Clinical bottom line
Novel anti-fibrotic therapies represent a promising, yet still investigational, approach to modifying cardiac remodeling in patients with heart failure (HF). Emerging evidence suggests these agents may reduce myocardial fibrosis, potentially improving cardiac structure and function, especially in heart failure with preserved ejection fraction (HFpEF). However, clinical outcome data remain limited, and the precise role of anti-fibrotic interventions in routine HF management is not yet established. Clinicians should consider these therapies as putative adjuncts pending further validation from ongoing trials.
What the evidence shows
Cardiac fibrosis is a key pathological driver of adverse remodeling in HF, contributing to stiffness, impaired relaxation, and progressive dysfunction (Shannon et al., 2024). This remodeling process differs between ventricular chambers and HF phenotypes, with ventricle-specific fibrotic patterns influencing clinical outcomes (Shannon et al., 2024). Traditional HF therapies have limited direct anti-fibrotic effects, prompting interest in novel agents targeting fibrogenic pathways.
The Reduce-MFA DZHK25 trial (Puls et al., 2026) is a notable ongoing study designed to evaluate the effect of anti-fibrotic therapy on regression of myocardial fibrosis after transcatheter aortic valve implantation (TAVI). Although results are pending, the trial’s rationale highlights the potential for these therapies to reverse established fibrosis, which may translate into improved ventricular compliance and function.
Editorial commentary by Mapelli et al. (2024) underscores the concept of cardiac reverse remodeling as a therapeutic goal, emphasizing that novel HF therapies with anti-fibrotic properties could complement existing treatments by targeting myocardial structural abnormalities. This approach may be particularly relevant in HFpEF, where fibrosis and stiffening predominate.
Additional mechanistic insights come from studies of myokines and their complex roles in adverse remodeling and myopathy in HF [4]. These findings suggest that modulation of fibrotic signaling pathways could influence clinical outcomes, although direct clinical trial evidence remains sparse.
Caveats and uncertainty
Current evidence for anti-fibrotic therapies in HF is largely hypothesis-generating and derived from early-phase trials or mechanistic studies. The Reduce-MFA DZHK25 trial (Puls et al., 2026) is ongoing, and definitive clinical outcome data are not yet available. The heterogeneity of HF phenotypes, especially between HFpEF and heart failure with reduced ejection fraction (HFrEF), complicates extrapolation of anti-fibrotic effects.
Fibrosis quantification methods, such as cardiac MRI with late gadolinium enhancement or T1 mapping, are evolving but not yet standardized for routine clinical decision-making. Additionally, the safety profile and long-term effects of novel anti-fibrotic agents require further elucidation.
The interplay between anti-fibrotic therapies and other HF treatments, including neurohormonal blockade and SGLT2 inhibitors, remains to be clarified. There is also uncertainty regarding which patient subgroups might derive the greatest benefit.
How this may change practice
If ongoing trials confirm that anti-fibrotic therapies can safely reduce myocardial fibrosis and improve clinical outcomes, these agents could become an important adjunct in HF management, particularly for patients with HFpEF or those with significant fibrotic burden.
Clinicians should remain informed about emerging data and consider fibrosis assessment in selected patients as part of comprehensive phenotyping. Integration of anti-fibrotic therapy may eventually personalize treatment, targeting myocardial structural abnormalities beyond conventional hemodynamic and neurohormonal parameters.
For now, anti-fibrotic therapies should be viewed as investigational, with use confined to clinical trials or specialized centers. Awareness of this evolving field will prepare clinicians for potential future shifts in HF therapeutic paradigms.