Journal ArticleDOI
The M cell: its contribution to the ECG and to normal and abnormal electrical function of the heart.
Charles Antzelevitch,Wataru Shimizu,Gan-Xin Yan,Serge Sicouri,J Weissenburger,Vladislav V. Nesterenko,Alexander Burashnikov,J. M. Di Diego,Jeffrey E. Saffitz,George Thomas +9 more
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TLDR
A comprehensive characterization of the M cell, its contribution to transmural heterogeneity, and its role in the normal electrical function of the heart, in the inscription of the ECG, and in the development of QT dispersion, T wave alternans, long QT intervals, and cardiac arrhythmias, such as torsades de pointes are provided.Abstract:
The discovery and characterization of the M cell, a unique cell type residing in the deep layers of the ventricular myocardium, has opened a new door in our understanding of the electrophysiology and pharmacology of the heart in both health and disease. The hallmark of the M cell is the ability of its action potential to prolong much more than that of other ventricular myocardial cells in response to a slowing of rate and/or in response to agents that act to prolong action potential duration. Our goal in this review is to provide a comprehensive characterization of the M cell, its contribution to transmural heterogeneity, and its role in the normal electrical function of the heart, in the inscription of the ECG (particularly the T wave), and in the development of QT dispersion, T wave alternans, long QT intervals, and cardiac arrhythmias, such as torsades de pointes. Our secondary goal is to address the controversy that has arisen relative to the functional importance of the M cell in the normal heart. The controversy derives largely from the failure of some investigators to demonstrate transmural heterogeneity of repolarization in the dog in vivo under control conditions and after administration of quinidine. The inability to demonstrate transmural heterogeneity under these conditions may be due to the use of bipolar recording techniques that, in our experience, seriously underestimate transmural dispersion of repolarization (TDR). The use of sodium pentobarbital and alpha-chloralose as anesthesia also is problematic, because these agents reduce or eliminate TDR by affecting a variety of ion channel currents. Finally, attempts to amplify transmural dispersion of repolarization with an agent such as quinidine must take into account that relatively high concentrations can result in effects opposite to those desired due to drug inhibition of multiple ion channels. These observations may explain the inability of earlier studies to detect the M cell.read more
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Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs : Evidence for a provisional safety margin in drug development
William S. Redfern,Leif Carlsson,A.S Davis,W G Lynch,I MacKenzie,S Palethorpe,Peter K. S. Siegl,I. Strang,A.T Sullivan,Rob Wallis,A. J. Camm,Tim Hammond +11 more
TL;DR: The dataset confirms the widely-held belief that most drugs associated with TdP in humans are also associated with hERG K(+) channel block at concentrations close to or superimposed upon the free plasma concentrations found in clinical use.
Journal ArticleDOI
Electrophysiological remodeling in hypertrophy and heart failure
TL;DR: Data from VHeFT (Veteran’s Administration Heart Failure Trial) and other trials suggest that death is disproportionately sudden in patients with more modest myocardial dysfunction, and there is no clear correlation between SCD and LV function or ventricular ectopy.
Journal ArticleDOI
Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties.
Charles Antzelevitch,Luiz Belardinelli,Andrew C. Zygmunt,Alexander Burashnikov,José M. Di Diego,Jeffrey M. Fish,Jonathan M. Cordeiro,George Thomas +7 more
TL;DR: The actions of ranolazine to suppress EADs and reduce TDR suggest that, in addition to its antianginal actions, the drug may possess antiarrhythmic activity.
Journal ArticleDOI
Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter
Bramah N. Singh,Stuart J. Connolly,Denis Roy,Peter R. Kowey,Alessandro Capucci,David Radzik,Etienne Aliot,Stefan H. Hohnloser +7 more
TL;DR: Dronedarone was significantly more effective than placebo in maintaining sinus rhythm and in reducing the ventricular rate during recurrence of arrhythmia.
Journal ArticleDOI
The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology.
Wilhelm Haverkamp,Günter Breithardt,Alan John Camm,Michiel J. Janse,Michael R. Rosen,Charles Antzelevitch,Denis Escande,Michael R. Franz,Marek Malik,Arthur J. Moss,R. Shah +10 more
TL;DR: The scientific and clinical basis of drug-induced QT prolongation and proarrhythmia was summarized by formal presentations and selected topics were discussed in detail in separate workshops.
References
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A mechanistic link between an inherited and an acquird cardiac arrthytmia: HERG encodes the IKr potassium channel
TL;DR: The finding that HERG encodes IKr channels provides a mechanistic link between certain forms of inherited and acquired LQT, and that an additional subunit may be required for drug sensitivity.
Journal ArticleDOI
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Journal ArticleDOI
Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.
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Journal ArticleDOI
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Michael C. Sanguinetti,Mark E. Curran,Anruo Zou,Jiaxiang Shen,Peter S. Spector,Donald L. Atkinson,M T Keating +6 more
TL;DR: KVLQT1 is the subunit that coassembles with minK to form IKS channels and IKS dysfunction is a cause of cardiac arrhythmia, and is shown to encode a K+ channel with biophysical properties unlike other known cardiac currents.
Journal ArticleDOI
K v LQT1 and IsK (minK) proteins associate to form the I KS cardiac potassium current
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