Background T-peak to T-end interval (Tp-e) is an independent marker of sudden cardiac death. Modulation of Tp-e by sympathetic nerve activation and circulating norepinephrine (NE) is not well understood. The purpose of this study was to characterize endocardial and epicardial dispersion of repolarization (DOR) and its effects on Tp-e with sympathetic activation. Methods and Results In Yorkshire pigs (n=13), a sternotomy was performed and the heart and bilateral stellate ganglia (SG) were exposed. A 56-electrode sock and 64-electrode basket catheter were placed around the epicardium and in the left ventricle (LV), respectively. Activation recovery interval (ARI), dispersion of repolarization (DOR), defined as variance in repolarization time, and Tp-e were assessed before and after left, right, and bilateral SG stimulation and NE infusion. LV endocardial and epicardial ARIs significantly decreased, and LV endocardial and epicardial DOR increased during sympathetic nerve stimulation. There were no LV epicardial vs. endocardial differences in ARI during sympathetic stimulation and regional endocardial ARI patterns were similar to the epicardium. Tp-e prolonged during left (from 40.4±2.2 ms to 92.4±12.4 ms; P<0.01), right (from 47.7±2.6 ms to 80.7±11.5 ms; P<0.01), and bilateral (from 47.5±2.8 ms to 78.1±9.8 ms; P<0.01) stellate stimulation and strongly correlated with whole heart DOR during stimulation (P<0.001, R=0.86). Of note, NE infusion did not increase DOR or Tp-e. Conclusions Regional patterns of LV endocardial sympathetic innervation are similar to that of LV epicardium. Tp-e correlated with whole heart DOR during sympathetic nerve activation. Circulating NE did not affect DOR or Tp-e.

Myocardial infarction (MI) induces neural and electrical remodeling at scar border zones. The impact of focal MI on global functional neural remodeling is not well understood. Sympathetic stimulation was performed in swine with anteroapical infarcts (MI; n ϭ 9) and control swine (n ϭ 9). A 56-electrode sock was placed over both ventricles to record electrograms at baseline and during left, right, and bilateral stellate ganglion stimulation. Activation recovery intervals (ARIs) were measured from electrograms. Global and regional ARI shortening, dispersion of repolarization, and activation propagation were assessed before and during sympathetic stimulation. At baseline, mean ARI was shorter in MI hearts than control hearts (365 Ϯ 8 vs. 436 Ϯ 9 ms, P Ͻ 0.0001), dispersion of repolarization was greater in MI versus control hearts (734 Ϯ 123 vs. 362 Ϯ 32 ms 2 , P ϭ 0.02), and the infarcted region in MI hearts showed longer ARIs than noninfarcted regions (406 Ϯ 14 vs. 365 Ϯ 8 ms, P ϭ 0.027). In control animals, percent ARI shortening was greater on anterior than posterior walls during right stellate ganglion stimulation (P ϭ 0.0001), whereas left stellate ganglion stimulation showed the reverse (P ϭ 0.0003). In infarcted animals, this pattern was completely lost. In 50% of the animals studied, sympathetic stimulation, compared with baseline, significantly altered the direction of activation propagation emanating from the intramyocardial scar during pacing. In conclusion, focal distal anterior MI alters regional and global pattern of sympathetic innervation, resulting in shorter ARIs in infarcted hearts, greater repolarization dispersion, and altered activation propagation. These conditions may underlie the mechanisms by which arrhythmias are initiated when sympathetic tone is enhanced. autonomic nervous system; sympathetic nerves; cardiac innervation; neural remodeling REMODELING of the cardiac sympathetic nervous system after myocardial infarction (MI) has been linked to ventricular arrhythmias in animal models (29) and in humans (4,12,24). Modulation of cardiac sympathetic signaling is a major therapeutic strategy to prevent and treat ventricular arrhythmias (1,8,22). Despite its importance, the global electrophysiological consequences of postinfarct neural remodeling from a focal infarct remain poorly characterized.Patchy myocardial scars with surviving islands of myocytes characterize human infarcts (10, 17). Heterogeneous intramyocardial sympathetic nerve sprouting at scar border zones leads to labile repolarization, increased peak Ca 2ϩ current, and susceptibility to ventricular fibrillation in hypercholesterolemic rabbits (15). Increased transmural dispersion of repolarization has also been reported (13, 28), along with alterations in transient outward and inward rectifier K ϩ currents (21) in a postinfarct model with nerve sprouts.However, the electrophysiological responses to sympathetic activation exhibited by myocytes at and remote to a focal infarction have not been characterized. Specifically, the functi...

Left stellate or right stellate ganglion stimulation (LGSG or RSGS, respectively) is associated with ventricular tachyarrhythmias; however, the electrophysiological mechanisms remain unclear. We assessed 1) regional dispersion of myocardial repolarization during RSGS and LSGS and 2) regional electrophysiological mechanisms underlying T-wave changes, including T-peak to T-end (Tp-e) interval, which are associated with ventricular tachyarrhythmia/ventricular fibrillation. In 10 pigs, a 56-electrode sock was placed around the heart, and both stellate ganglia were exposed. Unipolar electrograms, to asses activation recovery interval (ARI) and repolarization time (RT), and 12-lead ECG were recorded before and during RSGS and LSGS. Both LSGS and RSGS increased dispersion of repolarization; with LSGS, the greatest regional dispersion occurred on the left ventricular (LV) anterior wall and LV apex, whereas with RSGS, the greatest regional dispersion occurred on the right ventricular posterior wall. Baseline, LSGS, and RSGS dispersion correlated with Tp-e. The increase in RT dispersion, which was due to an increase in ARI dispersion, correlated with the increase in Tp-e intervals (R(2) = 0.92 LSGS; and R(2) = 0.96 RSGS). During LSGS, the ARIs and RTs on the lateral and posterior walls were shorter than the anterior LV wall (P < 0.01) and on the apex versus base (P < 0.05), explaining the T-wave vector shift posteriorly/inferiorly. RSGS caused greater ARI and RT shortening on anterior versus lateral or posterior walls (P < 0.01) and on base versus apex (P < 0.05), explaining the T-wave vector shift anteriorly/superiorly. LSGS and RSGS cause differential effects on regional myocardial repolarization, explaining the ECG T-wave morphology. Sympathetic stimulation, in line with its proarrhythmic effects, increases Tp-e interval, which correlates with increases in myocardial dispersion of repolarization.

(VNS) has been proposed as a cardioprotective intervention. However, regional ventricular electrophysiological effects of VNS are not well characterized. The purpose of this study was to evaluate effects of right and left VNS on electrophysiological properties of the ventricles and hemodynamic parameters. In Yorkshire pigs, a 56-electrode sock was used for epicardial (n ϭ 12) activation recovery interval (ARI) recordings and a 64-electrode catheter for endocardial (n ϭ 9) ARI recordings at baseline and during VNS. Hemodynamic recordings were obtained using a conductance catheter. Right and left VNS decreased heart rate (84 Ϯ 5 to 71 Ϯ 5 beats/min and 84 Ϯ 4 to 73 Ϯ 5 beats/min), left ventricular pressure (89 Ϯ 9 to 77 Ϯ 9 mmHg and 91 Ϯ 9 to 83 Ϯ 9 mmHg), and dP/dt max (1,660 Ϯ 154 to 1,490 Ϯ 160 mmHg/s and 1,595 Ϯ 155 to 1,416 Ϯ 134 mmHg/s) and prolonged ARI (327 Ϯ 18 to 350 Ϯ 23 ms and 327 Ϯ 16 to 347 Ϯ 21 ms, P Ͻ 0.05 vs. baseline for all parameters and P ϭ not significant for right VNS vs. left VNS). No anteriorposterior-lateral regional differences in the prolongation of ARI during right or left VNS were found. However, endocardial ARI prolonged more than epicardial ARI, and apical ARI prolonged more than basal ARI during both right and left VNS. Changes in dP/dt max showed the strongest correlation with ventricular ARI effects (R 2 ϭ 0.81, P Ͻ 0.0001) than either heart rate (R 2 ϭ 0.58, P Ͻ 0.01) or left ventricular pressure (R 2 ϭ 0.52, P Ͻ 0.05). Therefore, right and left VNS have similar effects on ventricular ARI, in contrast to sympathetic stimulation, which shows regional differences. The decrease in inotropy correlates best with ventricular electrophysiological effects.vagal nerve stimulation; ventricle; repolarization THE AUTONOMIC NERVOUS SYSTEM plays a significant role in the genesis and persistence of ventricular arrhythmias (54, 59). Sympathetic activation is proarrhythmic (16,32,53), whereas parasympathetic activation is thought to be cardioprotective (17, 31). The vagal nerve trunk provides important cardiomotor efferent fibers to the heart and also carries afferent signals from the heart. Vagal nerve stimulation (VNS) has been shown to decrease infarct size (48), reduce the ventricular fibrillation (VF) threshold (39), and decrease the incidence of ventricular arrhythmias and mortality during ischemia (13,27,38,52). Furthermore, a preserved parasympathetic reflex has been reported to be protective during myocardial infarction (46). Stimulation of the right vagal nerve (RVN) has shown benefits in a series of patients with cardiomyopathy and is undergoing evaluation in clinical trials (20,47). The mechanisms of the antiarrhythmic effects of VNS are less clear and are thought to be multifactorial, with a decrease in heart rate (HR) (15), release of nitric oxide (9), and antagonism of the sympathetic nervous system all thought to play a role (8,30,49).Modulation of repolarization by sympathetic nerve stimulation has been well characterized (1,25,41,55,58). However, the effects of parasympatheti...