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

Abstract

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.

Keywords: cyclosporine A; ischaemia; mitochondria; myocardial infarction; reperfusion.

Figure 1

Cyclosporine A and TRO40303 inhibit opening of mitochondrial permeability transition pores (MPTP). Proteins implicated in MPTP formation include the matrix cyclophilin D (CyD), the inner membrane (IMM) and the outer mitochondrial membrane (OMM). Additional proteins such as the translocator protein 18 kDa (TSPO), located in the OMM, interact with proteins implicated in MPTP formation. Under pathophysiological conditions, such as high Ca²⁺ concentration and increased oxidative stress, the complex forms an open pore between the inner and outer membranes that ultimately result in mitochondrial swelling, mitochondrial Ca²⁺ efflux and the release of apoptogenic proteins. Cyclosporine A targets matrix CyD, where Ca²⁺ overload triggers MPTP opening. TRO40303 binds to TSPO in the outer membrane