Regulation of Cardiac Contraction and Relaxation

Myocardial contraction and its control can be understood in terms of the interactions among six proteins. Each myosin molecule contains two heavy chains that extend through both head and tail, and four light chains that are associated with the head of the molecule. The heavy chains are the major determinants of myosin adenosine triphosphatase (ATPase) activity in vitro and of shortening velocity in the living muscle. Both the myosin heavy chains and light chains are members of multigene families. Isoform shifts involving the myosin heavy chains occur in chronically overloaded and failing hearts, where they participate in both the adaptive and the maladaptive response to chronic overloading. Myosin heavy chain isoforms can also change with endocrine abnormalities, notably thyroid disorders, and with aging. Cardiac muscle troponin I contains a serine residue that, when phosphorylated by a cyclic adenosine monophosphate (cAMP)-dependent protein kinase, reduces the calcium affinity of troponin C. The resulting desensitization of the response of the myocardium to calcium favors relaxation in the heart under the influence of β-adrenergic agonists. Although troponin T itself does not bind calcium, isoform switches involving this protein appear to modify the calcium sensitivity of tension development. One such change may contribute to the desensitization of the contractile proteins in the chronically overloaded heart. Physiologic control of the interactions between actin and myosin is brought about by variations in the calcium concentration around the myofibrils. Excitation-contraction coupling is the process by which depolarization of the cell surface membrane initiates the interactions between the contractile proteins that lead to tension development and shortening in the walls of the heart. Activation of contraction is effected by passive calcium fluxes, in which this activator moves downhill to reach its binding sites on troponin C. Relaxation, on the other hand, requires that energy be expended to move calcium uphill, out of the cytosol. Excitation-contraction coupling and relaxation depend on calcium fluxes through calcium channels and calcium pumps. These membrane proteins enable the heart to adjust its mechanical behavior to a variety of physiologic, pharmacologic, and pathophysiologic stimuli that modify the systems that participate in the delivery and subsequent removal of activator calcium. Most of the calcium that enters the cardiac cell during each action potential is removed by an ion exchanger in the plasma membrane, which can carry either sodium or calcium in both directions across the plasma membrane. The sodium-calcium exchanger is electrogenic because it transports three sodium ions in one direction across the membrane in exchange for a single calcium ion that moves in the opposite direction. This exchange of three monovalent sodium ions for one divalent calcium ion generates ionic current across the plasma membrane. Calcium efflux via this exchanger generates an inward (depolarizing) current that is responsible for afterdepolarizations that, in calcium-overloaded hearts, are a major cause of arrhythmias and sudden cardiac death. The sarcoplasmic reticulum is an intracellular membrane system whose major function is to regulate cytosolic calcium concentration by taking up, storing, and releasing calcium. Because the amount of calcium released for binding to the cardiac contractile proteins controls myocardial contractility, regulation of calcium release from the sarcoplasmic reticulum is a major determinant of the mechanical performance of the heart. The response of the heart to sympathetic stimulation, which is mediated by cAMP, includes stimulation of calcium transport by the sarcoplasmic reticulum. Phosphodiesterase inhibitors, which inhibit cAMP breakdown, also increase calcium uptake into the sarcoplasmic reticulum. Increased cytosolic levels of cAMP stimulate the sarcoplasmic reticulum by activating a cAMP-dependent protein kinase that phosphorylates phospholamban, a small regulatory protein that in its dephosphorylated state inhibits this calcium pump. Reversal of this inhibition when phospholamban is phosphorylated by either protein kinase A or a calcium-calmodulin-activated protein kinase increases calcium transport by the pump. The inhibition reappears when phospholamban is dephosphorylated by a phosphoprotein phosphatase. The response to cAMP-dependent protein kinase enables sympathetic stimulation to promote relaxation by accelerating calcium transport into the sarcoplasmic reticulum. Phosphorylation of phospholamban also increases myocardial contractility by favoring retention of activator calcium in intracellular stores at the expense of calcium efflux via the plasma membrane calcium pump and sodium-calcium exchange. The physiologic importance of the ability of cAMP-dependent protein kinase to stimulate calcium transport into the cardiac sarcoplasmic reticulum is related to the powerful effect of sympathetic stimulation in increasing myocardial contractility, which is mediated by increased calcium entry through the plasma membrane calcium channels (dihydropyridine receptors). At the same time, sympathetic stimulation markedly increases heart rate and therefore shortens diastole. Together, these responses require that a greater amount of calcium be pumped back into the sarcoplasmic reticulum in a shorter time period to allow the ventricle to fill. This is accomplished through two phosphorylation reactions: phospholamban phosphorylation, which increases both the rate and the calcium sensitivity of calcium transport into the cardiac sarcoplasmic reticulum, and troponin I phosphorylation, which decreases the calcium sensitivity of the heart’s contractile proteins. Excitation-contraction coupling and relaxation can be described in terms of two calcium cycles in which calcium moves between five compartments within the heart: extracellular space, sarcoplasmic reticulum, cytosol, troponin, and mitochondria (see Fig. 52.5). The calcium fluxes among these compartments, which initiate and terminate systole and play a major role in the regulation of myocardial contractility and filling, can be viewed as two distinct calcium cycles: an external circulation across the plasma membrane and an internal circulation within the cell. The most important consequences of energy starvation are caused by slowed rephosphorylation of adenosine diphosphate (ADP) and accumulation of inorganic phosphate (Pi), both of which reduce the free energy made available through hydrolysis of the terminal (high-energy) phosphate bond of adenosine triphosphate (ATP). This free energy is proportional to the phosphorylation potential, which is defined as the ratio (ATP/ADP × Pi). ADP levels in the normal heart are much lower than those of ATP, so even a relatively minor decrease in ATP content in an energy-starved heart causes a much greater rise in ADP levels. The resulting decrease in the ATP/ ADP ratio reduces the free energy available for energyconsuming reactions, which can seriously impair the ability of ATP to power key cellular function. Because there is very little reserve in the phosphorylation potential of the heart, even a 15% to 25% reduction in this ratio can inhibit ATP-dependent reactions. The sarcoplasmic reticulum calcium pump is especially sensitive to reduced free energy release from ATP, which may explain why relaxation is more sensitive to energy starvation than is contraction.