Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 24, Issue 5, Pages 2717-2729Publisher
WILEY
DOI: 10.1111/jcmm.14953
Keywords
cyclosporine A; ischaemia; mitochondria; myocardial infarction; reperfusion
Categories
Funding
- Novo Nordisk Foundation [NNF14OC0013337, NNF15OC0016674]
- Russian Government Program for competitive growth of Kazan Federal University, Kazan (Russian Federation)
- Singapore Heart Foundation [SHF/FG657P/2017]
- von Behring-Rontgen-Foundation (Marburg, Germany)
- ISCIII [PI19-01196]
- CIBER-CV
- SEC-2016
- European Regional Development Fundings (ERDF-FEDER)
- German Research Foundation [SFB 1116 B8]
- COST Action EU-CARDIOPROTECTION [CA16225]
- COST (European Cooperation in Science and Technology)
- [MTV3-122/C/2015]
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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.
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