Myocardial Ca2+handling and cell-to-cell coupling, key factors in prevention of sudden cardiac deathThis article is one of a selection of papers published in a special issue on Advances in Cardiovascular Research.

Abstract

Using whole-heart preparations, we tested our hypothesis that Ca2+handling is closely related to cell-to-cell coupling at the gap junctions and that both are critical for the development and particularly the termination of ventricular fibrillation (VF) and hence the prevention of sudden arrhythmic death. Intracellular free calcium concentration ([Ca2+]i), ECG, and left ventricular pressure were continuously monitored in isolated guinea pig hearts before and during development of low K+-induced sustained VF and during its conversion into sinus rhythm facilitated by stobadine. We also examined myocardial ultrastructure to detect cell-to-cell coupling alterations. We demonstrated that VF occurrence was preceded by a 55.9% ± 6.2% increase in diastolic [Ca2+]i, which was associated with subcellular alterations indicating Ca2+overload of the cardiomyocytes and disorders in coupling among the cells. Moreover, VF itself further increased [Ca2+]iby 58.2% ± 3.4% and deteriorated subcellular and cell-to-cell coupling abnormalities that were heterogeneously distributed throughout the myocardium. In contrast, termination of VF and its conversion into sinus rhythm was marked by restoration of basal [Ca2+]i, resulting in recovery of intercellular coupling linked with synchronous contraction. Furthermore, we have shown that hearts exhibiting lower SERCA2a (sarcoplasmic reticulum Ca2+-ATPase) activity and abnormal intercellular coupling (as in older guinea pigs) are more prone to develop Ca2+overload associated with cell-to-cell uncoupling than hearts with higher SERCA2a activity (as in young guinea pigs). Consequently, young animals are better able to terminate VF spontaneously. These findings indicate the crucial role of Ca2+handling in relation to cell-to-cell coupling in both the occurrence and termination of malignant arrhythmia.