Abstract
BackgroundSubcellular localization and function of L-type calcium channels (LTCCs) play an important role in regulating contraction of cardiomyocytes. Understanding how this is affected by the disruption of transverse tubules during heart failure could lead to new insights into the disease.MethodsCardiomyocytes were isolated from healthy donor hearts, as well as from patients with cardiomyopathies and with left ventricular assist devices. Scanning ion conductance and confocal microscopy was used to study membrane structures in the cells. Super-resolution scanning patch-clamp was used to examine LTCC function in different microdomains. Computational modeling predicted the impact of these changes to arrhythmogenesis at the whole-heart level.FindingsWe showed that loss of structural organization in failing myocytes leads to re-distribution of functional LTCCs from the T-tubules to the sarcolemma. In ischemic cardiomyopathy, the increased LTCC open probability in the T-tubules depends on the phosphorylation by protein kinase A, whereas in dilated cardiomyopathy, the increased LTCC opening probability in the sarcolemma results from enhanced phosphorylation by calcium-calmodulin kinase II. LVAD implantation corrected LTCCs pathophysiological activity, although it did not improve their distribution. Using computational modeling in a 3D anatomically-realistic human ventricular model, we showed how LTCC location and activity can trigger heart rhythm disorders of different severity.InterpretationOur findings demonstrate that LTCC redistribution and function differentiate between disease aetiologies. The subcellular changes observed in specific microdomains could be the consequence of the action of distinct protein kinases.FundingThis work was supported by 10.13039/100000002NIH grant (ROI-HL 126802 to NT-JG) and British Heart Foundation (grant RG/17/13/33173 to JG, project grant PG/16/17/32069 to RAC). Funders had no role in study design, data collection, data analysis, interpretation, writing of the report
Highlights
The progression of structural heart diseases from an early form towards advanced heart failure (HF) is accompanied by an increased risk of arrhythmia and sudden cardiac death [1,2]
A well-known characteristic phenotype of human failing cardiomyocytes is their increased size [18,19], which was observed in all the cases studied in this work (Fig. 1); the average cell length increased by 20À49%
In human failing myocytes from both ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) patients, we observed a significant decrease in regularity and internal density of T-tubules as compared to controls (Fig. 2; decrease of 36.3% for ICM TT density, p
Summary
The progression of structural heart diseases from an early form towards advanced heart failure (HF) is accompanied by an increased risk of arrhythmia and sudden cardiac death [1,2]. Cardiomyocyte L-type calcium channels, essentials for the contraction of the heart, have been the focus of studies of human heart failure in the last decades, no emphasis has been placed on their regional variation within the cell. This study found that despite the same end-stage time point, major differences exist at the sub-cellular level between aetiologies These findings describe new targets specific to each disease, and this could open the door to new pharmacological treatments. A critical subpopulation of LTCCs, which participates in excitation-contraction coupling, is located in the specialized transverse tubules (T-tubules, TT) microdomains These structures represent highly branched invaginations of the cardiomyocyte sarcolemma [12]. We used a combination of electrophysiological and optical techniques and a multi-scale computational model to understand how changes at the cellular level affect the behavior of the whole organ and how different aetiologies may be distinguished
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