Starling's law of the heart is explained by an intimate ...

lACC Vol. 10. No.5 November 19K7:1157~64

1157

BASIC CONCEPTS IN CARDIOLOGY

Arnold M. Katz, MO, FACC, Guest Editor

Starling's Law of the Heart Is Explained by an Intimate Interaction of Muscle Length and Myofilament Calcium Activation

EDWARD G. LAKATTA, MD

Baltimore. Marvland

The results of several different types of investigations over the last decade clearly indicate that muscle length modulates the extent of myofilament calcium ion (CaZ+) activation. Similarly, the fiber length during a contraction, which is determined in part by the load encountered during shortening, also determines the extent of myofilament Ca'" activation. Thus, "contractile" or "inotropic" state as it refers to the extent of myofilament

activation can, in theory, no longer be considered independent of the muscle length, as was formerly thought to be the case. Accordingly, terms such as preload, afterload and myocardial contractile state as they pertain to cardiac muscle properties lose part of their significance in light of current knowledge.

(J Am Coli Cardiol 1987;10:1157-64)

The effect of stretch to enhance myocardial performance has been known for at least 150 years ( I). The isolated heart experiments of Frank and Starling around the turn of the century showed that an increase in diastolic volume caused an increase in systolic performance. Although subsequent studies have shown that the stretch effect persists across a range of myocardial contractile states, some physiologists have maintained that it plays only a minor role augmenting ventricular function in normal humans during high myocardial contractile states, for example, during exercise (I). The main reason for this ambiguity regarding whether Starling's law of the heart has physiologic relevance in healthy human subjects is that adrenergic reflex mechanisms modulate myocardial performance, heart rate, vascular impedance and coronary flow during exercise and changes in these variables can overshadow the effect of fiber stretch or even prevent an increase in end-diastolic volume during stress.

Recent advances in noninvasive ultrasound technology

and radionuclide imaging of the heart have made possible a reinvestigation of the role of the Frank-Starling mechanism in the augmentation of stroke volume during upright exercise in healthy human subjects (2-4). Figure I demonstrates that at initial low exercise work loads, while end-systolic volume changes very little, both end-diastolic and stroke volume increase and contribute to the increase in cardiac output in subjects of all ages. Thus, the Frank-Starling mechanism is indeed utilized to augment stroke volume to meet the need for increased cardiac output during exercise. Figure I also shows that during strenuous exercise there is an increased reliance on this mechanism in elderly subjects in whom the effectiveness of catecholamine modulation of myocardial performance and stroke volume is diminished (5). Whereas an increase in end-diastolic volume may affect several determinants of the heart's pumping capacity, only its effect of stretching the myocardial fibers and the resultant change in muscle performance are discussed here. More detailed reviews of this issue have recently been provided (6-8).

From the Laboratory of Cardiovascular Science. Gerontology Research Center, National Institute on Aging. National Institutes of Health. Baltimore. Maryland.

Manuscript received February 26, 1987; revised manuscript received May 6,1987, accepted May 18, 1987.

Address for reprints: Edward G. Lakatta, MD. Laboratory of Cardiovascular Science, Gerontology Research Center. 4940 Eastern Avenue. Baltimore. Maryland 21224.

?)19K7 by the American College of Cardiology

This article is part (~t' a series of informal teaching reviews devoted to subjects in basic cardiology that are ()t' particular interest because ot'their high potentialfor clinical application. The intent ofthe series is to help the clinician keep abreast ojimportant advances in our understanding ojthe basic mechanisms underlving normal and abnormal cardiac function.

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1158

LAKATTA LENGTH DEPENDENCE OF MYOCAR[)IAI. Ca" ACTIVATION

JACC Vol. 10. No.5 November 1987: 1157-64

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Length Modulation of Contractile Force in Cardiac Muscle

In isolated cardiac muscle studied in vitro a small change in rest length produces large changes in the extent of shortening and force developed during the contraction (Fig. 2). The mechanisms of this effect of fiber length have been and continue to be the focus of considerable study, and our current concepts regarding these mechanisms have evolved both from inferences made from relatively simple experiments and from the application of innovative technology. One major technologic advance of the last decade was the ability to observe the sarcomere during contraction. Studies employing this technique (9-12) have shown that changes in myofilament geometry (sarcomere length) with changes in muscle length cannot account for the steepness of the relation between force and muscle length depicted in Figure 2. This is the case because, for a given change in sarcomere length that results from a change in muscle length, the change in force is not unique but varies with the experi-

mental condition; under some conditions, in fact, force can remain constant when a sarcomere length is varied across a wide range.

Mechanisms that govern excitation-activation-contraction coupling. Other studies have investigated whether the extent of stretch can modulate the effectiveness of excitation contraction coupling or myofilament activation of cardiac muscle. After excitation, activation of the myofilaments occurs because of an increase in myoplasmic calcium concentration (Ca.), producing myofilament displacement and force. The effectiveness of excitation-activation-contraction coupling in cardiac muscle can be made to vary by changes in the rate and pattern of stimulation, that is, the Bowditch phenomenon or rate treppe, by changes in the

calcium ion concentration ICa2 +] in the solution bathing

the muscle or by many additional physical and pharmacologic influences as well (13). Thus, changes in performance in cardiac muscle at a given rest length can be considered to occur through changes in the effectiveness of mechanisms that govern excitation-activation-contraction coupling. These mechanisms include calcium transport across cell membranes, calcium loading of the sarcoplasmic reticulum, calcium sensitivity of the contractile filaments and force generation and displacement of myofilaments in response to calcium ion Ca 2 + activation (collectively these have been referred to as determinants of the "inotropic" or "contractile" state). Is it possible that the rest fiber length, in itself, also modulates these excitation-activation-contraction mechanisms? Specifically, does variation in the overlap of myofilaments that accompanies a muscle or sarcomere length change alter the myofilament Ca 2 + sensitivity? Does the

l ACC Vol. 10. No 5 November 1987:11 57-64

LAKATTA LENGTH DEPENDENCE OF MYOCARDIAL Ca" ACl IVAllON

1159

variation in cell length that accompanies a change on muscle length lead to a change in cell Ca2 t homeostasis?

Role of muscle length in these mechanisms. A simple experimental approach to whether muscle length modulates these mechanisms would be to determine whether the response to inotropic interventions, that is. the Bowditch phenomenon or a change in [Ca1 t 1 in the fluid bathing the muscle. proceeds more efficiently at longer than at shorter rest muscle lengths. The results of studies of this sort are depicted in Figure 3, which illustrates that the kinetics of the force staircase in cat papillary muscles on stimulation from quiescence are more rapid in muscles at longer than at shorter rest lengths; that is. less time (or fewer fiber excitations) is required to complete the transient (or any given portion of it) at the longer versus the shorter length. Experiments of this type permit a strong influence that factors that govern the effectiveness of the excitation-activation-contraction cycle are length dependent; that is. this coupling is more effective at longer than at shorter muscle lengths.

Mechanisms of the Length Dependence of Excitation-Activation -Contraction Coupling

Factors that determine myofilament activation and thus the force of contraction fall into three general categories: I) those that determine the transient increase in cytosolic Ca1 I concentration (Ca.) that occurs subsequent to excitation; 2) those that determine the extent of Ca1 t myofilament interaction at a given Ca.; and 3) those that determine the extent of synchronization among the individual contractile units (14,15), although this has not usually been emphasized in models of excitation-activation-contraction coupling. Studies of the effects of length on each of these factors require experimental strategies that go beyond measurements of force and shortening relative to sarcomere cell or muscle length.

Length Effects on Ca2 + Release lnto the Mvoplasm After Excitation

The strategy here has been to measure the effect of length on the transient change in Ca, that results from excitation. This has been estimated utilizing the chernilurninescent protein, aequorin. In the steady state, at lengths and conditions corresponding roughly to those of the length-tension curve depicted in Figure 2, the increase in contractile force at longer muscle lengths is associated with an increase in the peak of the Ca, transient, as well as alterations in the shape of this transient (Fig. 4). This result has been interpreted to indicate that more Ca2+ is released into the myoplasm subsequent to excitation in cardiac muscle contracting in the steady state at longer lengths than at shorter lengths (16) . Note, however, in Figure 4 that the enhancement of the

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that accompany stretch (21). In the isovolumic intact isolated heart, similar time-dependent changes in developed pressure occur after a change in preload (22).

The Anrep effect or homeometric autoregulation in the intact heart. In the intact ejecting heart, a sudden and

constant increase in aortic and ventricular pressure causes an initial increase in ventricular volume; this is followed by a secondary slow increase in myocardial performance that results in enhanced pump performance during the maintenance of the higher afterload, thus allowing the ventricle to decrease toward its original size. This has sometimes been referred to as the "Anrep effect" or "homeometric auto-

Figure 4. Effect of an increase in muscle length from 0.82 Lmax to Llllax on (A) twitch force and (B) aequorin luminescence in a cat papillary muscle. The aequorin luminescence and force in B are the averaged levels in time periods 1, 2 and 3 in A. Note that in the steady state at the longer length (3) the enhanced twitch force is preceded by an increase in peak aequorin luminescence. Note also, that immediately after stretch, twitch force had increased but peak aequorin luminescence did not increase from the level at the shorter length. (Redrawn with permission from Allen and Kurihara [16].)

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Figure 5. A, The effect of pCa on force in a rat right ventricular preparation that had previously been made hyperpermeable to Ca' + and ethylene glycol bis(f}-aminoethyl ether)N,N' -tetraacetic acid by" chemical skinning" of the muscle for 30 minutes in 1% Triton- X. The pCa of the relaxing solution (RS) is >8. (Reproduced with permission from Bhatnagar et al. [431.) B, [Ca" + l-force curves for "chemically skinned" cat ventricular muscle bundles at long and short sarcomere lengths. Each point shows pooled data for seven preparations in which the force production at a given [Cal + 1 was measured at rest sarcomere lengths of 2.3 to 2.5 /Lm (filled circles) or at 1.9 to 2.04 /Lm (open circles). The bars on the points show ? I SEM when this exceeds the diameter of the plotted point. In the top panel all forces are expressed as a fraction of the maximal force produced at the longer sarcomere length. The bottom panel shows the data from the top panel after normalization so that the forces produced at each sarcomere length are expressed as a fraction of the maximal absolute force at that sarcomere length. Values on the abscissa are the average [Ca- + ] at which 50% of maximal force was achieved at each length. (Reproduced with permission from Hibberd and Jewell [28J.)

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regulation," in contrast to "heterometric autoregulation" or the Frank-Starling effect that pertains to situations in which ventricular size remains increased (23). This secondary increase in myocardial performance could share common mechanisms with the secondary increase in force

lACC Vol. 10. No.5 November 1987: 1157-64

LAKATTA LENGTH DEPENDENCE OF MYOCARDIAL Ca" ACTIVATION

1161

and shortening that occurs within isolated muscle preparations after a stretch in Figure 4 (although in the muscle experiment the ends of the muscle remain fixed at the long length, whereas in studies of the intact heart the ventricle can undergo a reduction in size). Thus, explanations for the "Anrep effect" in the intact heart need not invoke transient regional ischemia with stretch followed by a redistribution of coronary flow (24), although a concomitant increase in or redistribution of flow may also occur. In fact, a length dependence of excitation-activation coupling of cardiac muscle means that both "homeometric" and "heterometric" autoregulation (23) can be construed as resulting from an effect of stretch to enhance contractile activation and, thus, can be considered as two facets of the same phenomenon.

Enhanced Ca2 + release from an intracellular store in response to excitation, all else being equal, could explain the enhanced aequorin luminescence at the long length in the steady state in Figure 4. Experiments in single cardiac cells in which the sarcolemma has been mechanically removed have been interpreted to indicate that sarcoplasmic Ca 2 +- release mechanisms are indeed length dependent (2527). These studies appear to indicate that the Ca"" -induced release of Ca2 + is acutely affected by length or the degree of stretch. The implication here is that the effectiveness of Cal + as a trigger (perhaps by way of a length-induced change in its diffusion pathway causing a change in the rate at which its concentration changes at the surface of the sarcoplasmic reticulum) is altered by the stretch of the preparation.

Is the myotilament-Ca'" interaction length depen-

dent? That contractile force changes immediately after a change in rest length without a detectable change in the Ca, transient (Fig. 4) may indicate that some mechanism other than a length dependence of Cal +- release into the myoplasm after excitation is required to explain the immediate change in contractile force. Another experimental approach has examined whether the myofilament-Ca' t interaction is length dependent. Experiments of this sort can be made either by soaking small bundles of isolated muscle in a detergent, for example, Triton X, to "chemically skin" the membranes within the preparation, or by mechanically removing the sarcolemma. Application of solutions with graded constant pCa to such a preparation results in graded steady levels of force (Fig. 5A). These studies, in which no electrical excitation is needed for myofilament Cal -t- activation, have also provided information regarding the range of Ca, to which the myofilaments respond after excitation. The results of such studies show that at lower lengths, a lower pCa (higher [Cal +)) is required to produce a given relative level of force (Fig. 5B, lower panel). A length-dependent shift of the force-pCa curves in experiments of this sort has been interpreted to indicate a change in sensitivity of the myofilaments for Cal' (28,29), and in the study in Figure 5B the magnitude of the force shift was such that, at the pCa

required for 50% contractile activation at the long length, the force at the low length was reduced by a factor of 1.6 (28).

Is sarcomere length a unique determinant of force production? Because it is possible to maintain constant myofilament activation in preparations such as those in Figure 5, that is, to maintain steady rather than phasic Ca 2 t activation of myofilaments such as that which occurs during a contraction, it is possible to "clamp" the magnitude of activation at different levels and to determine whether the length-tension relation varies with the level at which Cal + activation is "clamped." It has been shown in single cardiac cells and in small bundles of rat cells that the drop in force with a decrease in muscle length is highly dependent on the level at which activation is clamped (Fig. 6). In other words, for a given reduction in sarcomere overlap, the reduction in force is greater when Cal + activation of the myofilaments

Figure 6. Effect of the level of myofilament Ca2 I activation on the reduction of force as sarcomere length is reduced over that range that is applicable to the Frank-Starling law of the heart. The force in multicellular rat preparations at the maximal (open squares) and submaximal (closed squares) Ca 2 ' activation have been normalized to their respective absolute level at sarcomere length 2.4 11m; the mechanically skinned single cell preparation (circles) was maximally (closed symbols) or submaximally (open symbols) activated. Note that in the multicellular preparations a marked decline (>90%) of force occurred with a reduction in length during submaximal activation; in contrast, during maximal Ca2 ' activation, only a 25% reduction in force occurred in this preparation, and only a 5% reduction occurred in the maximally activated single cell preparation. (Reproduced with permission from Hibberd and Jewell [281 and Alexandre Fabiato [private communication].)

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