Pathophysiology of Congestive Heart

ILLIAM W. PARMLEY, MD

Congestive heart failure is a syndrome that can be caused by a variety of abnormalities, including pressure and volume overload, loss of muscle, pri- mary muscle disease or excessive peripheral de- mands such as high output failure. In the usual form of heart failure, the heart muscle has reduced con- tractility. This produces a reduction in cardiac out- put, which then becomes inadequate to meet the peripheral demands of the body. The 4 primary de- terminants of left ventricular (LV) performance are generally altered as follows: (1) There is an intrinsic decrease in muscle contractility. (2) Preload or left atrial filling pressure is increased, resulting in pul- monary congestion and dyspnea. (3) Although systemic blood pressure is often reduced, there is an increase in systemic vascular resistance (af- terload), which can further reduce cardfac output. (4) Heart rate is generally increased as part of a compensatory mechanism associated with an in- crease in sympathetic tone and circulating cate-

Congestive heart failure (CHF)l is a common clinical syndrome that is due to different causes and manifests itself in different ways. A useful working definition of CHF is the inability of the heart to deliver sufficient blood to the peripheral tissues to meet their metabolic demands. Four clinical syndromes of CHF can be rec- ognized. The first, owing to failure of the left ventricle as a pump, is manifested by a low cardiac output and pulmonary venous congestion. The second syndrome, pulmonary venous congestion, can exist without the presence of left-sided heart failure, as, for example, in mitral stenosis. In the third syndrome, failure of the right ventricle as a pump is associated with a low cardiac output and an elevation of right atria1 pressure. Eleva- tion of systemic venous’ pressure can also occur in the absence of right-sided heart failure (the fourth syn-

From the University of California and the Cardiovascular Division, H. C. Moffitt Hospital, San Francisco, California. This work was supported in part by the Susan and Don Schleicher Cardiology Research Fund, San Francisco, California.

Address for reprints: William W. Parmley, MD, Room 1186, Moffitt Hospital, University of California, 505 Parnassus Avenue, San Fran- cisco, California 94143.

cholamines. In patients with coronary disease, there is often an imbalance between myocardial oxygen supply and demand. An increase in heart size may be particularly deleterious by increasing wall tension because of the Laplace relation and increasin myocardial oxygen consumption.

Intrinsic compensatory mechanisms include an increase in catecholamines, which increase con- tractility and heart rate in an attempt to maintain cardiac output; cardiac muscle hypertrophy, which helps maintain cardiac function; a rise in LV fil pressure, which can optimize performance cording to the Frank-Starling mechanism; an increase in peripheral arterial-venous oxygen ex- traction so as to maximize the oxygen delivered for a given cardiac output. Although these compensa- tory mechanisms are initially helpful, many of them may actually be excessive, such as an increase in catecholamines and systemic vascular resistance.

(Am J Cardiol 1985;58:7A-11

drome) as manifested, for example, by pericardial restriction.

In this article the primary focus will be failure of the left ventricle as a pump because this is the most con?- mon heart failure syndrome. There are 3 major factors that contribute to failure of the left ventricle as a pump. The first is loss of muscle, as, for example, in patients with coronary artery disease (CAD) and myocardial infarction. Similarly, ischemic dysfunction of the left ventricle can contribute to left-sided heart failure. Second, primary muscle involvement as with cardio- myopathy is also a relatively common cause of heart failure. The muscle involvement may be due to infec- tious agents, exposure to toxins, metabolic factors or unknown causes. Cardiomyopathies may be further divided on the basis of whether they present as dilated, hypertrophic or restrictive cardiomyopathies. The third major category of causes that contribute to left-sided heart failure includes mechanical problems such as sys- temic hypertension, valvular stenosis and regurgitation or various forms of congenital heart disease. In general, these impose volume or pressure overload on the ven- tricles, which leads over time to a decrease in intrinsic

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8A A SYMPOSIUM: ROLE OF NITRATES IN CONGESTIVE HEART FAILURE

contractility of the heart muscle, finally leading to CHF.

A number of other contributory factors may exacer- bate CHF. Chief among these are interventions that increase the need for cardiac output, such as fever, hot weather, anemia, atrioventricular fistula and hyper- thyroidism. Associated cardiovascular factors, such as pulmonary embolism or infection, arrhythmias and salt and water retention, may also aggravate CHF ,in an appropriate setting. In general, therefore, it is critical for the physician to define (1) the specific syndrome of CHF, (2) the etiology of CHF and (3) the precipitating or aggravating causes that might be corrected.

To better understand the pathophysiologic factors that contribute to CHF, it is first necessary to discuss some general aspects of overall cardiovascular func- tion.2y3 Figure 1 represents a simplified conceptual di- agram of the cardiovascular system. There are 4 primary factors affecting left ventricular (LV) performance. The first is preload, which can be thought of as the filling pressure of the left ventricle. The second factor, after- load, represents the load against which the heart must work, as generally represented by systemic arterial pressure and systemic vascular resistance.

Although arterial pressure and peripheral vascular resistance are reasonable indexes of afterload, perhaps the most direct afterload determinant of LV perfor- mance is wall stress during systolic contraction. In this regard it should be pointed out that both preload and afterload contribute to an increase in wall stress. This occurs because of the Laplace relation:

wall stress = LV pressure X radius

2 X wall thickness

With an increase in arterial pressure, there is an increase in wall stress. Similarly, with an increase in heart size, there is also an increase in wall stress or afterload. In a strict sense, therefore, both arteriolar and venous dila- tors can reduce wall stress, and thus, can reduce the “afterload” faced by cardiac muscle.

Third, the contractility of the heart represents the intrinsic ability of the muscle to develop force and to

FIGURE 1. Schematic representation of the circulatory system. See text for details. Reproduced with permission from W. B. Saunders.2

shorten. Contractility can be modified by positive or negative inotropic agents. The fourth factor, heart rate, is modified by the relative balance of sympathetic and parasympathetic tone. For example, in a well-trained athlete with a slow heart rate, there is a predominance of parasympathetic tone to maintain the low heart rate at rest. During exercise, there is initially a withdrawal of parasympathetic tone to increase heart rate, followed by increasing sympathetic tone at higher levels of exercise.

In general, the cardiac output is determined by the peripheral needs of the body. During exercise, for ex- ample, vasodilation increases flow to skeletal muscle, which then increases the venous return and cardiac output. In addition, the pumping action of the skeletal muscles during exercise helps to maintain venous return and an appropriate cardiac output.

As represented in Figure 1, the arteries represent the conduit system for delivery of blood to the body. Blood pressure remains relatively constant up to the level of the terminal arteries and arterioles, where there is an approximate 80% drop in pressure. Arteriolar resistance, therefore, is the site of systemic vascular resistance and is under intrinsic, neural and hormonal influence. The relative distribution of cardiac output at rest to the various organs is shown in Figure 1. Note the relatively large proportion of cardiac output that goes to the kidneys. The cerebral and coronary circulations have powerful autoregulatory capabilities, so that if blood pressure is reasonably maintained, they usually receive blood flow appropriate to their needs. The venous sys- tem serves as the capacitance system of the circulation, in that 75 to 80% of the blood volume is present in veins at any 1 time.

The central nervous system is an important regula- tory organ. For example, the autonomic nerves have a major effect on the heart, arterioles and veins. Several regulatory systems help to maintain blood pressure. The carotid and aortic baroreceptors are particularly ef- fective. Pressure sensitive nerve endings in the wall of these receptors alter their discharge rate according to the pressure that is applied. At high pressures, the dis- charge rate is increased. These impulses pass through the central cardiovascular regulatory centers, which then alter the relative magnitude of parasympathetic and sympathetic tone. Sympathetic tone via the auto- nomic nervous system regulates peripheral vascular resistance by producing arteriolar constriction or vasodilation. The sympathetic nervous system may also affect cardiac contractility, heart rate and venous compliance.

Figure 1, right, shows some of the factors responsible for regulating extracellular fluid and blood volume. Excretion of salt and water by the kidney tends to bal- ance intake of salt and water to maintain a relatively constant fluid volume. Arginine vasopressin secretion, caused by a decrease in plasma volume, also helps to decrease water loss. Part of the reason for retention of fluid in patients with CHF may be an elevation in plasma arginine vasopressin levels. Decreased arterial pressure, decreased sodium or increased sympathetic tone releases renin from the juxtaglomerular apparatus,

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which promotes the formation of angiotensin II from angiotensin I. Angiotensin II is a potent vasoconstrictor that facilitates sympathetic outflow and feeds back on the adrenal glands to release aldosterone, which then retains salt and water. With normal renal and cardio- vascular function, these compensatory mechanisms provide for a relatively constant arterial pressure, and salt and water balance, despite considerable changes in cardiac output.

One of the best quantitative ways of describing LV function is the so-called LV function curve as shown in Figure 2.3 Some measure of LV performance, such as stroke work or stroke volume, is plotted as a function of the preload of the left ventricle. The preload is gen- erally represented by left atria1 pressure, which can be measured indirectly as pulmonary capillary wedge pressure with a balloon-tipped catheter in the pulmo- nary artery. There is an ascending limb of function as pulmonary capillary wedge pressure rises to 15 mm Hg. Between 15 and 20 mm Hg, there is generally a plateau of function in patients with cardiac disease, with a slight descending limb beyond a wedge pressure of about 25 mm Hg. Normally, the left ventricle functions at filling pressure of <12 mm Hg. With the onset of CHF, how- ever, the pressure often rises to beyond the optimal range.

A number of pathophysiologic alterations occur during the development of CHF.4 Severe hypertrophy and an eventual decrease in intrinsic contractility of the heart muscle occur with prolonged pressure or volume overload, leading to irreversible changes in function, including a reduction in actomyosin ATPase, a decrease in catecholamine stores and an increase in collagen content. This decrease in intrinsic contractility sets the stage for the use of positive inotropic agents, which can improve the contractility of depressed cardiac muscle and potentially improve cardiac performance.

There is generally an increase in preload with the onset of CHF, due to the retention of salt and water and anincrease in circulating blood volume. With an in- crease in left atria1 pressure between 15 and 20 mm Hg, there is a compensatory increase in cardiac output. When preload reaches the range of 20 to 35 mm Hg, however, pulmonary venous congestion with extrava-

51 roke Work

or

Stroke

Pulmonary Copillory Wedge (mm Hg) FIGURE 2. Representative left ventricular function curve. See text for details. Reproduced with permission from Prog Cardiovasc Dis.5

sation of fluid into the extracellular space begins, leading to dyspnea and eventually pulmonary edema. In general, therefore, it is important to reduce an ele- vated filling pressure to relieve the symptoms of dys- pnea. This is done commonly with the use of diuretics and venodilator drugs.

Although there is frequently a reduction in arterial pressure in patients with severe heart failure, this is often accompanied by a marked increase in peripheral vascular resistance, which can produce excessive “af- terload” for the left ventricle. This potential vicious cycle of chronic CHF is illustrated in Figure 3.5 With the decrease in cardiac output, there is an increase in sys- temic vascular resistance, primarily due to an increase in circulating catecholamines and an increase in sym- pathetic tone at the arteriolar level. An increase in an- giotensin II levels may also contribute to the increase in systemic vascular resistance, and certainly increases the retention of salt and water due to increased aldo- sterone levels. This increase in systemic vascular re- sistance further increases the resistance to ejection of blood, which leads to a further decrease in cardiac out- put. Patients tend to spiral down the vicious cycle until the cardiac output is lower and systemic resistance is higher than is optimal for the individual patient. This increase in systemic vascular resistance, therefore, sets the stage for the potential use of vasodilator drugs, which can decrease resistance and increase forward cardiac output.

The significant increase in sympathetic tone and circulating catecholamines also produces venocon- striction. Initially, this mechanism might be thought of as compensatory by attempting to maintain cardiac output through increasing venous return. Venocon- striction, however, shifts some of the blood volume from the peripheral veins to the central circulation and con- tributes to an elevation of right and left atrial pressures. This change sets the stage for the use of venodilators in patients with CHF, which can increase the capacitance of the peripheral veins and redistribute blood. This will lead to greater blood volume in the peripheral veins, less in the central chest and a reduction in left and right atria1 pressures.

An increase in heart rate frequently accompanies the process of CHF and is an extremely important com- pensatory mechanism. Cardiac output is the product of heart rate and stroke volume. As the ventricular

t /

RESISTANCE SYSTEMIC VASCULAR TO EJECTION ESISTANCE

IS THE SYSTEMIC VASCULAR RESISTANCE HIGHER THAN NECESSARY FOR OPTIMAL CARDIOVASCULAR FUNCTION?

FIGURE 3. Vicious cycle of chronic congestive heart failure. See text for details. Reproduced with permlssion from Prog Cardiovasc Dis.5

IOA A SYMPOSIUM: ROLE OF NITRATES IN CONGESTIVE HEART FAILURE

function curve shifts down to the right, and the patient moves onto the plateau of a depressed ventricular function curve, stroke volume becomes relatively fixed. Therefore, any increase in cardiac output must be produced by an increase in heart rate. In fact, marked sinus tachycardia is often a sign of extremely severe heart failure, in that it implies an extremely low fixed stroke volume with an inability to increase cardiac output by any mechanism other than heart rate.

In patients with CAD, one of the most important factors in determining cardiovascular performance is not only the decrease in muscle mass owing to previous myocardial infarction, but the presence of myocardial ischemia. Ischemia is best thought of as an imbalance between myocardial oxygen supply and demand.6 Myocardial oxygen demand is determined by 4 primary factors. These are heart rate, systemic arterial pressure, cardiac contractility and heart size. As previously dis- cussed, arterial pressure and heart size go together to determine wall tension by the Laplace relation. In the presence of myocardial ischemia, it is very beneficial to reduce any or all of these determinants of myocardial oxygen demand in order to be in balance with a given supply of oxygen.

Coronary blood flow is carefully autoregulated in accordance with the needs of the heart. In the presence of CAD, however, there is often an insufficient flow to maintain oxygen supply appropriate to oxygen demand. The heart nearly maximally extracts oxygen from the blood flowing through it, so that coronary blood flow and oxygen supply tend to be synonymous. Other im- portant determinants of coronary flow include the di- astolic arterial perfusing pressure and the LV diastolic pressure, which acts as a back pressure for subendo- cardial perfusion. In addition, any degree of coronary spasm or increased tone on top of a major stenosis can further reduce coronary flow. In patients with CHF and associated ischemia, it is generally useful to reduce the determinants of myocardial oxygen consumption, maintain an appropriate myocardial perfusing pressure and relieve any tendency for increased tone or spasm.

In CHF, a number of important compensatory mechanisms come into play. With the decrease in in- trinsic contractility of the myocardium, there is an in-

CHRONIC MYOCARDIAL FAILURE

I MILD I SEVERE

AFTERLOAD

FIGURE 4. Schematic alterations of force-velocity changes in the presence of left ventricirlar failure. See text for details. Reproducbd with permission from Prog Cardiovasc Dis7

crease in sympathetic tone and circulating catechol- amines, which can at least partially increase contractility of the depressed myocardium. An increase in heart rate is one of the most important compensatory mechanisms because it tends to maintain cardiac output in the face of a decrease in stroke volume. The increase in heart rate is produced primarily by an increase in sympathetic tone and circulating catecholamines. An increase in preload to an optimal filling pressure is also a compensatory mechanism caused by the retention of salt and water. Venoconstriction will also enhance the blood volume in the chest. As this overshoots, however, it leads to pulmonary congestion and dyspnea on the left side of the heart, and on the right, an elevated central venous pressure and peripheral edema. Another im- portant compensatory mechanism is the ability of pe- ripheral tissue to extract moremoxygen from the blood passing through it. This increase in arterial venous oxygen difference in the periphery provides more oxy- gen to peripheral tissue in the face of a decrease in car- diac output.

One of the important relations between loading fac- tors is the concept of a mismatch between an increased afterload without a sufficient preload reserve to main- tain cardiac function7 This principle is illustrated in Figure 4. The normal relation between velocity of shortening (VcF) and the afterload is shown by the dashed (- . -) lines in Figure 4, left. With a mild de- pression of contractility, there is a slight reduction in maximum VcF. By increasing preload, however, one can shift the curves to the right and maintain VcF at higher afterloads. Thus, if one is at point B on the middle curve, with an increase in afterload, the heart can in- crease its preload and move to points C and D with a relative maintenance of VcF because of the preload reserve. In Figure 4, right, with severe CHF, there is a marked reduction in velocity of shortening,.and the patient at point B is already at the maximum preload point. With an increase in load at the same preload, there is striking reduction in function to point C. This can be reversed by decreasing afterload (point D). A decrease in both preload and afterload moves the pa- tient to point E with a depression of function. This framework points out the importance of preload reserve in maintaining function when afterload is increased. It also points out how reduction of afterload can increase performance in the presence of severe CHF.

One clinical circumstance in which an increased af- terload is of considerable importance is the patient with mitral regurgitation5 In this setting, the left ventricle is pumping blood back into the left atrium, in addition to pumping blood forward into the aorta. It has been shown that arteriolar vasodilators that reduce systemic vascular resistance can enhance forward flow and reduce regurgitant fraction. Similarly, venodilators that reduce left heart size and apparently improve the overall competency of the mitral valve apparatus can also re- duce regurgitant fraction. Of all the drugs available to treat patients with mitral regurgitation, the evidence supports the thesis that the medical therapy of choice is vasodilator therapy. It produces the most beneficial

July 10. 1985 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 56 IIA

hemodynamic effects, and may be lifesaving in patients with acute, severe mitral regurgitation. Conversely, vasoconstrictor drugs may worsen mitral regurgitation by increasing the regurgitant fraction and decreasing forward cardiac output. Therefore, drugs that have peripheral vasoconstrictor effects are relatively con- traindicated and should be used with great caution in patients with mitral regurgitation.

These general considerations regarding the patho- physiology of CHF point out that alterations in preload, afterload, contractile state and heart rate provide the basis for most of the therapeutic interventions that we use. To counteract the marked decrease in intrinsic contractility that occurs in heart failure, such drugs as digitalis or catecholamines can improve contractile state and improve cardiovascular performance. The increased preload that exists in CHF can be lowered with diuretics and vasodilator drugs to bring the filling pressure down toa more optimal level. The excess increase in systemic vascular resistance can be reduced by arteriolar vaso- dilators, which result in an increase in forward cardiac output. Although we do not generally manipulate heart rate in patients with CHF, in patients with mchycardias, such as atria1 fibrillation or atria1 flutter, great benefit can be achieved by reducing the ventricular response. The same is true of patients with ventricular arrhyth- mias, in whom a reduction of the tachyarrhythmia will benefit ventricular function. In patients with an ex- tremely low heart rate, an increase in rate with drugs or cardiac pacing can also produce a marked improvement in cardiovascular function. In patients with a marked sinus tachycardia caused by an intrinsically low stroke volume, it is generally unwise to reduce heart rate as with p blockers. If patients are at an optimal level of filling pressure, the increase in heart rate appears to be an important compensatory mechanism for maintaining function. There is at least 1 study, however, which suggests that this increase in heart rate can be coun- terproductive, perhaps by markedly increasing oxygen consumption. In a series of patients with dilated car- diomyopathy, the /? blocker metoprolol was helpful in improving the signs and symptoms of CHF, at least partially supporting the hypothesis that an excessive heart rate, and the increase in oxygen consumption it produces, may be deleterious in this form of CHF.8 Further studies are required, however, to verify this hypothesis, because the administration of ,f3 blockers may reduce cardiac output and certainly can worsen CHF.

The increased activity of the renin angiotensin system that occurs in ,CHF also sets the stage for another therapeutic intervention, namely the inhibition of an- giotensin converting enzyme, which prevents the for- mation of angiotensin IL9 Its beneficial effects include an increase in cardiac output, a reduction in LV filling pressure and an overall improvement in cardiac signs and symptoms. The major drawback to such therapy is that converting enzyme inhibitors tend to decrease ar- terial pressure. An excessive decrease in arterial pres- sure may impair, coronary perfusion or perfusion of other peripheral beds such as the central nervous sys- tem, resulting in either coronary or cerebral ischemia. tiyootension with episodes of fainting or coronary in- sufficiency are potential problems with these and other drugs, that lower arterial pressure too far. Similarly, potentially adverse effects on renal function can occur if blood pressure is reduced excessively.

In summary, we now understand in much greater detail the pathophysiologic changes that accompany the process of CHF. It appears that many of these changes are compensatory, although in some cases the com- pensatory influence may become excessive, as with an increase in peripheral vascular resistance. Most of our therapeutic interventions, therefore, are designed to counter the pathophysiologic changes that have oc- curred. Alterations of preload, afterload, contractile state and heart rate form an important framework by which to consider the management of patients with CHF by giving therapeutic agents designed to counter the adverse changes that have occurred in each of these important variables.

References

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2. Parmley WW. Cir&latory function and control. In: Beeson PB, McDermott W, Wyngarrden JB, eds. Cecil Textbock of Medicine. Philadelphia: W.B. Saunders, 1979:1063-1072.

3. Parmley WW. Cardiac failure. In: Rosen M, Hoffman B, eds. Cardiac Therapy. The Hague: Martinus Nijhoff. 1981:21-44.

4. Braunwald E. Pathophysiol ??

of heart failure. In: Braunwald E, ed. Heart Disease. Philadelphia: W.B. aunders. 1980:453-47 I.

5. Chatterjee K, Pannley WW. The role of vasodilator therapy in heart failure. Prog Cardiovasc Dis 1977;19:301-325.

6. Parmley WW. The combination of beta-adrenergic blocking agents and ni- trates in the treatment of stable angina pectoris. Cardiovasc Rev Rep 1982;3:1425-1430.

7. Ross J. Afterload mismatch and preload reserve. Prog Cardiovasc Dis 1976;18:255-270.

6. Swedberg K, Hjalmarson A, Waagsteln F, Wallentln I. Long-term treatment of congestive cardiomyopathy with beta blockade. Am J Cardiol 1979;43: 408-412.

9. Parmley WW. Captopril in heart failure. In: Cohn J. ed. Drug Treatment of the Heart Failure Patient. New York: ADIS Press, 1984:179-198.