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Updated: Jan 7, 2026
Ambulatory ECG Recording in Mice
Published on: May 27, 2010
Acute arrhythmias in a long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency mouse model
Gabriela Elizondo1, Arianna Scalco2, Ayah Asal2
1Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, United States.
Insights
Mitochondrial fatty acid oxidation disorder (LCHADD) causes cardiomyopathy with impaired cardiac function, lipid accumulation, and fibrosis. This leads to arrhythmias and increased risk of sudden cardiac death.
Area of Science:
- Cardiology
- Mitochondrial Biology
- Genetics
Background:
- Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a mitochondrial fatty acid oxidation (FAO) disorder.
- Patients often develop cardiomyopathy, arrhythmias, and heart failure, leading causes of death.
- The underlying pathophysiology of LCHADD cardiomyopathy remains largely unknown.
Purpose of the Study:
- To investigate the mechanisms of impaired cardiac function in a mouse model of LCHADD.
- To elucidate the pathophysiology of LCHADD-associated cardiomyopathy.
Main Methods:
- Utilized LCHADD mouse model (Hadha c.1528G>C homozygotes) that recapitulates human disease.
- Performed electrophysiological testing on LCHADD and wild-type (WT) mice.
- Conducted cardiac tissue and molecular expression analysis.
Main Results:
- LCHADD mice exhibited increased arrhythmias (premature beats, VT, AF) and prolonged QRS/QT intervals post-stimulation.
- Cardiac analysis revealed hypertrophic cardiomyocytes, lipid and collagen deposition, and reduced glycogen.
- Molecular analysis showed altered gene expression favoring glycolysis over FAO, with impaired Ca2+ signaling and contraction proteins.
Conclusions:
- LCHADD cardiomyopathy presents as hypertrophy with fibrosis, lipid accumulation, and glycogen depletion, independent of obesity.
- Metabolic shift towards glycolysis and oxidative stress contribute to cardiac dysfunction.
- Energy deficiency, lipotoxicity, sympathetic denervation, and altered Ca2+ signaling predispose LCHADD hearts to arrhythmias and sudden death.
Abstract:
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.
