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Acute Arrhythmias in a Long-chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD) Mouse Model

ABSTRACT: 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, and atrial and ventricular fibrillation after b-agonist stimulation compared to WT mice. Long QRS and long QT intervals were also observed. 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, decreased gene 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE309626 | GEO | 2025/10/15

REPOSITORIES: GEO

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Project description:Aims Ischemic cardiomyopathy with comorbid sleep apnea syndrome (SAS) is associated with worse long-term outcomes. Intermittent hypoxia (IH), a key feature of SAS, exacerbates sympathetic activity, hastening cardiac dysfunction and remodeling in ischemic cardiomyopathy rat models. This study explores whether targeted cardiac sympathetic denervation (CSD) can limit IH-induced progression of ischemic cardiomyopathy. Methods and results Male Wistar rats underwent myocardial infarction (MI) via permanent left coronary artery ligation, and CSD was simultaneously achieved through ablation of the left middle cervical and stellate ganglions. Rats were exposed to IH (21–5% fraction of inspired O2, 60 s cycle, 8 h/day) or normoxia (N) for 14 weeks starting 3 days post-surgery. Throughout the intervention period, cardiac sympathetic activity was assessed using spectral analysis of heart rate variability (HRV) from vigil ECG collected with a specialized jacket. Cardiac function and remodeling were monitored via echocardiography. Additionally, isolated cardiomyocytes from rats exposed to IH or N for 6 weeks were assessed for calcium transient, sarcomere shortening and adrenergic reserve using isoproterenol stimulation (100 nM). CSD reduced cardiac sympathetic activity and prevented IH-induced blunting of cardiomyocyte response to isoproterenol challenge. In hypoxic animals, CSD reduced alterations in long-term ejection fraction and mitigated cardiomyocyte hypertrophy. Transcriptomic analysis unveiled that CSD triggered biological processes related to cardiac repair and regeneration. Immunohistochemistry further supported these findings, demonstrating increased cardiomyocyte proliferation in the hypoxic group, as indicated by elevated Ki67 expression colocalized with MF20 markers. Conclusions Our data demonstrate that cardiac sympathetic denervation prevents IH-induced depletion of cardiac adrenergic reserve and deterioration of cardiac function in a rat model of ischemic cardiomyopathy. This study questions the role of sympathetic activity and hypoxia in cardiac regeneration and on the optimal management of sympathetic hyperactivity in ischemic cardiomyopathy in the specific context of associated SAS.

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Acute Arrhythmias in a Long-chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD) Mouse Model

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