Heart Failure
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[edit] Heart Failure
Michael M. Givertz
Wilson S. Colucci
[edit] DEFINITION
Heart failure, often referred to as congestive heart failure, is a clinical syndrome resulting from cardiac decompensation and characterized by signs and symptoms of interstitial volume overload and/or inadequate tissue perfusion. In pathophysiologic terms, heart failure occurs when the heart is unable to pump blood at a rate sufficient to meet the metabolic needs of the body or when it can do so only with an elevated filling pressure. The contractile performance of the heart may be preserved when impairment of cardiac filling or emptying leads to symptoms and signs of heart failure. Myocardial failure, a term used to denote abnormal systolic or diastolic function, may be asymptomatic or progress to heart failure. Circulatory failure is not synonymous with heart failure, since a variety of noncardiac conditions (e.g., hemorrhagic shock) can lead to circulatory collapse while cardiac function is preserved.
[edit] EPIDEMIOLOGY
[edit] Incidence and Prevalence
Heart failure is a major cause of morbidity and mortality in the United States. It is estimated that 4.8 million Americans suffer from heart failure (∼2% of the population), with greater than 400,000 new cases diagnosed each year. The prevalence of heart failure increases dramatically with age, occurring in 1% to 2% of patients aged 50 to 59, and up to 10% of patients over the age of 75[1](Fig. 65-1). Heart failure is the leading discharge diagnosis in Medicare patients. Despite a steady decrease in the incidence of coronary artery disease and stroke, the prevalence of heart failure continues to rise. This may be due in part to the aging of the population and the improved survival of patients with cardiovascular disease. Heart failure has an enormous economic impact on the U.S. health care system due to direct medical costs, disability, and loss of employment. Estimated treatment costs in 1994 were $38 billion, of which $23 billion was spent on hospitalizations.
[edit] Prognosis
Once heart failure is diagnosed, the prognosis is poor. The overall 5-year mortality for all patients with heart failure is approximately 50%, and the 1-year mortality in patients with severe heart failure may be as high as 35% to 40%. In the United States alone, approximately 250,000 patients die of heart failure each year. Recent data from the Framingham Heart Study showed a median survival of 1.7 years for men and 3.2 years for women[2] (Fig. 65-2). Over 90% of deaths are due to cardiovascular causes, most commonly progressive heart failure or sudden cardiac death. Several clinical and laboratory parameters have been shown to be important independent predictors of mortality in heart failure (Box 65-1).
| Box 65-1 - Negative Prognostic Factors |
Clinical
NYHA, New York Heart Association. |
[edit] PATHOPHYSIOLOGY
Ventricular performance may be quantified by the amount of blood that the heart is able to pump each minute, also termed the cardiac output. Cardiac output (liters per minute) is equal to the stroke volume (liters/beat) times the heart rate (beats/min). In the intact human heart, the three main determinants of stroke volume are preload, afterload, and cardiac contractility.
[edit] Preload
Preload refers to the passive stretch on the myocardium just prior to contraction, or the ventricular wall tension at the end of diastole. In the intact heart, preload corresponds to the end-diastolic volume or end-diastolic pressure. In clinical terms, left ventricular end-diastolic pressure may be approximated by the pulmonary capillary wedge pressure, whereas right ventricular filling pressure is reflected by central venous or right atrial pressure. According to Starling's law, the higher the preload, the greater the force of ventricular contraction and the greater the stroke volume. When heart failure develops, cardiac output may be maintained within normal limits by an increase in preload. Diastolic filling increases in part due to an increase in venous return resulting from vasoconstriction and intravascular volume expansion. However, in severe heart failure, the ventricular function curve may be flat at higher end-diastolic volumes; thus cardiac output may not be augmented by an increase in filling, and a marked increase in end-diastolic pressure causes pulmonary venous congestion (Fig. 65-3).
[edit] Afterload
Afterload refers to the ventricular wall stress during systole or the force that the ventricle must overcome to eject its contents. According to Laplace's law, systolic wall stress is directly proportional to ventricular pressure and chamber radius and inversely proportional to ventricular wall thickness. The major determinant of left ventricular afterload is systemic vascular resistance. Afterload is typically increased in systemic hypertension and aortic stenosis. Additionally, in patients with heart failure and reduced left ventricular (LV) systolic function, systemic vascular resistance may be increased secondary to neurohormonal activation (see below).
[edit] Contractility
Contractility or inotropic state is a fundamental property of the myocardium that determines the strength of contraction. At a constant preload and afterload, an increase in contractility results in an increase in the extent and velocity of fiber shortening. Circulating catecholamines or positive inotropic agents such as digoxin may increase contractility. By contrast, negative inotropic agents such as calcium channel blockers, myocyte loss, or acidosis may decrease contractility. In the clinical setting, contractility is difficult to measure. Commonly used measures of LV performance such as ejection fraction may be altered by changes in preload and afterload and thus do not necessarily reflect changes in contractility. Isovolumic indices of cardiac performance, such as the peak rate of rise of LV pressure (peak % dP/dt), are not used clinically because of the need for invasive measurements and their dependence on cardiac loading conditions. Recently, use of the pressure-volume relationship to determine end-systolic elastance has been suggested as a load-independent method of assessing myocardial contractility.
[edit] Systolic and Diastolic Dysfunction
Most commonly, heart failure reflects an abnormality of ventricular contractile function (Fig. 65-4). End-systolic volume, end-diastolic volume, and end-diastolic pressure are increased, and stroke volume falls. Symptoms of reduced cardiac output (e.g., fatigue) develop. In addition, increased LV end-diastolic pressure is transmitted back to the pulmonary veins, resulting in transudation of fluid into the pulmonary interstitium and symptoms of pulmonary congestion. The most common cause of contractile dysfunction is loss of myocytes due to myocardial infarction. Other causes of systolic heart failure include dilated cardiomyopathy, myocarditis, and chronic alcohol use.
One third to one half of patients with heart failure have normal ventricular contractile function, and are said to have diastolic heart failure[3](Table 65-1). Abnormal diastolic function may be due to impaired early relaxation, increased stiffness of the ventricle, or both. Diastolic dysfunction results in impairment in ventricular filling. LV end-diastolic pressures are elevated, leading to pulmonary venous congestion. Diastolic dysfunction is most commonly associated with left ventricular hypertrophy (LVH) due to hypertension, and occurs frequently in elderly women. Increased resistance to filling results from the increased LV mass itself, and also from interstitial fibrosis and subendocardial ischemia. Diastolic dysfunction can occur in the absence of LVH due to ischemia, myocardial infiltration (e.g., amyloidosis), or pericardial constriction.
Table 65-1 Systolic vs. Diastolic Dysfunction
| Parameter | Systolic | Diastolic |
|---|---|---|
| History | ||
| Coronary artery disease | ++++ | ++ |
| Hypertension | ++ | ++++ |
| Diabetes | +++ | ++ |
| Physical Examination | ||
| Cardiomegaly | +++ | + |
| S3 gallop | +++ | + |
| S4 gallop | + | +++ |
| Rales | ++ | ++ |
| Peripheral edema | +++ | + |
| Electrocardiogram | ||
| Low voltage | +++ | − |
| Left ventricular hypertrophy | ++ | ++++ |
| Echocardiogram | ||
| Low ejection fraction | ++++ | − |
| Left ventricular hypertrophy | ++ | ++++ |
The most common form of heart failure, that due to coronary artery disease, often reflects a combination of systolic and diastolic dysfunction. Systolic dysfunction is due to prior infarction and ischemia-induced decrease in contractility. Diastolic dysfunction is due to chronic replacement fibrosis and ischemia-induced decrease in distensibility.
[edit] Myocardial Hypertrophy and Remodeling
Increased ventricular wall stress due to LV dilation or increased afterload stimulates the development of myocardial hypertrophy. Increased wall thickness, in turn, normalizes wall stress and helps to maintain normal contractile function. When the primary stimulus to remodeling is chronic volume overload, the radius of the ventricle enlarges in proportion to a mild increase in wall thickness. By contrast, chronic pressure overload results in a moderate to severe increase in wall thickness. If additional chamber dilation occurs or the increase in wall thickness is insufficient, systolic and diastolic wall stresses remain abnormally elevated, and hemodynamic failure ensues.
Cellular events contributing to ventricular remodeling include increases in mitochondrial and myofibrillar mass and myocyte size, and alterations in the quantity and composition of the extracellular matrix. Molecular events include the regression to a molecular phenotype characterized by the expression of fetal genes and the production of abnormal contractile proteins. In addition to mechanical stress, other factors that contribute to myocardial hypertrophy and remodeling in heart failure include neurohormones such as angiotensin and norepinephrine, ischemia, and inflammatory cytokines. These mediators also cause loss of myocytes due to both necrosis and apoptosis (programmed cell death)[4](Fig. 65-5)
[edit] Neurohormonal Activation
Reduced cardiac output and increased filling pressures cause activation of several important neurohormonal systems, including the sympathetic nervous system and the renin-angiotensin system. Primary consequences of neurohormonal activation include an increase in systemic vascular resistance and sodium and water retention. During an initial compensatory phase, cardiac output, blood pressure, and vital organ perfusion are maintained. If chronic, neurohormonal activation may lead to decompensation due to excessive vasoconstriction and volume retention, electrolyte abnormalities, direct myocardial toxicity, and cardiac arrhythmias.
[edit] Autonomic Nervous System
Decreased perfusion pressure sensed by carotid sinus and aortic arch receptors results in increased sympathetic and decreased parasympathetic tone. Circulating catecholamines are elevated, and direct sympathetic outflow to the heart, peripheral vasculature, and muscles is increased. Short-term consequences include increased contractility and heart rate to augment cardiac output, systemic vasoconstriction to increase preload and maintain blood pressure, and redistribution of blood flow away from the skin, muscles, and kidneys to vital organs. The long-term cardiovascular effects of sympathetic activation, however, are deleterious.[5] These include myocyte necrosis and apoptosis, and interstitial fibrosis causing further impairment in systolic and diastolic function; cardiac norepinephrine depletion and β-receptor down-regulation, resulting in inotropic and chronotropic incompetence; calcium overload and proarrhythmia; and activation of the renin-angiotensin system (see below).
Baroreflex control of adrenergic outflow from the central nervous system is also impaired in heart failure. Examples include blunted reflex tachycardia in response to vasodilators and orthostatic hypotension. In addition, desensitization of atrial stretch receptors results in a reduced ability to excrete salt and water in response to increased atrial pressures and release of natriuretic peptides.
[edit] Renin-Angiotensin System.
Reduced cardiac output results in activation of the renin-angiotensin system, which acts in concert with increased sympathetic activity to maintain arterial pressure. Stimuli for renin secretion by the kidney include decreased renal perfusion, increased sympathetic activity, and a reduction in serum sodium. Angiotensin II, formed by the action of angiotensin-converting enzyme (ACE) on angiotensin I, is a potent vasoconstrictor. Elevated levels in heart failure result in systemic vasoconstriction and intravascular volume expansion. Release of angiotensin also results in increased levels of aldosterone, which has potent sodium-retaining properties. Vasoconstriction and volume retention may initially be compensatory in helping to maintain arterial pressure and stroke volume, but over time contribute to the clinical manifestations of heart failure.
Greater than 90% of ACE in the body is found in tissues (e.g., heart and kidney), and less than 10% is in the circulation. Myocardial production of ACE is increased in heart failure, and stimulation of local angiotensin receptors leads to myocardial hypertrophy and fibrosis. As with systemic responses to circulating angiotensin II, cellular remodeling may be compensatory at first, but ultimately results in progressive myocardial dysfunction.
[edit] Arginine Vasopressin.
Circulating levels of the pituitary hormone arginine vasopressin (AVP) are elevated in patients with LV dysfunction. In heart failure, AVP levels are hyperresponsive to reductions in plasma osmolality or increases in atrial stretch, and thus contribute to the inadequate ability to excrete free water. The increase in intravascular volume serves to augment preload and cardiac output, but ultimately contributes to clinical decompensation. Increased aldosterone and AVP levels are both responsible for hyponatremia in advanced heart failure. In addition to its antidiuretic effects, AVP is a vasoconstrictor.
[edit] Natriuretic Peptides.
Circulating levels of atrial natriuretic peptide (ANP) and b-type or brain natriuretic peptide (BNP) are elevated in patients with heart failure. ANP is stored mainly in the right atrium and released in response to increased atrial stretch or pressure, whereas BNP is stored and secreted mainly by the cardiac ventricles. In contrast to norepinephrine and angiotensin II, ANP and BNP are potent vasodilators and thus serve as counterregulatory hormones in heart failure. Other beneficial actions include increased sodium and water excretion, inhibition of the renin-angiotensin system, and a reduction in heart rate via baroreceptor modulation and/or a direct effect on the sinus node.
[edit] Endothelin, Inflammatory Cytokines, and Oxidative Stress.
Whereas systemic vasoconstriction and volume retention contribute to the progression of LV failure, increased pulmonary vascular tone may contribute to right ventricular failure and reduced exercise tolerance. Endothelin (ET)-1 is a potent vasoconstrictor peptide with growth-promoting effects that may play an important role in pulmonary hypertension associated with heart failure. ET-1 also mediates hypertrophy and fibrosis in failing myocardium. Other factors that have the potential to cause or contribute to myocardial remodeling in heart failure include inflammatory cytokines such as tumor necrosis factor-α, nitric oxide, and other reactive oxygen species.[6]
[edit] ETIOLOGY
[edit] Classification
Heart failure has been described by various terms. Some such as backward or forward heart failure are of historical significance only. In current practice, one or more categories may be used to try and describe a pathophysiologic state. Treatment, however, may be similar regardless of the type of heart failure.
[edit] Systolic vs. Diastolic Heart Failure.
For the heart to eject blood commensurate with metabolic requirements during systole, it first has to receive blood during diastole. As stated, heart failure is deemed to be present if the heart is unable to receive blood without an increase in ventricular filling pressure. Symptoms and signs of systemic or pulmonary venous congestion result from diastolic impairment. Symptoms of systolic impairment generally result from inadequate cardiac output with weakness, fatigue, and other symptoms of hypoperfusion. Although isolated diastolic dysfunction is being increasingly recognized as the cause of heart failure with normal systolic function, in chronic heart failure, both forms often coexist.
[edit] Acute vs. Chronic Heart Failure.
The clinical manifestations of heart failure depend on the rate at which the syndrome develops, and specifically on whether enough time has elapsed for compensatory mechanisms to become operative and interstitial fluid to accumulate (Table 65-2). In acute heart failure, symptoms are due to the sudden reduction in cardiac output with poor organ perfusion and/or marked pulmonary congestion. Examples include acute myocardial infarction, sustained tachyarrhythmia, and valve rupture due to infective endocarditis. When the reduction in cardiac output occurs gradually (e.g., due to chronic valvular regurgitation or remodeling postmyocardial infarction), compensatory mechanisms become operative and allow the patient to tolerate hemodynamic abnormalities with few or no signs and symptoms. However, an intercurrent event such as infection, myocardial ischemia, or medication noncompliance may precipitate manifestations of acute heart failure.
Table 65-2 Acute vs. Chronic Heart Failure
| Feature | Acute heart failure | Chronic heart failure |
|---|---|---|
| Symptom severity | Marked | Mild to moderate |
| Pulmonary edema | Frequent | Infrequent |
| Peripheral edema | Rare | Frequent |
| Total body fluid | No change or mild increase | Increased |
| Cardiomegaly | Uncommon | Common |
| Sympathetic activation | Marked | Mild to marked |
| Repairable lesion | Common | Occasional |
[edit] Left-sided vs. Right-sided Heart Failure.
According to the ‘backward failure’ hypothesis, fluid accumulates behind the ventricle that is initially affected. Thus patients with left-sided heart failure (e.g., due to anterior myocardial infarction or mitral regurgitation) initially develop pulmonary venous congestion. Elevated pulmonary venous pressures in turn lead to pulmonary hypertension and subsequent right-sided heart failure. Fluid accumulation becomes generalized and patients develop signs of right-sided failure including lower extremity edema, tender hepatomegaly, and pleural effusions. Pure right-sided failure may occur secondary to primary pulmonary hypertension or chronic pulmonary emboli.
[edit] Low-output vs. High-output Heart Failure.
Low cardiac output at rest, or in milder cases during exercise or stress, characterizes most etiologies of heart failure. Peripheral vasoconstriction may result in cold, pale extremities, a narrow pulse pressure, and a widened arterial-venous oxygen (A-V-O2) gradient. High-output states in which the pumping function of the heart is unable to meet the abnormally high metabolic demands of the body less commonly lead to heart failure. Examples include thyrotoxicosis, anemia, arteriovenous fistula, thiamine deficiency (beriberi), and Paget's disease. The extremities are often warm and flushed, the pulse pressure normal or widened, and the A-V-O2 difference narrowed.
[edit] Underlying Causes
Many structural or functional abnormalities of the cardiovascular system can result in heart failure. These include loss of contractility, volume or pressure overload, abnormal cardiac filling, and increased metabolic demand (Table 65-3). The underlying causes of heart failure may vary depending on the demographics of the study population. In a 1971 report from the Framingham Study, 75% of patients with heart failure had hypertension, with coronary artery disease present alone in only 10%. In more recent data from the Studies of Left Ventricular Dysfunction (SOLVD), nearly three quarters of patients had ischemic heart failure, with hypertension considered to be the primary etiology in less than 5%.
Table 65-3 Etiology of Heart Failure
| Contractile dysfunction | Pressure overload | Volume overload | Impaired filling | Increased demand | |
|---|---|---|---|---|---|
| Valvular dysfunction | Diastolic dysfunction | ||||
| Ischemic heart disease | Hypertension | Aortic regurgitation | Mitral stenosis | Hypertrophic cardiomyopathy | Anemia |
| Dilated Cardiomyopathy | Aortic stenosis | Mitral regurgitation | Tricuspid stenosis | Amyloidosis | Thyrotoxicosis |
| Myocarditis | Aortic coarctation | Left-to-right shunt | Atrial myxoma | Constrictive pericarditis | Arteriovenous fistula |
| Toxins (alcohol, doxorubicin) | Thiamine deficiency | ||||
| Infection (HIV, sepsis) | Paget's disease | ||||
[edit] Precipitating Factors
Patients with heart failure may be asymptomatic or mildly symptomatic either because the cardiac impairment is mild or because compensatory mechanisms help to normalize cardiac function. However, symptoms of heart failure may develop when precipitating factors increase cardiac workload and disrupt the balance in favor of decompensation. Precipitants may be identified in 50% to 90% of hospital admissions and can be divided into patient-related factors, physician-related factors, heart failure–related disease states, and other causes (Box 65-2). Inability to recognize and correct these factors promptly may lead to persistent heart failure despite adequate treatment.
| Box 65-2 - Precipitating Factors |
Patient-Related Factors
|
[edit] PATIENT EVALUATION
[edit] History
[edit] Symptoms of Pulmonary Venous Congestion.
Dyspnea or breathlessness is a cardinal manifestation of left-sided heart failure. Mechanisms of dyspnea include pulmonary venous congestion and transudation of fluid into the interstitium, leading to decreased lung compliance, increased airway resistance, hypoxemia, and ventilation/perfusion mismatch. Stimulation of J receptors leading to an increased ventilatory drive and reduced blood flow to respiratory muscles may cause lactic acidosis and the sensation of dyspnea.
In the early stages of heart failure, dyspnea occurs primarily on effort. As the disease progresses, the extent of effort required to provoke dyspnea decreases. Finally, the patient becomes dyspneic at rest. The New York Heart Association (NYHA) classification may be used to categorize patients based on the relation between symptoms and the amount of effort required to provoke them (Box 65-3). Although NYHA class has been used to stratify patients in clinical studies and provides prognostic information, its accuracy and reproducibility are limited. In addition, there is a poor correlation between NYHA class and other, more objective functional measures of heart failure severity such as exercise duration and peak oxygen consumption.
| Box 65-3 - New York Heart Association Classification |
Class I
|
Orthopnea refers to dyspnea that occurs in the recumbent position. It is due to redistribution of fluid from the abdomen and the lower body into the chest, an increase in the work of breathing when a patient with decreased lung compliance lies flat, and elevation of the diaphragm by ascites and hepatomegaly. Orthopnea usually occurs within a minute or two of assuming recumbency, and develops when the patient is awake. Initially, breathing at night is made easier by elevating the head on two or more pillows. As heart failure progresses, the patient may have to sleep sitting up.
Two symptoms related to orthopnea are nocturnal cough and trepopnea (or dyspnea limited to one lateral decubitus position). The exact mechanism for trepopnea is unclear but may be related to distortions of the great vessels or alterations in coronary perfusion pressure. With advanced biventricular failure, orthopnea may diminish as symptoms of right-sided failure supervene (see below).
Paroxysmal nocturnal dyspnea is a form of orthopnea, and may occur with further progression of LV failure. The patient awakens suddenly with a feeling of severe anxiety and suffocation, and has to sit bolt upright for relief. In contrast to orthopnea, paroxysmal nocturnal dyspnea usually occurs after prolonged recumbency, is less predictable in its occurrence, and may require 30 minutes or longer in the upright position for relief. Episodes are often accompanied by coughing and wheezing and may be extremely frightening to the patient and family.
When significant wheezing is associated with paroxysmal nocturnal dyspnea, it resembles an acute asthmatic attack and may be referred to as cardiac asthma. Bronchospasm, which is caused by congestion of the bronchial mucosa and by interstitial pulmonary edema compressing small airways, increases the work of breathing. Acute pulmonary edema can be a further extension of paroxysmal nocturnal dyspnea. Alternatively, acute pulmonary edema may occur as a primary manifestation of acute myocardial infarction or accelerated hypertension. The patient is extremely short of breath and coughs up pink, frothy sputum. Acute pulmonary edema occurs when there is marked elevation of the pulmonary capillary wedge pressure leading to alveolar edema. Untreated, it can be fatal.
[edit] Symptoms of Decreased Cardiac Output.
Symptoms related to decreased cardiac output can occur with right-sided or left-sided heart failure but more commonly occur in patients with chronic biventricular failure. Fatigue and weakness, particularly in the lower extremities, are nonspecific symptoms thought to be due to decreased cardiac output to exercising muscles. Impaired flow-mediated vasodilation, autonomic imbalance, and altered skeletal muscle metabolism may also play contributory roles. Mental dullness and confusion, especially in older patients with cerebrovascular disease, may result from decreased cerebral perfusion. Other causes of fatigue in patients with heart failure include hyponatremia, volume depletion, and medications (e.g., β-blockers).
[edit] Symptoms of Systemic Venous Congestion.
Whereas symptoms of left-sided heart failure are related to pulmonary venous congestion and fluid accumulation in the lungs, symptoms of right-sided heart failure result from systemic venous congestion. One of the earliest symptoms of right heart failure may be an inappropriate weight gain. In ambulatory patients, this is followed by swelling in the feet or ankles at the end of the day, which generally resolves overnight. In bedridden patients, edema first develops in the presacral region. With progressive right heart failure, dependent edema becomes persistent. Finally, the development of massive edema involving the entire body is termed anasarca.
Elevated systemic venous pressures may result in right upper quadrant abdominal pain as the liver becomes engorged with fluid and its capsule is stretched. Other symptoms associated with edema of the gastrointestinal tract include nausea, vomiting, anorexia, early satiety, and constipation. These symptoms are nonspecific, and digoxin toxicity should be ruled out. Ascites results in an increase in abdominal girth, and unilateral or bilateral pleural effusions can contribute to the sensation of dyspnea.
[edit] Cardiac Cachexia.
Longstanding, severe heart failure may lead to chronic weight loss. Factors contributing to cardiac cachexia include poor oral intake due to anorexia, and impaired fat absorption due to bowel wall edema. Metabolic pathways that cause catabolic/anabolic imbalance have also been implicated in this syndrome including the growth hormone–insulin-like growth factor-1 system and the pituitary-thyroid hormone axis. Circulating levels of tumor necrosis factor-α, a proinflammatory cytokine, are elevated in patients with severe heart failure and contribute to cardiac cachexia.
[edit] Nocturia and Oliguria.
Urinary symptoms are common in heart failure. Nocturia may occur early in the course of disease. During daytime activities, urine output is reduced due to the redistribution of blood flow away from the kidneys. When the patient lies down at night, improved cardiac output and renal vasodilation lead to increased urine formation. With biventricular failure, insomnia due to nocturia may be exacerbated by orthopnea and paroxysmal nocturnal dyspnea. Oliguria is a sign of end-stage heart failure and is due to severe reductions in cardiac output and renal blood flow.
[edit] Physical Examination
The physical signs of left-sided heart failure relate to pulmonary venous congestion, whereas signs of right-sided heart failure relate to systemic venous congestion. In the discussion that follows, physical signs are presented in the order in which they are typically assessed. Rigorous criteria for identifying heart failure based on both the clinical history and physical findings were developed for the Framingham Study (Box 65-4). However, heart failure may not be recognized in up to 40% of patients due to the limited reliability of these findings.[7]
| Box 65-4 - Framingham Study Criteria for Congestive Heart Failure |
Major Criteria
|
[edit] General Appearance.
Patients with compensated chronic heart failure often appear well nourished and comfortable at rest. Even patients with moderate heart failure may appear to be in no distress after resting for several minutes, but become dyspneic during or immediately after activity. By contrast, patients with decompensated heart failure may appear anxious, dusky, and diaphoretic, and are often dyspneic at rest or on lying down. Other findings suggestive of severe heart failure include cool extremities and peripheral cyanosis resulting from low cardiac output and systemic vasoconstriction. As noted, chronic biventricular failure can result in cardiac cachexia. In severe right heart failure, hepatic congestion can cause scleral icterus and jaundice. Patients with recent onset of heart failure often appear acutely ill but are usually well nourished.
[edit] Vital Signs.
Resting sinus tachycardia is common, and is due to increased adrenergic tone. In mild heart failure, the heart rate at rest may be normal, but increases excessively with exercise and is slow to normalize with rest. The pulse may be irregular if atrial fibrillation is present or in the presence of frequent premature ventricular complexes. In severe LV failure, the peripheral pulse may be alternatingly strong and weak and is referred to as pulsus alternans. Pulsus alternans is attributed to reduced LV contraction in every other cardiac cycle due to incomplete recovery causing alternation in the LV stroke volume. Rarely, weaker beats may fail to open the aortic valve, resulting in an apparent halving of the pulse rate, a condition termed total alternans.
Tachypnea may be present in patients with severe LV failure and dyspnea at rest, or secondary to pleural effusions or ascites in patients with right heart failure. The respiratory rate may be normal in the sitting position, but increase in the patient with pulmonary venous congestion on lying down. Advanced heart failure may be associated with Cheyne-Stokes respiration, also called periodic breathing. Cheyne-Stokes respiration consists of periods of hyperpnea alternating with apnea, and is probably caused by prolonged circulation time from the heart to the brain, which affects the normal regulation of breathing. In addition, there is diminished sensitivity of the respiratory center to the arterial carbon dioxide pressure, which waxes and wanes during periods of hyperpnea and apnea. The fall in oxygen pressure and rise in carbon dioxide pressure during the apneic phase stimulate the respiratory center and result in hyperpnea, and the cycle continues. Cheyne-Stokes respiration is common among elderly patients with LV failure in whom the presence of cerebral arteriosclerosis and use of hypnotics may be contributory. The patient is usually unaware of the altered breathing pattern, but other family members may notice it and become alarmed. Cheyne-Stokes respiration may contribute to daytime somnolence in patients who are awakened frequently during periods of hyperpnea.
The systolic blood pressure may be elevated in diastolic heart failure due to chronic hypertension, normal in compensated systolic heart failure, or low in advanced heart failure. Diastolic blood pressure may be slightly elevated due to increased adrenergic activity. A significant reduction in cardiac output is reflected by a narrow pulse pressure, which is defined as the difference between the systolic and diastolic blood pressures. For example, when the pulse pressure is less than 25% of the systolic pressure, the cardiac index is generally less than 2.2 L/min/m2. When the volume status is unclear in a patient with dyspnea, a bedside Valsalva's maneuver may be used to detect elevated left ventricular filling pressures.
A low-grade fever resulting from cutaneous vasoconstriction may occur in severe heart failure, and subside when compensation is restored. Temperatures greater than 101°F should suggest infection.
[edit] Jugular Venous Pulse.
Elevation of the jugular venous pressure is a hallmark of elevated systemic venous pressure. The upper limit of normal is approximately 4 cm above the sternal angle when the patient is examined at a 45-degree angle, corresponding to a right atrial pressure of less than 10 cm of water. Higher levels of venous pressure, approaching the angle of the jaw, are common in right sided failure. When tricuspid regurgitation is present, the descending limb of the a wave is attenuated, and the height of the v wave increases with a rapid y descent. Rarely, venous pressure is so high that veins under the tongue or on the dorsum of the hand are dilated. Kussmaul's sign is present when jugular venous pressure increases with inspiration.
In patients with mild right heart failure, jugular venous pressure may be normal at rest but increase with compression of the right upper quadrant. Hepatojugular reflux may be elicited by gently applying firm, continuous pressure over the liver for up to 1 minute while observing the neck veins. The patient must breathe normally and not strain during this maneuver. Normally, abdominal or hepatic compression leads to a transient increase in jugular venous pressure. In heart failure, the abnormal right ventricle is unable to accept an increase in venous return and jugular venous pressure remains elevated. In biventricular failure, elevated jugular venous pressure at rest or after hepatic or abdominal compression is a moderately sensitive and highly specific marker of increased pulmonary capillary wedge pressure.
[edit] Examination of the Heart
[edit] Precordial Palpation.
Chronic heart failure is accompanied by cardiac enlargement. Commonly, the apical impulse is displaced downward and to the left, and may be either diffuse (in dilated cardiomyopathy) or sustained (in pressure-overloaded states such as aortic stenosis). In biventricular heart failure or severe right-sided heart failure, a right ventricular impulse may be palpated along the lower sternal edge. A palpable third heart sound may also be present. In acute heart failure or heart failure secondary to constrictive pericarditis or restrictive cardiomyopathy, cardiac enlargement is usually not present.
[edit] Auscultation.
Although the presence of a third heart sound is common in healthy children and young adults, in adults over age 40, an S3 gallop generally implies ventricular dysfunction. In patients with mitral or tricuspid regurgitation or left-to-right shunts, excessive flow into the ventricles can also cause a third heart sound without ventricular dysfunction. In heart failure, the presence of a third heart sound is probably related to a sudden deceleration of ventricular inflow that takes place after the early filling phase. Abnormal compliance or diastolic dysfunction may also contribute to a gallop rhythm.
Ventricular remodeling in heart failure may lead to incompetence of the atrioventricular (AV) valves. Thus holosystolic murmurs of mitral or tricuspid regurgitation may be present in the absence of structural valvular abnormalities, especially in advanced heart failure. These murmurs typically decrease in intensity or disappear after successful treatment of decompensation. In biventricular failure or isolated right heart failure, pulmonary hypertension is reflected in a loud pulmonary component of the second heart sound.
[edit] Examination of the Lungs.
Rales result from the transudation of fluid into the alveoli and airways. In general, rales are heard at the lung bases; but in severe heart failure, they may be heard throughout the lung fields. Wheezing and rhonchi can occur with congestion of the bronchial mucosa, and can lead to the misdiagnosis of reactive airways disease. In biventricular failure, bilateral pleural effusions can occur, and are recognized as dullness to percussion and decreased breath sounds at the bases. When rales or pleural effusion is limited to one side, the right side of the chest is typically involved. Importantly, the absence of pulmonary rales does not exclude significant elevation of the pulmonary capillary wedge pressure in patients with chronic LV systolic failure.
[edit] Examination of the Abdomen and Extremities.
Hepatomegaly is an early sign of systemic venous congestion. In the early stages of right heart failure, the liver may be tender due to stretching of its capsule, but with progression of disease, tenderness may disappear. In patients with tricuspid regurgitation, the liver may be pulsatile due to transmission of the v wave. Longstanding hepatic congestion may lead to cardiac cirrhosis with portal hypertension and congestive splenomegaly. Ascites results from increased pressure in the hepatic veins and the veins draining the peritoneum. In most patients with heart failure, ascites is minimal. With massive ascites, the physician should suspect constrictive pericarditis or primary liver failure.
Dependent lower extremity edema is common in biventricular or isolated right heart failure, and is typically symmetrical and pitting. In chronic heart failure, the amount of edema does not correlate well with systemic venous pressure; in acute heart failure, edema may be absent despite marked systemic venous hypertension. With advanced heart failure, edema may become massive and generalized (anasarca). Chronic edema of the distal lower extremities may cause reddening and induration of the skin.
[edit] DIAGNOSIS
[edit] Diagnostic Procedures
[edit] Laboratory Studies.
Anemia is not diagnostic of heart failure, but when present may exacerbate underlying ischemic heart disease and should be corrected. Rarely, severe anemia may cause high-output failure. The erythrocyte sedimentation rate often decreases in heart failure because of impaired fibrinogen synthesis and decreased fibrinogen concentration. A marked increase in sedimentation rate may suggest infective endocarditis.
[edit] Serum Electrolytes.
Dilutional hyponatremia is common in severe heart failure and is the result of prolonged sodium restriction, diuretic therapy, and expansion of extracellular volume. Increased vasopressin levels may also contribute to hyponatremia. Hyponatremia is a negative prognostic indicator at the time of hospital admission for heart failure, and predicts decreased long-term survival.
Hypokalemia is most often due to thiazide or loop diuretics given without oral potassium supplementation, but may also result from increased aldosterone levels due to activation of the renin-angiotensin system. If uncorrected, hypokalemia may lead to ventricular arrhythmias, especially in the presence of digoxin. Hyperkalemia may result from marked reductions in glomerular filtration rate and inadequate delivery of sodium to the distal renal tubule. Excess total body potassium may be exacerbated by the use of potassium-sparing diuretics or angiotensin-converting enzyme inhibitors, and in particular, their concurrent use. During hospitalization for heart failure, hyperkalemia is a common cause of iatrogenic morbidity, and even mortality. Other electrolyte abnormalities seen in heart failure include hypophosphatemia and hypomagnesemia, both of which are commonly associated with chronic alcohol use.
[edit] Renal and Hepatic Function.
Blood urea nitrogen and creatinine levels are often moderately elevated in severe heart failure because of a reduction in renal blood flow and glomerular filtration rate. Proteinuria may also be present, especially in the setting of longstanding hypertension or diabetes. Chronic right-sided heart failure with congestive hepatomegaly leads to abnormal liver function. Serum aminotransferase, lactic dehydrogenase, and alkaline phosphatase levels are elevated, typically 2 to 3 times normal. Marked elevation in transaminases suggesting ‘shock liver’ can be associated with severe low output states. Hyperbilirubinemia is common in heart failure, and in severe cases of acute heart failure jaundice may occur. In patients with cardiac cirrhosis, hypoalbuminemia may exacerbate fluid accumulation.
[edit] Chest Radiograph.
The size and shape of the cardiac silhouette provide important information regarding the nature of the underlying heart disease. A cardiothoracic ratio greater than 0.5, for example, is a good indicator of increased LV volume. The other major radiographic abnormality associated with left heart failure is pulmonary venous congestion. The degree of pulmonary venous congestion often parallels increases in the pulmonary capillary wedge pressure. Early radiologic signs of pulmonary venous hypertension and interstitial edema include distention of the pulmonary veins extending upward from the hila, haziness of hilar shadows, and thickening of interlobular septa (Kerley's B lines). When the pulmonary capillary wedge pressure is moderate to severely elevated, often greater than 25 mm Hg, alveolar edema is present as diffuse haziness extending downward toward the lower portions of the lung fields (so-called butterfly pattern). In patients with chronic LV failure, higher pressures can be accommodated with fewer radiologic signs due to enhanced lymphatic drainage. Pleural effusions of varying size and distribution are common in biventricular failure.
[edit] Electrocardiogram.
No specific electrocardiographic pattern is diagnostic of heart failure. However, the ECG may provide important information regarding the nature of the underlying cardiac disease. For example, LVH and left atrial enlargement suggest left heart failure resulting from antecedent hypertension or aortic stenosis. Pathologic Q waves in ischemic heart disease indicate the presence and location of myocardial infarction, while nonpathologic Q waves (pseudoinfarction) may be seen with restrictive or dilated cardiomyopathy. Abnormal cardiac rhythms such as atrial fibrillation may be secondary to heart failure or may represent inadequacy of therapy if the ventricular response is uncontrolled. If present, ventricular ectopic activity may indicate increased risk of sudden cardiac death, or reflect digoxin toxicity or electrolyte imbalance (e.g., hypokalemia).
[edit] Cardiopulmonary Exercise Testing.
Treadmill or bicycle exercise testing with continuous gas-exchange analysis provides a safe, objective, and reproducible measure of functional capacity in patients with LV failure. In advanced heart failure, peak oxygen consumption carries important prognostic information, and is used to decide on the timing of cardiac transplantation. Cardiopulmonary exercise testing may also be used to differentiate cardiac from pulmonary causes of dyspnea.
[edit] Noninvasive Studies.
Echocardiography is commonly performed in the evaluation and management of heart failure. Two-dimensional echocardiographic imaging provides an accurate and rapid determination of ventricular size and function, and valvular morphology and function, and can detect intracavitary thrombi and pericardial effusions. Important hemodynamic data including cardiac output, pulmonary artery pressures, and valve areas can be obtained using Doppler echocardiographic techniques. Diastolic function is more difficult to assess, although newer techniques may provide accurate, load-independent measures of LV relaxation. The advent of transesophageal echocardiography has made it possible to obtain reliable information when transthoracic ‘windows’ are inadequate.
Two other noninvasive techniques commonly used in the assessment of cardiac function are radionuclide ventriculography (RVG) and cardiac magnetic resonance imaging (MRI). RVG provides a reliable quantification of right and left ventricular ejection fraction, and can characterize wall motion abnormalities in ischemic heart disease. Recently, cardiac MRI has emerged as a highly accurate and quantitative tool for the evaluation of ventricular function and myocardial mass. Serial MRI studies can assess ventricular remodeling in response to therapy.
[edit] Invasive Studies.
In the intensive care setting, assessment of volume status and/or cardiac output may be necessary to differentiate cardiogenic from noncardiogenic pulmonary edema, and manage hemodynamic instability. The gold standard for evaluating cardiac hemodynamics is right heart (or Swan-Ganz) catheterization using a balloon-tipped flotation catheter. This procedure may be performed safely at the bedside, and is used primarily to determine response to parenteral inotropic and/or vasodilator therapy in severe heart failure. Simultaneous measurement of right and left heart filling pressures in the cardiac catheterization laboratory can be used to distinguish restrictive cardiomyopathy from constrictive pericarditis.
Coronary angiography is indicated to exclude ischemic heart disease as an underlying, potentially reversible cause of left ventricular dysfunction. The presence of multivessel or left main disease with viable myocardium and adequate distal vessels may be an indication for surgical revascularization. Diagnostic angiography is also used to guide percutaneous revascularization (e.g., percutaneous transluminal coronary angioplasty [PTCA] or stent) in the treatment of angina or acute myocardial infarction. Complications associated with routine coronary angiography include local vascular complications, myocardial infarction, stroke, and death. Left ventriculography provides an assessment of LV size, function, and the severity of mitral regurgitation.
The role of right ventricular endomyocardial biopsy in the management of heart failure and cardiomyopathy remains controversial. Proposed clinical indications include detection and monitoring of myocarditis, and differentiation of restrictive cardiomyopathy (e.g., cardiac amyloidosis) from constrictive pericarditis. Following cardiac transplantation, endomyocardial biopsy is used to diagnose cardiac allograft rejection. Although the overall complication rate from endomyocardial biopsy is low (2% to 6%), cardiac perforation and death may rarely occur.
[edit] Differential Diagnosis
Many symptoms and physical findings suggesting heart failure may be caused by other conditions (Table 65-4). In a patient with dyspnea, the physician must distinguish cardiac from pulmonary causes. Sometimes, this differentiation is difficult. For example, orthopnea may be a well-established symptom in some patients with severe chronic obstructive pulmonary disease. Patients with underlying pulmonary disease may also experience episodic dyspnea during sleep that mimics paroxysmal nocturnal dyspnea. In pulmonary disease, this is usually due to accumulation of tracheobronchial secretions and is relieved by coughing and expectoration, but in cardiac disease, the patient has to sit upright. Wheezing caused by bronchoconstriction may be a prominent symptom when left-sided heart failure supervenes in individuals with reactive airways disease. Patients with cardiac asthma more frequently exhibit diaphoresis and varying degrees of cyanosis than those with bronchial asthma. Differentiating dyspnea related to heart disease from that related to pulmonary disease may be impossible when the diseases coexist, a situation common in chronically ill elderly patients. Pulmonary function studies may help distinguish whether pulmonary or cardiac disease is the predominant condition causing dyspnea. In ambulatory patients, cardiopulmonary exercise testing can help to make this distinction.
Table 65-4 Differential Diagnosis
| Symptom or sign | Differential diagnosis |
|---|---|
| Dyspnea | Pulmonary disease |
| Anxiety | |
| Anemia | |
| Edema | Venous insufficiency |
| Nephrotic syndrome | |
| Deep vein thrombosis | |
| Ascites | Hepatic cirrhosis |
| Portal vein thrombosis | |
| Distended neck veins | Superior vena cava syndrome |
| Constrictive pericarditis | |
| Pericardial effusion |
[edit] MANAGEMENT
The overall goals in the management of heart failure are to prevent or eliminate symptoms, improve quality of life, and prolong survival. The relative importance of these goals varies depending on the clinical stage of disease and on patient preference. For example, although delay of disease progression is central to the management of asymptomatic LV dysfunction, improvement in quality of life may be the primary aim of therapy for advanced heart failure. Three general approaches to achieving therapeutic goals include recognition and treatment of underlying cardiac disease, removal of precipitating factors, and management of heart failure symptoms:
- Remove Underlying Cause. All patients with heart failure should undergo evaluation for treatable causes. This includes but is not limited to improvement in coronary blood flow with coronary artery bypass grafting (CABG) or percutaneous revascularization, repair or replacement of dysfunctional cardiac valves, surgical correction of hypertrophic cardiomyopathy or congenital heart disease, control of severe hypertension, and removal of cardiac toxins (e.g., alcohol). If heart failure is due to impaired relaxation with preserved systolic function, treatment of hypertension and/or ischemia may be indicated.
- Remove Precipitating Factors. The prompt recognition, treatment, and, if possible, prevention of exacerbating factors (seeBox 65-2) are crucial to the successful management of heart failure.[8] Examples include the treatment of acute ischemia or infection, pharmacologic control or cardioversion of arrhythmias, discontinuation of negative inotropic agents, and anticoagulation for pulmonary emboli. Other important precipitants to address when present include excessive alcohol use and medication noncompliance.
- Control Symptoms. Symptoms of heart failure reflect the hemodynamic abnormalities of elevated cardiac filling pressures and reduced cardiac output. Less commonly, symptoms may be secondary to arrhythmias (e.g., atrial fibrillation with rapid ventricular response), thromboembolic events, or adverse drug effects. As discussed below, ACE inhibitors can prevent the development of symptoms, while digoxin and diuretics decrease symptoms once they occur.
[edit] Nonpharmacologic Therapy
[edit] Rest vs. Exercise.
Appropriate restriction of physical activity is essential in the treatment of patients with heart failure. Physical rest reduces metabolic demands and thus the overall work of the failing heart. Bed rest in the hospital is usually necessary in the management of acute heart failure and other forms of severe cardiac decompensation. Progressive mobilization is initiated when the patient's condition permits and is encouraged as further clinical improvement results. Explicit instructions regarding physical activity are discussed before discharge. Patients who work full-time may need to reduce their hours or stop working altogether, depending on the physical and mental demands of the job. It may be beneficial to avoid emotional stress and use relaxation techniques.
Exercise is not contraindicated in patients with heart failure. Supervised cardiac rehabilitation in selected patients may increase exercise tolerance, reduce symptoms, and improve quality of life. Reduction in morbidity and mortality has been reported. These clinical benefits are associated with important physiologic changes including improved vascular endothelial function and skeletal muscle metabolism and decreased sympathetic tone. Thus a program of regular, aerobic exercise for patients with heart failure is recommended.
[edit] Diet.
Expanded extracellular volume, due in part to avid sodium retention by the kidney, may be treated in most patients with diuretics (see below) and reduction in the dietary intake of sodium. The average American diet without salt restriction contains as much as 10 gm/day of salt. Prohibiting the addition of salt to cooked food and eliminating some salty foods (e.g., potato chips) often reduce salt intake to about 4 to 5 gm/day (Table 65-5). A salt substitute or herbs and spices may be used to flavor food. Removal of salt from cooking altogether reduces intake to about 2 gm of salt per day but often results in unpalatable food and poor compliance. This degree of salt restriction is often unnecessary unless edema persists after vigorous diuretic therapy. Further reduction of salt intake requires elimination of most processed foods and when possible, substitution with low-sodium foods (e.g., fresh vegetables, low-sodium milk, cheese, and bread).
Table 65-5 Salt Content of Foods
| Food | Portion | Sodium (mg) |
|---|---|---|
| Dill pickle | 1 | 928 |
| McDonald's Big Mac | 1 | 980 |
| Corn chips | 1 oz | 231 |
| Chicken noodle soup | 1 cup | 1107 |
| Spaghetti sauce | 7 oz | 1054 |
| Hot dog | 1 | 639 |
| Pepperoni pizza | ½ pie | 813 |
| Ham | 3 oz | 1114 |
| Canned corn or beans | 1 cup | 350 |
| Frozen corn or beans | 1 cup | 5 |
In obese patients with heart failure, supervised weight reduction is of critical importance in reducing the workload of the heart. Specific advice regarding caloric restriction is given, and the therapeutic goal of weight loss is reinforced during follow-up.
[edit] Risk Factor Management.
For all patients with cardiovascular disease, control of modifiable risk factors should be emphasized. Treatment of hypertension and hyperlipidemia, as well as smoking cessation, have all been shown to have favorable effects on the primary and secondary prevention of ischemic heart disease and cerebrovascular disease. In patients with ischemic heart disease, antihypertensive therapy reduces the risk of developing heart failure.
[edit] Pharmacologic Therapy
Therapy for LV dysfunction is generally escalated in relation to severity of symptoms and hemodynamic compromise[9] (Fig. 65-6). ACE inhibitors have been shown to improve survival in all patients with heart failure, including those with asymptomatic LV dysfunction, and β-blockers improve survival in patients with mild to moderate heart failure. Digoxin and diuretics decrease symptoms once they have developed. For patients who remain severely symptomatic despite conventional therapy, including parenteral inotropes and/or vasodilators, mechanical assist and cardiac transplantation may be indicated.
An important goal of combination therapy is to maximally restore a normal relationship between stroke volume and LV filling pressure (Fig. 65-7). The combination of an inotropic agent and a vasodilator with or without a diuretic may achieve more normal LV function than does the administration of an inotrope, vasodilator, or diuretic alone.
[edit] Diuretics.
Diuretic therapy is an important element in the treatment of edema associated with heart failure. By reducing the reabsorption of sodium and water by the renal tubule, diuretics improve symptoms related to excess volume and may prevent ventricular remodeling by reducing cardiac filling pressures. Current recommendations are to reserve diuretic therapy for patients with signs and symptoms of fluid retention on an ACE inhibitor (or other vasodilator) and moderate salt restriction, with or without digoxin. Commonly used diuretics in heart failure are thiazides, loop diuretics, and potassium-sparing diuretics (Table 65-6).
Table 65-6 Diuretic Therapy in Heart Failure
| Generic name | Trade name | Usual dose | Duration of action (h) |
|---|---|---|---|
| Thiazides | |||
| Chlorothiazide | Diuril | 500-1000 mg/day | 6-12 hours |
| Hydrochlorothiazide | HydroDIURIL | 50-100 mg/day | >12 |
| Metolazone | Zaroxolyn | 5-10 mg/day | 24-48 |
| Chlorthalidone | Hygroton | 100 mg/day | 24 |
| Indapamide | Lozol | 1.25-5 mg/day | 24 |
| Loop diuretics | |||
| Furosemide | Lasix | 40-160 mg/day po 20-80 mg IV | 6-8 (po) |
| Bumetanide | Bumex | 0.5-4 mg/day po 0.5-2 mg IV | 4-6 (po) |
| Ethacrynic acid | Edecrin Sodium Edecrin | 50-150 mg/day po 50-100 mg IV | 6-8 (po) |
| Torsemide | Demadex | 5-20 mg/day po 5-20 mg IV | 1-4 (po) |
| Potassium-sparing diuretics | |||
| Spironolactone | Aldactone | 25-100 mg/day | 3 days after starting |
| Triamterene | Dyrenium | 100-200 mg/day | 12-16 |
| Amiloride | Midamor | 5-10 mg/day | 24 |
[edit] Thiazides and Related Compounds.
Thiazides, including chlorothiazide and hydrochlorothiazide, exert their diuretic effects primarily by inhibiting sodium and chloride reabsorption in the distal convoluted tubule. They are well absorbed orally and may be used in the management of mild to moderate heart failure, or in combination with loop diuretics to treat refractory edema. However, their utility may be limited by avid solute reabsorption in the more proximal nephron (diuretic resistance), especially when renal function is impaired. Also, because thiazides enhance the secretion of potassium, hypokalemia and potassium depletion can result. Metabolic alkalosis, hyperglycemia, hyperuricemia, and dilutional hyponatremia are other complications of thiazide use.
Although chemically different from thiazides, chlorthalidone, metolazone, and indapamide have similar sites of action and potency. Metolazone has a long duration of action (24 to 48 hours) because of serum protein binding and retains its diuretic properties even when renal function is compromised. Indapamide has vasodilatory and diuretic effects, and does not significantly alter serum cholesterol and triglyceride levels.
[edit] Loop Diuretics.
These agents, which include furosemide, bumetanide, and ethacrynic acid, are potent inhibitors of sodium and chloride reabsorption in the thick ascending limb of the loop of Henle. Because their initial action augments renal blood flow, loop diuretics, unlike the thiazides, generally retain their diuretic potency when glomerular filtration rates are reduced. Once-or twice-daily oral administration is recommended in the outpatient management of moderate to severe heart failure, while IV administration is reserved for hospitalized patients with acute pulmonary edema or decompensated heart failure. Because of their potent diuretic effects, high doses may result in a severe reduction in intravascular volume and hypotension. Other side effects include hypokalemia, azotemia, metabolic alkalosis, hyperuricemia, ototoxicity (particularly with ethacrynic acid), and neurohormonal activation. Efficacy of loop diuretics may be diminished by nonsteroidal antiinflammatory agents or by decreased gastrointestinal absorption due to bowel wall edema. Torsemide, a new loop diuretic with improved bioavailability, may be used to treat right heart failure resistant to oral furosemide.
[edit] Potassium-Sparing Diuretics.
The potassium-sparing drugs include spironolactone, triamterene, and amiloride. All three have relatively mild diuretic potency when used alone. However, when used with a thiazide or loop diuretic, they enhance sodium excretion and counteract the potassium-wasting properties of these drugs. Therefore combination therapy may be of particular use in patients with refractory edema and hypokalemia. Potassium-sparing diuretics are contraindicated in renal failure because they may result in life-threatening hyperkalemia.
A recent study (RALES) demonstrated a survival benefit of spironolactone in patients with severe heart failure, and favorable effects on LV remodeling have been suggested. Newer selective aldosterone receptor antagonists (SARAs) are being developed for the treatment of heart failure.
[edit] Mechanical Fluid Removal.
In patients with massive edema resistant to high-dose or combination diuretics, cautious mechanical removal of fluid from the pleural or peritoneal spaces occasionally results in marked improvement of symptoms. In heart failure associated with compromised renal function, isolated ultrafiltration without hemodialysis has been used successfully to remove excess fluid and has resulted in sustained clinical benefits.
[edit] Vasodilators.
An important advance in the treatment of heart failure was the recognition that pump function was critically dependent on afterload.[10] Agents that preferentially dilate arteriolar resistance vessels (e.g., hydralazine) shift the ventricular function curve upward and to the left, resulting in an increase in cardiac output often with little or no change in blood pressure. Agents that preferentially increase capacitance in the venous system (e.g., nitrates) redistribute blood volume from the central to peripheral reservoirs and decrease the signs and symptoms of elevated filling pressures. ACE inhibitors, which have a balanced effect on the arterial and venous system, also slow the progression of heart failure by interfering with the renin-angiotensin system. The dosage and characteristics of vasodilators commonly used in the treatment of heart failure are shown in Table 65-7.
Table 65-7 Vasodilator Therapy in Heart Failure
| Generic name | Trade names | Route of administration | Usual dose |
|---|---|---|---|
| ACE inhibitors | |||
| Captopril | Capoten | Oral | 6.25-50 mg tid |
| Enalapril | Vasotec | Oral | 2.5-20 mg bid |
| Lisinopril | Zestril, Prinivil | Oral | 5-40 mg qd |
| Fosinopril | Monopril | Oral | 10-40 mg qd |
| Nitrates | |||
| Nitroglycerin | Nitrostat | Sublingual | 0.3-0.4 mg initial |
| Nitroglycerin | Nitro-Dur, Nitrodisc | Transdermal | 0.1-0.6 mg patch 12 h/day |
| Isosorbide dinitrate | Isordil | Oral | 10-40 mg tid |
| Isosorbide mononitrate | Imdur | Oral | 30-120 mg qd |
| Other vasodilators | |||
| Hydralazine | Apresoline | Oral | 25-100 mg tid-qid |
| Losartan | Cozaar | Oral | 25-100 mg qd |
| Amlodipine | Norvasc | Oral | 2.5-10 mg qd |
Several large, prospective, controlled trials have demonstrated the beneficial effects of ACE inhibitors and other vasodilators on exercise tolerance, clinical signs and symptoms, neurohormonal activation, quality of life, and survival in patients with chronic heart failure (Table 65-8).
Table 65-8 Randomized Controlled Trials of Vasodilators in Heart Failure
| Study | Drug(s) studied | Number enrolled | NYHA class (%) | Patients with IDC (%) | Key findings |
|---|---|---|---|---|---|
| CONSENSUS I | Enalapril | 253 | IV (100) | 15 | Enalapril reduced symptoms and mortality in severe heart failure |
| V-HeFT I | Hydralazine plus isosorbide dinitrate, prazosin | 642 | II (NA) | NA | Hydralazine-isosorbide dinitrate reduced mortality in mild-moderate heart failure |
| III (NA) | |||||
| V-HeFT II | Hydralazine plus isosorbide dinitrate, enalapril | 804 | I (6) | NA | Enalapril was superior to hydralazine-isosorbide in reducing mortality in mild-moderate heart failure |
| II (51) | |||||
| III (43) | |||||
| SOLVD Treatment | Enalapril | 2569 | I (11) | 18 | Enalapril reduced mortality and hospitalizations in mild-moderate heart failure |
| II (57) | |||||
| III (30) | |||||
| SOLVD Prevention | Enalapril | 4228 | I (67) | 10 | Enalapril reduced heart failure and hospitalizations in patients with asymptomatic LV dysfunction |
| II (33) | |||||
| SAVE | Captopril | 2231 | I (100) | 0 | Captopril reduced mortality in patients with asymptomatic LV dysfunction postmyocardial infarction |
| ATLAS | Lisinopril | 3164 | II (16) | 35 | High-dose Lisinopril was superior to low-dose Lisinopril in reducing death or hospitalization in mild-moderate heart failure |
| III (77) | |||||
| IV (7) | |||||
| ELITE II | Captopril, losartan | 3152 | II (52) | 21 | Losartan was not superior to captopril in improving survival in elderly heart failure patients |
| III (43) | |||||
| IV (5) | |||||
| IDC, Idiopathic dilated cardiomyopathy. | |||||
[edit] ACE Inhibitors.
By inhibiting the enzyme that converts angiotensin I to angiotensin II, ACE inhibitors exert several important hemodynamic and neurohormonal effects in heart failure. A decrease in circulating angiotensin II causes balanced vasodilation and inhibition of aldosterone secretion; inhibition of tissue angiotensin II prevents myocardial hypertrophy and fibrosis; and reduced bradykinin metabolism stimulates prostaglandin and nitric oxide synthesis. Cardiovascular effects include reduction in right and left ventricular filling pressures and increases in stroke volume and cardiac output.
All patients with heart failure due to left ventricular systolic dysfunction should receive an ACE inhibitor, unless contraindicated. Similar mortality benefits are observed with several different agents, including captopril, enalapril, and lisinopril, and in a broad range of patients,[11] and a recent study (ATLAS) demonstrated the superiority of high-dose therapy. ACE inhibitors are generally added to diuretics and may be used together with β-blockers or digoxin. In clinical practice, the choice of an ACE inhibitor may be dictated more by cost and frequency of administration.
Hypotension and lightheadedness are common side effects of ACE inhibitors, particularly in patients with marked activation of the renin-angiotensin system (identified by the presence of hyponatremia or the recent occurrence of rapid diuresis). Symptomatic hypotension can be avoided by holding diuretic therapy on the first day of treatment, and by starting with low doses and titrating slowly to target doses. Hyperkalemia may occur with ACE inhibitors, and potassium supplementation should be carefully monitored. Nonproductive cough occurs in 5% to 15% of patients and is the most common reason for drug discontinuation. Major adverse effects include anuric renal failure, especially in the presence of bilateral renal artery stenosis, and angioedema. ACE inhibitors are contraindicated in pregnancy.
[edit] Other Vasodilators.
In patients who are intolerant of ACE inhibitors, the combination of hydralazine and isosorbide dinitrate should be considered as a therapeutic option. These agents may also be used in advanced heart failure in addition to ACE inhibition. Hydralazine reduces systemic vascular resistance by preferentially dilating arterioles. Reductions in pulmonary and renal vascular resistance also occur. Reflex tachycardia, typically seen in patients without cardiomegaly, is uncommon in heart failure. As with ACE inhibitors, treatment with hydralazine should be started at a low dose (10 to 25 mg orally four times daily) and slowly titrated over days to weeks to a target dose of ≥200 mg/day. Side effects include flushing, headaches, and gastrointestinal upset. Patients treated with high doses for prolonged periods frequently develop positive ANA titers. Less commonly, a lupus-like syndrome develops, which usually resolves with drug withdrawal.
Due to their preferential venodilator effects, nitrates reduce ventricular filling pressures and may be used to treat pulmonary congestion without significantly affecting cardiac output or blood pressure. In patients with underlying ischemic heart disease, nitrates can reduce myocardial ischemia via coronary vasodilation. Nitroglycerin can be given sublingually, topically, or intravenously. Isosorbide dinitrate is typically given by mouth three to four times daily in a dose of 20 to 60 mg, although longer-acting oral formulations are now available. A daily nitrate-free interval is recommended to avoid the development of nitrate tolerance. The most common adverse effects of nitrate therapy include hypotension, flushing, and headaches.
Although the use of angiotensin receptor antagonists in ACE inhibitor–intolerant patients remains unproved, increasing evidence suggests that these agents may prevent ventricular remodeling and reduce symptoms in heart failure. The recently completed ELITE II study failed to demonstrate superiority of losartan over captopril in elderly patients with heart failure. Several other large, randomized trials (CHARM, Val-HeFT, Valiant) are currently underway to test whether ACE inhibition, angiotensin receptor blockade, or the combination is more effective at slowing disease progression. Long-acting calcium channel blockers such as amlodipine may be used safely in heart failure patients on ACE inhibitors to treat angina or hypertension.
[edit] Digitalis Glycosides.
Although digoxin and related compounds have been used for over 200 years to treat heart failure, debate continues regarding their safety and efficacy. Multicenter trials have shown that digoxin increases ejection fraction and exercise tolerance, and decreases symptoms in patients with systolic heart failure, and withdrawal of digoxin leads to increased symptoms and hospitalizations (Table 65-9). The recently completed DIG trial showed no difference in survival with digoxin compared with placebo when given with an ACE inhibitor and diuretic.[12] In the digoxin-treated group, fewer deaths attributable to the progression of heart failure were offset by an increase in deaths due to other causes.
Table 65-9 Randomized Controlled Trials of Digoxin in Heart Failure
| Study | Drug(s) studied | Number enrolled | NYHA class (%) | Patients with IDC (%) | Key findings |
|---|---|---|---|---|---|
| Captopril-Digoxin Multicenter Research Group | Captopril, digoxin | 300 | I (26) | 32 | Digoxin improved ejection fraction and decreased hospitalizations for heart failure |
| II (50) | |||||
| III (24) | |||||
| PROVED | Digoxin withdrawal | 88 | II (84) | 36 | Withdrawal of digoxin worsened exercise tolerance and increased hospitalizations in patients not on ACE inhibitor |
| III (16) | |||||
| RADIANCE | Digoxin withdrawal | 178 | II (73) | 37 | Withdrawal of digoxin worsened heart failure, exercise tolerance, and ejection fraction in patients on ACE inhibitor |
| III (27) | |||||
| Digitalis Investigation Group (DIG) | Digoxin | 6800 | I (13) | 15 | Digoxin decreased hospitalizations for heart failure, but did not reduce overall mortality in LV dysfunction |
| II (54) | |||||
| III (31) |
Digoxin increases cardiac contractility by inhibiting sacrolemmal Na-K-ATPase, thereby increasing the amount of intracellular calcium available to the contractile apparatus. Cardiac output increases and diuresis ensues. Digoxin also increases baroreceptor sensitivity, attenuates neurohormonal activation, slows heart rate, and decreases systemic vasoconstriction. Finally, digoxin decreases AV nodal conduction velocity, which makes it a useful agent for treating heart failure in patients with atrial fibrillation or flutter with rapid ventricular response.
Digoxin is given to outpatients as a maintenance oral dose of 0.125 to 0.25 mg per day. In the presence of normal renal function, full digitalization occurs within 5 to 7 days. If rapid digitalization is required (e.g., in a hospitalized patient with rapid atrial fibrillation), an initial dose of 0.25 to 0.5 mg is given intravenously, followed by 0.125 to 0.25 mg every 2 to 4 hours up to a total of 1 mg. The peak effect is usually achieved between 1.5 and 6 hours. Electrocardiographic monitoring should be used to monitor for proarrhythmia, with the knowledge that some changes (e.g., shortening of the QT interval, flattening or inversion of the T wave) reflect drug effect rather than drug toxic