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

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    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 Medicine
    Background 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.
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    Automatic Detection and Characterization of Autonomic Dysreflexia Using Multi-Modal Non-Invasive Sensing and Neural Networks
    (Mary Ann Liebert, 2022-11-10) Suresh, Shruthi; Everett, Thomas H., IV; Shi, Riyi; Duerstock, Bradley S.; Medicine, School of Medicine
    Autonomic dysreflexia (AD) frequently occurs in persons with spinal cord injuries (SCIs) above the T6 level triggered by different stimuli below the level of injury. If improperly managed, AD can have severe clinical consequences, even possibly leading to death. Existing techniques for AD detection are time-consuming, obtrusive, lack automated detection capabilities, and have low temporal resolution. Therefore, a non-invasive, multi-modal wearable diagnostic tool was developed to quantitatively characterize and distinguish unique signatures of AD. Electrocardiography and novel skin nerve activity (skNA) sensors with neural networks were used to detect temporal changes in the sympathetic and vagal systems in rats with SCI. Clinically established metrics of AD were used to verify the onset of AD. Five physiological features reflecting different metrics of sympathetic and vagal activity were used to characterize signatures of AD. An increase in sympathetic activity, followed by a lagged increase in vagal activity during the onset of AD, was observed after inducing AD. This unique signature response was used to train a neural network to detect the onset of AD with an accuracy of 93.4%. The model also had a 79% accuracy in distinguishing between sympathetic hyperactivity reactions attributable to different sympathetic stressors above and below the level of injury. These neural networks have not been used in previous work to detect the onset of AD. The system could serve as a complementary non-invasive tool to the clinically accepted gold standard, allowing an improved management of AD in persons with SCI.
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    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 Medicine
    Background 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.
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    Concomitant SK current activation and sodium current inhibition cause J wave syndrome
    (American Society for Clinical Investigation, 2018-11-15) Chen, Mu; Xu, Dong-Zhu; Wu, Adonis Z.; Guo, Shuai; Wan, Juyi; Yin, Dechun; Lin, Shien-Fong; Chen, Zhenhui; Rubart-von der Lohe, Michael; Everett, Thomas H., IV; Qu, Zhilin; Weiss, James N.; Chen, Peng-Sheng; Medicine, School of Medicine
    The mechanisms of J wave syndrome (JWS) are incompletely understood. Here, we showed that the concomitant activation of small-conductance calcium-activated potassium (SK) current (IKAS) and inhibition of sodium current by cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) recapitulate the phenotypes of JWS in Langendorff-perfused rabbit hearts. CyPPA induced significant J wave elevation and frequent spontaneous ventricular fibrillation (SVF), as well as sinus bradycardia, atrioventricular block, and intraventricular conduction delay. IKAS activation by CyPPA resulted in heterogeneous shortening of action potential (AP) duration (APD) and repolarization alternans. CyPPA inhibited cardiac sodium current (INa) and decelerated AP upstroke and intracellular calcium transient. SVFs were typically triggered by short-coupled premature ventricular contractions, initiated with phase 2 reentry and originated more frequently from the right than the left ventricles. Subsequent IKAS blockade by apamin reduced J wave elevation and eliminated SVF. β-Adrenergic stimulation was antiarrhythmic in CyPPA-induced electrical storm. Like CyPPA, hypothermia (32.0°C) also induced J wave elevation and SVF. It facilitated negative calcium-voltage coupling and phase 2 repolarization alternans with spatial and electromechanical discordance, which were ameliorated by apamin. These findings suggest that IKAS activation contributes to the development of JWS in rabbit ventricles.
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    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 Medicine
    Background 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.
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    Effects of ondansetron on apamin-sensitive small conductance calcium-activated potassium currents in pacing-induced failing rabbit hearts
    (Elsevier, 2019) Yin, Dechun; Yang, Na; Tian, Zhipeng; Wu, Adonis Z.; Xu, Dongzhu; Chen, Mu; Kamp, Nicholas J.; Wang, Zhuo; Shen, Changyu; Chen, Zhenhui; Lin, Shien-Fong; Rubart-von der Lohe, Michael; Chen, Peng-Sheng; Everett, Thomas H., IV; Medicine, School of Medicine
    Background Ondansetron, a widely prescribed antiemetic, has been implicated in drug-induced long QT syndrome. Recent patch clamp experiments have shown that ondansetron inhibits the apamin-sensitive small conductance calcium-activated potassium current (IKAS). Objective The purpose of this study was to determine whether ondansetron causes action potential duration (APD) prolongation by IKAS inhibition. Methods Optical mapping was performed in rabbit hearts with pacing-induced heart failure (HF) and in normal hearts before and after ondansetron (100 nM) infusion. APD at 80% repolarization (APD80) and arrhythmia inducibility were determined. Additional studies with ondansetron were performed in normal hearts perfused with hypokalemic Tyrode's (2.4 mM) solution before or after apamin administration. Results The corrected QT interval in HF was 326 ms (95% confidence interval [CI] 306–347 ms) at baseline and 364 ms (95% CI 351–378 ms) after ondansetron infusion (P < .001). Ondansetron significantly prolonged APD80 in the HF group and promoted early afterdepolarizations, steepened the APD restitution curve, and increased ventricular vulnerability. Ventricular fibrillation was not inducible in HF ventricles at baseline, but after ondansetron infusion, ventricular fibrillation was induced in 5 of the 7 ventricles (P = .021). In hypokalemia, apamin prolonged APD80 from 163 ms (95% CI 146–180 ms) to 180 ms (95% CI 156–204 ms) (P = .018). Subsequent administration of ondansetron failed to further prolong APD80 (180 ms [95% CI 156–204 ms] vs 179 ms [95% CI 165–194 ms]; P = .789). The results were similar when ondansetron was administered first, followed by apamin. Conclusion Ondansetron is a specific IKAS blocker at therapeutic concentrations. Ondansetron may prolong the QT interval in HF by inhibiting small conductance calcium-activated potassium channels, which increases the vulnerability to ventricular arrhythmias.
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    Effects of renal sympathetic denervation on the stellate ganglion and brain stem in dogs
    (Elsevier, 2017-02) Tsai, Wei-Chung; Chan, Yi-Hsin; Chinda, Kroekkiat; Chen, Zhenhui; Patel, Jheel; Shen, Changyu; Zhao, Ye; Jiang, Zhaolei; Yuan, Yuan; Ye, Michael; Chen, Lan S.; Riley, Amanda A.; Persohn, Scott A.; Territo, Paul R.; Everett, Thomas H., IV; Lin, Shien-Fong; Vinters, Harry V.; Fishbein, Michael C.; Chen, Peng-Sheng; Medicine, School of Medicine
    BACKGROUND: Renal sympathetic denervation (RD) is a promising method of neuromodulation for the management of cardiac arrhythmia. OBJECTIVE: We tested the hypothesis that RD is antiarrhythmic in ambulatory dogs because it reduces the stellate ganglion nerve activity (SGNA) by remodeling the stellate ganglion (SG) and brain stem. METHODS: We implanted a radiotransmitter to record SGNA and electrocardiogram in 9 ambulatory dogs for 2 weeks, followed by a second surgery for RD and 2 months SGNA recording. Cell death was probed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. RESULTS: Integrated SGNA at baseline and 1 and 2 months after RD were 14.0 ± 4.0, 9.3 ± 2.8, and 9.6 ± 2.0 μV, respectively (P = .042). The SG from RD but not normal control dogs (n = 5) showed confluent damage. An average of 41% ± 10% and 40% ± 16% of ganglion cells in the left and right SG, respectively, were TUNEL positive in RD dogs compared with 0% in controls dogs (P = .005 for both). The left and right SG from RD dogs had more tyrosine hydroxylase-negative ganglion cells than did the left SG of control dogs (P = .028 and P = .047, respectively). Extensive TUNEL-positive neurons and glial cells were also noted in the medulla, associated with strongly positive glial fibrillary acidic protein staining. The distribution was heterogeneous, with more cell death in the medial than lateral aspects of the medulla. CONCLUSION: Bilateral RD caused significant central and peripheral sympathetic nerve remodeling and reduced SGNA in ambulatory dogs. These findings may in part explain the antiarrhythmic effects of RD.
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    Feature Selection Techniques for a Machine Learning Model to Detect Autonomic Dysreflexia
    (Frontiers Media, 2022-08-10) Suresh, Shruthi; Newton, David T.; Everett, Thomas H., IV; Lin, Guang; Duerstock, Bradley S.; Medicine, School of Medicine
    Feature selection plays a crucial role in the development of machine learning algorithms. Understanding the impact of the features on a model, and their physiological relevance can improve the performance. This is particularly helpful in the healthcare domain wherein disease states need to be identified with relatively small quantities of data. Autonomic Dysreflexia (AD) is one such example, wherein mismanagement of this neurological condition could lead to severe consequences for individuals with spinal cord injuries. We explore different methods of feature selection needed to improve the performance of a machine learning model in the detection of the onset of AD. We present different techniques used as well as the ideal metrics using a dataset of thirty-six features extracted from electrocardiograms, skin nerve activity, blood pressure and temperature. The best performing algorithm was a 5-layer neural network with five relevant features, which resulted in 93.4% accuracy in the detection of AD. The techniques in this paper can be applied to a myriad of healthcare datasets allowing forays into deeper exploration and improved machine learning model development. Through critical feature selection, it is possible to design better machine learning algorithms for detection of niche disease states using smaller datasets.
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    Ganglionated plexi as neuromodulation targets for atrial fibrillation
    (Wiley, 2017) Choi, Eue-Keun; Zhao, Ye; Everett, Thomas H., IV; Chen, Peng-Sheng; Department of Medicine, School of Medicine
    The autonomic nervous system plays an important role in the genesis of atrial fibrillation and is one of the candidate targets for atrial fibrillation therapy. This review focuses on the role of the autonomic nervous system in atrial fibrillation development and discusses the results of the ganglionated plexi catheter and surgical ablation in preclinical and clinical studies. The heart is innervated by the extrinsic and intrinsic autonomic nervous systems. The intrinsic autonomic nervous system consists of multiple ganglionated plexi and axons, which innervate the neighboring atrial myocardium and control their electrophysiological properties. Abnormal autonomic innervation has been observed in an animal model of atrial fibrillation and in humans. Direct recordings of autonomic nerve activity in canine models showed that atrial tachyarrhythmia episodes were invariably preceded by intrinsic cardiac autonomic nerve activity, thus supporting the importance of intrinsic cardiac autonomic nerve activity as the triggers for atrial tachyarrhythmia. Targeting ganglionated plexi with catheter ablation improves the outcomes of paroxysmal atrial fibrillation ablation in addition to pulmonary vein antrum isolation. Ablation of ganglionated plexi alone without pulmonary vein isolation is also useful in controlling paroxysmal atrial fibrillation in some patients. However, surgical ganglionated plexi ablation in patients with a large left atrium, persistent atrial fibrillation, and/or a history of prior catheter ablation does not result in additional benefits. These different outcomes suggest that ganglionated plexi ablation is effective in managing patients with paroxysmal atrial fibrillation, but its effects in patients with persistent atrial fibrillation and advanced atrial diseases might be limited.
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    Heart rate variability parameters indicate altered autonomic tone in subjects with COVID-19
    (Springer Nature, 2024-12-28) Gruionu, Gabriel; Aktaruzzaman, Md; Gupta, Anita; Nowak, Thomas V.; Ward, Matthew; Everett, Thomas H., IV; Medicine, School of Medicine
    COVID-19 is associated with long-term cardiovascular complications. Heart Rate Variability (HRV), a measure of sympathetic (SNS) and parasympathetic (PNS) control, has been shown to predict COVID-19 outcomes and correlate with disease progression but a comprehensive analysis that includes demographic influences has been lacking. The objective of this study was to determine the balance between SNS, PNS and heart rhythm regulation in hospitalized COVID-19 patients and compare it with similar measurements in healthy volunteers and individuals with cardiovascular diseases (CVD), while also investigating the effects of age, Body Mass Index (BMI), gender and race. Lead I ECG recordings were acquired from 50 COVID-19 patients, 31 healthy volunteers, and 51 individuals with cardiovascular diseases (CVD) without COVID-19. Fourteen HRV parameters were calculated, including time-domain, frequency-domain, nonlinear, and regularity metrics. The study population included a balanced demographic profile, with 55% of participants being under 65 years of age, 54% identifying as male, and 68% identifying as White. Among the COVID-19 patients, 52% had a BMI ≥ 30 compared to 29% of healthy volunteers and 33% of CVD patients. COVID-19 and CVD patients exhibited significantly reduced time-domain HRV parameters, including SDNN and RMSSD, compared to healthy volunteers (SDNN: 0.02 ± 0.02 s vs. 0.06 ± 0.03 s, p < 0.001; RMSSD: 0.02 ± 0.02 s vs. 0.05 ± 0.03 s, p = 0.08). In the frequency domain, both COVID-19 and CVD patients showed increased low-frequency (LF) power and lower high-frequency (HF) power compared to healthy volunteers (COVID-19 LF: 18.47 ± 18.18%, HF: 13.69 ± 25.80%; Healthy LF: 23.30 ± 11.79%, HF: 22.91 ± 21.86%, p < 0.01). The LF/HF ratio was similar in COVID-19 patients (1.038 ± 1.54) and healthy volunteers (1.03 ± 0.78). Nonlinear parameters such as SD1 were significantly lower in COVID-19 patients (0.04 ± 0.04 s vs. 0.08 ± 0.05 s, p < 0.01), indicating altered autonomic regulation. Variations in HRV were observed based on demographic factors, with younger patients, females, and non-white individuals showing more pronounced autonomic dysfunction. COVID-19 patients exhibit significant alterations in HRV, indicating autonomic dysfunction, characterized by decreased vagal tone and sympathetic dominance, similar to patients with severe cardiovascular comorbidities. Despite higher heart rates, the HRV analysis suggests COVID-19 is associated with substantial disruption in autonomic regulation, particularly in patients with specific demographic risk factors.