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

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.

A systematic review was conducted according to PRISMA 2020.

PROSPERO CRD420251238589.

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.

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.

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.

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.