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Background Myocardial infarction (MI) induces remodeling in stellate ganglion neurons (SGNs). Objective We investigated whether infarct site has any impact on the laterality of morphologic changes or neuropeptide expression in stellate ganglia. Methods Yorkshire pigs underwent left circumflex coronary artery (LCX; n=6) or right coronary artery (RCA; n=6) occlusion to create left- and right-sided MI, respectively (control: n=10). At 5 ± 1 weeks after MI, left and right stellate ganglia (LSG and RSG, respectively) were collected to determine neuronal size, as well as tyrosine hydroxylase (TH) and neuropeptide Y immunoreactivity. Results Compared with control, LCX and RCA MIs increased mean neuronal size in the LSG (451 ± 25 vs 650 ± 34 vs 577 ± 55 μm 2 , respectively; P = .0012) and RSG (433 ± 22 vs 646 ± 42 vs 530 ± 41 μm 2 , respectively; P = .002). TH immunoreactivity was present in the majority of SGNs. Both LCX and RCA MIs were associated with significant decreases 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 animals with LCX and RCA MI, respectively, for LSG ( P = .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 = .002). Both TH-negative and TH-positive neurons increased in size after LCX and RCA MI. Neuropeptide Y immunoreactivity was also increased significantly by LCX and RCA MI in both ganglia. Conclusion Left- and right-sided MIs equally induced morphologic and neurochemical changes in LSG and RSG neurons, independent of infarct site. These data indicate that afferent signals transduced after MI result in bilateral changes and provide a rationale for bilateral interventions targeting the sympathetic chain for arrhythmia modulation.

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 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 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, DOR, defined as variance in repolarization time, and Tp-e were assessed before and after left, right, and bilateral stellate ganglia stimulation and norepinephrine infusion. LV endocardial and epicardial activation recovery intervals significantly decreased, and LV endocardial and epicardial DOR increased during sympathetic nerve stimulation. There were no LV epicardial versus endocardial differences in activation recovery interval during sympathetic stimulation, and regional endocardial activation recovery interval patterns were similar to the epicardium. Tp-e prolonged during left (from 40.4±2.2 ms to 92.4±12.4 ms; P P P P R =0.86). Of note, norepinephrine 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 norepinephrine 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 = 9) and control swine ( n = 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 ± 8 vs. 436 ± 9 ms, P < 0.0001), dispersion of repolarization was greater in MI versus control hearts (734 ± 123 vs. 362 ± 32 ms2, P = 0.02), and the infarcted region in MI hearts showed longer ARIs than noninfarcted regions (406 ± 14 vs. 365 ± 8 ms, P = 0.027). In control animals, percent ARI shortening was greater on anterior than posterior walls during right stellate ganglion stimulation ( P = 0.0001), whereas left stellate ganglion stimulation showed the reverse ( P = 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.

Background— Radiofrequency ablation for ventricular tachycardia is an established therapy. Use of chemical agents for scar homogenization represents an alternative approach. The purpose of this study was to characterize the efficacy of collagenase (CLG) application on epicardial ventricular scar homogenization. Methods and Results— Myocardial infarcts were created in Yorkshire pigs (n=6) by intracoronary microsphere injection. After 46.6±4.3 days, CLG type 2, type 4, and purified CLG were applied in vitro (n=1) to myocardial tissue blocks containing normal myocardium, border zone, and dense scar. Histopathologic studies were performed to identify the optimal CLG subtype. In vivo high-density electroanatomic mapping of the epicardium was also performed, and border zone and dense scar surface area and late potentials were quantified before and after CLG-4 application (n=5). Of the CLG subtypes tested in vitro, CLG-4 provided the best scar modification and least damage to normal myocardium. During in vivo testing, CLG-4 application decreased border zone area (21.3±14.3 to 17.1±11.1 mm 2 , P =0.043) and increased dense scar area (9.1±10.3 to 22.0±20.6 mm 2 , P =0.043). The total scar area before and after CLG application was 30.4±23.4 and 39.2±29.5 mm 2 , respectively ( P =0.08). Late potentials were reduced by CLG-4 application (28.8±21.8 to 13.8±13.1, P =0.043). During CLG-4 application (50.0±15.5 minutes), systolic blood pressure and heart rate were not significantly changed (68.0±7.7 versus 61.8±5.3 mmHg, P =0.08; 77.4±7.3 versus 78.8±6.0 beats per minute, P =0.50, respectively). Conclusions— Ventricular epicardial scar homogenization by CLG-4 application is feasible and effective. This represents the first report on bioenzymatic ablation of arrhythmogenic tissue as an alternative strategy for lesion formation.