Acute arrhythmias in a long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency mouse model.

Patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), a mitochondrial fatty acid oxidation (FAO) disorder, frequently present with cardiomyopathy and can suffer from life-threatening arrhythmias and heart failure. Although these remain the leading causes of death, the pathophysiology remains unknown. We used an LCHADD mouse model to examine the mechanisms of impaired cardiac function. We previously determined that LCHADD mice (Hadha c.1528G>C homozygotes) recapitulate human disease and develop cardiomyopathy. We performed electrophysiological tests on LCHADD and wild-type (WT) mice, followed by cardiac tissue and molecular expression analysis. LCHADD mice showed significantly increased frequency of atrial premature beats, premature ventricular contractions, atrial flutter, atrial fibrillation, and nonsustained ventricular tachycardia (NSVT) after β-agonist stimulation compared with WT mice. Long QRS and long QT intervals were also observed when compared with WT mice. LCHADD heart sections demonstrated increased cardiomyocyte cross-sectional area, increased lipid and collagen deposition, and decreased glycogen deposits. There was global sympathetic denervation in LCHADD hearts compared with WT. Differentially expressed gene analysis showed increased expression of glycolytic and glutathione synthesis enzymes, and decreased expression of tricarboxylic acid (TCA) cycle enzymes, Ca++ signaling, and cardiac muscle contraction proteins. LCHADD cardiomyopathy has a hypertrophic phenotype with diffuse fibrosis, accumulation of lipids, and lower glycogen storage in the absence of obesity. LCHADD cardiomyocyte metabolism suggests a shift from FAO toward glycolysis with chronic oxidative stress. Energy deficiency and lipotoxicity likely influence Ca++ signaling and cardiac contraction. Long QRS and QT intervals with global sympathetic denervation may predispose the heart to repolarization abnormalities susceptible to arrhythmias and increased risk of sudden cardiac arrest and death.NEW & NOTEWORTHY As major cardiac events and heart failure are the leading causes of death among individuals with LCHADD, we are committed to identify better treatment options. To undertake this, we characterized LCHADD cardiomyopathy using a mouse model. We identified a hypertrophic cardiomyopathy with diffuse fibrosis, extensive lipid accumulation, increased oxidative stress, and global sympathetic denervation with long QT intervals and arrhythmia susceptibility likely caused by cardiomyocyte energetic remodeling, altered homeostasis, and cardiac conduction dysregulation.