© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Electrophysiological changes in heart failure and their relationship to arrhythmogenesis
Center for Molecular Therapeutics, Department of Pharmacology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, PH7 West-318, New York, NY 10032, USA
* Tel.: +1-212-305-8754; fax: +1-212-305-8351. mjj2102{at}columbia.edu
This review focuses mainly on studies in non-ischemic animal models of heart failure. These animals develop ventricular arrhythmias, mostly non-sustained ventricular tachycardia, and often die suddenly. Clinical studies suggest that sudden death is due to ventricular tachycardia or fibrillation in about 50% of cases, the other half to bradyarrhythmias or electromechanical dissociation.
Electrophysiologic changes in heart failure are not confined to the ventricles: the intrinsic sinus rate is reduced due to a downregulation of If and sensitivity to acetylcholine is enhanced by upregulation of the muscarinic receptor. Reduction of heart rate may be a protective mechanism since at rapid rates contractility is reduced and the likelihood for triggered activity due to delayed afterdepolarizations is enhanced. The beneficial effect of β-adrenergic blockade in patients may be partly due to the reduction in sinus rate.
Although the results of different studies often vary, the most consistent electrophysiological changes in the ventricles are prolongation of the action potential, especially at slow rates, a reduction in the transient outward current Ito, the rapid and slow components of the delayed rectifier Ikr and Iks, and the inward rectifier Ik1. Abnormalities in intracellular calcium handling play a major role in the genesis of delayed afterdepolarizations. Triggered activity based on delayed afterdepolarizations has been demonstrated in failing myocardium and are caused by spontaneous release of calcium from the sarcoplasmic reticulum (SR), especially in the presence of noradrenaline. Three factors combine to the enhanced propensity for the occurrence of delayed afterdepolarizations: (1) increased activity of the Na/Ca exchanger, (2) a reduced inward rectifier, (3) residual β-adrenergic responsiveness required to raise the reduced sarcoplasmic calcium content to a level where spontaneous calcium release occurs.
Early afterdepolarizations have also been demonstrated, especially in human myocytes from failing hearts in the presence of noradrenaline.
Mapping experiments have shown that the ventricular arrhythmias are mainly due to non-reentrant mechanisms, most likely triggered activity based on delayed afterdepolarizations.
KEYWORDS Heart failure; Ion channels; SR function; Ventricular arrhythmias
Time for primary review 17 days
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