THE ROLE OF ACTION-POTENTIAL PROLONGATION AND ALTERED INTRACELLULAR CALCIUM HANDLING IN THE PATHOGENESIS OF HEART-FAILURE

Action potential prolongation is a common finding in human heart failu re and in animal models of cardiac hypertrophy. The mechanism of actio n potential prolongation involves altered expression of a variety of d epolarising and hyperpolarising currents in the myocardium. In particu lar, decreased density of the transient outward potassium current seem s to play a prominent role, regardless of species, precipitating facto rs or the severity of hypertrophy. The decreased density of the transi ent outward current appears to be caused by reduced transcription of K v4.2 and Kv4.3 and may be caused in part by an inhibitory effect of a- adrenoceptor stimulation. During the early stage of the disease proces s, action potential prolongation may increase the amplitude of the int racellular calcium transient, causing positive inotropy. we argue ther efore, that action prolongation may be a compensatory response which m ay acutely support the compromised cardiac output. In severe hypertrop hy and end-stage heart failure however, despite continued action poten tial prolongation, the amplitude of the calcium transient becomes seve rely reduced. The mechanism underlying this event appears to involve r educed 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, chron ic activation of compensatory mechanisms including action potential pr olongation may trigger these late events. In the present article we ou tline a hypothesis which describes a potential role for action potenti al prolongation, and the associated elevation in the levels of intrace llular calcium, in maladaptive gene expression and the progression tow ard cardiac failure. (C) 1998 Elsevier Science B.V.