion. If not previously performed, a two-dimensional echocardiogram should be obtained in all patients with a clinical diagnosis of heart failure to assess LV function. This is particularly important because heart failure due to LV systolic dysfunction may be difficult to distinguish from heart failure with normal LV function (i.e., diastolic dysfunction) by history and physical examination alone (see below). Echocardiography should be considered for patients with suspected valvular or pericardial disease or for patients in whom the cause of heart failure is unclear. In the primary care setting, echocardiography is unlikely to be useful in the evaluation of patients with suspected heart failure who have a normal ECG, a normal heart size on chest x-ray film, or a normal BNP or NT-proBNP level. (Use of echocardiography in the diagnosis of valvular heart disease is discussed more fully in Chapter 65.)
Two-dimensional echocardiography with color-flow Doppler is useful in estimating the ejection fraction and detecting valvular stenosis or regurgitation. Pulmonary artery pressures may be estimated accurately but only in patients who have tricuspid regurgitation; this includes most patients with heart failure. Two-dimensional echocardiography with pulsed Doppler evaluation of mitral valve flow velocity also is useful in differentiating between systolic and diastolic dysfunction (13,14).
Radionuclide Angiography and Single-Photon Emission Computed Tomography Scanning
Radionuclide angiography (gated blood pool scan or multigated acquisition study) is a technique for visualizing the cardiac chambers throughout the cardiac cycle. The major advantages of this technique over echocardiography are that good images can be obtained even in patients who are obese or who have severe chronic lung disease, and the ejection fraction can be determined precisely.
Radionuclide angiography is an effective tool for evaluating LV wall-motion abnormalities, including ventricular aneurysm, and for evaluating LV function and diastolic compliance. The primary care provider does not ordinarily consider radionuclide angiography without the advice of a cardiologist. In most institutions, echocardiography has largely replaced radionuclide angiography as a diagnostic
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tool because it provides much more information regarding systolic and diastolic function, without radiation.
Single-photon emission computed tomography (SPECT) scanning may be used to assess possible ischemia and to determine if viable myocardium is present in patients with heart failure. LV function and wall-motion abnormalities can be assessed. This test usually is ordered after consultation with a cardiologist.
Cardiac Catheterization and Myocardial Biopsy
Cardiac catheterization (see Chapter 62) should be considered in any patient in chronic heart failure in whom an etiologic and anatomic diagnosis has not been made by noninvasive techniques. Sudden onset of heart failure with cardiomegaly in a previously healthy patient is an indication for immediate referral to a cardiologist. Cardiac catheterization may be important in the diagnosis of pericardial disease. Myocardial biopsy may be useful in young patients suspected of having a cardiomyopathy who have sudden onset of heart failure of uncertain cause. Approximately one third of patients with chronic dilated cardiomyopathy are found by cardiac catheterization to have significant coronary disease (33). The procedure should be considered in all patients who have dilated cardiomyopathy of uncertain origin, especially in patients who have diabetes or who may have severe coronary heart disease with mild or no symptoms of chest pain.
Exercise Testing
It often is difficult to determine the functional status of patients with heart failure, and functional limitation often is overestimated or underestimated. Studies show that the most precise determination of functional classification is given by exercise testing with assessment of oxygen consumption (34). The protocol used should be one in which the level of exercise is increased in small increments. The test should be obtained in consultation with a cardiologist or pulmonologist and only if functional classification cannot be satisfactorily determined by clinical means. The 6-minute walk test, in which the distance that the patient is able to walk in 6 minutes is measured, correlates well with function assessed by measurement of oxygen consumption and also with prognosis. It is a useful, inexpensive tool for the assessment of functional status, especially in patients with more advanced heart failure, and changes in performance can be tracked over time (35,36). A carefully taken history is also useful and inexpensive (see above).
Systolic versus Diastolic Dysfunction
The clinical signs and symptoms of heart failure may result from systolic or diastolic dysfunction of the myocardium (see above). It is important to determine whether one or both of these mechanisms are operative in order to prescribe appropriate treatment.
In patients with heart failure caused by systolic dysfunction, the heart is typically dilated, often hypertrophied, and the inotropic state of the heart is impaired relative to the afterload so that the ejection fraction, and often the blood pressure, is decreased. A reduced ejection fraction, detected by echocardiography or gated blood pool scan, and an S4 on auscultation may be the only signs of compensated systolic dysfunction. In uncompensated systolic dysfunction, resting tachycardia usually is present, and an S3 may be heard. The heart usually is enlarged on chest x-ray film, and Q waves, QRS widening, or left bundle-branch block may be present on the ECG.
In patients with signs and symptoms of heart failure caused by diastolic dysfunction, the ventricle is less compliant (i.e., stiffer) and early diastolic passive filling of the left ventricle is decreased. Therefore, immediately before atrial systole, the atrium has a greater than normal volume and pressure and, by the Frank-Starling principle, the force of atrial contraction is increased. Clinically, this may be detected by a palpable presystolic apical filling wave or heard as a loud S4. On pulsed Doppler echocardiography, diastolic dysfunction may be diagnosed by the increased velocity of the atrial component of diastolic filling relative to the peak velocity of the early diastolic rapid filling phase (seeChapter 65 for a more detailed discussion of this topic) (13).
The diagnosis of diastolic dysfunction should be suspected in patients with evidence of increased filling pressure (jugular venous distention and pulmonary redistribution of blood flow) and concomitant elevation of blood pressure. ECG signs of LVH and elevated levels of natriuretic peptides do not reliably differentiate between systolic and diastolic heart failure. The distinction must be made by echocardiography (13).
Management
The goal of therapy is not merely to control symptoms but to treat specifically the underlying causes of heart failure if possible (Table 66.1). If the underlying disease cannot be effectively treated (Fig. 66.3), an attempt should be made to increase the capacity of the heart to do work or to decrease the amount of work that the heart has to do. Table 66.6 lists the various measures that can be used to accomplish these goals in ambulatory patients. These measures are discussed in detail here.
General Principles
Lifestyle and Nonpharmacologic Therapies
It is not always possible to improve the function of the failing heart, but it usually is possible to decrease the
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metabolic needs of the body by encouraging a patient to stop smoking (see Chapter 27), to avoid emotional stress, and to get an adequate amount of rest (Table 66.7). Obstructive sleep apnea, if present, must be treated. A thorough understanding of the patient's home and work environments and of the relationship of the patient to his or her supporting family members and caregivers is important. When possible, the recommended treatment regimen should be discussed with both the patient and the patient's family.
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FIGURE 66.3. Algorithm for treatment of heart failure. |
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TABLE 66.6 Measures Used in Ambulatory Treatment of Heart Failure |
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The ambulatory patient should be encouraged to exercise (see Chapter 63) but to take care to avoid exertion to the point of causing further symptomatic cardiac decompensation. Sometimes this simply means performing the same activities more slowly.
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TABLE 66.7 Suggested Topics for Patient, Family, and Caregiver Education and Counseling |
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There is a decreased stimulus to renin, angiotensin, and aldosterone production during supine rest, and even severely disabled patients may be able to lead socially useful and satisfying lives if they rest in the afternoon and in the early evening or before social or business engagements. Strict bed rest, which causes muscle weakness and deconditioning, should be strongly discouraged. The best advice for patients with chronic stable heart failure may be to participate in an exercise training regimen in which the exercise is supervised at levels shown to be beneficial in controlled trials (37,38).
The temperature and humidity of the patient's home and work environment must be controlled. Patients should be encouraged to have air conditioners for the summer months to reduce the extra demand placed on the heart by hot humid weather.
Diet
Surprisingly little experimental evidence supports the long-term benefit of a severely salt-restricted diet in controlling heart failure in patients who respond well to moderate dosages of diuretics. However, it is commonly observed that sudden increases in salt intake may precipitate acute pulmonary edema in patients who have moderately well-compensated chronic heart failure. Holiday seasons are particularly dangerous in this regard, probably because of the increased physical activity and emotional stress. The various types of salty food that the patient is likely to eat should be anticipated, based on the patient's cultural background. Examples of frequently eaten salty food include breakfast meats such as sausage, bacon, and scrapple; deli meats including “low-salt” ham; salt pork or fatback in cooking vegetables; and many foods prepared by traditional ethnic cooks. Many patients attempt to substitute condiments in place of salt and are not aware that ketchup, hot sauce, soy sauce, and many other sauces have high sodium concentrations. Homebound patients may eat prepared foods such as frozen pancakes and waffles or frozen convenience dinners, or they may have fast food brought to their home by family and neighbors. Most patients are unaware that the sodium content of these foods often is higher than Atlantic Ocean seawater (1 g sodium/100 g seawater) (39). A no-added-salt diet, which contains approximately 2 to 3 g of sodium, suffices for most patients in compensated heart failure. Patients with poorly compensated heart failure may require a diet that contains 500 mg to 1 g of sodium, along with a restriction of volume intake to no more than 1.5 L. The caregiver must take the time to give specific concrete advice about diet and nutrition.
A high-soluble-fiber diet may help prevent constipation and straining (see Chapter 45). Referral to a dietitian may be essential for patients with frequent episodes of cardiac decompensation caused by noncompliance with salt and fluid restriction. Chapter 67 gives guidelines for planning these diets and a list of foods to be avoided by patients being treated for heart failure.
Patients with heart failure may wish to know whether they can continue to drink alcoholic beverages. More than 2 oz of alcohol per day may increase blood pressure and may impair cardiac function. In any patient with a cardiomyopathy apparently related to prolonged heavy alcohol use, total abstinence from alcohol is essential. However, a published large prospective cohort study suggests that moderate alcohol consumption (approximately 1 oz/day) may decrease the risk of development of heart failure in older persons. This effect may result from the association of moderate alcohol consumption with lower risk of development of coronary artery disease and type
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2 diabetes. Moderate alcohol consumption may also decrease blood pressure (40).
Drugs That Promote Positive Sodium Balance
A number of commonly used drugs can promote a positive sodium balance, for example, corticosteroids and estrogens cause renal sodium retention. NSAIDs other than aspirin are strongly associated with the development of heart failure. One study showed an odds ratio of 10.5 for the development of heart failure among patients with known heart disease who took NSAIDs (23). Of note, the effects of cyclooxygenase-2 inhibitors on kidney function may be similar to those of the nonselective NSAIDs (41). Some antacid preparations contain a significant amount of sodium. Patients with heart failure should not take these drugs; however, if the drugs are necessary, the patients should be monitored closely for symptoms of increased heart failure or electrolyte disturbance. There is no convincing evidence that aspirin has a deleterious effect on patients with heart failure; indeed, its use appears to be associated with lower mortality, especially in patients with coronary disease and heart failure (42). Unless patients have a definite history of aspirin allergy or a history of aspirin-induced gastrointestinal or intracerebral bleeding, it seems advisable for patients with heart failure who are not taking warfarin to take daily aspirin, especially if they also have coronary disease or diabetes.
Drugs That May Directly or Indirectly Impair Left Ventricular Function
Calcium channel blockers depress LV function and should be avoided in patients with systolic dysfunction. Second-generation drugs (felodipine and amlodipine; see below) may be exceptions, but they should be considered only if the patient's blood pressure remains poorly controlled despite the careful titration to appropriate doses of ACE inhibitors, β-blockers, and diuretics. The antiarrhythmic agents disopyramide and flecainide should not be used in patients with systolic dysfunction. Use of the insulin sensitizer drugs of the thiazolidinedione class in patients with heart failure (currently pioglitazone and rosiglitazone are available) has been controversial. These drugs are associated with fluid retention in patients with advanced systolic dysfunction. A large observational study, however, showed improved outcomes in patients with type 2 diabetes and heart failure who took insulin sensitizing drugs in the thiazolidinedione class or metformin (43). A consensus panel urges close monitoring of patients with heart failure and diabetes who are taking these drugs (44).
Drug Therapy
The goal of drug therapy for heart failure is to relieve symptoms, improve function, and prolong life. Clinical trials demonstrate that achieving these goals is possible in most patients with chronic heart failure, although in clinical practice appropriate drugs often are not titrated to doses shown to achieve these goals in randomized controlled trials (45).
There may be important differences in the therapeutic approach to patients whose heart failure is caused by systolic dysfunction (dilated left ventricle with decreased ejection fraction) as opposed to patients whose heart failure is caused primarily by diastolic dysfunction (hypertrophied stiff heart with a normal or increased ejection fraction) (see above). Although many patients, especially older patients with chronic hypertension, have heart failure due to diastolic dysfunction, few clinical trials are available to guide therapy for this condition. Control of hypertension, when present, appears to be important in the treatment of diastolic heart failure. Although many antihypertensive drugs may prove beneficial in the treatment of diastolic heart failure, the angiotensin receptor blocker (ARB) candesartan was shown to decrease heart failure hospitalizations in a randomized controlled trial in patients with heart failure and preserved LV function (46).
Diuretic Drugs
Diuretic drugs are used when treatment of the underlying cause of heart failure is not possible or when signs and symptoms of congestion persist despite treatment of the underlying condition. Although diuretic drugs have not been shown to prolong life (with the exception of spironolactone in certain patients with heart failure; see below), they relieve symptoms and improve function in most patients with heart failure. Diuretics reduce symptoms of circulatory congestion by increasing sodium and water excretion.
The goal of diuretic therapy is to reach and maintain the patient's “dry weight.” Physiologically, this is the weight at which signs of peripheral congestion are substantially relieved and the LV filling pressure remains near the preload reserve (i.e., function is optimized via the Frank-Starling principle). Clinically, this is the weight at which peripheral edema is no more than a trace, jugular venous distention is absent, hepatojugular reflux, if present, is no more than a few centimeters above the clavicle, the blood urea nitrogen and creatinine determinations are at, or slightly above, baseline, no symptomatic orthostatic blood pressure changes are present, urine output is maintained, and diuretic drug doses do not require adjustment. After diuresis to the dry weight, the decrease in ventricular wall stress (i.e., afterload) and the improvement in ventricular contraction brought about by a decrease in heart size and peripheral vascular resistance often lead to prompt improvement in ventricular function and, in hypertensive patients, a reduction in blood pressure.
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TABLE 66.8 Characteristics of Selected Diuretic Drugs |
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Three classes of diuretics are in common use: thiazides (e.g., hydrochlorothiazide) and thiazidelike agents (e.g., metolazone, chlorthalidone), the so-called loop diuretics (e.g., furosemide, bumetanide, and torsemide), and the potassium-sparing diuretics (spironolactone, eplerenone, triamterene, and amiloride) (Table 66.8).
The thiazides and the thiazidelike diuretics act on the early portion of the distal convoluted tubule of the nephron. They cause a moderate increase in sodium and chloride excretion. Potassium and hydrogen losses are accentuated because of the increased delivery of solute to the terminal portion of the distal tubule, where potassium secretion occurs and is modulated by aldosterone. Thiazidelike agents such as metolazone act on both the proximal and distal convoluted tubules of the nephron and may be particularly effective in patients with very low renal blood flow.
The loop diuretics inhibit tubular resorption of chloride and sodium in the ascending limb of the loop of Henle. These diuretics are potent and result in substantially increased excretion of sodium, chloride, and water. Like the thiazides, the loop diuretics increase the delivery of solute to the more distal portion of the nephron, where potassium and hydrogen secretion is accentuated.
Potassium-sparing diuretics act on the terminal portion of the distal convoluted tubule, where only a small proportion of sodium is reabsorbed. By themselves they are only weak diuretics. However, they may be especially useful in combination with a thiazide or loop diuretic in preventing hypokalemia or when a patient becomes refractory to the more potent diuretics. The effect of thiazides and loop diuretics may be dampened by resorption of sodium in the terminal portion of the distal convoluted tubule because they act proximal to the portion of the distal nephron where aldosterone influences sodium resorption. Spironolactone is structurally similar to aldosterone and competitively inhibits aldosterone binding to cellular receptors. It causes gynecomastia or breast pain in approximately 10% of men taking the drug. Eplerenone is a more selective aldosterone blocker that does not appear to cause gynecomastia or breast pain, but it is more expensive than spironolactone (47). Triamterene and amiloride block sodium resorption and potassium excretion but do not compete with aldosterone or even depend on its presence to be effective. These diuretics may cause life-threatening increases in the serum potassium level. Patients usually should not receive potassium supplementation while taking these diuretics. Patients with renal failure or patients
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taking an ACE inhibitor are at increased risk for developing hyperkalemia if given these diuretics. Serum potassium levels must be monitored carefully when these agents are used.
Use of Diuretic Drugs
When used for treatment of heart failure, diuretics should always be prescribed with another agent (e.g., ACE inhibitor or β-blocker). In patients with normal renal function, therapy should start with the lowest effective dosage of a thiazide compound (Table 66.8). Generic hydrochlorothiazide is the drug of choice. Many patients with mild heart failure may effectively control symptoms by taking the drug every other day or three times per week, along with an ACE inhibitor and β-blocker. Patients with progressive disease, associated with worsening renal perfusion and albuminuria, should not be treated with a thiazide diuretic, which may decrease renal perfusion. In these cases, a loop diuretic—furosemide, bumetanide, torsemide—should be prescribed (Table 66.8) (ethacrynic acid is no longer widely used). These drugs often are effective in low oral dosages. Furosemide, bumetanide, and torsemide are available in generic forms. Bumetanide and torsemide are less ototoxic than furosemide, and their bioavailability orally is higher than that of furosemide. However, furosemide is still the most popular of these drugs, in part because of cost and custom. Furosemide should be started at a dosage of 20 mg/day and increased as necessary for control of symptoms. Although a single dose of furosemide or bumetanide is commonly administered each day, these drugs are short acting (half-life of 1–1.5 hours), and patients with moderate to severe heart failure may require a second dose in the late afternoon to affect a negative sodium balance. Torsemide has a longer half-life and may be effective given once daily, even in patients with moderately severe heart failure.
Dosages of furosemide higher than 160 to 240 mg/day are rarely required and may cause ototoxicity. Patients who require such large doses of diuretic for control of congestive symptoms probably should be referred to a cardiologist for evaluation. In these cases, substituting bumetanide or torsemide for furosemide or adding a thiazide diuretic in modest dosages (hydrochlorothiazide 12.5–25 mg or metolazone 2.5–5 mg) may be necessary. Combination with a thiazide diuretic may markedly potentiate the effect of loop diuretics, leading to rapid mobilization of fluid, thereby allowing treatment of these patients in an ambulatory setting without the use of intravenous diuretics. Careful monitoring of electrolyte levels is essential (see below). A potassium-sparing diuretic may be appropriate in certain circumstances. In particular, spironolactone or eplerenone should be considered in patients with severe heart failure due to systolic dysfunction because aldosterone blockers have been shown to reduce morbidity and mortality in these patients (48). The diuretic dosage should be reduced when the dry weight is achieved, and the patient should be weighed daily and should keep a written record of the weights to review with the care provider.
Side Effects of Diuretics
Hypokalemia
The thiazides and loop diuretics have marked kaliuretic effects, and hypokalemia is a common complication of the use of diuretic therapy, especially in edematous patients. Hypokalemia may lead to fatigue, muscle cramps, and depression and often precipitates arrhythmias or digitalis toxicity. A high-sodium diet predisposes to hypokalemia in patients taking loop diuretics because of aldosterone-mediated sodium/potassium exchange in the distal tubule. Patients with persistent hypokalemia should be encouraged to adhere to a very-low-sodium diet. The justification for sodium restriction must be explained to the patient in concrete terms. If hypokalemia persists despite a low-sodium diet and treatment with an ACE inhibitor, a potassium-sparing diuretic such as triamterene, spironolactone, or eplerenone should be used in preference to potassium salts. Potassium supplementation should be discontinued before administration of a potassium-sparing diuretic. The patient's electrolyte concentration must be monitored carefully when these medications are started, when the dosage is adjusted, or when there is a change in the severity of heart failure. Patients with diabetes and renal disease, who commonly have some degree of hypoaldosteronism and hyperkalemia (type 4 renal tubular acidosis), may be very sensitive to the potassium-sparing effects of these drugs. The serum potassium level should be measured again 3 days to 1 week later; the goal is to maintain serum potassium concentration in the high–normal range. The usual dosage of triamterene is 50 to 100 mg one to three times per day, spironolactone 12.5 to 100 mg once or twice daily, and eplerenone 25 to 50 mg once daily. The higher dose ranges must be used with caution, especially in diabetics, as noted above. Chapter 50 fully discusses the indications for, and use of, potassium salts in patients taking diuretics.
Hyponatremia
The loop diuretics and the thiazides occasionally are associated with hyponatremia by impairing free water clearance, so caution is especially appropriate in patients who tend to consume large quantities of fluid. These diuretics also may be associated with hyponatremia when the extracellular volume has become contracted (a potent stimulus to release of antidiuretic hormone) and fluid intake has not been restricted. Usually, the hyponatremia can be corrected by restricting water intake to <1 L/day. Finally, the thiazides are associated rarely with hyponatremia in
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euvolemic patients who also are severely potassium depleted. This situation clinically resembles the syndrome of inappropriate secretion of antidiuretic hormone, although the exact mechanism of the complication is not fully known. The drug must be withdrawn until hyponatremia is corrected.
Contraction of the Extracellular Volume
Diuretics exert their therapeutic effect by causing a net loss of sodium, chloride, and water. If the response is excessive, depletion of the extracellular fluid compartment (the maintenance of which depends on sodium and chloride) occurs. This may have catastrophic consequences, such as postural hypotension, sometimes with loss of consciousness, precipitation of ischemia caused by changes in cerebral, coronary, or renal blood flow, or precipitation of hyperosmolar coma in diabetics. These complications are especially common when loop diuretics are used but may occur after the use of thiazides or combination diuretics, especially in patients also taking an ACE inhibitor. Patients should be monitored carefully for evidence of excessive contraction of extracellular volume by daily self-assessment of weight and for the presence or absence of edema. The caregiver should frequently assess the degree of fullness of the neck veins and evaluate for orthostatic changes in blood pressure and pulse. Glucose levels in diabetics should be checked.
Acid–Base Disturbance
Diuretics have an effect on acid–base balance via their different actions on the nephron. The thiazides and the loop diuretics are often associated with the generation and maintenance of a metabolic alkalosis. This usually requires no therapy. To correct the alkalosis, the associated volume and potassium deficiency would have to be corrected. If the volume were replenished, the effect of the diuretic would be negated. Therefore, usually only potassium-sparing diuretics or potassium chloride supplements are given (see Chapter 50). If the alkalosis is thought to be detrimental, for example, in patients with respiratory failure, the diuretic should be discontinued or the dosage reduced.
Potassium-sparing diuretics may be associated with diminished hydrogen ion excretion and therefore with a mild metabolic acidosis. This usually is of no consequence and requires no treatment.
Hyperuricemia
Thiazides and loop diuretics commonly elevate the concentration of serum urate by blocking urate secretion by the proximal renal tubules or by enhancing resorption through contraction of extracellular volume. However, symptomatic gout is not usual, nor is an elevated uric acid level likely to cause renal injury or stone formation. Therefore, routine measurement of uric acid and treatment are unnecessary unless gout occurs. Chapter 76 discusses treatment of diuretic-induced gout; in general, treatment is the same as for primary gout and does not require discontinuation of the diuretic. If NSAIDs or corticosteroids are used in treatment, the patient should be monitored closely for volume overload and for changes in renal function. Consultation with a rheumatologist may be advisable if gout is severe or recurrent in a patient with heart failure.
Hyperglycemia
Thiazides and, less commonly, loop diuretics may cause glucose intolerance. Hypoglycemic therapy may be required (or changed in diabetic patients already receiving a hypoglycemic agent) if the diuretic is to be continued (see Chapter 79).
Lipid Abnormalities
Thiazides may increase triglyceride concentrations in the blood. In patients with lipid abnormalities, a loop diuretic at low dosages (10–20 mg) may be preferable to a thiazide.
Other Effects
Thiazides occasionally are associated with a hypersensitivity-induced small vessel vasculitis, thrombocytopenia (see Chapter 56), and hypercalcemia and may be associated with impotence. Furosemide at high dosages has been associated with the development of interstitial nephritis and renal failure, especially in patients with marked proteinuria. As noted above, spironolactone, which structurally is closely related to estrogen, may cause gynecomastia, reduce libido in men, or cause impotence. These side effects usually resolve within a few weeks of discontinuing the drug. Eplerenone reportedly has a significantly lower incidence of these side effects. Even when diuretics have substantially relieved the signs and symptoms of CHF, other medications usually are necessary to optimize function and prolong life.
Digitalis
Digitalis may help restore cardiac compensation by increasing the inotropic state, or contractility, of cardiac muscle, thereby increasing the ejection fraction at a given preload and afterload, as described above. It appears to act by increasing calcium delivery to the contractile apparatus of the heart. Digoxin is the only positive inotropic agent that has been convincingly shown both to improve function and quality of life and to not increase mortality in patients with symptomatic heart failure (49). Because digoxin is indicated only for patients with heart failure caused by systolic dysfunction, it is ordinarily used in patients also being treated with a diuretic and an ACE inhibitor (see below).
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Indications for Use of Digitalis Drugs
Digitalis reduces symptoms of heart failure and decreases the hospitalization rate for heart failure (49). It improves ventricular performance by moderating the heart rate of patients in atrial fibrillation or atrial flutter and by improving contractility in patients with heart failure due to systolic dysfunction. Digitalis has been shown to be most beneficial in patients who are the most symptomatic and who have marked LV dysfunction. However, the degree to which digitalis preparations increase ventricular contractility is modest, and the toxic/therapeutic ratio is small. Particular caution is warranted in older patients and/or those with renal dysfunction because high serum digoxin concentrations may be associated not only with drug toxicity but also with increased mortality (50). Furthermore, the indiscriminate use of digitalis as a first-line medication for control of heart failure has led to its use in many patients in whom heart failure is not caused primarily by a decreased inotropic state of myocardial muscle. Such patients include those whose heart failure is caused by systemic hypertension, those with diastolic dysfunction or restriction to LV filling, and those in whom symptoms of fatigue are caused by decreased cardiac output induced by excessive diuresis.
Recommendations for Use of Digitalis Compounds
Digitalis glycosides should be prescribed only for patients with symptomatic CHF caused by systolic dysfunction (LV ejection fraction ≤40%, cardiothoracic ratio ≥0.5). They also are useful for certain types of arrhythmias (see Chapter 64).
The Glaxo-Burroughs-Wellcome preparation of digoxin (Lanoxin) has a bioavailability of approximately 75% and an intermediate duration of action (half-life 36–48 hours). Digitalis elixir in capsules (Lanoxicaps, 100- and 200-µg capsules) has a bioavailability of nearly 100% and is useful when careful titration of the dosage is important, as in small elderly patients. Digitalization is best accomplished in an ambulatory patient by daily administration of the drug at the maintenance dosage (see below). Full digitalization is ordinarily achieved within four or five half-lives of the drug (approximately 7 days).
The effect of digitalis on the patient's condition should be monitored and reassessed periodically. If no objective decrease in heart size or improvement in exercise capacity is seen after a 1- or 2-month trial of digitalis therapy, the drug probably should be discontinued. Digitalis should be used cautiously in older patients and in any patient known to have impaired renal function. There is no evidence that elderly patients are intrinsically more sensitive to digitalis compounds, but they have a smaller body mass, often have impaired renal excretion of the drug, and have higher serum levels for a given oral dosage of the drug.
The average dosage of digoxin in patients with normal renal function is 250 µg/day (200 µg/day of Lanoxicaps). Lower doses should be prescribed to many older patients or to patients with known impairment of renal function.
Digitalis may interact with other medications, and, because of its low therapeutic ratio, the possibility of an interaction should be considered when any medication is added to the regimen of a patient already taking digoxin. The administration of quinidine, although now rarely used, causes decreased renal excretion of digoxin, which may lead to digitalis toxicity. Similar effects are seen when digitalis is prescribed along with either of the calcium channel blockers verapamil or diltiazem (but not with nifedipine). The antiarrhythmic agent amiodarone may increase bioavailability of digoxin; the dosage of digoxin must be reduced and levels monitored when these drugs are used concomitantly. The use of thiazides and loop diuretics may lead to digitalis toxicity because of either increased retention of digoxin secondary to decreased renal blood flow or increased sensitivity to digitalis as the result of hypokalemia or hypomagnesemia. Cholestyramine and some antacids impair digoxin absorption and may result in a subtherapeutic effect.
Recognition and Treatment of Digitalis Toxicity
Digitalis toxicity commonly is caused by administration of too much digitalis, overdiuresis (often with associated hypokalemia and/or hypomagnesemia), intercurrent development of renal insufficiency, or administration of drugs that interact with digitalis to increase its plasma concentration. Digitalis toxicity is especially common in older patients in an ambulatory practice. In one large trial, 2% of digitalized patients required hospitalization for suspected digitalis toxicity (49).
The manifestations of digitalis toxicity may be difficult to recognize in older patients and in patients whose normal baseline level of function is not familiar to the practitioner. The manifestations include changes in the cardiovascular system, gastrointestinal tract, and central nervous system. The most common cardiac manifestations of digitalis toxicity are progressive slowing and regularization of the heart rate (i.e., development of a nodal rhythm) of patients in atrial fibrillation and frequent premature ventricular contractions. Digitalis toxicity should be suspected in any patient who is taking digitalis and has premature ventricular contractions or in any patient in atrial fibrillation whose heart rate falls to <60 bpm and becomes regular. Because digitalis both increases automaticity and decreases conduction through the atrioventricular node, paroxysmal atrial tachycardia with block may be seen. The peripheral pulse in paroxysmal atrial tachycardia with block usually is 100 to 120 bpm (see Chapter 64). Cardiac toxicity may occur in the absence of other signs or symptoms of digitalis overdose.
Gastrointestinal side effects are common manifestations of digitalis intoxication. They include anorexia, mild nausea, and occasionally vomiting and diarrhea.
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Digitalis may cause changes in the sensorium, ranging from mild confusional states to frank delirium and psychosis. Determining whether these symptoms are caused by primary cerebral disease or by digitalis excess without stopping the drug may be difficult in older patients. Digitalis is structurally related to estrogen and may cause gynecomastia, decreased libido, or impotence in men.
The diagnosis of digitalis toxicity is based on clinical and laboratory findings. If symptoms compatible with digitalis toxicity are present, especially in elderly patients, the drug should be stopped immediately. The patient should be reassessed in approximately 3 to 5 days. If symptoms abate, a presumptive diagnosis of digitalis intoxication is warranted.
Although routine checks of digoxin levels are not necessary, they are appropriate in cases of suspected toxicity. Levels should be checked 24 hours after the previous dose. An adequately digitalized patient has a serum digoxin concentration of approximately 0.8 to 1.2 ng/mL; most toxic patients have concentrations >1.8 ng/mL. However, if a patient has symptoms compatible with digitalis toxicity and his or her serum digoxin level is within the normal range, toxicity has not been ruled out because hypokalemic patients may develop digitalis toxicity at therapeutic digoxin levels. Most patients with digitalis toxicity can be treated by temporary withdrawal of the medication and reinstitution of digitalis at a lower dosage. Often, diuretic therapy also must be modified or potassium or magnesium supplements administered. However, patients with symptomatic arrhythmias are best hospitalized so that they can be monitored closely or given digoxin-specific antibody Fab fragments (i.e., Digibind) if hemodynamic instability, life-threatening arrhythmias, or severe bradycardia is present.
For all patients taking digitalis and certainly for those who develop toxicity, careful review of the indications for digitalis therapy is appropriate to ensure that the patient clearly has systolic dysfunction or requires the drug for control of atrial arrhythmias (see Chapter 64).
β-Blockers
Activation of the neurohormonal system in heart failure leads to a chronic increase in sympathetic stimulation of the heart. This is facilitated by the resetting of aortic and cardiac baroreceptors that lose their inhibitory effectiveness. Chronic sympathetic stimulation of the heart leads to down-regulation of β1-adrenergic receptors and may directly damage cardiac myocytes, thereby leading to further deterioration of myocardial function in CHF. A series of clinical trials shows convincingly that β-blockers improve LV function, quality of life, and survival in patients with heart failure (51, 52, 53). Certainly all patients with moderate and stable heart failure due to LV systolic dysfunction should receive β-blockers unless there is a specific and definite contraindication to this therapy. The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study shows that the beta-blocker carvedilol improves morbidity and mortality even in patients with more severe heart failure due to LV dysfunction (54). The usual protocol begins with low doses of either metoprolol, a β1-selective inhibitor, or carvedilol, an α1- and nonselective β-receptor inhibitor. Doses then are titrated upward in an attempt to achieve doses similar to those used in the Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (51) (approximately 150 mg of the long-acting microencapsulated Toprol-XL) or in the U.S. Carvedilol Heart Failure Trials Program (52) (approximately 25 mg of carvedilol twice daily). In practice, titration of β-blockers to the doses used in clinical trials may be limited by bradycardia or symptomatic hypotension, particularly in older patients and in those receiving ACE inhibitors concomitantly. It is important to note that β-blocker therapy should not be initiated if the patient has signs of uncompensated heart failure. However, β-blockers should be started soon after a patient's symptoms have improved or the patient's “dry weight” has been reached. A patient hospitalized for heart failure should be seen soon after discharge—generally within 1 or 2 weeks—to determine whether beta blockers are now appropriate to use.
Importance of Hypertension Control in Patients in Heart Failure
Hypertension increases ventricular wall stress, and therefore the afterload on the heart, and reduces cardiac output, especially as the heart begins to fail. It also triggers vascular remodeling (8,21). Therefore, control of hypertension in patients in heart failure is essential. Chapter 67 discusses this subject in detail.
Vasodilators
Physiologic Rationale for Vasodilator Therapy
The signs and symptoms of heart failure are caused by the compensatory responses triggered by the heart's inability, at a normal filling pressure, to maintain tissue perfusion (see above). Neurohumoral compensatory mechanisms result in increased LV preload and afterload. In the setting of LV dysfunction, these compensatory mechanisms lead to further deterioration of cardiac function. The judicious use of vasodilator agents may optimize cardiac function, prevent further deterioration of LV function, improve the patient's functional state, and prolong the life of patients in chronic heart failure. Drugs that are predominantly venodilators, such as nitroglycerin preparations, primarily cause a decrease in preload, thereby relieving symptoms of vascular congestion. Venodilators are most useful in patients with severe heart failure in whom preload reserve is exceeded during exercise, which leads to increased LVEDP and to pulmonary vascular congestion.
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This also may occur at rest in association with ischemia in patients with ischemic heart disease or in association with progression of disease in patients with cardiomyopathy or valvular heart disease. Venodilators should not be used in patients with heart failure caused by restriction to ventricular filling (e.g., hypertrophic cardiomyopathy) or in patients with aortic stenosis in whom a reduction in preload may lead to a marked decrease in cardiac output. Arteriolar vasodilators increase cardiac output primarily by decreasing afterload (i.e., decreasing ventricular wall stress during contraction), thereby allowing the myocardium to contract more efficiently. These medications are most effective in patients with severe peripheral and central congestion who have signs of peripheral hypoperfusion, such as cool hands and acrocyanosis. It is important to note that arteriolar vasodilators increase cardiac output only if preload remains near the preload reserve. With afterload reduction, the left ventricle unloads more efficiently and volume shifts from the thorax to the abdomen and the peripheral venous circulation, thereby lowering preload. However, if preload drops significantly, cardiac output cannot be maintained, and the blood pressure falls. Thus, in an ambulatory setting, vasodilators must be used with caution and often with a concomitant adjustment of diuretic dosage.
Nitrates
Nitroglycerin in various formulations is an effective venodilator at the low end of the dosage range and a mixed venodilator and arteriolar dilator at higher dosages. The practitioner should be familiar with the use of nitrates in several forms (see Chapter 62): short-acting sublingual nitrates, long-acting nitrates taken orally, and nitroglycerin dermal patches. Sublingual nitroglycerin generally is used at a dose of 0.4 mg. The medication is sensitive to body heat, light, and moisture and must be kept in a sealed dark glass or metal container. Patients should be encouraged to purchase new sublingual nitroglycerin every 6 months to ensure that the medication is active. Sublingual nitroglycerin can be used liberally to control symptoms of pulmonary congestion during normal physical activity, such as walking up stairs, shopping, and sexual intercourse. Small bottles of 25 tablets can be prescribed and should be kept in strategic locations in the patient's home, car, and workplace. An effective long-acting medication is isosorbide dinitrate (generic, Isordil, Sorbitrate) in dosages of 5 to 20 mg orally, two to three times per day. If symptoms do not improve within a few days, the dosage should be increased. Dosages as high as 40 to 60 mg orally, three times per day, can be used safely depending on the patient's blood pressure response. The patient should be checked for orthostatic hypotension before and after each increase in the dosage. If systolic blood pressure drops >15 to 20 mm Hg 3 minutes after the patient rises from the supine to the standing position, the dosage should be decreased slightly. Nitroglycerin dermal patches give sustained high blood levels of nitrate. Tolerance to the effect of sustained levels of nitroglycerin develops after 7 to 10 days of continuous use of nitroglycerin patches. Patients should be advised to remove the patch at bedtime and to reapply a fresh patch upon awakening. The usual dosage is a 0.2- to 0.6-mg/h patch, applied in the morning and removed at bedtime. The patient should not be concerned about the patch contacting water during bathing or swimming; however, if the patch does fall off, a new one should be applied.
The most common side effects of nitrate therapy are headache and nausea. Skin irritation is seen occasionally with use of dermal patches. Headache usually can be controlled by aspirin or acetaminophen, and it usually abates after several days of nitrate therapy. Gastrointestinal side effects of long-acting oral nitrates occasionally can be eliminated by switching to a different preparation of long-acting nitroglycerin or switching to nitroglycerin patches. Rubbing alcohol should be used to remove nitroglycerin dermal patches. If skin irritation develops, a different brand of patch should be tried.
Angiotensin-Converting Enzyme Inhibitors
The syndrome of heart failure is caused in large part by stimulation of the renin–angiotensin–aldosterone system by the kidney (Fig. 66.4). ACE inhibitors block the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor and a regulator of renin and aldosterone production. They cause a marked decrease in angiotensin II levels approximately 30 minutes to 2 hours after administration. ACE inhibitors also inhibit the degradation of bradykinin,
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a potent vasodilator. Thus ACE inhibitors are effective vasodilators; they also block aldosterone-mediated salt and water retention.
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FIGURE 66.4. Interaction between myocardial injury, activation of the renin–angiotensin system, altered gene expression, and ventricular remodeling, which leads to myocardial dysfunction. (From Braunwald E, Bristow MR. Congestive heart failure: fifty years of progress. Circulation 2000;102:IV-14 , with permission.) |
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TABLE 66.9 Vasodilators Useful in Treating Heart Failure |
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ACE inhibitors appear to be the most effective vasodilators currently available for treatment of heart failure. They retain their effectiveness after long-term use and have been shown to decrease the rate of progression of LV dysfunction and to decrease the rate of hospital admission in patients with heart failure (55). ACE inhibitors are first-line agents for treatment of heart failure caused by systolic dysfunction. All such patients should be prescribed an ACE inhibitor, unless a significant contraindication to its use, such as a history of allergic reactions to the drug or significant renal failure, is present. ACE inhibitors also are recommended to prevent or delay the development of symptomatic heart failure in patients with asymptomatic LV systolic dysfunction (56).
Table 66.9 lists the ACE inhibitors currently available for treatment of CHF and their dosage ranges. Captopril is most useful for initiating ACE inhibitor therapy because of its short half-life, rapid onset of action (approximately 30 minutes), and wide dosage range. In patients with obvious signs of circulatory congestion, a 12.5-mg dose of captopril should be given and the blood pressure checked in 1 hour. The usual effective dosage of captopril for heart failure is 12.5 to 50 mg three times per day. Patients who are hyponatremic, are at their dry weight, or are known to have significant renal vascular disease should be started at 6.25 mg (half of a 12.5-mg cross-scored tablet). In addition, their diuretic dosage should be decreased because the danger of symptomatic hypotension is greater in such situations. Longer-acting ACE inhibitors such as enalapril (initially 2.5 mg twice per day) or lisinopril (initially 5 mg once per day) can be used as initial therapy for patients who are stable and have mild heart failure symptoms.
Because ACE inhibitors block the effect of aldosterone, potassium-sparing diuretics or supplementation may need to be decreased. Potassium levels and renal function should be monitored 3 to 7 days after initiation of therapy, again at 2 to 4 weeks, and periodically thereafter.
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ACE inhibitors also block angiotensin-mediated vasoconstriction, which may maintain renal perfusion pressure in patients with renal insufficiency. If the serum creatinine or the potassium level rises after initiation of ACE inhibitor therapy, diuretic dosages should be halved; the ACE inhibitor dose may need to be reduced and titrated upward more gradually. Consultation with a cardiologist or nephrologist may be helpful in this situation. Some studies suggest that aspirin, especially at high dosages, may interfere with the vasodilating effects of ACE inhibitors (42); this effect does not seem to be clinically important at the usual dosages of aspirin used in patients with concomitant coronary heart disease and heart failure.
Side Effects
The most common side effect of ACE inhibitors is cough. A persistent, nonproductive, hacking cough is seen in 2% to 10% of patients treated with these drugs, although a less bothersome cough may be noted in many patients. This rate tends to be higher in women and may be as high as 44% in Asian populations (56). Decreasing the dosage or switching to a different converting enzyme inhibitor is only occasionally helpful. The cough is thought to be caused by stimulation by bradykinin (the levels of which are increased by these drugs) of vagal afferents that trigger the cough reflex. Patients who had significant symptomatic relief of heart failure after ACE inhibitor therapy may wish to try continuing the drug at a lower dosage or to learn to live with the cough. Often, the drug must be discontinued, in which case therapy with an ARB should be considered (see below). Because cough may itself be a symptom of heart failure (see above) or of a number of other conditions (see Chapter 59), the practitioner should be as certain as possible that the drug is the cause of the cough before discontinuing the drug.
Other Side Effects Related to Angiotensin-Converting Enzyme Inhibitors
Other side effects related to ACE inhibitors are uncommon. Those seen most often are skin rash in patients taking captopril and angioedema in patients taking long-acting inhibitors (enalapril, lisinopril). These side effects warrant discontinuation of the drug. Taste alteration and neutropenia are rarely seen. Rarely, ACE inhibitors cause an interstitial nephritis with sudden and profound decrease in renal function. This complication requires immediate consultation with a nephrologist.
Angiotensin Receptor Blockers
This class of drugs binds directly to the angiotensin II receptor. ARBs share many important effects with ACE inhibitors, with some important differences. They do not increase bradykinin levels, and they do not cause cough. Clinical trials suggest that they are equipotent to ACE inhibitors in reducing all-cause mortality in patients with moderate to severe heart failure and that significantly fewer patients discontinue the ARB because of side effects (57, 58, 59). Although ACE inhibitors should be used as initial treatment of heart failure, ARBs are a reasonable alternative when ACE inhibitors are contraindicated or are not tolerated because of cough. Several ARBs currently are available that may be given once per day (Table 66.9). The same cautions with regard to dosing apply as for ACE inhibitors.
Hydralazine
Hydralazine is an effective direct arteriolar vasodilator. In properly selected patients and when used in effective dosages, hydralazine may increase the cardiac output as much as twofold. The improved cardiac output may persist chronically in patients who respond initially. The combination of hydralazine and long-acting nitroglycerin has been shown to prolong survival in patients with severe heart failure treated concomitantly with diuretics and digitalis (60). A fixed dose combination of hydralazine and isosorbide dinitrate has been shown to significantly reduce mortality in African American patients with systolic dysfunction who were receiving standard therapy for heart failure (61). Because the benefit of ACE inhibitors (see above) is greater than that of hydralazine and isosorbide, this combination should be used only when patients cannot tolerate ACE inhibitors or ARBs.
Calcium Channel Blockers
These drugs interfere with contractility of smooth muscle by blocking the entry of calcium into muscle cells, resulting in vasodilation, especially of the arterioles. All currently available calcium channel blockers also depress myocardial contractility, although with calcium channel blockers of the nifedipine class, afterload reduction caused by vasodilation may offset the direct cardiac depressant effects and cardiac output may be maintained or may increase. In such patients afterload reduction is predominant, but these drugs still should be used with great caution in patients with severe LV dysfunction (ejection fraction ≤30%) and only if blood pressure is not controlled using ACE inhibitors, β-blockers, and diuretics.
Verapamil is an arteriolar vasodilator that has a significant negative effect on cardiac contraction and relaxation. It may be particularly useful at dosages of 120 to 360 mg/day (in sustained-release preparations) in patients with heart failure caused by diastolic dysfunction. However, because of its negative inotropic effect, verapamil should not be used in patients who have congestive cardiomyopathy or an ejection fraction <45%. Diltiazem in sustained-release dosages of 120 to 360 mg/day and the second-generation drugs felodipine andamlodipine also may be used for treatment of angina or hypertension in patients with heart failure caused by diastolic dysfunction. Common side effects of calcium channel blockers include headache, hypotension, nausea, constipation, and pedal edema (not caused by volume overload).
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Summary of General Recommendations for Use of Afterload Reduction Therapy in an Ambulatory Setting
Unless specifically contraindicated, all patients with LV systolic dysfunction should be treated with an ACE inhibitor for treatment and/or prevention of heart failure. If ACE inhibitors are contraindicated because of rash or angioedema or are poorly tolerated because of cough, an ARB can be substituted. If neither an ACE inhibitor nor an ARB is tolerated (e.g., because of renal failure), the combination of hydralazine and isosorbide is appropriate and may be particularly effective in African Americans.
The patient's weight should be measured daily. Signs of circulatory congestion (dependent edema, jugular venous distention, hepatojugular reflux, and liver enlargement) should be assessed each time the clinician sees the patient.
Symptomatic postural hypotension is a common complication of vasodilator therapy in patients in whom diuresis has been excessive. If this happens, the dosage of diuretic, not that of the vasodilator, should be reduced.
Other Treatment Considerations: Anemia, Sleep-Disordered Breathing, Compliance Issues, Home Oxygen, and Anticoagulation
Anemia
Patients with heart failure are frequently noted to be anemic. In some cases this condition is due to hemodilution; in others it is related to renal failure. In many cases, the etiology is uncertain. Marked degrees of anemia require investigation to determine the etiology (seeChapter 55) and treatment as appropriate.
Sleep-Disordered Breathing
Cheyne-Stokes respirations are a form of periodic breathing in which central apneas or hypopneas alternate with hyperpneas in an episodic, crescendo–decrescendo pattern. This breathing abnormality is common in patients with advanced systolic heart failure and is associated with poor sleep quality. Cheyne-Stokes respirations may become less frequent with intensive treatment of heart failure. Obstructive sleep apneais frequently seen in patients with obesity and diastolic heart failure. These patients also often have hypertension and diabetes. Obstructive sleep apnea may contribute to progression of heart failure. Continuous positive airway pressure (CPAP) and weight loss are the mainstays of therapy (see Chapter 7).
Compliance Issues
A major cause of mortality and morbidity in patients with heart failure is poor compliance with prescribed regimens. The average heart failure patient takes three to seven medications, and patients with other common comorbidities, such as diabetes and depression, may be taking many more (62,63). Not surprisingly, patients often do not appropriately take the medications they are prescribed. Both overdosing and underdosing of medications occur, particularly as regimens become more complicated. Poor compliance with medications is a particular problem in those with depression, a common comorbidity in patients with heart failure. Patients with depression are three times as likely to be noncompliant with medical treatment regimens as are patients without depression (64).
Suggestions for enhancing compliance with medical treatment regimens in heart failure patients are as follows:
Home Oxygen
Patients with severe end-stage heart failure and arterial oxygen desaturation at rest caused by low cardiac output or concomitant pulmonary disease may feel more comfortable, especially while sleeping, with the use of low-flow nasal oxygen. The most efficient way to supply oxygen for therapy at home is by means of an oxygen generator, which usually is rented. The presence of oxygen desaturation should be documented (most easily using a pulse oximeter) before oxygen is prescribed.
Anticoagulation
Patients with chronic severe CHF are at increased risk for pulmonary and peripheral emboli. Studies show the incidence of peripheral arterial embolization in these patients ranges from 2% to 5% per year (65). A patient with a markedly dilated LV cavity or with an LV aneurysm, especially if the patient is in atrial fibrillation, should be considered for treatment with warfarin anticoagulants
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(see Chapter 57). There have not been any completed controlled trials of anticoagulation in patients with heart failure. After adjusting for differences in baseline characteristics, warfarin use was associated with improved survival and reduced morbidity in patients with LV systolic dysfunction among patients enrolled in the Studies of Left Ventricular Dysfunction (66). Of note, warfarin use was not assigned in a randomized controlled fashion, and data on compliance with therapy, the intensity of anticoagulation, and complications of therapy were not reported. Warfarin therapy may be hazardous in patients with severe heart failure who may have wide swings in prothrombin time caused by hepatic dysfunction and multiple drug interactions. In such circumstances, the prothrombin time should be checked more frequently, perhaps every few weeks, or within 2 to 4 days after a medication known to interact with warfarin has been introduced or discontinued or if the dosage of warfarin or an interacting medication is changed.
Control of Arrhythmias in Heart Failure and Cardiac Resynchronization Therapy
One of the cardinal features of CHF is a tendency to develop arrhythmias. Between 30% and 50% of patients with chronic heart failure die suddenly, presumably of ventricular tachyarrhythmias, although some studies show bradyarrhythmia is as likely a cause of death. Holter monitoring seldom is useful in evaluating patients without symptomatic arrhythmias.
Patients with heart failure and arrhythmias should be evaluated and treated in consultation with a cardiologist. Consultation also should be considered for patients with severe LV dysfunction and/or advanced symptomatic heart failure. This is especially true because some of these patients, particularly those with an intraventricular conduction delay, might benefit from permanent transvenous biventricular pacing (leads simultaneously pacing both ventricles), “cardiac resynchronization therapy,” or placement of an implantable defibrillator (see Chapter 64). Cardiac resynchronization therapy can improve cardiac function by synchronizing ventricular contraction. The rationale for this therapy is that a significant intraventricular conduction delay may adversely affect LV systolic function by producing asynchronous ventricular contraction. Cardiac resynchronization therapy has been shown to significantly improve symptoms and quality of life and to reduce morbidity and mortality in patients with severe heart failure symptoms due to LV systolic dysfunction despite standard pharmacologic therapy (67). The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial studied patients at high risk for death due to advanced heart failure with conduction delays. This trial showed that cardiac resynchronization therapy, with or without a defibrillator, significantly lowered the risk of death from, or hospitalization for, heart failure (68). A pacemaker alone reduces the risk of death from any cause by 24% (p = 0.059), and a pacemaker–defibrillator significantly reduced the risk by 36%. In the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), patients with LV systolic dysfunction were treated with conventional therapy for CHF plus either placebo, the antiarrhythmic drug amiodarone, or an implantable defibrillator. Whereas amiodarone did not have any significant effect on survival, defibrillator therapy significantly reduced overall mortality (69).
Operative Correction of Problems Causing Heart Failure
The most commonly encountered surgically correctable problems in patients with chronic congestive failure include ischemic heart disease with revascularizable lesions or with resectable ventricular aneurysm, valvular heart disease, and atrial septal defect. Any patient who is in heart failure caused by a surgically correctable cause of myocardial dysfunction should be considered for operative correction, and consultation with a cardiologist should be obtained. Patients whose heart failure is secondary to reversible LV dysfunction may not be easily distinguished by history, physical examination, and echocardiography from those with irreversible ventricular impairment. Noninvasive stress testing may be helpful for detecting ischemia or assessing myocardial viability in patients who are candidates for revascularization. Referral to a cardiologist may help select the appropriate noninvasive test or to determine which patients are appropriate for cardiac catheterization and coronary angiography.
Heart transplants should be considered for patients in severe refractory heart failure. The procedure is being performed in specialized centers throughout the United States. A number of contraindications to transplantation include age ≥70 years; irreversible severe renal, hepatic, or pulmonary disease; severe peripheral or cerebral vascular disease; and psychiatric impairment, so the proportion of eligible patients with heart failure is small. Even so, because of the scarcity of donated cadaver organs, the wait for an available compatible heart can be many months, during which time the patient may succumb to his or her disease.
Community Health Services
Many community health services are available to help the caregiver deal with the patient and to help the patient deal with the illness.
Home Visits
In at least two situations, home visits by the patient's health care provider or a visiting nurse should be considered in the management of a patient in heart failure: when the patient has repeatedly returned to the office or has been
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readmitted to the hospital with heart failure caused by dietary neglect or by failure to use medications correctly (see below) and when the homebound patient's symptoms are so severe (New York Heart Association class IV, Table 66.2) that he or she is unable to come for an office visit without becoming exhausted.
Information Booklets
The American Heart Association has useful free booklets that describe low-salt diets and the management of CHF for the patient and family. These booklets can be obtained from local chapters of the American Heart Association. The American Heart Association website also has excellent information for patients with heart failure (http://www.americanheart.org/chf/working/index.htm). Extensive information that is pertinent and useful is available at other World Wide Web sites, including that of the Heart Failure Society of America (http://www.hfsa.org).
Exercise Programs
Graduated regular exercise may improve exercise tolerance and increase daily activities and general well-being in some patients with heart failure, even in patients with severe LV dysfunction caused by ischemic heart disease. The improvement in function is thought to be caused by improved efficiency of the skeletal muscles; there is no evidence that myocardial function can be improved by exercise. Patients may also develop a sense of increased confidence in their ability to function.
Patients with class I to III CHF may be trained to exercise to 60% of their maximal heart rate for 20 minutes per day, 3 days per week. Exercise may be contraindicated entirely in patients who have uncompensated heart failure or whose heart failure is caused by valvular heart disease. Isometric exercise should be prescribed with caution in patients in heart failure because of the extra afterload imposed by this form of exercise on the heart. Well-supervised circuit weight training may be safe. Muscle toning exercises using 1-kg hand weights are safe and can be used safely to help maintain function in all but the most frail patients with heart failure.
Management Programs Comprehensive Disease
Patients with heart failure require the type of coordinated, multidisciplinary care that has been shown to be most efficiently and effectively delivered by a comprehensive disease management program (70). These programs provide frequent contact with trained nurses or pharmacists and close coordination of care between primary care providers and cardiovascular specialists. Patients should be encouraged to participate in these programs if they are available in the community.
Prognosis
The prognosis in heart failure is related clinically to the LV ejection fraction, the functional status of the patient, the initial response to treatment, the patient's compliance with the treatment regimen, the patient's age and comorbidities, and the cause of the heart failure. Physiologically, prognosis is related most importantly to LVEDP and to the degree of neurohumoral activation and LV remodeling. One available measure of these factors is the plasma BNP or NT-proBNP level (see above). Most patients in chronic CHF die suddenly, presumably from ventricular arrhythmia (71). Other common causes of death are progressive heart failure and cerebral and peripheral embolization (65). In the Framingham study reported in 1993, which included heart failure from all causes, the probability of dying within 5 years of onset of heart failure was 62% for men and 42% for women (4,71). The median survival after the onset of heart failure was 1.7 years in men and 3.2 years in women (71). The cause of heart failure in most of these patients was hypertension or ischemic heart disease. Heart failure complicating uncorrected aortic stenosis is particularly ominous, and most of these patients die within 3 years (see Chapter 65) unless aortic valve surgery is performed.
In general, prognosis is related to the patient's functional class (Table 66.2). Patients in functional class I have an annual mortality of approximately 10%. Patients in functional class IV have an annual mortality of nearly 50% (71). The practitioner should avoid discussing prognosis with the patient and family until after the optimal level of response to therapy has been achieved. It has been observed that the median survival in advanced heart failure is similar to that of patients with metastatic breast cancer. Hence, it is appropriate to discuss advance directives and living wills with the patient early in the course of treatment.
Over the 40-year period from 1948 to 1988 (before the widespread use of ACE inhibitors and β-blockers), there was no improvement in survival for patients with heart failure (71). Heart failure remains a lethal disease: age-adjusted 5-year mortality during the period from 1990 to 1999 (the most recent period for which data are available) was approximately 50% (72). However, the treatment of CHF in the ambulatory setting is evolving rapidly. Important advances in nonpharmacologic, pharmacologic, and device therapy for heart failure likely will continue to improve the outlook for patients with this condition.
Hospital Readmission
Patients discharged from the hospital with the diagnosis of heart failure have a high readmission rate. Factors associated with hospitalization include poor adherence to medical therapy and dietary restrictions, inadequate treatment of associated hypertension and ischemic heart disease, and
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underuse of ACE inhibitors (73). Comprehensive outpatient programs, which include intensive education of the patient and family, social service support, titration of medications, and close followup, have demonstrated reductions in hospitalization rates of up to 87%, associated with clinically significant decreases in sodium intake from 3,400 to 2,100 mg/day and increases in the daily dosages of ACE inhibitors (74,75).
Patients treated successfully for heart failure should be advised to pay attention to even subtle signs and symptoms that may precede overt decompensation. Mild dyspnea or a slight change in weight should not be ignored because these signs may be followed not by a gradual escalation in the severity of the condition but by severe and seemingly abrupt deterioration that requires readmission to the hospital. Decreasing the likelihood of hospital readmission requires (a) patient education about the importance of sodium restriction and careful monitoring of weight, (b) titration of medications to doses shown to be effective in clinical trials, (c) patient compliance with the medical treatment regimen, (d) decreasing the incidence of potentially preventable disease (e.g., influenza or pneumonia), (e) meticulous management of other medical illness (e.g., diabetes and hypertension), (f) constant monitoring of symptoms, and (g) timely reporting of increases in weight or development of symptoms to the patient's health care provider.
End-of-Life Issues
Patients with heart failure have a progressive, complex, costly, and often fatal disease. The primary care provider and/or cardiologist should discuss end-of-life issues with the patient or with friends or family designated by the patient. The clinical course of heart failure is marked by frequent exacerbations with other periods of relative comfort and good function. When symptoms become persistent and are refractory to the maximal medical therapy that can be tolerated by the patient, and when no other options are appropriate for, or desirable to, the patient (e.g., transplantation, cardiac resynchronization therapy), it is appropriate to discuss palliative measures (see Chapter 13) (76). It is important to clarify the patient's health care goals and to identify a person who will make health care decisions when the patient can no longer do so. A useful resource is available on the Internet at http://www.fivewishes.org.
Prevention of Heart Failure
It has been shown in asymptomatic patients that the development of symptomatic heart failure may be predicted by the finding of cardiac enlargement on echocardiography (55). The prognosis of these patients may be improved by treatment with ACE inhibitors, which may delay the development of overt heart failure in patients with LV dysfunction (55).
Although preventing or delaying the development of symptoms in individuals with existent LV dysfunction is important and feasible, the major impact on heart failure prevention will result from a reduction in the prevalence of hypertension, diabetes mellitus, hyperlipidemia, and cigarette smoking and the adoption of a healthier diet and regular exercise programs by a greater proportion of the population. Much time and effort have been expended in identifying the medicines and interventions that will improve and prolong the lives of those with heart failure. The focus now must shift to ensure that patients get those medicines and, more importantly, that a greater number of our population will never need them.
Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
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