title: Microdomain-Specific Modulation of L-Type Calcium Channels Leads to Triggered Ventricular Arrhythmia in Heart Failure.
abstract: BACKGROUND
  Disruption in subcellular targeting of Ca(2+) signaling complexes secondary to changes in cardiac myocyte structure may contribute to the pathophysiology of a variety of cardiac diseases, including heart failure (HF) and certain arrhythmias.
  
  
  OBJECTIVE
  To explore microdomain-targeted remodeling of ventricular L-type Ca(2+) channels (LTCCs) in HF.
  
  
  RESULTS
  Super-resolution scanning patch-clamp, confocal and fluorescence microscopy were used to explore the distribution of single LTCCs in different membrane microdomains of nonfailing and failing human and rat ventricular myocytes. Disruption of membrane structure in both species led to the redistribution of functional LTCCs from their canonical location in transversal tubules (T-tubules) to the non-native crest of the sarcolemma, where their open probability was dramatically increased (0.034±0.011 versus 0.154±0.027, P<0.001). High open probability was linked to enhance calcium-calmodulin kinase II-mediated phosphorylation in non-native microdomains and resulted in an elevated ICa,L window current, which contributed to the development of early afterdepolarizations. A novel model of LTCC function in HF was developed; after its validation with experimental data, the model was used to ascertain how HF-induced T-tubule loss led to altered LTCC function and early afterdepolarizations. The HF myocyte model was then implemented in a 3-dimensional left ventricle model, demonstrating that such early afterdepolarizations can propagate and initiate reentrant arrhythmias.
  
  
  CONCLUSIONS
  Microdomain-targeted remodeling of LTCC properties is an important event in pathways that may contribute to ventricular arrhythmogenesis in the settings of HF-associated remodeling. This extends beyond the classical concept of electric remodeling in HF and adds a new dimension to cardiovascular disease.
authors: From the Department of Cardiovascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute (J.L.S.-A., A.B., A.V.G., S.S., N.B., M.B.S., C.M., A.R.L., P.P.P., J.G.), Department of Medicine (Y.E.K.), and Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute (P.P.P.), Imperial College London, United Kingdom; Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD (T.O., N.A.T.); NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom (A.R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (S.S., V.O.N.); and Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Telangana, India (A.B.).
authors: Jose L
authors: JL
authors: Sanchez-Alonso
authors: From the Department of Cardiovascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute (J.L.S.-A., A.B., A.V.G., S.S., N.B., M.B.S., C.M., A.R.L., P.P.P., J.G.), Department of Medicine (Y.E.K.), and Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute (P.P.P.), Imperial College London, United Kingdom; Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD (T.O., N.A.T.); NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom (A.R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (S.S., V.O.N.); and Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Telangana, India (A.B.).
authors: Anamika
authors: A
authors: Bhargava
authors: From the Department of Cardiovascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute (J.L.S.-A., A.B., A.V.G., S.S., N.B., M.B.S., C.M., A.R.L., P.P.P., J.G.), Department of Medicine (Y.E.K.), and Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute (P.P.P.), Imperial College London, United Kingdom; Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD (T.O., N.A.T.); NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom (A.R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (S.S., V.O.N.); and Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Telangana, India (A.B.).
authors: Thomas
authors: T
authors: O'Hara
authors: From the Department of Cardiovascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute (J.L.S.-A., A.B., A.V.G., S.S., N.B., M.B.S., C.M., A.R.L., P.P.P., J.G.), Department of Medicine (Y.E.K.), and Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute (P.P.P.), Imperial College London, United Kingdom; Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD (T.O., N.A.T.); NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom (A.R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (S.S., V.O.N.); and Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Telangana, India (A.B.).
authors: Alexey V
authors: AV
authors: Glukhov
authors: From the Department of Cardiovascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute (J.L.S.-A., A.B., A.V.G., S.S., N.B., M.B.S., C.M., A.R.L., P.P.P., J.G.), Department of Medicine (Y.E.K.), and Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute (P.P.P.), Imperial College London, United Kingdom; Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD (T.O., N.A.T.); NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom (A.R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (S.S., V.O.N.); and Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Telangana, India (A.B.).
authors: Sophie
authors: S
authors: Schobesberger
authors: From the Department of Cardiovascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute (J.L.S.-A., A.B., A.V.G., S.S., N.B., M.B.S., C.M., A.R.L., P.P.P., J.G.), Department of Medicine (Y.E.K.), and Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute (P.P.P.), Imperial College London, United Kingdom; Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD (T.O., N.A.T.); NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom (A.R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (S.S., V.O.N.); and Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Telangana, India (A.B.).
authors: Navneet
authors: N
authors: Bhogal
authors: From the Department of Cardiovascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute (J.L.S.-A., A.B., A.V.G., S.S., N.B., M.B.S., C.M., A.R.L., P.P.P., J.G.), Department of Medicine (Y.E.K.), and Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute (P.P.P.), Imperial College London, United Kingdom; Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD (T.O., N.A.T.); NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom (A.R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (S.S., V.O.N.); and Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Telangana, India (A.B.).
authors: Markus B
authors: MB
authors: Sikkel
authors: From the Department of Cardiovascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute (J.L.S.-A., A.B., A.V.G., S.S., N.B., M.B.S., C.M., A.R.L., P.P.P., J.G.), Department of Medicine (Y.E.K.), and Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute (P.P.P.), Imperial College London, United Kingdom; Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD (T.O., N.A.T.); NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom (A.R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (S.S., V.O.N.); and Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Telangana, India (A.B.).
authors: Catherine
authors: C
authors: Mansfield
authors: From the Department of Cardiovascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute (J.L.S.-A., A.B., A.V.G., S.S., N.B., M.B.S., C.M., A.R.L., P.P.P., J.G.), Department of Medicine (Y.E.K.), and Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute (P.P.P.), Imperial College London, United Kingdom; Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD (T.O., N.A.T.); NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom (A.R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (S.S., V.O.N.); and Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Telangana, India (A.B.).
authors: Yuri E
authors: YE
authors: Korchev
authors: From the Department of Cardiovascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute (J.L.S.-A., A.B., A.V.G., S.S., N.B., M.B.S., C.M., A.R.L., P.P.P., J.G.), Department of Medicine (Y.E.K.), and Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute (P.P.P.), Imperial College London, United Kingdom; Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD (T.O., N.A.T.); NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom (A.R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (S.S., V.O.N.); and Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Telangana, India (A.B.).
authors: Alexander R
authors: AR
authors: Lyon
authors: From the Department of Cardiovascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute (J.L.S.-A., A.B., A.V.G., S.S., N.B., M.B.S., C.M., A.R.L., P.P.P., J.G.), Department of Medicine (Y.E.K.), and Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute (P.P.P.), Imperial College London, United Kingdom; Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD (T.O., N.A.T.); NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom (A.R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (S.S., V.O.N.); and Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Telangana, India (A.B.).
authors: Prakash P
authors: PP
authors: Punjabi
authors: From the Department of Cardiovascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute (J.L.S.-A., A.B., A.V.G., S.S., N.B., M.B.S., C.M., A.R.L., P.P.P., J.G.), Department of Medicine (Y.E.K.), and Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute (P.P.P.), Imperial College London, United Kingdom; Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD (T.O., N.A.T.); NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom (A.R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (S.S., V.O.N.); and Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Telangana, India (A.B.).
authors: Viacheslav O
authors: VO
authors: Nikolaev
authors: From the Department of Cardiovascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute (J.L.S.-A., A.B., A.V.G., S.S., N.B., M.B.S., C.M., A.R.L., P.P.P., J.G.), Department of Medicine (Y.E.K.), and Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute (P.P.P.), Imperial College London, United Kingdom; Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD (T.O., N.A.T.); NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom (A.R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (S.S., V.O.N.); and Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Telangana, India (A.B.).
authors: Natalia A
authors: NA
authors: Trayanova
authors: From the Department of Cardiovascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute (J.L.S.-A., A.B., A.V.G., S.S., N.B., M.B.S., C.M., A.R.L., P.P.P., J.G.), Department of Medicine (Y.E.K.), and Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute (P.P.P.), Imperial College London, United Kingdom; Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD (T.O., N.A.T.); NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom (A.R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (S.S., V.O.N.); and Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Telangana, India (A.B.). j.gorelik@imperial.ac.uk.
authors: Julia
authors: J
authors: Gorelik
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000453:epidemiology / Q000209:etiology / Q000503:physiopathology*; D020746:Calcium Channels, L-Type / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D006333:Heart Failure / Q000453:epidemiology / Q000209:etiology / Q000503:physiopathology*; D006801:Humans; D008297:Male; D021962:Membrane Microdomains / Q000502:physiology*; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020746:Calcium Channels, L-Type
keywords: L-type calcium channel; electrophysiology; heart failure; membrane microdomains; myocardial infarction