Hydrogen sulfide (H2S) is an endogenous, gaseous signaling molecule that plays a critical role in cardiac and vascular biology. H2S regulates vascular tone and oxidant defenses and exerts cytoprotective effects in the heart and circulation. Recent studies indicate that H2S modulates various components of metabolic syndrome, including obesity and glucose metabolism. This review will discuss studies exhibiting H2S -derived cardioprotective signaling in heart failure with reduced ejection fraction (HFrEF). We will also discuss the role of H2S in metabolic syndrome and heart failure with preserved ejection fraction (HFpEF).

Background Recent studies have suggested that cardiac nitrosative stress mediated by pathological overproduction of nitric oxide (NO) via inducible NO synthase (iNOS) contributes to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Other studies have suggested that endothelial NO synthase (eNOS) dysfunction and attenuated NO bioavailability contribute to HFpEF morbidity and mortality. We sought to further investigate dysregulated NO signaling and to examine the effects of a NO‐based dual therapy (sodium nitrite+hydralazine) following the onset of HFpEF using a “2‐hit” murine model. Methods and Results Nine‐week‐old male C57BL/6 N mice (n=15 per group) were treated concurrently with high‐fat diet and N(ω)‐nitro‐L‐arginine methyl ester (L‐NAME) (0.5 g/L per day) via drinking water for 10 weeks. At week 5, mice were randomized into either vehicle (normal saline) or combination treatment with sodium nitrite (75 mg/L in the drinking water) and hydralazine (2.0 mg/kg IP, BID). Cardiac structure and function were monitored with echocardiography and invasive hemodynamic measurements. Cardiac mitochondrial respiration, aortic vascular function, and exercise performance were also evaluated. Circulating and myocardial nitrite were measured to determine the bioavailability of NO. Circulating markers of oxidative or nitrosative stress as well as systemic inflammation were also determined. Severe HFpEF was evident by significantly elevated E/E', LVEDP, and Tau in mice treated with L‐NAME and HFD, which was associated with impaired NO bioavailability, mitochondrial respiration, aortic vascular function, and exercise capacity. Treatment with sodium nitrite and hydralazine restored NO bioavailability, reduced oxidative and nitrosative stress, preserved endothelial function and mitochondrial respiration, limited the fibrotic response, and improved exercise capacity, ultimately attenuating the severity of “two‐hit” HFpEF. Conclusions Our data demonstrate that nitrite, a well‐established biomarker of NO bioavailability and a physiological source of NO, is significantly reduced in the heart and circulation in the “2‐hit” mouse HFpEF model. Furthermore, sodium nitrite+hydralazine combined therapy significantly attenuated the severity of HFpEF in the “2‐hit” cardiometabolic HFpEF. These data suggest that supplementing NO‐based therapeutics with a potent antioxidant and vasodilator agent may result in synergistic benefits for the treatment of HFpEF.

In recent decades, the growing epidemic of heart failure (HF) has left us feeling as victims of our own success. The victories of increasing treatment and survival of patients with ischemic heart disease and acute myocardial infarction has simultaneously increased the the number of patients with a high-risk of developing heart failure. 1 Consequently, we find ourselves in the modern era of cardiovascular disease, where heart failure accounts for 1.2 million hospital discharges, 86 000 deaths, over 30 billion in medical cost, and 1 million new diagnoses per year. 2,3

Background HFpEF is a complex multi‐organ disease expected to represent >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.

Background Heart failure with preserved ejection fraction (HFpEF) is the most predominant form of heart failure in the United States. This multi‐system pathology results in a 5‐year mortality rate for which there are very few treatment options. The obese ZSF1 rat model has previously been shown to recapitulate much of the human phenotype including obesity, metabolic syndrome, diabetes, and hypertension. In this study, we investigated the complex and largely unknown role of abnormal nitric oxide signaling and nitrosative stress in the pathobiology of HFpEF. Materials and Methods Male ZSF1 rats and normotensive controls of Wistar Kyoto (WKY) background strain (n=7 each group) were studied at 10, 14 and 18 weeks of age to monitor disease progression and alterations in nitric oxide signaling. Cardiac protein nitrosylation (RxNO) was measured by chemiluminescence. Analysis of circulating plasma nitrite bioavailability was performed using high performance liquid chromatography. GSNOR, one of the enzymes that degrade nitrosothiols, mRNA expression was measured and plotted as relative fold difference to WKY expression in this model of cardiometabolic HFpEF. Results ZSF1 rats exhibited significantly increased cardiac protein nitrosylation as the HFpEF phenotype progressed from 10 to 18 weeks of age as compared to the WKY rat group. GSNOR mRNA expression was significantly decreased in the ZSF1 rat relative to the WKY at all time points. During the later 18‐week timepont, cardiac GSNOR activity was found to be decreased compared to that of the WKY. Circulating plasma nitrite, a measure of eNOS function, was decreased in the ZSF1 rat at 14 and 18 weeks compared to the WKY at subsequent aging timepoints. These data correlate to an increasing left ventricular end diastolic pressure (LVEDP) and decreased vascular relaxation as the ZSF1 animals age and develop more severe HFpEF disease pathology. Conclusion Our data suggests that nitric oxide signaling is dysregulated in the setting of HFpEF resulting in a significant increase in cardiac protein nitrosylation coupled with a reduction in circulating nitrite and NO signaling in the vasculature. Excessive cardiac nitrosative stress resulting in pathological myocardial signaling has been previously implicated as a driver of HFpEF. Reduced vascular nitrite bioavailability resulting in attenuated physiological NO signaling could account for the profound vascular dysfunction observed in HFpEF patients. Future studies are aimed at the further elucidation of the role of various NO storage pools in HFpEF.