Compensation and overcompensation congestive heart failure

in

The compensatory mechanisms that develop in response to heart failure have been well defined. In this review, it is argued that each compensatory mechanism leads to overcompensation and that there is no way to distinguish between the beneficial aspects of the former and the harmful effects of the latter. Therapeutic agents that maintain rather than decrease blood pressure might perhaps be more beneficial because of the crucial role of hypotenslon in lntiating both compensation and overcompensation. (AM HEART J 1990;120:1552-7.)

Lionel H. Opie, MD, PhD Cape Town, South Africa

“The first indication of cardiac failure is to be found in diminished tolerance to exercise. Of the very numerous tests of cardiac efficiency. . . there is none that approaches in delicacy the symptom breathlessness.” (Sir Thomas Lewis, 1933).l The failing myocardium is not without support. The neurohumoral and hemodynamic changes that come to the aid of the ailing ventricle are by now well known-increased sympathetic drive causing tachycardia and maintaining the blood pressure, increased venous filling pressure to help keep stroke volume at a maximum via the Starling mechanism, and secretion of atria1 natriuretic peptide (ANP) to cause peripheral vasodilation and diuresis. The purpose of this article is to outline the extent to which each of these compensatory mechanisms can lead to overcompensation and harmful vicious cycles. PRESSUREOVERLOADHYPERTROPHY: COMPENSATION AND OVERCOMPENSATION

Hypertrophy of the myocardium means that the increased wall stress is compensated for by an increased wall thickness. However, the hypertrophied myocardium is not normal. In particular, there is a close link between increasing hypertrophy and increasing diastolic dysfunction.2 Increasing diastolic dysfunction means that as myocardial hypertrophy occurs and systolic function remains normal or actually increases, diastolic dysfunction develops, in spite of the increased afterload as in aortic stenosis and severe hypertension. The latter may lead to clinical From the Heart Research Cape Town, South Africa.

Unit,

University

of Cape

Reprint requests: Professor L. H. Opie, Heart Research Cape Town, Medical School, Cape Town 7925, South ‘ml23937

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Medical

Unit, Africa.

Center.

University

of

symptoms such as dyspnea or even pulmonary congestion. Therefore compensation (myocardial hypertrophy) is closely associated with overcompensation (diastolic dysfunction). Collagen in hypertrophy. Hypertrophy also brings with it problems in the maintenance of an adequate myocardial blood flow because the capillary circulation does not entirely keep up in growth with that of the myocardial cells. The result is that the hypertrophied myocardium “outstrips its blood supply,” the coronary vascular reserve is diminished, and the scene is set for focal fibrosis and myocardial impairment. Focal fibrosis is not the same as myocardial necrosis, although there is such an entity as the reparative fibrosis, which is found as myocardial cells die and collagen grows in. Rather, focal fibrosis corresponds to an increase in the interstitial collagen content3 The early collagen formation helps to maintain systolic function while unfortunately impairing diastolic function.3 As collagen formation progressively occurs during the progression of myocardial hypertrophy, the earlier interstitial fibrosis progresses to perimuscular fibrosis, a process that actually impedes systolic function and contributes now to both systolic and diastolic failure.3 Thus fibrosis is another example of a compensatory mechanism with risks of overcompensation. VOLUME

OVERLOAD

In the volume-overloaded myocardium, the problem is not increased collagen formation, which, for example, is not found in the early stages of experimental models such as arteriovenous fistula or anemia.3 Rather, what happens is “slippage” of fibers with an excessive increase in left ventricular (LV) chamber size that leads to increased wall tension.

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TRADITIONAL

SARCOMERE

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in CHF

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LENGTH -TENSION

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1. The conventional picture of increasingsarcomerelength leading to the downward fall of the tension can no longer explain the downward limb of the Frank-Starling curve, becausenew observations with modern techniques showthat the tension increasesuntil the sarcomerelength can no longer grow. (Figure copyright L. H. Opie.)

Much of the adaptation to a volume overload can be explained within the framework of Starling’s law. Starling’s law of the heart-compensation and overcompensation. It was Starling4 who first studied in

detail the mechanical performance of the isolated mammalian heart and first matched mechanics to metabolism. His fundamental observations were that “ . . . within wide limits, the output of the heart is independent of arterial resistance and of temperature; up to a certain point, the output of the heart is proportional to the venous flow. When this point is exceeded, the venous pressure rises and edema of the lungs supervenes.” The basic adaptation of the heart to increased venous pressure is seen as an increased heart volume, and within physiologic limits, the larger the volume of the heart, the greater the energy of its contraction and the greater the amount of chemical change at each contraction. Starling also gave a very early view on molecular mechanisms in heart failure, proposing that the “concentration of active molecules becomes less,“4 which leads to the modern view of abnormalities of the calcium cycle. Overcompensation of myocardium and abnormalities of the Starling curve in CHF. Normally there is a “fam-

ily of curves,” each representing a different inotropic state of the myocardium. In congestive heart failure (CHF), the curve is at a lower level than normal because of the decreased inotropic state. The impaired inotropic state is not fully understood but may relate to abnormalities of internal calcium cycling such as poor function of the sarcoplasmic reticulum in CHF.

However, the decreased inotropic state is not caused by actin-myosin overstretch as was previously thought. A host of external factors contribute to the plateau and apparent descending limb of the curve in severe CHF. Thus the “descending limb” of the Starling curve must be explained by a variety of other factors such as (1) the development of mitral incompetence, (2) the high LV end-diastolic pressure that promotes subendocardial ischemia, (3) oxygen supply and demand imbalance, and (4) the effects of increasing afterload as noradrenaline and angiotensin levels rise to promote vasoconstriction and to an increased afterload in CHF. Chief among these factors is the pathologically increased afterload. Clinically, the position of the myocardium on the Frank-Starling curve is revealed by upon balloontipped pulmonary artery catheterization. The position of the heart on the plateau or the downward slope of the Frank-Starling curve is of importance for Paul Wood’s5 definition of CHF, which exists when a further elevation of venous pressure causes a reduction in cardiac output. Because, however, the cause of the downward slope of the Starling curve is so complex, this definition is not exact. Nonetheless, once the descending limb of the curve has been reached, compensation has become overcompensation. Cellular mechanisms: Sarcomere length and Starling law. It was previously thought that as the myocardial

fibers continue

to work against an afterload

(as for

example in hypertension or aortic stenosis), the sarcomere length gradually increases so that there is

December

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CORRECT

SARCOMERE

LENGTH

Heart

1990 Journal

-TENSION

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2. Modern techniquesshow a different sarcomerelength-tension relationship from the traditional view (Fig. 1). There is no evidence that sarcomereoverstretch causesthe descendinglimb of the Starling curve. For data sources,seereferences14 and 15. Fig.

MYOCARDIAL

MECHANICS

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Fig. 3. As the sarcomerelength increases,LV end-diastolic diameter increasesand then

levels off at a sarcomerelength of between 2.2 and 2.4 Mm.As the myocardial compliance falls (fibrosis formation), the LV end-diastolic diameter decreasesfor any given sarcomere length. Resting tension increaseswith increasedLV end-diastolic pressurein LV failure. For data sources,seereferences16 and 17. overstretch and no longer an optimal overlap between actin and myosin. The result was believed to explain decreased myocardial contractility (impaired actin-myosin overlap) and thereby provide an ultrastructural basis for the plateau and the “descending limb” of the Starling curve. In that way, compensation could again lead to overcompensation. However, the data of Ross et aL6 have shown that myocardial sarcomere length is at a maximum of 2.2 pm in myocardial dilation and failure.

Experimental problems with the overlap theory. Early data showed that as sarcomere length increased, there was a definite descending slope to the lengthtension relationship of papillary muscle (Fig. 1). However, such data7 were obtained on papillary muscles with clamped and functionally impaired “ends,” including some dead cells. Thus there was a mixture of fully functional and impaired cells; this combina-

tion gave the curve its descending limb. Modern

techniques using sarcomere length in the central part

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I. Compensationand overcompensationin congestive heart failure Change

Mechanism

Peripheral adaptation Tachycardia

Compensatory advantages

Disadvantages: “overcompensation”

Baroceptor-mediated in response to hypotension resulting from depressed inotropic state

Helps to maintain cardiac output as stroke volume falls

MVOz increases

1. Adrenergic drive increases 2. Renin-angiotensin activation Aldosterone release and poor renal perfusion

Helps to maintain blood pressure

Afterload increases and stroke volume falls

Helps to maintain filling pressure

Increases afterload and causes excess venous filling pressure

Unknown. Altered isoenzymes in animal experiments

Pressure work at low speed more easily achieved

Slower rate of contraction, decreased inotropic state

Pressure overload (hypertrophy)

Systolic pressure effect on mechanoreceptors of myocardial cells

Lessens wall stress, decreases MVOz

Volume overload

Fiber slippage

Helps to maintain stroke volume by unknown mechanism, possibly by improved diastolic compliance

Hypertrophied myocardium does not have normal properties; focal necrosis is a risk; early diastolic dysfunction Increased chamber size means that wall stress rises, MVOz increases, and there is risk of hypertrophy

Arteriolar

vasoconstriction

Volume retention (edema) Myocardial adaptation Myosin ATPase activity reduced

MV02.

Myocardial

oxygen uptake.

of the muscle, as measured by laser diffraction, show increasing force development with sarcomere lengths up to the maximum found in CHF, namely 2.2 or at the most 2.3 pm (Fig. 2). From these observations it follows that the downward slope of the Starling curve cannot be explained by excess actin-myosin stretching. LV end-diastolic

pressure

and myocardial

mechanics.

As LV failure increases, LV end-diastolic pressure rises above the normal limit of about 18 mm Hg. Sarcomere length does not increase beyond the limit of 2.2 to 2.3 pm (Fig. 3). However, resting tension rises rapidly to compromise LV endocardial perfusion pressure, with the risk of myocardial oxygen imbalance that predisposes to fibrosis thereby decreasing myocardial compliance, so that the myocardial enddiastolic diameter for a given LV filling pressure falls. Therefore LV myocardial mechanics will be impaired. Fiber slippage. If sarcomere length does not increase beyond a certain fixed limit, how can the increased chamber size of the volume-overloaded heart be explained? There are two main types of compensation. First, an increase in the length of the myocytes, a longitudinal hypertrophy of up to 22%) occurs experimentally.8 Second, fiber slippage occurs through a mechanism that remains poorly under-

stood. (Similarly, the way in which a volume load communicates itself to the cell in such a way that the hypertrophy is longitudinal rather than radial in direction is equally poorly understood.) A possible explanation for fiber slippage is as follows. In dilated cardiomyopathy, thinning of the myocardial walls is associated with a reduction of collagen fibers that normally bind myocytes into an optimal position, and at the same time, there is an increase of thin collagen fibers.3 Possibly during the process of longitudinal hypertrophy, the interaction of myocytes with collagen has been disturbed. Because the collagen fibers fail to provide normal support, the intracavity pressure can push the myocytes apart by means of fiber slippage. Once this whole process has occurred, the wall stress must increase, and pressure hypertrophy will be added to volume hypertrophy. Although it has been supposed that an increased fiber length of the volume-hypertrophied myocyte compensates for increased diastolic tension of the volume-loaded heart, there appears to be a logical fallacy in this supposition. If, indeed, sarcomere length cannot extend beyond a maximum of say, 2.3 pm, then no amount of longitudinal hypertrophy will improve the position on the Starling curve. Rather, another mechanism must be sought. Thus, for example,

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ICLINICAL

FEATURES

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HEART

FAILUREI

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RENAL i

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LIVER

December 1990 Heart Journal

FAILURE

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terload increasein CHF. (Figure copyright L. H. Opie.)

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5. Becauseof the crucial role of the LV inotropic state in determining systemic hypotension, positively inotropic vasodilating agentsmay play a role in reversingsome of the disadvantageousneurohumoralcompensatorymechanisms (overcompensation) that occur in CHF. (Figure copyright L. H. Opie.) Fig.

longer fiber length with the stretched collagen could increase compliance so that the opposite to diastolic dysfunction of the hypertrophied myocardium could occur, that is, improved diastolic function that could compensate for the volume load in diastole.

COMPENSATION

Exactly when along the course of development of CHF the sympathetic nervous system becomes stimulated is not clear. We know, by the work of Cohn et al.,g that in severe heart failure plasma norepinephrine is elevated, that the degree of elevation is related to the severity of heart failure, and that the plasma level of norepinephrine is related to mortality independent of heart rate, plasma renin activity, serum sodium decrease, or fall in stroke work. Therefore it is reasonable to suppose that myocardial failure results in sympathetic activation. The intervening steps are not known, but a hypothetical proposal is that impaired myocardial function results in relative hypotension that stimulates the baroreceptors to activate the sympathetic nervous system.*O As shown in Fig. 4, the major hemodynamic consequences of sympathetic stimulation include : (1) A sinus tachycardia and peripheral vasoconstriction occur, both of which have initially beneficial effects on the failing myocardium, with “overcompensation” occurring as the former increases myocardial oxygen demand and the latter increases the afterload (Table I). (2) Sympathetic activation also has a potentially beneficial positive inotropic effect, which may, in part, compensate for decreased stroke volume and the inherent contractile failure of the myocardium; eventually such myocardial sympathetic stimulation “overcompensates” leading to PI-receptor downgrading with an impaired inotropic response.” (3) Sympathetic activation leads to renin release and formation of vasoconstrictive angiotensin-II; again the benefit is an increased vasoconstriction that helps to

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Compensationand overcompensationin CHF

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maintain the blood pressure, and overcompensation occurs as a result of the increased afterload. (4) Angiotensin-II increases the release of aldosterone with retention of fluid and formation of edema; this is another example of overcompensation. (5) In some severe cases, there is excess secretion of vasopressin (antidiuretic hormone), which in turn causes considerable extracellular fluid retention with hyponatremia, which is yet another example of overcompensation. Such hyponatremia is in contrast to overall sodium retention. The fluid retention increases cardiac work by causing volume overload and vascular edema. Excess vasopressin may also increase the afterload by peripheral vasoconstriction. Renal function. When renal perfusion is impaired (as in renal artery stenosis or as a result of severe CHF with hypotension), renal autoregulation acts to conserve intrarenal pressure. Distal (efferent) arteriolar tone is kept high by angiotensin-II, a benefit of the compensatory process, because renal function is maintained. However, there is risk of intraglomerular hypertension with damage to the glomerulus and impaired excretion of urea and creatinine. Systems

opposing

sympathetic

stimulation.

Atrial

natriuretic peptide, which is released from the atria by increased left and right atrial pressure, has properties that are beneficial for the circulation in CHF: diuretic activity, vasodilation, and inhibition of aldosterone secretion. Circulating levels of atria1 natriuretic peptide are increased in CHF, in proportion to atrial pressure. l2 One may well ask why these beneficial effects are not apparent. Presumably it is because of the overriding harmful effects of enhanced sympathetic activity and activation of the reninaldosterone system. The opioid system also plays a role. Accompanying experimental CHF is opioid system activation that can modify or lessen the effects of sympathetic stimulation.13 lnodilator therapy (Fig. 5). It will be seen that many of the systemic neurohumoral adaptations have hypotension as their origin. Hypotension, in turn, results from poor systolic function. An inotropic agent with sustained benefit could avoid such a fall in blood pressure, and, indeed, hypotension has not been a feature of therapy with the inodilator, ibo-

1557

pamine. It might, therefore, be supposed that ibopamine could play a role in the inhibition of the overcompensation that inevitably occurs as a consequence of hypotension. In such a way, ibopamine might have a theoretical advantage in comparison with some other dilators that tend to cause hypotension. REFERENCES

1. Lewis T. Diseases of the Heart. London: MacMillan, 1933:1-2. 2. Douglas PS, Berko B, Lesh M, Reicheck N. Alterations in diastolic function in response to progressive left ventricular hypertrophy. J Am Coil Cardiol1989;13:461-7. Weber KT. Cardiac interstitium in health and disease: the fibrillar collagen network. J Am Co11Cardiol1989;13:1637-52. Starling EH. In: Chapman CB, Mitchell JH, eds. Starling on the Heart. London: Dawsons, 1920:148-65. Wood P. Diseases of the heart and circulation. 2nd rev. London: Eyre and Spottiswoode, 1952154-92. Ross JR Jr, Sonnenblick EH, Taylor RR, Spotnitz HM, Covell JW. Diastolic geometry and sarcomere lengths in the chronically dilated canine left ventricle. Circ Res 1971;28:4961. 7. Kentish JC, ter Keurs HED, Ricciardi L, Bucx JJJ, Noble MIM. Comparison between sarcomere length-force relations of intact and skinned trabeculae from rat right ventricle. Circ Res 1986;58:755-68. 8. Anversa P, Ricci R, Olivetti G. Quantitative structural analysis of the myocardium during physiologic growth and induced cardiac hypertrophy: a review. J Am Coil Cardiol 1986;7: 1140-g. 9. Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984;311:819-23. 10. Harris P. Congestive cardiac failure: central role of the arterial blood pressure. Br Heart J 1987;58:190-203. 11. Bristow MR, Port JD, Gilbert EM. The role of adrenergic receptor regulation in the treatment of heart failure. Cardiovasc Drugs Ther 1989;3(suppl 3):971-B. 12. Raine AEG. Erne P. Buraisser E. et al. Atriai natriuretic pentide and at& pressure i’; patients with congestive heart-failure. N Engl J Med 1986,315:533-7. 13. Liang C-S, Imai N, Stone CK, Woolf PD, Kawashima S, Tuttle RR. The role of endogenous opioids in congestive heart failure: effects of nalmefeneon systemic and regional hemodynamics in dogs. Circulation 1987;?5:443-51. 14. Gordon AM, Pohack GH. Effects of calcium on the sarcomere length-tension relation in rat cardiac muscle: implications for the Frank Starling mechanism. Circ Res 1980,47:610-9. 15. Ter Keurs HEDJ. Calcium and contractility. In DrakeHolland AJ, Noble MIM, eds. Cardiac metabolism. Chichester: John Wiley, 1983;73-99. 16. Spotnitz HM, Sonnenblick EH, Spiro D. Relation of ultrastructure to function in the intact heart. Circ Res 1966;18:4966. 17. Boettcher DH, Vatner SF, Heyndrickz GR, Braunwald E. Extent of utilization of the Frank-Starling mechanism in conscious dogs. Am J Physiol 1978;234:H338-45.