PATHOPHYSIOLOGIC EFFECTS OF SPONTANEOUS CA2+ RELEASE IN THE HEART

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All mammalian cardiac preparation, given sufficient Ca2+ loading, exhibit spontaneous release of Ca2+ from the sarcoplasmic reticulum (SR). Videomicroscopy in muscle and myocytes has shown that the myofilament motion due to this type of Ca2+ release is (1) spatially non-uniform and (2) propagates at approximately 100 um sec as a contractile wave, indicating that the spontaneous Ca2+ release occurs locally, and, in diffusing down its concentration gradient, cause a regenerative Ca2+ induced Ca2+ release from the SR. The localized (Ca2+) achieved as result of spontaneous SR release has been estimated to range from a few um to 40 mu M. Myofilaments in areas of high Ca2+ shorten and stretch neighboring myofilaments where (Ca2+ is lower. Since, in bulk cardiac tissue this occurs asynchronously among cells, quiescent cells are stretched and therefore sarcomere loading in these cells is affected. The net result of these events is Ca2+-dependent diastolic tonus. The diastolic oscillatory Ca2+ modulation of sarcolemmal ion conductances within areas of high Cai results in sarcolemmal depolarization, which, if sufficient in magnitude, triggers a spontaneous action potential and leads to arrhythmias. Finally, the resultant inhomogeneity in the potential and lads to arrhythmias. Finally, the resultant inhomogeneity in the extent of SR Ca2+ loading and phases of SR Ca2+ recycling that occur in the presence of spontaneous SR Ca2+ release cause a reduction in the net extent and synchrony of systolic Ca2+ release from the SR by a subsequent action potential. This impairs systolic function. Enhanced diastolic tone, the occurrence of arrhythmias, and compromised systolic function are cardinal signs of many myocardial disease states. The conceptualization of spontaneous SR Ca2+ release as interpreted and discussed in the context of the present findings in cardiac myocytes, though speculative is some regard, provides a logical framework in which no structure testable hypotheses about its potential role in the pathophysiology of some forms of heart disease.