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

Schauer A, Jahn D, Vahle B, Barthel P, Männel A, Fabig G, Linke A, Adams V, Augstein A

International journal of molecular sciences21 Jan 2026Cited by 3 (Europe PMC)

PMID41596703PMCIDPMC12841679DOI10.3390/ijms27021060PepBankPUB-41596703

Summary

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.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study15

15 results from studies that gave the peptide. No result from this study comes from people.

01AnimalAnimal study (in vivo)Mechanism
In obese ZSF1 rats with HFpEF, elamipretide modestly improved complex I and II mitochondrial respiration.
In plain wordsIn rats with a heart failure model, elamipretide modestly improved how well heart mitochondria used oxygen.
Peptide
Elamipretide (SS-31)
Outcome
IncreaseComplex I and II mitochondrial respiration
Study
ratn: not reported in source
Female obese ZSF1 rat model of HFpEF
Comparator
Vehicle-treated HFpEF rats
Outcome group
Mitochondrial function · Cardiovascular
Studied dose
Dose not stated · 12 weeksAs given in this study (rat).
Source sentences
Summary
Ela modestly improved complex I and II respiration
1 context sentence(design, population, supporting numbers)
Summary · context
Female obese ZSF1 rats received vehicle or Ela for 12 weeks, with age-matched lean rats as controls.
Show in the study text Report a problemFND-4159670301
02AnimalAnimal study (in vivo)Mechanism
In obese ZSF1 rats with HFpEF, elamipretide did not change mitochondrial ultrastructure.
In plain wordsIn rats with a heart failure model, elamipretide did not change the inner structure of heart mitochondria.
Peptide
Elamipretide (SS-31)
Outcome
No significant changeMitochondrial ultrastructure
Study
ratn: not reported in source
Female obese ZSF1 rat model of HFpEF
Comparator
Vehicle-treated HFpEF rats
Outcome group
Mitochondrial function · Cardiovascular
Studied dose
Dose not stated · 12 weeksAs given in this study (rat).
Source sentences
Summary
whereas mitochondrial ultrastructure, cardiolipin composition, and tafazzin expression were unchanged.
1 context sentence(design, population, supporting numbers)
Summary · context
Female obese ZSF1 rats received vehicle or Ela for 12 weeks, with age-matched lean rats as controls.
Show in the study text Report a problemFND-4159670302
03AnimalAnimal study (in vivo)Mechanism
In obese ZSF1 rats with HFpEF, elamipretide did not change cardiolipin composition.
In plain wordsIn rats with a heart failure model, elamipretide did not change the make-up of cardiolipin, a mitochondrial fat.
Peptide
Elamipretide (SS-31)
Outcome
No significant changeCardiolipin composition
Study
ratn: not reported in source
Female obese ZSF1 rat model of HFpEF
Comparator
Vehicle-treated HFpEF rats
Outcome group
Mitochondrial function · Cardiovascular
Studied dose
Dose not stated · 12 weeksAs given in this study (rat).
Source sentences
Summary
whereas mitochondrial ultrastructure, cardiolipin composition, and tafazzin expression were unchanged.
1 context sentence(design, population, supporting numbers)
Summary · context
Female obese ZSF1 rats received vehicle or Ela for 12 weeks, with age-matched lean rats as controls.
Show in the study text Report a problemFND-4159670303
04AnimalAnimal study (in vivo)Mechanism
In obese ZSF1 rats with HFpEF, elamipretide did not change tafazzin expression.
In plain wordsIn rats with a heart failure model, elamipretide did not change tafazzin expression.
Peptide
Elamipretide (SS-31)
Outcome
No significant changeTafazzin expression
Study
ratn: not reported in source
Female obese ZSF1 rat model of HFpEF
Comparator
Vehicle-treated HFpEF rats
Outcome group
Mitochondrial function · Cardiovascular
Studied dose
Dose not stated · 12 weeksAs given in this study (rat).
Source sentences
Summary
whereas mitochondrial ultrastructure, cardiolipin composition, and tafazzin expression were unchanged.
1 context sentence(design, population, supporting numbers)
Summary · context
Female obese ZSF1 rats received vehicle or Ela for 12 weeks, with age-matched lean rats as controls.
Show in the study text Report a problemFND-4159670304
05AnimalAnimal study (in vivo)Efficacy outcome
In obese ZSF1 rats with HFpEF, diastolic dysfunction persisted with elamipretide, with unchanged E/e'.
In plain wordsIn rats with a heart failure model, elamipretide did not improve the heart's filling function (E/e').
Peptide
Elamipretide (SS-31)
Outcome
No significant changeDiastolic function, E/e'
Study
ratn: not reported in source
Female obese ZSF1 rat model of HFpEF
Comparator
Vehicle-treated HFpEF rats
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated · 12 weeksAs given in this study (rat).
Source sentences
Summary
Diastolic dysfunction persisted, reflected by unchanged E/é, ventricular stiffness factor β, and titin phosphorylation.
1 context sentence(design, population, supporting numbers)
Summary · context
Female obese ZSF1 rats received vehicle or Ela for 12 weeks, with age-matched lean rats as controls.
Show in the study text Report a problemFND-4159670305
06AnimalAnimal study (in vivo)Efficacy outcome
In obese ZSF1 rats with HFpEF, ventricular stiffness factor beta was unchanged with elamipretide.
In plain wordsIn rats with a heart failure model, elamipretide did not change heart wall stiffness.
Peptide
Elamipretide (SS-31)
Outcome
No significant changeVentricular stiffness factor beta
Study
ratn: not reported in source
Female obese ZSF1 rat model of HFpEF
Comparator
Vehicle-treated HFpEF rats
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated · 12 weeksAs given in this study (rat).
Source sentences
Summary
Diastolic dysfunction persisted, reflected by unchanged E/é, ventricular stiffness factor β, and titin phosphorylation.
1 context sentence(design, population, supporting numbers)
Summary · context
Female obese ZSF1 rats received vehicle or Ela for 12 weeks, with age-matched lean rats as controls.
Show in the study text Report a problemFND-4159670306
07AnimalAnimal study (in vivo)Efficacy outcome
In obese ZSF1 rats with HFpEF, titin phosphorylation was unchanged with elamipretide.
In plain wordsIn rats with a heart failure model, elamipretide did not change titin phosphorylation in the heart.
Peptide
Elamipretide (SS-31)
Outcome
No significant changeTitin phosphorylation
Study
ratn: not reported in source
Female obese ZSF1 rat model of HFpEF
Comparator
Vehicle-treated HFpEF rats
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated · 12 weeksAs given in this study (rat).
Source sentences
Summary
Diastolic dysfunction persisted, reflected by unchanged E/é, ventricular stiffness factor β, and titin phosphorylation.
1 context sentence(design, population, supporting numbers)
Summary · context
Female obese ZSF1 rats received vehicle or Ela for 12 weeks, with age-matched lean rats as controls.
Show in the study text Report a problemFND-4159670307
08AnimalAnimal study (in vivo)Efficacy outcome
In obese ZSF1 rats with HFpEF, elamipretide was followed by a small reduction in LV ejection fraction compared with untreated HFpEF.
In plain wordsIn rats with a heart failure model, elamipretide was linked to a small drop in the heart's pumping fraction compared with untreated rats.
Peptide
Elamipretide (SS-31)
Outcome
DecreaseLeft ventricular ejection fraction
Study
ratn: not reported in source
Female obese ZSF1 rat model of HFpEF
Comparator
Vehicle-treated HFpEF rats
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated · 12 weeksAs given in this study (rat).
Source sentences
Summary
Compared to untreated HFpEF, systolic performance showed a mild decline, with small reductions in LV ejection fraction and end-systolic elastance.
1 context sentence(design, population, supporting numbers)
Summary · context
Female obese ZSF1 rats received vehicle or Ela for 12 weeks, with age-matched lean rats as controls.
Show in the study text Report a problemFND-4159670308
09AnimalAnimal study (in vivo)Efficacy outcome
In obese ZSF1 rats with HFpEF, elamipretide was followed by a small reduction in end-systolic elastance compared with untreated HFpEF.
In plain wordsIn rats with a heart failure model, elamipretide was linked to a small drop in a measure of heart contraction strength compared with untreated rats.
Peptide
Elamipretide (SS-31)
Outcome
DecreaseEnd-systolic elastance
Study
ratn: not reported in source
Female obese ZSF1 rat model of HFpEF
Comparator
Vehicle-treated HFpEF rats
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated · 12 weeksAs given in this study (rat).
Source sentences
Summary
Compared to untreated HFpEF, systolic performance showed a mild decline, with small reductions in LV ejection fraction and end-systolic elastance.
1 context sentence(design, population, supporting numbers)
Summary · context
Female obese ZSF1 rats received vehicle or Ela for 12 weeks, with age-matched lean rats as controls.
Show in the study text Report a problemFND-4159670309
10AnimalAnimal study (in vivo)Efficacy outcome
In obese ZSF1 rats with HFpEF, cardiac hypertrophy remained unaltered with elamipretide.
In plain wordsIn rats with a heart failure model, elamipretide did not change heart muscle thickening.
Peptide
Elamipretide (SS-31)
Outcome
No significant changeCardiac hypertrophy
Study
ratn: not reported in source
Female obese ZSF1 rat model of HFpEF
Comparator
Vehicle-treated HFpEF rats
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated · 12 weeksAs given in this study (rat).
Source sentences
Summary
Accordingly, cardiac remodeling, including hypertrophy, fibrosis, and inflammatory activation, remained unaltered.
1 context sentence(design, population, supporting numbers)
Summary · context
Female obese ZSF1 rats received vehicle or Ela for 12 weeks, with age-matched lean rats as controls.
Show in the study text Report a problemFND-4159670310
11AnimalAnimal study (in vivo)Efficacy outcome
In obese ZSF1 rats with HFpEF, cardiac fibrosis remained unaltered with elamipretide.
In plain wordsIn rats with a heart failure model, elamipretide did not change heart scarring.
Peptide
Elamipretide (SS-31)
Outcome
No significant changeCardiac fibrosis
Study
ratn: not reported in source
Female obese ZSF1 rat model of HFpEF
Comparator
Vehicle-treated HFpEF rats
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated · 12 weeksAs given in this study (rat).
Source sentences
Summary
Accordingly, cardiac remodeling, including hypertrophy, fibrosis, and inflammatory activation, remained unaltered.
1 context sentence(design, population, supporting numbers)
Summary · context
Female obese ZSF1 rats received vehicle or Ela for 12 weeks, with age-matched lean rats as controls.
Show in the study text Report a problemFND-4159670311
12AnimalAnimal study (in vivo)Efficacy outcome
In obese ZSF1 rats with HFpEF, inflammatory activation in the heart remained unaltered with elamipretide.
In plain wordsIn rats with a heart failure model, elamipretide did not change inflammation in the heart.
Peptide
Elamipretide (SS-31)
Outcome
No significant changeCardiac inflammatory activation
Study
ratn: not reported in source
Female obese ZSF1 rat model of HFpEF
Comparator
Vehicle-treated HFpEF rats
Outcome group
Inflammation markers · Cardiovascular
Studied dose
Dose not stated · 12 weeksAs given in this study (rat).
Source sentences
Summary
Accordingly, cardiac remodeling, including hypertrophy, fibrosis, and inflammatory activation, remained unaltered.
1 context sentence(design, population, supporting numbers)
Summary · context
Female obese ZSF1 rats received vehicle or Ela for 12 weeks, with age-matched lean rats as controls.
Show in the study text Report a problemFND-4159670312
13AnimalAnimal study (in vivo)Efficacy outcome
In obese ZSF1 rats with HFpEF, vascular stiffness slightly increased with elamipretide.
In plain wordsIn rats with a heart failure model, elamipretide was linked to a slight increase in blood vessel stiffness.
Peptide
Elamipretide (SS-31)
Outcome
IncreaseVascular stiffness
Study
ratn: not reported in source
Female obese ZSF1 rat model of HFpEF
Comparator
Vehicle-treated HFpEF rats
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated · 12 weeksAs given in this study (rat).
Source sentences
Summary
Vascular stiffness slightly increased, while carotid reactivity and morphology were preserved.
1 context sentence(design, population, supporting numbers)
Summary · context
Female obese ZSF1 rats received vehicle or Ela for 12 weeks, with age-matched lean rats as controls.
Show in the study text Report a problemFND-4159670313
14AnimalAnimal study (in vivo)Efficacy outcome
In obese ZSF1 rats with HFpEF, carotid reactivity was preserved with elamipretide.
In plain wordsIn rats with a heart failure model, elamipretide did not change how the carotid artery reacted.
Peptide
Elamipretide (SS-31)
Outcome
No significant changeCarotid reactivity
Study
ratn: not reported in source
Female obese ZSF1 rat model of HFpEF
Comparator
Vehicle-treated HFpEF rats
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated · 12 weeksAs given in this study (rat).
Source sentences
Summary
Vascular stiffness slightly increased, while carotid reactivity and morphology were preserved.
1 context sentence(design, population, supporting numbers)
Summary · context
Female obese ZSF1 rats received vehicle or Ela for 12 weeks, with age-matched lean rats as controls.
Show in the study text Report a problemFND-4159670314
15AnimalAnimal study (in vivo)Efficacy outcome
In obese ZSF1 rats with HFpEF, carotid morphology was preserved with elamipretide.
In plain wordsIn rats with a heart failure model, elamipretide did not change the shape of the carotid artery.
Peptide
Elamipretide (SS-31)
Outcome
No significant changeCarotid morphology
Study
ratn: not reported in source
Female obese ZSF1 rat model of HFpEF
Comparator
Vehicle-treated HFpEF rats
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated · 12 weeksAs given in this study (rat).
Source sentences
Summary
Vascular stiffness slightly increased, while carotid reactivity and morphology were preserved.
1 context sentence(design, population, supporting numbers)
Summary · context
Female obese ZSF1 rats received vehicle or Ela for 12 weeks, with age-matched lean rats as controls.
Show in the study text Report a problemFND-4159670315

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
10 Oct 2026, 08:19 UTC
Study results updated
Version 1
9 Oct 2026, 02:47 UTC
First added · source update from Europe PMC

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