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- Ling Xiao
- From the Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QC, Canada (L.X., B.O., M.A.M., S.N.); Department of Clinical and Experimental Cardiology (T.T.K., P.G.P., G.J., J.B., A.A.W., C.R.B.) and Department of Anatomy, Embryology and Physiology (A.O.V.), Heart Failure Research Center, Academic Medical Center, Amsterdam, the Netherlands; Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY (V.I., K.J.S., R.S.K.);...
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- Tamara T. Koopmann
- From the Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QC, Canada (L.X., B.O., M.A.M., S.N.); Department of Clinical and Experimental Cardiology (T.T.K., P.G.P., G.J., J.B., A.A.W., C.R.B.) and Department of Anatomy, Embryology and Physiology (A.O.V.), Heart Failure Research Center, Academic Medical Center, Amsterdam, the Netherlands; Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY (V.I., K.J.S., R.S.K.);...
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- Balázs Ördög
- From the Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QC, Canada (L.X., B.O., M.A.M., S.N.); Department of Clinical and Experimental Cardiology (T.T.K., P.G.P., G.J., J.B., A.A.W., C.R.B.) and Department of Anatomy, Embryology and Physiology (A.O.V.), Heart Failure Research Center, Academic Medical Center, Amsterdam, the Netherlands; Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY (V.I., K.J.S., R.S.K.);...
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- Pieter G. Postema
- From the Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QC, Canada (L.X., B.O., M.A.M., S.N.); Department of Clinical and Experimental Cardiology (T.T.K., P.G.P., G.J., J.B., A.A.W., C.R.B.) and Department of Anatomy, Embryology and Physiology (A.O.V.), Heart Failure Research Center, Academic Medical Center, Amsterdam, the Netherlands; Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY (V.I., K.J.S., R.S.K.);...
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- Arie O. Verkerk
- From the Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QC, Canada (L.X., B.O., M.A.M., S.N.); Department of Clinical and Experimental Cardiology (T.T.K., P.G.P., G.J., J.B., A.A.W., C.R.B.) and Department of Anatomy, Embryology and Physiology (A.O.V.), Heart Failure Research Center, Academic Medical Center, Amsterdam, the Netherlands; Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY (V.I., K.J.S., R.S.K.);...
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- Vivek Iyer
- From the Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QC, Canada (L.X., B.O., M.A.M., S.N.); Department of Clinical and Experimental Cardiology (T.T.K., P.G.P., G.J., J.B., A.A.W., C.R.B.) and Department of Anatomy, Embryology and Physiology (A.O.V.), Heart Failure Research Center, Academic Medical Center, Amsterdam, the Netherlands; Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY (V.I., K.J.S., R.S.K.);...
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- Kevin J. Sampson
- From the Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QC, Canada (L.X., B.O., M.A.M., S.N.); Department of Clinical and Experimental Cardiology (T.T.K., P.G.P., G.J., J.B., A.A.W., C.R.B.) and Department of Anatomy, Embryology and Physiology (A.O.V.), Heart Failure Research Center, Academic Medical Center, Amsterdam, the Netherlands; Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY (V.I., K.J.S., R.S.K.);...
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- Gerard J.J. Boink
- From the Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QC, Canada (L.X., B.O., M.A.M., S.N.); Department of Clinical and Experimental Cardiology (T.T.K., P.G.P., G.J., J.B., A.A.W., C.R.B.) and Department of Anatomy, Embryology and Physiology (A.O.V.), Heart Failure Research Center, Academic Medical Center, Amsterdam, the Netherlands; Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY (V.I., K.J.S., R.S.K.);...
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- Maya A. Mamarbachi
- From the Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QC, Canada (L.X., B.O., M.A.M., S.N.); Department of Clinical and Experimental Cardiology (T.T.K., P.G.P., G.J., J.B., A.A.W., C.R.B.) and Department of Anatomy, Embryology and Physiology (A.O.V.), Heart Failure Research Center, Academic Medical Center, Amsterdam, the Netherlands; Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY (V.I., K.J.S., R.S.K.);...
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- Andras Varro
- From the Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QC, Canada (L.X., B.O., M.A.M., S.N.); Department of Clinical and Experimental Cardiology (T.T.K., P.G.P., G.J., J.B., A.A.W., C.R.B.) and Department of Anatomy, Embryology and Physiology (A.O.V.), Heart Failure Research Center, Academic Medical Center, Amsterdam, the Netherlands; Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY (V.I., K.J.S., R.S.K.);...
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- Luc Jordaens
- From the Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QC, Canada (L.X., B.O., M.A.M., S.N.); Department of Clinical and Experimental Cardiology (T.T.K., P.G.P., G.J., J.B., A.A.W., C.R.B.) and Department of Anatomy, Embryology and Physiology (A.O.V.), Heart Failure Research Center, Academic Medical Center, Amsterdam, the Netherlands; Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY (V.I., K.J.S., R.S.K.);...
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- Jan Res
- From the Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QC, Canada (L.X., B.O., M.A.M., S.N.); Department of Clinical and Experimental Cardiology (T.T.K., P.G.P., G.J., J.B., A.A.W., C.R.B.) and Department of Anatomy, Embryology and Physiology (A.O.V.), Heart Failure Research Center, Academic Medical Center, Amsterdam, the Netherlands; Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY (V.I., K.J.S., R.S.K.);...
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- Robert S. Kass
- From the Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QC, Canada (L.X., B.O., M.A.M., S.N.); Department of Clinical and Experimental Cardiology (T.T.K., P.G.P., G.J., J.B., A.A.W., C.R.B.) and Department of Anatomy, Embryology and Physiology (A.O.V.), Heart Failure Research Center, Academic Medical Center, Amsterdam, the Netherlands; Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY (V.I., K.J.S., R.S.K.);...
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- Arthur A. Wilde
- From the Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QC, Canada (L.X., B.O., M.A.M., S.N.); Department of Clinical and Experimental Cardiology (T.T.K., P.G.P., G.J., J.B., A.A.W., C.R.B.) and Department of Anatomy, Embryology and Physiology (A.O.V.), Heart Failure Research Center, Academic Medical Center, Amsterdam, the Netherlands; Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY (V.I., K.J.S., R.S.K.);...
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- C.R. Bezzina
- From the Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QC, Canada (L.X., B.O., M.A.M., S.N.); Department of Clinical and Experimental Cardiology (T.T.K., P.G.P., G.J., J.B., A.A.W., C.R.B.) and Department of Anatomy, Embryology and Physiology (A.O.V.), Heart Failure Research Center, Academic Medical Center, Amsterdam, the Netherlands; Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY (V.I., K.J.S., R.S.K.);...
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- Stanley Nattel
- From the Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QC, Canada (L.X., B.O., M.A.M., S.N.); Department of Clinical and Experimental Cardiology (T.T.K., P.G.P., G.J., J.B., A.A.W., C.R.B.) and Department of Anatomy, Embryology and Physiology (A.O.V.), Heart Failure Research Center, Academic Medical Center, Amsterdam, the Netherlands; Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY (V.I., K.J.S., R.S.K.);...
書誌事項
- タイトル別名
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- A Potential Molecular Link to Idiopathic Ventricular Fibrillation
抄録
<jats:sec> <jats:title> <jats:underline>Rationale:</jats:underline> </jats:title> <jats:p> A chromosomal haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial idiopathic ventricular fibrillation. The molecular basis of transient outward current ( <jats:italic>I</jats:italic> <jats:sub>to</jats:sub> ) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF <jats:italic>I</jats:italic> <jats:sub>to</jats:sub> and that its overexpression might specifically alter PF <jats:italic>I</jats:italic> <jats:sub>to</jats:sub> properties and repolarization. </jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Objective:</jats:underline> </jats:title> <jats:p> To assess the potential role of DPP6 in PF <jats:italic>I</jats:italic> <jats:sub>to</jats:sub> . </jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Methods and Results:</jats:underline> </jats:title> <jats:p> Clinical data in 5 idiopathic ventricular fibrillation patients suggested arrhythmia origin in the PF-conducting system. PF and ventricular muscle <jats:italic>I</jats:italic> <jats:sub>to</jats:sub> had similar density, but PF <jats:italic>I</jats:italic> <jats:sub>to</jats:sub> differed from ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, <jats:italic>I</jats:italic> <jats:sub>to</jats:sub> density and tetraethylammonium sensitivity in canine PF but not in ventricular muscle cells. The K <jats:sup>+</jats:sup> -channel interacting β-subunit K <jats:sup>+</jats:sup> -channel interacting protein type-2, essential for normal expression of <jats:italic>I</jats:italic> <jats:sub>to</jats:sub> in ventricular muscle, was weakly expressed in human PFs, whereas DPP6 and frequenin (neuronal calcium sensor-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary cells produced small <jats:italic>I</jats:italic> <jats:sub>to</jats:sub> ; <jats:italic>I</jats:italic> <jats:sub>to</jats:sub> amplitude was greatly enhanced by coexpression with K <jats:sup>+</jats:sup> -channel interacting protein type-2 or DPP6. Coexpression of DPP6 with Kv4.3 and K <jats:sup>+</jats:sup> -channel interacting protein type-2 failed to alter <jats:italic>I</jats:italic> <jats:sub>to</jats:sub> compared with Kv4.3/K <jats:sup>+</jats:sup> -channel interacting protein type-2 alone, but DPP6 expression with Kv4.3 and neuronal calcium sensor-1 (to mimic PF <jats:italic>I</jats:italic> <jats:sub>to</jats:sub> composition) greatly enhanced <jats:italic>I</jats:italic> <jats:sub>to</jats:sub> compared with Kv4.3/neuronal calcium sensor-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that <jats:italic>I</jats:italic> <jats:sub>to</jats:sub> enhancement can greatly accelerate PF repolarization. </jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Conclusions:</jats:underline> </jats:title> <jats:p> These results point to a previously unknown central role of DPP6 in PF <jats:italic>I</jats:italic> <jats:sub>to</jats:sub> , with DPP6 gain of function selectively enhancing PF current, and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of idiopathic ventricular fibrillation. </jats:p> </jats:sec>
収録刊行物
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- Circulation Research
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Circulation Research 112 (10), 1310-1322, 2013-05-10
Ovid Technologies (Wolters Kluwer Health)