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Cellular basis for inotropic changes in the heart
Cellular
basis for inotropic
changes
in the heart
Cardiac contraction is a highly regulated process that involves nearly every aspect of the cardiac cell function. Many steps in the process are regulated by the cell to optimize contraction, and these can often be modified to benefit the patient with heart damage. These include the action potential, calcium channels, release and uptake of cellular calcium, sensitlvity of contractile proteins to calcium, and energy utillration. A dramatic expansion of our understanding of these cellular contractile and regulatory processes gives us an unprecedented opportunity to devise new ways of modifying cardiac contraction to the benefit of our patients. (AM HEART J 1988; 116:230.)
Harry A. Fozzard, MD. Chicago, Ill.
The normal heart is able to increase its force of contraction as much as tenfold under appropriate stimuli. Increase in force, or the counterpart in muscle shortening, is defined as positive inotropy. Decrease in contraction is negative inotropy. Regulation of contraction strength in heart muscle is very different from that in typical skeletal muscle, where alteration in the pattern of nerve stimulation regulates muscle force. In the heart, regulatory processes are intrinsic to the individual cardiac muscle cells, involving responses to hormones or neurotransmitters, regulation of transmembrane ion transport, cytoplasmic metabolic processes, and perhaps direct physical changes in cell shape. This article is a brief review of the cellular basis for force generation and the regulatory processes that determine the inotropic state of the heart cells. It will attempt to identify the sites in the normal force-generating process within the cell that are, or might eventually be, subject to modification in the interest of the patient with cardiac failure. It will not consider important mechanical factors related to the geometry of the heart and its filling-emptying sequence, which are also central to the effectiveness of the heart as a pump. Three ways that the cardiac cell can change its force development are (1) alteration of the delivery of calcium (Ca) to the contractile proteins, (2) change in the sensitivity of the contractile proteins to calcium, and (3) change in the contractile proteins to alter the chemical-mechanical transduction. The area that is best understood is alteration of delivery From the Departments of Medicine and the Pharmacological & Physiological Sciences, The University of Chicago. Reprint requests: H. A. Fozzard, MD, Box 440, 5841 South Maryland, Chicago, IL 60637.
230
of calcium. The other two areas represent exciting new approaches to modification of cardiac contraction, thus discussion of those areas will be more speculative. CELLULAR
EVENTS
IN THE NORMAL
CONTRACTION
The normal cardiac contractile cycle begins with the action potential. The action potential is generated by a sequence of changes in the surface membrane permeability to sodium (Na), potassium (K), and calcium. It is the trigger for contraction, as well as the means for coordinating contraction of all the cells to make the heart into an effective pump. In addition, the action potential regulates the steady state of contractile force. The trigger for contraction is Ca entry into the cell from the outside solution via voltage-dependent Ca channels. Duration of the action potential also plays an important role in contraction. It provides an absolute refractory period during which the cell cannot have another action potential, thereby triggering another contraction. The refractory period provides sufficient time for the contraction and its relaxation to occur before another contraction. In addition, depolarization of several hundred milliseconds’ duration allows flow of Ca into the cell that will be used to prepare for subsequent contractions. The triggering Ca entry causes release of an intracellular store of Ca in the terminal cisternae of the sarcoplasmic reticulum (SIX). The release mechanism appears to be a Ca-sensitive Ca channel, which allows the stored Ca to enter the cytoplasm ---u’-1aprury . Ca Gi%asa ti the myofibrils and initiates contraction. The myofibrils are a highly organized set of filaments and their attachments. They extend longitudinally within the cell, effectively from one end to
vdum* Mimkr
116 1, Part 1
the other, and provide the molecular machinery for cell shortening or for force development. The myofibril is a series of sarcomeres, attached end-to-end at the Z lines. From two adjacent Z lines extend two arrays of actin filaments, interdigitated with myosin filaments. Myosin filaments are themselves twisted coils of myosin molecules, each of which has a head structure that extends from the filament and which can interact with the actin filaments. The actin filaments have a backbone of actin molecules, but interwoven with them are tropomyosin molecules that prevent the actin-myosin interaction, and sets of three troponin molecules. One of the troponin molecules is the binding site for Ca. When Ca binds, the troponin molecules interact with each other and with tropomyosin so that the tropomyosin inhibition of actin-myosin interaction is released. Binding of the myosin heads to actin initiates a set of molecular movements that causes the two filaments to slide past each other, or to exert force favoring such sliding. Adenosine triphosphate (ATP) is responsible for priming the myosin to be able to interact, and when the myosin head releases from the actin filament, the ATP reaction products dissociate from the myosin. After another ATP nucleotide has bound to myosin, a second binding step and force generation can then occur. In a way not yet clarified, the chemical energy of the ATP supports the molecular conformational changes that result in force generation or movement of the two filaments relative to each other. After Ca release from the SR, the cytoplasmic level of Ca rises and this activates several systems to restore Ca to its resting level. The most immediately important system is an ATP-dependent Ca pump in the SR. This pump transfers Ca back into the terminal cisternae, from which it is available for subsequent release. This process appears to be the major means of lowering Ca to permit dissociation from troponin and for consequent relaxation of the contraction. The lowering of cytoplasmic Ca does not result immediately in relaxation, either because Ca is not immediately dissociated from troponin or because the molecular machinery must go through a complete force-generating cycle before relaxation can occur. Some additional Ca has entered the cell as Ca current during the activation of contraction, requiring some means of Ca efflux if the cell is to maintain a steady state. The two Ca efflux processes are Na/Ca exchange and an ATP-dependent Ca pump. The latter is similar to the SR Ca pump, although it is a different molecule. It may be responsible for fine tuning of the cytoplasmic Ca level between contrac-
Cellular
basis for inotropic
changes
231
tions. The Na/Ca exchange system is a transport process that uses energy derived from the entry of Na down its electrochemical gradient to move Ca out of the cell up its energetic gradient. This is a high-volume system that can prevent Ca overload, but its role in fine tuning of Ca for contraction is not yet clear. The role of Na/Ca exchange will be discussed later. SR slowly recovers its ability to release Ca after the Ca uptake phase is completed. Finally, sufficient ATP must be produced by the mitochondria to sustain contraction. There is no reason to believe that variation in the ATP level or in the levels of other metabolites regulates contraction, except for very low ATP levels in ischemia or for severe acidosis. CALCIUM
CHANNELS
AND THEIR REGULATION
The two roles for Ca channels in contraction are triggering of Ca release from the SR and adjusting the cellular load of Ca.’ Ca channels are integral surface membrane proteins of about 240,000 Kdaltons molecular weight,2 with a density of 1 to 5 channels/Ccm.* They permit Ca to enter the cell passively, driven by the large concentration difference between the outside and the cytoplasm. The channels are gated by the membrane electrical field and by inside Ca ions. There are two types of Ca channels in the heart, often called T and L channels3 While it is tempting to assign triggering to the T-type and loading to the L-type, the present evidence is insufhcient for this conclusion. The distribution of these channels in the heart is not uniform; all cardiac cells have abundant L channels, while atria1 cells’ and Purkinje cell@ also have abundant T channels. At this point we need to learn about the role of T channels in regulating cardiac contraction. The L-type Ca channels play a crucial role in cardiac contraction by providing Ca influx to main+ain or increase the Ca stored in the SR5 Enhancement of current experimentally by exposure to catecholamines, by voltage control, or by increased external Ca, all increase contraction. Reduction in Ca current by reducing external Ca or by blocking Ca channels reduces contraction. Modulation of Ca current is a major clinical tool for control of contraction. Enhancement of calcium current. The prototype intervention that is used to increase Ca current in the heart is by stimulation of the /3-adrenergic receptors on the cardiac cells by such neurotransmitters as norepinephrine or by sympathomimetic drugs. The ,&receptor is coupled by a special G-
232
Fozzard
protein to the adenylate cyclase. Stimulation of the &receptor leads to the activation of the enzyme to cause or to increase production of cyclic adenosine monophosphate (CAMP), which then sets into motion a series of events to increase Ca current.6 The adenylate cyclase is also coupled to the muscarinic receptor through another G-protein. When the muscarinic receptor is activated by acetylcholine released from the vagal nerves, this system reduces the activity of adenylate cyclase, counteracting the effect of ,&receptor activation. The level of CAMP in the cytoplasm is also controlled by its rate of breakdown, which is accomplished by a phosphodiesterase enzyme. Similar inotropic effects can be produced by decreasing breakdown of CAMP or by increasing its production. A number of clinically active drugs act, at least in part, by inhibiting the phosphodiesterase, thereby increasing the cellular levels of CAMP. CAMP as a second messenger acts in turn on a protein kinase (PK-A), releasing an active catalytic subunit. This system is capable of phosphorylating the L-type Ca channel and a host of other proteins.7 This phosphorylation changes the kinetic properties of the Ca channel to increase the Ca current. The mechanism of the increase is not yet entirely resolved, but it appears to be an increase in the probability that the channel will open. The amino acid structure of one type of Ca channel has now been determined, and this should help in understanding the role of phosphorylation in altering Ca channel behavior. Block of calcium current. Block of the L-type calcium channel can be achieved by three types of clinically effective drugs: (1) papaverine derivatives such as verapamil, (2) dephenylalkylamines such as diltiazem, and (3) the dihydropyridine family. These drugs act by binding to specific regions of the channels, rather than by obstructing the channel physically. There may be separate binding sites for each type of blocking, and the sites show some stearic interaction. Binding to the blocking sites has two special and clinically important characteristics. Binding appears to be both voltage-dependent and state-dependent.* The result is that depolarized cells and/or cells with repeated depolarization cycles (e.g., action potentials) show more block. Repeated depolarizations produce progressively more block until a new steady state is reached, a process called “use-denendence.” Conneqllent.ly, the state or activity of cells plays a large role in the extent of block produced. For example, the affinity of binding of some of the dihydropyridine to heart cells is low at normal cell resting potentials, and is increased a
thousandfold by depolarization to near zero.9 The clinical result is that the drugs have less effect on normal cells, but become effective blockers if there is a rapid rhythm and/or if the cells are depolarized. The Ca channel blockers may have very different actions on different tissues. Because the blockers have different binding sites, small changes in structure between tissues can have large effects. Diversity of Ca channel structure between heart and vascular smooth muscle cells could permit some drugs to have no cardiac effect but still have large and possibly selective effects on resistance in certain vascular beds. The state of voltage dependence of binding may explain why some blockers appear so different from others. These factors offer the pharmaceutical industry great opportunity to explore different molecules for selective action of Ca channel blockers, or for combinations of action that are mutually advantageous to patients. Calcium channel agonists. A surprising and exciting development is the discovery that some of the dihydropyridines enhance Ca current rather than depress it. Indeed, some optical isomers have opposite effectslO This stearic difference appears to be sufficient to change the effect of drug binding from channel block to channel opening, and it emphasizes that the drugs are altering some important kinetic element in the channel structure. The experimental study of these complex effects is far from complete. There are some suggestions that a drug may be an agonist at some voltages and a blocker at others.” It is especially exciting for the future to imagine a combination of selective rearrangement of the structure of cloned Ca channels, expression of these modified channels in naive cells, and patch clamping to elucidate the structure-function relationship underlying these complex agonist-blocker properties. Such progress has begun for the acetylcholine activated end-plate channel.12 This might allow further tailoring of Ca channel active agents to produce such combinations as a positive inotropic effect on the heart simultaneous with afterload reduction and coronary vasodilation. CYTOPLASMIC
CALCIUM
REGULATION
The entry of Ca into cells via channels alters the total Ca available for contraction. Typically, this achieves a new steady state after 10 to 100 beats. The Ca entering with Ca current probably contributes little to the contraction triggered by that depolarization, I3 but it is taken up by the SR, to be used for subsequent contraction. SR store is normally not completely filled, so that an increase in the
Volum* Number
116 1, Part 1
store can lead to more Ca released.14 The troponin is also not normally fully saturated, so that greater release of Ca may be translated into greater contraction. The large amount of Ca sequestered by the SR is accomplished through buffering of free Ca by a high concentration of calsequestrin. The capacity of the SR might be altered if the calsequestrin system was affected, but no pharmacologic or pathologic means to do this has been reported. The release mechanism is by a process called “calcium-triggered calcium release.“15 It appears to depend on both an increase in cytoplasmic Ca and the rate at which the increase occurs. The underlying mechanism of release appears to be a Ca channel in the SR that allows Ca to enter the cytoplasm rapidly and is gated by cytoplasmic Ca.16 This channel can be affected by the drug Ryanodine and perhaps by caffeine. The SR uptake system for Ca is the ATP-dependent Ca pump. Muscle relaxation is dependent on its action. It may be modified by its interaction with an associated molecule called phospholamban.17 This molecule can be phosphorylated by PK-A, the CAMP-dependent protein kinase. A rise in CAMP has the dual action of increasing Ca current by phosphorylating the Ca channel in the surface membrane, and by increasing the rate of SR Ca uptake by phosphorylating phospholamban. Phospholamban has additional phosphorylation sites that may be responsive to the calcium-calmodulin-dependent PK and/or to PK-C.‘* The role of this step in control of contraction is not yet clear, but since these kinases are under careful cellular regulation, it could be an important means to affect contraction. Cellular calcium eflux. If there were a finite entry of Ca with each action potential and no means for its exit, the cell would soon be loaded with Ca. A major means of Ca efflux appears to be Na/Ca exchange.lg The process is a countertransport system that uses energy from Na entry into the cell down its electrochemical gradient to prime the carrier so that it can move more Ca up its gradient out of the cell. It appears that there might be 2- ‘/2 to 3 Na moved in for each Ca moved out.20r21 The major role for Na/Ca exchange in regulation of normal contraction is probably Ca efflux after each contraction to maintain the steady-state level of cellular Ca load. Under some circumstances, it may also be responsible for Ca entry during the action potential plateau. The second process for Ca efflux is by an ATP-dependent Ca pump in the surface membrane. The relative roles of the Ca pump and Na/Ca exchange are not yet clear.22*23 A
Cellular basis for inotropic
changes
233
wide variety of interventions appears to affect Nal Ca exchange under nonphysiologic conditionsZ4 but no specific blockers or stimulators are known, and cellular regulation is obscure. Clearly, drugs that affect either Na/Ca exchange or Ca pumping would be expected to have large effects on cardiac contraction. The popular interpretation of the mechanism of action of cardiac glycosides invokes the Na/Ca exchange system. 25 Cardiac glycosides inhibit the Na/K pump, leading to a rise in intracellular Na, which then stimulates the NalK pump rate to bring Na efflux and influx back into balance. The higher intracellular Na reduces the Na gradient that is used to drive Ca out of the cell through Na/Ca exchange, resulting in a higher cytoplasmic Ca. This loads the SR with more Ca, so more is released for contraction. A second possible means of altering intracellular Na is by increasing influx by stimulating action potentials at a higher frequency.26 The rise in intracellular Na would act like cardiac glycosides to increase Ca27 and to increase contraction. The importance of this mechanism in explaining ratedependent changes in contraction strength remains to be resolved.28r29 CALCIUM PROTEIN
SENSITIVITY
OF THE CONTRACTILE
Ca binds to troponin C (Tn-C), which is one of a three-membered troponin complex. This complex, and its associated tropomyosin, is part of the thin actin filament, and it prevents the interaction of the heads of activated myosin molecules from binding to actin. When Ca binds to Tn-C, it interacts with troponin T (Tn-T) and troponin I (Tn-I) to release the tropomyosin-produced inhibition of a segment of the actin. The affinity of Tn-C for Ca is high, but somewhat less than that for the SR Ca pump, so that the SR can remove Ca to produce relaxation. The troponin system is a prime site for intervention that alters the amount of force generated by submaximal cytoplasmic Ca levels. This could occur by altering the Tn-C affinity for Ca, but if the affinity became higher than for the SR Ca pump, relaxation would be compromised. There have been some suggestions that caffeine might alter this Ca sensitivity,30 and pH may be important, through proton competition with Ca for the Tn-C silz31 There is recent evidence of isoforms of Tn-T in heart muscle,32 which do show a difference in Ca sensitivity of the troponin-tropomyosin interaction. This might be a means of modulating Ca sensitivity and perhaps provide a site for drug intervention.
234
Fozzard
Modulation of the actin-myosin interaction. The actin-myosin interaction (the cross-bridge cycle) is a rich matrix for interventions that alter contraction, although there is little that is yet clinically important. Two interesting concepts are perhaps worth mentioning: alteration of the myosin molecule and influence of metabolic intermediates on the chemical reactions. There are many myosin molecule isoforms in muscle. Two main types are described for adult cardiac ventricular muscle, and these differ in their velocity of ATP splitting.33 The balance between these two forms in the ventricle can be altered in some animal species by hormones, especially by thyroid hormones, perhaps also by some component of cardiac work. These different ATP splitting rates can be correlated with experimental measures of contractility. The relevance of this experimental work to human cardiac disease has not yet been resolved, but it represents an important area to explore. The energy in ATP that is used for contraction is obtained by its breakdown to adenosine diphosphate (ADP) and inorganic phosphate (Pi) through a complicated sequence of events. This reaction is potentially influenced by the cytoplasmic levels of ATP, ADP. Pi, and perhaps other related intermediates. ATP does not appear to be limiting until it is reduced to a small fraction of its normal levels, which is achieved only during severe ischemia or metabolic deprivation. j4 Levels of ADP and Pi also do not seem to play much of role in the heart, although they probably do for skeletal muscle.35 The mitochondria, where most of the ATP for contraction is produced, depends on a complex set of membrane transport processes involving Ca cycling, and this represents an almost unexplored area for drug interaction. REFERENCES
1. Gibbons WR. Cellular control of cardiac contraction. In: Fozzard HA, Haber E, Jennings RB, Katz AM, Morgan HE, eds. The heart and cardiovascular system. New York: Raven Press, 1986:747-78. 2. Noda M, Shimizu S, Tsutomu T, et al. Primary structure of Electrophorus electricus sodium channel deduced from CDNA sequence. Nature (Lond) 1984;312:121-7. 3. Nilius B, Hess P, Lansman JB, Tsien RW. A novel type of calcium channel in ventricular heart cells. Nature (Lond) 1985;316:443-6. 4. Bean BP. Two kinds of calcium channels in canine atria1 cells. J Gen Physiol 1985;85:1-30. 1ILL. TT. llllnll” T, Jal,oary CT, Fox~ard HA. Unpubiished observations. 5. Morad M, Cleeman L. Role of Ca*+ channel in development of tension in heart muscle. J Mol Cell Cardiol 1987;19:527-54. 6. Tsien RW. Calcium channels in excitable membranes. Ann Rev Physiol 1983;45:341-58.
American
July 1968 Heart Journal
7. Kamayama M, Heschler J, Hofmann F, Trantwein W. Modulation of Ca current during the phosphorylation cycle in guinea pig heart. Pflugers Arch 1986;407:123-8. 8. Sanguinetti MC, Kass RS. Voltage-dependent block of calciurn channel current in the calf cardiac Purkinje fiber by dihydropyridine calcium channel antagonists. Circ Res 1984; 55336-48. 9. Bean BP. Nitrendioine block of cardiac calcium channels: high-affinity binding to the inactivated state. Proc Nat1 Acad Sci USA 1984;81:6388-92. 10. Hof RP, Ruegg UT, Hof A, Vogel A. Stereoselectivity at the calcium channel: ouposite effects of enantiomers of a 1.4dihydropyridine. J Cardiovasc Pharmacol 1985;4:689-93. 11. Sanguinetti MC, Kass RS. Regulation of cardiac calcium channel current and contractile activity by the dihydropyridine Bay K 8644 is voltage dependent. J Mol Cell Cardiol 1984;16:667-70. 12. Sakmann B, Methfessel C, Mishima M, et al. Role of acetylcholine receptor subunits in gating of the channel. Nature (Land) 1985;318:538-43. 13. Fozzard HA. Heart: excitation-contraction coupling. Ann Rev Physiol 1977;39:201-20. 14. Fabiato A. Myoplasmic free calcium concentration reached durine the twitch of an intact isolated cardiac cell and durine calcium-induced release of calcium from the sarcoplasmic reticulum. J Gen Physiol 1981;78:457-97. 15. Fabiato A. Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol 1983;245 (Cell Physiol 14):61-14. 16. Rousseau E, Smith JS, Henderson JS, Meissner G. Single channel and 45CaZ+ measurements of the cardiac sarcoplasmic reticulum calcium channel. Biophys J 1986$0:1009-14. 17. Katz AM, Takenaka H, Watras J. The sarcoplasmic reticulum. In: Fozzard HA, Haber E, Jennings RB, Katz AM, Morgan HE, eds. The heart and cardiovascular system. New York: Raven Press. 1986731-46. 18. Movsesian MA, Nishikawa M, Adelstein RS. Phosphorylation of phospholamban by calcium-activated, phospholipiddependent protein kinase. J Biol Chem 1984;259:8029-32. 19. Chanman RA. Excitation-contraction counline in cardiac muscle. Prog Biophys Mol Biol 1979;35:1-52. 20. Mullins LJ. Ion transport in heart. New York: Raven Press, 1981:20-43. 21. Sheu S-S. Fozzard HA. Transmembrane Na+ and Ca2+ electrochemical gradients in cardiac muscle and their relationship to force development. J Gen Physiol 1982;80:325-51. 22. Caroni P, Carafoli E. An ATP-dependent Ca*+-pumping system in dog heart sarcolemma. Nature (Lond) 1980; 283:765-7. 23. Sheu S-S, Blaustein MP. Sodium/calcium exchange and regulation of cell calcium and contractility in cardiac muscle. In: Fozzard HA, Haber E, Jennings RB, Katz AM, Morgan HE, eds. The heart and cardiovascular system. New York: Raven Press, 1986:509-36. 24. Phillipson KD. Sodium-calcium exchange in plasma membrane vesicles. Ann Rev Physiol 1985;47:561-71. 25. Fozzard HA, Sheets MF. Cellular mechanisms of action of cardiac glycosides. J Am Co11 Cardiol 1985;5:10A-15A. 26. Cohen CJ, Fozzard HA, Sheu S-S. Increase in intracellular sodium ion activity during stimulation in mammalian cardiac muscle. Circ Res 1982;50:651-62. 27. Lado MG, Sheu S-S, Fozzard HA. Changes in intracellular Ca2+ activity with stimulation in sheep cardiac Purkinje strands. Am J Phvsiol 1982:(Cell Phvsiol 12l:H133-H137. 28. Boyett MR, Hart-G, Levi AJ. Factors affecting intracellular sodium during repetitive activity in isolated sheep Purkinje fibres. J Physiol 1987;384:405-30. 29. Brill DM, Fozzard HA, Makielski JC, Wasserstrom JA. Effect of prolonged depolarizations on twitch tension and intracellular sodium activity in sheep cardiac Purkinje fibres. J Physiol 1987;384:365-76. 30. Marban E, Rink TJ, Tsien RW, Tsien RY. Free calcium in
V0lom0 Number
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Cellular
1
heart muscle at rest and during contraction measured with Ca*+-sensitive microelectrodes. Nature (Land) 1980;286:84550. 31. Fabiato A, Fabiato F. Effects of pH on the myofilaments and the sarcoplasmic reticulum of skinned cells from cardiac and skeletal muscle. J Physiol 1978,276:233-55. 32. Tobacman LS, Lee R. Isolation and functional comparison of bovine cardiac troponin T isoforms. J Biol Chem 1987; 262:4059-64. 33. Mahdavi V, Izumo S, Nadal-Ginard G. Developmental and
basis for inotropic
changes
hormonal regulation of sarcomeric myosin heavy chain gene family. Circ Res 1987;60:804-14. 34. Allen DG, Morris PG, Orchard CH, Pirolo JS. A nuclear magnetic resonance study of metabolism in the ferret heart during hypoxia and inhibition of glycolysis. J Physiol 1985;361:185-204. 35. Nosek TM, Fender KY, Godt RE. It is diprotonated inorganic phosphate that depresses force in skinned sleletal muscle fibers. Science 1987;236:191-3.
Clinical utility of exercise, pacing, and pharmacologic stress testing for the noninvasive determination of myocardial contractility and reserve The ability of the left ventricle to modulate its performance is an important and integral component in the cardiovascular system’s adaptive response to increased workload. Abnormalities in ventricular contractility can blunt this response and thus slgniflcantly limit the patient’s functional capacity. The accurate determination and quantitatlon of cardiac contractility and reserve is a dlfficutt task in the symmetrically contracting ventricle and more so when regional contraction abnormalities are present. Moreover, derangements In other physiologic variables, such as ventricular loading conditions, heart rate, systemic vascular tone, cardiac autonomic function, and Pulmonary gas exchange, can diminish cardiopulmonary reserve. This report relates the determinants of myocardiai oxygen demand and efficiency to the currently available forms of exercise, Pacing, and pharmacologic stress testing. Within this framework, commonly used as well as newer approaches to the noninvasive assessment of stress-induced changee In left ventricular performance and contractility are addressed. In addition, several examples are presented in which noninvasive techniques for assessing intracardiac structures, pressures, and flows (es, echo/Doppler, radionuclide angiography, rapid acqulsitlon computed tomography, and magnetic resonance imaging) are combined with various cardiovascular stress tests to achieve more reliable measures of myocardial contractility and reserve. (AM HEART J 1988;116:235.)
Daniel David, MD, Roberto
M. Lang, MD, and Kenneth
Clinical evaluation of ventricular contractility has always been a major focus of investigation in the field of cardiovascular physiology. This long-standing interest is justified by three important facts.
From the Section of Cardiology, Department of Medicine, The University of Chicago Medical Center. Supported in part by National Institute of Health grant AA-006677, and by a grant-in-aid Reprint requests: gy Lab, University Box 44, Chicago,
from
the American
Heart
Kenneth M. Borow, of Chicago Medical IL 60637.
Association,
Chicago
Affiliate.
MD, Cardiac Noninvasive PhysioloCenter, 5641 South Maryland Ave.,
M. Borow, MD. Chicago, IU.
First, left ventricular (LV) contractile state reflects the calcium-dependent interaction between actin and myosin filaments. As such, it is a fundamental property of the myocardium. Second, contractility is a major determinant of overall LV performance, myocardial oxygen consumption, and long-term clinical prognosis. Finally, information about timerelated changes in contractility and reserve is useful for assessing the efficacy of pharmacologic, surgical, and other therapeutic interventions in various disease states. However, accurate quantitation of cardiac con235
basis for inotropic
changes
in the heart
Cardiac contraction is a highly regulated process that involves nearly every aspect of the cardiac cell function. Many steps in the process are regulated by the cell to optimize contraction, and these can often be modified to benefit the patient with heart damage. These include the action potential, calcium channels, release and uptake of cellular calcium, sensitlvity of contractile proteins to calcium, and energy utillration. A dramatic expansion of our understanding of these cellular contractile and regulatory processes gives us an unprecedented opportunity to devise new ways of modifying cardiac contraction to the benefit of our patients. (AM HEART J 1988; 116:230.)
Harry A. Fozzard, MD. Chicago, Ill.
The normal heart is able to increase its force of contraction as much as tenfold under appropriate stimuli. Increase in force, or the counterpart in muscle shortening, is defined as positive inotropy. Decrease in contraction is negative inotropy. Regulation of contraction strength in heart muscle is very different from that in typical skeletal muscle, where alteration in the pattern of nerve stimulation regulates muscle force. In the heart, regulatory processes are intrinsic to the individual cardiac muscle cells, involving responses to hormones or neurotransmitters, regulation of transmembrane ion transport, cytoplasmic metabolic processes, and perhaps direct physical changes in cell shape. This article is a brief review of the cellular basis for force generation and the regulatory processes that determine the inotropic state of the heart cells. It will attempt to identify the sites in the normal force-generating process within the cell that are, or might eventually be, subject to modification in the interest of the patient with cardiac failure. It will not consider important mechanical factors related to the geometry of the heart and its filling-emptying sequence, which are also central to the effectiveness of the heart as a pump. Three ways that the cardiac cell can change its force development are (1) alteration of the delivery of calcium (Ca) to the contractile proteins, (2) change in the sensitivity of the contractile proteins to calcium, and (3) change in the contractile proteins to alter the chemical-mechanical transduction. The area that is best understood is alteration of delivery From the Departments of Medicine and the Pharmacological & Physiological Sciences, The University of Chicago. Reprint requests: H. A. Fozzard, MD, Box 440, 5841 South Maryland, Chicago, IL 60637.
230
of calcium. The other two areas represent exciting new approaches to modification of cardiac contraction, thus discussion of those areas will be more speculative. CELLULAR
EVENTS
IN THE NORMAL
CONTRACTION
The normal cardiac contractile cycle begins with the action potential. The action potential is generated by a sequence of changes in the surface membrane permeability to sodium (Na), potassium (K), and calcium. It is the trigger for contraction, as well as the means for coordinating contraction of all the cells to make the heart into an effective pump. In addition, the action potential regulates the steady state of contractile force. The trigger for contraction is Ca entry into the cell from the outside solution via voltage-dependent Ca channels. Duration of the action potential also plays an important role in contraction. It provides an absolute refractory period during which the cell cannot have another action potential, thereby triggering another contraction. The refractory period provides sufficient time for the contraction and its relaxation to occur before another contraction. In addition, depolarization of several hundred milliseconds’ duration allows flow of Ca into the cell that will be used to prepare for subsequent contractions. The triggering Ca entry causes release of an intracellular store of Ca in the terminal cisternae of the sarcoplasmic reticulum (SIX). The release mechanism appears to be a Ca-sensitive Ca channel, which allows the stored Ca to enter the cytoplasm ---u’-1aprury . Ca Gi%asa ti the myofibrils and initiates contraction. The myofibrils are a highly organized set of filaments and their attachments. They extend longitudinally within the cell, effectively from one end to
vdum* Mimkr
116 1, Part 1
the other, and provide the molecular machinery for cell shortening or for force development. The myofibril is a series of sarcomeres, attached end-to-end at the Z lines. From two adjacent Z lines extend two arrays of actin filaments, interdigitated with myosin filaments. Myosin filaments are themselves twisted coils of myosin molecules, each of which has a head structure that extends from the filament and which can interact with the actin filaments. The actin filaments have a backbone of actin molecules, but interwoven with them are tropomyosin molecules that prevent the actin-myosin interaction, and sets of three troponin molecules. One of the troponin molecules is the binding site for Ca. When Ca binds, the troponin molecules interact with each other and with tropomyosin so that the tropomyosin inhibition of actin-myosin interaction is released. Binding of the myosin heads to actin initiates a set of molecular movements that causes the two filaments to slide past each other, or to exert force favoring such sliding. Adenosine triphosphate (ATP) is responsible for priming the myosin to be able to interact, and when the myosin head releases from the actin filament, the ATP reaction products dissociate from the myosin. After another ATP nucleotide has bound to myosin, a second binding step and force generation can then occur. In a way not yet clarified, the chemical energy of the ATP supports the molecular conformational changes that result in force generation or movement of the two filaments relative to each other. After Ca release from the SR, the cytoplasmic level of Ca rises and this activates several systems to restore Ca to its resting level. The most immediately important system is an ATP-dependent Ca pump in the SR. This pump transfers Ca back into the terminal cisternae, from which it is available for subsequent release. This process appears to be the major means of lowering Ca to permit dissociation from troponin and for consequent relaxation of the contraction. The lowering of cytoplasmic Ca does not result immediately in relaxation, either because Ca is not immediately dissociated from troponin or because the molecular machinery must go through a complete force-generating cycle before relaxation can occur. Some additional Ca has entered the cell as Ca current during the activation of contraction, requiring some means of Ca efflux if the cell is to maintain a steady state. The two Ca efflux processes are Na/Ca exchange and an ATP-dependent Ca pump. The latter is similar to the SR Ca pump, although it is a different molecule. It may be responsible for fine tuning of the cytoplasmic Ca level between contrac-
Cellular
basis for inotropic
changes
231
tions. The Na/Ca exchange system is a transport process that uses energy derived from the entry of Na down its electrochemical gradient to move Ca out of the cell up its energetic gradient. This is a high-volume system that can prevent Ca overload, but its role in fine tuning of Ca for contraction is not yet clear. The role of Na/Ca exchange will be discussed later. SR slowly recovers its ability to release Ca after the Ca uptake phase is completed. Finally, sufficient ATP must be produced by the mitochondria to sustain contraction. There is no reason to believe that variation in the ATP level or in the levels of other metabolites regulates contraction, except for very low ATP levels in ischemia or for severe acidosis. CALCIUM
CHANNELS
AND THEIR REGULATION
The two roles for Ca channels in contraction are triggering of Ca release from the SR and adjusting the cellular load of Ca.’ Ca channels are integral surface membrane proteins of about 240,000 Kdaltons molecular weight,2 with a density of 1 to 5 channels/Ccm.* They permit Ca to enter the cell passively, driven by the large concentration difference between the outside and the cytoplasm. The channels are gated by the membrane electrical field and by inside Ca ions. There are two types of Ca channels in the heart, often called T and L channels3 While it is tempting to assign triggering to the T-type and loading to the L-type, the present evidence is insufhcient for this conclusion. The distribution of these channels in the heart is not uniform; all cardiac cells have abundant L channels, while atria1 cells’ and Purkinje cell@ also have abundant T channels. At this point we need to learn about the role of T channels in regulating cardiac contraction. The L-type Ca channels play a crucial role in cardiac contraction by providing Ca influx to main+ain or increase the Ca stored in the SR5 Enhancement of current experimentally by exposure to catecholamines, by voltage control, or by increased external Ca, all increase contraction. Reduction in Ca current by reducing external Ca or by blocking Ca channels reduces contraction. Modulation of Ca current is a major clinical tool for control of contraction. Enhancement of calcium current. The prototype intervention that is used to increase Ca current in the heart is by stimulation of the /3-adrenergic receptors on the cardiac cells by such neurotransmitters as norepinephrine or by sympathomimetic drugs. The ,&receptor is coupled by a special G-
232
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protein to the adenylate cyclase. Stimulation of the &receptor leads to the activation of the enzyme to cause or to increase production of cyclic adenosine monophosphate (CAMP), which then sets into motion a series of events to increase Ca current.6 The adenylate cyclase is also coupled to the muscarinic receptor through another G-protein. When the muscarinic receptor is activated by acetylcholine released from the vagal nerves, this system reduces the activity of adenylate cyclase, counteracting the effect of ,&receptor activation. The level of CAMP in the cytoplasm is also controlled by its rate of breakdown, which is accomplished by a phosphodiesterase enzyme. Similar inotropic effects can be produced by decreasing breakdown of CAMP or by increasing its production. A number of clinically active drugs act, at least in part, by inhibiting the phosphodiesterase, thereby increasing the cellular levels of CAMP. CAMP as a second messenger acts in turn on a protein kinase (PK-A), releasing an active catalytic subunit. This system is capable of phosphorylating the L-type Ca channel and a host of other proteins.7 This phosphorylation changes the kinetic properties of the Ca channel to increase the Ca current. The mechanism of the increase is not yet entirely resolved, but it appears to be an increase in the probability that the channel will open. The amino acid structure of one type of Ca channel has now been determined, and this should help in understanding the role of phosphorylation in altering Ca channel behavior. Block of calcium current. Block of the L-type calcium channel can be achieved by three types of clinically effective drugs: (1) papaverine derivatives such as verapamil, (2) dephenylalkylamines such as diltiazem, and (3) the dihydropyridine family. These drugs act by binding to specific regions of the channels, rather than by obstructing the channel physically. There may be separate binding sites for each type of blocking, and the sites show some stearic interaction. Binding to the blocking sites has two special and clinically important characteristics. Binding appears to be both voltage-dependent and state-dependent.* The result is that depolarized cells and/or cells with repeated depolarization cycles (e.g., action potentials) show more block. Repeated depolarizations produce progressively more block until a new steady state is reached, a process called “use-denendence.” Conneqllent.ly, the state or activity of cells plays a large role in the extent of block produced. For example, the affinity of binding of some of the dihydropyridine to heart cells is low at normal cell resting potentials, and is increased a
thousandfold by depolarization to near zero.9 The clinical result is that the drugs have less effect on normal cells, but become effective blockers if there is a rapid rhythm and/or if the cells are depolarized. The Ca channel blockers may have very different actions on different tissues. Because the blockers have different binding sites, small changes in structure between tissues can have large effects. Diversity of Ca channel structure between heart and vascular smooth muscle cells could permit some drugs to have no cardiac effect but still have large and possibly selective effects on resistance in certain vascular beds. The state of voltage dependence of binding may explain why some blockers appear so different from others. These factors offer the pharmaceutical industry great opportunity to explore different molecules for selective action of Ca channel blockers, or for combinations of action that are mutually advantageous to patients. Calcium channel agonists. A surprising and exciting development is the discovery that some of the dihydropyridines enhance Ca current rather than depress it. Indeed, some optical isomers have opposite effectslO This stearic difference appears to be sufficient to change the effect of drug binding from channel block to channel opening, and it emphasizes that the drugs are altering some important kinetic element in the channel structure. The experimental study of these complex effects is far from complete. There are some suggestions that a drug may be an agonist at some voltages and a blocker at others.” It is especially exciting for the future to imagine a combination of selective rearrangement of the structure of cloned Ca channels, expression of these modified channels in naive cells, and patch clamping to elucidate the structure-function relationship underlying these complex agonist-blocker properties. Such progress has begun for the acetylcholine activated end-plate channel.12 This might allow further tailoring of Ca channel active agents to produce such combinations as a positive inotropic effect on the heart simultaneous with afterload reduction and coronary vasodilation. CYTOPLASMIC
CALCIUM
REGULATION
The entry of Ca into cells via channels alters the total Ca available for contraction. Typically, this achieves a new steady state after 10 to 100 beats. The Ca entering with Ca current probably contributes little to the contraction triggered by that depolarization, I3 but it is taken up by the SR, to be used for subsequent contraction. SR store is normally not completely filled, so that an increase in the
Volum* Number
116 1, Part 1
store can lead to more Ca released.14 The troponin is also not normally fully saturated, so that greater release of Ca may be translated into greater contraction. The large amount of Ca sequestered by the SR is accomplished through buffering of free Ca by a high concentration of calsequestrin. The capacity of the SR might be altered if the calsequestrin system was affected, but no pharmacologic or pathologic means to do this has been reported. The release mechanism is by a process called “calcium-triggered calcium release.“15 It appears to depend on both an increase in cytoplasmic Ca and the rate at which the increase occurs. The underlying mechanism of release appears to be a Ca channel in the SR that allows Ca to enter the cytoplasm rapidly and is gated by cytoplasmic Ca.16 This channel can be affected by the drug Ryanodine and perhaps by caffeine. The SR uptake system for Ca is the ATP-dependent Ca pump. Muscle relaxation is dependent on its action. It may be modified by its interaction with an associated molecule called phospholamban.17 This molecule can be phosphorylated by PK-A, the CAMP-dependent protein kinase. A rise in CAMP has the dual action of increasing Ca current by phosphorylating the Ca channel in the surface membrane, and by increasing the rate of SR Ca uptake by phosphorylating phospholamban. Phospholamban has additional phosphorylation sites that may be responsive to the calcium-calmodulin-dependent PK and/or to PK-C.‘* The role of this step in control of contraction is not yet clear, but since these kinases are under careful cellular regulation, it could be an important means to affect contraction. Cellular calcium eflux. If there were a finite entry of Ca with each action potential and no means for its exit, the cell would soon be loaded with Ca. A major means of Ca efflux appears to be Na/Ca exchange.lg The process is a countertransport system that uses energy from Na entry into the cell down its electrochemical gradient to prime the carrier so that it can move more Ca up its gradient out of the cell. It appears that there might be 2- ‘/2 to 3 Na moved in for each Ca moved out.20r21 The major role for Na/Ca exchange in regulation of normal contraction is probably Ca efflux after each contraction to maintain the steady-state level of cellular Ca load. Under some circumstances, it may also be responsible for Ca entry during the action potential plateau. The second process for Ca efflux is by an ATP-dependent Ca pump in the surface membrane. The relative roles of the Ca pump and Na/Ca exchange are not yet clear.22*23 A
Cellular basis for inotropic
changes
233
wide variety of interventions appears to affect Nal Ca exchange under nonphysiologic conditionsZ4 but no specific blockers or stimulators are known, and cellular regulation is obscure. Clearly, drugs that affect either Na/Ca exchange or Ca pumping would be expected to have large effects on cardiac contraction. The popular interpretation of the mechanism of action of cardiac glycosides invokes the Na/Ca exchange system. 25 Cardiac glycosides inhibit the Na/K pump, leading to a rise in intracellular Na, which then stimulates the NalK pump rate to bring Na efflux and influx back into balance. The higher intracellular Na reduces the Na gradient that is used to drive Ca out of the cell through Na/Ca exchange, resulting in a higher cytoplasmic Ca. This loads the SR with more Ca, so more is released for contraction. A second possible means of altering intracellular Na is by increasing influx by stimulating action potentials at a higher frequency.26 The rise in intracellular Na would act like cardiac glycosides to increase Ca27 and to increase contraction. The importance of this mechanism in explaining ratedependent changes in contraction strength remains to be resolved.28r29 CALCIUM PROTEIN
SENSITIVITY
OF THE CONTRACTILE
Ca binds to troponin C (Tn-C), which is one of a three-membered troponin complex. This complex, and its associated tropomyosin, is part of the thin actin filament, and it prevents the interaction of the heads of activated myosin molecules from binding to actin. When Ca binds to Tn-C, it interacts with troponin T (Tn-T) and troponin I (Tn-I) to release the tropomyosin-produced inhibition of a segment of the actin. The affinity of Tn-C for Ca is high, but somewhat less than that for the SR Ca pump, so that the SR can remove Ca to produce relaxation. The troponin system is a prime site for intervention that alters the amount of force generated by submaximal cytoplasmic Ca levels. This could occur by altering the Tn-C affinity for Ca, but if the affinity became higher than for the SR Ca pump, relaxation would be compromised. There have been some suggestions that caffeine might alter this Ca sensitivity,30 and pH may be important, through proton competition with Ca for the Tn-C silz31 There is recent evidence of isoforms of Tn-T in heart muscle,32 which do show a difference in Ca sensitivity of the troponin-tropomyosin interaction. This might be a means of modulating Ca sensitivity and perhaps provide a site for drug intervention.
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Fozzard
Modulation of the actin-myosin interaction. The actin-myosin interaction (the cross-bridge cycle) is a rich matrix for interventions that alter contraction, although there is little that is yet clinically important. Two interesting concepts are perhaps worth mentioning: alteration of the myosin molecule and influence of metabolic intermediates on the chemical reactions. There are many myosin molecule isoforms in muscle. Two main types are described for adult cardiac ventricular muscle, and these differ in their velocity of ATP splitting.33 The balance between these two forms in the ventricle can be altered in some animal species by hormones, especially by thyroid hormones, perhaps also by some component of cardiac work. These different ATP splitting rates can be correlated with experimental measures of contractility. The relevance of this experimental work to human cardiac disease has not yet been resolved, but it represents an important area to explore. The energy in ATP that is used for contraction is obtained by its breakdown to adenosine diphosphate (ADP) and inorganic phosphate (Pi) through a complicated sequence of events. This reaction is potentially influenced by the cytoplasmic levels of ATP, ADP. Pi, and perhaps other related intermediates. ATP does not appear to be limiting until it is reduced to a small fraction of its normal levels, which is achieved only during severe ischemia or metabolic deprivation. j4 Levels of ADP and Pi also do not seem to play much of role in the heart, although they probably do for skeletal muscle.35 The mitochondria, where most of the ATP for contraction is produced, depends on a complex set of membrane transport processes involving Ca cycling, and this represents an almost unexplored area for drug interaction. REFERENCES
1. Gibbons WR. Cellular control of cardiac contraction. In: Fozzard HA, Haber E, Jennings RB, Katz AM, Morgan HE, eds. The heart and cardiovascular system. New York: Raven Press, 1986:747-78. 2. Noda M, Shimizu S, Tsutomu T, et al. Primary structure of Electrophorus electricus sodium channel deduced from CDNA sequence. Nature (Lond) 1984;312:121-7. 3. Nilius B, Hess P, Lansman JB, Tsien RW. A novel type of calcium channel in ventricular heart cells. Nature (Lond) 1985;316:443-6. 4. Bean BP. Two kinds of calcium channels in canine atria1 cells. J Gen Physiol 1985;85:1-30. 1ILL. TT. llllnll” T, Jal,oary CT, Fox~ard HA. Unpubiished observations. 5. Morad M, Cleeman L. Role of Ca*+ channel in development of tension in heart muscle. J Mol Cell Cardiol 1987;19:527-54. 6. Tsien RW. Calcium channels in excitable membranes. Ann Rev Physiol 1983;45:341-58.
American
July 1968 Heart Journal
7. Kamayama M, Heschler J, Hofmann F, Trantwein W. Modulation of Ca current during the phosphorylation cycle in guinea pig heart. Pflugers Arch 1986;407:123-8. 8. Sanguinetti MC, Kass RS. Voltage-dependent block of calciurn channel current in the calf cardiac Purkinje fiber by dihydropyridine calcium channel antagonists. Circ Res 1984; 55336-48. 9. Bean BP. Nitrendioine block of cardiac calcium channels: high-affinity binding to the inactivated state. Proc Nat1 Acad Sci USA 1984;81:6388-92. 10. Hof RP, Ruegg UT, Hof A, Vogel A. Stereoselectivity at the calcium channel: ouposite effects of enantiomers of a 1.4dihydropyridine. J Cardiovasc Pharmacol 1985;4:689-93. 11. Sanguinetti MC, Kass RS. Regulation of cardiac calcium channel current and contractile activity by the dihydropyridine Bay K 8644 is voltage dependent. J Mol Cell Cardiol 1984;16:667-70. 12. Sakmann B, Methfessel C, Mishima M, et al. Role of acetylcholine receptor subunits in gating of the channel. Nature (Land) 1985;318:538-43. 13. Fozzard HA. Heart: excitation-contraction coupling. Ann Rev Physiol 1977;39:201-20. 14. Fabiato A. Myoplasmic free calcium concentration reached durine the twitch of an intact isolated cardiac cell and durine calcium-induced release of calcium from the sarcoplasmic reticulum. J Gen Physiol 1981;78:457-97. 15. Fabiato A. Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol 1983;245 (Cell Physiol 14):61-14. 16. Rousseau E, Smith JS, Henderson JS, Meissner G. Single channel and 45CaZ+ measurements of the cardiac sarcoplasmic reticulum calcium channel. Biophys J 1986$0:1009-14. 17. Katz AM, Takenaka H, Watras J. The sarcoplasmic reticulum. In: Fozzard HA, Haber E, Jennings RB, Katz AM, Morgan HE, eds. The heart and cardiovascular system. New York: Raven Press. 1986731-46. 18. Movsesian MA, Nishikawa M, Adelstein RS. Phosphorylation of phospholamban by calcium-activated, phospholipiddependent protein kinase. J Biol Chem 1984;259:8029-32. 19. Chanman RA. Excitation-contraction counline in cardiac muscle. Prog Biophys Mol Biol 1979;35:1-52. 20. Mullins LJ. Ion transport in heart. New York: Raven Press, 1981:20-43. 21. Sheu S-S. Fozzard HA. Transmembrane Na+ and Ca2+ electrochemical gradients in cardiac muscle and their relationship to force development. J Gen Physiol 1982;80:325-51. 22. Caroni P, Carafoli E. An ATP-dependent Ca*+-pumping system in dog heart sarcolemma. Nature (Lond) 1980; 283:765-7. 23. Sheu S-S, Blaustein MP. Sodium/calcium exchange and regulation of cell calcium and contractility in cardiac muscle. In: Fozzard HA, Haber E, Jennings RB, Katz AM, Morgan HE, eds. The heart and cardiovascular system. New York: Raven Press, 1986:509-36. 24. Phillipson KD. Sodium-calcium exchange in plasma membrane vesicles. Ann Rev Physiol 1985;47:561-71. 25. Fozzard HA, Sheets MF. Cellular mechanisms of action of cardiac glycosides. J Am Co11 Cardiol 1985;5:10A-15A. 26. Cohen CJ, Fozzard HA, Sheu S-S. Increase in intracellular sodium ion activity during stimulation in mammalian cardiac muscle. Circ Res 1982;50:651-62. 27. Lado MG, Sheu S-S, Fozzard HA. Changes in intracellular Ca2+ activity with stimulation in sheep cardiac Purkinje strands. Am J Phvsiol 1982:(Cell Phvsiol 12l:H133-H137. 28. Boyett MR, Hart-G, Levi AJ. Factors affecting intracellular sodium during repetitive activity in isolated sheep Purkinje fibres. J Physiol 1987;384:405-30. 29. Brill DM, Fozzard HA, Makielski JC, Wasserstrom JA. Effect of prolonged depolarizations on twitch tension and intracellular sodium activity in sheep cardiac Purkinje fibres. J Physiol 1987;384:365-76. 30. Marban E, Rink TJ, Tsien RW, Tsien RY. Free calcium in
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Cellular
1
heart muscle at rest and during contraction measured with Ca*+-sensitive microelectrodes. Nature (Land) 1980;286:84550. 31. Fabiato A, Fabiato F. Effects of pH on the myofilaments and the sarcoplasmic reticulum of skinned cells from cardiac and skeletal muscle. J Physiol 1978,276:233-55. 32. Tobacman LS, Lee R. Isolation and functional comparison of bovine cardiac troponin T isoforms. J Biol Chem 1987; 262:4059-64. 33. Mahdavi V, Izumo S, Nadal-Ginard G. Developmental and
basis for inotropic
changes
hormonal regulation of sarcomeric myosin heavy chain gene family. Circ Res 1987;60:804-14. 34. Allen DG, Morris PG, Orchard CH, Pirolo JS. A nuclear magnetic resonance study of metabolism in the ferret heart during hypoxia and inhibition of glycolysis. J Physiol 1985;361:185-204. 35. Nosek TM, Fender KY, Godt RE. It is diprotonated inorganic phosphate that depresses force in skinned sleletal muscle fibers. Science 1987;236:191-3.
Clinical utility of exercise, pacing, and pharmacologic stress testing for the noninvasive determination of myocardial contractility and reserve The ability of the left ventricle to modulate its performance is an important and integral component in the cardiovascular system’s adaptive response to increased workload. Abnormalities in ventricular contractility can blunt this response and thus slgniflcantly limit the patient’s functional capacity. The accurate determination and quantitatlon of cardiac contractility and reserve is a dlfficutt task in the symmetrically contracting ventricle and more so when regional contraction abnormalities are present. Moreover, derangements In other physiologic variables, such as ventricular loading conditions, heart rate, systemic vascular tone, cardiac autonomic function, and Pulmonary gas exchange, can diminish cardiopulmonary reserve. This report relates the determinants of myocardiai oxygen demand and efficiency to the currently available forms of exercise, Pacing, and pharmacologic stress testing. Within this framework, commonly used as well as newer approaches to the noninvasive assessment of stress-induced changee In left ventricular performance and contractility are addressed. In addition, several examples are presented in which noninvasive techniques for assessing intracardiac structures, pressures, and flows (es, echo/Doppler, radionuclide angiography, rapid acqulsitlon computed tomography, and magnetic resonance imaging) are combined with various cardiovascular stress tests to achieve more reliable measures of myocardial contractility and reserve. (AM HEART J 1988;116:235.)
Daniel David, MD, Roberto
M. Lang, MD, and Kenneth
Clinical evaluation of ventricular contractility has always been a major focus of investigation in the field of cardiovascular physiology. This long-standing interest is justified by three important facts.
From the Section of Cardiology, Department of Medicine, The University of Chicago Medical Center. Supported in part by National Institute of Health grant AA-006677, and by a grant-in-aid Reprint requests: gy Lab, University Box 44, Chicago,
from
the American
Heart
Kenneth M. Borow, of Chicago Medical IL 60637.
Association,
Chicago
Affiliate.
MD, Cardiac Noninvasive PhysioloCenter, 5641 South Maryland Ave.,
M. Borow, MD. Chicago, IU.
First, left ventricular (LV) contractile state reflects the calcium-dependent interaction between actin and myosin filaments. As such, it is a fundamental property of the myocardium. Second, contractility is a major determinant of overall LV performance, myocardial oxygen consumption, and long-term clinical prognosis. Finally, information about timerelated changes in contractility and reserve is useful for assessing the efficacy of pharmacologic, surgical, and other therapeutic interventions in various disease states. However, accurate quantitation of cardiac con235