Olujimi A. Ajijola

Cardiac sympathetic denervation in patients with refractory ventricular arrhythmias or electrical storm: Intermediate and long-term follow-up

BACKGROUND Left and bilateral cardiac sympathetic denervation (CSD) have been shown to reduce burden of ventricular arrhythmias acutely in a small number of patients with ventricular tachyarrhythmia (VT) storm. The effects of this procedure beyond the acute setting are unknown. OBJECTIVE The purpose of this study was to evaluate the intermediate and long-term effects of left and bilateral CSD in patients with cardiomyopathy and refractory VT or VT storm. METHODS Retrospective analysis of medical records for patients who underwent either left or bilateral CSD for VT storm or refractory VT between April 2009 and December 2012 was performed. RESULTS Forty-one patients underwent CSD (14 left CSD, 27 bilateral CSD). There was a significant reduction in the burden of implantable cardioverter-defibrillator (ICD) shocks during follow-up compared to the 12 months before the procedure. The number of ICD shocks was reduced from a mean of 19.6 ± 19 preprocedure to 2.3 ± 2.9 postprocedure (P < .001), with 90% of patients experiencing a reduction in ICD shocks. At mean follow-up of 367 ± 251 days postprocedure, survival free of ICD shock was 30% in the left CSD group and 48% in the bilateral CSD group. Shock-free survival was greater in the bilateral group than in the left CSD group (P = .04). CONCLUSION In patients with VT storm, bilateral CSD is more beneficial than left CSD. The beneficial effects of bilateral CSD extend beyond the acute postsympathectomy period, with continued freedom from ICD shocks in 48% of patients and a significant reduction in ICD shocks in 90% of patients.

Bilateral Cardiac Sympathetic Denervation for the Management of Electrical Storm

To the Editor: The sympathetic nervous system plays an important role in ventricular arrhythmogenesis. Left cardiac sympathetic denervation (LCSD) decreases the incidence of ventricular arrhythmias (VAs) and sudden cardiac death in patients with severe VAs ([1,2][1]). However, when LCSD is

Clinical neurocardiology defining the value of neuroscience‐based cardiovascular therapeutics

The autonomic nervous system regulates all aspects of normal cardiac function, and is recognized to play a critical role in the pathophysiology of many cardiovascular diseases. As such, the value of neuroscience‐based cardiovascular therapeutics is increasingly evident. This White Paper reviews the current state of understanding of human cardiac neuroanatomy, neurophysiology, pathophysiology in specific disease conditions, autonomic testing, risk stratification, and neuromodulatory strategies to mitigate the progression of cardiovascular diseases.

Myocardial infarction induces structural and functional remodelling of the intrinsic cardiac nervous system.

Intrinsic cardiac (IC) neurons undergo differential morphological and phenotypic remodelling that reflects the site of myocardial infarction (MI). Afferent neural signals from the infarcted region to IC neurons are attenuated, while those from border and remote regions are preserved post‐MI, giving rise to a ‘neural sensory border zone’. Convergent IC local circuit (processing) neurons have enhanced transduction capacity following MI. Functional network connectivity within the intrinsic cardiac nervous system is reduced post‐MI. MI reduces the response and alters the characteristics of IC neurons to ventricular pacing.

Remodeling of stellate ganglion neurons after spatially targeted myocardial infarction: Neuropeptide and morphologic changes

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.

Focal myocardial infarction induces global remodeling of cardiac sympathetic innervation: neural remodeling in a spatial context

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 ms(2), 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.

Modulation of regional dispersion of repolarization and T-peak to T-end interval by the right and left stellate ganglia

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.

Sympathetic Nerve Stimulation, Not Circulating Norepinephrine, Modulates T-Peak to T-End Interval by Increasing Global Dispersion of Repolarization

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<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, 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.

Cardioprotection of electroacupuncture against myocardial ischemia-reperfusion injury by modulation of cardiac norepinephrine release

Augmentation of cardiac sympathetic tone during myocardial ischemia has been shown to increase myocardial O(2) demand and infarct size as well as induce arrhythmias. We have previously demonstrated that electroacupuncture (EA) inhibits the visceral sympathoexcitatory cardiovascular reflex. The purpose of this study was to determine the effects of EA on left ventricular (LV) function, O(2) demand, infarct size, arrhythmogenesis, and in vivo cardiac norepinephrine (NE) release in a myocardial ischemia-reperfusion model. Anesthetized rabbits (n = 36) underwent 30 min of left anterior descending coronary artery occlusion followed by 90 min of reperfusion. We evaluated myocardial O(2) demand, infarct size, ventricular arrhythmias, and myocardial NE release using microdialysis under the following experimental conditions: 1) untreated, 2) EA at P5-6 acupoints, 3) sham acupuncture, 4) EA with pretreatment with naloxone (a nonselective opioid receptor antagonist), 5) EA with pretreatment with chelerythrine (a nonselective PKC inhibitor), and 6) EA with pretreatment with both naloxone and chelerythrine. Compared with the untreated and sham acupuncture groups, EA resulted in decreased O(2) demand, myocardial NE concentration, and infarct size. Furthermore, the degree of ST segment elevation and severity of LV dysfunction and ventricular arrhythmias were all significantly decreased (P < 0.05). The cardioprotective effects of EA were partially blocked by pretreatment with naloxone or chelerythrine alone and completely blocked by pretreatment with both naloxone and chelerythrine. These results suggest that the cardioprotective effects of EA against myocardial ischemia-reperfusion are mediated through inhibition of the cardiac sympathetic nervous system as well as opioid and PKC-dependent pathways.

Relationship Between Sinus Rhythm Late Activation Zones and Critical Sites for Scar-Related Ventricular Tachycardia Systematic Analysis of Isochronal Late Activation Mapping

Background—It is not known whether the most delayed late potentials are functionally most specific for scar-related ventricular tachycardia (VT) circuits. Methods and Results—Isochronal late activation maps were constructed to display ventricular activation during sinus rhythm over 8 isochrones. Analysis was performed at successful VT termination sites and prospectively tested. Thirty-three patients with 47 scar-related VTs where a critical site was demonstrated by termination of VT during ablation were retrospectively analyzed. In those who underwent mapping of multiple surfaces, 90% of critical sites were on the surface that contained the latest late potential. However, only 11% of critical sites were localized to the latest isochrone (87.5%–100%) of ventricular activation. The median percentage of latest activation at critical sites was 78% at a distance from the latest isochrone of 18 mm. Sites critical to reentry were harbored in regions with slow conduction velocity, where 3 isochrones were present within a 1-cm radius. Ten consecutive patients underwent ablation prospectively guided by isochronal late activation maps, targeting concentric isochrones outside of the latest isochrone. Elimination of the targeted VT was achieved in 90%. Termination of VT was achieved in 6 patients at a mean ventricular activation percentage of 78%, with only 1 requiring ablation in the latest isochrone. Conclusions—Late potentials identified in the latest isochrone of activation during sinus rhythm are infrequently correlated with successful ablation sites for VT. The targeting of slow conduction regions propagating into the latest zone of activation may be a novel and promising strategy for substrate modification.