Comparative Effects of Heart Failure Medications on Cardiac Remodeling via the Hydrogen Sulfide (H2S) Pathway: A Systematic Review

Objectives: The aim of this study was to determine whether direct evidence shows that contemporary guideline-directed heart failure (HF) pharmacotherapies influence cardiac remodeling through hydrogen sulfide (H2S) signaling, and to define the resulting evidence gap. Design: A systematic review was conducted according to PRISMA 2020. Registration: PROSPERO CRD420251238589. Data Sources: MEDLINE (PubMed), Web of Science, Scopus, and the Cochrane Library; searches were initiated in March 2025, covered publications from January 2007 onward, and were last updated in November 2025. Eligibility Criteria: Primary studies had to include (A) an HF or cardiac-remodeling model, (B) an HF-relevant pharmacological intervention, (C) direct assessment or manipulation of H2S biology, and (D) at least one cardiac-remodeling endpoint. Results: Of the 40,796 unique records screened, 50 reports underwent full-text assessment and 14 unique studies were included. No study demonstrated that the remodeling benefits of ACE inhibitors, ARBs, ARNIs, beta-blockers, MRAs, hydralazine/isosorbide dinitrate, or SGLT2 inhibitors are mediated by endogenous H2S signaling. Doiron et al. evaluated empagliflozin with or without the H2S donor SG1002 in experimental HFpEF; the combination improved several outcomes beyond empagliflozin alone, but this adjunctive design does not establish H2S mediation of empagliflozin action. Most eligible evidence concerned exogenous H2S donors in animal models and reported improvements in fibrosis, hypertrophy, oxidative stress, mitochondrial injury, and cardiac function. The overall certainty was low because of preclinical predominance, heterogeneous models and H2S assays, donor-specific pharmacology, and incompletely reported randomization and blinding. Conclusions: The principal finding is negative but clinically important: direct evidence that H2S mediates established HF pharmacotherapy is currently absent. H2S remains a promising experimental therapeutic candidate rather than an established shared mechanism or clinically validated treatment target.