The proposed research is designed around the concept that the evolution of arrhythmias occurs in the setting of a changing substrate that must be studied in light of its dynamic properties. The goal is to study the molecular, ionic and signal transduction mechanisms of electrical remodeling of ventricle, as well as its phenotypic expression in the T wave and effective refractory period. The applicant hypothesizes that (1) the cardiac renin-angiotensin II system is vital to the evolution of short-term (lasting minutes) and long-term (last weeks) electrical remodeling; (2) the sympathetic nervous system is an important modulator of this; (3) short-term remodeling induces specific changes in ion channels via alterations in phosphorylation, and long-term remodeling induces changes in channels via altered message and/or expression; and (4) remodeling induces potentially antiarrhythmic or arrhythmic changes in repolarization and refractoriness that have important implications as well, for antiarrhythmic drug actions. The hypotheses will be tested in a multidimensional fashion, via electrophysiologic, biophysical and molecular studies. Short-term pacing and resultant electrical remodeling will be used as surrogates of sustained arrhythmias. The approach will be integrative, incorporating the T wave, the effective refractory period, antiarrhythmic drugs and pertinent signal transduction systems in electrophysiologic studies of the intact heart and isolated tissues, and studying underling mechanisms and expression molecular and biophysical experiments on ion channels. The applicant anticipates that the results will enhance our understanding of the plasticity of and control of the events that determine cardiac repolarization, and with this, identify new strategies for arrhythmia prevention.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Schools of Medicine
New York
United States
Zip Code
Dun, Wen; Yagi, Takuya; Rosen, Michael R et al. (2003) Calcium and potassium currents in cells from adult and aged canine right atria. Cardiovasc Res 58:526-34
Yagi, Takuya; Pu, Jielin; Chandra, Parag et al. (2002) Density and function of inward currents in right atrial cells from chronically fibrillating canine atria. Cardiovasc Res 54:405-15
Herweg, B; Chang, F; Chandra, P et al. (2001) Cardiac memory in canine atrium : identification and implications. Circulation 103:455-61
Rosen, M R (2001) The heart remembers: clinical implications. Lancet 357:468-71
Plotnikov, A N; Shvilkin, A; Xiong, W et al. (2001) Interactions between antiarrhythmic drugs and cardiac memory. Cardiovasc Res 50:335-44
Patel, P M; Plotnikov, A; Kanagaratnam, P et al. (2001) Altering ventricular activation remodels gap junction distribution in canine heart. J Cardiovasc Electrophysiol 12:570-7
Yu, H; Gao, J; Wang, H et al. (2000) Effects of the renin-angiotensin system on the current I(to) in epicardial and endocardial ventricular myocytes from the canine heart. Circ Res 86:1062-8
Rosen, M R (2000) What is cardiac memory? J Cardiovasc Electrophysiol 11:1289-93
Hara, M; Shvilkin, A; Rosen, M R et al. (1999) Steady-state and nonsteady-state action potentials in fibrillating canine atrium: abnormal rate adaptation and its possible mechanisms. Cardiovasc Res 42:455-69
Sosunov, E A; Gainullin, R Z; Danilo Jr, P et al. (1999) Electrophysiological effects of LU111995 on canine hearts: in vivo and in vitro studies. J Pharmacol Exp Ther 290:146-52

Showing the most recent 10 out of 14 publications