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.
Zaugg
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University Hospital, Department of Research, ZLF 319, Hebelstr. 20, 4031 Basel, Switzerland. Christian.Zaugg@unibas.ch
Buser
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PT
D002118:Calcium / Q000378:metabolism*; D006333:Heart Failure / Q000453:epidemiology / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000453:epidemiology / Q000209:etiology* / Q000378:metabolism; D015994:Incidence; D017136:Ion Transport / Q000502:physiology*; D018570:Risk Assessment; D012307:Risk Factors; D012680:Sensitivity and Specificity; D017180:Tachycardia, Ventricular / Q000453:epidemiology / Q000209:etiology* / Q000378:metabolism
D002118:Calcium