A Hydrogen Sulfide Donor, JK1, Preserves Endothelial Function and Improves Exercise Capacity in Pressure Overload ‐ Induced Heart Failure

Background and Hypothesis Hydrogen sulfide (H 2 S) protects against heart failure by ameliorating oxidative stress, improving mitochondrial function, and attenuating apoptosis. At present there is a lack of data demonstrating the protective actions of H 2 S in the late stages of heart failure. And the effects of H 2 S on exercise intolerance, the clinical hallmark of heart failure, has not been evaluated in preclinical models. In current study, we tested the efficacy of delayed therapy with a novel H 2 S donor, JK1, on cardiac function, endothelial function, and exercise capacity in a murine model of pressure overload‐induced heart failure. Methods Male C57/BL6J mice at 10 weeks (wks) of age were subjected to transverse aortic constriction (TAC) for 18 weeks. JK1 (200 μg/kg/d, n=20) or the H 2 S deficient control compound (200 μg/kg/d, n=18) was administered via i.p. injection twice per day starting at 10 wks post TAC, in which time all mice had EF lower than 45%. Echocardiography was performed at baseline and tri‐weekly to assess LV structure and function. LV hemodynamics, cardiac fibrosis, vascular reactivity (isolated thoracic aorta), and exercise capacity were measured at the endpoint, 18 wks post TAC. Results Delayed treatment with JK1 initiated at 10 wks post TAC reduced LV dilation (p < 0.01) and attenuated eccentric hypertrophy (p < 0.01). However, no significant difference was noted in LV ejection fraction and cardiac fibrosis. JK1 treated mice displayed lower LV end‐diastolic pressure (LVEDP 17.8 ± 1.8 mmHg vs. 22.9 ± 1.23 mmHg, p < 0.05) and improved relaxation time constant (Tau 8 ± 0.27 ms vs. 10.05 ± 0.58 ms, p < 0.01). In addition, aortic vasorelaxation in response to acetylcholine treatment was markedly improved in mice received JK1 treatment (Max. Relaxation 51.8 ± 4.2% vs. 31.5 ± 3.6%, p < 0.01). More importantly, mice received JK1 treatment exhibited improved exercise capacity (Distance 312 ± 13.4 m vs. 89 ± 6.3 m, p < 0.05) as compared to those received control. Conclusion These results demonstrate that delayed administration of a novel H 2 S donor, JK1, improves exercise capacity in severe heart failure following TAC. JK1 treatment initiated at 10 weeks post TAC did not improve systolic function or reduce cardiac fibrosis, suggesting that the beneficial effects of 10‐wks‐delayed H 2 S therapy in pressure overload heart failure are a result of the improved vascular function and LV hemodynamics. Support or Funding Information