Therapeutic targeting of mitochondrial dysfunction in heart failure: A grade-assessed systematic review & meta-analysis of clinical outcomes

Introduction:

Mitochondrial dysfunction is increasingly recognized as a central contributor to heart failure (HF) pathophysiology, driving oxidative stress, apoptosis, and energy loss in cardiomyocytes. While therapeutic agents targeting to restore mitochondrial function like elamipretide, resveratrol, ubiquinol, and trimetazidine have shown promise in animal models and early phase human trials, their clinical efficacy remains uncertain. The objective of this meta-analysis is to assess the efficacy of these therapeutic agents in improving the outcomes of people with HF.

Materials & Methods:

A comprehensive literature search was performed in PubMed, Cochrane Library, ScienceDirect, Google Scholar, and ClinicalTrials.gov using keywords: “heart failure”, “elamipretide”, “resveratrol”, “mitochondria”,”ubiquinol”, “trimetazidine”, “levocarnitine”,"coenzyme Q10" for studies through May 2025. From 853 initial articles identified, 52 underwent full-text screening, with 23 randomized controlled trials (RCTs), 5 clinical trials & 1 prospective cohort included for meta-analysis. The outcomes analyzed included changes in left ventricular ejection fraction (LVEF), change in NYHA class, change in distance covered after 6-minute walk test (6MWT), number of hospitalizations & all-cause mortality.

Results:

Twenty-nine studies (n=2460) were included. Mitochondrial targeted therapy significantly improved LVEF compared to pre-treatment levels [SMD: 0.56; 95% CI: 0.44-0.68; p<0.00001] & when compared to controls [SMD: 0.38; 95% CI: 0.17-0.58; p=0.0003]. NYHA class showed significant improvement in mean values after therapy [SMD: -2.28; 95% CI: −3.64 to -0.92; p=0.001] & when compared to controls (RR = 2.38; 95% CI:1.48-3.84; p = 0.0004) indicating better functional outcomes & reduction of symptoms. No significant change was seen in distance walked after 6MWT following therapy [SMD: 0.90; 95% CI: −0.06-1.85; p=0.07], although significant improvement was noted compared to control group [SMD: 17.58; 95% CI: 8.56-26.61; p=0.0001]. There was a significant reduction in 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).

Conclusion:

Mitochondria-targeted therapies provide significant improvements in LV ejection fraction and NYHA class, along with reductions in hospitalizations and all-cause mortality. These findings support the role of these agents as a viable adjunctive strategy in HF management.

Dr Shabrin Abdul Rasheed is a doctor currently working in the NHS as a clnical fellow In Emergency Medicine.She completed her Medical school from Travaancore Medical college Kerala and worked in ITU and Critical care before moving to United Kingdom