Abstract
A growing number of metabolomic studies have associated high circulating levels of the amphiphilic fatty acid metabolites, long-chain acylcarnitines (LCACs), with cardiovascular disease (CVD) risk. These studies show that plasma LCAC levels can be correlated with the stage and severity of CVD and with indices of cardiac hypertrophy and ventricular function. Complementing these recent clinical associations is an extensive body of basic research that stems mostly from the twentieth century. These works, performed in cardiomyocyte and multicellular preparations from animal and cell models, highlight stereotypical derangements in cardiac electrophysiology induced by exogenous LCAC treatment that promote arrhythmic muscle behavior. In many cases, this is coupled with acute inotropic modulation; however, whether LCACs increase or decrease contractility is inconclusive. Linked to the electromechanical alterations induced by LCAC exposure is an array of effects on cardiac excitation-contraction coupling mechanisms that overload the cardiomyocyte cytosol with Na+ and Ca2+ ions. The aim of this review is to revisit this age-old literature and collate it with recent findings to provide a pathophysiological context for the growing body of metabolomic association studies that link circulating LCACs with CVD.
Highlights
Metabolomic studies have identified numerous circulating metabolites that correspond to an enhanced risk of cardiovascular disease (CVD) (McGarrah et al, 2018)
The electrical and mechanical alterations to cardiac muscle induced by LCAC exposure can be attributed to a pleiotropy of modulations in ECC mechanisms
LCACs inhibit the NKA and promote an INa(L), thereby increasing the intracellular Na+ concentration and driving arrhythmogenic Na+/Ca2+ exchange (Wu and Corr, 1994, 1995). This inhibited Na+-extrusion is coupled with increases in trans-sarcolemma Ca2+ influx, SR Ca2+ release, mitochondrial Ca2+ efflux, and SERCA2a inhibition that overload cytosolic Ca2+ levels
Summary
Metabolomic studies have identified numerous circulating metabolites that correspond to an enhanced risk of cardiovascular disease (CVD) (McGarrah et al, 2018). The aim of this review is to collate what is currently known about LCACs as effectors of cardiac function and to provide a pathophysiological basis for the recent metabolomic interest of circulating LCACs in the plasma of CVD patients. This will include discussion of LCAC effects on myocardial electrophysiology, contractility, and arrhythmias, as well as the underlying excitation-contraction coupling modulations. We refer to LCACs as a general acylcarnitine class throughout this review; if specific LCAC species (such as palmitoylcarnitine) are discussed this will be stated
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