Long-Chain Acylcarnitines and Cardiac Excitation-Contraction Coupling: Links to Arrhythmias

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.

Keywords: arrhythmias; calcium; cardiac pathophysiology; electrophysiology; excitation-contraction coupling; long-chain acylcarnitines; metabolomics.

FIGURE 1

Long-chain acylcarnitine biogenesis. Long-chain acylcarnitines (LCACs) are the product of long-chain fatty acyl-CoA (LCFA-CoA) esterification to a free cytosolic carnitine, which is catalyzed by carnitine O-palmitoyltransferase I (CPT I) at the outer mitochondrial membrane (OMM). LCAC translocation across the inner mitochondrial membrane (IMM) and into the mitochondrial matrix occurs via the action of carnitine acylcarnitine translocase (CACT). Once in the matrix, the LCAC genesis reaction is reversed by carnitine O-palmitoyltransferase II (CPT II) to yield the constituent LCFA-CoA and carnitine. The LCFA-CoA can then continue to oxidative metabolism via β-oxidation. Note, that the reactions of CPT II and CACT are bi-directionally catalytic and cytosolic LCACs can be exported, presumably via a member of the solute carrier family (SLC). Figure created using BioRender.com.

FIGURE 2

LCAC effects of electrophysiology and arrhythmia. (A) Long-chain acylcarnitines (LCACs) stereotypically alter the cardiac action potential (AP). Normal ventricular AP schematic represented in black, LCAC-altered AP in red hatched line. Characteristic effects of LCACs include reductions in AP duration (APD), amplitude (APA), the maximal rate of depolarization (V_max), and a depolarization of the resting membrane potential (RMP). These AP alterations predispose cardiac muscle to arrhythmias. (B) Representative trace from echocardiogram of a mouse model infused with 10 μM LCAC (palmitoylcarnitine). Relative to control trace, observable electrical arrhythmia occurred with LCAC infusion, notable are premature ventricular complexes. Figure reprinted from Roussel et al. (2015), with permission from Elsevier.

FIGURE 3

LCAC effects on cardiac excitation-contraction coupling. Schematic illustration of long-chain acylcarnitine (LCAC) effects on key cardiac excitation-contraction coupling proteins and compartment ion concentrations. Proteins or enzymes inhibited by LCACs are annotated as red, those that are stimulated are green, and those that are controversially affected by LCACs are in yellow. LCACs promote a sarcolemmal late Na⁺ current (I_Na(L)), which contributes to an increase in cytosolic Na⁺ concentration ([Na⁺]c, black line, inset figure). LCACs also inhibit the Na⁺/K⁺-ATPase (NKA), further increasing the [Na⁺]c. The cytosolic Ca²⁺ concentration ([Ca²⁺]c, yellow line, inset figure) is increased by LCAC application. This is contributed to by influx of Ca²⁺ from the extracellular fluid, either through the L-type Ca²⁺ channel (LTCC) or via membrane disruption; this is currently inconclusive. LCACs reduce the sarcoplasmic reticulum (SR) Ca²⁺ concentration ([Ca²⁺]SR, blue line, inset figure), thereby contributing to cytosolic Ca²⁺ overload. The dependence of ryanodine receptor (RyR2)-mediated SR Ca²⁺ release is unclear in cardiac cardiomyocytes. The sarcoendoplasmic reticulum Ca²⁺ ATPase (SERCA2a) is inhibited by LCACs, impairing Ca²⁺ removal from the cytosol. Ca²⁺ release from the mitochondria is stimulated by LCACs but uptake is inhibited. The I_Na(L) promoted by LCACs induces sarcolemmal Na⁺/Ca²⁺ exchange (NCX) via NCX1, which augments Ca²⁺ overload and stimulates a transient inward current (I_ti) that provides the ionic substrate for spontaneous electrical activity. Ca²⁺ may also enter the cytosol from the extracellular environment or from the SR independently of protein facilitation, instead traversing the membranes due to amphipathic properties of LCACs. LCACs have been shown to inhibit the I_K1, which contributes to resting membrane potential depolarization. Cardiac K_ATP channels and transient outward K⁺ current (I_to) are inhibited by LCACs, thereby slowing repolarization. In contrast, LCACs stimulate the hERG K⁺ channels, resulting in enhanced repolarization and reduction of the action potential duration. Figure created using BioRender.com.