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Item An afferent explanation for sexual dimorphism in the aortic baroreflex of rat(American Physiological Society (APS), 2014-09-15) Santa Cruz Chavez, Grace C.; Li, Bai-Yan; Glazebrook, Patricia A.; Kunze, Diana L.; Schild, John H.; Department of Biomedical Engineering, Purdue School of Engineering and Technology, IUPUISex differences in baroreflex (BRx) function are well documented. Hormones likely contribute to this dimorphism, but many functional aspects remain unresolved. Our lab has been investigating a subset of vagal sensory neurons that constitute nearly 50% of the total population of myelinated aortic baroreceptors (BR) in female rats but less than 2% in male rats. Termed “Ah,” this unique phenotype has many of the nonoverlapping electrophysiological properties and chemical sensitivities of both myelinated A-type and unmyelinated C-type BR afferents. In this study, we utilize three distinct experimental protocols to determine if Ah-type barosensory afferents underlie, at least in part, the sex-related differences in BRx function. Electron microscopy of the aortic depressor nerve (ADN) revealed that female rats have less myelin (P < 0.03) and a smaller fiber cross-sectional area (P < 0.05) per BR fiber than male rats. Electrical stimulation of the ADN evoked compound action potentials and nerve conduction profiles that were markedly different (P < 0.01, n = 7 females and n = 9 males). Selective activation of ADN myelinated fibers evoked a BRx-mediated depressor response that was 3–7 times greater in female (n = 16) than in male (n = 17) rats. Interestingly, the most striking hemodynamic difference was functionally dependent upon the rate of myelinated barosensory fiber activation. Only 5–10 Hz of stimulation evoked a rapid, 20- to 30-mmHg reduction in arterial pressure of female rats, whereas rates of 50 Hz or higher were required to elicit a comparable depressor response from male rats. Collectively, our experimental results are suggestive of an alternative myelinated baroreceptor afferent pathway in females that may account for, at least in part, the noted sex-related differences in autonomic control of cardiovascular function.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 Circadian variability patterns predict and guide premature ventricular contraction ablation procedural inducibility and outcomes(Elsevier, 2017) Hamon, David; Abehsira, Guillaume; Gu, Kai; Liu, Albert; Sadron, Marie Blaye-Felice; Billet, Sophie; Kambur, Thomas; Swid, Mohammed Amer; Boyle, Noel G.; Dandamudi, Gopi; Maury, Philippe; Chen, Minglong; Miller, John M.; Lellouche, Nicolas; Shivkumar, Kalyanam; Bradfield, Jason S.; Department of Medicine, School of MedicineBackground Infrequent intraprocedural premature ventricular complexes (PVCs) may impede radiofrequency catheter ablation (RFA) outcome, and pharmacologic induction is unpredictable. Objective The purpose of this study was to determine whether PVC circadian variation could help predict drug response. Methods Consecutive patients referred for RFA with detailed Holter monitoring and frequent monomorphic PVCs were included. Patients were divided into 3 groups based on hourly PVC count relationship to corresponding mean heart rate (HR) during each of the 24 hours on Holter: fast-HR-dependent PVC (F-HR-PVC) type for a positive correlation (Pearson, P <.05), slow-HR-dependent PVC (S-HR-PVC) type for a negative correlation, and independent-HR-PVC (I-HR-PVC) when no correlation was found. Results Fifty-one of the 101 patients (50.5%) had F-HR-PVC, 39.6% I-HR-PVC, and 9.9% S-HR-PVC; 30.7% had infrequent intraprocedural PVC requiring drug infusion. The best predictor of infrequent PVC was number of hours with PVC count <120/h on Holter (area under the curve 0.80, sensitivity 83.9%, specificity 74.3%, for ≥2 h). Only F-HR-PVC patients responded to isoproterenol. Isoproterenol washout or phenylephrine infusion was successful for the 3 S-HR-PVC patients, and no drug could increase PVC frequency in the 12 I-HR-PVC patients. Long-term RFA success rate in patients with frequent PVCs at baseline (82.9%) was similar to those with infrequent PVC who responded to a drug (77.8%; P = .732) but significantly higher than for those who did not respond to any drug (15.4%; P <.0001). Conclusion A simple analysis of Holter PVC circadian variability provides incremental value to guide pharmacologic induction of PVCs during RFA and predict outcome. Patients with infrequent I-HR-PVC had the least successful outcomes from RF ablation.Item 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 MedicineThe 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.Item Interventional and Device-based Autonomic Modulation in Heart Failure(Elsevier, 2015) Shen, Mark J.; Zipes, Douglas P.; Department of Medicine, IU School of MedicineHeart failure is an increasingly prevalent disease with high mortality and public health burden. It is associated with autonomic imbalance characterized by sympathetic hyperactivity and parasympathetic hypoactivity. Evolving novel interventional and device-based therapy has sought to restore autonomic balance by neuromodulation. Results of preclinical animal studies and early clinical trials have demonstrated its safety and efficacy in heart failure. In this review article, we will discuss specific neuromodulatory treatment modalities individually—spinal cord stimulation, vagus nerve stimulation, baroreceptor activation therapy and renal sympathetic nerve denervation.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 Oscillatory behavior of P wave duration and PR interval in experimental congestive heart failure: a preliminary study(IOP Publishing, 2018-03) Piccirillo, Gianfranco; Magrì, Damiano; D'Alessandro, Gaetana; Fiorucci, Claudia; Moscucci, Federica; Iorio, Claudia Di; Mastropietri, Fabiola; Parrotta, Ilaria; Ogawa, Masahiro; Lin, Shien-Fong; Chen, Peng-Sheng; Medicine, School of MedicineObjective: The relationship between the autonomic nervous system (ANS) modulation of the sinus node and heart rate variability has been extensively investigated. The current study sought to evaluate, in an animal experimental model of pacing-induced tachycardia congestive heart failure (CHF), a possible ANS influence on the P wave duration and PR interval oscillations. Approach: Short-term (5 min) time and frequency domain analysis has been obtained in six dogs for the following electrocardiographic intervals: P wave duration (P), from the onset to peak of P wave (P p), from the onset of P wave to the q onset (PR) and from the end of P wave to the onset of q wave (P e R). Direct vagal nerve activity (VNA), stellate ganglion nerve activity (SGNA) and electrocardiogram (ECG) intervals have been evaluated contextually by implantation of three bipolar recording leads. Main results: At the baseline, multiple regression analysis pointed out that VNA was strongly positively associated with the standard deviation of PP and P e R intervals (r 2:0.997, p < 0.05). The same variable was also positively associated with high-frequency (HF) of P expressed in normalized units, of P p, and of P e R (b: 0.001) (r 2: 0.993; p < 0.05). During CHF, most of the time and frequency domain variability significantly decreased from 20% to 50% in comparison to the baseline values (p < 0.05) and SGNA correlated inversely with the low frequency (LF) obtained from P e R (p < 0.05) and PR (p < 0.05) (r 2:0.899, p < 0.05). LF components, expressed in absolute and normalized power, obtained from all studied intervals, were reduced significantly during CHF. Any difference between the RR and PP spectral components was observed. Significance: The data showed a significant relationship between ANS and atrial ECG variables, independent of the cycle duration. In particular, the oscillations were vagal mediated at the baseline, while sympathetic mediated during CHF. Whereas P wave variability might have a clinical utility in CHF management, it needs to be addressed in specific studies.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 Refractory Syncope and Presyncope Associated with Atlantoaxial Instability: Preliminary Evidence of Improvement Following Surgical Stabilization(Elsevier, 2021) Henderson, Fraser C., Sr.; Rowe, Peter C.; Narayanan, Malini; Rosenbaum, Robert; Koby, Myles; Francomano, Clair A.; Medical and Molecular Genetics, School of MedicineBackground The proclivity to atlantoaxial instability (AAI) has been widely reported for conditions such as rheumatoid arthritis and Down syndrome. Similarly, we have found a higher than expected incidence of AAI in hereditary connective tissue disorders. We demonstrate a strong association of AAI with manifestations of dysautonomia, in particular syncope and lightheadedness, and make preliminary observations as to the salutary effect of surgical stabilization of the atlantoaxial motion segment. Methods In an institutional review board–approved retrospective study, 20 subjects (16 women, 4 men) with hereditary connective tissue disorders had AAI diagnosed by computed tomography. Subjects underwent realignment (reduction), stabilization, and fusion of the C1-C2 motion segment. All subjects completed preoperative and postoperative questionnaires in which they were asked about performance, function, and autonomic symptoms, including lightheadedness, presyncope, and syncope. Results All patients with AAI reported lightheadedness, and 15 had refractory syncope or presyncope despite maximal medical management and physical therapy. Postoperatively, subjects reported a statistically significant improvement in lightheadedness (P = 0.003), presyncope (P = 0.006), and syncope (P = 0.03), and in the frequency (P < 0.05) of other symptoms related to autonomic function, such as nausea, exercise intolerance, palpitations, tremors, heat intolerance, gastroesophageal reflux, and sleep apnea. Conclusions This study draws attention to the potential for AAI to present with syncope or presyncope that is refractory to medical management, and for surgical stabilization of AAI to lead to improvement of these and other autonomic symptoms.Item Simultaneous Recordings of Intrinsic Cardiac Nerve Activities and Skin Sympathetic Nerve Activities From Human Patients During the Postoperative Period(Elsevier, 2017) Shen, Mark J.; Coffey, Arthur C.; Straka, Susan; Adams, David E.; Wagner, David B.; Kovacs, Richard J.; Clark, Michael; Shen, Changyu; Chen, Lan S.; Everett, Thomas H., IV; Lin, Shien-Fong; Chen, Peng-Sheng; Department of Medicine, IU School of MedicineBackground Intrinsic cardiac nerve activity (ICNA) and skin nerve activity (SKNA) are both associated with cardiac arrhythmias in dogs. Objective The purpose of this study was to test the hypothesis that ICNA and SKNA correlate with postoperative cardiac arrhythmias in humans. Methods Eleven patients (mean age 60 ± 13 years; 4 women) were enrolled in this study. Electrical signals were simultaneously recorded from electrocardiogram (ECG) patch electrodes on the chest wall and from 2 temporary pacing wires placed during open heart surgery on the left atrial epicardial fat pad. The signals were filtered to display SKNA and ICNA. Premature atrial contractions (PACs) and premature ventricular contractions were determined manually. The SKNA and ICNA of the first 300 minutes of each patient were calculated minute by minute to determine baseline average amplitudes of nerve activities and to determine their correlation with arrhythmia burden. Results We processed 1365 ± 973 minutes of recording per patient. Low-amplitude SKNA and ICNA were present at all time, while the burst discharges were observed much less frequently. Both SKNA and burst ICNA were significantly associated with the onset of PACs and premature ventricular contractions. Baseline average ICNA (aICNA), but not average SKNA, had a significant association with PAC burden. The correlation coefficient (r) between aICNA and PAC burden was 0.78 (P < .01). A patient with the greatest aICNA developed postoperative atrial fibrillation. Conclusion ICNA and SKNA can be recorded from human patients in the postoperative period. The baseline magnitude of ICNA correlates with PAC burden and development of postoperative atrial fibrillation.