Arritmias Agudas en un Modelo Murino de Deficiencia de 3-Hidroxiacil-CoA Deshidrogenasa de Cadena Larga (LCHADD)

Background: Patients with LCHADD, a mitochondrial fatty acid oxidation (FAO) disorder, frequently present with cardiomyopathy and can suffer life-threatening arrhythmias and heart failure. While 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. Methods: We previously determined that LCHADD mice (Hadha c.1528G>C homozygotes) recapitulate human disease and develop cardiomyopathy. We performed electrophysiological tests on LCHADD and WT mice, followed by cardiac tissue and molecular expression analysis. Results: LCHADD mice showed significantly increased frequency of atrial premature beats, premature ventricular contractions, atrial flutter, atrial fibrillation and non-sustained ventricular tachycardia after β-agonist stimulation compared to WT mice. Long QRS and long QT intervals were also observed when compared to 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 to WT. Differentially expressed gene analysis showed increased expression of glycolytic and glutathione synthesis enzymes, and decreased expression of TCA cycle enzymes, Ca⁺⁺ signaling, and cardiac muscle contraction proteins. Conclusions: 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.