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Abstract
As we face the ever-changing nature of medicine, the landscape of cardiovascular disease has similarly shifted and evolved. With the confluence of multiple, systemic comorbidities that detrimentally increase cardiac demand, one of the most prominent dilemmas now faced by physicians is heart failure with preserved ejection fraction (HFpEF). HFpEF represents the major subtype of heart failure and its increasing footprint can be explained by our lack of pathophysiological understanding that has ultimately resulted in a paucity of efficacious treatment options. A similarly underappreciated concept is the influence of hydrogen sulfide (H2S) signaling in cardiac homeostasis. While H2S has been thoroughly investigated in different cardiovascular disease contexts, its potential role in HFpEF has yet to be fully expanded upon.
The work herein aimed to elucidate the bioavailability of H2S in HFpEF and the potential role of dysregulated H2S signaling as a contributor to HFpEF development. We hypothesize that H2S is diminished in HFpEF and that the restoration of bioavailable H2S can improve HFpEF pathology. To test this, we initially quantified H2S in circulating and tissue samples of wellestablished preclinical HFpEF models as well as from HFpEF patient blood samples. Further, we investigated the impact of H2S dysregulation in HFpEF through genetic manipulation of the endogenous H2S production pathway and its subsequent effects on HFpEF progression. Lastly, to test the translational relevance of our hypotheses, we studied the effects of pharmacologic H2S donation alone and or in combination with standard-of-care HFpEF therapeutics in preclinical models.
From these studies, it was demonstrated that H2S is reduced by up to 80% in human HFpEF patient blood samples with nearly equivalent decreases exhibited by each of the two investigated preclinical HFpEF models. The decreases in H2S were not only limited to the circulation, as tissue specimens (i.e. heart, liver, kidney) from our animal models also showed progressively depreciating bioavailable H2S and sulfur species as HFpEF severity worsened.
Knowing that a feature of a worsening HFpEF phenotype was an apparent simultaneous decrease in H2S, the installment of further dysregulation in endogenous H2S production was evaluated through genetic manipulation of H2S-producing enzymes 3-mercaptopyruvate sulfurtransferase and cystathionine-γ-lyase. Knockout of these enzymes lead to a notably exacerbated HFpEF phenotype while genetic overexpression of cystathionine-γ-lyase conversely remediated HFpEF pathology. Similar to our overexpression experiments, we tested the effects of increasing H2S through pharmacologic H2S donors, JK-1 and SG1002, and observed ameliorated cardiometabolic dysfunction characteristic of the two investigated preclinical models. The improvements seen with pharmacologic H2S donation were also maintained and shown to be additive when evaluated as an adjunct therapy to the recently established standard-of-care therapeutic for HFpEF, sodiumglucose transporter 2 inhibitors.
These results provide conclusive evidence that derangements in H2S and its related bioactivity fundamentally contributes to HFpEF pathogenesis. H2S is systemically reduced in HFpEF across multiple models of the disease. Further depletion of endogenous H2S increased HFpEF severity whereby this effect was reversed with endogenous or exogenous increases in bioavailable H2S. Importantly, the effects of H2S donor therapy were also shown to be significantly beneficial and additive when included as an adjunct to sodium-glucose cotransporter 2 inhibition. This work provides the foundation for our current and future understanding of the role of H2S in HFpEF and will hopefully contribute to the eventual remediation of this devastating condition.
