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Browsing by Author "Doytchinova, Anisiia"
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Item Evaluation of the Genetic Basis of Familial Aggregation of Pacemaker Implantation by a Large Next Generation Sequencing Panel(Public Library of Science (PloS), 2015) Celestino-Soper, Patrícia B. S.; Doytchinova, Anisiia; Steiner, Hillel A.; Uradu, Andrea; Lynnes, Ty C.; Groh, William J.; Miller, John M.; Lin, Hai; Gao, Hongyu; Wang, Zhiping; Liu, Yunlong; Chen, Peng-Sheng; Vatta, Matteo; Department of Medical and Molecular Genetics, IU School of MedicineBACKGROUND: The etiology of conduction disturbances necessitating permanent pacemaker (PPM) implantation is often unknown, although familial aggregation of PPM (faPPM) suggests a possible genetic basis. We developed a pan-cardiovascular next generation sequencing (NGS) panel to genetically characterize a selected cohort of faPPM. MATERIALS AND METHODS: We designed and validated a custom NGS panel targeting the coding and splicing regions of 246 genes with involvement in cardiac pathogenicity. We enrolled 112 PPM patients and selected nine (8%) with faPPM to be analyzed by NGS. RESULTS: Our NGS panel covers 95% of the intended target with an average of 229x read depth at a minimum of 15-fold depth, reaching a SNP true positive rate of 98%. The faPPM patients presented with isolated cardiac conduction disease (ICCD) or sick sinus syndrome (SSS) without overt structural heart disease or identifiable secondary etiology. Three patients (33.3%) had heterozygous deleterious variants previously reported in autosomal dominant cardiac diseases including CCD: LDB3 (p.D117N) and TRPM4 (p.G844D) variants in patient 4; TRPM4 (p.G844D) and ABCC9 (p.V734I) variants in patient 6; and SCN5A (p.T220I) and APOB (p.R3527Q) variants in patient 7. CONCLUSION: FaPPM occurred in 8% of our PPM clinic population. The employment of massive parallel sequencing for a large selected panel of cardiovascular genes identified a high percentage (33.3%) of the faPPM patients with deleterious variants previously reported in autosomal dominant cardiac diseases, suggesting that genetic variants may play a role in faPPM.Item Left cervical vagal nerve stimulation reduces skin sympathetic nerve activity in patients with drug resistant epilepsy(Elsevier, 2017-12) Yuan, Yuan; Hassel, Jonathan L.; Doytchinova, Anisiia; Adams, David; Wright, Keith C.; Meshberger, Chad; Chen, Lan S.; Guerra, Maria P.; Shen, Changyu; Lin, Shien-Fong; Everett IV, Thomas H.; Salanova, Vincenta; Chen, Peng-Sheng; Neurology, School of MedicineBACKGROUND: We recently reported that skin sympathetic nerve activity (SKNA) can be used to estimate sympathetic tone in humans. In animal models, vagal nerve stimulation (VNS) can damage the stellate ganglion, reduce stellate ganglion nerve activity, and suppress cardiac arrhythmia. Whether VNS can suppress sympathetic tone in humans remains unclear. OBJECTIVE: The purpose of this study was to test the hypothesis that VNS suppresses SKNA in patients with drug-resistant epilepsy. METHODS: ECG patch electrodes were used to continuously record SKNA in 26 patients with drug-resistant epilepsy who were admitted for video electroencephalographic monitoring. Among them, 6 (2 men, age 40 ± 11 years) were previously treated with VNS and 20 (7 men, age 37 ± 8 years) were not. The signals from ECG leads I and II were filtered to detect SKNA. RESULTS: VNS had an on-time of 30 seconds and off-time of 158 ± 72 seconds, with output of 1.92 ± 0.42 mA at 24.17 ± 2.01 Hz. Average SKNA during VNS off-time was 1.06 μV (95% confidence interval [CI] 0.93-1.18) in lead I and 1.13 μV (95% CI 0.99-1.27) in lead II, which was significantly lower than 1.38 μV (95% CI 1.01-1.75; P = .036) and 1.38 μV (95% CI 0.98-1.78; P = .035) in the control group, respectively. Heart rate was 65 bpm (95% CI 59-71) in the VNS group, which was significantly lower than 77 bpm (95% CI 71-83) in the control group. CONCLUSION: Patients with VNS had significantly lower SKNA than those without VNS.Item Left Cervical Vagal Nerve Stimulation Reduces Skin Sympathetic Nerve Activity in Patients with Drug Resistant Epilepsy(Elsevier, 2017) Yuan, Yuan; Hassel, Jonathan L.; Doytchinova, Anisiia; Adams, David; Wright, Keith C.; Meshberger, Chad; Chen, Lan S.; Guerra, Maria P.; Shen, Changyu; Lin, Shien-Fong; Everett, Thomas H., IV; Salanova, Vicenta; Chen, Peng-Sheng; Department of Medicine, School of MedicineBackground We recently reported that skin sympathetic nerve activity (SKNA) can be used to estimate sympathetic tone in humans. In animal models, vagal nerve stimulation (VNS) can damage the stellate ganglion, reduce stellate ganglion nerve activity, and suppress cardiac arrhythmia. Whether VNS can suppress sympathetic tone in humans remains unclear. Objective The purpose of this study was to test the hypothesis that VNS suppresses SKNA in patients with drug-resistant epilepsy. Methods ECG patch electrodes were used to continuously record SKNA in 26 patients with drug-resistant epilepsy who were admitted for video electroencephalographic monitoring. Among them, 6 (2 men, age 40 ± 11 years) were previously treated with VNS and 20 (7 men, age 37 ± 8 years) were not. The signals from ECG leads I and II were filtered to detect SKNA. Results VNS had an on-time of 30 seconds and off-time of 158 ± 72 seconds, with output of 1.92 ± 0.42 mA at 24.17 ± 2.01 Hz. Average SKNA during VNS off-time was 1.06 μV (95% confidence interval [CI] 0.93–1.18) in lead I and 1.13 μV (95% CI 0.99–1.27) in lead II, which was significantly lower than 1.38 μV (95% CI 1.01–1.75; P = .036) and 1.38 μV (95% CI 0.98–1.78; P = .035) in the control group, respectively. Heart rate was 65 bpm (95% CI 59–71) in the VNS group, which was significantly lower than 77 bpm (95% CI 71–83) in the control group. Conclusion Patients with VNS had significantly lower SKNA than those without VNS.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 sympathetic nerve activity from the skin(Elsevier, 2017-10) Everett IV, Thomas H.; Doytchinova, Anisiia; Cha, Yong-Mei; Chen, Peng-Sheng; Medicine, School of MedicineSympathetic tone is important in cardiac arrhythmogenesis; however, methods to estimate sympathetic tone are either invasive or require proper sinus node function that may be abnormal in disease states. Because of the direct and extensive connections among various nerve structures, it is possible for the sympathetic nerves in the various structures to activate simultaneously. Therefore, we hypothesized that nerve activity can be recorded from the skin and it can be used to estimate the cardiac sympathetic tone. Preclinical studies in canines demonstrated that nerve activity is detectable using conventional ECG electrodes and can be used to estimate cardiac sympathetic tone. Subsequent clinical studies further supported this concept. In addition to studying the autonomic mechanisms of cardiac arrhythmia, these new methods may have broad application in studying both cardiac and non-cardiac diseases.Item Simultaneous noninvasive recording of skin sympathetic nerve activity and electrocardiogram(Elsevier, 2017-01) Doytchinova, Anisiia; Hassel, Jonathan L.; Yuan, Yuan; Lin, Hongbo; Yin, Dechun; Adams, David; Straka, Susan; Wright, Keith; Smith, Kimberly; Wagner, David; Shen, Changyu; Salanova, Vicenta; Meshberger, Chad; Chen, Lan S.; Kincaid, John C.; Coffey, Arthur; Wu, Gang; Li, Yan; Kovacs, Richard J.; Everett, Thomas H., IV; Victor, Ronald; Cha, Yong-Mei; Lin, Shien-Fong; Chen, Peng-Sheng; Medicine, School of MedicineBACKGROUND: Sympathetic nerve activity is important to cardiac arrhythmogenesis. OBJECTIVE: The purpose of this study was to develop a method for simultaneous noninvasive recording of skin sympathetic nerve activity (SKNA) and electrocardiogram (ECG) using conventional ECG electrodes. This method (neuECG) can be used to adequately estimate sympathetic tone. METHODS: We recorded neuECG signals from the skin of 56 human subjects. The signals were low-pass filtered to show the ECG and high-pass filtered to show nerve activity. Protocol 1 included 12 healthy volunteers who underwent cold water pressor test and Valsalva maneuver. Protocol 2 included 19 inpatients with epilepsy but without known heart diseases monitored for 24 hours. Protocol 3 included 22 patients admitted with electrical storm and monitored for 39.0 ± 28.2 hours. Protocol 4 included 3 patients who underwent bilateral stellate ganglion blockade with lidocaine injection. RESULTS: In patients without heart diseases, spontaneous nerve discharges were frequently observed at baseline and were associated with heart rate acceleration. SKNA recorded from chest leads (V1-V6) during cold water pressor test and Valsalva maneuver (protocol 1) was invariably higher than during baseline and recovery periods (P < .001). In protocol 2, the average SKNA correlated with heart rate acceleration (r = 0.73 ± 0.14, P < .05) and shortening of QT interval (P < .001). Among 146 spontaneous ventricular tachycardia episodes recorded in 9 patients of protocol 3, 106 episodes (73%) were preceded by SKNA within 30 seconds of onset. Protocol 4 showed that bilateral stellate ganglia blockade by lidocaine inhibited SKNA. CONCLUSION: SKNA is detectable using conventional ECG electrodes in humans and may be useful in estimating sympathetic tone.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.Item Skin sympathetic nerve activity precedes the onset and termination of paroxysmal atrial tachycardia and fibrillation(Elsevier, 2017) Uradu, Andrea; Wan, Juyi; Doytchinova, Anisiia; Wright, Keith C.; Lin, Andrew Y. T.; Chen, Lan S.; Shen, Changyu; Lin, Shien-Fong; Everett, Thomas H., IV; Chen, Peng-Sheng; Department of Medicine, IU School of MedicineBackground Skin sympathetic nerve activity (SKNA) is useful for estimating sympathetic tone in humans. Objective The purpose of this study was to test the hypotheses that (1) increased SKNA is associated with the onset and termination of paroxysmal atrial tachycardia (AT) and atrial fibrillation (AF) and (2) sinoatrial node response to SKNA is reduced in patients with more frequent AT or AF episodes. Methods SKNA and electrocardiogram were recorded in 11 patients (4 men and 7 women; average age 66 ± 10 years), including 3 patients with AT (11 ± 18 episodes per patient) and 8 patients with AF (24 ± 26 episodes per patient). Results The average SKNA (aSKNA) 10 seconds before AT onset was 1.07 ± 0.10 μV and 10 seconds after termination was 1.27 ± 0.10 μV; both were significantly (P = .032 and P < .0001) higher than that during sinus rhythm (0.97 ± 0.09 μV). The aSKNA 10 seconds before AF onset was 1.34 ± 0.07 μV and 10 seconds after termination was 1.31 ± 0.07 μV; both were significantly (P < .0001) higher than that during sinus rhythm (1.04 ± 0.07 μV). The aSKNA before onset (P < .0001) and after termination (P = .0011) was higher in AF than in AT. The sinus rate correlated (P < .0001) with aSKNA in each patient (average r = 0.74; 95% confidence interval 0.65–0.84). The r value in each patient negatively correlated with the number of AT and AF episodes (r = −0.6493; 95% confidence interval −0.8990 to −0.08073; P = .0306). Conclusion Increased SKNA was observed both at the onset and termination of AT and AF. Patients with more frequent AT and AF episodes had a weak correlation between sinus rate and aSKNA, suggesting sinoatrial node remodeling by tachycardia.