(Circulation. 1999;99:674-681.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Genetic and Molecular Basis of Cardiac Arrhythmias: Impact on Clinical Management Part III1 2
From the Molecular Cardiology and Electrophysiology Laboratory (S.G.P.), Fondazione S. Maugeri, IRCCS, Pavia, Italy; Institut de Pharmacologie Moleculaire et Cellulaire (J.B.), Laboratoire de Genetique de la Neurotrasmission, CNRS, Valbonne, France; University Hospital of Utrecht, Heart Lung Institute (R.N.W.H.), Netherlands; Medizinische Klinik und Poliklinik (W.H.), Innere Medizin C-Universitat Munster, Germany; Physiologic Laboratory (H.J.J.), University of Utrecht, Netherlands; Department of Physiology (A.G.K.), University of Bern, Switzerland; Department of Cardiological Sciences (W.J.M), St. George's Hospital Medical School, London, UK; Division of Medicine and Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, Tenn; Department of Biomedical Engineering (Y.R.), Case Western Reserve University, Cleveland, Ohio; UR 153 INSERM (K.S.), Pavillon Rambuteau, Groupe Hopitalier Pitie-Salpetriere, Paris, France; Dipartimento di Cardiologia (P.J.S.), Policlinico S. Matteo, IRCCS, Pavia, Italy; Ped Molecular Cardiology (J.A.T.), Baylor College of Medicine, Texas Children's Hospital, Houston, Tex; and Department of Clinical and Experimental Cardiology (A.M.W.), Academic Medical Centre, Amsterdam, Netherlands.
Correspondence to Silvia G. Priori, MD, PhD, Molecular Cardiology and Electrophysiology Laboratory, Fondazione "S. Maugeri" IRCCS, Via Ferrata, 8, 27100 Pavia, Italy. E-mail spriori@fsm.it
Key Words: death, sudden • genetics • arrhythmia • molecular biology • electrophysiology
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Part III: Molecular Basis of Cardiac Electrophysiology and Arrhythmias |
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In Parts I and II of this article,* we discussed monogenic arrhythmic disorders. These are determined or favored by an inborn alteration and for the most part are characterized by a single genetic alteration. This has allowed the use of "paradigms"; namely, diseases, such as the long-QT syndrome (LQTS), in which it has been possible to trace specific mutations on ion channel genes to their electrophysiological consequences in the patient. Unfortunately for the practicing cardiologist, these "simple" diseases constitute only a small part of the clinical conditions associated with cardiac arrhythmias. The majority of cases affect patients in whom the arrhythmogenic substrate is complex. Indeed, the expression of the molecular systems responsible for normal and abnormal electrical activity vary significantly, depending on a variety of factors, including age, regional factors (type of cells, myocardial perfusion), and such underlying chronic diseases as cardiac hypertrophy, myocardial infarction, and heart failure.
The study of this complex system of interacting molecular functions requires an approach somewhat different from that required to consider monogenic disease. Accordingly, in this section we discuss broader themes that are essential to understand the integration of gene expression, ion channel function, and cell coupling in multicellular networks as a first step toward the comprehension of more frequent and more complex arrhythmogenic conditions.
Diversity of Gene Expression in the Heart
Understanding cell-to-cell variability in the cardiac action
potential shape and the mechanisms underlying impulse propagation is
the key to understanding normal and abnormal cardiac electrophysiology.
Much of this variability can be attributed to variability in the
characteristics of
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