Long recognized as a malodorous and highly toxic gas, recent experimental studies have revealed that hydrogen sulfide (H ₂ S) is produced enzymatically in all mammalian species including man and exerts several critical actions to promote cardiovascular homeostasis and health. During the past 15 years, scientists have determined that H ₂ S is produced by 3 endogenous enzymes and exerts powerful effects on endothelial cells, smooth muscle cells, inflammatory cells, mitochondria, endoplasmic reticulum, and nuclear transcription factors. These effects have been reported in multiple organ systems, and the majority of data clearly indicate that H ₂ S produced by the endogenous enzymes exerts cytoprotective actions. Recent preclinical studies investigating cardiovascular diseases have demonstrated that the administration of physiological or pharmacological levels of H ₂ S attenuates myocardial injury, protects blood vessels, limits inflammation, and regulates blood pressure. H ₂ S has emerged as a critical cardiovascular signaling molecule similar to nitric oxide and carbon monoxide with a profound effect on the heart and circulation. Our improved understanding of how H ₂ S elicits protective actions, coupled with the rapid development of novel H ₂ S-releasing agents, has resulted in heightened enthusiasm for the clinical translation of this ephemeral gaseous molecule. This review will examine our current state of knowledge about the actions of H ₂ S within the cardiovascular system with an emphasis on the therapeutic potential and molecular cross talk between H ₂ S, nitric oxide, and carbon monoxide.

Background—: Trimethylamine N-oxide (TMAO), a gut microbe–dependent metabolite of dietary choline and other trimethylamine-containing nutrients, is both elevated in the circulation of patients having heart failure and heralds worse overall prognosis. In animal studies, dietary choline or TMAO significantly accelerates atherosclerotic lesion development in ApoE-deficient mice, and reduction in TMAO levels inhibits atherosclerosis development in the low-density lipoprotein receptor knockout mouse. Methods and Results—: C57BL6/J mice were fed either a control diet, a diet containing choline (1.2%) or a diet containing TMAO (0.12%) starting 3 weeks before surgical transverse aortic constriction. Mice were studied for 12 weeks after transverse aortic constriction. Cardiac function and left ventricular structure were monitored at 3-week intervals using echocardiography. Twelve weeks post transverse aortic constriction, myocardial tissues were collected to evaluate cardiac and vascular fibrosis, and blood samples were evaluated for cardiac brain natriuretic peptide, choline, and TMAO levels. Pulmonary edema, cardiac enlargement, and left ventricular ejection fraction were significantly ( P <0.05, each) worse in mice fed either TMAO- or choline-supplemented diets when compared with the control diet. In addition, myocardial fibrosis was also significantly greater ( P <0.01, each) in the TMAO and choline groups relative to controls. Conclusions—: Heart failure severity is significantly enhanced in mice fed diets supplemented with either choline or the gut microbe–dependent metabolite TMAO. The present results suggest that additional studies are warranted examining whether gut microbiota and the dietary choline→TMAO pathway contribute to increased heart failure susceptibility.

Significance: Physiological concentrations of hydrogen sulfide (H ₂ S) exert potent prosurvival actions. We demonstrate that the cytoprotective actions of H ₂ S are mediated in part via a second gaseous signaling molecule, nitric oxide (NO). We found that cystathionine γ-lyase (CSE) KO mice with reduced H ₂ S levels exhibit increased oxidative stress and an exacerbated response to myocardial ischemia/reperfusion injury. CSE KO mice also exhibit reduced levels of NO and reduced NO synthesis via endothelial NO synthase (eNOS). Both oxidative stress and myocardial injury in CSE KO mice were attenuated by exogenous H ₂ S therapy, with increased eNOS function and restoration of NO levels. These findings provide insight into H ₂ S-mediated cytoprotetion and important information regarding the translation of H ₂ S therapy to the clinic.

Hydrogen sulfide (H ₂ S)—a potent gaseous signaling molecule—has emerged as a critical regulator of cardiovascular homeostasis. H ₂ S is produced enzymatically by 3 constitutively active endogenous enzymes in all mammalian species. Within the past 2 decades, studies administering H ₂ S-donating agents and the genetic manipulation of H ₂ S-producing enzymes have revealed multiple beneficial effects of H ₂ S, including vasodilation, activation of antiapoptotic and antioxidant pathways, and anti-inflammatory effects. More recently, the heightened enthusiasm in this field has shifted to the development of novel H ₂ S-donating agents that exert favorable pharmacological profiles. This has led to the discovery of novel H ₂ S-mediated signaling pathways. This review will discuss recently developed H ₂ S therapeutics, introduce signaling pathways that are influenced by H ₂ S-dependent sulfhydration, and explore the dual-protective effect of H ₂ S in cardiorenal syndrome.

Background: Patients at increased risk for coronary artery disease and adverse prognosis during heart failure exhibit increased levels of circulating trimethylamine N‐oxide ( TMAO ), a metabolite formed in the metabolism of dietary phosphatidylcholine. We investigated the efficacy of dietary withdrawal of TMAO as well as use of a gut microbe‐targeted inhibitor of TMAO production, on cardiac function and structure during heart failure. Methods and Results: Male C57 BLK /6J mice were fed either control diet, a diet containing TMAO (0.12% wt/wt), a diet containing choline (1% wt/wt), or a diet containing choline (1% wt/wt) plus a microbial choline trimethylamine lyase inhibitor, iodomethylcholine (0.06% wt/wt), starting 3 weeks before transverse aortic constriction. At 6 weeks after transverse aortic constriction, a subset of animals in the TMAO group were switched to a control diet for the remainder of the study. Left ventricular structure and function were monitored at 3‐week intervals. Withdrawal of TMAO from the diet attenuated adverse ventricular remodeling and improved cardiac function compared with the TMAO group. Similarly, inhibiting gut microbial conversion of choline to TMAO with a choline trimethylamine lyase inhibitor, iodomethylcholine, improved remodeling and cardiac function compared with the choline‐fed group. Conclusions: These experimental findings are clinically relevant, and they demonstrate that TMAO levels are modifiable following long‐term exposure periods with either dietary withdrawal of TMAO or gut microbial blockade of TMAO generation. Furthermore, these therapeutic strategies to reduce circulating TMAO levels mitigate the negative effects of dietary choline and TMAO in heart failure.

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