Therapeutic targeting of mitochondrial dysfunction in heart failure: a systematic review & meta-analysis of clinical...

Mitochondrial dysfunction is recognised as a key driver of heart failure (HF) pathophysiology, contributing to oxidative stress, apoptosis, and impaired energy production in cardiomyocytes. Although therapeutic agents aimed at restoring mitochondrial function have demonstrated promise in animal models and early-phase clinical trials, their efficacy in clinical practice remains uncertain. This meta-analysis evaluated the impact of these agents on clinical outcomes in HF patients.

A systematic literature search was conducted across PubMed, Cochrane Library, ScienceDirect, Google Scholar, and ClinicalTrials.gov for studies published through May 2025. Thirty one studies (24 RCTs and 7 crossover trials) were included in meta-analysis. Standardized mean difference was pooled for changes in left ventricular ejection fraction (LVEF), NYHA class and six-minute walk test (6MWT) distance compared to baseline, and risk ratios (RR) were pooled for heart failure-related hospitalisations, and all-cause mortality.

Interventions significantly improved LVEF compared with baseline (SMD: 0.53; 95% CI: 0.42-0.65; p < 0.00001) and control groups (SMD: 0.42; 95% CI: 0.31-0.53). Treatment reduced NYHA functional class (RR: 2.38; 95% CI: 1.48-3.84; p = 0.0004), all-cause mortality (RR: 0.62; 95% CI: 0.47-0.82; p = 0.0007), and HF-related hospitalizations (RR: 0.60; 95% CI: 0.42-0.85; p = 0.004). The certainty of evidence was rated as low across all outcomes owing to substantial heterogeneity and high risk of bias.

These findings suggest a potential role for mitochondrial-targeted agents as adjunctive strategies in HF, although the evidence base requires further strengthening through high-quality, adequately powered trials before firm clinical recommendations can be made.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251075951, PROSPERO CRD420251075951.