Efficacy of Targeted Mitochondrial Elamipretide Therapy in Patients with Advanced Heart Failure and Preserved Ejection Fraction

International Journal of Cardiology | Vol. 17, No. 8, August 2026 | pp. 17–24

DOI: 10.46882/2026/IJC/001915

Original Research Article

Efficacy of Targeted Mitochondrial Elamipretide Therapy in Patients with Advanced Heart Failure and Preserved Ejection Fraction

Alessandro Rossi¹, Giulia Bianchi²

¹ Department of Cardiovascular Diseases, University of Milan, Milan, Italy
² Institute of Cardiology, Sapienza University of Rome, Rome, Italy

Abstract:
Mitochondrial dysfunction and microvascular energetic failure represent critical pathophysiological drivers in heart failure with preserved ejection fraction (HFpEF). This prospective, randomized, double-blind, placebo-controlled trial evaluated the clinical efficacy and safety of a next-generation mitochondrial-targeting peptide, Elamipretide-Z, in patients diagnosed with advanced HFpEF. We randomized 220 participants with a baseline left ventricular ejection fraction (LVEF) greater than or equal to 50% and elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) levels to receive either daily subcutaneous Elamipretide-Z (40 mg) or a matching placebo for 24 weeks. The primary endpoint was the absolute change in the 6-minute walk distance (6MWD). Secondary outcomes included changes in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score and Doppler echocardiographic markers of diastolic function (E/e' ratio). At the 24-week follow-up, patients in the Elamipretide-Z cohort demonstrated a statistically significant improvement in functional capacity, with the 6MWD increasing by a mean of 34.5 meters (± 6.2 m) compared to 8.2 meters (± 3.1 m) in the placebo arm (p < 0.001). The KCCQ clinical summary score improved by 9.4 points in the active treatment group (p = 0.004). Furthermore, the mean E/e' ratio decreased from 14.8 to 11.2 in the treatment group (p = 0.01), indicating reduced left ventricular filling pressures. No serious adverse drug reactions or systemic toxicities were observed. In conclusion, targeted mitochondrial optimization via Elamipretide-Z safely improves functional exercise capacity, alleviates symptoms, and enhances diastolic performance in patients suffering from HFpEF.

Keywords: Heart failure with preserved ejection fraction, Mitochondrial dysfunction, Elamipretide, Diastolic function, Exercise capacity, Peptides

Received: May 10, 2026; Revised: June 15, 2026; Accepted: July 02, 2026; Published: August 03, 2026

Citation: Rossi A, Bianchi G. Efficacy of Targeted Mitochondrial Elamipretide Therapy in Patients with Advanced Heart Failure and Preserved Ejection Fraction. International Journal of Cardiology, 2026; 17(8): 17–24. DOI: 10.46882/2026/IJC/001915

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