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Role of Structural Barriers in the Mechanism of AlternansInduced Reentry Joseph M. Pastore, M.S., Manish H. Shah, B.S., David S. Rosenbaum, M.D. The Heart and Vascular Center, MetroHealth Campus of Case Western Reserve University, Cleveland, Ohio Short Title: Alternans-Induced Reentry Presented in part at the 20th annual scientific sessions of the North American Society of Pacing and Electrophysiology, Toronto, 1999 Address correspondence to: David S. Rosenbaum, M.D. Director, Heart and Vascular Center Professor of Medicine, Biomedical Engineering, Physiology and Biophysics MetroHealth Campus, Case Western Reserve University 2500 MetroHealth Drive, Hamman 330 Cleveland, Ohio 44109-1998 TEL: (216) 778-2005 FAX: (216) 778-4924 e-mail: [email protected] Pastore et al Mechanisms of reentry 2 ABSTRACT Background: Previously, using an animal model of T wave alternans in structurally normal myocardium, we demonstrated that action potential duration (APD) can alternate with opposite phase between neighboring cells (i.e. discordant alternans) causing spatial dispersions of repolarization which form the substrate for functional block, reentry, and ventricular fibrillation (VF). We hypothesize that electrotonic 5 uncoupling between neighboring regions of cells by structural barriers is a mechanism for discordant alternans. Methods and Results: Optical action potentials were recorded simultaneously from 128 ventricular sites in 24 Langendorff perfused guinea pig hearts. In 5 experiments, the ventricle was paced over a broad range of steady-state heart rates in the absence (i.e. control) and presence of a structural barrier 10 produced by a 10x2 mm epicardial laser-lesion. In controls, APD alternated in phase at all ventricular sites above a critical heart rate, i.e. concordant alternans. Also, above a faster critical heart rate threshold, APD alternated with opposite phase between sites, i.e. discordant alternans. In contrast, only discordant alternans, not concordant alternans, was observed in 80% of hearts with the structural barrier, and discordant alternans always occurred at a significantly (p<.05) slower heart rate (by 6 15 bpm) compared to control. Conclusions: These data also suggest a singular mechanism by which T-wave alternans forms a substrate for initiation of both VF and VT. Key Words: reentry, alternans, torsade de points, action potentials, arrhythmia, ion channels, mapping Pastore et al Mechanisms of reentry 3 20 T-wave alternans is a beat-to-beat fluctuation in the amplitude of the electrocardiographic T wave that repeats once every other beat, and has been closely associated with ventricular arrhythmias and sudden cardiac death1-4. Visually-apparent T-wave alternans is known to hasten cardiac electrical instability in a surprisingly wide variety of experimental5-10 and clinical4, 11-13 conditions. More recently, using sensitive signal processing techniques, we found that the detection of microvolt-level, 25 visually-inapparent T-wave alternans is also a strong predictor of vulnerability to ventricular arrhythmias in patients14. Interestingly, T-wave alternans has been closely associated with polymorphic VT15, VF16, Torsade de Pointes4, 17, and sustained monomorphic VT18 both in the absence of structural heart disease, and in patients with advanced cardiomyopathy. Therefore, a greater understanding of the mechanisms underlying T-wave alternans may provide important new insights into the pathophysiology 30 of sudden cardiac death in a variety of clinical circumstances. METHODS Experimental Preparation Hearts from 24 male retired breeder guinea pigs were rapidly excised and perfused as Langendorff preparations with oxygenated (95% O2, 5% CO2) Tyrode’s solution containing (mmol/L) 35 experiments, the endocardial surface was eliminated using a cryoablation procedure described previously25. This procedure produces a th electrophysiological properties25 and served to restrict propagation to the surface from which action potentials were recorded. Hearts were stained with 100 ml of the voltage-sensitive dye di-4-ANEPPS (20 40 Pastore et al Mechanisms of reentry 4 Optical Mapping System Previously, we have developed an optical action potential mapping system that is capable of resolving membrane potential changes as small as 0.5 mV simultaneously from 128 sites across the anterior epicardial surface of the intact guinea pig ventricle (see 25-27 for details). In order to map 45 ventricular action potentials from sites around the entire periphery of the structural barrier, an optical magnification of 1.2X was used which corresponded to a total mapping area of 15 mm x 15 mm, 1.25 mm inter-pixel spatial resolution, and 1 ms temporal resolution. Measurement of Electrical Alternans A previously validated experimental model of pacing-induced steady-state T-wave alternans16 50 was used because, as is the case in patients, electrical alternans in this model persists over time (i.e. alternans are not transient), does not require ischemic damage, and principally involves the T-wave rather than the QRS complex14. Alternans of cellular repolarization time (RT) was determined by measuring differences in local RT (relative to the stimulus artifact) on consecutive beats. RT and activation times (AT) were determined from each action potential using previously described 55 algorithms25, 27, 29, and all analyses were visually verified by one investigator (JMP). RESULTS Effect of Structural Barrier on Baseline Electrophysiology To verify that the application of the structural barrier did not substantially alter the baseline electrophysiology of the myocardium, conduction velocity and APD were compared at a baseline heart 60 rate of 150 bpm during control and in the presence of the structural barrier. Mean conduction velocity transverse to fibers measured during control (24 Pastore et al Mechanisms of reentry 5 est) DISCUSSION 65 For more than three quarters of a century, T-wave alternans has been closely associated with susceptibility to ventricular arrhythmias in remarkably broad patient populations both with14 and without4 structural heart disease. Furthermore, T-wave alternans is now available as a clinical tool to screen for patients at risk for sudden cardiac death. Recently, we demonstrated that T-wave alternans 70 is linked to the mechanism of reentry by discordant alternans which develop between cells possessing different electrophysiological properties16. Importantly, discordant alternans greatly amplifies dispersion of repolarization which produce conditions necessary for functional block and reentry. We hypothesized that electrical uncoupling by a structural barrier increases the propensity for discordant alternans which may explain a mechanism for T-wave alternans and arrhythmias in patients with 75 structural heart disease. ACKNOWLEDGMENTS This study was supported by National Institutes of Health grant RO1-HL54807 TABLES 80 Pastore et al Mechanisms of reentry 6 REFERENCES 1. 85 Lewis T: Notes upon alternation of the heart. Quart.J.Med. 1910;4:141-144 This is the continuation of the reference FIGURE LEGENDS 90 Figure 1. Experimental setup. Langendorff-perfused guinea pig heart was stained with voltage sensitive dye and action potentials were mapped form a 1.5 cm x 1.5 cm mapping area (square grid). The left ventricle was stimulated (square pulse symbol) over a broad range of CLs in absence (i.e. control) and presence of a structural barrier. ECGs were recorded from electrodes immersed in the saline effluent. RA: Right Atrium; LA: Left Atrium; RV: Right Ventricle; LV: Left Ventricle; LAD: Left Anterior Descending 95 Coronary Artery. Figure 2. Effect of structural barrier on repolarization alternans. Top graph illustrates relationship between local repolarization alternans and heart rate in absence (i.e. control, open circles) and presence (filled circles) of structural barrier. Notice in both cases repolarization alternans occurs above a threshold heart rate that is lower with structural barrier (240 bpm) compared to control (300 bpm). 100 Repolarization alternans is also demonstrated by superposition of average even and odd action potentials at right. Bottom graph plots relationship between T-wave alternans and heart rate. Notice that presence of structural barrier shifts curve to the left.