| Abstract
| - Abstract. The link between cardiac contractile dysfunction in patients with end-stage heart failure and aberrant myocardial intracellular calcium handling is now well established. The precise intracellular protein(s) responsible for this breakdown in calcium handling is at present unclear. However, a number of distinct sarcolemmal (L-type, N-type, T-type, P-type, Q-type) and sarcoplasmic reticular (calcium release, ryanodine) calcium channels that have been defined on a biophysical, biochemical, and molecular basis lend valuable insights into possible factors that may contribute to the abnormal calcium handling in the hearts of these patients. What is now clear is that cardiac muscle contraction is a rigorously regulated event that follows the organized cycling of calcium from the sarcoplasmic reticulum (SR) into the cytosol and back into the SR, and that this cycle follows the graded entry of trigger calcium that enters the cell through the voltage-sensitive calcium channel. Furthermore, the voltage-dependent properties of potential-dependent calcium channels provide the underpinning for the vascular selectivity of the clinically available calcium channel drugs. Moreover, it has also been reported that the efficacy of these agents is augmented in pathologic (ischemic) tissue owing to the state dependence of these channels. Recently, the basis for the critical role of the SR in calcium signaling has started to emerge. The SR calcium handling proteins (SR calcium release channel/ryanodine receptor, SR Ca2+ ATPase, phospholamban, calsequestrin) play a critical role in maintaining intracellular free ionized calcium concentrations ([Ca2+i), which therefore regulate systolic and diastolic function on a beat-to-beat basis within the cardiac cell. This rigorous control of [Ca2+]i is in part the result of the highly developed junctional regions of the cardiac SR. Elucidation of the calcium handling process in these regions and the potential damage resulting from cardiovascular disease has been greatly aided by the invaluable molecular tool, ryandine. From an expanding volume of information provided by animal models of ischemia, hypertrophy, and heart failure, it now appears that changes in cardiac voltage-sensitive calcium channels are likely to be the result of a secondary process that may not be directly linked to the onset of these cardiovascular diseases. Conversely, the regulation of ryanodine receptors has been suggested to be a mechanism initiating the decline in myocardial contractility leading to heart failure. These reports have been supported by studies demonstrating SR calcium release channel/ryanodine receptor changes in pressure overload hypertrophy and myocardial ischemia. Further support for the role of SR calcium release channels in cardiovascular disease is found in reports that couple leaking SR channels with ischemia and cardiac failure. These results suggest that changes in SR calcium handling proteins may be critically linked to cardiovascular disease. A more central question stemming from these results is exactly how these altered SR calcium handling proteins are involved with the onset and progression of cardiovascular disease. Application of transgenic technologies and animal models of chronic heart failure that parallel the human condition will provide the means necessary for unequivocally determining if the apparent adaptive changes in calcium handling are associated with the onset and progression of this syndrome.
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