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Prognostic impact of atrial fibrillation in cardiogenic shock complicating acute myocardial infarction: a substudy of the IABP-SHOCK II trial Relationship Between Infarct Size and Outcomes Following Primary PCI: Patient-Level Analysis From 10 Randomized Trials Intravascular ultrasound-guided percutaneous coronary intervention in left main coronary bifurcation lesions: a review Predicting lifetime risk for developing atherosclerotic cardiovascular disease in Chinese population: the China-PAR project Prognostic impact of non-culprit chronic total occlusions in infarct-related cardiogenic shock: results of the randomised IABP-SHOCK II trial Risk of Early Adverse Events After Clopidogrel Discontinuation in Patients Undergoing Short-Term Dual Antiplatelet Therapy: An Individual Participant Data Analysis Risk Stratification for Patients in Cardiogenic Shock After Acute Myocardial Infarction Non-eligibility for reperfusion therapy in patients presenting with ST-segment elevation myocardial infarction: Contemporary insights from the National Cardiovascular Data Registry (NCDR) Intracoronary Optical Coherence Tomography 2018: Current Status and Future Directions Predicting the 10-Year Risks of Atherosclerotic Cardiovascular Disease in Chinese Population: The China-PAR Project (Prediction for ASCVD Risk in China)

Original Research2020 Dec 11;S1550-4131(20)30658-6.

JOURNAL:Cell Metab. Article Link

The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure

AA Cluntun, R Badolia, SG Drakos et al. Keywords: LVAD; MCT4; MPC; VB124; cardiac metabolism; heart failure; hypertrophy; lactate; mitochondria; pyruvate

ABSTRACT

The metabolic rewiring of cardiomyocytes is a widely accepted hallmark of heart failure (HF). These metabolic changes include a decrease in mitochondrial pyruvate oxidation and an increased export of lactate. We identify the mitochondrial pyruvate carrier (MPC) and the cellular lactate exporter monocarboxylate transporter 4 (MCT4) as pivotal nodes in this metabolic axis. We observed that cardiac assist device-induced myocardial recovery in chronic HF patients was coincident with increased myocardial expression of the MPC. Moreover, the genetic ablation of the MPC in cultured cardiomyocytes and in adult murine hearts was sufficient to induce hypertrophy and HF. Conversely, MPC overexpression attenuated drug-induced hypertrophy in a cell-autonomous manner. We also introduced a novel, highly potent MCT4 inhibitor that mitigated hypertrophy in cultured cardiomyocytes and in mice. Together, we find that alteration of the pyruvate-lactate axis is a fundamental and early feature of cardiac hypertrophy and failure.