The term cardiomyopathy is an ill-described, general category for a large group of unrelated disease processes that share only the clinical characteristic of substantially reduced cardiac pumping function and power output. Practical and graphic descriptions have been used to describe cardiomyopathy, and this classification is firmly anchored in the pathologic description of the heart. Thus dilated cardiomyopathy, hypertrophic cardiomyopathy, and infiltrative cardiomyopathy are descriptive pathologic terms. Alternatively, cardiomyopathy is characterized by the specific clinical or disease process with which it is associated. Thus terms such as peripartum cardiomyopathy, diabetic cardiomyopathy, and toxic cardiomyopathy are used. In clinical practice, the etiology of left ventricular systolic dysfunction can be identified in patients with coronary artery ischemia or infarction, infectious vectors, toxins, hereditary conditions, and conditions for which no cause can be identified (idiopathic) (Table 14.1). These disorders, in aggregate,
account for the majority of cases of heart failure resulting from myocardial disease.

Studies have shed light on the role of the genetic background in the onset and the development of heart failure due to diastolic dysfunction (hypertrophic disease) and systolic dysfunction. Familial forms of dilated cardiomyopathy are common and have been described in as many as 30% of patients with nonischemic cardiomyopathy. This condition appears genetically highly heterogeneous. Inheritance patterns are usually autosomal dominant, but X-linked, autosomal recessive, and mitochondrial inheritance have been described as well. Genetic abnormalities found to be associated with familial dilated cardiomyopathy include mutations in genes encoding cytoskeletal/sarcolemmal, sarcomere, nuclear envelope, and transcriptional coactivator proteins. It has been postulated that the molecular defects involved in hereditary forms of dilated cardiomyopathy cause an abnormality in the transmission of contractile force. Polymorphisms in the Ile164 β₂-adrenergic receptor have been shown to be associated with poor prognosis in patients with dilated cardiomyopathy (10). In a study of 259 patients with dilated cardiomyopathy and NYHA classes II to IV symptoms, patients with the Ile164 polymorphism displayed a striking difference in survival rates, with a relative risk of death or need for cardiac transplantation of 4.81. Further studies of the genetic determinants of dilated cardiomyopathy should allow
better understanding of the underlying mechanisms that promote the progression of the disease, to identify subjects at risk of the disease who would benefit from early medical management and to promote the development of pharmacogenetics.

Idiopathic remains the designation for many forms of dilated cardiomyopathy, when coronary artery disease and specific causes such as those listed earlier have been excluded. With the exception of primary causes, which are clinically identified, limited screening procedures can identify a specific cause. Of these, perhaps the most fruitful is the screen test for thyroid disease, which may be particularly important in the evaluation of the elderly patient. Both hyperthyroidism and hypothyroidism may produce left ventricular dysfunction. Abnormalities of trace substances such as selenium have been suggested, but deficiencies do not routinely occur in Western diets. Patients may also have left ventricular systolic dysfunction due to chronic tachycardia conditions, such as atrial fibrillation with rapid ventricular response. Rate control with β-blockers, digitalis, or both has been shown to lead to improvements in left ventricular function on follow-up testing.

Activation of the renin-angiotensin-aldosterone system is one of the predominant abnormalities of heart failure. The degree of increase in plasma renin activity provides an indicator for prognosis in patients with heart failure (14). Studies in mild and asymptomatic heart failure demonstrate relatively less activation, but even these values are increased in comparison with normal. The degree of renin activity is intensified in the presence of diuretic therapy. Angiotensin II causes constriction of the systemic vasculature and vasoconstriction of both the afferent and efferent renal arterioles. In some patients with severe heart failure, treatment with angiotensin-converting enzyme (ACE) inhibitors may cause a deterioration of renal function. This may be related to fixed renal artery disease or, alternatively, to selective blocking of the constrictor action of angiotensin II on the efferent arteriole (15). Renin-system components have been identified in the myocardium and vasculature, where they adversely affect fibrosis and remodeling, as well as cellular dysfunction. These findings suggest that the renin-angiotensin-aldosterone system has effects on cardiac function beyond altering sodium excretion and cardiac afterload. Not only is angiotensin II a potent vasoconstrictor, but it also causes a direct effect on hypertrophy of myocytes and may lead to energy-supply mismatch as the capillary bed perfuses a larger bed.

In addition to vasoconstriction, angiotensin II stimulates aldosterone secretion by the adrenal gland, producing sodium retention and potassium excretion at the distal nephron. Elevations in the activity of aldosterone lead to a sodiumretentive state found in patients with heart failure. Although adrenergic stimulation and angiotensin II increase sodium transport in the proximal tubule of the kidney, patients with increased activity from aldosterone overcome this effect, and sodium delivery to the distal tubules is attenuated, leading to the edematous state. It was shown previously that although ACE inhibition continues to suppress angiotensin II levels over the course of 1 year, levels of aldosterone are initially suppressed during the first 1 to 3 months of therapy but fail to be suppressed beyond 6 months of therapy (16). This is thought to occur because stimuli in the form of glucocorticoids, hyperkalemia, hypermagnesemia, melanocytestimulating hormone, and endothelin continue to increase aldosterone secretion, although angiotensin II levels are low. Analysis of the Cooperative North Scandinavian Enalapril Survival Study (CONSEN-SUS) revealed that elevated levels of aldosterone were associated with the lowest rates of survival, and a reduction in plasma aldosterone during the course of therapy was associated with a favorable impact on survival (17). Although elevated aldosterone levels may track the clinical state of patients with congestive heart failure, they may also be responsible in part for progression of myocardial dysfunction through mechanisms that lead to abnormal accumulation of collagen, which surrounds and encases myocytes, resulting in diastolic and systolic ventricular dysfunction. Such deposition of collagen may lead to pathologic hypertrophy of the myocardium and has been shown to be prevented by spironolactone in a rat model of arterial hypertension (18). Spironolactone at doses of 25 to 50 mg per day can be used safely in conjunction with ACE inhibitors, diuretics, and digitalis. In a minority of patients, however, hyperkalemia may occur, leading to discontinuation of the drug. Findings of the Randomized Aldactone Evaluation Study (RALES) revealed that doses of spironolactone as low as 12.5 mg per day significantly reduce atrial natriuretic factor levels in patients with classes II to IV heart failure without a significant effect on serum potassium levels (19). Moreover, the RALES investigators also found that treatment groups had lower levels of aldosterone, norepinephrine, and plasma renin activity.

The baroreceptor-mediated increase in sympathetic tone that occurs with ventricular dysfunction has several consequences, including increased myocardial contractility, tachycardia, arterial vasoconstriction and thus increased cardiac afterload, and venoconstriction with increased cardiac preload. β-Adrenergic receptors in the heart either are downregulated (β₁-adrenegic receptors) or have abnormalities in signal-transduction activity that effectively uncouple them from effector mechanisms (β₁– and β₂-adrenergic receptors) (15). Increased local and circulating concentrations of norepinephrine may contribute to myocyte hypertrophy, either directly through stimulation of α₁– and β-adrenergic receptors or secondarily by activating the renin-angiotensin-aldosterone system. Norepinephrine is directly toxic to myocardial cells, an effect mediated through calcium overload, the induction of apoptosis, or both. Norepinephrine-induced death of myocytes can be prevented by concomitant nonselective β-adrenergic blockade. Patients with plasma norepinephrine concentrations greater than 800 pg per milliliter (4.7 nM) have a 1-year survival rate of less than 40% (20). Through renal vasoconstriction, stimulation of the renin-angiotensin-aldosterone system, and direct effects on the proximal convoluted tubule, increased renal adrenergic activity contributes to the avid renal sodium and water retention that occurs in patients with heart failure.

Substantiating the importance of the sympathetic nervous system in the heart failure syndrome, multiple randomized controlled trials have demonstrated the benefits of β-adrenergic blockade on clinical outcomes in patients with heart failure (21,22,23). In the past, β-adrenergic blockade was thought to be contraindicated in patients with heart failure. However, if patients can tolerate short-term β-adrenergic blockade, ventricular function subsequently improves.

The roles of atrial natriuretic peptide (ANP) and brain natriuretic peptide (or B-type natriuretic; BNP) in congestive heart failure and mitral regurgitation are not well understood. Investigators have shown that these compounds are produced by cardiac myocytes and their levels correlate inversely with left ventricular ejection fraction, directly with left atrial pressure, and directly with New York Heart Association (NYHA) class and mortality (24). Administration of exogenous ANP, 0.10 µg per kilogram per minute to normal subjects, was found to increase sodium (450%) and free water (100%) excretion, while decreasing plasma renin (33%) and aldosterone (40%). Similar administration of ANP to patients with congestive heart failure had no effect on sodium or free-water excretion, although significant decreases in pulmonary capillary wedge pressure (19%), systemic vascular resistance (13%), and plasma aldosterone (51%), and increases of cardiac index (17%) were noted. More recently, nesiritide, an intravenous form of BNP, has been shown to improve symptoms and reduce elevated filling pressures in patients treated for heart failure in various hospital settings (25). Although use of nesiritide has become routine in clinical practice, concern over long-term safety of this drug has surfaced as a result of recently published meta-analyses of several randomized clinical trials demonstrating possible decrements in both renal function and survival (26,27). Results of an ongoing randomized, placebo-controlled mortality trial should help us understand better the potential benefit of the use of nesiritide in patients with heart failure.

Serum level of endogenous BNP has been shown to be an independent prognostic indicator in patients with cardiac disease. Because of this, point-of-care BNP testing has also become part of routine clinical practice, and although it has been demonstrated to be helpful for aiding in establishing a diagnosis in patients with new-onset dyspnea (28), the value of serial measurements of BNP to guide therapy for patients with established heart failure is not well established.

Endothelin (ET) is a family of potent vasoconstrictor peptides of vascular endothelial
origin. Although it has been proposed that the vasoconstrictor effects of ET are produced at the local vascular level, increased plasma concentration of ET has been identified in cardiovascular disorders (29). ET levels have been demonstrated to be nearly threefold higher in patients with congestive heart failure than in normal controls. ET was used a decade ago as a potent vasoconstrictor. The peptides were originally identified from rodent sources (ET-3) as well as human and porcine sources (ET-1). ET-1, ET-2, and ET-3 all have potent vasoconstrictor properties. ET-1 levels have a close association with pulmonary pressures, as well as the resistance ratio (pulmonary vascular resistance/systemic vascular resistance). Preliminary studies of ET antagonists have suggested that ET may provide relative selectivity for pulmonary vasculature vasoconstriction. Whether ET-1 is a regional mediator of pulmonary hypertension or a marker for its occurrence is unknown.

According to current data, the increase of plasma ET represents a biologic marker for vascular damage, and ET probably contributes to the pathophysiologic processes of vasoconstrictive disorders. To resolve the issue of the pathophysiologic contribution of ET to heart failure, specific inhibitors of ET are required. Several ET antagonists are either on the market (currently used for treatment of primary pulmonary hypertension) or in varying stages of development. They vary according to the extent of ET_A– and ET_B-receptor activity. The vasoconstrictor effects of ET at the ET_A receptor suggest that this should be the site of blockade. However, some authorities have argued that blockade of both receptors would be important for improved endothelial cell function. It is too early to comment on the potential clinical role of ET antagonists for the patient with heart failure. Thus far, clinical trials have not supported the use of this class of neurohormonal blocking agents in patients with heart failure due to left ventricular systolic dysfunction.

Arginine vasopressin (AVP) has affinity for two receptor subsets, V₁ and V₂, which govern free-water clearance by the kidney and vasoconstriction, respectively. AVP production is increased in heart failure (30), as a result of angiotensin II stimulation and the indirect effect of thirst. Under resting conditions, AVP level is increased in patients with heart failure, in comparison with normal subjects and hypertensive patients. During the postural adjustment of head-up tilt, little additional modulation could be identified. Additional physiologic studies demonstrated that AVP exhibits the spectrum of abnormalities observed with other major hormonal pathways, while still maintaining responsiveness to adjustment of free water and other known physiologic changes. Preliminary clinical studies with AVP-receptor antagonists have been performed. Design and outcomes of these studies have been determined by the receptor subtype against which the compound has physiologic activity. The spectrum of current compounds under experimental or clinical evaluation include primary V₁, primary V₂, and compounds with combined receptor activity.

The effects of tolvaptan, an oral vasopressin V₂-receptor antagonist, have been studied in a recent randomized, placebo-controlled trial in patients hospitalized for heart failure. Although tolvaptan use was associated with improvements in hyponatremia, short-term improvements in dyspnea, edema, and body weight, no effects on long-term mortality or heart failure-related morbidity were found (31).

Functional status of patients has been standardized according to the NYHA classification system, a system that allows physicians to compare functional strata within the population of patients with heart failure (Table 14.2.) This approach assigns patients to one of four functional classes, depending on the degree of effort that brings on either fatigue or dyspnea. Patients with NYHA class I designation are without symptoms with any activity, except those that would bring on symptoms in normal individuals. NYHA class II represents patients in whom fatigue or dyspnea develops on ordinary exertion (e.g., with one or more flights of stairs or with walking one or more blocks on a flat surface). NYHA class III represents patients in whom symptoms develop at less than ordinary exertion (e.g., with less than one flight of stairs or with less than one block of walking on a flat surface). NYHA class IV represents patients who experience symptoms at rest (e.g., sitting in a chair, lying in bed) or with minimal activity (e.g., eating, dressing, showering). Although much effort is made to assign a NYHA classification to patients, the functional status of a given patient need not be static. Patients may be first seen in NYHA class IV and, after appropriate medical therapy, change to being asymptomatic, or NYHA class I. Nevertheless, assignment of a functional classification is important in the care of patients with heart failure, because current therapies indicated for treatment may have been tested only in patient populations selected on the basis of distinct NYHA classifications.

Exercise tolerance and functional status are not necessarily determined by resting left ventricular function; instead, they correlate better with exercise cardiac reserve. Patients with very low ejection fraction may be entirely asymptomatic, whereas others with mild to moderate dysfunction are symptomatic at rest or with mild exertion. Many factors contribute to exercise tolerance, including skeletal muscle function, respiratory function, peripheral vascular function, ventilatory disturbances, and psychological factors.

Because NYHA classification is a designation in flux, the American College of Cardiology and American Heart Association (ACC/AHA) Task Force on Practice Guidelines, in the ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult, originally published in 2001 and updated in 2005 (32), established a staging system to act as a complement to the NYHA classification. The ACC/AHA stages represent the evolution and the progression of heart failure (Table 14.3). Stage A represents patients who are at high risk for developing a structural disorder of the heart but have not yet done so. This stage includes patients with hypertension, coronary artery disease risk factors, or a family history of cardiomyopathy. Stage B represents patients with a structural disorder of the heart but without
symptoms. These patients are analogous to those represented by NYHA class I. Stage C represents patients with a structural disease of the heart and with prior or current symptoms of heart failure. This stage includes patients represented by NYHA classes II to IV. Stage D represents patients in the terminal phase of the disease who require repeated and prolonged hospitalizations or specialized treatment strategies such as mechanical circulatory support, continuous inotropic infusions, cardiac transplantation, or hospice care. These patients have marked symptoms of heart failure at rest despite maximal medical therapy and may require specialized interventions. The classification scheme recognizes that heart failure has established risk factors; that the evolution of heart failure has asymptomatic and symptomatic phases, and that interventions may be necessary at every stage to help prevent the progression of the disease and to help relieve the suffering of the patient.

The usual reason the patient seeks medical attention is breathlessness or fatigue that limits exercise tolerance. Sometimes the first recognized manifestation of heart failure is orthopnea or paroxysmal nocturnal dyspnea; in other patients, pedal edema may be the first recognized abnormality. Thus the secondary manifestations of heart failure (such as circulatory congestion) bring the patient to medical attention, rather than the primary cardiac contractile abnormality. A complete history and review of systems are crucial for understanding the cause of heart failure. Direct inquiry may reveal prior evidence of myocardial ischemia, infarction, or both; valvular disease; or a family history of heart ailments.

When documenting a history from the patient with heart failure, the examiner should begin by identifying the dominant symptom of the patient, whether it be fatigue, dyspnea, chest discomfort, palpitations, syncope or near syncope, edema, cough, or wheezing. Clarifying the conditions in which the symptom occurs is critical: whether they occur at rest, with recumbency, or with mild, moderate, or heavy exertion; how long the episodes have been occurring; how frequently the episodes last; how severe the symptoms are; and what relieves the symptoms. Establishing the activity level of the patient is important, because many patients will report no symptoms and yet they have assumed a sedentary lifestyle to avoid experiencing the effects of their heart condition. Patients with modest limitations of activity should be asked about their participation in sports or their ability to carry out strenuous exercise, whereas patients with substantial limitations of activity should be asked about their ability to get dressed without stopping, take a shower, climb stairs, or carry out specific routine household chores. Documenting a dietary history is helpful, particularly for the patient with edema, because some patients may be consuming large amounts of sodium and free water that may override attempts to establish euvolemia. Patients should be asked about a history of hypertension, diabetes, hypercholesterolemia, coronary disease, valvular disease, peripheral vascular disease, rheumatic fever, chest irradiation, and exposure to cardiotoxic agents. Patients should be questioned
carefully regarding illicit drug use, alcohol consumption, tobacco use, and exposure to sexually transmitted diseases. A travel history may be helpful in identifying patients exposed to trypanosomes, which lead to Chagas disease. The history should also include questions related to noncardiac diseases such as collagen vascular diseases, infections, and thyroid excess or deficiency.