Browsing by Author "Everett, Thomas H., IV."

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    Antiarrhythmic effects of stimulating the left dorsal branch of the thoracic nerve in a canine model of paroxysmal atrial tachyarrhythmias
    (Elsevier, 2018) Zhao, Ye; Yuan, Yuan; Tsai, Wei-Chung; Jiang, Zhaolei; Tian, Zhi-peng; Shen, Changyu; Lin, Shien-Fong; Fishbein, Michael C.; Everett, Thomas H., IV.; Chen, Zhenhui; Chen, Peng-Sheng; Medicine, School of Medicine
    Background Stellate ganglion nerve activity (SGNA) precedes paroxysmal atrial tachyarrhythmia (PAT) episodes in dogs with intermittent high-rate left atrial (LA) pacing. The left dorsal branch of the thoracic nerve (LDTN) contains sympathetic nerves originating from the stellate ganglia. Objective The purpose of this study was to test the hypothesis that high-frequency electrical stimulation of the LDTN can cause stellate ganglia damage and suppress PAT. Methods We performed chronic LDTN stimulation in 6 dogs with and 2 dogs without intermittent rapid LA pacing while monitoring SGNA. Results LDTN stimulation reduced average SGNA from 4.36 μV (95% confidence interval [CI] 4.10–4.62 μV) at baseline to 3.22 μV (95% CI 3.04–3.40 μV) after 2 weeks (P = .028) and completely suppressed all PAT episodes in all dogs studied. Tyrosine hydroxylase staining showed large damaged regions in both stellate ganglia, with increased percentages of tyrosine hydroxylase–negative cells. The terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed that 23.36% (95% CI 18.74%–27.98%) of ganglion cells in the left stellate ganglia and 11.15% (95% CI 9.34%–12.96%) ganglion cells in the right stellate ganglia were positive, indicating extensive cell death. A reduction of both SGNA and heart rate was also observed in dogs with LDTN stimulation but without high-rate LA pacing. Histological studies in the latter 2 dogs confirmed the presence of extensive stellate ganglia damage, along with a high percentage of terminal deoxynucleotidyl transferase dUTP nick end labeling–positive cells. Conclusion LDTN stimulation damages both left stellate ganglia and right stellate ganglia, reduces left SGNA, and is antiarrhythmic in this canine model of PAT.
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    Renal Denervation Update From the International Sympathetic Nervous System Summit: JACC State-of-the-Art Review
    (Elsevier, 2019-06-18) Kiuchi, Márcio G.; Esler, Murray D.; Fink, Gregory D.; Osborn, John W.; Banek, Christopher T.; Böhm, Michael; Denton, Kate M.; DiBona, Gerald F.; Everett, Thomas H., IV.; Grassi, Guido; Katholi, Richard E.; Knuepfer, Mark M.; Kopp, Ulla C.; Lefer, David J.; Lohmeier, Thomas E.; May, Clive N.; Mahfoud, Felix; Paton, Julian F.R.; Schmieder, Roland E.; Pellegrino, Peter R.; Sharabi, Yehonatan; Schlaich, Markus P.; Medicine, School of Medicine
    Three recent renal denervation studies in both drug-naïve and drug-treated hypertensive patients demonstrated a significant reduction of ambulatory blood pressure compared with respective sham control groups. Improved trial design, selection of relevant patient cohorts, and optimized interventional procedures have likely contributed to these positive findings. However, substantial variability in the blood pressure response to renal denervation can still be observed and remains a challenging and important problem. The International Sympathetic Nervous System Summit was convened to bring together experts in both experimental and clinical medicine to discuss the current evidence base, novel developments in our understanding of neural interplay, procedural aspects, monitoring of technical success, and others. Identification of relevant trends in the field and initiation of tailored and combined experimental and clinical research efforts will help to address remaining questions and provide much-needed evidence to guide clinical use of renal denervation for hypertension treatment and other potential indications.
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    Role of apamin sensitive small conductance calcium-activated potassium currents in long term cardiac memory in rabbits
    (Elsevier, 2018) Yin, Dechun; Chen, Mu; Yang, Na; Wu, Adonis Z.; Xu, Dongzhu; Tsai, Wei-Chung; Yuan, Yuan; Tian, Zhipeng; Chan, Yi-Hsin; Shen, Changyu; Chen, Zhenhui; Lin, Shien-Fong; Weiss, James N.; Chen, Peng-Sheng; Everett, Thomas H., IV.; Medicine, School of Medicine
    Background Apamin-sensitive small conductance calcium-activated K current (IKAS) is upregulated during ventricular pacing and masks short-term cardiac memory (CM). Objective – To determine the role of IKAS in long-term CM. Methods – CM was created with 3-5 weeks of ventricular pacing and defined by a flat or inverted T-wave off pacing. Epicardial optical mapping was performed in both paced and normal ventricles. Action potential duration (APD80) was determined during RA pacing. Ventricular stability was tested before and after IKAS blockade. Four paced hearts and 4 normal hearts were used for western blotting and histology. Results – There were no significant differences in either the echocardiographic parameters or in fibrosis levels between groups. Apamin induced more APD80 prolongation in CM than in normal ventricles (9.6% [8.8%-10.5%] vs 3.1% [1.9%-4.3%], p<0.001). Apamin significantly lengthend the APD80 in the CM model at late activation sites, indicating significant IKAS upregulation at those sites. The CM model also had altered Ca2+ handling as the 50% Ca2+ transient duration and amplitude were increased at distal sites compared to a proximal site (near the pacing site). After apamin, the CM model had increased VF inducibility (paced vs control, 33/40 (82.5%) vs 7/20 (35%) P<0.001), and longer VF durations (124 vs 26 seconds, P<0.001). Conclusions Chronic ventricular pacing increases Ca2+ transients at late activation sites which activates IKAS to maintain repolarization reserve. IKAS blockade increases VF vulnerability in chronically paced rabbit ventricles.
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    Sex-specific IKAS activation in rabbit ventricles with drug-induced QT prolongation
    (Elsevier, 2021) Wu, Adonis Z.; Chen, Mu; Yin, Dechun; Everett, Thomas H., IV.; Chen, Zhenhui; Rubart, Michael; Weiss, James N.; Qu, Zhilin; Chen, Peng-Sheng; Medicine, School of Medicine
    Background: Female sex is a known risk factor for drug-induced long QT syndrome (diLQTS). We recently demonstrated a sex difference in apamin-sensitive small-conductance Ca2+-activated K+ current (IKAS) activation during β-adrenergic stimulation. Objective: The purpose of this study was to test the hypothesis that there is a sex difference in IKAS in the rabbit models of diLQTS. Methods: We evaluated the sex difference in ventricular repolarization in 15 male and 22 female Langendorff-perfused rabbit hearts with optical mapping techniques during atrial pacing. HMR1556 (slowly activating delayed rectifier K+ current [IKs] blocker), E4031 (rapidly activating delayed rectifier K+ current [IKr] blocker) and sea anemone toxin (ATX-II, late Na+ current [INaL] activator) were used to simulate types 1-3 long QT syndrome, respectively. Apamin, an IKAS blocker, was then added to determine the magnitude of further QT prolongation. Results: HMR1556, E4031, and ATX-II led to the prolongation of action potential duration at 80% repolarization (APD80) in both male and female ventricles at pacing cycle lengths of 300-400 ms. Apamin further prolonged APD80 (pacing cycle length 350 ms) from 187.8±4.3 to 206.9±7.1 (P=.014) in HMR1556-treated, from 209.9±7.8 to 224.9±7.8 (P=.003) in E4031-treated, and from 174.3±3.3 to 188.1±3.0 (P=.0002) in ATX-II-treated female hearts. Apamin did not further prolong the APD80 in male hearts. The Cai transient duration (CaiTD) was significantly longer in diLQTS than baseline but without sex differences. Apamin did not change CaiTD. Conclusion: We conclude that IKAS is abundantly increased in female but not in male ventricles with diLQTS. Increased IKAS helps preserve the repolarization reserve in female ventricles treated with IKs and IKr blockers or INaL activators.
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    Simultaneous activation of the small conductance calcium-activated potassium current by acetylcholine and inhibition of sodium current by ajmaline cause J-wave syndrome in Langendorff-perfused rabbit ventricles
    (Elsevier, 2021) Fei, Yu-Dong; Chen, Mu; Guo, Shuai; Ueoka, Akira; Chen, Zhenhui; Rubart-von der Lohe, Michael; Everett, Thomas H., IV.; Qu, Zhilin; Weiss, James N.; Chen, Peng-Sheng; Medicine, School of Medicine
    Background: Concomitant apamin-sensitive small conductance calcium-activated potassium current (IKAS) activation and sodium current inhibition induce J-wave syndrome (JWS) in rabbit hearts. Sudden death in JWS occurs predominantly in men at night when parasympathetic tone is strong. Objective: The purpose of this study was to test the hypotheses that acetylcholine (ACh), the parasympathetic transmitter, activates IKAS and causes JWS in the presence of ajmaline. Methods: We performed optical mapping in Langendorff-perfused rabbit hearts and whole-cell voltage clamp to determine IKAS in isolated ventricular cardiomyocytes. Results: ACh (1 μM) + ajmaline (2 μM) induced J-point elevations in all (6 male and 6 female) hearts from 0.01± 0.01 to 0.31 ± 0.05 mV (P<.001), which were reduced by apamin (specific IKAS inhibitor, 100 nM) to 0.14 ± 0.02 mV (P<.001). More J-point elevation was noted in male than in female hearts (P=.037). Patch clamp studies showed that ACh significantly (P<.001) activated IKAS in isolated male but not in female ventricular myocytes (n=8). Optical mapping studies showed that ACh induced action potential duration (APD) heterogeneity, which was more significant in right than in left ventricles. Apamin in the presence of ACh prolonged both APD at the level of 25% (P<.001) and APD at the level of 80% (P<.001) and attenuated APD heterogeneity. Ajmaline further increased APD heterogeneity induced by ACh. Ventricular arrhythmias were induced in 6 of 6 male and 1 of 6 female hearts (P=.015) in the presence of ACh and ajmaline, which was significantly suppressed by apamin in the former. Conclusion: ACh activates ventricular IKAS. ACh and ajmaline induce JWS and facilitate the induction of ventricular arrhythmias more in male than in female ventricles.
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    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 Health
    Background: 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.
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    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 Medicine
    Background: 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.
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    Skin Sympathetic Nerve Activity as a Biomarker for Neurological Recovery during Therapeutic Hypothermia for Cardiac Arrest
    (Elsevier, 2021) Kutkut, Issa; Uceda, Domingo; Kumar, Awaneesh; Wong, Johnson; Li, Xiaochun; Wright, Keith C.; Straka, Susan; Adams, David; Deckard, Michelle; Kovacs, Richard; Chen, Peng-Sheng; Everett, Thomas H., IV.; Medicine, School of Medicine
    Background: Targeted temperature management (TTM) improves neurologic outcome after cardiac arrest. However, better neurologic prognostication is needed. Objective: The purpose of this study was to test the hypothesis that noninvasive recording of skin sympathetic nerve activity (SKNA) and its association with heart rate (HR) during TTM may serve as a biomarker of neurologic status. Methods: SKNA recordings were analyzed from 29 patients undergoing TTM. Patients were grouped based on Clinical Performance Category (CPC) score into group 1 (CPC 1-2) representing a good neurologic outcome and group 2 (CPC 3-5) representing a poor neurologic outcome. Results: Of the 29 study participants, 18 (62%) were deemed to have poor neurologic outcome. At all timepoints, low average skin sympathetic nerve activity (aSKNA) was associated with poor neurologic outcome (odds ratio 22.69; P = .002) and remained significant (P = .03) even when adjusting for presenting clinical factors. The changes in aSKNA and HR during warming in group 1 were significantly correlated (ρ = 0.49; P <.001), even when adjusting for corresponding temperature and mean arterial pressure measurements (P = .017), whereas this correlation was not observed in group 2. Corresponding to high aSKNA, there was increased nerve burst activity during warming in group 1 compared to group 2 (0.739 ± 0.451 vs 0.176 ± 0.231; P = .013). Conclusion: Neurologic recovery was retrospectively associated with SKNA. Patients undergoing TTM who did not achieve neurologic recovery were associated with low SKNA and lacked a significant correlation between SKNA and HR. These preliminary results indicate that SKNA may potentially be a useful biomarker to predict neurologic status in patients undergoing TTM.
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    Skin Sympathetic Nerve Activity as a Biomarker for Syncopal Episodes during a Tilt Table Test
    (Elsevier, 2020-05) Kumar, Awaneesh; Wright, Keith; Uceda, Domingo E.; Vasallo, Peter A., III.; Rabin, Perry L.; Adams, David; Wong, Johnson; Das, Mithilesh; Lin, Shien-Fong; Chen, Peng-Sheng; Everett, Thomas H., IV.; Medicine, School of Medicine
    Background: Autonomic imbalance is the proposed mechanism of syncope during a tilt table test (TTT). We have recently demonstrated that skin sympathetic nerve activity (SKNA) can be noninvasively recorded using electrocardiographic electrodes. Objective: The purpose of this study was to test the hypothesis that increased SKNA activation precedes tilt-induced syncope. Methods: We studied 50 patients with a history of neurocardiogenic syncope undergoing a TTT. The recorded signals were band-pass filtered at 500-1000 Hz to analyze nerve activity. Results: The average SKNA (aSKNA) value at baseline was 1.38 ± 0.38 μV in patients without syncope and 1.42 ± 0.52 μV in patients with syncope (P = .77). On upright tilt, aSKNA was 1.34 ± 0.40 μV in patients who did not have syncope and 1.39 ± 0.43 μV in patients who had syncope (P = .65). In all 14 patients with syncope, there was a surge of SKNA before an initial increase in heart rate followed by bradycardia, hypotension, and syncope. The peak aSKNA immediately (<1 minute) before syncope was significantly higher than baseline aSKNA (2.63 ± 1.22 vs 1.39 ± 0.43 μV; P = .0005). After syncope, patients were immediately placed in the supine position and aSKNA dropped significantly to 1.26 ± 0.43 μV; (P = .0004). The heart rate variability during the TTT shows a significant increase in parasympathetic tone during syncope (low-frequency/high-frequency ratio: 7.15 vs 2.21; P = .04). Conclusion: Patients with syncope do not have elevated sympathetic tone at baseline or during the TTT except immediately before syncope when there is a transient surge of SKNA followed by sympathetic withdrawal along with parasympathetic surge.
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    Skin sympathetic nerve activity in patients with obstructive sleep apnea
    (Elsevier, 2020) He, Wenbo; Tang, Yuzhu; Meng, Guannan; Wang, Danning; Wong, Johnson; Mitscher, Gloria A.; Adams, David; Everett, Thomas H., IV.; Chen, Peng-Sheng; Manchanda, Shalini; Medicine, School of Medicine
    Background: Obstructive sleep apnea (OSA) is associated with increased cardiac arrhythmia and sudden cardiac death. We recently developed a new method (neuECG) to noninvasively measure electrocardiogram and skin sympathetic nerve activity (SKNA). Objective: The purpose of this study was to test the hypothesis that SKNA measured during sleep study is higher in patients with OSA than in those without OSA. Methods: We prospectively recorded neuECG and polysomnography in 26 patients undergoing a sleep study. Sleep stages were scored into rapid eye movement (REM), and non-REM sleep stages 1 (N1), 2 (N2), and 3 (N3). Average voltage of skin sympathetic nerve activity (aSKNA) and SKNA burst area were calculated for quantification. Apnea/hypopnea index (AHI) >5 per hour was used to diagnose OSA. Results: There was a positive correlation (r = 0.549; P = .018) between SKNA burst area and the arousal index in OSA but not in the control group. aSKNA during sleep was 0.61 ± 0.09 μV in OSA patients (n = 18) and 0.53 ± 0.04 μV in control patients (n = 8; P = .025). Burst area was 3.26 (1.90-4.47) μV·s/min in OSA patients and 1.31 (0.67-1.94) μV·s/min in control (P = .047). More apparent differences were found during N2, when the burst area in OSA (3.06 [1.46-5.52] μV·s/min) was much higher than that of the control (0.89 [0.79-1.65] μV·s/min; P = .03). Conclusion: OSA patients have higher SKNA activity than control patients, with the most pronounced differences observed during N2. Arousal at the end of apnea episodes is associated with large SKNA bursts. Overlaps of aSKNA and SKNA burst area between groups suggest that not all OSA patients have increased sympathetic tone.