Background Myocardial infarction (MI) induces remodeling in stellate ganglion neurons (SGNs). Objective We investigated whether infarct site has any impact on the laterality of morphological changes or neuropeptide expression in stellate ganglia. Methods Yorkshire pigs underwent left circumflex artery (LCX, n=6) or right coronary artery (RCA, n=6) occlusion, to create left and right-sided MI, respectively (control: n=10). 5±1 weeks post-MI, left and right stellate ganglia (LSG and RSG, respectively) were collected to determine neuronal size, tyrosine hydroxylase (TH) and neuropeptide Y (NPY) immunoreactivity. Results Compared to control, LCX and RCA MI increased mean neuronal size in the LSG (451±25μm2 vs. 650±34μm2 vs. 577±55 μm2, respectively, p=0.0012); and RSG (433±22 μm2 vs. 646±42 μm2 vs. 530±41μm2, respectively, p=0.002). TH-immunoreactivity was present in the majority of SGNs. Both LCX and RCA MI were associated with significant decrease in the percentage of TH-negative SGNs; from 2.58±0.2% in controls to 1.26±0.3% and 0.7±0.3% in LCX and RCA MI respectively for LSG (p=0.001); and from 3.02±0.4 in controls to 1.36±0.3% and 0.68±0.2% in LCX and RCA MI respectively for RSG (p=0.002). Both TH-negative and TH-positive neurons increased in size following LCX and RCA MI. Neuropeptide Y immunoreactivity was also significantly increased by LCX and RCA MI in both ganglia. Conclusions Left and right-sided MI equally induced morphologic and neurochemical changes in LSG and RSG neurons, independent of infarct site. These data indicate that afferent signals transduced following MI result in bilateral changes, and provide a rationale for bilateral interventions targeting the sympathetic chain for arrhythmia modulation.

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...

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.

Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic (DA) neuronal cell loss in the substantia nigra. Although the entire pathogenesis of PD is still unclear, both environmental and genetic factors contribute to neurodegeneration. Epidemiologic studies show that prevalence of PD is lower in smokers than in nonsmokers. Nicotine, a releaser of dopamine from DA neurons, is one of the candidates of antiparkinson agents in tobacco. To assess the protective effect of nicotine against rotenone-induced DA neuronal cell toxicity, we examined the neuroprotective effects of nicotine in rotenone-induced PD models in vivo and in vitro. We observed that simultaneous subcutaneous administration of nicotine inhibited both motor deficits and DA neuronal cell loss in the substantia nigra of rotenone-treated mice. Next, we analyzed the molecular mechanisms of DA neuroprotective effect of nicotine against rotenone-induced toxicity with primary DA neuronal culture. We found that DA neuroprotective effects of nicotine were inhibited by dihydro-beta-erythroidine (DHbetaE), alpha-bungarotoxin (alphaBuTx), and/or PI3K-Akt/PKB (protein serine/threonine kinase B) inhibitors, demonstrating that rotenone-toxicity on DA neurons are inhibited via activation of alpha4beta2 or alpha7 nAChRs-PI3K-Akt/PKB pathway or pathways. These results suggest that the rotenone mouse model may be useful for assessing candidate antiparkinson agents, and that nAChR (nicotinic acetylcholine receptor) stimulation can protect DA neurons against degeneration.

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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.

Cardiac sympathetic denervation (CSD) is reported to reduce the burden of ventricular tachyarrhythmias [ventricular tachycardia (VT)/ventricular fibrillation (VF)] in cardiomyopathy patients, but the mechanisms behind this benefit are unknown. In addition, the relative contribution to cardiac innervation of the middle cervical ganglion (MCG), which may contain cardiac neurons and is not removed during this procedure, is unclear. The purpose of this study was to compare sympathetic innervation of the heart via the MCG vs. stellate ganglia, assess effects of bilateral CSD on cardiac function and VT/VF, and determine changes in cardiac sympathetic innervation after CSD to elucidate mechanisms of benefit in 6 normal and 18 infarcted pigs. Electrophysiological and hemodynamic parameters were evaluated at baseline, during bilateral stellate stimulation, and during bilateral MCG stimulation in 6 normal and 12 infarcted animals. Bilateral CSD (removal of bilateral stellates and T ganglia) was then performed and MCG stimulation repeated. In addition, in 18 infarcted animals VT/VF inducibility was assessed before and after CSD. In infarcted hearts, MCG stimulation resulted in greater chronotropic and inotropic response than stellate ganglion stimulation. Bilateral CSD acutely reduced VT/VF inducibility by 50% in infarcted hearts and prolonged global activation recovery interval. CSD mitigated effects of MCG stimulation on dispersion of repolarization and T-peak to T-end interval in infarcted hearts, without causing hemodynamic compromise. These data demonstrate that the MCG provides significant cardiac sympathetic innervation before CSD and adequate sympathetic innervation after CSD, maintaining hemodynamic stability. Bilateral CSD reduces VT/VF inducibility by improving electrical stability in infarcted hearts in the setting of sympathetic activation. Sympathetic activation in myocardial infarction leads to arrhythmias and worsens heart failure. Bilateral cardiac sympathetic denervation reduces ventricular tachycardia/ventricular fibrillation inducibility and mitigates effects of sympathetic activation on dispersion of repolarization and T-peak to T-end interval in infarcted hearts. Hemodynamic stability is maintained, as innervation via the middle cervical ganglion is not interrupted.

(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...