Abstract 16049: Hydrogen Sulfide Attenuates Duchenne Cardiomyopathy via Suppression of Sterile Inflammation

Abstract

Background: Duchenne muscular dystrophy (DMD) is a lethal, X-linked recessive disease caused by mutations in dystrophin. There is currently no cure for DMD, and the main cause of death is dilated cardiomyopathy. Hydrogen sulfide (H 2 S) is a gaseous molecule produced endogenously, and disruptions in basal H 2 S levels have been associated with various pathophysiological conditions, including heart failure. In this study, we investigated whether H 2 S could prevent cardiac dysfunction in a mouse model of DMD. Methods: Male mdx 4cv /mTR KO mice received early treatment (ET) with the H 2 S donor, SG1002 (40 mg/kg/day in chow starting at the time of weaning) or no treatment (NT), and wildtype C57BL (WT) mice were used as control. Left ventricular ejection fraction (LVEF) was assessed by transthoracic echocardiography. Skeletal and cardiac fibrosis was determined by picrosirius red staining. NLRP3 inflammasome activity was measured through apoptosis speck like protein (ASC) staining in cardiac muscle tissue. Results: NT mice exhibited significant LVEF decline by 4 months compared to ET and WT mice and declined further by 12 months (n=15-17, NT: 45.2% ± 7.9 vs ET: 57.1% ± 8.9% and WT: 56.5% ± 7.0%, P<0.001). In addition, ET mice showed significantly reduced fibrosis compared to NT mice in the myocardium (n=5-8, 2.62% ± 0.87% vs 11.32% ± 4.70%, respectively, P=0.002), diaphragm (n=11-14, 15.84% ± 9.0% vs 31.14% ± 7.1%, respectively, P<0.001), and gastrocnemius (n=12-17, 7.60% ± 3.14% vs 13.48% ± 5.97%, respectively, P=0.004) at 12 months. ASC aggregation score was significantly higher in cardiac tissue samples (Fig 1) from NT mice at 12 months compared with WT mice. ET attenuated the increase in cardiac ASC aggregation at 12 months compared with NT mice (P<0.001). Conclusions: Our results demonstrate that early treatment with SG1002 preserves cardiac function in a mouse model of DMD and suggest a potential therapeutic role of NLRP3 inflammasome suppression as a protective strategy in DMD.