The Dynamics of Cardiac Fibrillation James N. Weiss, MD; Zhilin Qu, PhD; Peng-Sheng Chen, MD; Shien-Fong Lin, PhD; Hrayr S. Karagueuzian, PhD; Hideki Hayashi, MD, PhD; Alan Garfinkel, PhD; Alain Karma, PhD Abstract—Reentry occurs when the electrical wave propagating through the atria or ventricles breaks locally and forms a rotor (also called a scroll wave or functional reentry). If the waves propagating outward from a rotor develop additional wavebreaks (which may form new rotors), fibrillation results. Tissue heterogeneity, exacerbated by electrical and structural remodeling from cardiac disease, has traditionally been considered the major factor promoting wavebreak and its degeneration to fibrillation. Recently, however, dynamic factors have also been recognized to play a key role. Dynamic factors refer to cellular properties of the cardiac action potential and Ca i cycling, which dynamically generate wave instability and wavebreak, even in tissue that is initially completely homogeneous. Although the latter situation can only be created in computer simulations, its relevance to real (heterogeneous) cardiac tissue has been unequivocally demonstrated. Dynamic factors are related to membrane voltage (V m ) and Ca i .V m factors include electrical restitution of action potential duration and conduction velocity, short-term cardiac memory, and electrotonic currents. Ca i factors are related to dynamic Ca i cycling properties. They act synergistically, as well as with tissue heterogeneity, to promote wavebreak and fibrillation. As global properties, rather than local electrophysiological characteristics, dynamic factors represent an attractive target for novel therapies to prevent ventricular fibrillation. (Circulation. 2005;112:1232-1240.) Key Words: fibrillation  calcium  action potentials  antiarrhythmia agents  death, sudden V entricular fibrillation (VF) is the most common cause of sudden death, and atrial fibrillation, the most prevalent clinical arrhythmia, accounts for nearly one third of strokes in the elderly. Fibrillation results when an electrical wavebreak induces reentry and triggers a cascade of new wavebreaks. In the diseased heart, the increased predis- position to wavebreak3reentry3fibrillation has traditionally been ascribed to increased tissue heterogeneity caused by structural and electrical remodeling associated with disease processes. However, recent evidence indicates that dynamic factors operate synergistically with tissue heterogeneity, as well as among themselves, to promote wavebreak. Unlike tissue heterogeneity (which refers to local structure and fixed electrophysiological dispersion), dynamic factors create func- tional electrophysiological dispersion that destabilizes wave propagation. Dynamic factors are related to cellular mem- brane voltage (V m ) and Ca i . The former include action potential duration (APD) and conduction velocity (CV) res- titution, short-term cardiac memory, and electrotonic cur- rents. The latter are related to Ca i cycling between the sarcoplasmic reticulum (SR) and cytoplasm. Although dy- namic factors can vary in different regions of the heart and exacerbate tissue heterogeneity, dynamic instability also has global aspects. Suppressing dynamic instability may be a promising therapeutic target if it can be accomplished without exacerbating tissue heterogeneity. In this review, we provide a brief overview of how dynamic factors synergistically interact with preexisting tissue heterogeneity to promote fibrillation. Electrical Waves and Wavebreak Cardiac excitation can be viewed as an electrical wave, with a wavefront corresponding to the AP upstroke (phase 0) and a waveback corresponding to rapid repolarization (phase 3). The wavelength, ie, the distance between the wavefront and waveback, is defined as the product of APD and CV (Figure 1A). Normally, when a wave propagates through tissue, wavefront and waveback never touch. If they do, their point of intersection defines a wavebreak, sometimes called a phase singularity. When wave propagation fails simultaneously along the full length of the wavefront, the electrical wave extinguishes everywhere and no harm is done. However, if the wavebreak is spatially localized, reentry may result. Reentry begins at a localized wavebreak because the curva- ture of the wavefront at that point is very high. The high curvature produces a source-sink mismatch (ie, too little depolarizing current with respect to the number of locally coupled unexcited cells), which slows conduction of the propagating wave near this point, 1 causing the wave to rotate around the wavebreak point. If this wavebreak rotates around an anatomically defined circuit (such as a scar), it is called anatomic reentry. However, the wavebreak point can also From the Cardiovascular Research Laboratory and the Departments of Medicine (Cardiology; J.N.W., Z.Q., A.G.), and Physiological Science (A.G.), David Geffen School of Medicine at UCLA, and Cedars-Sinai Medical Center (P.-S.C., S.-F.L., H.S.K., H.H.), Los Angeles, Calif, and the Department of Physics (A.K.), Northeastern University, Boston, Mass. Correspondence to James N. Weiss, MD, Division of Cardiology, 3641 MRL Bldg, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1760. E-mail jweiss@mednet.ucla.edu © 2005 American Heart Association, Inc. Circulation is available at http://www.circulationaha.org DOI: 10.1161/CIRCULATIONAHA.104.529545 1232 Basic Science for Clinicians by guest on October 18, 2015 http://circ.ahajournals.org/ Downloaded from