Browsing by Author "Shen, Changyu"
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Item 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 MedicineBackground 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.Item 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 MedicineBackground 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.Item Apamin-Sensitive Calcium-Activated Potassium Currents in Rabbit Ventricles with Chronic Myocardial Infarction(Wiley Online Library, 2013-10-24) Lee, Young Soo; Chang, Po-Cheng; Hsueh, Chia-Hsiang; Maruyama, Mitsunori; Park, Hyung Wook; Rhee, Kyoung-Suk; Hsieh, Yu-Cheng; Shen, Changyu; Weiss, James N.; Chen, Zhenhui; Lin, Shien-Fong; Chen, Peng-Sheng; Department of Medicine, IU School of MedicineIntroduction Apamin-sensitive small-conductance calcium-activated potassium current (IKAS) is increased in heart failure. It is unknown if myocardial infarction (MI) is also associated with an increase of IKAS. Methods and Results We performed Langendorff perfusion and optical mapping in 6 normal hearts and 10 hearts with chronic (5 weeks) MI. An additional 6 normal and 10 MI hearts were used for patch clamp studies. The infarct size was 25% [95% confidence interval, 20 to 31] and the left ventricular ejection fraction was 0.5 [0.46 to 0.54]. The rabbits did not have symptoms of heart failure. The action potential duration measured to 80% repolarization (APD80) in the peri-infarct zone (PZ) was150 [142 to 159] ms, significantly (p=0.01) shorter than in the normal ventricles (158 to 177] ms). The intracellular Ca transient duration was also shorter in the PZ (148 [139 to 157] ms) than in normal ventricles (168 [157 to 180] ms; P=0.017). Apamin prolonged the APD80 in PZ by 9.8 [5.5 to 14.1] %, which is greater than in normal ventricles (2.8 [1.3 to 4.3] %, p=0.006). Significant shortening of APD80 was observed at the cessation of rapid pacing in MI but not in normal ventricles. Apamin prevented postpacing APD80 shortening. Patch clamp studies showed that IKAS was significantly higher in the PZ cells (2.51 [1.55 to 3.47] pA/pF, N=17) than in the normal cells (1.08 [0.36 to 1.80] pA/pF, N=15, p=0.019). Conclusion We conclude that IKAS is increased in MI ventricles and contributes significantly to ventricular repolarization especially during tachycardia.Item Assessing the impact of a primary care electronic medical record system in three Kenyan rural health centers(Oxford University Press, 2016-05) Tierney, William M.; Sidle, John E.; Diero, Lameck O.; Sudoi, Allan; Kiplagat, Jepchirchir; Macharia, Stephen; Shen, Changyu; Yeung, Ada; Were, Martin C.; Slaven, James E.; Wools-Kaloustian, Kara; Medicine, School of MedicineObjective: Efficient, effective health care requires rapid availability of patient information. We designed, implemented, and assessed the impact of a primary care electronic medical record (EMR) in three rural Kenyan health centers. Method: Local clinicians identified data required for primary care and public health reporting. We designed paper encounter forms to capture these data in adult medicine, pediatric, and antenatal clinics. Encounter form data were hand-entered into a new primary care module in an existing EMR serving onsite clinics serving patients infected with the human immunodeficiency virus (HIV). Before subsequent visits, Summary Reports were printed containing selected patient data with reminders for needed HIV care. We assessed effects on patient flow and provider work with time-motion studies before implementation and two years later, and we surveyed providers' satisfaction with the EMR. Results: Between September 2008 and December 2011, 72 635 primary care patients were registered and 114 480 encounter forms were completed. During 2011, 32 193 unique patients visited primary care clinics, and encounter forms were completed for all visits. Of 1031 (3.2%) who were HIV-infected, 85% received HIV care. Patient clinic time increased from 37 to 81 min/visit after EMR implementation in one health center and 56 to 106 min/visit in the other. However, outpatient visits to both health centers increased by 85%. Three-quarters of increased time was spent waiting. Despite nearly doubling visits, there was no change in clinical officers' work patterns, but the nurses' and the clerks' patient care time decreased after EMR implementation. Providers were generally satisfied with the EMR but desired additional training. Conclusions: We successfully implemented a primary care EMR in three rural Kenyan health centers. Patient waiting time was dramatically lengthened while the nurses' and the clerks' patient care time decreased. Long-term use of EMRs in such settings will require changes in culture and workflow.Item Autonomic Nerve Activity and Blood Pressure in Ambulatory Dogs(Elsevier, 2014-02) Hellyer, Jessica; Akingba, A. George; Rhee, Kyoung-Suk; Tan, Alex Y.; Lane, Kathleen A.; Shen, Changyu; Patel, Jheel; Fishbein, Michael C; Chen, Peng-Sheng; Department of Medicine, IU School of MedicineBackground The relationship between cardiac autonomic nerve activity and blood pressure (BP) changes in ambulatory dogs is unclear. Objective To test the hypotheses that simultaneous termination of stellate ganglion nerve activity (SGNA) and vagal nerve activity (VNA) predisposes to spontaneous orthostatic hypotension and that specific β2 adrenoceptor blockade prevents the hypotensive episodes. Methods We used a radiotransmitter to record SGNA, VNA and blood pressure (BP) in 8 ambulatory dogs. Video imaging was used to document postural changes. Results Out of these 8 dogs, 5 showed simultaneous sympathovagal discharges in which the minute by minute integrated SGNA correlated with integrated VNA in a linear pattern (“Group 1”). In these dogs abrupt termination of simultaneous SGNA-VNA at the time of postural changes (as documented by video imaging) was followed by abrupt (>20 mmHg over 4 beats) drops in BP. Dogs without simultaneous on/off firing (“Group 2”) did not have drastic drops in pressure. ICI 118,551 (ICI, a specific β2-blocker) infused at 3.1 µg/kg/hr for 7 days significantly increased BP from 126 (95% confidence interval, CI: 118 to 133) mmHg to 133 (95% CI 125 to141) mmHg (p=0.0001). The duration of hypotension (mean systolic BP < 100 mmHg) during baseline accounted for 7.1% of the recording. The percentage was reduced by ICI to 1.3% (p = 0.01). Conclusions Abrupt simultaneous termination of SGNA-VNA was observed at the time of orthostatic hypotension in ambulatory dogs. Selective β2 adrenoceptor blockade increased BP and reduced the duration of hypotension in this model.Item Chronic Low-Level Vagus Nerve Stimulation Reduces Stellate Ganglion Nerve Activity and Paroxysmal Atrial Tachyarrhythmias in Ambulatory Canines(Office of the Vice Chancellor for Research, 2011-04-08) Shen, Mark J.; Shinohara, Tetsuji; Park, Hyung-Wook; Frick, Kyle; Ice, Daniel S.; Choi, Eue-Keun; Han, Seongwook; Sharma, Rahul; Shen, Changyu; Fishbein, Michael C.; Chen, Lan S.; Lopshire, John C.; Zipes, Douglas P.; Lin, Shien-Fong; Chen, Peng-ShengIntroduction: Left sided low-level vagus nerve stimulation (LL-VNS) is used clinically for epilepsy and depression. We hypothesize that LL-VNS can suppress sympathetic outflow and reduce atrial tachyarrhythmias in ambulatory dogs. Methods: We implanted in 12 dogs a neurostimulator in left cervical vagus nerve and a radiotransmitter for continuous recording of left stellate ganglion nerve activities (SGNA), left thoracic vagal nerve activities (VNA) and electrocardiograms. The first 6 dogs (Group 1) underwent 1 week continuous LL-VNS. Another 6 dogs (Group 2) underwent intermittent rapid atrial pacing followed by active or sham LL-VNS on alternate weeks. Results: Integrated SGNA was significantly reduced during LL-VNS (7.8±0.9 mV-s vs. 9.4±0.9 mVs at baseline, P<0.05) in Group 1.The reduction was most apparent from 7 to 9 AM, (31% reduction, 10.8±2.5 mV-s versus 15.6±2.9 mV-s at baseline, P<0.01), along with a significantly reduced heart rate (P<0.05). SGNA-induced heart rate acceleration averaged 107.9±9.0 bpm during LL-VNS and 129.2±9.3 bpm at baseline (P<0.05). LL-VNS did not change VNA. The tyrosine hydroxylase-positive nerve structures in the left stellate ganglion were 99,684±22,257 µm2/mm2 in LL-VNS dogs and 186,561±11,383 µm2/mm2 (P<0.01) in normal control dogs. In Group 2, the frequencies of paroxysmal atrial fibrillation and atrial tachycardia during active LLVNS were 1.4±2.5/d and 8.0±5.8/d, respectively, significantly lower than during sham stimulation (9.2±6.2/d, P<0.01 and 22.0±4.4/d, P<0.001, respectively). Conclusion: LL-VNS suppresses SGNA and reduces the incidences of paroxysmal atrial tachyarrhythmias in ambulatory dogs. Significant neural remodeling of the left stellate ganglion is evident one week after cessation of chronic LL-VNS.Item Clinical characteristics and 12-month outcomes of patients with valvular and non-valvular atrial fibrillation in Kenya(PLOS, 2017-09-21) Temu, Tecla M.; Lane, Kathleen A.; Shen, Changyu; Ng'ang'a, Loise; Akwanalo, Constantine O.; Chen, Peng-Sheng; Emonyi, Wilfred; Heckbert, Susan R.; Koech, Myra M.; Manji, Imran; Vatta, Matteo; Velazquez, Eric J.; Wessel, Jennifer; Kimaiyo, Sylvester; Inui, Thomas S.; Bloomfield, Gerald S.; Biostatistics, School of Public HealthBackground Atrial fibrillation (AF) is a major contributor to the global cardiovascular disease burden. The clinical profile and outcomes of AF patients with valvular heart diseases in sub-Saharan Africa (SSA) have not been adequately described. We assessed clinical features and 12-month outcomes of patients with valvular AF (vAF) in comparison to AF patients without valvular heart disease (nvAF) in western Kenya. Methods We performed a cohort study with retrospective data gathering to characterize risk factors and prospective data collection to characterize their hospitalization, stroke and mortality rates. Results The AF patients included 77 with vAF and 69 with nvAF. The mean (SD) age of vAF and nvAF patients were 37.9(14.5) and 69.4(12.3) years, respectively. There were significant differences (p<0.001) between vAF and nvAF patients with respect to female sex (78% vs. 55%), rates of hypertension (29% vs. 73%) and heart failure (10% vs. 49%). vAF patients were more likely to be taking anticoagulation therapy compared to those with nvAF (97% vs. 76%; p<0.01). After 12-months of follow-up, the overall mortality, hospitalization and stroke rates for vAF patients were high, at 10%, 34% and 5% respectively, and were similar to the rates in the nvAF patients (15%, 36%, and 5%, respectively). Conclusion Despite younger age and few comorbid conditions, patients with vAF in this developing country setting are at high risk for nonfatal and fatal outcomes, and are in need of interventions to improve short and long-term outcomes.Item Complex Arrhythmia Syndrome in a Knock-In Mouse Model Carrier of the N98S Calm1 Mutation(American Heart Association, 2020) Tsai, Wen-Chin; Guo, Shuai; Olaopa, Michael A.; Field, Loren J.; Yang, Jin; Shen, Changyu; Chang, Ching-Pin; Chen, Peng-Sheng; Rubart, Michael; Medicine, School of MedicineBackground: Calmodulin mutations are associated with arrhythmia syndromes in humans. Exome sequencing previously identified a de novo mutation in CALM1 resulting in a p.N98S substitution in a patient with sinus bradycardia and stress-induced bidirectional ventricular ectopy. The objectives of the present study were to determine if mice carrying the N98S mutation knocked into Calm1 replicate the human arrhythmia phenotype and to examine arrhythmia mechanisms. Methods: Mouse lines heterozygous for the Calm1N98S allele (Calm1N98S/+) were generated using CRISPR/Cas9 technology. Adult mutant mice and their wildtype littermates (Calm1+/+) underwent electrocardiographic monitoring. Ventricular de- and repolarization was assessed in isolated hearts using optical voltage mapping. Action potentials and whole-cell currents and [Ca2+]i, as well, were measured in single ventricular myocytes using the patch-clamp technique and fluorescence microscopy, respectively. The microelectrode technique was used for in situ membrane voltage monitoring of ventricular conduction fibers. Results: Two biologically independent knock-in mouse lines heterozygous for the Calm1N98S allele were generated. Calm1N98S/+ mice of either sex and line exhibited sinus bradycardia, QTc interval prolongation, and catecholaminergic bidirectional ventricular tachycardia. Male mutant mice also showed QRS widening. Pharmacological blockade and activation of β-adrenergic receptors rescued and exacerbated, respectively, the long-QT phenotype of Calm1N98S/+ mice. Optical and electric assessment of membrane potential in isolated hearts and single left ventricular myocytes, respectively, revealed β-adrenergically induced delay of repolarization. β-Adrenergic stimulation increased peak density, slowed inactivation, and left-shifted the activation curve of ICa.L significantly more in Calm1N98S/+ versus Calm1+/+ ventricular myocytes, increasing late ICa.L in the former. Rapidly paced Calm1N98S/+ ventricular myocytes showed increased propensity to delayed afterdepolarization-induced triggered activity, whereas in situ His-Purkinje fibers exhibited increased susceptibility for pause-dependent early afterdepolarizations. Epicardial mapping of Calm1N98S/+ hearts showed that both reentry and focal mechanisms contribute to arrhythmogenesis. Conclusions: Heterozygosity for the Calm1N98S mutation is causative of an arrhythmia syndrome characterized by sinus bradycardia, QRS widening, adrenergically mediated QTc interval prolongation, and bidirectional ventricular tachycardia. β-Adrenergically induced ICa.L dysregulation contributes to the long-QT phenotype. Pause-dependent early afterdepolarizations and tachycardia-induced delayed afterdepolarizations originating in the His-Purkinje network and ventricular myocytes, respectively, constitute potential sources of arrhythmia in Calm1N98S/+ hearts.Item Computer-generated reminders and quality of pediatric HIV care in a resource-limited setting(American Academy of Pediatrics (AAP), 2013-03) Were, Martin C.; Nyandiko, Winstone M.; Huang, Kristin T. L.; Slaven, James E.; Shen, Changyu; Tierney, William M.; Vreeman, Rachel C.; Department of Medicine, IU School of MedicineOBJECTIVES: To evaluate the impact of clinician-targeted computer-generated reminders on compliance with HIV care guidelines in a resource-limited setting. METHODS: We conducted this randomized, controlled trial in an HIV referral clinic in Kenya caring for HIV-infected and HIV-exposed children (<14 years of age). For children randomly assigned to the intervention group, printed patient summaries containing computer-generated patient-specific reminders for overdue care recommendations were provided to the clinician at the time of the child's clinic visit. For children in the control group, clinicians received the summaries, but no computer-generated reminders. We compared differences between the intervention and control groups in completion of overdue tasks, including HIV testing, laboratory monitoring, initiating antiretroviral therapy, and making referrals. RESULTS: During the 5-month study period, 1611 patients (49% female, 70% HIV-infected) were eligible to receive at least 1 computer-generated reminder (ie, had an overdue clinical task). We observed a fourfold increase in the completion of overdue clinical tasks when reminders were availed to providers over the course of the study (68% intervention vs 18% control, P < .001). Orders also occurred earlier for the intervention group (77 days, SD 2.4 days) compared with the control group (104 days, SD 1.2 days) (P < .001). Response rates to reminders varied significantly by type of reminder and between clinicians. CONCLUSIONS: Clinician-targeted, computer-generated clinical reminders are associated with a significant increase in completion of overdue clinical tasks for HIV-infected and exposed children in a resource-limited setting.Item Design and rationale of the high-sensitivity Troponin T Rules Out Acute Cardiac Insufficiency Trial(Dove Press, 2017-05-18) Hunter, Benton R.; Collins, Sean P.; Fermann, Gregory J.; Levy, Phillip D.; Shen, Changyu; Ayaz, Syed Imran; Cole, Mette L.; Miller, Karen F.; Soliman, Adam A.; Pang, Peter S.; Emergency Medicine, School of MedicineBACKGROUND: Acute heart failure (AHF) is a common presentation in the Emergency Department (ED), and most patients are admitted to the hospital. Identification of patients with AHF who have a low risk of adverse events and are suitable for discharge from the ED is difficult, and an objective tool would be useful. METHODS: The highly sensitive Troponin T Rules Out Acute Cardiac Insufficiency Trial (TACIT) will enroll ED patients being treated for AHF. Patients will undergo standard ED evaluation and treatment. High-sensitivity troponin T (hsTnT) will be drawn at the time of enrollment and 3 hours after the initial draw. The initial hsTnT draw will be no more than 3 hours after initiation of therapy for AHF (vasodilator, loop diuretic, noninvasive ventilation). Treating clinicians will be blinded to hsTnT results. We will assess whether hsTnT, as a single measurement or in series, can accurately predict patients at low risk of short-term adverse events. CONCLUSION: TACIT will explore the value of hsTnT measurements in isolation, or in combination with other markers of disease severity, for the identification of ED patients with AHF who are at low risk of short-term adverse events.