Translational issues for mitoprotective agents as adjunct to reperfusion therapy in patients with ST-segment elevation myocardial infarction

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DOI

  • Hans Erik Bøtker
  • Hector Alejandro Cabrera-Fuentes, University of Singapore Medical School, National Heart Centre Singapore, Justus-Liebig University, Centro de Biotecnologia‐FEMSA, Kazan Volga Region Federal University
  • ,
  • Marisol Ruiz-Meana, University Hospital Vall d'Hebron‐Universitat Autònoma, Centro de Investigación Biomédica en Red‐CV, CIBER‐CV
  • ,
  • Gerd Heusch, West German Heart and Vascular Center, University of Essen
  • ,
  • Michel Ovize, INSERM U1060, CarMeN Laboratory, Université de Lyon and Explorations Fonctionnelles Cardiovasculaires, Hôpital Louis Pradel, Hospices Civils de Lyon, Lyon, France.

Pre-clinical studies have indicated that mitoprotective drugs may add cardioprotection beyond rapid revascularization, antiplatelet therapy and risk modification. We review the clinical efficacy of mitoprotective drugs that have progressed to clinical testing comprising cyclosporine A, KAI-9803, MTP131 and TRO 40303. Whereas cyclosporine may reduce infarct size in patients undergoing primary angioplasty as evaluated by release of myocardial ischaemic biomarkers and infarct size imaging, the other drugs were not capable of demonstrating this effect in the clinical setting. The absent effect leaves the role of the mitochondrial permeability transition pore for reperfusion injury in humans unanswered and indicates that targeting one single mechanism to provide mitoprotection may not be efficient. Moreover, the lack of effect may relate to favourable outcome with current optimal therapy, but conditions such as age, sex, diabetes, dyslipidaemia and concurrent medications may also alter mitochondrial function. However, as long as the molecular structure of the pore remains unknown and specific inhibitors of its opening are lacking, the mitochondrial permeability transition pore remains a target for alleviation of reperfusion injury. Nevertheless, taking conditions such as ageing, sex, comorbidities and co-medication into account may be of paramount importance during the design of pre-clinical and clinical studies testing mitoprotective drugs.

Original languageEnglish
JournalJournal of Cellular and Molecular Medicine (Online)
Volume24
Issue5
Pages (from-to)2717-2729
Number of pages13
ISSN1582-4934
DOIs
Publication statusPublished - Mar 2020

    Research areas

  • cyclosporine A, ischaemia, mitochondria, myocardial infarction, reperfusion, ISCHEMIA/REPERFUSION INJURY, OXIDATIVE STRESS, PROTEIN-KINASE-C, PROTECTION, MITOCHONDRIAL PERMEABILITY TRANSITION, CYCLOSPORINE-A, ATP SYNTHASE, CARDIAC ISCHEMIA, PORE, CARDIOPROTECTION

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