Abstract P2052: Lowered Pro-fibrotic And Damage Associated Molecular Pattern Gene Expressions After Exercise Training In A Mouse Model Of Hypertrophic Cardiomyopathy

Abstract

Background: Hypertrophic cardiomyopathy (HCM) is the most frequent inherited cardiac disease, most often caused by mutations in sarcomere genes. The disease is characterized by left ventricular (LV) hypertrophy, increased risk of arrhythmias and diastolic dysfunction, due to cardiomyocyte hypercontractility, myocyte disarray and fibrosis. Fibrosis is a marker of worse prognosis, adverse remodeling and an increased risk of sudden cardiac death. Hypothesis: We hypothesized that exercise training could attenuate fibrosis development in mice genetically predisposed to HCM. Methods: We allocated male α-Myh6 R403Q/+ to high intensity interval treadmill running or sedentary behavior (N=11 per group) for a total of 6 weeks. HCM was induced in all mice by cyclosporine A given via the feed for the last 3 of the 6 week exercise protocol. All mice underwent echocardiography and an exercise test at weeks 0, 3, and 6, before harvesting LVs for digital droplet PCR (ddPCR) and a qPCR immune array. Results: Exercise training lead to a 2-fold increase in exercise capacity as measured by total distance ran during exercise testing (p<0.0001). In exercised HCM mice, several key fibrosis-related genes were lowered compared to sedentary HCM mice as measured by ddPCR (N=11 per group): Collagen 1 by 51 % (p=0.03), collagen 3 by 54 % (p=0.02), fibronectin by 51 % (p=0.01) and lysyl oxidase by 42 % (p=0.05). An array of 87 selected immune-related genes showed that 39 genes were upregulated >1.5 fold in sedentary HCM mice compared to sedentary wild type controls (N=3 samples, pooled). Twelve upregulated genes belonged to damage associated-molecular patterns (DAMPs). Several of the DAMP genes were lower in exercised HCM mice compared to sedentary HCM mice (N=10-11 per group): Biglycan was lowered by 29 %, versican by 22 % and fibronectin by 55 %. Trends were also found for lowered expression of syndecan 1 (by 26 %), fibromodulin (by 55 %), and tenacin C (by 49 %) (0.07<p<0.08). There was no difference in maximal wall thickness or function measured by echocardiography. Conclusion: Exercise training led to a lower expression of key fibrosis-related genes in an inducible mouse model of HCM. Initial results indicate that attenuation of DAMP signaling might be involved in the mechanism for this effect.