News Physiol Sci 17: 185-190, 2002;
doi:10.1152/nips.01396.2002
1548-9213/02 $5.00
News in Physiological Sciences, Vol. 17, No. 5, 185-190,
October 2002
© 2002 Int. Union Physiol. Sci./Am. Physiol. Soc.
It Takes "Heart" to Win: What Makes the Heart Powerful?
Kerry S. McDonald and
Todd J. Herron
Department of Physiology, University of Missouri, Columbia, Missouri 65212
Current address for T. J. Herron: Centre for Cardiovascular Biology and Medicine, King’s College London, The Rayne Institute, St. Thomas Hospital, London SE1 7EH, UK.
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Abstract
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The pumping action of the heart varies considerably on a beat-to-beat basis and is ultimately determined by the extent of ventricular myocyte shortening during systole. The use of isolated myocardial preparations has provided new insights about the subcellular factors that modulate power output of the ventricles.
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Introduction
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Although it is a cliché to speak of the need for "heart" to become a champion, physiologists never lose sight of the heart’s biological function, which is to pump blood for the transport of gases, nutrients, and water to cells throughout the body. Since peripheral demand for cellular substrates varies widely, the heart must demonstrate functional plasticity to alter its output rapidly and significantly. For instance, during strenuous exercise such as running, cardiac output of the human heart increases from 5 l/min to upwards of 35 l/min in highly trained endurance athletes. The increase in cardiac output results from an approximately threefold increase in heart rate and a nearly twofold increase in stroke volume (i.e., the volume of blood pumped by one ventricle during a heartbeat). Stroke volume is limited by several factors, including ventricular chamber size and afterload; however, since every myocyte contracts during each heartbeat, stroke volume is ultimately regulated by the rate of loaded shortening or power output generated by individual myocytes. This article focuses on the subcellular factors that modulate power output of individual ventricular myocytes.
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Cardiac cycle
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A clear understanding of how stroke volume is modulated necessitates a review of the four phases of the cardiac cycle (Fig. 1
). The first phase of the cycle is ventricular filling, in which pressure in the atria exceeds pressure in the ventricles and blood enters the ventricles through the atrioventricular (AV) valves. During ventricular filling, myoplasmic Ca2+ is low (
10-7 M) and force-generating interactions are minimal between myosin on thick filaments and actin on thin filaments.
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FIGURE 1. Pressure-volume relationship depicting the 4 phases of the cardiac cycle and coincident myofilament activation states. During phase 1 or ventricular filling (bottom), myoplasmic Ca2+ is low and thin filaments are inactivated due to tropomyosin (Tm) occupying the "blocked" state, which inhibits strong binding of myosin cross bridges. Phase 2 of the cardiac cycle (isovolumic contraction; middle right) begins following electrical depolarization of the ventricles and an increase in myoplasmic Ca2+ concentration ([Ca2+]). Ca2+ binds to troponin C, causing conformational changes of troponin I (TnI) and troponin T. Conformational changes in troponin allow Tm to undergo the transition to the "closed" state, whereby myosin cross bridges can strongly bind actin. Strongly bound myosin cross bridges promote additional movement of Tm to the "open" state. It is only in the open state that myosin cross bridges can undergo force-generating transitions. The open state of Tm is depicted in the myofilament drawings during both phase 2 and phase 3. Phase 3 of the cardiac cycle (top) begins when the semilunar valves open and blood is ejected as the ventricular wall thickens as myocytes perform work on the blood. Myocyte shortening and power is driven by conformational changes in myosin cross bridges that propel thin and thick filaments past each other. During the latter part of ejection, ventricular pressure falls, causing the semilunar valves to close. Pressure falls during phase 4 (isovolumic relaxation; middle left) as the ventricles relax in response to decreased myoplasmic [Ca2+] and inactivation of the thin filament as Tm returns to the blocked state.
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Following electrical excitation of the ventricles, myoplasmic Ca2+ increases to 10-6–10-5 M, initiating force-generating transitions between myosin and actin that raise ventricular pressure, causing the AV valves to close. During this second phase, pressures in the pulmonary artery and aorta are greater than ventricular pressures, so both semilunar valves are closed; thus pressure rises with no change in volume (i.e., isovolumic contraction).
Once pressure in the ventricles exceeds pressure in the pulmonary artery and aorta, the semilunar valves open, the heart enters phase 3, and blood is ejected as individual myocytes perform work by shortening against a load. The rate of work production or power output of individual myocytes during phase 3 is the main determinant of how much blood is ejected. During the latter part of phase 3, ventricular ejection rate is reduced and ventricular pressure begins to gradually decline. Pressure continues to fall following electrical repolarization and relaxation of individual myocytes.
When pressure in the pulmonary artery and aorta exceeds pressure in the respective ventricles, the semilunar valves close and phase 4 begins (i.e., isovolumic relaxation). Since ventricular pressures are still greater than atrial pressures, the AV valves are also closed, so pressure falls with no change in ventricular volume during phase 4.
Stroke volume is the difference between the volume after filling (i.e., end-diastolic volume) and the volume after ejection (i.e., end-systolic volume). In the context of the cardiac cycle, it can be inferred that any factor that influences work performed by individual myocytes during ejection will alter stroke volume. For instance, simply increasing the time spent in ejection would increase ventricular work and stroke volume. This may arise by speeding phase 2, in which, for example, less time is needed for left ventricular pressure to exceed aortic pressure; thus a greater fraction of time during ventricular contraction is used for work production and ejection. Also, given the well-established load dependence of striated muscle shortening (7), any factor that decreases the relative load that myocytes work against will also increase stroke volume by speeding the rate of loaded shortening (i.e., increasing power output). For instance, an increase in the number of force-generating myosin cross bridges will increase myocyte force, making a given afterload less of a relative load (see force-velocity curve in Fig. 1
). The contracting myocyte will shorten more rapidly, thus yielding more power and more stroke work per unit time. The remainder of this review will focus on physiological factors that modulate myocyte force, rate of force production, and myocyte shortening, all of which will affect myocyte power-generating capacity and, ultimately, stroke volume.
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Ca2+ regulation of force
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The factors that regulate force production in cardiac myocytes involve rather complex interactions between Ca2+, thin filament regulatory proteins, and myosin cross bridges. Current models of regulation propose that thin filaments exist in three distinct states, which depend on the relative position of tropomyosin (see Ref. 4 for review). In the absence of Ca2+, thin filaments are thought to be in a "blocked" state in which tropomyosin sterically hinders myosin from interacting strongly with actin (see phase 1 in Fig. 1). When Ca2+ binds to troponin C, conformational changes in the three subunits of troponin cause the thin filament to undergo a transition to the "closed" state as tropomyosin changes position, which allows increased numbers of weakly bound myosin cross bridges to interact with actin. When thin filaments are in the closed state, a population of cross bridges undergoes the transition to a strongly bound, non-force-generating state, which promotes further movement of tropomyosin into an "open" state (phases 2 and 3 in Fig. 1). It is only in the open state that strongly bound cross bridges can undergo isomerization transitions to force-generating states. Thus, in this model, complete activation of thin filaments occurs only in the presence of both Ca2+ and strongly bound myosin cross bridges, wherein Ca2+ first allows cross bridges to bind and these in turn promote additional binding.
One factor that changes on a beat-to-beat basis in the heart is myoplasmic Ca2+ concentration ([Ca2+]), which, as mentioned above, rises from a diastolic level of 10-7 M to systolic levels ranging from 10-6 to 10-5 M. Myoplasmic [Ca2+] may change in response to a number of signals, including intrinsic signals such as stretch, extrinsic signals such as sympathetic neural stimulation of 
- and ß-adrenergic receptor systems, and autocrine/paracrine signals, including angiotensin II, endothelin, and nitric oxide. Alterations in myoplasmic [Ca2+] may affect stroke volume by modulating several aspects of the cardiac cycle. First, increased [Ca2+] accelerates the rate of pressure development in intact hearts, thus decreasing the fraction of systolic time spent in phase 2 and providing more time for ejection. The subcellular basis for faster ventricular pressure development involves the Ca2+ dependence of force-generating kinetics, recently characterized in isolated cardiac myofilaments (18). In these experiments, myocardial preparations were permeabilized, allowing precise control of the level of myofilament activation by simply bathing the preparation in Ca2+-buffered solutions. The rate of force development was measured after a mechanical perturbation that dissociates strongly binding myosin cross bridges and reduces force to near zero. The rate constant of force development was observed to increase nearly threefold from submaximal Ca2+ activations to maximal Ca2+ activations. A similar Ca2+ dependence is observed in response to the rapid release of caged Ca2+ to activate permeabilized myocardial preparations and in intact myocardium during Ca2+ activations that were varied by changing the level of extracellular Ca2+ and inhibiting Ca2+ reuptake by the sarcoplasmic reticulum (for review, see Ref. 4). These results indicate that Ca2+ regulates the rate of force-generating transitions between myosin and actin. The exact mechanism by which Ca2+ modulates force development rates remains unclear. Current theories include 1) stochastic Ca2+ activation of the thin filament; 2) cooperative activation of the thin filament by strongly binding cross bridges, whereby at lower Ca2+ levels there is a larger pool of noncycling cross bridges that takes time to recruit; and/or 3) a direct effect of Ca2+ on myosin-actin interaction kinetics. Regardless of the exact mechanism, faster rates of force development due to greater myoplasmic [Ca2+] would tend to shorten phase 2, allowing more time for ejection. Additionally, faster force-generation rates and a greater [Ca2+] per se will increase the number of force-generating cross bridges, and thus force, during phase 3. This will invariably make the load that myocytes are working against a smaller relative load (as a percentage of maximum), which will increase velocity of loaded shortening in accordance with the force-velocity curve and will increase power during ejection.
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Ca2+ regulation of myocyte-loaded shortening rates
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Greater myoplasmic [Ca2+] may also augment power-generating capacity of myocytes by directly increasing myocyte shortening rates during loaded contractions. The direct role that Ca2+ plays in modulating shortening velocity has been investigated in both intact and permeabilized myocardial preparations. In rat myocardial trabeculae preparations, the velocity of very lightly loaded shortening progressively increased as a function of extracellular [Ca2+] (2). Similarly, instantaneous loaded shortening velocities increased as a function of [Ca2+] in permeabilized myocyte preparations (Ref. 9 and Fig. 2). In these studies, peak absolute power output increased more than fivefold as Ca2+ activation levels increased from 30 to 100%. This increase in power was due to both an increase in force and an increase in velocity of shortening, because force-velocity curves progressively shifted upward with greater [Ca2+] even after normalization for the increase in force (Fig. 2B). Thus it appears that Ca2+ activation levels provide very tight regulation of loaded shortening velocities of cardiac myocytes. Here again, the exact subcellular mechanisms by which Ca2+ increases loaded shortening velocity of myocytes are not entirely clear but may be due to an effect of Ca2+ to allow strongly binding cross bridges to cooperatively activate the thin filament. Consistent with this idea, activation of the thin filament by strongly bound myosin cross bridges has been shown to speed loaded shortening independent of [Ca2+] per se and force levels (10). According to this theory, as [Ca2+] increases, the fraction of thin filaments in the open state increases in response to cooperative activation by strongly binding myosin cross bridges. Thus a greater number of cycling cross bridges are able to bear a given load, so each cross bridge bears less force and can cycle faster in accordance with its force-velocity characteristics. Conversely, at lower levels of Ca2+ activation, fewer thin filaments are in the open state due to less activation by strongly bound myosin cross bridges, so there is a decrease in the number of cycling cross bridges to bear the given load and each cross bridge must bear more load, which it may accomplish by slowing down in accordance with its inherent force-velocity properties. Thus [Ca2+] may vary loaded shortening by modulating the number of cycling cross bridges working against a load. Another interesting aspect about Ca2+ regulation of loaded shortening is that myocyte shortening velocity actually decreases during isotonic contractions, as shown in permeabilized myocyte preparations during lightly loaded contractions at submaximal [Ca2+] (9). This phenomenon may arise as thin filaments undergo the transition from the open to the closed state in response to loss of strongly bound cross bridges as force was stepped from isometric to subisometric levels. Here again, the loss of cycling cross bridges would require remaining cycling cross bridges to bear a greater load, which may be accomplished by slower cross-bridge cycling. Whether myocyte thin filaments are inactivated and myocyte shortening slows in the heart during ventricular ejection is unknown, but inactivation is plausible given that the space between thick and thin filaments widens during myocyte shortening and myofilament spacing is known to be a potent regulator of the number of force-generating cross bridges. If such a reduction in the number of force-generating cross bridges occurs during ejection, this may provide a myofilament-mediated "brake" system that helps tune ventricular wall stress with pressure as chamber size is dynamically falling.
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FIGURE 2. Ca2+ effects on loaded shortening and power output in permeabilized myocyte preparations. A: increased Ca2+ activation levels progressively shifted the force-velocity and power-load relationships upward. The increase in absolute power with greater [Ca2+] (i.e., lower pCa) was due in part to faster loaded shortening, since force-velocity and power-load curves were shifted upward even after normalization for increases in force (B, redrawn from Fig. 3 in Ref. 9).
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Covalent modulation of myofibrillar proteins
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Another factor besides myoplasmic [Ca2+] that may affect power output of individual myocytes in response to ß-adrenergic stimulation is covalent modulation of myofibrillar proteins. In response to ß-adrenergic stimulation, 3'-5' cAMP-dependent protein kinase (PKA) is activated, and it phosphorylates two myofibrillar proteins: myosin binding protein-C (MyBP-C) on the thick filament and troponin I (TnI) on the thin filament (Fig. 1). The cardiac isoform of MyBP-C contains a cardiac-specific motif having three serines that serve as PKA substrates. PKA-induced phosphorylation of MyBP-C correlates with the time course of the inotropic response in the heart and yields less order of thick filaments, which has been interpreted as an extension of myosin cross bridges toward the thin filaments (17). This may increase the effective myosin concentration available to interact with actin, thereby facilitating force production. Mammalian cardiac TnI contains two serines at the cardiac-specific NH2-terminal end that serve as PKA phosphorylation substrates. Phosphorylation of these sites is known to reduce the Ca2+ affinity of troponin C, decrease Ca2+ sensitivity of force, and accelerate relaxation (13,14). Recent studies have shown that PKA increased absolute power output by 35% in maximally Ca2+-activated permeabilized myocyte preparations (6). Power output was also increased following ß-adrenergic stimulation of intact myocardium in which Ca2+ transients were unaltered by inhibiting sarcoplasmic reticulum membrane function (8). In permeabilized myocytes, the increase in power was due to an increase in both force and velocity since force-velocity curves were shifted upward even after normalization of force (Fig. 3). Thus PKA-induced phosphorylation of MyBP-C and TnI appears to augment myocyte power output capacity by modulating cross-bridge steps that limit force production and loaded shortening rates.
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Myosin heavy chain
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Variable expression of myofibrillar proteins may also regulate power-generating capacity of myocytes and ultimately the whole heart. One specific myofibrillar protein that is a plausible regulator of power output is myosin. Myosin is a hexamer consisting of two myosin heavy chains (MHC) and four myosin light chains (MLC). There are two cardiac MHC isoforms, -MHC and ß-MHC. In small mammals, MHC is expressed in a developmentally regulated manner, in which ß-MHC is expressed in the fetus and expression switches to -MHC after birth. -MHC predominates in adult rodents, but there is increased ß-MHC expression with age. Larger mammals, on the other hand, express primarily ß-MHC during development and maintain ß-MHC expression throughout life. However, recent evidence indicates that normal adult human hearts express considerable amounts of -MHC RNA (35%), which translates into 7% -MHC expression (11). Interestingly, failing human hearts appear to express ß-MHC exclusively (11). Structurally, -MHC and ß-MHC are highly homologous, having 93% amino acid identity; yet functionally, -MHC and ß-MHC are quite different, with -MHC exhibiting two to three times the myofibrillar ATPase activity and actin filament sliding velocity (16). In the context of ventricular function, myocardial preparations expressing -MHC exhibit twofold faster rates of force development than ß-MHC preparations (3), which would tend to shorten phase 2 and allow more time for ejection. In addition, single myocyte studies have shown that instantaneous loaded shortening velocities were significantly faster at all loads and peak power output was nearly threefold greater in myocyte preparations that expressed -MHC compared with ß-MHC myocytes (5). This difference resulted primarily from a difference in loaded shortening velocity because peak force was not found to differ between -MHC and ß-MHC myocytes. A reduction in loaded shortening velocity would tend to reduce stroke volume by reducing the rate of work production (i.e., power output) during ejection. These changes in power and stroke volume resulting from altered MHC isoform expression are likely to affect myocardial performance on a chronic basis, unlike the changes in Ca2+ and phosphorylation of myofibrillar proteins, which would affect power output and stroke volume on a beat-to-beat basis. One functional consequence of the expression of -MHC in small mammals may be the optimization of stroke volume in the presence of high heart rates during which the cardiac cycle and, in particular, ejection times are very short (e.g., tens of milliseconds). With regard to the human heart, the impact of small amounts of -MHC isoform on power output is unknown, but it may serve to provide a necessary functional reserve in times of increased peripheral demand, such as during endurance exercise. Thus, although the exclusive expression of ß-MHC in failing human hearts may improve energetic efficiency of the ventricles, this may occur at the expense of the potential to augment hemodynamics.
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Summary and additional questions
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Any factor that increases cardiac myocyte work or power will increase stroke volume and, ultimately, cardiac output. Greater myocyte work may occur by simply extending the fraction of time during systole used for ejection. All three of the physiological factors discussed, greater [Ca2+], PKA-induced phosphorylation of myofibrillar proteins (12), and expression of -MHC, have been shown to yield faster myofibrillar force-development rates, which would tend to shorten phase 2 and provide more fractional time for ejection (Fig. 4). Also, faster force-development rates would give rise to more force-generating cross bridges during ejection. Greater force during ejection would speed myocyte shortening and increase power output since any given afterload would become less of a relative load. Hence the myocyte would shorten more rapidly, as predicted by the force-velocity curve (represented by the transition from a to b in Fig. 4). Additionally, any factor that shifts the force-velocity relationship upward such that myocyte shortening is faster at any given relative load would also increase power output and thus stroke volume. Here again, experimental evidence supports the idea that greater [Ca2+], PKA-induced phosphorylation of myofibrillar proteins, and -MHC all enhance (albeit to different extents) myocyte shortening rates and thus power output at any given relative load (represented by the transition from b to c in Fig. 4). Thus any factor that increases force during phase 3 and/or directly speeds loaded cross-bridge cycling rates would increase myocardial power during ejection and yield greater stroke volume (Fig. 4).
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FIGURE 4. Pressure-volume curves depicting how greater [Ca2+], PKA-induced phosphorylation of MyBP-C and TnI, and -myosin heavy chain (MHC) expression might increase stroke volume. All three factors appear to speed the rate of pressure development during phase 2 by increasing the rate of myocyte force production. This reduces the time spent in phase 2 and extends the fraction of time during systole used for ejection. Faster rates of force development also give rise to greater force during ejection. Greater force makes any afterload less of a relative load; hence myocytes could shorten faster in accordance with the force-velocity curve (moving from a to b). All three factors also result in faster loaded shortening at a given relative load (moving from b to c). Overall, more ejection time and greater power during ejection cause a greater stroke volume. LV, left ventricular; SV, stroke volume.
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Still, many questions remain as to the cellular and subcellular regulators of myocardial power output and stroke volume. For instance, it is unclear which step in the cross-bridge cycle limits power output. Unloaded or lightly loaded shortening is thought to be limited by the detachment of compressively strained cross bridges or cross bridges that have undergone their working power stroke and if further strained would generate substantial force opposing shortening. Isometric force, on the other hand, is limited by the number of positively strained cross bridges, which is determined by the attachment and detachment rates of positively strained cross bridges. The question remains as to what step limits shortening at intermediate loads at which power rises to an optimum and striated muscle is thought to operate in vivo. The answer to this question will rely on probing how individual steps in the cross-bridge cycle affect power output. For instance, the replacement of ATP with CTP as an energy source reduced unloaded shortening velocity but did not affect the power output of skinned skeletal muscle fibers (15). This finding suggests an uncoupling between the steps that limit shortening at light loads and at intermediate loads. Similar experiments are needed in cardiac myocytes. It is also of interest as to whether phosphorylation of MyBP-C or TnI is most important in increasing myocyte power generation and which step in the cross-bridge cycle is modulated by phosphorylation of either or both of these myofibrillar proteins. Answers to these questions may be forthcoming through the use of transgenic animals that lack specific phosphorylation sites and by dissecting out the step(s) in the cross-bridge cycle that are affected by covalent modulation.
The need to understand the determinants of myofibrillar power output is underscored by the various transcriptional, translational, and posttranslational modifications that occur to compensate for chronically altered hemodynamic stress such as high blood pressure or damaged myocardium. For example, one consequence of signaling mechanisms that are activated to compensate for hemodynamic stress is altered covalent modulation of myofibrillar proteins, including lower PKA-induced phosphorylation due to downregulation of ß-receptors and elevated protein kinase C (PKC)-induced phosphorylation (1). PKC-induced phosphorylation of TnI and troponin T are known to reduce myofibrillar ATPase activity and force, which implies depressed myocyte power output, but this remains to be directly tested. Additionally, hemodynamic overload alters the isoform expression of myofilament proteins, including MHC, MLC, and troponin T. Similarly, both familial hypertrophic cardiomyopathies and dilated cardiomyopathies are correlated with genetic mutations of several different myofilament proteins, including MHC, MLC, MyBP-C, and troponin subunits. It remains to be seen how either altered isoform expression or these various mutations modify cardiac myofibrillar power output and if any such changes act to compensate for the altered hemodynamic stress or actually contribute to the cause of the disease by rendering the heart less powerful.
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Acknowledgments
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We thank Richard L. Moss for reviewing a previous version of the article and Darla Tharp for assisting in preparation of figures.
Work from our lab is supported by grants from the National Heart, Lung, and Blood Institute and the American Heart Association.
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References
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Introduction
Cardiac cycle
