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.
Highlights
The prevalence of heart failure (HF) in Western countries is at present known to be over 23 million worldwide.[1]
Several mechanisms are responsible for this: disrupted cleft spacing between the L-type Ca2+ channel and ryanodine receptors 2 (RyR2) by reduced density of transverse (T) tubules;[2] increased RyR2 Ca2+ sensitivity leading to increased spontaneous Ca2+ release events from sarcoplasmic reticulum (SR) causing afterdepolarization and trigger arrhythmias;[3] reduced SR Ca2+ adenosine triphosphatase 2a (SERCA2a) and increased Na+/ Ca2+ exchanger activities.[4]
Human cardiomyocyte fractional shortening was similar between patients with non-myocardial infarction (MI) and MI at 0.5 Hz stimulation frequency (i.e. 30 b.p.m.), but in contrast to cardiomyocytes from non-MI, we found a negative shortening–frequency relationship in MI cardiomyocytes: at a 2 Hz stimulation rate, cardiomyocyte shortening was significantly depressed (P < 0.001, Figure 1)
Summary
The prevalence of heart failure (HF) in Western countries is at present known to be over 23 million worldwide.[1] In the industrialized part of the world, a common cause of HF is ischaemic heart disease, where a myocardial infarction (MI). Often signals the onset of cardiac dysfunction that may progress to failure. HF is characterized by several abnormalities in the excitation–contraction coupling, such as reduced and slower systolic Ca2+ release from the sarcoplasmic reticulum (SR), elevated diastolic cytoplasmic Ca2+, and reduced diastolic Ca2+ removal, leading to reduced contractile function. Attenuated SERCA2a response, with reduced SR Ca2+ uptake at increased stimulation frequencies, is especially important since this leads to a blunted frequency-dependent acceleration of relaxation (FDAR), thereby impairing diastolic filling at high heart rates.[3]
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