Background: HFpEF is a complex multi-organ disease expected to represent gt;60% of all clinical heart failure cases by 2030. To date, the majority of therapeutic approaches to treat HFpEF have largely failed in either preclinical or clinical trials. Given the recent reports of diminished H2S bioavailability in HFpEF combined with the robust cardioprotective actions of H2S in cardiovascular disease, we sought out to test the effects of H2S therapy in a well-established pre-clinical HFpEF murine model.
Methods: HFpEF was induced in nine-week-old C57/BL6N mice (n=10 per group) by high fat diet and L-NAME (0.5g/L/day) via drinking water for 5 weeks. Mice were treated with either vehicle or the H2S donor, JK-1 (100 mg/kg/day B.I.D., I.P.) for a period of 5 weeks. Echocardiography and exercise capacity were performed at study weeks 0, 5, and 10 for monitoring of cardiac function and progression of exercise intolerance. At week 10, endothelium-dependent and independent aortic vascular reactivity and left ventricular invasive hemodynamic studies were performed.
Results: Treatment with JK-1 significantly improved cardiac function as measured by decreases in both left ventricular end diastolic pressure (LVEDP) and E/e’ after 5 weeks of treatment. Similarly, endothelium-dependent vascular relaxation with acetylcholine exhibited significant improvement. Treadmill exercise performance expressed as total work showed improvement for the JK-1 group, demonstrating changes in exercise capacity are irrespective of body weight.
Conclusion: These results suggest that the H2S donation therapy exerts beneficial effects in the setting of severe HFpEF. Studies are currently ongoing to determine the mechanisms by which H2S therapy improves both cardiac and vascular function in this devastating cardiovascular disease.
Figure 1. Effects of 5-week JK-1 treatment in HFpEF murine model. A. Echocardiographic (E/e’) measure of diastolic function (E = mitral inflow velocity, e’ = mitral annular velocity) B. Endpoint hemodynamic (LVEDP) measure of diastolic function (LVEDP = left ventricular end diastolic pressure) C. Exercise capacity represented by work (*P <0.05, **P <0.01). D. Endothelium-dependent aortic relaxation and maximal aortic relaxation (Ach = acetylcholine, SNP = sodium nitroprusside)
