Browsing by Author "Wong, Johnson"
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Item Antiarrhythmic and proarrhythmic effects of subcutaneous nerve stimulation in ambulatory dogs(Elsevier, 2019) Wan, Juyi; Chen, Mu; Yuan, Yuan; Wang, Zhuo; Shen, Changyu; Fishbein, Michael C.; Chen, Zhenhui; Wong, Johnson; Grant, Maria B.; Everett, Thomas H., IV; Chen, Peng-Sheng; Medicine, School of MedicineBackground High output subcutaneous nerve stimulation (ScNS) remodels the stellate ganglia and suppresses cardiac arrhythmia. Objective To test the hypothesis that long duration low output ScNS causes cardiac nerve sprouting, increases plasma norepinephrine concentration and the durations of paroxysmal atrial tachycardia (PAT) in ambulatory dogs. Methods We prospectively randomized 22 dogs (11 males and 11 females) into 5 different output groups for 2 months of ScNS: 0 mA (sham) (N=6), 0.25 mA (N=4), 1.5 mA (N=4), 2.5 mA (N=4) and 3.5 mA (N=4). Results As compared with baseline, the changes of the durations of PAT episodes per 48 hours were significantly different among different groups (sham, -5.0±9.5 s; 0.25 mA 95.5±71.0 s; 1.5 mA, -99.3±39.6 s; 2.5 mA, -155.3±87.8 s and 3.5 mA, -76.3±44.8 s, p<0.001). The 3.5 mA group had greater reduction of sinus heart rate than the sham group (-29.8±15.0 bpm vs -14.5±3.0 bpm, p=0.038). Immunohistochemical studies showed that the 0.25 mA group had a significantly increased while 2.5 mA and 3.5 mA stimulation had a significantly reduced growth-associated protein 43 nerve densities in both atria and ventricles. The plasma Norepinephrine concentrations in 0.25 mA group was 5063.0±4366.0 pg/ml, which was significantly higher than other groups of dogs (739.3±946.3, p=0.009). There were no significant differences in the effects of simulation between males and females. Conclusions In ambulatory dogs, low output ScNS causes cardiac nerve sprouting, increases plasma norepinephrine concentration and the duration of PAT episodes while high output ScNS is antiarrhythmic.Item Characterization of skin sympathetic nerve activity in patients with cardiomyopathy and ventricular arrhythmia(Elsevier, 2019) Zhang, Pei; Liang, Jin-jun; Cai, Cheng; Tian, Ying; Dai, Ming-yan; Wong, Johnson; Everett, Thomas H., IV; Wittwer, Erica D.; Barsness, Gregory W.; Chen, Peng-Sheng; Jiang, Chen-yang; Cha, Yong-Mei; Medicine, School of MedicineBackground Heightened sympathetic nerve activity is associated with occurrence of ventricular arrhythmia (VA). Objective To investigate the association of skin sympathetic nerve activity (SKNA) and VA occurrence. Methods We prospectively enrolled 65 patients with severe cardiomyopathy. Of these, 39 had recent sustained VA episodes (VA-1 group), 11 had intractable VA undergoing sedation with general anesthesia (VA-2 group), and 15 had no known history of VA (VA-Ctrl group). All patients had simultaneous SKNA and electrocardiogram recording. SKNA was assessed using an average value (aSKNA), a variable value (vSKNA), and the number of bursts of SKNA (bSKNA). Results The VA-1 group had higher aSKNA and vSKNA compared with the VA-Ctrl group (aSKNA: 1.41 ± 0.53 μV vs 0.98 ± 0.41 μV, P = .003; vSKNA: 0.52 ± 0.22 μV vs 0.30 ± 0.16 μV, P < .001) and the VA-2 group (aSKNA: 0.83 ± 0.22 μV, P < .001; vSKNA: 0.23 ± 0.11 μV; P < .001). Although the VA-2 group had more VA episodes than the VA-1 group (median, 5 vs 2; P = .01), their SKNA was the lowest among the 3 groups. Multivariate Cox regression analysis showed that a higher aSKNA at baseline was an independent predictor of lower VA recurrence rate during a 417 ± 279-day follow-up (hazard ratio, 0.325; 95% confidence interval [CI], 0.119–0.883; P = .03). A >15% reduction in aSKNA after therapy was associated with a lower subsequent VA event rate (hazard ratio, 0.222; 95% CI, 0.057–0.864; P = .03). Conclusion Patients with VA had increased SKNA as compared with control. Both SKNA and sustained VA could be suppressed by general anesthesia. The aSKNA at baseline was an independent predictor of VA recurrence.Item Effects of anesthetic and sedative agents on sympathetic nerve activity(Elsevier, 2019) Liu, Xiao; Rabin, Perry Lee; Yuan, Yuan; Kumar, Awaneesh; Vasallo, Peter, III; Wong, Johnson; Mitscher, Gloria A.; Everett, Thomas H., IV; Chen, Peng-Sheng; Medicine, School of MedicineBackground The effects of sedative and anesthetic agents on sympathetic nerve activity (SNA) are poorly understood. Objective The purpose of this study was to determine the effects of commonly used sedative and anesthetic agents on SNA in ambulatory dogs and humans. Methods We implanted radiotransmitters in 6 dogs to record stellate ganglion nerve activity (SGNA), subcutaneous nerve activity (ScNA), and blood pressure (BP). After recovery, we injected dexmedetomidine (3 μg/kg), morphine (0.1 mg/kg), hydromorphone (0.05 mg/kg), and midazolam (0.1 mg/kg) on different days. We also studied 12 human patients (10 male; age 68.0 ± 9.1 years old) undergoing cardioversion for atrial fibrillation with propofol (0.77 ± 0.18 mg/kg) or methohexital (0.65 mg/kg) anesthesia. Skin sympathetic nerve activity (SKNA) and electrocardiogram were recorded during the study. Results SGNA and ScNA were significantly suppressed immediately after administration of dexmedetomidine (P = .000 and P = .000, respectively), morphine (P = .011 and P = .014, respectively), and hydromorphone (P = .000 and P = .012, respectively), along with decreased BP and heart rate (HR) (P <.001 for each). Midazolam had no significant effect on SGNA and ScNA (P = .248 and P = .149, respectively) but increased HR (P = .015) and decreased BP (P = .004) in ambulatory dogs. In patients undergoing cardioversion, bolus propofol administration significantly suppressed SKNA (from 1.11 ± 0.25 μV to 0.77 ± 0.15 μV; P = .001), and the effects lasted for at least 10 minutes after the final cardioversion shock. Methohexital decreased chest SKNA from 1.59 ± 0.45 μV to 1.22 ± 0.58 μV (P = .000) and arm SKNA from 0.76 ± 0.43 μV to 0.55 ± 0.07 μV (P = .001). The effects lasted for at least 10 minutes after the cardioversion shock. Conclusion Propofol, methohexital, dexmedetomidine, morphine, and hydromorphone suppressed, but midazolam had no significant effects on, SNA.Item Effects of Stellate Ganglion Cryoablation on Subcutaneous Nerve Activity and Atrial Tachyarrhythmias in a Canine Model of Pacing-Induced Heart Failure(Elsevier, 2018-05) Shelton, Richard S.; Ogawa, Masahiro; Lin, Hongbo; Shen, Changyu; Wong, Johnson; Lin, Shien-Fong; Chen, Peng-Sheng; Everett, Thomas H.; Medicine, School of MedicineOBJECTIVES: This study aimed to test the hypothesis that subcutaneous nerve activity (SCNA) can adequately estimate the cardiac sympathetic tone and the effects of cryoablation of the stellate ganglion in dogs with pacing-induced heart failure (HF). BACKGROUND: Recording of SCNA is a new method to estimate sympathetic tone in dogs. HF is known to increase sympathetic tone and atrial arrhythmias. METHODS: Twelve dogs with pacing-induced HF were studied using implanted radiotransmitters to record the stellate ganglia nerve activity (SGNA), vagal nerve activity, and SCNA. Of these, 6 dogs (ablation group) underwent bilateral stellate ganglia cryoablation before the rapid ventricular pacing; the remaining 6 dogs (control group) had rapid ventricular pacing only. In both groups, SCNA was compared with SGNA and the occurrence of arrhythmias. RESULTS: SCNA invariably increased before the 360 identified atrial tachyarrhythmia episodes in the 6 control dogs before and after HF induction. SCNA and SGNA correlated in all dogs with an average correlation coefficient of 0.64 (95% confidence interval: 0.58 to 0.70). Cryoablation of bilateral stellate ganglia significantly reduced SCNA from 0.34 ± 0.033 μV to 0.25 ± 0.028 μV (p = 0.03) and eliminated all atrial tachyarrhythmias. CONCLUSIONS: SCNA can be used to estimate cardiac sympathetic tone in dogs with pacing-induced HF. Cryoablation of the stellate ganglia reduced SCNA and arrhythmia vulnerability.Item Epigenetic response to environmental stress: Assembly of BRG1–G9a/GLP–DNMT3 repressive chromatin complex on Myh6 promoter in pathologically stressed hearts(Elsevier, 2016-03-04) Han, Pei; Li, Wei; Yang, Jin; Shang, Ching; Lin, Chiou-Hong; Cheng, Wei; Hang, Calvin T.; Cheng, Hsiu-Ling; Chen, Chen-Hao; Wong, Johnson; Xiong, Yiqin; Zhao, Mingming; Drakos, Stavros G.; Ghetti, Andrea; Li, Dean Y.; Bernstein, Daniel; Chen, Huei-sheng Vincent; Quertermous, Thomas; Chang, Ching-Pin; Medicine, School of MedicineChromatin structure is determined by nucleosome positioning, histone modifications, and DNA methylation. How chromatin modifications are coordinately altered under pathological conditions remains elusive. Here we describe a stress-activated mechanism of concerted chromatin modification in the heart. In mice, pathological stress activates cardiomyocytes to express Brg1 (nucleosome-remodeling factor), G9a/Glp (histone methyltransferase), and Dnmt3 (DNA methyltransferase). Once activated, Brg1 recruits G9a and then Dnmt3 to sequentially assemble repressive chromatin—marked by H3K9 and CpG methylation—on a key molecular motor gene (Myh6), thereby silencing Myh6 and impairing cardiac contraction. Disruption of Brg1, G9a or Dnmt3 erases repressive chromatin marks and de-represses Myh6, reducing stress-induced cardiac dysfunction. In human hypertrophic hearts, BRG1–G9a/GLP–DNMT3 complex is also activated; its level correlates with H3K9/CpG methylation, Myh6 repression, and cardiomyopathy. Our studies demonstrate a new mechanism of chromatin assembly in stressed hearts and novel therapeutic targets for restoring Myh6 and ventricular function. The stress-induced Brg1–G9a–Dnmt3 interactions and sequence of repressive chromatin assembly on Myh6 illustrates a molecular mechanism by which the heart epigenetically responds to environmental signals. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.Item Method for Detection and Quantification of Non-Invasive Skin Sympathetic Nerve Activity(IEEE, 2018) Liu, Chun; Wong, Johnson; Doytchinova, Anisiia; Chen, Peng-Sheng; Lin, Shien-Fong; Medicine, School of MedicineSympathetic nerve activity is an important trigger of cardiac arrhythmia. Our laboratory recently developed a new method for non-invasive recording of the skin sympathetic nerve activity (SKNA) using conventional electrocardiography (ECG) patch electrodes. Recent studies showed that SKNA can adequately estimate sympathetic tone in humans. In order to improve the analysis of SKNA, we developed automatic standard assessment system based on the concept of microneurography and applied to non-invasive SKNA recording via 4 steps of signal processing. Every parameters in procedures can be manually selected by users in order to meet requirements. After using these signal processing, the results obtained by this system show improved nerve burst morphology and trend. Intuitive nerve discharge pattern and occurrence frequency can be automatically generated. Verification of the method with the cold water pressor test data further established the reliability and usefulness of the system. This new method offered a convenient tool to evaluate SKNA for comprehensive and detailed application in neurocardiology. The analysis system may facilitate the study between SKNA and cardiac arrhythmia, thus advance the field of neurocardiology research.Item Recording Intrinsic Nerve Activity at the Sinoatrial Node in Normal Dogs With High-Density Mapping(AHA, 2021-02) Yang, Yufan; Yuan, Yuan; Wong, Johnson; Fishbein, Michael C.; Chen, Peng-Sheng; Everett, Thomas H., IV; Medicine, School of MedicineBackground: It is known that autonomic nerve activity controls the sinus rate. However, the coupling between local nerve activity and electrical activation at the sinoatrial node (SAN) remains unclear. We hypothesized that we would be able to record nerve activity at the SAN to investigate if right stellate ganglion (RSG) activation can increase the local intrinsic nerve activity, accelerate sinus rate, and change the earliest activation sites. Methods: High-density mapping of the epicardial surface of the right atrium including the SAN was performed in 6 dogs during stimulation of the RSG and after RSG stellectomy. A radio transmitter was implanted into 3 additional dogs to record RSG and local nerve activity at the SAN. Results: Heart rate accelerated from 108±4 bpm at baseline to 125±7 bpm after RSG stimulation (P=0.001), and to 132±7 bpm after apamin injection (P<0.001). Both electrical RSG stimulation and apamin injection induced local nerve activity at the SAN with the average amplitudes of 3.60±0.72 and 3.86±0.56 μV, respectively. RSG stellectomy eliminated the local nerve activity and decreased the heart rate. In ambulatory dogs, local nerve activity at the SAN had a significantly higher average Pearson correlation to heart rate (0.72±0.02, P=0.001) than RSG nerve activity to HR (0.45±0.04, P=0.001). Conclusions: Local intrinsic nerve activity can be recorded at the SAN. Short bursts of these local nerve activities are present before each atrial activation during heart rate acceleration induced by stimulation of the RSG.Item Skin Sympathetic Nerve Activity and the Short-Term QT Interval Variability in Patients With Electrical Storm(Frontiers Media, 2021-12-22) Chen, Songwen; Meng, Guannan; Doytchinova, Anisiia; Wong, Johnson; Straka, Susan; Lacy, Julie; Li, Xiaochun; Chen, Peng-Sheng; Everett, Thomas H., IV.; Biostatistics, School of Public HealthBackground: Skin sympathetic nerve activity (SKNA) and QT interval variability are known to be associated with ventricular arrhythmias. However, the relationship between the two remains unclear. Objective: The aim was to test the hypothesis that SKNA bursts are associated with greater short-term variability of the QT interval (STVQT) in patients with electrical storm (ES) or coronary heart disease without arrhythmias (CHD) than in healthy volunteers (HV). Methods: We simultaneously recorded the ECG and SKNA during sinus rhythm in patients with ES (N = 10) and CHD (N = 8) and during cold-water pressor test in HV (N = 12). The QT and QTc intervals were manually marked and calculated within the ECG. The STVQT was calculated and compared to episodes of SKNA burst and non-bursting activity. Results: The SKNA burst threshold for ES and HV was 1.06 ± 1.07 and 1.88 ± 1.09 μV, respectively (p = 0.011). During SKNA baseline and burst, the QT/QTc intervals and STVQT for ES and CHD were significantly higher than those of the HV. In all subjects, SKNA bursts were associated with an increased STVQT (from 6.43 ± 2.99 to 9.40 ± 5.12 ms, p = 0.002 for ES; from 9.48 ± 4.40 to 12.8 ± 5.26 ms, p = 0.016 for CHD; and from 3.81 ± 0.73 to 4.49 ± 1.24 ms, p = 0.016 for HV). The magnitude of increased STVQT in ES (3.33 ± 3.06 ms) and CHD (3.34 ± 2.34 ms) was both higher than that of the HV (0.68 ± 0.84 ms, p = 0.047 and p = 0.020). Conclusion: Compared to non-bursting activity, SKNA bursts were associated with a larger increase in the QTc interval and STVQT in patients with heart disease than in HV.Item Skin sympathetic nerve activity and the temporal clustering of cardiac arrhythmias(American Society for Clinical Investigation, 2019-02-21) Kusayama, Takashi; Wan, Juyi; Doytchinova, Anisiia; Wong, Johnson; Kabir, Ryan A.; Mitscher, Gloria; Straka, Susan; Shen, Changyu; Everett, Thomas H.; Chen, Peng-Sheng; Medicine, School of MedicineBACKGROUND: Simultaneous noninvasively recorded skin sympathetic nerve activity (SKNA) and electrocardiogram (neuECG) can be used to estimate cardiac sympathetic tone. We tested the hypothesis that large and prolonged SKNA bursts are associated with temporal clustering arrhythmias. METHODS: We recorded neuECG in 10 patients (69 ± 10 years old) with atrial fibrillation (AF) episodes and in 6 patients (50 ± 13 years old) with ventricular tachycardia (VT) or fibrillation (VF) episodes. Clustering was defined by an arrhythmic episode followed within 1 minute by spontaneous recurrences of the same arrhythmia. The neuECG signals were bandpass filtered between 500-1000 Hz to display SKNA. RESULTS: There were 22 AF clusters, including 231 AF episodes from 6 patients, and 9 VT/VF clusters, including 99 VT/VF episodes from 3 patients. A total duration of SKNA bursts associated with AF was longer than that during sinus rhythm (78.9 min/hour [interquartile range (IQR) 17.5-201.3] vs. 16.3 min/hour [IQR 14.5-18.5], P = 0.022). The burst amplitude associated with AF in clustering patients was significantly higher than that in nonclustering patients (1.54 μV [IQR 1.35-1.89], n = 114, vs. 1.20 μV [IQR 1.05-1.42], n = 21, P < 0.001). The SKNA bursts associated with VT/VF clusters lasted 9.3 ± 3.1 minutes, with peaks that averaged 1.13 ± 0.38 μV as compared with 0.79 ± 0.11 μV at baseline (P = 0.041). CONCLUSION: Large and sustained sympathetic nerve activities are associated with the temporal clustering of AF and VT/VF. FUNDING: This study was supported in part by NIH grants R42DA043391 (THE), R56 HL71140, TR002208-01, R01 HL139829 (PSC), a Charles Fisch Cardiovascular Research Award endowed by Suzanne B. Knoebel of the Krannert Institute of Cardiology (TK and THE), a Medtronic-Zipes Endowment, and the Indiana University Health-Indiana University School of Medicine Strategic Research Initiative (PSC).Item Skin sympathetic nerve activity and ventricular rate control during atrial fibrillation(Elsevier, 2020-04) Kusayama, Takashi; Douglas, Anthony, II.; Wan, Juyi; Doytchinova, Anisiia; Wong, Johnson; Mitscher, Gloria; Straka, Susan; Shen, Changyu; Everett, Thomas H., IV.; Chen, Peng-Sheng; Medicine, School of MedicineBackground: The relationship between the ventricular rate (VR) during atrial fibrillation (AF) and skin sympathetic nerve activity (SKNA) remains unclear. Objective: The purpose of this study was to test the hypothesis that SKNA bursts accelerate VR during AF. Methods: We simultaneously recorded electrocardiogram and SKNA in 8 patients (median age 66.0 years [interquartile range {IQR} 59.0-77.0 years]; 4 men [50%]) with 30 paroxysmal AF episodes (all >10-minute long) and 12 patients (73.0 years [IQR 60.5-80.0 years]; 6 men [50%]) with persistent AF. The average amplitude of SKNA (aSKNA [μV]) during AF was analyzed in 1-minute windows and binned, showing 2 Gaussian distributions. We used the mean + 3SD of the first Gaussian distribution as the threshold that separates burst from baseline (nonburst) SKNA. All 1-minute aSKNA values above the threshold were detected, and the area between aSKNA and baseline of every 1 minute was calculated and added as burst area. Results: VR was higher during SKNA bursts than during the nonburst period (103 beats/min [IQR 83-113 beats/min] vs 88 beats/min [IQR 76-101 beats/min], respectively; P = .003). In the highest quartile of the burst area during persistent AF, the scatterplot of maximal aSKNA and VR during each SKNA burst shows higher aSKNA and VR. The overall estimate of the correlation between maximal VR and aSKNA during bursts show a positive correlation in the highest quartile of the burst area (0.64; 95% confidence interval 0.54-0.74; P < .0001). Conclusion: SKNA bursts are associated with VR acceleration. These SKNA bursts may be new therapeutic targets for rate control during AF.