Human cardiomyocyte calcium handling and transverse tubules in mid‐stage of post‐myocardial‐infarction heart failure

Abstract

AimsCellular 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 resultsNine 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.ConclusionsDepressed cardiomyocyte contraction and relaxation were associated with impaired intracellular Ca2+ handling due to impaired SERCA2a activity caused by a combination of alteration in the PLB/SERCA2a ratio and chronic dephosphorylation of PLB as well as loss of transverse tubules, which disrupts normal intracellular Ca2+ homeostasis and handling. This is the first study that presents these mechanisms from viable and intact cardiomyocytes isolated from the left ventricle of human hearts at mid‐stage of post‐MI HF.

Numerical Simulation of Excitation-Contraction in Isolated Cardiomyocytes

“…For case 1, the result was a concentration of 0.45µM and a % of shortening around 10% corresponds to the results obtained by DelMonte et al [18] and Høydal et al [19]. These results are the ones expected for the physiological function of a real cardiomyocyte.…”

Proarrhythmic Remodeling of Calcium Homeostasis in Cardiac Disease; Implications for Diabetes and Obesity

“…Although larger animal models have been studied more recently ( Xie et al, 2013 ; Zhang et al, 2017 ; Liang et al, 2018 ; Yang et al, 2018 ), most research investigating diabetes-related ventricular arrhythmias to date has been performed on rodents and remains limited. Conversely, functional alterations of Ca 2+ handling proteins and EC coupling in HF have been extensively researched over several decades, in both small and large animal models as well as failing human cardiomyocytes ( Hasenfuss et al, 1994 ; Studer et al, 1994 ; Schmidt et al, 1999 ; Louch et al, 2004 ; Sossalla et al, 2010 ; Crossman et al, 2011 ; Ottolia et al, 2013 ; Zima et al, 2014 ; Gorski et al, 2015 ; Høydal et al, 2018 ).…”

Adrenergic supersensitivity and impaired neural control of cardiac electrophysiology following regional cardiac sympathetic nerve loss

“…Altered Ca 2+ handling is a hallmark of post-MI remodeling, which is often associated with abnormal sarcoplasmic reticulum (SR) Ca 2+ release and reuptake 30 , 31 . We did not observe differences in the CaTD or tau (either at baseline or in response to ISO) between control and DBH-Sap hearts (Fig.…”