Abstract
Patients with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) can present with life-threatening cardiac arrhythmias. The pathophysiological mechanism is unknown. We reprogrammed fibroblasts from one mildly and one severely affected VLCADD patient, into human induced pluripotent stem cells (hiPSCs) and differentiated these into cardiomyocytes (VLCADD-CMs). VLCADD-CMs displayed shorter action potentials (APs), more delayed afterdepolarizations (DADs) and higher systolic and diastolic intracellular Ca2+ concentration ([Ca2+]i) than control CMs. The mitochondrial booster resveratrol mitigated the biochemical, electrophysiological and [Ca2+]i changes in the mild but not in the severe VLCADD-CMs. Accumulation of potentially toxic intermediates of fatty acid oxidation was blocked by substrate reduction with etomoxir. Incubation with etomoxir led to marked prolongation of AP duration and reduced DADs and [Ca2+]i in both VLCADD-CMs. These results provide compelling evidence that reduced accumulation of fatty acid oxidation intermediates, either by enhanced fatty acid oxidation flux through increased mitochondria biogenesis (resveratrol) or by inhibition of fatty acid transport into the mitochondria (etomoxir), rescues pro-arrhythmia defects in VLCADD-CMs and open doors for new treatments.
Highlights
Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) (OMIM 201475), an autosomal recessive inborn error of metabolism, caused by pathogenic mutations in the ACADVL gene, is a mitochondrial long-chain fatty acid oxidation disorder [1,2]
Added long-chain acylcarnitines (LCACs) can induce a variety of electrophysiological alterations in ventricular myocytes, including action potentials (APs) shortening [13], cellular uncoupling [18] and delayed afterdepolarizations (DADs) [13,14], the latter representing an important cellular mechanism for arrhythmias [19,20]
In order to progress towards prevention or therapeutic interventions for VLCADD-induced cardiac arrhythmias, we generated human induced pluripotent stem cells (hiPSCs)-CMs from two patients harboring distinct ACADVL genetic defects and studied the underlying mechanism of the pro-arrhythmic phenotype using compounds affecting different aspects of long-chain fatty acid oxidation (lcFAO) biochemistry, namely resveratrol and etomoxir
Summary
Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) (OMIM 201475), an autosomal recessive inborn error of metabolism, caused by pathogenic mutations in the ACADVL gene, is a mitochondrial long-chain fatty acid oxidation (lcFAO) disorder [1,2]. Previous work showed that resveratrol increases lcFAO flux and decreases LCAC accumulation in fibroblasts of VLCADD patients with milder phenotypes [21,22]. In these studies, the effects of resveratrol were thought to be mediated by an increase in the amount of mutated VLCAD protein via sirtuin 1 activation [21]. In order to progress towards prevention or therapeutic interventions for VLCADD-induced cardiac arrhythmias, we generated hiPSC-CMs from two patients harboring distinct ACADVL genetic defects and studied the underlying mechanism of the pro-arrhythmic phenotype using compounds affecting different aspects of lcFAO biochemistry, namely resveratrol and etomoxir
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