Human Cardiomyocyte Calcium Handling and Transverse Tubules in Mid-Stage of Post-Myocardial-Infarction Heart Failure

作者：Morten A. Høydal, Idar Kirkeby‐Garstad, Asbjørn Karevold, Rune Wiseth, Rune Haaverstad, Alexander Wahba, Tomas Stølen, Riccardo Contu, Gianluigi Condorelli, Øyvind Ellingsen, Godfrey L. Smith, Ole Johan Kemi, Ulrik Wisløff · 发表于：ESC Heart Failure · 年份：2018 · DOI：10.1002/ehf2.12271 · 被引用次数：45 · 研究领域：Cardiac electrophysiology and arrhythmias、Ion channel regulation and function、Cardiomyopathy and Myosin Studies

Abstract Aims Cellular processes in the heart rely mainly on studies from experimental animal models or explanted hearts from patients with terminal end-stage heart failure (HF). To address this limitation, we provide data on excitation contraction coupling, cardiomyocyte contraction and relaxation, and Ca2+ handling in post-myocardial-infarction (MI) patients at mid-stage of HF. Methods and results Nine MI patients and eight control patients without MI (non-MI) were included. Biopsies were taken from the left ventricular myocardium and processed for further measurements with epifluorescence and confocal microscopy. Cardiomyocyte function was progressively impaired in MI cardiomyocytes compared with non-MI cardiomyocytes when increasing electrical stimulation towards frequencies that simulate heart rates during physical activity (2 Hz); at 3 Hz, we observed almost total breakdown of function in MI. Concurrently, we observed impaired Ca2+ handling with more spontaneous Ca2+ release events, increased diastolic Ca2+, lower Ca2+ amplitude, and prolonged time to diastolic Ca2+ removal in MI (P < 0.01). Significantly reduced transverse-tubule density (−35%, P < 0.01) and sarcoplasmic reticulum Ca2+ adenosine triphosphatase 2a (SERCA2a) function (−26%, P < 0.01) in MI cardiomyocytes may explain the findings. Reduced protein phosphorylation of phospholamban (PLB) serine-16 and threonine-17 in MI provides further mechanisms to the reduced function. Conclusions Dep...