Mitochondrial care in acute myocardial infarction.

Rapid restoration of blood flow has the greatest impact on reducing infarct size and improving patient prognosis in patients with ST-elevation myocardial infarction (MI). However, reperfusion itself can exacerbate myocardial damage on top of the initial ischaemic damage. Lethal reperfusion injury develops when sudden restoration of blood flow causes necrosis of myocytes that—albeit injured by the preceding ischaemia—were potentially salvageable at the time of reperfusion. In animal models, reperfusion injury may account for up to 50% of the final infarct size. Reperfusion injury is modifiable. Pre-infarct angina and repetitive episodes of ischaemia before ST-elevation MI reduce final infarct size, and are thought to be innate forms of pre-conditioning that reduce reperfusion injury. Hence, reperfusion injury is a target for improving outcomes in patients with acute MI undergoing optimal revascularization. Pre-conditioning by mechanical intervention, with repeated cycles of brief ischaemia and reperfusion before extended ischaemia, cannot be applied in acute MI due to its unpredictable nature. Repeated cycles of re-occlusion and reperfusion of the coronary artery within the first minute of reflow (postconditioning) and repeated cycles of brief ischaemia and reperfusion in a distant organ (remote conditioning), typically the upper arm, can protect from lethal reperfusion injury and reduce infarct size by 30–70% according to experimental animal studies. Although the initial promising results with post-conditioning, which ultimately confirmed a specific intervention against reperfusion injury, have not been quite consistent in more recent studies, the intervention by remote conditioning has been translated into the clinical setting in proof-of-concept studies, and also demonstrated improvement in clinical outcome. The demonstration of cardioprotective effects by various forms of ischaemic conditioning therapies have encouraged the pursuit of underlying mechanisms and drugs that recapitulate mechanical conditioning by specifically addressing signal transduction pathways. Mechanical conditioning activates several protective mechanisms in the target organ, including three parallel signalling cascades: the nitric oxide-dependent G-protein coupled receptor-eNOS-protein kinase G pathway, the reperfusion-injury salvage kinase (RISK) pathway and the survivor activating factor enhancement (SAFE) signalling pathway (Figure 1). The pathways interact and converge on the mitochondria to modify membrane integrity by inhibiting the opening of the membrane permeability transition pore (MPTP). The MPTP is closed during myocardial ischaemia but opens during reperfusion, causing mitochondrial swelling, loss of function and, potentially, cellular necrosis. Cyclosporine A prevents MPTP opening, provided that it is ‘on board’ at start of reperfusion. In the clinical setting, cyclosporine has been shown to reduce infarct size in patients undergoing primary PCI. Other pharmacological approaches for preventing or modifying the MPTP opening, e.g. by volatile anaesthetics or metformin, have shown cardioprotective capacity in experimental studies, but remain to be tested systematically in clinical trials. In this light, the MITOCARE study—a proof-of-concept study investigating the cardioprotective effect of TRO40303, a new mitochondrial-targeted drug, as an adjunct to primary percutaneous coronary intervention in patients with acute ST-elevation MI—is appropriate and timely. However, the study demonstrated no protection from TRO40303 as measured by biomarker release over 3 days, cardiac magnetic resonance (CMR)-assessed myocardial salvage index, CMR-assessed infarct size or left ventricular ejection fraction. The strength of the study is its multicentre design, inclusion of patients with totally occluded culprit vessels and large area-at-risk, use of CMR in a subgroup of patients and independent measurement of left ventricular function as secondary endpoints. The active study group started out on slightly more negative premises with respect to age, baseline biomarkers and unsuccessful revascularization. Endpoint limitations include lack of individual area-at-risk assessment using biomarkers and potential interference with the area-at-risk determination from T2-weighted oedema with CMR by any cardioprotective intervention. The study is challenged by the excellent outcomes from modern, standard therapy of ST-elevation MI and the power is borderline. The translation of the cardioprotective efficacy of TRO40303 from healthy animals to humans may be attenuated