Heart and Metabolism

Number 33, 2006
Arrhythmia and metabolism

Arrhythmia and metabolism

Danielle Feuvray
UMR CNRS 8078 & Université Paris-Sud XI, France
Correspondence: Professor Danielle Feuvray, CNRS UMR 8078 & Université Paris-Sud XI, Marie Lannelongue Hospital, 92350 Le Plessis Robinson, France.
E-mail: danielle.feuvray@ibaic.u-psud.fr

The observation that plasma free fatty acid concentrations are increased during and immediately after myocardial infarction was made several decades ago [1]. Clinical observations showed that plasma free fatty acid concentrations greater than those that could bind to the two primary affinity-binding sites on albumin were associated with an increase in the incidence of ventricular arrhythmias during myocardial infarction [2]. Subsequently, it was proposed that certain arrhythmias have a metabolic basis [3]. The oxygen-wasting effects of increased provision of free fatty acids to the acutely ischemic myocardium were found to be augmented by impairment of the uptake or utilization of glucose [4]. These early findings led to the views that provision of glucose is “good” [5] and that the presence of increased circulating free fatty acid concentrations is “bad” [3] for the ischemic myocardium.
During ischemia, β-oxidation of long-chain fatty acids in mitochondria is inhibited and there is an intracellular accumulation of metabolites such as long-chain acyl carnitine and acyl coenzyme A. The metabolites that accumulate during ischemia-reperfusion may, indirectly, lead to ionic disturbances; in particular, they may alter both sodium and calcium homeostasis and contribute to electrical dysfunction. Increases in intracellular sodium (Na⁺_i), which have been demonstrated during ischemia-reperfusion [6], may indeed have functional and proarrhythmogenic consequences [7], because increases in Na⁺_i in turn generate Ca²⁺ loading via reverse Na⁺–Ca²⁺ exchange. Interestingly, it has been shown that trimetazidine, which inhibits fatty acid oxidation in the heart [8], also significantly reduces the increase in Na⁺_i during ischemia and early reperfusion [6]. The most plausible underlying mechanisms for the gain in Na⁺_i during ischemia are a decrease in Na⁺ extrusion via Na⁺/K⁺-ATPase or an influx of Na⁺ via Na⁺–H⁺ exchange and the voltage-gated Na⁺ channel, or both. Na⁺–H⁺ exchange activity may be rapidly inhibited by extracellular acidosis during total ischemia, which suggests that voltage-gated Na⁺ channels may have a significant role as mediators of ischemic Na⁺ loading [9]. A large proportion of these channels become rapidly non recruitable in ischemic tissues after resting membrane potential depolarization, and action potentials initially shorten and subsequently cease with exhaustion of cellular ATP. Na⁺ influx continues, however, through non inactivated voltage-gated sodium channels, giving rise to persistent window currents [10,11]. Moreover, the slowly inactivating component of the Na⁺ current also increases substantially during ischemia, amplifying Na⁺ influx [11,12]. In this context, it has been shown that long-chain acyl carnitine, which accumulates in the cell membrane during ischemia, markedly increases the slowly inactivating component of the Na⁺ current [12]. Experimental data also indicate that acyl carnitine, like ouabain, produces a reversible inhibition of the Na⁺/K⁺ pump current [13] and thereby a decrease in Na⁺ extrusion. Therefore, specific myocardial metabolic modulation such as with trimetazidine, which limits the accumulation of long-chain acyl carnitine during ischemia [14], may well limit the increase in Na⁺_i via slowly inactivating the sodium channels and causing a relative increase in Na⁺/K⁺ pump function. This would be particularly important in reducing ionic disturbances and the susceptibility of the myocardium to malignant arrhythmogenic events.
The experimental evidence summarized above probably represents only a few aspects of the fascinating machinery that may underlie the metabolic signals of arrhythmia. This issue of Heart and Metabolism will highlight the importance of metabolic disturbances, associated either with an imbalance of metabolic substrates or, as most recently reported, with genetic mutations that can alter the function of a key regulatory enzyme of cardiac energy metabolism [15] and downstream effectors such as cardiac ion channels [16] and, possibly, other ion transporters.

REFERENCES

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Number 33, 2006Arrhythmia and metabolism Arrhythmia and metabolism

Number 33, 2006Arrhythmia and metabolism

Number 33, 2006
Arrhythmia and metabolism

Arrhythmia and metabolism

Number 33, 2006
Arrhythmia and metabolism