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Heart failure: Pathophysiology and treatment
Heart failure: Eugene Braunwald,
Pathophysiology
M.D. Boston, Mass.
Heart failure, the consequence of many forms of heart disease, is one of the most common serious disorders affecting individuals of all ages. It afflicts at least four million Americans, is generally associated with a poor prognosis, and is one of the most common causes of death. For many decades there were few advances in the treatment of heart failure, which consisted of restriction of physical activity and sodium intake and administration of digitalis and diuretics. During the past few years, however, two new therapeutic modalities-vasodilators and nonglycoside inotropic agents-have given promise of altering the treatment of heart failure favorably and decisively. This symposium is devoted to some of the key observations in this rapidly advancing area of cardiac therapeutics. This paper provides a review of the pathophysiology of congestive heart failure (CHF) as currently understood and the treatment of heart failure as currently practiced, in an effort to provide the background on which the important new advances described in the symposium may be viewed. Heart failure, the pathophysiologic state in which an abnormality of cardiac function is responsible for failure of the heart to pump blood at a rate commensurate with the requirements of the metabolizing tissues, is frequently but not always caused by a defect in myocardial contraction, that is, by myocardial failure.’ In the presence of a defect in myocardial contraction or an excessive hemodynamic burden on the ventricle, the heart depends on three principal compensatory mechanisms for maintenance of its pumping function: (1) the FrankStarling mechanism, in which an increased preload (i.e., lengthening of sarcomeres to provide optimal overlap between thick and thin myofilaments) acts to sustain cardiac performance; (2) increased release of catecholamines by adrenergic cardiac nerves and the adrenal medulla, which augments myocardial contractility; and (3) myocardial hypertrophy with From the Departments and Women’s Hospital, Reprint Harvard
486
requests: Medical
and treatment
of Medicine, Harvard Medical and Beth Israel Hospital.
Eugene Braunwald, School, 75 Francis
School,
M.D., Department St., Boston, MA 02115.
Brigham
of Medicine,
or without cardiac chamber dilation, in which the mass of contractile tissue is augmented. Initially these three compensatory mechanisms may be adequate to maintain the pumping performance of the heart at a relatively normal level, even though the intrinsic contractility of the myocardium may be substantially depressed. However, each of these mechanisms has a limited potential and ultimately fails. The clinical syndrome of heart failure occurs as a consequence of the limitations and/or the ultimate failure of these compensatory mechanisms. When the volume of blood delivered into the systemic vascular bed is chronically reduced, and when one (or both) ventricle(s) fails to expel the normal fraction of its end-diastolic volume, a complex sequence of adjustments occurs that ultimately results in an abnormal accumulation of fluid. Although many of the clinical manifestations of heart failure are secondary to this excessive retention of fluid, the expansion of blood volume also constitutes an important compensatory mechanism that tends to maintain cardiac output by elevating ventricular preload, because in most instances of heart failure the ventricle operates on an ascending limb of a depressed function curve (Fig. l), and except in the terminal stages of heart failure the augmented ventricular end-diastolic volume must be regarded as helping to maintain cardiac output. However, elevation of ventricular end-diastolic pressure also causes pulmonary or systemic venous congestion and promotes the formation of pulmonary or peripheral edema. EXCITATION-CONTRACTION
COUPLING
Although the molecular basis of heart failure is unknown, the critical role played by calcium ions in the initiation of contraction and as a determinant of the contractile state is well known. Studies in a number of in vitro systems indicate that there may be impairment of the delivery of Ca+ + for activation of the contractile process in heart failure. A variety of cellular structures, including the sarcolemma, the sarcoplasmic reticulum, and the mitochrondria, affect the myoplasmic Ca+ + concentration, [Ca+ +1. It has been proposed that structural damage to 0002-8703/81/090486
+ 05$00.50/O
0 1981
The
C. V. Mosby
Co.
Volume
102
Number
3, part 2
Pathophysiology
and therapy of CHF
407
DEPRESSION PUL.
VENTRICULAR
EDEMA
E. 0. v *
Fig. 1. Diagram showing the interrelationship of influences on ventricular end-diastolic volume (EDV)
through stretching of the myocardium and the contractile state of the myocardium. Abscissa:Levels of ventricular EDV associatedwith filling pressuresthat result in dyspnea and pulmonary edema.Ordinate: Levels of ventricular performance required during rest, walking, and maximal activity. Dotted lines represent descendinglimbs of the ventricular performance curves, which are rarely seenduring life but which show what the level of ventricular performance would be if end-diastolic volume could be elevated to very high levels. (From Braunwald E, RossJ Jr, Sonnenblick EH: Mechanisms of contraction of the normal and failing heart. Boston, 1968,Little, Brown & Co.) these organelles or changes in the intracellular concentrations of other cations, adenonucleotides, or free fatty acids may interfere with the mechanism regulating myoplasmic [Ca+ ‘1 and thereby participate in the production of heart failure. The uptake of Ca+ + by the sarcoplasmic reticulum is dependent on a Ca++-activated adenosine triphosphatase (ATPase), and depressedactivity of this enzyme, leading to defects in Ca+ + accumulation, could play a role in the development of myocardial failure in that a depression of Ca+ + pumping could be responsible for a reduction of Ca++ bound to the sarcoplasmic reticulum and eventually for a reduction of the Ca+ * available for “regenerative release” for the contractile process. ALTERATIONS IN FUNCTION NERVOUS SYSTEM
OF THE ADRENERGIC
In view of the well-established importance of the adrenergic nervous system in normal regulation of the circulation, considerable attention has been directed to the activity of this system in patients with heart failure. Measurements of the concentration of norepinephrine (NE) in arterial blood provide a crude index of the activity of this system at
rest and during exercise. Either no change or very small increases occur during exercise in normal subjects, but much greater elevations occur in patients with heart failure, presumably reflecting greater activity of the adrenergic nervous system during exercise in these patients. Measurements of 24-hour urinary NE excretion have revealed marked elevations in patients with heart failure, indicating that the activity of the adrenergic nervous system, and presumably secretion of catecholamines by the adrenal medulla, are also augmented at rest. A further abnormality of adrenergic nervous activity is reflected in the very low concentration of NE in cardiac tissue removed at operation from patients with heart failure. In some patients with heart failure the values are extremely low, with NE concentrations less than 10% of normal. CIRCULATORY
DYNAMICS
It is useful to consider normal and impaired myocardial function, whatever the cause and pathogenesis,within the framework of the familiar FrankStarling mechanism. The normal relation between ventricular end-diastolic volume and performance is shown in Fig. 1, curve 1. Normally assumption of the
September,
408
Braunwald
upright posture tends to reduce venous return; as a consequence, at any particular level of exercise cardiac output is lower in the upright than in the recumbent position. On the other hand, the hyperventilation of exercise, the pumping action of the exercising muscles, and the venoconstriction that occur all tend to augment ventricular filling. Simultaneously the increase in sympathetic nerve impulses to the myocardium and in the concentration of circulating catecholamines and the tachycardia that occur during exercise all augment the contractile state of the myocardium and stroke volume, with either no change or even a reduction in end-diastolic pressure and volume. This state is represented by a shift from point A to point B in Fig. 1. Vasodilation occurs in the exercising muscles, reducing peripheral vascular resistance and aortic impedance. This ultimately allows achievement of a greatly elevated cardiac output during exercise at an arterial pressure only slightly higher than that in the resting state. During intense exercise cardiac output can rise to a maximal level if use is made of the Frank-Starling mechanism, as reflected in increases in the left ventricular end-diastolic volume and pressure (Fig. 1, point C). In heart failure the fundamental abnormality resides in depression of the length-active tension curve, reflecting reductions in myocardial contractility. In many cases, such as those represented in Fig. 1, curve 3, cardiac output and external ventricular performance at rest are within normal limits but are maintained at these levels only because the end-diastolic fiber length and the ventricular enddiastolic volume are above normal, that is, through the operation of the Frank-Starling mechanism. The elevations of left ventricular end-diastolic volume and pressure are associated with elevated levels of the pulmonary capillary pressure, contributing to the dyspnea experienced by patients with heart failure (Fig. 1, point D). As noted, because heart failure is frequently accompanied by a depletion of cardiac NE stores and a reduction of the inotropic response to impulses in the cardiac adrenergic nerves, ventricular performance curves cannot be elevated to normal levels by the adrenergic nervous system, and the normal improvement of contractility that takes place during exercise is attenuated or even prevented (Fig. 1, curves 3 and 3’). The factors that tend to augment ventricular filling during exercise in the normal subject push the failing myocardium even further along its flattened length-active tension curve, and although left ventricular performance may be augmented somewhat, this occurs only as a consequence
American
Marl
1981 Journal
of an inordinate elevation of ventricular enddiastolic volume and pressure and therefore of pulmonary capillary pressure. The elevation of the latter intensifies dyspnea and therefore plays an important role in limiting the level of exercise that the patient can perform. According to this concept, left ventricular failure becomes fatal when the myocardial length-active tension curve becomes depressed (Fig. 1, curve 4) to the point at which either cardiac performance fails to satisfy the requirements of the peripheral tissues even at rest or the left ventricular end-diastolic and pulmonary capillary pressures are elevated to levels that result in pulmonary edema (Fig. 1, point E). CLINICAL
MANIFESTATIONS
OF HEART
FAILURE
The clinical manifestations of heart failure arise as a consequence of either an inadequate cardiac output or the damming up of blood behind one or both ventricles. These two principal mechanisms are the basis for the so-called forward and backward pressure theories of heart failure. The backward failure hypoth esisindicates that when the ventricle fails to discharge its contents, blood accumulates and pressure rises in the atrium and in the venous system emptying into it. The inability of cardiac muscle to shorten against a load alters the relationship between ventricular end-systolic pressure and volume so that the end-systolic volume rises. A sequence of adaptations then occurs that at first tends to maintain normal cardiac output: (1) ventricular end-diastolic volume and pressure increase, (2) pressure rises in the venous and capillary beds behind the failing ventricle, (3) transudation of fluid occurs, and (4) extracellular fluid volume increases. Many of the symptoms characteristic of heart failure result from this sequence of events and the subsequent increase in fluid in the interstitial spaces of the lungs, liver, subcutaneous tissues, and serous cavities. The forward failure hypothesis relates the clinical manifestations of heart failure to the inadequate delivery of blood into the arterial system. According to this hypothesis, the principal clinical manifestations of heart failure result from reduced cardiac output, which results in diminished perfusion of vital organs, including the brain, leading to mental confusion; skeletal muscles, leading to weakness; and kidneys, leading to sodium and water retention through a series of complex mechanisms. This renal effect in turn augments extracellular fluid volume and ultimately leads to symptoms caused by congestion of organs and tissues. Although these two seemingly opposing views
Volume
102
Number
3, part 2
Pathophysiology and therapy of CHF
concerning the pathogenesis of heart failure led to lively controversy during the first half of this century, it no longer seems fruitful to make a rigid distinction between backward and forward heart failure, because both mechanisms operate in the majority of patients with chronic heart failure. CAUSES
OF HEART
A THERAPEUTIC HEART FAILURE
III
II I I I I I I I I I
FAILURE
It is useful to consider the causes of heart failure in three separate categories: (1) fundamental causes, or the biochemical and physiologic mechanisms through which either an increased hemodynamic burden or a reduction in oxygen delivery to the myocardium results in impairment of cardiac contraction; (2) underlying causes, or the structural abnormalities, congenital or acquired, that affect the peripheral and coronary vessels, pericardium, myocardium, or cardiac valves and which lead to the increased hemodynamic burden or myocardial or coronary insufficiency responsible for heart failure; and (3) precipitating causes, or specific causes or incidents that precipitate heart failure in approximately 50% of episodes of clinical heart failure. In developing a strategy for the treatment of heart failure it is vital to recognize both the underlying and the precipitating causes of heart failure. Appropriate management of the underlying heart disease(e.g., surgical correction of a congenital heart defect or of an acquired valvular abnormality or pharmacologic management of hypertension) may prevent the development or recurrence of heart failure. Similarly, treatment of the precipitating cause, such as an arrhythmia, infection, or pulmonary embolus, will usually rapidly terminate an episode of heart failure and may be lifesaving. STRATEGY
FOR TREATMENT
OF
Control of congestive heart failure consists of three general therapeutic modalities’: (1) improvement of the heart’s pumping performance, which results from efforts to restore the contractility of the failing heart toward normal; (2) reduction of the heart’s work load, which involves reduction of the demands placed on the heart to generate pressure or to pump blood; (3) control of excessive salt and water retention, that is, control of the expansion of extracellular fluid volume, which is the principal cause of many manifestations of heart failure, such as dyspnea and edema. In each of these three categories a number of therapeutic measures are available. Thus digitalis and some of the newer inotropic agents discussed in this symposium contribute to the direct improve-
489
I I I I
I
I
I
fl’III’E’ FUNCTIONAL
CLASS
Fig. 2. Strategy of treatment of chronic congestiveheart failure in the adult. Various modes of therapy and the intensity of their application at various stages of the patient’s courseare plotted. (From Smith TW, Braunwald E. In Braunwald E, editor: Heart diseases:A textbook of cardiovascular medicine. Philadelphia, 1980, WB Saunders Co.)
ment of cardiac function; restriction of physical activity and vasodilators, the latter also discussed here, involve. reducing the heart’s work load, and restriction of sodium intake, administration of diuretics, and physical removal of excess fluid involve control of retention of sodium and water. A condition as variable as CHF cannot be treated according to a simple formula. Intelligent management depends on an appreciation of the nature of the underlying condition and the rapidity of its progression; the presence of associated illnesses; the patient’s age, occupation, personality, life-style, family setting, and ability and motivation to cooper-
September,
490
Braunwald
ate with treatment; and of importance, the response to therapeutic measures. With the recognition that wide differences exist among individual patients, Fig. 2 is presented as a general guide to the therapy of chronic CHF in adult patients in whom the underlying disease is not amenable to further treatment and in whom precipitating causes have been eliminated to the maximum extent possible. The general strategy is to utilize, first, relatively simple means, such as administration of digitalis glycosides, mild restriction of physical activity, and reduction of dietary sodium intake. If symptoms and signs of heart failure persist despite these measures, progressively stricter and more aggressive measures must be employed. Ordinarily, treatment of heart failure is not begun until the first symptoms of diminished cardiac reserve occur, that is, New York Heart Association (NYHA) functional class II. When it has become clear that these symptoms are indeed related to impaired cardiovascular reserve, two forms of treatment are begun simultaneously: discontinuation of intense physical exertion, such as heavy labor and competitive or exhausting sports (Fig. 2, IA ), and improvement of the pumping performance of the heart with a usual maintenance dose of a digitalis glycoside (Fig. 2, ZA). Most patients initially respond to these relatively simple measures, but if sympt,oms secondary to extracellular fluid accumulation reappear, dietary sodium intake should be restricted. This may consist merely of removing the salt shaker from the table (Fig. 2, 3A). If heart failure persists or advances despite these measures, treatment with a diuretic taken orally, such as a thiazide or an agent of equivalent potency, should be initiated (Fig. 2, 4A).
American
Hear!
1981 Journal
When a patient has symptoms on ordinary exertion, that is, when deterioration into functional class III has occurred, certain of the measures already taken should be intensified. Physical activity is restricted further (Fig. 2, 1B), and a more powerful diuretic such as furosemide is substituted for the thiazide (Fig. 2,4B). When late class III occurs and symptoms increase on ordinary activity, vasodilators may be given (Fig. 2, 5A). In patients with symptoms at rest or with minimal activity, that is, functional class IV, confinement to the home is necessary (Fig. 2, IC), and the dose of the cardiac glycoside may be cautiously raised to achieve the maximum level consistent with an adequate margin of safety (Fig. 2,2B). All salt is eliminated at the table and in cooking (Fig. 2, 3B), and a potassium-sparing diuretic that acts on the distal tubule, such as spironolactone, is added to the “loop” diuretic (Fig. 2, 4C). If further deterioration occurs, hospitalization is usually required. Other inotropic agents such as the sympathomimetic amines are administered, physical activity is drastically curtailed (Fig. 2, ID), a diet rigidly restricted in salt is instituted (Fig. 2,3C), the number or dose or diuretics is increased (Fig. 2, 4D), intravenous vasodilators may be administered (Fig. 2, 5B), and the application of special measures (Fig. 2, 7) such as the physical removal of fluid (thoracentesis, paracentesis, or dialysis) or under special circumstances the application of assisted circulation or even heart transplantation may be considered. REFERENCE
1.
Smith TW, Braunwald E: The management of heart failure. In Braunwald, E, editor: Heart disease: A textbook of cardiovascular medicine. Philadelphia, 1980, WB Saunders, pp 509-570.
Pathophysiology
M.D. Boston, Mass.
Heart failure, the consequence of many forms of heart disease, is one of the most common serious disorders affecting individuals of all ages. It afflicts at least four million Americans, is generally associated with a poor prognosis, and is one of the most common causes of death. For many decades there were few advances in the treatment of heart failure, which consisted of restriction of physical activity and sodium intake and administration of digitalis and diuretics. During the past few years, however, two new therapeutic modalities-vasodilators and nonglycoside inotropic agents-have given promise of altering the treatment of heart failure favorably and decisively. This symposium is devoted to some of the key observations in this rapidly advancing area of cardiac therapeutics. This paper provides a review of the pathophysiology of congestive heart failure (CHF) as currently understood and the treatment of heart failure as currently practiced, in an effort to provide the background on which the important new advances described in the symposium may be viewed. Heart failure, the pathophysiologic state in which an abnormality of cardiac function is responsible for failure of the heart to pump blood at a rate commensurate with the requirements of the metabolizing tissues, is frequently but not always caused by a defect in myocardial contraction, that is, by myocardial failure.’ In the presence of a defect in myocardial contraction or an excessive hemodynamic burden on the ventricle, the heart depends on three principal compensatory mechanisms for maintenance of its pumping function: (1) the FrankStarling mechanism, in which an increased preload (i.e., lengthening of sarcomeres to provide optimal overlap between thick and thin myofilaments) acts to sustain cardiac performance; (2) increased release of catecholamines by adrenergic cardiac nerves and the adrenal medulla, which augments myocardial contractility; and (3) myocardial hypertrophy with From the Departments and Women’s Hospital, Reprint Harvard
486
requests: Medical
and treatment
of Medicine, Harvard Medical and Beth Israel Hospital.
Eugene Braunwald, School, 75 Francis
School,
M.D., Department St., Boston, MA 02115.
Brigham
of Medicine,
or without cardiac chamber dilation, in which the mass of contractile tissue is augmented. Initially these three compensatory mechanisms may be adequate to maintain the pumping performance of the heart at a relatively normal level, even though the intrinsic contractility of the myocardium may be substantially depressed. However, each of these mechanisms has a limited potential and ultimately fails. The clinical syndrome of heart failure occurs as a consequence of the limitations and/or the ultimate failure of these compensatory mechanisms. When the volume of blood delivered into the systemic vascular bed is chronically reduced, and when one (or both) ventricle(s) fails to expel the normal fraction of its end-diastolic volume, a complex sequence of adjustments occurs that ultimately results in an abnormal accumulation of fluid. Although many of the clinical manifestations of heart failure are secondary to this excessive retention of fluid, the expansion of blood volume also constitutes an important compensatory mechanism that tends to maintain cardiac output by elevating ventricular preload, because in most instances of heart failure the ventricle operates on an ascending limb of a depressed function curve (Fig. l), and except in the terminal stages of heart failure the augmented ventricular end-diastolic volume must be regarded as helping to maintain cardiac output. However, elevation of ventricular end-diastolic pressure also causes pulmonary or systemic venous congestion and promotes the formation of pulmonary or peripheral edema. EXCITATION-CONTRACTION
COUPLING
Although the molecular basis of heart failure is unknown, the critical role played by calcium ions in the initiation of contraction and as a determinant of the contractile state is well known. Studies in a number of in vitro systems indicate that there may be impairment of the delivery of Ca+ + for activation of the contractile process in heart failure. A variety of cellular structures, including the sarcolemma, the sarcoplasmic reticulum, and the mitochrondria, affect the myoplasmic Ca+ + concentration, [Ca+ +1. It has been proposed that structural damage to 0002-8703/81/090486
+ 05$00.50/O
0 1981
The
C. V. Mosby
Co.
Volume
102
Number
3, part 2
Pathophysiology
and therapy of CHF
407
DEPRESSION PUL.
VENTRICULAR
EDEMA
E. 0. v *
Fig. 1. Diagram showing the interrelationship of influences on ventricular end-diastolic volume (EDV)
through stretching of the myocardium and the contractile state of the myocardium. Abscissa:Levels of ventricular EDV associatedwith filling pressuresthat result in dyspnea and pulmonary edema.Ordinate: Levels of ventricular performance required during rest, walking, and maximal activity. Dotted lines represent descendinglimbs of the ventricular performance curves, which are rarely seenduring life but which show what the level of ventricular performance would be if end-diastolic volume could be elevated to very high levels. (From Braunwald E, RossJ Jr, Sonnenblick EH: Mechanisms of contraction of the normal and failing heart. Boston, 1968,Little, Brown & Co.) these organelles or changes in the intracellular concentrations of other cations, adenonucleotides, or free fatty acids may interfere with the mechanism regulating myoplasmic [Ca+ ‘1 and thereby participate in the production of heart failure. The uptake of Ca+ + by the sarcoplasmic reticulum is dependent on a Ca++-activated adenosine triphosphatase (ATPase), and depressedactivity of this enzyme, leading to defects in Ca+ + accumulation, could play a role in the development of myocardial failure in that a depression of Ca+ + pumping could be responsible for a reduction of Ca++ bound to the sarcoplasmic reticulum and eventually for a reduction of the Ca+ * available for “regenerative release” for the contractile process. ALTERATIONS IN FUNCTION NERVOUS SYSTEM
OF THE ADRENERGIC
In view of the well-established importance of the adrenergic nervous system in normal regulation of the circulation, considerable attention has been directed to the activity of this system in patients with heart failure. Measurements of the concentration of norepinephrine (NE) in arterial blood provide a crude index of the activity of this system at
rest and during exercise. Either no change or very small increases occur during exercise in normal subjects, but much greater elevations occur in patients with heart failure, presumably reflecting greater activity of the adrenergic nervous system during exercise in these patients. Measurements of 24-hour urinary NE excretion have revealed marked elevations in patients with heart failure, indicating that the activity of the adrenergic nervous system, and presumably secretion of catecholamines by the adrenal medulla, are also augmented at rest. A further abnormality of adrenergic nervous activity is reflected in the very low concentration of NE in cardiac tissue removed at operation from patients with heart failure. In some patients with heart failure the values are extremely low, with NE concentrations less than 10% of normal. CIRCULATORY
DYNAMICS
It is useful to consider normal and impaired myocardial function, whatever the cause and pathogenesis,within the framework of the familiar FrankStarling mechanism. The normal relation between ventricular end-diastolic volume and performance is shown in Fig. 1, curve 1. Normally assumption of the
September,
408
Braunwald
upright posture tends to reduce venous return; as a consequence, at any particular level of exercise cardiac output is lower in the upright than in the recumbent position. On the other hand, the hyperventilation of exercise, the pumping action of the exercising muscles, and the venoconstriction that occur all tend to augment ventricular filling. Simultaneously the increase in sympathetic nerve impulses to the myocardium and in the concentration of circulating catecholamines and the tachycardia that occur during exercise all augment the contractile state of the myocardium and stroke volume, with either no change or even a reduction in end-diastolic pressure and volume. This state is represented by a shift from point A to point B in Fig. 1. Vasodilation occurs in the exercising muscles, reducing peripheral vascular resistance and aortic impedance. This ultimately allows achievement of a greatly elevated cardiac output during exercise at an arterial pressure only slightly higher than that in the resting state. During intense exercise cardiac output can rise to a maximal level if use is made of the Frank-Starling mechanism, as reflected in increases in the left ventricular end-diastolic volume and pressure (Fig. 1, point C). In heart failure the fundamental abnormality resides in depression of the length-active tension curve, reflecting reductions in myocardial contractility. In many cases, such as those represented in Fig. 1, curve 3, cardiac output and external ventricular performance at rest are within normal limits but are maintained at these levels only because the end-diastolic fiber length and the ventricular enddiastolic volume are above normal, that is, through the operation of the Frank-Starling mechanism. The elevations of left ventricular end-diastolic volume and pressure are associated with elevated levels of the pulmonary capillary pressure, contributing to the dyspnea experienced by patients with heart failure (Fig. 1, point D). As noted, because heart failure is frequently accompanied by a depletion of cardiac NE stores and a reduction of the inotropic response to impulses in the cardiac adrenergic nerves, ventricular performance curves cannot be elevated to normal levels by the adrenergic nervous system, and the normal improvement of contractility that takes place during exercise is attenuated or even prevented (Fig. 1, curves 3 and 3’). The factors that tend to augment ventricular filling during exercise in the normal subject push the failing myocardium even further along its flattened length-active tension curve, and although left ventricular performance may be augmented somewhat, this occurs only as a consequence
American
Marl
1981 Journal
of an inordinate elevation of ventricular enddiastolic volume and pressure and therefore of pulmonary capillary pressure. The elevation of the latter intensifies dyspnea and therefore plays an important role in limiting the level of exercise that the patient can perform. According to this concept, left ventricular failure becomes fatal when the myocardial length-active tension curve becomes depressed (Fig. 1, curve 4) to the point at which either cardiac performance fails to satisfy the requirements of the peripheral tissues even at rest or the left ventricular end-diastolic and pulmonary capillary pressures are elevated to levels that result in pulmonary edema (Fig. 1, point E). CLINICAL
MANIFESTATIONS
OF HEART
FAILURE
The clinical manifestations of heart failure arise as a consequence of either an inadequate cardiac output or the damming up of blood behind one or both ventricles. These two principal mechanisms are the basis for the so-called forward and backward pressure theories of heart failure. The backward failure hypoth esisindicates that when the ventricle fails to discharge its contents, blood accumulates and pressure rises in the atrium and in the venous system emptying into it. The inability of cardiac muscle to shorten against a load alters the relationship between ventricular end-systolic pressure and volume so that the end-systolic volume rises. A sequence of adaptations then occurs that at first tends to maintain normal cardiac output: (1) ventricular end-diastolic volume and pressure increase, (2) pressure rises in the venous and capillary beds behind the failing ventricle, (3) transudation of fluid occurs, and (4) extracellular fluid volume increases. Many of the symptoms characteristic of heart failure result from this sequence of events and the subsequent increase in fluid in the interstitial spaces of the lungs, liver, subcutaneous tissues, and serous cavities. The forward failure hypothesis relates the clinical manifestations of heart failure to the inadequate delivery of blood into the arterial system. According to this hypothesis, the principal clinical manifestations of heart failure result from reduced cardiac output, which results in diminished perfusion of vital organs, including the brain, leading to mental confusion; skeletal muscles, leading to weakness; and kidneys, leading to sodium and water retention through a series of complex mechanisms. This renal effect in turn augments extracellular fluid volume and ultimately leads to symptoms caused by congestion of organs and tissues. Although these two seemingly opposing views
Volume
102
Number
3, part 2
Pathophysiology and therapy of CHF
concerning the pathogenesis of heart failure led to lively controversy during the first half of this century, it no longer seems fruitful to make a rigid distinction between backward and forward heart failure, because both mechanisms operate in the majority of patients with chronic heart failure. CAUSES
OF HEART
A THERAPEUTIC HEART FAILURE
III
II I I I I I I I I I
FAILURE
It is useful to consider the causes of heart failure in three separate categories: (1) fundamental causes, or the biochemical and physiologic mechanisms through which either an increased hemodynamic burden or a reduction in oxygen delivery to the myocardium results in impairment of cardiac contraction; (2) underlying causes, or the structural abnormalities, congenital or acquired, that affect the peripheral and coronary vessels, pericardium, myocardium, or cardiac valves and which lead to the increased hemodynamic burden or myocardial or coronary insufficiency responsible for heart failure; and (3) precipitating causes, or specific causes or incidents that precipitate heart failure in approximately 50% of episodes of clinical heart failure. In developing a strategy for the treatment of heart failure it is vital to recognize both the underlying and the precipitating causes of heart failure. Appropriate management of the underlying heart disease(e.g., surgical correction of a congenital heart defect or of an acquired valvular abnormality or pharmacologic management of hypertension) may prevent the development or recurrence of heart failure. Similarly, treatment of the precipitating cause, such as an arrhythmia, infection, or pulmonary embolus, will usually rapidly terminate an episode of heart failure and may be lifesaving. STRATEGY
FOR TREATMENT
OF
Control of congestive heart failure consists of three general therapeutic modalities’: (1) improvement of the heart’s pumping performance, which results from efforts to restore the contractility of the failing heart toward normal; (2) reduction of the heart’s work load, which involves reduction of the demands placed on the heart to generate pressure or to pump blood; (3) control of excessive salt and water retention, that is, control of the expansion of extracellular fluid volume, which is the principal cause of many manifestations of heart failure, such as dyspnea and edema. In each of these three categories a number of therapeutic measures are available. Thus digitalis and some of the newer inotropic agents discussed in this symposium contribute to the direct improve-
489
I I I I
I
I
I
fl’III’E’ FUNCTIONAL
CLASS
Fig. 2. Strategy of treatment of chronic congestiveheart failure in the adult. Various modes of therapy and the intensity of their application at various stages of the patient’s courseare plotted. (From Smith TW, Braunwald E. In Braunwald E, editor: Heart diseases:A textbook of cardiovascular medicine. Philadelphia, 1980, WB Saunders Co.)
ment of cardiac function; restriction of physical activity and vasodilators, the latter also discussed here, involve. reducing the heart’s work load, and restriction of sodium intake, administration of diuretics, and physical removal of excess fluid involve control of retention of sodium and water. A condition as variable as CHF cannot be treated according to a simple formula. Intelligent management depends on an appreciation of the nature of the underlying condition and the rapidity of its progression; the presence of associated illnesses; the patient’s age, occupation, personality, life-style, family setting, and ability and motivation to cooper-
September,
490
Braunwald
ate with treatment; and of importance, the response to therapeutic measures. With the recognition that wide differences exist among individual patients, Fig. 2 is presented as a general guide to the therapy of chronic CHF in adult patients in whom the underlying disease is not amenable to further treatment and in whom precipitating causes have been eliminated to the maximum extent possible. The general strategy is to utilize, first, relatively simple means, such as administration of digitalis glycosides, mild restriction of physical activity, and reduction of dietary sodium intake. If symptoms and signs of heart failure persist despite these measures, progressively stricter and more aggressive measures must be employed. Ordinarily, treatment of heart failure is not begun until the first symptoms of diminished cardiac reserve occur, that is, New York Heart Association (NYHA) functional class II. When it has become clear that these symptoms are indeed related to impaired cardiovascular reserve, two forms of treatment are begun simultaneously: discontinuation of intense physical exertion, such as heavy labor and competitive or exhausting sports (Fig. 2, IA ), and improvement of the pumping performance of the heart with a usual maintenance dose of a digitalis glycoside (Fig. 2, ZA). Most patients initially respond to these relatively simple measures, but if sympt,oms secondary to extracellular fluid accumulation reappear, dietary sodium intake should be restricted. This may consist merely of removing the salt shaker from the table (Fig. 2, 3A). If heart failure persists or advances despite these measures, treatment with a diuretic taken orally, such as a thiazide or an agent of equivalent potency, should be initiated (Fig. 2, 4A).
American
Hear!
1981 Journal
When a patient has symptoms on ordinary exertion, that is, when deterioration into functional class III has occurred, certain of the measures already taken should be intensified. Physical activity is restricted further (Fig. 2, 1B), and a more powerful diuretic such as furosemide is substituted for the thiazide (Fig. 2,4B). When late class III occurs and symptoms increase on ordinary activity, vasodilators may be given (Fig. 2, 5A). In patients with symptoms at rest or with minimal activity, that is, functional class IV, confinement to the home is necessary (Fig. 2, IC), and the dose of the cardiac glycoside may be cautiously raised to achieve the maximum level consistent with an adequate margin of safety (Fig. 2,2B). All salt is eliminated at the table and in cooking (Fig. 2, 3B), and a potassium-sparing diuretic that acts on the distal tubule, such as spironolactone, is added to the “loop” diuretic (Fig. 2, 4C). If further deterioration occurs, hospitalization is usually required. Other inotropic agents such as the sympathomimetic amines are administered, physical activity is drastically curtailed (Fig. 2, ID), a diet rigidly restricted in salt is instituted (Fig. 2,3C), the number or dose or diuretics is increased (Fig. 2, 4D), intravenous vasodilators may be administered (Fig. 2, 5B), and the application of special measures (Fig. 2, 7) such as the physical removal of fluid (thoracentesis, paracentesis, or dialysis) or under special circumstances the application of assisted circulation or even heart transplantation may be considered. REFERENCE
1.
Smith TW, Braunwald E: The management of heart failure. In Braunwald, E, editor: Heart disease: A textbook of cardiovascular medicine. Philadelphia, 1980, WB Saunders, pp 509-570.