Dataset Information

Nanoscale regulation of L-type calcium channels differentiates between ischemic and dilated cardiomyopathies.

ABSTRACT:

Background

Subcellular 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.

Methods

Cardiomyocytes 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.

Findings

We 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.

Interpretation

Our 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.

Funding

This work was supported by NIH 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.

SUBMITTER: Sanchez-Alonso JL

PROVIDER: S-EPMC7317229 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Nanoscale regulation of L-type calcium channels differentiates between ischemic and dilated cardiomyopathies.

Sanchez-Alonso Jose L JL Loucks Alexandra A Schobesberger Sophie S van Cromvoirt Ankie M AM Poulet Claire C Chowdhury Rasheda A RA Trayanova Natalia N Gorelik Julia J

EBioMedicine 20200621

<h4>Background</h4>Subcellular 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.<h4>Methods</h4>Cardiomyocytes were isolated from healthy donor hearts, as well as from patients with cardiomyopathies and with left ventricular assist devices. Scanning ion conductance and confocal m ...[more]

PMID: 32580140

Similar Datasets

Project description:ObjectiveThis work aimed to derive a machine learning (ML) model for the differentiation between ischemic cardiomyopathy (ICM) and non-ischemic cardiomyopathy (NICM) on non-contrast cardiovascular magnetic resonance (CMR).MethodsThis retrospective study evaluated CMR scans of 107 consecutive patients (49 ICM, 58 NICM), including atrial and ventricular strain parameters. We used these data to compare an explainable tree-based gradient boosting additive model with four traditional ML models for the differentiation of ICM and NICM. The models were trained and internally validated with repeated cross-validation according to discrimination and calibration. Furthermore, we examined important variables for distinguishing between ICM and NICM.ResultsA total of 107 patients and 38 variables were available for the analysis. Of those, 49 were ICM (34 males, mean age 60 ± 9 years) and 58 patients were NICM (38 males, mean age 56 ± 19 years). After 10 repetitions of the tenfold cross-validation, the proposed model achieved the highest area under curve (0.82, 95% CI [0.47-1.00]) and lowest Brier score (0.19, 95% CI [0.13-0.27]), showing competitive diagnostic accuracy and calibration. At the Youden's index, sensitivity was 0.72 (95% CI [0.68-0.76]), the highest of all. Analysis of predictions revealed that both atrial and ventricular strain CMR parameters were important for the identification of ICM patients.ConclusionThe current study demonstrated that using a ML model, multi chamber myocardial strain, and function on non-contrast CMR parameters enables the discrimination between ICM and NICM with competitive diagnostic accuracy.Clinical relevance statementA machine learning model based on non-contrast cardiovascular magnetic resonance parameters may discriminate between ischemic and non-ischemic cardiomyopathy enabling wider access to cardiovascular magnetic resonance examinations with lower costs and faster imaging acquisition.Key points• The exponential growth in cardiovascular magnetic resonance examinations may require faster and more cost-effective protocols. • Artificial intelligence models can be utilized to distinguish between ischemic and non-ischemic etiologies. • Machine learning using non-contrast CMR parameters can effectively distinguish between ischemic and non-ischemic cardiomyopathies.

Dataset Information

Nanoscale regulation of L-type calcium channels differentiates between ischemic and dilated cardiomyopathies.

Background

Methods

Findings

Interpretation

Funding

Publications

Nanoscale regulation of L-type calcium channels differentiates between ischemic and dilated cardiomyopathies.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets