From genome to physiome: integrative models of cardiac excitation.
The last decade has generated extensive information on the genetic and molecular basis of disease. A major challenge remains the integration of this information into the physiological environment of the functioning cell and tissue. This article illustrates the use of computational biology in meeting this challenge in the context of cardiac excitation and arrhythmia. (1) Genetics to Cell Function: Mutations that alter the kinetics of the cardiac sodium channel, INa, give rise to a congenital form of the long QT syndrome that can lead to sudden death. Using a computer modelof the cardiac cell, we simulated the effects of the mutations on the action potential, demonstrating its prolongation at slowrate and the develop-rate and the development of arrhythmogenic early afterdepolarizations due to reactivation of L-type Ca channels, ICa(L) [Clancy and Rudy, Nature (London) 400:566, 1999]. (2) Multicellular Tissue: Slow conduction is an important property of propagation arrhythmias (reentry). Very slow conduction is supported by reduced intercellular coupling through gap junctions. Using a multicellular fiber model, we have shown that slow conduction is very stable and, in contrast to normal conduction which depends solely on INa, requires a major contribution from ICa(L) (Shaw and Rudy, Circ. Res. 81:727, 1997).
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Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106-7207, USA. yxr@po.cwru.edu
D000200:Action Potentials / Q000235:genetics; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D003198:Computer Simulation; D017629:Gap Junctions / Q000378:metabolism; D006329:Heart Conduction System / Q000378:metabolism / Q000503:physiopathology; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism*; D008955:Models, Cardiovascular; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism; D009154:Mutation; D009200:Myocardial Contraction / Q000502:physiology; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism
D020746:Calcium Channels, L-Type; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels