When calcium turns arrhythmogenic: Intracellular calcium handling during the development of hypertrophy and heart failure

Alterations of intracellular Ca2+ handling in hypertrophied myocardium have been proposed as a mechanism of ventricular tachyarrhythmias, which are a major cause of sudden death in patients with heart failure. In this review, alterations in intracellular Ca2+ handling and Ca2+ handling proteins in t he development of myocardial hypertrophy and the transition to heart failur e are discussed. The leading question is at what stage of hypertrophy or he art failure Ca2+ handling can turn arrhythmogenic. During the development o f myocardial hypertrophy and the transition to failure, Ca2+ handling is pr ogressively altered. Recordings of free myocyte Ca2+ concentrations during a cardiac cycle (Ca2+ transients) are prolonged early in the development of hypertrophy. However, resting (or diastolic) Ca2+ does not increase before end-stage heart failure has developed. These alterations are due to progre ssively defective Ca2+ uptake into the sarcoplasmic reticulum that scums to be caused by quantitative changes of gene expression of the Ca2+ ATPase of the sarcoplasmic reticulum. Increased expression and activity of the Na+/C a2+ exchanger might compensate for this defective Ca2+ uptake, probably at the expense of increased arrhythmogenicity. When the Ca2+ handling proteins no longer efficiently counterbalance increasing intracellular Ca2+ - durin g stress conditions, resulting Ca2+ overload can lead to spontaneous intrac ellular Ca2+ oscillations, after depolarizations. Thus, after the transitio n to heart failure, Ca2+ overloaded sarcoplasmic reticulum, increasing rest ing intracellular Ca2+, and increased Na+/Ca2+ activity may all provoke aft erdepolarizations, triggered activity, and finally, life-threatening ventri cular arrhythmias. This increased susceptibility to ventricular arrhythmias in heart failure should not be treated with calcium antagonists.