© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
The role of action potential prolongation and altered intracellular calcium handling in the pathogenesis of heart failure
aThe Centre for Cardiovascular Research, Division of Cardiology, The Toronto Hospital, The Department of Medicine and The Institute of Medical Sciences, University of Toronto, 101 College Street, CCRW 3-802, Toronto, Ontario M5G 2C4, Canada
bSection of Molecular Cardiology, Albert Einstein College of Medicine, New York, USA
* Corresponding author. Tel. (+1-416) 340 4083; Fax (+1-416) 340 4596; E-mail: p.backx@utoronto.ca
Action potential prolongation is a common finding in human heart failure and in animal models of cardiac hypertrophy. The mechanism of action potential prolongation involves altered expression of a variety of depolarising and hyperpolarising currents in the myocardium. In particular, decreased density of the transient outward potassium current seems to play a prominent role, regardless of species, precipitating factors or the severity of hypertrophy. The decreased density of the transient outward current appears to be caused by reduced transcription of Kv4.2 and Kv4.3 and may be caused in part by an inhibitory effect of 
-adrenoceptor stimulation. During the early stage of the disease process, action potential prolongation may increase the amplitude of the intracellular calcium transient, causing positive inotropy. We argue therefore, that action prolongation may be a compensatory response which may acutely support the compromised cardiac output. In severe hypertrophy and end-stage heart failure however, despite continued action potential prolongation, the amplitude of the calcium transient becomes severely reduced. The mechanism underlying this event appears to involve reduced expression of calcium handling proteins, and these late events may herald the onset of failure. At present the events leading to the late changes in calcium handling are poorly understood. However, chronic activation of compensatory mechanisms including action potential prolongation may trigger these late events. In the present article we outline a hypothesis which describes a potential role for action potential prolongation, and the associated elevation in the levels of intracellular calcium, in maladaptive gene expression and the progression toward cardiac failure.
KEYWORDS Heart failure; K+ channels; Action potential; Calcium
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