Simulation and experimental evidence support the hypothesis that restitution of the cardiac action potential duration (APD) and conduction velocity (CV) are key dynamical factors determining whether spiral wave reentry remains stable as ventricular tachycardia (VT) or breaks up into multiple reentrant wavefronts as ventricular fibrillation (VF). A major objective of the SCOR renewal is to test the concept of targeting cardiac restitution as a primary antifibrillatory strategy, i.e. the Restitution Hypothesis. To assess its validity, it is essential to have a clear mechanistic understanding of cardiac restitution and how it is affected by antiarrhythmic drugs and other factors such as acute ischemia, specifically at rapid heart rates relevant to VT. In Project 3, cardiac restitution and its response to antiarrhythmic drugs and various ischemic components will be analyzed experimentally in isolated rabbit, porcine and canine ventricular myocytes (using patch clamp and fluorescent dye techniques), cultured monolayers of ventricular myocytes (using a newly-developed fast CCD camera-based optical mapping system), intact porcine and canine ventricular muscle and in situ hearts (using intracellular microelectrode recordings and optical mapping techniques), in situ human hearts (using monophasic action potential recordings during programmed ventricular stimulation). These experimental studies will be complemented by 2-D and 3-D computer simulations of cardiac tissue. The broad objective is to provide detailed mechanistic insights into the factors governing cardiac restitution. Specific objectives are: 1). To define a pacing protocol for measuring restitution properties which optimizes predictive value for VT stability/instability; 2). To characterize the role of the major ionic currents on APD and CV restitution (using dV/dtmax as a surrogate) in isolated myocytes at cycle lengths relevant to VT and VF; 3). To evaluate the effects of diffusive currents and wavefront curvature on cardiac restitution; 4). To characterize the influence of intracellular Ca dynamics on cardiac restitution properties and VT stability; 5). To evaluate the effects of various ischemic components on cardiac restitution properties in isolated ventricular myocytes and isolated intact tissue; 6). To characterize the effects of antiarrhythmic drugs on cardiac restitution properties at short cycle lengths relevant to VT/VF; 7). To characterize the effects of various antiarrhythmic drugs on restitution properties in humans at short cycle lengths relevant to VT/VF.
| de Diego, Carlos; Chen, Fuhua; Xie, Yuanfang et al. (2011) Anisotropic conduction block and reentry in neonatal rat ventricular myocyte monolayers. Am J Physiol Heart Circ Physiol 300:H271-8 |
| Liu, Yen-Bin; Lee, Yuan-Teh; Pak, Hui-Nam et al. (2009) Effects of simvastatin on cardiac neural and electrophysiologic remodeling in rabbits with hypercholesterolemia. Heart Rhythm 6:69-75 |
| Weiss, James N (2008) Beyond the implantable cardioverter-defibrillator: are we making progress? Heart Rhythm 5:S45-7 |
| Swissa, Moshe; Zhou, Shengmei; Tan, Alex Y et al. (2008) Atrial sympathetic and parasympathetic nerve sprouting and hyperinnervation induced by subthreshold electrical stimulation of the left stellate ganglion in normal dogs. Cardiovasc Pathol 17:303-8 |
| de Diego, Carlos; Chen, Fuhua; Xie, Lai-Hua et al. (2008) Cardiac alternans in embryonic mouse ventricles. Am J Physiol Heart Circ Physiol 294:H433-40 |
| Wu, Tsu-Juey; Lin, Shien-Fong; Hsieh, Yu-Cheng et al. (2008) Early recurrence of ventricular fibrillation after successful defibrillation during prolonged global ischemia in isolated rabbit hearts. J Cardiovasc Electrophysiol 19:203-10 |
| de Diego, Carlos; Pai, Rakesh K; Dave, Amish S et al. (2008) Spatially discordant alternans in cardiomyocyte monolayers. Am J Physiol Heart Circ Physiol 294:H1417-25 |
| Hayashi, Hideki; Shiferaw, Yohannes; Sato, Daisuke et al. (2007) Dynamic origin of spatially discordant alternans in cardiac tissue. Biophys J 92:448-60 |
| Tan, Alex Y; Chen, Peng-Sheng; Chen, Lan S et al. (2007) Autonomic nerves in pulmonary veins. Heart Rhythm 4:S57-60 |
| Chen, Peng-Sheng; Tan, Alex Y (2007) Autonomic nerve activity and atrial fibrillation. Heart Rhythm 4:S61-4 |
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