The endogenous mechanisms contributing to tissue survival following myocardial infarction are not fully understood. We investigated the alterations in the mitochondrial proteome after ischemia-reperfusion (I/R) and its possible implications on cell survival. Mitochondrial proteomic analysis of cardiac tissue from an in vivo porcine I/R model found that surviving tissue in the peri-infarct border zone showed increased expression of several proteins. Notably, these included subunits of the mitochondrial pyruvate carrier (MPC), namely MPC1 and MPC2. Western blot, immunohistochemistry, and mRNA analysis corroborated the elevated expression of MPC in the surviving tissue. Furthermore, MPC1 and MPC2 protein levels were found to be markedly elevated in the myocardium of ischemic cardiomyopathy patients. These findings led to the hypothesis that increased MPC expression is cardioprotective due to enhancement of mitochondrial pyruvate uptake in the energy-starved heart following I/R. To test this, isolated mouse hearts perfused with a modified Krebs buffer (containing glucose, pyruvate, and octanoate as metabolic substrates) were subjected to I/R with or without the MPC transport inhibitor UK5099. UK5099 increased myocardial infarction and attenuated post-ischemic recovery of left ventricular end-diastolic pressure. However, aerobically perfused control hearts that were exposed to UK5099 did not modulate contractile function, although pyruvate uptake was blocked as evidenced by increased cytosolic lactate and pyruvate levels. Our findings indicate that increased expression of MPC leads to enhanced uptake and utilization of pyruvate during I/R. We propose this as a putative endogenous mechanism that promotes myocardial survival to limit infarct size. Ischemic heart disease resulting from the obstruction of coronary arteries commonly culminates in myocardial infarction. Although restoring blood flow is necessary to re-establish oxygen and nutrients to the ischemic myocardium, reperfusion itself may promote damage due to exacerbated oxidative stress and inflammation (1). Even when patients survive, the damage caused to the heart typically triggers events leading to heart failure. Unfortunately, there are still no effective interventions for limiting injury after ischemia despite the potential of such therapeutic options to reduce morbidity and mortality.Laboratory and clinical studies suggest that the post-infarction failing heart is characterized by a diminished capacity to convert chemical energy into mechanical work due to mitochondrial imbalances (2). The primary function of mitochondria is to generate ATP via oxidative phosphorylation, which is used by the heart to meet its significant energy demands. In the well perfused healthy heart, ϳ70 -90% of ATP is via ␤-oxidation of fatty acids, with most of the remaining amount coming from the oxidation of glucose and lactate (3, 4). However, when oxygen is restricted as occurs during ischemia or sub-optimal reperfusion, there is a metabolic shift with glycolysis becoming the ...

BackgroundCoronary artery disease (CAD) is a common finding in patients undergoing transcatheter aortic valve implantation (TAVI). However, its prognostic significance and its management remains controversial.AimsThis study sought to determine whether the presence of CAD, its complexity, and angiography‐guided percutaneous coronary intervention (PCI) are associated with outcomes after TAVI.MethodsAll patients undergoing TAVI at a tertiary referral center between 2008 and 2018 were included in a prospective observational study. Baseline SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) score (SS) and a residual SS after PCI were calculated. The endpoints on the 5 year follow‐up were all‐cause mortality and a composite of mayor cardiovascular adverse events (MACE).ResultsIn 379 patients, the presence of CAD and its complexity were not significantly associated with worse 5‐year survival after TAVI, with a mortality for SS0 of 45%; for SS 1–22 of 36.5% (HR 0.77; 95% CI 0.53–1.11, p = 0.15) and for SS > 22 of 42.1% (HR 1.24; 95% CI 0.59–2.63, p = 0.57). Regarding the combined event of MACE, there were also no statistically significant differences between patients with CAD and without CAD (56.8% in patients without CAD and 54.9% in patients with CAD; HR 1.06; 95% CI 0.79–1.43, p = 0.7). Angiography‐guided PCI or completeness of revascularization was not associated with different outcomes.ConclusionsIn the present analysis, neither the presence nor the extent of CAD, nor the degree of revascularization, was associated with a prognostic impact in patients undergoing TAVI at 5‐year follow‐up.

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