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Cardiovascular Research 1998 37(2):300-311; doi:10.1016/S0008-6363(97)00273-3
© 1998 by European Society of Cardiology
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Copyright © 1998, European Society of Cardiology

Ca2+ currents in compensated hypertrophy and heart failure

Sylvain Richard*, Florence Leclercq, Stéphanie Lemaire, Christophe Piot and Joël Nargeot

Centre de Recherches de Biochimie Macromoléculaire, CNRS ERS-155, 1919, Route de Mende, BP 5051, 34033 Montpellier Cedex, France

* Corresponding author. Tel. (33) 467 61 33 55; Fax (33) 467 52 15 59; E-mail: richard@xerxes.crbm.cnrs-mop.fr

Transmembrane voltage-gated Ca2+ channels play a central role in the development and control of heart contractility which is modulated by the concentration of free cytosolic calcium ions (Ca2+). Ca2+ channels are closed at the normal membrane resting potential of cardiac cells. During the fast upstroke of the action potential (AP), they are gated into an open state by membrane depolarisation and thereby transduce the electrical signal into a chemical signal. In addition to its contribution to the AP plateau, Ca2+ influx through L-type Ca2+ channels induces a release of Ca2+ ions from the sarcoplasmic reticulum (SR) which initiates contraction. Because of their central role in excitation-contraction (E-C) coupling, L-type Ca2+ channels are a key target to regulate inotropy [1]. The role of T-type Ca2+ channels is more obscure. In addition to a putative part in the rhythmic activity of the heart, they may be implicated at early stages of development and during pathology of contractile tissues [2]. Despite therapeutic advances improving exercise tolerance and survival, congestive heart failure (HF) remains a major problem in cardiovascular medicine. It is a highly lethal disease; half of the mortality being related to ventricular failure whereas sudden death of the other patients is unexpected [3]. Although HF has diverse aetiologies, common abnormalities include hypertrophy, contractile dysfunction and alteration of electrophysiological properties contributing to low cardiac output and sudden death. A significant prolongation of the AP duration with delayed repolarisation has been observed both during compensated hypertrophy (CH) and in end-stage HF caused by dilated cardiomyopathy (Fig. 1A) [4–8]. This lengthening can result from either an increase in inward currents or a decrease in outward currents or both. A reduction of K+ currents has been demonstrated [6, 9]. Prolonged Na+/Ca2+ exchange current may also be involved [9]. In contrast, there is a large variability in the results concerning Ca2+ currents (ICa). The purpose of this paper is to review results obtained in various animal models of CH and HF with special emphasis on recent studies in human cells. We focus on: (i) the pathophysiological role of T-type Ca2+ channels, present in some animal models of hypertrophy; (ii) the density and properties of L-type Ca2+ channels and alteration of major physiological regulations of these channels by heart rate and β-adrenergic receptor stimulation; and (iii) recent advances in the molecular biology of the L-type Ca2+ channel and future directions.


Figure 1
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  		Fig. 1 APs and Ca2+ transients recorded in diseased human cardiac cells. (A) Graph shows representative APs recorded in two different single ventricular cells. Stimulation frequency was 0.5 Hz. AP duration in myocytes from patients with heart failure (dilated cardiomyopathy) was significantly prolonged (AP90 1,038±223 msec; n=7) as compared to controls (649±101 msec; n=4). (B) Graph shows representative [Ca2+]i transients of two different ventricular cells loaded with Ca2+ indicator fura-2 during external stimulation at a frequency of 0.5 Hz. Resting [Ca2+]i were significantly higher in the myopathic cells compared to the control cell (165±61 nmol/l, n=31 vs. 96±47 nmol/l, n=8). In contrast, the peak [Ca2+]i was lower (367±109 nmol/l vs. 746±249 nmol/l) and the decline of [Ca2+]i was slower (t1/2 692±166 msec vs. 320±68 msec). Temperature was 35°C. (Data in panel A and panel B and numbers were taken from [7]with permission).

 

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