Circulation. 2004;109:30-35
Published online before print December 15, 2003, doi: 10.1161/01.CIR.0000109482.92774.3A
Published online before print December 15, 2003, doi: 10.1161/01.CIR.0000109482.92774.3A
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(Circulation. 2004;109:30-35.)
© 2004 American Heart Association, Inc.
Clinical Investigation and Reports |
Sudden Death Associated With Short-QT Syndrome Linked to Mutations in HERG
From the Molecular Genetics (R.B., K.H., G.D.P., E.B., K.M., A.G.), Molecular Biology (R.D., Y.S.W.), and Experimental Cardiology (J.C., C.A.) Programs, Masonic Medical Research Laboratory, Utica, NY; Division of Cardiology (F.G., F.B., C.G.), Ospedale Mauriziano Umberto I, Torino, Italy; First Department of Medicine (M.B., C.W., R.S.), University Hospital Mannheim, University of Heidelberg, Mannheim, Germany; North Texas Heart Center (T.M.M.), Dallas, Tex; Arrhythmia Section (J.B.), Cardiovascular Institute, Hospital Clínic, Barcelona, Spain; and Cardiovascular Research and Teaching Institute of Aalst (P.B.), Belgium.
Correspondence to Ramon Brugada, MD, Director of Molecular Genetics Program, Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY 13501. E-mail brugada{at}mmrl.edu
Received October 21, 2003; revision received November 4, 2003; accepted November 14, 2003.
Background— Sudden cardiac death takes the lives of more than 300 000 Americans annually. Malignant ventricular arrhythmias occurring in individuals with structurally normal hearts account for a subgroup of these sudden deaths. The present study describes the genetic basis for a new clinical entity characterized by sudden death and short-QT intervals in the ECG.
Methods and Results— Three families with hereditary short-QT syndrome and a high incidence of ventricular arrhythmias and sudden cardiac death were studied. In 2 of them, we identified 2 different missense mutations resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac IKr channel HERG (KCNH2). The mutations dramatically increase IKr, leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduce the affinity of the channels to IKr blockers.
Conclusions— We demonstrate a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2. The occurrence of sudden cardiac death in the first 12 months of life in 2 patients suggests the possibility of a link between KCNH2 gain of function mutations and sudden infant death syndrome. KCNH2 is the binding target for a wide spectrum of cardiac and noncardiac pharmacological compounds. Our findings may provide better understanding of drug interaction with KCNH2 and have implications for diagnosis and therapy of this and other arrhythmogenic diseases.
Key Words: genetics • death, sudden • arrhythmia • ion channels
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