Author + information
- Received October 22, 2018
- Revision received December 11, 2018
- Accepted December 13, 2018
- Published online April 29, 2019.
- Kathryn C. Chatfield, MD, PhDa,∗,
- Genevieve C. Sparagna, PhDb,∗,
- Sarah Chau, BSb,
- Elisabeth K. Phillips, BSb,
- Amrut V. Ambardekar, MDb,
- Muhammad Aftab, MDc,d,
- Max B. Mitchell, MDc,
- Carmen C. Sucharov, PhDb,
- Shelley D. Miyamoto, MDa and
- Brian L. Stauffer, MDb,e,∗ ()
- aDepartment of Pediatrics, University of Colorado School of Medicine, Children’s Hospital of Colorado, Aurora, Colorado
- bDepartment of Medicine/Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado
- cDepartment of Surgery/Division of Cardiothoracic Surgery, University of Colorado School of Medicine, Aurora, Colorado
- dDepartment of Surgery, Veterans Administration Hospital, Denver, Colorado
- eDepartment of Medicine/Division of Cardiology, Denver Health Medical Center, Denver, Colorado
- ↵∗Address for correspondence:
Dr. Brian L. Stauffer, University of Colorado Anschutz Medical Campus, 12700 East 19th Avenue, B139, Aurora, Colorado 80045.
• Mitochondrial function is impaired in explanted failing pediatric and adult human hearts.
• Elamipretide is a novel mitochondria-targeted drug that is targeted to cardiolipin on the inner mitochondrial membrane and improves coupling of the electron transport chain.
• Treatment of explanted human hearts with elamipretide improves human cardiac mitochondrial function.
• The study provides novel methods to evaluate the influence of compounds on mitochondria in the human heart and provides proof of principle for the use of elamipretide to improve mitochondrial energetics in failing myocardium due to multiple etiologies and irrespective of age.
Negative alterations of mitochondria are known to occur in heart failure (HF). This study investigated the novel mitochondrial-targeted therapeutic agent elamipretide on mitochondrial and supercomplex function in failing human hearts ex vivo. Freshly explanted failing and nonfailing ventricular tissue from children and adults was treated with elamipretide. Mitochondrial oxygen flux, complex (C) I and CIV activities, and in-gel activity of supercomplex assembly were measured. Mitochondrial function was impaired in the failing human heart, and mitochondrial oxygen flux, CI and CIV activities, and supercomplex-associated CIV activity significantly improved in response to elamipretide treatment. Elamipretide significantly improved failing human mitochondrial function.
↵∗ Drs. Chatfield and Sparagna have contributed equally to this paper.
This work was supported by the Addison Scott Memorial Fund, the Boedecker Foundation Award, the Jack Cooper Millisor Chair in Pediatric Heart Disease, a gift from the Nair Family, research support from Stealth BioTherapeutics, Inc., and the following National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute grants: K08 HL127294, R01 HL107715 (to Dr. Stauffer) and R01 HL126928 (to Dr. Miyamoto). This study was supported by NIH/National Center for Advancing Translational Sciences Colorado CTSA Grant Number UL1 TR001082. The contents are the authors’ sole responsibility and do not necessarily represent official NIH views. Drs. Sucharov, Miyamoto, and Stauffer are founders and scientific advisors for CoramiR Biomedical, LLC. Dr. Stauffer received research support from Stealth BioTherapeutics, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received October 22, 2018.
- Revision received December 11, 2018.
- Accepted December 13, 2018.
- 2019 The Authors