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 the development of myocardial hypertrophy and the transition to heart failure are discussed. The leading question is at what stage of hypertrophy or heart failure Ca2+ handling can turn arrhythmogenic. During the development of myocardial hypertrophy and the transition to failure, Ca2+ handling is progressively 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 progressively defective Ca2+ uptake into the sarcoplasmic reticulum that seems to be caused by quantitative changes of gene expression of the Ca2+ ATPase of the sarcoplasmic reticulum. Increased expression and activity of the Na+/Ca2+ 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+ - during stress conditions, resulting Ca2+ overload can lead to spontaneous intracellular Ca2+ oscillations, after depolarizations. Thus, after the transition to heart failure, Ca2+ overloaded sarcoplasmic reticulum, increasing resting intracellular Ca2+, and increased Na+/Ca2+ activity may all provoke afterdepolarizations, triggered activity, and finally, life-threatening ventricular arrhythmias. This increased susceptibility to ventricular arrhythmias in heart failure should not be treated with calcium antagonists.