pathophysiology and current therapy of congestive heart ... · 772 parmley jacc vol. 13, no. 4...

772 PARMLEY JACC Vol. 13, No. 4 PATHOPHYSIOLOGY AND THERAPY OF HEART FAILURE March 15, 1989:771-85

Rate/l000

”

45-54 55-54 8674 TOtal Age (Years)

Figure 1. The average annual incidence of congestive heart failure for men and women at different ages. In all age groups there is a reduced incidence of the development of heart failure in women as compared with men. Reprinted with permission from McFate-Smith (2).

prevalence of congestive heart failure have been increasing. These trends may be due, in part, to the aging population, and in part to the improvements in therapy that have allowed patients with cardiovascular disease to live longer, so that congestive heart failure becomes a more common clinical problem.

Definition A traditional definition of congestive heart failure is “the

inability of the heart to deliver enough blood to peripheral tissues to meet metabolic demands.” This definition, however, does not fully describe the syndrome of congestive heart failure as we see it in clinical practice. The two major symptom complexes of congestive heart failure are dyspnea (particularly dyspnea with exercise) and fatigue. It is presumed that these two major symptoms relate to the two major hemodynamic abnormalities of congestive heart failure-namely, an increase in left atria1 pressure and a decrease in cardiac output. Thus, from a functional viewpoint, it is clear that congestive heart failure also includes the symptoms of dyspnea and fatigue and a decrease in exercise tolerance. Therefore, there is not only a decrease in peripheral blood flow to meet metabolic demands, but also an increase in atria1 pressures leading to the signs and symptoms of either right or left heart failure, or both.

Etiology In the Framingham study (7) which prospectively exam-

ined the development of heart failure in a cohort of the population of Framingham, Massachusetts, it appeared that hypertension was one of the major factors leading to heart failure. Over the past 2 decades, however, better recognition and treatment of high blood pressure have reduced the relative importance of this factor. Certainly, better treatment of hypertension has dramatically reduced the incidence of stroke. In current series in the United States, it appears that

in about 50 to 75% of patients with heart failure, coronary artery disease is the underlying cause (8). Hypertension may be a contributing factor in some patients, but is clearly less important than myocardial infarction and ischemia. The next most common cause appears to be cardiomyopathy. Rheu- matic heart disease is declining significantly in the United States, although valvular heart disease due to mitral regurgitation or aortic stenosis is still reasonably common in the population at large. Congenital heart disease represents only a small portion of patients presenting with congestive heart failure.

General Principles When a patient presents with the signs and symptoms of

congestive heart failure it is important that the etiology of this syndrome be carefully identified. In addition to history and physical examination, echocardiography and other non- invasive and invasive tests can be very helpful in assessing the precise cause of the congestive heart failure. It is also important to determine whether the signs and symptoms are due primarily to ventricular systolic dysfunction, diastolic dysfunction or a combination of the two. In most cases systolic dysfunction, as manifested by a decreased ejection fraction, will be the most common cause of congestive heart failure. In a minority of cases, diastolic dysfunction will be the predominant cause (9). The latter circumstances would include patients with hypertrophic cardiomyopathy, hypertrophy from any cause, restrictive cardiomyopathy, pericar- dial disease, certain infiltrative diseases such as amyloid or any process that impedes filling of the ventricle and thus leads to an increase in atria1 pressures when cardiac output is increased. It is likely that almost all patients who have systolic dysfunction have some element of diastolic dysfunction as a contributing cause. Our inability to effectively treat diastolic dysfunction, however, limits our ability to provide major therapeutic benefit to patients with this disorder. Certainly if patients have constrictive pericarditis, removal

Figure 2. Survival curves of men and women after the onset of congestive heart failure (CHF) in the Framingham study. The data are compared with the total population sample at the top of each graph. The survival of women is higher than that of men throughout the follow-up. Reprinted with permission from Stamler (4).

Men m Total Population Sample

Cl CHF

Women

JACC Vol. 13. No. 4 PARMLEY March 15. 1989:771-X5 PATHOPHYSIOLOGY AND THERAPY OF HEART FAILURE

773

of the pericardium can be quite dramatic in improving function. Similarly, valvotomy in patients with mitral stenosis can also produce a dramatic benefit in what is primarily a filling problem of the left ventricle. Some patients with severe hypertrophic cardiomyopathy may benefit from calcium channel blocker therapy, which can increase left ventricular volume at the same end-diastolic pressure (10). Similarly, in patients with severe hypertensive hypertrophy, which may restrict ventricular filling, control of hypertension with antiadrenergic drugs, the angiotensin-converting enzyme inhibitors or calcium channel blockers can cause regression of the hypertrophy (11) and thus reduce diastolic dysfunction. It is clear, however, that we need to learn much more about diastolic dysfunction and ways to alter it to effectively treat this component of congestive heart failure.

Our current understanding of congestive heart failure is based on our understanding of changes that occur in the myocardium as well as peripheral changes, including neurohumoral alterations, that affect the circulation. These changes will be described in the next sections.

Decrease in Myocardial Contractility A fundamental problem for patients with systolic dys-

function is a decline in myocardial contractility. This can be the result of prolonged pressure or volume overload or an intrinsic decline associated with cardiomyopathy. In patients with ischemic heart disease, loss of muscle with myocardial infarction imposes an additional volume and wall stress overload on the remaining normal myocardium. These changes lead to remodeling of the ventricle over time and, eventually, to a similar intrinsic decline in contractility. In general, therefore, therapy has been directed toward earlier recognition and treatment of increased loading conditions of the ventricle. For example, angiotensin-converting enzyme inhibitors may prevent remodeling and delay or attenuate the irreversible decline in contractility that occurs with increased loading after myocardial infarction (12).

Indexes of reduced muscle contraction. A reduction in myocardial contractility is manifested by decreased force development, decreased rate of force development and decreased velocity of shortening at given loading conditions. These changes are frequently accompanied by a delay in relaxation (Table 1). These indexes of muscle contraction (13) are reflected in the intact heart by a decrease in ejection fraction and stroke volume and by a shift downward in the ventricular function curve with an increase in atria1 pressure.

Biochemical changes. A number of biochemical changes have been noted to accompany the process of congestive heart failure. Although it is outside the scope of this review

to examine all of these, a few are listed in Table I. A reduction in contractility is frequently accompanied by a shift in myosin isozymes, such that rapidly contracting V, forms with high adenosine triphosphatase (ATPase) activity

Table 1. Myocardial Changes in Congestive Heart Failure

Mechanical I, Decreased force development 2. Decreased rate of force development 3. Decreased velocity of shortening 4. Delayed relaxation

Biochemical I. Shift in myosin isozymes 2. Hypertrophy and increase in connective tissue 3. Calcium overload 4. Decreased function of sarcoplasmic reticulum 5. Decreased stores of myocardial norepinephrine 6. Decreased production of norepinephrine 7. Decreased beta-receptors

are converted into slower contracting V, forms with slower ATPase activity (14). The relation between maximal velocity of shortening and myosin ATPase activity seen over a wide variety of species (15) also occurs in animal models of congestive heart failure and in patients. A reduction in velocity of shortening and actomysin ATPase activity has the potential benefit of reducing oxygen consumption and thus conserving energy in circumstances where it may be limited. Clearly, however, this compensatory aspect does not make up for the dramatic reduction in function that leads to reduced cardiovascular performance.

Hypertrophy is one of the most important compensatory mechanisms available to heart muscle as function decreases, and it is accompanied by an increase in connective tissue that may stiffen the diastolic properties of the heart (16). In animal models of heart failure, calcium overload may play an important role in the development of congestive heart failure (17). This may occur through damage of the sarcolemma or perhaps through increased calcium entry due to increased sympathetic tone or increased sodium-calcium exchange. Certainly, the sarcoplasmic reticulum exhibits decreased function (18). An excess of myoplasmic calcium can reduce mitochondrial function and decrease the production of high energy phosphates. At least in animal models of congestive heart failure, such as the hereditary cardiomyopathy of the Syrian hamster, calcium overload plays a major role (19). The calcium channel blocker, verapamil, is effective in attenuating or treating this form of experimental heart failure. Microvascular spasm (20) has also been implicated in some experimental models of congestive heart failure and has responded to a vasodilator, such as prazosin (21). It is not clear, however, whether these specific biochemical changes in experimental models of heart failure have any application to the clinical syndrome of congestive heart failure.

Sympathetic nervous system and neuroendocrine activity. The activity of the sympathetic nervous system is increased in congestive heart failure (22). A reflex increase in sympathetic tone is presumably designed to maintain cardiovascu-

774 PARMLEY JACC Vol. 13, No. 4 PATHOPHYSIOLOGY AND THERAPY OF HEART FAILURE March 15. 1989:771-85

lar compensation by increasing heart rate and contractility. This increased tone leads to a decline in stores of norepinephrine in the myocardium (23) that spill over into the circulation. In some animal species there is also a decline in the production of norepinephrine (24). Increased catecholamines lead to a decline in beta,-receptors (25), although beta,-receptors may be little affected. These latter changes reduce the responsiveness of the myocardium to catecholamines, but the marked increase in plasma catecholamines in congestive heart failure is still sufficient to produce important sympathetic support of the circulation. Some studies in dilated cardiomyopathy suggest that this increased sympathetic drive may actually be deleterious. Some patients with dilated cardiomyopathy have responded beneficially to low dose metoprolol (26); this finding suggests that excess sympathetic drive may be directly harmful to the heart. Certainly high dose catecholamine infusions can directly cause myocardial necrosis in experimental animals (27). The combination of tachycardia and prolonged sympathetic stimulation may be deleterious in some patients with congestive cardiomyopathy. Tachycardia in and of itself not only increases myocardial oxygen demand, but also, by reducing diastolic time, can reduce coronary blood flow to the myocardium and contribute to an imbalance between supply and demand.

Although beta-blocker therpay may be benejicial for some patients with cardiomyopathy, it is clear that it does not have widespread application to all forms of heart failure. In fact, beta-blockade can suddenly and dramatically worsen function in some patients who have severe congestive heart failure. The precise role, therefore, of the sympathetic nervous system and its potential benefit and harm have yet to be firmly elucidated in different patient subsets.

Pressure and volume overloading. If increased loading factors are deleterious to heart muscle, it is clear that unloading therapy may be one of the most beneficial ways to attenuate the adverse effects of prolonged pressure or volume overloading. In general, the decline in contractility that accompanies severe heart failure appears to be mostly irreversible and to continue in a downward spiral. Relief of pressure or volume overload in circumstances of valvular disease, however, has shown that there can be some resti- tution of function (28). This emphasizes the importance of earlier intervention before these irreversible changes produced by pressure and volume overloading cause an irreversible decline in cardiac contractility.

Neurohormonal and Other Peripheral Factors in Congestive Heart Failure

Increased sympathetic nerve reflexes and plasma catecholamines. A number of neurohormonal factors contribute to the syndrome of congestive heart failure. Three hormonal systems that are activated in congestive heart failure include the renin-angiotensin-aldosterone system (29), the sympa-

Table 2. Neurohormonal and Peripheral Changes in Congestive Heart Failure

Neurohormonal 1. Increased plasma catecholamines 2. Activation of renin-angiotensin-aldosterone system 3. Increased arginine vasopressin (antidiuretic hormone) 4. Increased atrial naturetic factors

Peripheral factors 1. Increased systemic vascular resistance 2. Blunting of baroreceptor reflexes 3. Decreased vasodilatory response of peripheral vasculature 4. Altered regional flows 5. Venoconstriction

thetic nervous system (22) and arginine vasopressin (antidiu- retie hormone) (30). The marked increased in catecholamines is probably a reflection of the overall severity of the heart failure state (31), because it is presumed that this increase in sympathetic tone is intended to be compensatory. For example, the decrease in stroke volume and cardiac output that accompanies heart failure leads to a decrease in arterial pressure. The baroreceptor-mediated reflex increase in systemic vascular resistance produced by an increase in sympathetic tone would initially be helpful in maintaining arterial pressure during a decrease in cardiac output. Similarly, the decline in contractility that occurs in heart failure would be supported by the increased activity of the sympathetic nervous system, which could thus help to maintain stroke volume and cardiac output. Not only is there an increase in plasma catecholamines, but also there is an abnormal response of the sympathetic nervous system to physiologic interventions. Some examples are listed below. When patients with heart failure are subjected to upright tilt, there may be no change in plasma norepinephrine, although in normal subjects there would be an increase in plasma norepinephrine levels (32). This blunting of baroreceptor responses appears to form a component of the heart failure syndrome (33). Whether this is due to a smaller reduction in atria1 pressures, changes in afferent stimulation or changes in central integration is not clear. Increasing or decreasing arterial pressures also does not produce the same responsiveness in patients with congestive heart failure. During exercise there may be a more abrupt increase of plasma norepinephrine at lower work loads in patients with failure, although the relative change in plasma norepinephrine may be less appropriate to the maximal achievable exercise response (34). Thus, overall there may be some blunting of the catecholamine response to exercise.

The arginine vasopressin system. This system is also increased in most patients with congestive heart failure (30). Because this antidiuretic hormone is such a potent vasoconstrictor, it could contribute to the peripheral vasoconstriction which can be so deleterious to patients with severe heart failure. Studies (35) suggest that osmoreceptor function is

JACC Vol. 13, No. 4 PARMLEY

March IS, 1989:771-X5 PATHOPHYSIOLOGY AND THERAPY OF HEART FAILURE 775

essentially intact in patients with congestive heart failure. In a few patients, arginine vasopressin may directly contribute to adverse sympathetic tone.

Atria1 natriuretic hormones. Patients with heart failure generally have higher levels of atria1 natriuretic factor than do normal persons (36). Data suggest that the effects of atria1 natriuretic factor on diuresis are diminished in patients with congestive heart failure. Although infusion of this hormone has produced increases in cardiac output and increased renal excretion (37), it is unclear that this will be a major therapeutic intervention in relation to all of the other drugs available in patients with congestive heart failure.

The renin-angiotensin-aldosterone system. This system is also activated in patients with congestive heart failure (29). The three primary mechanisms whereby renin increase is promoted include reduced serum sodium, an increase in sympathetic tone and decreased blood pressure perfusing the macula densa. All three of these factors are frequently present in patients with congestive heart failure. Further- more, diuretic usage is extremely common in such patients and may contribute directly to the observed rise in renin activity in this group. Renin, in turn, converts an angioten- sinogen made in the liver to angiotensin 1. which is an inactive decapeptide. Angiotensin I is then converted to angiotensin II by converting enzyme. Converting enzyme is located everywhere in the body but appears to predominate in pulmonary capillary endothelial cells.

Angiotensin II has three effects that may be deleterious to patients with congestive heart failure. First, it is a potent vasoconstrictor that may contribute to excess systemic vascular resistance. Second, it tends to facilitate sympathetic outflow that may contribute to the already elevated levels of plasma catecholamines. Third, it feeds back on the adrenal gland to release aldosterone and thus further contributes to the increased salt retention seen in patients with heart failure. Patients with a low serum sodium level appear to have the highest renin levels (38). They are also the patients who have the highest mortality rate (39) and may be the most respon- sive to the angiotensin-converting enzyme inhibitors.

Antagonists to the three neurohormonal systems. The relative importance of the three vasoconstrictor hormone systems was evaluated in a study by Creager et al. (40) (Fig. 3). In that study, patients were given antagonists to the three neurohormonal systems to counteract their vasoconstriction. The resultant hemodynamic response, therefore, represents the ability to reverse the adverse hemodynamic effects of these systems. On average, the antagonist to arginine vasopressin produced only minimal hemodynamic changes. Captopril, which interferes with the renin- angiotensin system, produced moderate beneficial hemodynamic effects, including an increase in cardiac output and a reduction in filling pressures. The greatest changes in hemodynamics were produced by an alpha-adrenergic blocker (phentolamine), which antagonized the peripheral vasocon-

-40 t

BP SVR cx SVI HR LVFP RAP

Figure 3. Effects of antagonists to three neurohormonal systems in patients with congestive heart failure. The percent change in hemodynamic values is shown with the administration of the three antagonists. The percent change was least with the arginine vasopressin (AVP) antagonist and greatest with the alpha-adrenergic blocker, phentolamine. Changes with captopril were intermediate. See text for discussion. Reprinted with permission from Creager et al. (40). BP = blood pressure; CI = cardiac index; HR = heart rate; LVFP = left ventricular filling pressure; RAP = right atrial pressure: SW = stroke volume index: SVR = systemic vascular resistance.

strictive effects of increased catecholamines. This produced the greatest change in forward cardiac output and the greatest reduction in filling pressures. These findings suggest that the relative effects of vasoconstriction are produced in order by 1) excess sympathetic stimulation and catecholamines, 2) the renin-angiotensin-aldosterone system, and 3) the arginine vasopressin system.

Peripheral vascular changes: alterations in regional flow. Several peripheral vascular changes accompany the heart failure state. In addition to the increase in systemic vascular resistance, some studies (41) have suggested that there is an inability of the peripheral vasculature to dilate normally in response to stimuli such as hyperemia after transient vascular occlusion. A blunting of the baroreceptor mechanism has also been found and may explain why some vasodilator drugs do not result ‘in an increase in heart rate in the same way that they do in patients with normal ventricular function. A limitation of cardiac output requires that regional flows be preserved for vital organs such as the heart and brain, whereas there may be a substantial reduction of the circulation in the skin, splanchnic bed, skeletal muscle and kidney (42). These alterations in regional flow may contribute greatly to some of the associated signs and symptoms accompanying severe congestive heart failure. In addition to arteriolar vasoconstriction, there is also venoconstriction especially due to increased catecholamines.

Compensatory Mechanisms The four primary determinants of cardiac function are

preload, afterload, contractility and heart rate. There is

776 PARMLEY JACC Vol. 13, No. 4 PATHOPHYSIOLOGY AND THERAPY OF HEART FAILURE March 15, 1989:771GG

______

Figure 4. Two interrelated vicious cycles in congestive heart failure. Left panel, the impairment of left ventricular (LV) function leads to a decrease in cardiac output. In turn, this leads to a reflex increase in systemic vascular resistance by the neurohormonal mechanisms that were described in Figure 3. This in turn, increases the effective afterload of the left ventricle and further reduces stroke volume. Right panel, a reduction in cardiac output and arterial pressure leads to a decrease in renal perfusion. This activates the renin-angiotensin-aldosterone system. Overall, there is retention of salt (NaCl) and water (H,O) leading to a further increase in filling pressure and to peripheral edema. These vicious cycles therefore can feed back on each other to worsen the heart failure state. Reprinted with permission from McCall et al. (43).

evidence that each of these mechanisms may provide some compensation for the failing circulatory system, especially early in its course. An important concept, however, devel- oped over the past decade, is that these compensatory mechanisms can overshoot and become deleterious (43).

Overshoot of compensatory mechanisms. The increase in extracellular volume that occurs through retention of sodium and water is initially helpful in augmenting preload and thus increasing stroke volume by the Frank-Starling mechanism. Clearly, this mechanism overshoots when increased atria1 pressures produce pulmonary or systemic congestion, or both. This overshoot then must be appropriately treated with diuretics or venodilators, or both. An increase in systemic vascular resistance, as an index of afterload, is initially helpful in maintaining blood pressure despite a decrease in cardiac output. It is clear, however, that this increase in systemic vascular resistance may eventually become harmful as shown by the beneficial effects of arteriolar vasodilators that can dramatically increase forward cardiac output. It is also clear that an increase in contractility can be beneficial in maintaining cardiac function. The increase in catecholamines that is required to produce this increase in contractility, however, may be too great and produce damage to heart muscle and result in arrhythmias. Heart rate is one of the most important compensatory mechanisms available to the circulation. With a decline in stroke volume, an increase in heart rate is essential to maintain a reasonably normal cardiac output. As heart rate increases, however, not only does it increase myocardial oxygen demand but also it impinges on diastolic time during which coronary flow can occur. Excess tachycardia, therefore, may contribute di-

rectly to continuing cardiac damage, by causing an imbalance between myocardial oxygen supply and demand.

Deleterious vicious cycles contributing to heart failure. This overshoot in compensatory mechanisms can produce vicious cycles such as those illustrated in Figure 4. The decline in cardiac contractility leads, by potent neurohumoral mechanisms, to an increase in systemic vascular resistance. This increased resistance can act as an increased afterload and impedance to ejection, and thus further reduce cardiac output. The downward spiral continues until a new low steady state level is reached at which cardiac output is lower and systemic resistance higher than is optimal for the circulation. Similarly, a reduction in cardiac output contributes to decreased renal perfusion, which also leads to an increase in salt and water retention. In excess, this can also worsen the heart failure state and contribute to a further downward spiral. It is clear that a complex interaction of a number of factors contributes to the development of heart failure. It is therefore possible for a variety of interventions to counteract the overshoot and thus beneficially affect cardiac function.

Therapeutic Approach to Congestive Heart Failure (Table 3)

After one has identified the syndrome of congestive heart failure, it is mandatory to determine its cause and to assess the relative contribution of diastolic dysfunction. These steps may indicate the need for therapeutic interventions apart from the pharmacologic treatment to be described later. For example, patients with severe aortic stenosis need replacement of the aortic valve. Similarly, patients with other types of valvular disease may be benefited by appro-

Table 3. Therapeutic Approach to Congestive Heart Failure

1. Determine the etiology 2. Evaluate relative importance of diastolic dysfunction 3. Surgical correction where possible 4. Nonpharmacologic treatment

A] Reduce salt intake; avoid salt excess B) Reduce physical and emotional stress

5. Pharmacologic approach A) Either diuretic, digoxin or vasodilator as first line therapy B) Add second and third drugs as necessary C) Vasodilators are generally used because they can prolong life

1) ACE inhibitors 2) Combination of hydralazine and isosorbide dinitrate

D) Add potent inotropic agents if the above is ineffective I) Intermittent dobutamine 2) Phosphodiesterase inhibitors

E) For dilated cardiomyopathy consider low dose metoprolol 6. Consider heart transplant for appropriate patients with end-stage heart

failure

ACE = angiotensin-converting enzyme.

JACC Vol. 13, No. 4 PARMLEY 777 March 15, 1989:771-x5 PATHOPHYSIOLOGY AND THERAPY OF HEART FAILURE

priate valve replacement or repair. In patients in whom ischemia is an important factor, revascularization proce- dures or antiischemic therapy may be of great benefit in alleviating some of the signs and symptoms of congestive heart failure, especially those that are transient and due to intermittent myocardial ischemia.

Nonsurgical, nonpharmacologic approaches. In some patients who do not need (or cannot undergo) surgical correction, a variety of nonpharmacologic approaches should be considered. Reduction of the work load of the heart by reducing overall activity, including both emotional and physical stress, can be of great benefit to some patients. Salt restriction and avoidance of salt overload can be useful in patients who are prone to retention of fluid and whose symptoms appear to be closely linked to an increase in extracellular volume. A number of specific, although rare, circumstances must also be addressed. For example, hyper- thyroidism can contribute dramatically to deterioration in patients who have an underlying cause for heart failure. Similarly, anemia and other causes of high cardiac output (44) may contribute to the borderline compensation seen in some patients. When attention has been paid to these nonpharmacologic approaches to therapy, one can then consider the use of drugs from the three major classes of antifailure drugs now available-the diuretics, inotropic agents and vasodilator drugs. These will be discussed in the sections that follow.

Diuretics Under normal circumstances, renal plasma flow is ap-

proximately 10% of the cardiac output and thus is about 500 mlimin (45). When mean arterial pressure ranges from about 80 to 200 mm Hg, glomerular filtration rate is kept approximately constant by autoregulation. Below these levels, however, renal blood flow is decreased as arterial pressure is decreased and glomerular filtration may stop at an arterial pressure of about 40 mm Hg. In general, about 20% of the plasma that enters the glomerulus is filtered and, as an end result, about 1% of the filtrate is excreted in the urine. In patients with congestive heart failure, there is a reduction in cardiac output and arterial pressure. The renal response to this hemodynamic change is retention of salt and water. This has led to the use of diuretics as the most practical way of improving diuresis. Not only can diuretics be effective in increasing salt and water excretion, but, for example, when given intravenously, furosemide directly increases venous capacitance and can acutely reduce left ventricular filling pressure by redistributing blood away from the chest (46).

Choice of diuretic. It is reasonable to begin treatment of congestive heart failure with a thiazide diuretic. Usually, however, a more potent loop diuretic will eventually be needed by patients who have at least moderate heart failure. Attention must be paid to electrolyte imbalance in patients

with congestive heart failure because hypokalemia and hy- pomagnesemia can lead to serious arrhythmias, especially in patients who are taking digitalis. Potassium supplementation is frequently required in patients with congestive heart failure who are taking potent diuretics. Alternatively, a potassium-retaining diuretic might be considered. It should be remembered, however, that the angiotensin-converting enzyme inhibitors retain potassium. Therefore, it is important to discontinue potassium-retaining diuretics and potassium supplementation in patients receiving angiotensin- converting enzyme inhibitors. In patients who become refractory to loop diuretics, one may get additional benefit by adding a thiazide such as metolazone (47). The fact that the two classes of diuretics work at different places in the nephron appears to explain their synergistic effect, which may be quite dramatic in some patients.

Clinical effect. Long-term experience has shown that diuretics can be extremely effective in some patients with congestive heart failure. They certainly are required in patients whose peripheral edema and excess fluid retention become major components of the syndrome of heart failure. Although we have no firm data suggesting that diuretics can prolong life in patients with heart failure, it is intuitive that these agents have been beneficial in alleviating symptoms and. in some circumstances, had the appropriate studies been done, they might have been found to have contributed to longevity.

Digitalis

Inotropic Agents

The most commonly used inotropic agent is digitalis. Numerous questions have arisen over the past few years about the potential benefit of digitalis and have probably led to a decline in its use, particularly in the United Kingdom. In the United States, however, digitalis is still a commonly used agent. It is effective in patients who have atria1 fibrillation and a rapid ventricular response. A reduction in the ventricular rate. together with a positive inotropic effect, are generally quite beneficial in these patients. The greatest controversy, however, has arisen about the use of digitalis in patients with congestive heart failure and sinus rhythm. In some studies of such patients discontinuation of digitalis produced no detrimental effects (48,49). In other studies of such patients (50) the patients’ heart failure clearly deterio- rated (50) after withdrawal of digitalis. In a double blind placebo-controlled crossover study. Lee et al. (51) compared the effects of digoxin and placebo in 25 outpatients with sinus rhythm. In general, there was benefit in patients with a dilated heart, a reduced ejection fraction and a third sound gallop. Other studies with digitalis have also suggested that this drug may be more beneficial in sicker patients as compared with patients with mild heart failure. Dobbs et al. (52) reported a double blind crossover comparison of digi-

778 PARMLEY JACC Vol. 13, No. 4 PATHOPHYSIOLOGY AND THERAPY OF HEART FAILURE March 15, 1989:771G35

talis versus placebo in 46 patients with sinus rhythm. Ap- proximately 33% of the patients receiving placebo showed deterioration that was followed by improvement after the reintroduction of digitalis therapy.

Clinical application. Overall, the data suggest that digitalis has modest beneficial effects in patients with congestive heart failure (53) and that these effects are probably of greater benefit as the heart failure becomes worse. Certainly, it has no benefit in patients with diastolic dysfunction when ejection fraction is preserved. It must also be used with caution in elderly patients, in whom toxicity may be a greater problem. Dose-response relations must be carefully considered as renal function becomes impaired because digoxin is cleared primarily by the kidney. Within these constraints, however, it appears that digoxin still has value in patients with sinus rhythm and congestive heart failure.

Toxicity and mortality. Some studies (54,55), however, have suggested that patient mortality may be increased by the administration of digoxin, especially after myocardial infarction. Other studies (56) in patients with coronary artery disease have not confirmed this finding. Nevertheless, the known toxicity of this agent raises important questions about its long-term effects. A proposed multicenter study to assess the effect of digoxin on mortality in congestive heart failure will soon be underway to provide a more definitive answer to this question. Until that time, however, it appears reasonable to consider digoxin for its modest inotropic support to the heart in an appropriate clinical setting.

Combination therapy. More recent studies have raised the question as to whether or not vasodilator therapy might be appropriately started before digoxin therapy. In the recent captopril-digoxin study (57), captopril was more effective in increasing exercise tolerance than was digoxin, whereas digoxin was more effective in increasing ejection fraction than was captopril. This study suggests that one can consider all three classes of drugs as initial therapy for heart failure. Thus, depending on the individual patient, one might want to begin treatment with a diuretic, an inotropic agent like digitalis or a vasodilator drug. Combination therapy may be more effective than either class alone.

Phosphodiesterase Inhibitors There has been considerable interest in the phosphodies-

terase inhibitors, which are potent inotropic agents and vasodilators (58). Inhibition of phosphodiesterase leads to an increase in cyclic adenosine monophosphate (AMP), which enhances calcium entry and thus improves contractility. These agents are also potent peripheral vasodilators, and produce significant hemodynamic effects in patients with heart failure. When given on a short-term basis to patients with heart failure, they result in an increase in cardiac output and a reduction in atria1 pressures (59). Similarly, exercise tolerance is increased acutely in most studies (60). Despite

these short-term beneficial effects, however, these drugs (amrinone and milrenone) are not yet available for oral use in the United States. Part of the uncertainty regarding their use relates to the long-term effects of these agents, both on exercise tolerance and on mortality (61). Until appropriate studies can clearly define a long-term clinical benefit or a reduction in mortality, these agents are best reserved for patients who have not responded in a beneficial fashion to usual therapy but continue to require some pharmacologic support to maintain an appropriate quality of life or to remain outside of the hospital.

Oral Catecholamines

A number of oral catecholamines have been used in patients with heart failure; these include L-dopa, pirbuterol, prenalterol and salbutamol (62-65). It appears that these agents can produce short-term beneficia! hemodynamic effects. However, a high side effect profile and problems with arrhythmias and potential sudden death have raised serious questions about the use of such agents in patients with congestive heart failure. Intermittent dobutamine in some controlled studies (66) has shown prolonged benefit in such patients. Short-term infusions for 24 to 72 h have been shown to improve both exercise time and ejection fraction over a subsequent period up to 4 weeks. Although the mechanism of this benefit is unclear, a potential training effect has been implicated as has an improvement in mitochondrial function. A recent multicenter study of patients with heart failure treated at home with dobutamine was stopped because of an increase in serious arrhythmias in the treated group. It appears, therefore, that this form of therapy is best administered in a controlled hospital setting.

Overall, it is clear that inotropic agents are much like a double-edged sword; although they can increase hemodynamics and exercise tolerance, their other effects may be potentially harmful to the patient. These include an increase in oxygen consumption, the generation of arrhythmias and the potential for more rapid deterioration of muscle function. It is less certain, therefore, about the long-term role of potent inotropic agents in the management of severe heart failure.

Vasodilator Drugs

Arteriolar Vasodiiators Hydralazine. As illustrated in Figure 4, a major compo-

nent of the vicious cycle in congestive heart failure is an excess increase in systemic vascular resistance. This increase sets the stage for arteriolar vasodilators, which can decrease systemic resistance and increase cardiac output. Hydralazine is the prototypic agent that has been used in this regard. When administered to patients with severe congestive heart failure, hydralazine increases cardiac output ap-

JACC Vol. 13. No. 4 PARMLEY March 15. 1989:771-X> PATHOPHYSIOLOGY AND THERAPY OF HEART FAILURE

779

proximately 50% in association with a concomitant reduction in systemic vascular resistance (67). In general, there is little change or a slight decrease in atrial pressures with hydralazine therapy. This pharmacologic result underscores the reality of the vicious cycle in congestive heart failure, where neurohumoral mechanisms have overshot in their compensatory response and set systemic vascular resistance too high. On the other hand, it is clear that this increase in cardiac output may not necessarily be directed to organs that need it. For example, in a placebo-controlled trial (68) examining the effects of hydralazine on exercise tolerance, hydralazine or placebo was given to patients with moderate heart failure already receiving digitalis and diuretics. Over several weeks there was a slight improvement in the exercise tolerance of the hydralazine-treated patients, but it was no greater than the improvement in exercise tolerance seen in the patients receiving placebo. Thus, this arteriolar vasodilator was effective in increasing cardiac output but ineffective in improving exercise tolerance.

Hydralazine has been used with some effectiveness, however, in unloading the ventricle in patients with volume overload due to valvular regurgitation (69). Hydralazine is effective in both mitral and aortic regurgitation in this regard. In patients who are still asymptomatic but with moderate volume overload due to valvular regurgitation, it seems intuitive that, if one could unload the ventricle, one might delay the rate at which the ventricle dilates and therefore delay the onset of irreversible changes in ventricular function.

In patients with aortic regurgitation it appears that hydralazine may be of some benefit in this regard (70). It should be emphasized, however, that unloading therapy should never act as a substitute for surgical replacement of the valve. When severe changes in contractility occur, they appear to be mostly irreversible.

The effective dose of hydralazine is generally between 200 to 300 mglday given in divided doses. Hydralazine is metab- olized by acetylation. Approximately 50% of the United States population are rapid acetylators and half are slow acetylators. In rapid acetylators, higher doses of hydralazine may be required. Similarly, the lupus syndrome tends to occur primarly in patients who are slow acetylators. The primary side effects of hydralazine are related to the gastro- intestinal tract and require discontinuation of this drug in a fair proportion of patients.

Minoxidil. Another potent arteriolar vasodilator that has been evaluated in congestive heart failure is minoxidil, which is approved for the treatment of resistant hypertension. The hemodynamic effects of minoxidil are similar to those of hydralazine (71). The drug produces a substantial increase in cardiac output, together with a minor decrease in atria1 pressures. In a placebo-controlled trial (72), however, minoxidil did not increase exercise tolerance as compared with placebo. Side effects included sodium retention and hair

growth, the latter being quite troublesome to female patients. Results with these two arteriolar vasodilators suggest a simple but important principle. namely, that arteriolar vasodilators do not increase exercise tolerance, although they are effective in increasing cardiac output.

Venodilators

Nitrates. Nitrates are the prototypic venodilators (73); they are available in many preparations, including sublingual, oral and transdermal. If given in effective doses, they can reduce atria1 pressures, presumably by dilating peripheral veins and redistributing blood so that more is in the peripheral veins and less in the chest. When nitrates are given to individuals with normal filling pressures, filling pressures frequently become too low and hypotension and tachycardia result. In patients with congestive heart failure, however, this is not a problem. Nitrates generally do not produce tachycardia in patients with congestive heart failure.

The nitrates have produced an improvement in exercise tolerance in patients with congestive heart failure, as compared with those receiving placebo (74,75). This appears to be true of virtually all agents that lower atria1 pressures. Thus, venodilators that lower atria1 pressures not only are effective in relieving dyspnea, but also are effective in improving exercise tolerance in patients with congestive heart failure.

Combination therapy. The fact that arteriolar vasodilators can increase cardiac output and that venodilators can reduce filling pressures has led to their combined use in patients with congestive heart failure (76). This combination was able to prolong life in patients with moderate heart failure in the V-HEFT trial (77). This trial was the first trial to demonstrate that vasodilator therapy could prolong life in patients with congestive heart failure and therefore becomes a landmark trial in encouraging physicians to use vasodilators relatively commonly in the management of patients with congestive heart failure.

Nitrate dosage and administration. The usual doses of isosorbide dinitrate range from 20 to 80 mg four times daily. Patches are generally ineffective at usual doses (78) and, even when they are given at high doses, one must employ a nitrate free interval to retain responsiveness to the drug. Shorter-acting forms of nitrates such as sublingual nitroglycerin can be effective for short-term episodes of dyspnea or ischemia. Nitroglycerin ointment can be effective in some patients whose dyspnea occurs primarily during the sleeping hours.

Drugs With Combined Arteriolar arid Venodilating Effects

Prazosin. The prototypic drug in this category is prazosin, which is an alpha, receptor blocker and can produce

780 PARMLEY PATHOPHYSIOLOGY AND THERAPY OF HEART FAILURE

JACC Vol. 13, No. 4 March 15, 1989:771-85

0.8

1 0.7

Figure 5. Cumulative total mortality in the CONSEN- SUS trial. The enalapril-treated patients showed a sta- tistically significant reduction in mortality as compared with placebo-treated patients. This was most marked in the first 3 months, with the curves remaining relatively parallel thereafter. Reprinted with permission from the CONSENSUS Trial Study Group (85).

o I 2 3 4 5 8 7 8 Q 10 Months

both arteriolar and venous dilation (79). Studies with prazosin have shown that it can reduce filling pressures and increase cardiac output, and thus produce the same hemodynamic effects as those of combined hydralazine and isosorbide dinitrate. Unfortunately, there appears to be a hemodynamic tachyphylaxis with prazosin, such that there are no sustained long-term effects (80). This may explain why prazosin was ineffective in the V-HEFT trial in prolonging life compared with placebo (77). Because of this hemodynamic tachyphylaxis and inability to prolong life, prazosin does not appear to have a role in the management of congestive heart failure as compared with the combination of hydralazine plus isosorbide dinitrate, and the angiotensin- converting enzyme inhibitors.

Angiotensin-Converting Enzyme Inhibitors

Captopril, enalapril and lisinopril. These agents have been extremely effective in managing congestive heart failure and appear to represent the vasodilators of choice at present (81). They currently are the three angiotensin- converting enzyme inhibitors available in the United States. The benefit produced by these drugs underscores the concept that the renin-angiotensin-aldosterone system has overshot in patients with congestive heart failure and can produce adverse hemodynamic effects. It should be remembered that diuretics and arteriolar vasodilators acti- vate this system and thus help to set the stage for the use of angiotensin-converting enzyme inhibitors. The short-term administration of these agents to patients with congestive heart failure produces a reduction in blood pressure and systemic vascular resistance and a striking reduction in left and right atria1 pressures. This is accompanied by a modest increase in cardiac output (82). Of some importance is the ability of angiotensin-converting enzyme inhibitors to in-

crease exercise tolerance in patients with congestive heart failure (83). This improvement in exercise tolerance occurs over a period of several weeks, which is different, for example, from the short-term improvement in exercise tolerance that occurs with the potent inotropic agents such as dobutamine or the phosphodiesterase inhibitors (84). More important, this improvement in exercise tolerance appears to be accompanied by an improvement in patient well-being and quality of life. The angiotensin-converting enzyme inhibitors have especially become popular because of their demonstrated effect in prolonging life in the CONSENSUS trial (85). In this trial, patients with severe heart failure (mostly functional class IV) had either an angiotensin- converting enzyme inhibitor (enalapril) or placebo added to their regimen; there was a reduction in mortality in the enalapril-treated group (Fig. 5). A review of some of the captopril data (86) suggests a similar beneficial effect on mortality. It is likely that all of the angiotensin-converting enzyme inhibitors will have generally similar effects, although their short-term effects may be slightly different, in part related to the time course of their action (87).

Dosage. An important aspect of the angiotensin- converting enzyme inhibitors is their dose response relation (81). When one has achieved inhibition of converting enzyme, one has reached the appropriate therapeutic dose. This makes it relatively easy to titrate the angiotensin- converting enzyme inhibitors to an appropriate level. One starts with a low dose to avoid or minimize hypotensive effects and then gradually works up to a standard dose. This would be approximately 25 mg three times daily of captopril, 5 to 10 mg twice daily of enalapril and 10 to 20 mg once daily of lisinopril. The newest of these agents, lisinopril, is a long-acting angiotensin-converting enzyme inhibitor and will thus have the advantage of being given only once daily, which may well improve patient compliance (88).

JACC Vol. 13. No. 4 PARMLEY 781 March 15. 1989:771-X5 PATHOPHYSIOLOGY AND THERAPY OF HEART FAILURE

Combination Therapy Selection of drugs for new onset congestive failure. In the

past a step-care approach to the management of heart failure has been suggested. This step-care approach generally included starting with a diuretic and then adding digoxin if necesary. This was followed by the addition of vasodilators if digoxin and diuretics were ineffective together. Recent studies (57), however, have suggested that the vasodilators may be appropriate alternatives to digoxin for first-line therapy. The following approach, therefore, is suggested for patients with new onset congestive heart failure (Table 3). If the patient has evidence of volume excess or systemic or pulmonary edema, it is likely that diuretics will be required as a permanent part of the therapy of these patients. It makes sense, therefore, to start with the diuretics as first-line therapy and then to add other drugs as appropriate. In patients with left ventricular dysfunction or early signs of congestive heart failure, there is important evidence that unloading therapy with the angiotensin-converting enzyme inhibitors may alter remodeling and slow the intrinsic decline in cardiac contractility (12). Thus, vasodilator therapy can be considered much earlier than in the past, and may prove useful in the earliest forms of heart failure to unload the ventricle. On the other hand, digoxin appears to be most effective in patients who have more severe heart failure (5 I ). The benefit of its use in mild heart failure is less certain.

Thus, this approach would consider any of the three classes of drugs as potential first-line therapy in patients with heart failure. Additional classes would be added as needed because of their demonstrated additive effects. For example, digoxin added to captopril has been shown to improve hemodynamics in patients with congestive heart failure (89). Similarly, hydralazine as an arteriolar vasodilator when added to captopril has been shown to be beneficial in further improving cardiac output (90).

Effect on survival. In selecting drugs one must remember that only the vasodilators have shown a prolongation of life in placebo-controlled trials (91). In the V-HEFT trial. the combination of hydralazine plus isosorbide dinitrate was effective in prolonging life in the treatment group as compared with the patients receiving placebo or prazosin (77). All had moderate heart failure and baseline therapy of digitalis and diuretics. In the CONSENSUS trial (85) enalapril was effective in prolonging life in patients with severe heart failure (Fig. 5). Thus. vasodilators have been shown to prolong life in patients with both moderate and severe heart failure. Because of their potential benefit in mild heart failure, or even in left ventricular dysfunction, it appears that a vasodilator regimen may emerge as core therapy for patients with all stages of congestive heart failure. Because of their potential beneficial effects they should be used in patients with severe heart failure unless there are contrain- dications such as renal insufficiency.

I = lnotropic Agent V = Vasodilator D = Diuretic

II i LeH Ventricular Fllhng Pressure .

Figure 6. Conceptual ventricular function curves showing the effects of single and combined therapy for congestive heart failure. Note that the individual beneficial effects of each of the three classes of drugs are additive when additional drugs are given. This sets the stage for the use of all three classes of drugs to provide maximal beneficial hemodynamic effects in patients with congestive heart failure.

Hemodynamic effects. In virtually all studies in which combination therapy with different classes of drugs has been used. it appears that their hemodynamic effects are generally additive. Thus, in patients with severe heart failure it makes good sense to consider the combination of diuretics, inotro- pit agents and vasodilators to maxmimize beneficial hemodynamic effects. This is conceptually shown in Figure 6. In general, therefore, one can start with any of the classes of drugs as suggested above and then gradually add other classes as the heart failure worsens so that patients are eventually receiving all three types of antifailure therapy.

Antiarrhythmic Drugs The mode of death in patients with severe heart failure is

sudden approximately 40% of the time (5). Studies (92) with Holter electrocardiographic (ECG) monitors in patients with congestive heart failure have demonstrated that arrhythmias occur in approximately 90% of patients and that non- sustained ventricular tachycardia or multifocal premature ventricular complexes are relatively common. The data suggest that arrhythmias add independently to an adverse prognosis in patients with congestive heart failure (93) although the level of left ventricular dysfunction remains the most important adverse prognostic factor. It has therefore been reasonable to consider some form of antiarrhythmic therapy in patients with severe heart failure and associated serious arrhythmias. The value of this therapy is uncertain at present. The following discussion represents potential direc- tions that one might take until more definitive data are available.

Reduction of proarrhythmic factors. It seems prudent initially to reduce or eliminate all proarrhythmic factors (94) that can be recognized (Table 4). These might include adverse effects of inotropic agents, such as digitalis in the presence of hypokalemia. Electrolyte imbalance should be

782 PARMLEY JACC Vol. 13, No. 4 PATHOPHYSIOLOGY AND THERAPY OF HEART FAILURE March 15, 1989:771-U

Table 4. Proarrhythmic Factors in Congestive Heart Failure

I. Arrhythmogenic effects of positive inotropic agents 2. Electrolyte imbalance 3. Ischemia 4. High cathecholamines 5. Myocardial damage 6. Myocardial stretch 7. Hypotension 8. Proarrhythmic effects of antiarrhythmic agents

corrected wherever possible. lschemia can be an important contributory factor to prognosis, and can be treated with appropriate anti-ischemic agents such as nitrates. High catecholamine levels may also contribute to arrhythmias. In patients with severe heart failure it would be difficult to consider using beta-blockers or calcium channel blockers as antianginal agents, although such therapy could be used in patients with less severe congestive heart failure. Because of the evidence that increased stretch might play a role in producing arrhythmias in heart failure, vasodilator therapy may be helpful in eliminating this proarrhythmic factor. Placebo-controlled trials with the angiotensin-converting enzyme inhibitors have shown a reduction in premature ventricular complexes in patients with severe heart failure (5735). Although there was no reduction in sudden death in the CONSENSUS trial (85) it still may be that reduction of premature ventricular complexes with the angiotensin- converting enzyme inhibitors could be of benefit in some patients with excess arrhythmias. The mechanism of reduced premature ventricular complexes with the angiotensin-converting enzyme inhibitors is unknown. Factors that might contribute, however, would include an increase in serum potassium, which is frequently seen with the angiotensin-converting enzyme inhibitors; unloading of the ventricle, which may reduce stretch-induced arrhythmias or ischemia; a decrease in myocardial oxygen consumption, which could also decrease episodes of ischemia; and a withdrawal of sympathetic tone. These or other factors may contribute to this beneficial antiarrhythmic effect.

Indications for antiarrhythmic therapy. When all proarrhythmic factors have been ruled out and a patient with congestive heart failure still has serious arrhythmias the physician must make a decision whether to treat the arrhythmia. One must remember that, in general, antiarrhythmic therapy has a proarrhythmic effect that is seen in approximately 10% of patients, a figure that may, in fact, be closer to 20% in patients with severe heart failure (94). In addition, studies (95) have shown that the efficacy of antiarrhythmic agents appears to be proportionally less as the degree of heart failure increases. At the present time, we do not have any placebo-controlled trials to suggest that antiarrhythmic therapy can prolong life, although such trials are either underway or in the planning stage. The physician is therefore left to his best judgment in regard to antiarrhythmic therapy.

Effect on survival. In a retrospective review (96) of the data in a group of patients whom we treated with potent oral inotropic agents (phosphodiesterase inhibitors) we noted that sudden death appeared to occur less often in patients treated with antiarrhythmic agents as those in patients not so treated. Cleland et al. (97) also suggested that the drug amiodarone may be effective in prolonging life in patients with severe heart failure and arrhythmias. Although such data are uncontrolled, they do suggest the possibility that antiarrhythmic drugs may be of some benefit. Certainly the toxic effects of amiodarone become less important in patients with severe heart failure when life span is generally shortened. Until well controlled studies are available, however, physician judgment must be used in the absence of firm data in determining whether to use antiarrhythmic therapy in selected patients.

Summary In conclusion, we have learned a tremendous amount

about the pathophysiology of congestive heart failure over the past 2 decades. One of the most important principles that has emerged is that compensatory mechanisms that are initially helpful may subsequently become deleterious. Counter- acting these compensatory mechanisms has formed one of the most important therapeutic approaches to patients with congestive heart failure. Of the three classes of drugs available to treat congestive heart failure, the vasodilator drugs have emerged as the most important, especially because of their demonstrated ability to prolong life. Of the available vasodilator drugs, the angiotensin-converting enzyme inhibitors have emerged as the most important single class of drugs to consider in patients with heart failure. Because of the additive effects of all three classes of drugs, it is reasonable to start with one agent and then sequentially add others as required so that most patients with severe heart failure will be receiving a combination of a diuretic, an inotropic agent and a vasodilator drug. The role of antiarrhythmic agents is not settled as yet, although the prevalence of severe arrhythmias and sudden death suggests the possibility that these agents may be of benefit to some patients with congestive heart failure and serious arrhythmias.

In looking to thefuture, it is clear that prevention of heart failure should be one of our most important goals as physicians. As with any disease, preventive measures are far more effective in the long run than is treating the end stage of the disease. Because coronary artery disease is the most common cause of congestive heart failure in the United States, preventive measures will be closely linked to the ability to control and alter risk factors in a way that will reduce the incidence of coronary disease and the damaging effects of myocardial infarction. Revascularization proce- dures both during acute infarction and in chronic coronary disease may also delay the adverse effects of myocardial

JACC Vol. 13, No. 4 PARMLEY March 15. 1989:771-X5 PATHOPHYSIOLOGY AND THERAPY OF HEART FAILURE

783

damage in this syndrome. Unloading agents early in the course of left ventricular dysfunction may also prove to be an effective way to delay the onset of heart failure. It is likely that this emphasis on prevention will, over time, produce greater benefit than the current benefit seen with the use of drugs in patients with established congestive heart failure.

I.

2.

3.

4.

6.

7.

8.

9.

10.

11

12.

13.

14.

15.

16.

17.

18.

19.

References Cohn JN, ed. Drug Treatment of Heart Failure. Advanced Therapeutics Communications. Secaucus. New Jersey, 1988.

McFate-Smith W. Epidemiology of congestive heart failure. Am J Cardiol 1985;55:3-8A.

Savage DD, Garrison RJ, Kannel WB, et al. The spectrum of left ventricuar hypertrophy in a general population sample-the Framingham study. Circulation 1983:68(suppl III):III-36.

McKee PA. Castelli WP, McNamara PM. et al. The natural history of congestive heart failure: The Framingham study. N Engl J Med 1971:2X5: 1441-6

Francis GS. Development of arrhythmias in the patient with congestive heart failure: pathophysiology, prevalence, and prognosis. Am J Cardiol 1986;57:3-7B.

Stamler J. Epidemtology, established major risk factors. and the primary prevention of coronary heart disease. In: Parmley WW, Chatterjee K. eds Cardiology, Vol. 2, Ch 1. Philadelphia: JB Lippincott Company. 1988.

Kannel WB. Castelli WP. McNamara PM. Role of blood pressure in the development of congestive heart failure: the Framingham Study. N Engl J Med 1972;287:781-7.

Franciosa JA, Wilen M, Ziesche S, et al. Survival in men with severe chronic left ventricular failure due to either coronary heart disease or idiopathic dilated cardiomyopathy. Am J Cardiol 198315 I:83 l-6.

Sonnenblick EH. Yellin E, LeJemtel TH. Congestive heart failure and intact systolic ventricular performance. Heart Failure 1988:4: l&73.

Chatterjee K, Raff G. Anderson D, Parmley WW. Hypertrophic cardiomyopathy-therapy with slow channel inhibiting agents. Prog Cardiovasc Dis 1982;25:193-210.

Wicker P, Fouad FM. Tarazi RC. Effects of antihypertensive treatment of left ventricular hypertrophy and coronary blood flow. In: Ref. 6: Ch 25

Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. New Engl J Med 1988:319:8%.

Spann JF, Covell JW. Eckberg DL, et al. Contractile performance in the hypertrophied and chronically failing cat ventricle. Am J Physiol 1972;2223: I 150-7

Entman ML, Michael LH. Molecular and cellular basis for myocardial failure. In: Ref. 6: Ch 4.

Barany M. ATPase acttvity of myosin correlated with speed of muscle shortening. J Cen Physiol 1967:50:197-201.

Buccino RA, Harris E, Spann JF Jr. et al. Response of myocardial connective tissue to development of experimental hypertrophy. Am J Physiol 1968:216:425-30.

Parmley WW. New approaches to the treatment of congestive heart failure. Circulation (in press).

Whitmer JT, Pankaj K, Solar0 RJ. L Calcium transport properties of cardiac sarcoplasmid reticulum from cardiomyopathic Syrian hamsters (BIO 53.58 and 14.6): evidence for a quantitative defect in dilated myopathic hearts not evidenced in hypertrophic hearts. Circ Res l988;62: 81-5.

Wikman-Coffelt J. Sievers R. Parmley WW. Jasmin G. Verapamil pre- serves adenine nucleotide pool in cardiomyopathic Syrian hamster, Am J Physiol 1986;19:H2?-8.

20.

?I.

22.

23.

24.

2.5.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

31.

38.

39.

40.

Factor SM, Sonnenblick EH. Hypothesis: is congestive cardiomyopathy caused by a hyperreactive myocardial microcirculation (microvascular spasm)? Am J Cardiol 1982:50:1149-52.

Sole MJ, Lien CC. Catecholamines. calcium and cardiomyopathy. Am J Cardiol 1988:62:20-4-46.

Levine TB. Francis GS, Goldsmith SR, et al. Activity of the sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relationship to hemodynamic abnormalities in congestive heart failure. Am J Cardiol 1982;49: 1659-66.

Spann JF Jr. Chidsey CA, Pool PE, et al. Mechanism of norepinephrine depletion in experimental heart failure produced by aortic constriction in guinea pig. Circ Res 1965;17:312.

Pool PE. Covell J. Levitt M et al. Reduction of tyrosine hydroxylase activity in experimental congestive heart failure. Circ Res 1967;20:349.

Bristow MR. Myocardial beta-adrenergic receptor down regulation in heart failure. Int J Cardiol 1984;5:648.

Swedberg K. Hjalmarson A, Waagstein F. et al. Beneficial effects of long-term beta blockade in congestive cardiomyopathy. Br Heart J 1980:44:117.

Rona G. Chappel Cl. Balazs T, Gaudry R. An infarct-like myocardial lesion and other toxic manifestations produced by isoproterenol in the rat. Arch Pathology 1959;67:443-5.

Greenberg B. Massie B, Bristow D. Cheitlin M. Siemienczuk D. et al: Long-term vasodilator therapy of chronic aortic insufficiency: a randomized double-blinded, placebo-controlled clinical trial. Circulation 1988:78: 92-103.

Curtiss C. Cohn NJ. Vrobel T. Role of the renin-angotensin system in the systemic vasoconstriction of chronic congestive heart failure. Circulation 1978:58:763-770.

Goldsmith SR. Francis GS, Cowley AW, et al. Increased plasma arginine vasopressin in patients with congestive heart failure. J Am Coll Cardiol 19X3:1:1385-90.

Cohn JN, Levine TB. Francis GS, et al. Neurohumoral control mecha- msms in congestive heart failure. Am Heart J 1981:509-14.

Goldsmith SR. Francis GS. Levine TB, et al. Regional blood flow response to orthostasis in patients with congestive heart failure. J Am Coll Cardiol 1983:1:1391-5.

Levine TB, Francis GS. Goldsmith SR, et al. Activity of the sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relationship to hemodynamic abnormalities in congestive heart failure. Am J Cardiol 1983:49: 165%6.

Francis GS, Goldsmith SR. Ziesche SM. et al. Response of plasma norepinephrine and epinephrine to dynamic exercise in patients with congestive heart failure. Am J Cardiol 1982:49: 1152-6.

Goldsmith SR, Cowley AW. Francis GS. et al. Arginine vasopressin and the renal response to water loading in congestive heart failure. Am J Cardiol 1986:58:295-9.

Raine AEG. Erne P. Burgisser E, et al. Atrial natriuretic peptide and atrial pressure in patients with congestive heart failure. N Engl J Med 19X6:315:533-7.

Cody RJ. Kubo SH. Atlas SA. et al. Direct demonstration of the vasodildtor properties of atrial natriuretic factor in normal man and heart failure patients tabstr). Clin Res 1986:34:476A.

Packer M. Medina N. Yushak M. Relation between serum sodium concentration and the hemodynamic and clinical responses to converting enzyme inhibition with captopril in severe heart failure. J Am Coil Cardiol. 1984:3: 1035-43.

Packer M. Lee WH, Kessler PD, et al. Role of neurohormonal mechanisms in determining survival in patients with severe chronic heart failure. Circulation 1987:75(suppl IV):IV-8&92.

Creager MA. Faxon DP, Cutler SS, Kohlmann 0, Ryan TJ, Gavras H. Contribution of vasopressin to vasoconstriction in patients with congestive heart failure: comparison with the renin-angiotensin system and the sympathetic nervous system. J Am Coil Cardiol 1986:7:75865.

784 PARMLEY JACC Vol. 13, No. 4 PATHOPHYSIOLOGY AND THERAPY OF HEART FAILURE March 15, 1989:77165

41. Zelis R, Mason DT, Braunwald E. A comparison of the effects of vasodilator stimuli on peripheral resistance vessels in normal subjects and in patients with congestive heart failure. .I Clin Invest 1%8;47:960-70.

42. Just, H, Drexler H, Zelis, R. Regional blood flow in congestive heart failure. Am J Cardiol 198&62:1-l 14E.

43. McCall, D, O’Rourke, R. Congestive heart failure. Mod Cone Card Dis 1985;52:5540.

44. Grossman W, Braunwald E. High cardiac output states. In: Braunwald E, ed. Heart Disease. Philadelphia: WB Saunders, 1988;778-92.

45. Hollenberg NK. The role of the kidney in heart failure. In: Ref. 1:53-72.

46. Dikshit K, Vyden JK, Forrester IS, et al. Renal and extrarenal hemodynamic effects of furosemide in congestive heart failure after acute myocardial infarction. N Engl J Med 197 1;288: 1087.

47. Puschett JB. Physiologic basis for the use of new and older diuretics in congestive heart failure. Cardiovasc Med 1977;2: 119-34.

48. Hull SM, Macintosh A. Discontinuation of maintenance therapy in general practice. Lancet 1977;2: 105&S.

49. Fonrose HA, Ahlbaum N, Bugatch E, et al. The efficacy of digitalis withdrawal in an institutional aged population. J Am Geriatr Sot 1974;22: 208-211.

50. Griffiths BE, Penny WI, Lewis MI, et al. Maintenance of the inotropic effect of digoxin on long-term treatment. Br Med J 1982;284:1819-22.

51. Lee DC, Johnson RA, Bingham JB. Heart failure in out-patients: a randomized trial of digoxin vs. placebo. N Engl J Med 1982;306:699.

52. Dobbs SM, Kenyon WL, Dobbs RJ. Maintenance digoxin after an episode of heart failure: placebo-controlled trial in outpatients. Br Med J 1977;1:749-52.

53. Kimmelstiel C, Benotti JR. How effective is digitalis in the treatment of congestive heart failure. Am Heart 3 1988;116: 1063-70.

54. Bigger JT Jr, Fleiss JL, Rolitsky LM. Merab JB, Ferrick KJ. Effect of digitalis treatment on survival after acute myocardial infarction. Am J Cardiol 1985;55:623.

55. Moss AJ, Davis HT, Conrad DL, DeCamila JJ, Odoroff CL. Digitalis- associated cardiac mortality after myocardial infarction. Circulation 1981;64:1150.

56. Ryan TJ, Bailey KR, McDabe CH, et al. The effects of digitalis on survival in high-risk patients with coronary artery disease. Circulation 1983;67:735.

57. Captopril-Digoxin Multicenter Research Group. Comparative effects of captopril and digoxin in patients with mild to moderate heart failure. JAMA 1988;259:539-44.

58. Francis GS. Inotropic agents in the management of heart failure. In Ref. 1: Ch 8.

59. Kereiakes D, Chatterjee K, Parmley WW, Atherton B, Curran D, Kereiakes A. Intravenous and oral MDL 17043 (a new inotrope- vasodilator agent) in congestive heart failure: hemodynamic and clinical evaluation in 38 patients. J Am Coll Cardiol 1984;4:844.

60. Weber KT, Andrews V, Janicki JS, et al. Amrinone and exercise performance in patients with chronic heart failure. Am J Cardiol 1981;48: 164-9.

61. Packer M, Medina N, Yushak M. Hemodynamic and clinical limitations of long-term inotropic therapy with amrinone in patients with severe chronic heart failure. Circulation 1984;70:1038.

62. Rajfer SL, Anton AH, Rossen JD, et al. Beneficial hemodynamic effects of oral levodopa in heart failure: relation to the generation of dopamine. N Engl J Med 1984;310:1357-62.

63. Rude RE, Turi Z, Brown EJ, et al. Acute effects of oral pirbuterol on congestive heart failure. Circulation 1981;64: 139.

64. Wahr DW, Swedberg K, Rabbino M, et al. Intravenous and oral prenalterol in congestive heart failure. Effects on systemic and coronary hemodynamics and myocardial catecholamine balance. Am J Med 1984;76:999-1055.

65.

66.

61.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

Sharma B, Goodwin JF. Beneficial effect of salbutamol on cardiac function in severe congestive cardiomyopathy. Circulation 1978;58:449.

Liang Chang-Seng, Sherman LG, Doherty JU, Wellington K, Lee VW, Hood WB. Sustained improvement of cardiac function in patients with congestive heart failure after short-term infusion of dobutamine. Circula- tion 1984;69: 113.

Chattejee K, Ports TA, Brundage BH, et al. Oral hydralazine in chronic heart failure: sustained beneficial hemodynamic effects. Ann Intern Med 1980;92:600.

Franciosa JA, Weber KT, Levine TB, et al. Hydralazine in the long-term treatment of chronic heart failure: Lack of difference from placebo. Am Heart J 1982;104:587.

Greenberg BH, Massie BM, Brundage BH, Botvinick EH, Parmley WW, Chattejee K. Beneficial effects of hydralazine in severe mitral regurgitation. Circulation 1978;58:273-9.

Greenberg B, DeMot H, Murphy E, et al. Beneficial effects of hydralazine on rest and exercise hemodynamics in patients with severe aortic insufficiency. Circulation 1980;62:49.

McKay C, Chattejee K, Ports TA, et al. Minoxidil in chronic congestive heart failure: A hemodynamic and clinical study. Am heart J 1982;104: 575.

Franciosa JA, Jordan RA, When MM, et al. Minoxidil in patients with chronic left heart failure: contrasting hemodynamic and clinical effects in a controlled trial. Circulation 1984;70:63.

Franciosa JA, Norstrom LA, Cohn JN. Nitrate therapy for congestive heart failure. J Am Med Assoc 1978;240:443.

Franciosa JA, Goldsmith SR, Cohn JN. Contrasting immediate and long-term effects of isosorbide dinitrate on exercise capacity in congestive heart failure. Am J Med 1980;69:559.

Leier CV, Huss P, Magorien RP, et al. Improved exercise capacity and differing arterial and venous tolerance during chronic isosorbide dinitrate therapy for congestive heart failure. Circulation 1983;67:817.

Massie B, Chatterjee K, Werner J, Greenberg B, Hart R, Parmley WW. Hemodynamic advantage of combined oral hydralazine and nonparenteral nitrates in the vasodilator therapy of chronic heart failure. Am J Cardiol 1977:40:794-801.

Cohn JN, Archibald DG. Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. N Engl J Med 1986;3 14: 1547.

Olivari MT, Cohn JN. Cutaneous administration of nitroglycerin: a review. Pharmacotherapy 1983;3:149-57.

Miller RR, Awan NA, Maxwell KS, et al. Sustained reduction of cardiac impedance and preload in congestive heart failure with the antihypertensive vasodilator, prazosin. N Engl J Med 1977;297:303.

Arnold SB, Williams RL, Ports TA, et al. Attenuation of prazosin effect on cardiac output in chronic heart failure. Ann Intern Med 1979;91:345- 49. Parmley WW. Angiotensin converting-enzyme inhibitors in the treatment of heart failure. In Ref 1: Ch 10, 227-250.

Ader R, Chatterjee K, Ports T, et al. Immediate and sustained hemodynamic and clinical improvement in chronic heart failure by an oral angiotensin-converting enzyme inhibitor. Circulation 1980;61:931-7. Chatterjee K, Parmley WW, Cohn JN, et al. A cooperative multicenter study of captopril in congestive heart failure: hemodynamic effects and long-term response. Am Heart J 1985;llO (suppl 2):439-47. White HD, Ribeiro JP, Hartley LH, Colucci WS. Immediate effects of milrinone on metabolic and sympathetic response to exercise in severe congestive heart failure. Am J Cardiol 1985;56:93. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 1987;316. Dennick LG, Maskin CS, Meyer JH, et al. Enalapril for congestive heart failure (Letter). N Engl J Med 1987;317:1350. Packer M, Lee WH, Yushak M, et al. Comparison of captopril and enalapril in patients with severe chronic heart failure. N Engl J Med 1986;315:847-53.

JACC Vol. 13, No. 4 PARMLEY 785 March 15. 1989:771-XS PATHOPHYSIOLOGY AND THERAPY OF HEART FAILURE

88. Chalmers JP, West MJ. Cyran et al. Placebo controlled study of lisinopril in congestive heart failure: a multicenter study. J Cardiovasc Pharmacol 1987;9 (suppl 3):589-97.

89. Gheorghiade M. St. Clair. J. St. Clair. C. Belier. GA. Hemodynamic effects of intravenous digoxin in patients with severe heart failure initially treated with diuretics and vasodilators. J Am Coll Cardiol 1987:9:849-57.

90. Massie BM. Packer M. Hanlon JT. et al. Hemodynamic responses to combined therapy with captopril and hydralazine in patients with severe heart failure. J Am Coil Cardiol 1983:2:338-44.

91. Packer M. Vasodilator and inotropic drugs for the treatment of chronic heart failure: distinguishing hype from hope. J Am Coil Cardiol 1988:12: 1299-317.

92. Francis GS. Development of arrhythmias in the patient with congestive

93.

94.

95.

96.

97.

heart failure: pathophysiology. prevalence, and prognosis. Am J Cardiol 1986:57:3B-78.

The CAPS Investigators. The cardiac arrhythmia pilot study (CAPS). Am J Cardiol 1986:57:91-5.

Parmley WW, Chatterjee K. Congestive heart failure and arrhythmias: an overview. Am J Cardiol 1986:57 tsuppl B):34B-7B.

Hohnloser SH. Raeder EA. Podrid PJ. Graboys TB, Lown B. Predictors of antiarrhythmic drug efficacy in patients with malignant ventricular tachyarrhythmias. Am Heart J 1987:114: l-7.

Simonton CA, Daly P. Kereiakes D, Sata H, Modin G. Chatterjee K. Survival in severe congestive heart failure treated with the new nongly- cosidic nonsympathomimetic oral inotropic agents. Chest 1987;92: 118-23.

Cleland JGJ. Dargie HJ. Ford 1: Mortality in heart failure: clinical variables of prognostic value. Br Heart J 1987:.58:572-82.

pathophysiology and current therapy of congestive heart ... · 772 parmley jacc vol. 13, no. 4...

Documents