# Mitochondrial Targeting by Elamipretide Improves Myocardial Bioenergetics Without Translating into Functional Benefits in HFpEF

## TL;DR

Elamipretide improves heart cell energy production in a rat model of heart failure but does not improve heart function or structure.

## Contribution

The study shows that Elamipretide's mitochondrial benefits do not translate to functional improvements in established HFpEF.

## Key findings

- Elamipretide improved complex I and II respiration in mitochondria.
- No changes in mitochondrial ultrastructure or cardiolipin composition were observed.
- Heart function, stiffness, and remodeling remained unchanged despite improved bioenergetics.

## Abstract

Mitochondrial dysfunction contributes to impaired myocardial energetics and performance in heart failure with preserved ejection fraction (HFpEF). Elamipretide (Ela) enhances mitochondrial bioenergetics in preclinical models, yet its relevance in HFpEF remains unclear. This study examined the effects of Ela on cardiac mitochondrial function, structure, and cardiovascular performance in a rodent HFpEF model. Female obese ZSF1 rats received vehicle or Ela for 12 weeks, with age-matched lean rats as controls. Cardiac function and hemodynamics were assessed by echocardiography and pressure–volume analysis. Mitochondrial respiration was measured in permeabilized fibers and ultrastructure evaluated by transmission electron microscopy. Molecular and histological analyses included cardiolipin lipidomics and mRNA/protein profiling of hypertrophic, fibrotic, and inflammatory markers. Ela modestly improved complex I and II respiration, whereas mitochondrial ultrastructure, cardiolipin composition, and tafazzin expression were unchanged. Diastolic dysfunction persisted, reflected by unchanged E/é, ventricular stiffness factor β, and titin phosphorylation. Compared to untreated HFpEF, systolic performance showed a mild decline, with small reductions in LV ejection fraction and end-systolic elastance. Accordingly, cardiac remodeling, including hypertrophy, fibrosis, and inflammatory activation, remained unaltered. Vascular stiffness slightly increased, while carotid reactivity and morphology were preserved. In conclusion, despite enhanced mitochondrial respiration following Ela treatment, no functional or structural benefits were observed in experimental HFpEF, suggesting limited therapeutic efficacy once HFpEF is established.