IU Indianapolis ScholarWorks :: Browsing by Author "Everett, Thomas H."

Browsing by Author "Everett, Thomas H."

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Arrhythmogenic Calmodulin Mutations Impede Activation of Small-conductance Calcium-Activated Potassium Current
(Elsevier, 2016-08) Yu, Chih-Chieh; Ko, Jum-Suk; Ai, Tomohiko; Tsai, Wen-Chin; Chen, Zhenhui; Rubart, Michael; Vatta, Matteo; Everett, Thomas H.; George, Alfred L.; Chen, Peng-Sheng; Medicine, School of Medicine
Background Apamin sensitive small-conductance Ca2+-activated K+ (SK) channels are gated by intracellular Ca2+ through a constitutive interaction with calmodulin. Objective We hypothesize that arrhythmogenic human calmodulin mutations impede activation of SK channels. Methods We studied 5 previously published calmodulin mutations (N54I, N98S, D96V, D130G and F90L). Plasmids encoding either wild type (WT) or mutant calmodulin were transiently transfected into human embryonic kidney (HEK) 293 cells that stably express SK2 channels (SK2 Cells). Whole-cell voltage-clamp recording was used to determine apamin-sensitive current (IKAS) densities. We also performed optical mapping studies in normal murine hearts to determine the effects of apamin in hearts with (N=7) or without (N=3) pretreatment with sea anemone toxin (ATX II). Results SK2 cells transfected with WT calmodulin exhibited IKAS density (in pA/pF) of 33.6 [31.4;36.5] (median and confidence interval 25%-75%), significantly higher than that observed for cells transfected with N54I (17.0 [14.0;27.7], p=0.016), F90L (22.6 [20.3;24.3], p=0.011), D96V (13.0 [10.9;15.8], p=0.003), N98S (13.7 [8.8;20.4], p=0.005) and D130G (17.6 [13.8;24.6], p=0.003). The reduction of SK2 current was not associated with a decrease in membrane protein expression or intracellular distribution of the channel protein. Apamin increased the ventricular APD80 (from 79.6 ms [63.4-93.3] to 121.8 ms [97.9-127.2], p=0.010) in hearts pre-treated with ATX-II but not in control hearts. Conclusion Human arrhythmogenic calmodulin mutations impede the activation of SK2 channels in HEK 293 cells.
The effects of remodeling with heart failure on mode of initiation of ventricular fibrillation and its spatiotemporal organization
(Springer, 2015-09) Everett, Thomas H.; Hulley, George S.; Lee, Ken W.; Chang, Roger; Wilson, Emily E.; Olgin, Jeffrey E.; Department of Medicine, IU School of Medicine
Purpose The effect of the heart failure substrate on the initiation of ventricular fibrillation (VF) and its resulting mechanism is not known. The objective of this study was to determine the effects of substrate on VF initiation and its spatiotemporal organization in the heart failure model. Methods Optical action potentials were recorded from LV wedge preparations either from structurally normal hearts (control, n = 11) or from congestive heart failure (CHF; n = 7), at the epicardial surface, endocardial surface which included a papillary muscle, and a transmural cross section. Action potential duration (APD80) was determined, and VF was initiated. A fast Fourier transform was calculated, and the dominant frequency (DF) was determined. Results The CHF group showed increased VF vulnerability (69 vs 26 %, p < 0.03), and every mapped surface showed an APD80 gradient which included islands of higher APDs on the transmural surface (M cells) which was not observed in controls. VF in the CHF group was characterized by stable, discrete, high-DF areas that correlated to either foci or spiral waves located on the transmural surface at the site of the papillary muscle. Overall, the top 10 % of DFs correlated to an APD of 101 ms while the bottom 10 % of DFs correlated to an APD of 126 ms (p < 0.01). Conclusions In the CHF model, APD gradients correlated with an increased vulnerability to VF, and the highest stable DFs were located on the transmural surface which was not seen in controls. This indicates that the CHF substrate creates unique APD and DF characteristics.
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 Medicine
OBJECTIVES: 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.
Effects of Vagal Nerve Stimulation on Ganglionated Plexi Nerve Activity and Ventricular Rate in Ambulatory Dogs With Persistent Atrial Fibrillation
(Elsevier, 2018-08) Jiang, Zhaolei; Zhao, Ye; Tsai, Wei-Chung; Yuan, Yuan; Chinda, Kroekkiat; Tan, Jian; Onkka, Patrick; Shen, Changyu; Chen, Lan S.; Fishbein, Michael C.; Lin, Shien-Fong; Chen, Peng-Sheng; Everett, Thomas H.; Medicine, School of Medicine
OBJECTIVES: This study was designed to test the hypothesis that low-level vagal nerve stimulation (VNS) reduces the ventricular rate (VR) during atrial fibrillation (AF) through the activation of the inferior vena cava (IVC)-inferior atrial ganglionated plexus nerve activity (IAGPNA). BACKGROUND: Increased IVC-IAGPNA can suppress atrioventricular node conduction and slow VR in canine models of AF. METHODS: Persistent AF was induced in 6 dogs and the IVC-IAGPNA, right vagal nerve activity, left vagal nerve activity, and an electrocardiogram were recorded. After persistent AF was documented, VNS was programed to 14 s "on" and 1.1 min "off." After 1 week, the VNS was reprogramed to 3 min off and stimulation continued for another week. Neural remodeling of the stellate ganglion (SG) was assessed with tyrosine hydroxylase staining and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling staining. RESULTS: Average IVC-IAGPNA was increased during both VNS 1.1 min off (8.20 ± 2.25 μV [95% confidence interval (CI): 6.33 to 9.53 μV]; p = 0.002) and 3 min off (7.96 ± 2.03 μV [95% CI: 6.30 to 9.27 μV]; p = 0.001) versus baseline (7.14 ± 2.20 μV [95% CI: 5.35 to 8.52 μV]). VR was reduced during both VNS 1.1 min off (123.29 ± 6.29 beats/min [95% CI: 116.69 to 129.89 beats/min]; p = 0.001) and 3 min off (120.01 ± 4.93 beats/min [95% CI: 114.84 to 125.18 beats/min]; p = 0.001) compared to baseline (142.04 ± 7.93 bpm [95% CI: 133.72 to 150.37]). Abnormal regions were observed in the left SG, but not in the right SG. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling-positive neurons were found in 22.2 ± 17.2% [95% CI: 0.9% to 43.5%] of left SG cells and 12.8 ± 8.4% [95% CI: 2.4% to 23.2%] of right SG cells. CONCLUSIONS: Chronic low-level VNS increases IVC-IAGPNA and damages bilateral stellate ganglia. Both mechanisms could contribute to the underlying mechanism of VR control during AF.
Ganglionated plexi and ligament of Marshall ablation reduces atrial vulnerability and causes stellate ganglion remodeling in ambulatory dogs
(Elsevier, 2016-10) Zhao, Ye; Jiang, Zhaolei; Tsai, Wei-Chung; Yuan, Yuan; Chinda, Kroekkiat; Choi, Eue-Keun; Fishbein, Michael C.; Lin, Shien-Fong; Chen, Peng-Sheng; Everett, Thomas H.; Medicine, School of Medicine
Background Simultaneous activation of the stellate ganglion (SGNA), the ligament of Marshall (LOM) and the ganglionated plexi (GP) often precedes the onset of paroxysmal atrial tachyarrhythmias (PAT). Objective To test the hypothesis that ablation of the LOM and the superior left GP (SLGP) reduces atrial vulnerability and results in remodeling of the stellate ganglion. Methods Nerve activity was correlated to PAT and ventricular rate (VR) at baseline, after ablation of the LOM and SLGP, and after AF. Neuronal cell death was assessed with Tyrosine hydroxylase (TH) and terminal deoxynucleotidyl transferase dUTP nick end label (TUNEL) staining. Results There were 4±2 PAT episodes per day in controls. None were observed in the ablation group; even though SGNA and VR increased from 2.2 μV (95% confidence interval (CI); 1.2 – 3.3 μV) and 80 bpm (CI 68 – 92 bpm) at baseline to 3.0 μV (CI 2.6 – 3.4 μV, p=0.046) and 90 bpm (CI 75 – 108 bpm, p=0.026) after ablation, and to 3.1 μV (CI 1.7 – 4.5 μV, p=0.116) and 95 bpm (CI 79 – 110 bpm, p=0.075) after AF. There was an increase in TH-negative cells in the ablation group and a 19.7% (CI, 8.6 – 30.8%) TUNEL-positive staining in both the left and right SG. None were observed in the control group. Conclusion LOM and SLGP ablation caused LSG remodeling and cell death. There was reduced correlation of the VR response and PAT to SGNA. These findings support the importance of SLGP and LOM in atrial arrhythmogenesis.
Heart Rate Variability Parameters Indicate Altered Autonomic Tone in Patients with COVID‐19
(Wiley, 2022) Gruionu, Gabriel; Gupta, Anita; Rattin, Megan; Nowak, Thomas V.; Ward, Matthew; Everett, Thomas H.; Medicine, School of Medicine
The COVID‐19 disease induces long term heart health complications and may induce autonomic nervous system dysfunction. Heart Rate Variability (HRV) is a measure of sympathetic (SNS) and parasympathetic (PNS) control of heart function. Recently, studies have shown that HRV analysis may be used as a predictor of COVID‐19 symptoms and correlates with progression of the disease. We aimed to uncover the interplay between SNS and PNS in hospitalized COVID‐19 patients at the time of admission and compare it with similar measurements in healthy patients (no comorbidities) and patients with cardiovascular disease. We hypothesized that COVID‐19 would induce autonomic dysfunction similar to patients with cardiovascular disease (CVD). ECG telemetry recordings of 30‐60 minutes in duration were acquired from patients that were admitted to Indiana University Health system hospitals for either COVID‐19 complications or for complications associated with cardiovascular disease (CVD) states (arrhythmia, heart failure, coronary artery disease). In addition, 20‐minute ECG Lead I recordings were obtained from healthy volunteers with no associated comorbidities. HRV parameters were calculated during sinus rhythm in the time, frequency, and nonlinear domains from the ECG telemetry recordings. The patient population was composed of 50 COVID‐19 patients (average age 63, range 26‐94), 32 healthy (average age 32.7, range 17‐69) and 49 patients with cardiovascular disease (average age 65.4, range 30‐88) as control groups. The COVID‐19 group had a higher percentage of patients with BMI>30 (obese) than the control groups (55% vs 36%). Also, the COVID‐19 and CVD patients had significantly higher heart rate and time‐domain HRV parameters (including SDRR, RMSSD, SDSD) and SD1 in the non‐linear domain when compared to healthy patients (88.8±53.0 and 87.9±55.2 vs 49.5±31.3, p<0.01). In the frequency domain, the LF/HF ratio was significantly lower in the COVID and CVD groups compared to healthy controls (0.5±0.76 and 0.55±0.50 vs 1.05±0.96, p<0.01). COVID‐19 patients have significant HRV alterations which suggest increased vagal tone than in healthy volunteers but similar to patients with severe cardiovascular disease comorbidities. Even though the COVID patients had an increased heart rate, the results of the HRV analysis indicate increased vagal tone which would support autonomic nervous system dysfunction in these patients.
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 Medicine
BACKGROUND: 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).
Subcutaneous nerve stimulation for rate control in ambulatory dogs with persistent atrial fibrillation
(Elsevier, 2019-09-01) Yuan, Yuan; Liu, Xiao; Wan, Juyi; Wong, Johnson; Bedwell, Amanda A.; Persohn, Scott A.; Shen, Changyu; Fishbein, Michael C.; Chen, Lan S.; Chen, Zhenhui; Everett, Thomas H.; Territo, Paul R.; Chen, Peng-Sheng; Medicine, School of Medicine
Background: Subcutaneous nerve stimulation (ScNS) damages the stellate ganglion and improves rhythm control of atrial fibrillation (AF) in ambulatory dogs. Objective: To test the hypothesis that thoracic ScNS can improve rate control in persistent AF. Methods: We created persistent AF in 13 dogs and randomly assigned them to ScNS (N=6) and sham control groups (N=7). 18F-2-Fluoro-2-deoxyglucose (18F-FDG) positron emission tomography / magnetic resonance imaging of the brain stem was performed at baseline and at the end of the study. Results: The average stellate ganglion nerve activity (aSGNA) reduced from 4.00±1.68 μV after the induction of persistent AF to 1.72±0.42 μV (p=0.032) after ScNS. In contrast, the aSGNA increased from 3.01±1.26 μV during AF to 5.52±2.69 μV after sham stimulation (p=0.023). The mean ventricular rate during persistent AF reduced from 149±36 bpm to 84±16 bpm (p=0.011) in ScNS group but no changes were observed in control. Left ventricular ejection fraction (LVEF) remained unchanged in ScNS group but reduced significantly in sham control group. Immunostaining showed damaged ganglion cells in bilateral stellate ganglia and increased brain stem glial cell reaction in the ScNS group but not in the controls. The 18F-FDG uptake in pons and medulla was significantly (p=0.011) higher in the ScNS group than the sham control group at the end of the study. Conclusions: Thoracic ScNS causes neural remodeling in the brain stem and stellate ganglia, controls the ventricular rate and preserves the LVEF in ambulatory dogs with persistent AF.
Using skin sympathetic nerve activity to estimate stellate ganglion nerve activity in dogs
(Elsevier, 2015-06) Jiang, Zhaolei; Zhao, Ye; Doytchinova, Anisiia; Kamp, Nicholas J.; Tsai, Wei-Chung; Yuan, Yuan; Adams, David; Wagner, David; Shen, Changyu; Chen, Lan S.; Everett, Thomas H.; Lin, Shien-Fong; Chen, Peng-Sheng; Department of Medicine, IU School of Medicine
BACKGROUND: Stellate ganglion nerve activity (SGNA) is important in cardiac arrhythmogenesis. However, direct recording of SGNA requires access to the thoracic cavity. Skin of upper thorax is innervated by sympathetic nerve fibers originating from the stellate ganglia and is easily accessible. OBJECTIVE: The purpose of this study was to test the hypothesis that thoracic skin nerve activity (SKNA) can be used to estimate SGNA. METHODS: We recorded SGNA and SKNAs using surface electrocardiogram leads in 5 anesthetized and 4 ambulatory dogs. Apamin injected into the right stellate ganglion abruptly increased both right SGNA and SKNA in 5 anesthetized dogs. We integrated nerve activities and averaged heart rate in each 1-minure window over 10 minutes. We implanted a radiotransmitter to record left SGNA in 4 ambulatory dogs (2 normal, 1 with myocardial infarction, 1 with intermittent rapid atrial pacing). After 2 weeks of recovery, we simultaneously recorded the SKNA and left SGNA continuously for 30 minutes when the dogs were ambulatory. RESULTS: There was a positive correlation [average r = 0.877, 95% confidence interval (CI) 0.732-1.000, P <.05 for each dog] between integrated skin nerve activity (iSKNA) and SGNA (iSGNA) and between iSKNA and heart rate (average r = 0.837, 95% CI 0.752-0.923, P <.05). Similar to that found in the anesthetized dogs, there was a positive correlation (average r = 0.746, 95% CI 0.527-0.964, P <.05) between iSKNA and iSGNA and between iSKNA and heart rate (average r = 0.706, 95% CI 0.484-0.927, P <.05). CONCLUSION: SKNAs can be used to estimate SGNA in dogs.

Browsing by Author "Everett, Thomas H."

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