Browsing by Author "Chen, Peng-Sheng"

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    Advancing Research on the Complex Interrelations between Atrial fibrillation and Heart Failure: A Report from a National Heart, Lung, and Blood Institute Virtual Workshop
    (American Heart Association, 2020-06-09) Al-Khatib, Sana M.; Benjamin, Emelia J.; Albert, Christine M.; Alonso, Alvaro; Chauhan, Cynthia; Chen, Peng-Sheng; Curtis, Anne B.; Desvigne-Nickens, Patrice; Ho, Jennifer E.; Lam, Carolyn S.P.; Link, Mark S.; Patton, Kristen K.; Redfield, Margaret M.; Rienstra, Michiel; Rosenberg, Yves; Schnabel, Renate; Spertus, John A.; Warner Stevenson, Lynne; Hills, Mellanie True; Voors, Adriaan A.; Cooper, Lawton S.; Go, Alan S.; Medicine, School of Medicine
    The interrelationships between atrial fibrillation (AF) and heart failure (HF) are complex and poorly understood, yet the number of patients with AF and HF continues to increase worldwide. Thus, there is a need for initiatives that prioritize research on the intersection between AF and HF. This report summarizes the proceedings of a virtual workshop convened by the National Heart, Lung, and Blood Institute to identify important research opportunities in AF and HF. Key knowledge gaps were reviewed and research priorities were proposed for characterizing the pathophysiological overlap and deleterious interactions between AF and HF; preventing HF in persons with AF; preventing AF in individuals with HF; and addressing symptom burden and health status outcomes in AF and HF. These research priorities will hopefully help inform, encourage, and stimulate innovative, cost-efficient, and transformative studies to enhance the outcomes of patients with AF and HF.
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    Amiodarone Inhibits Apamin-Sensitive Potassium Currents
    (Public Library of Science, 2013-07-29) Turker, Isik; Yu, Chih-Chieh; Chang, Po-Cheng; Chen, Zhenhui; Sohma, Yoshiro; Lin, Shien-Fong; Chen, Peng-Sheng; Ai, Tomohiko; Medicine, School of Medicine
    Background: Apamin sensitive potassium current (I KAS), carried by the type 2 small conductance Ca(2+)-activated potassium (SK2) channels, plays an important role in post-shock action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (VF) in failing ventricles. Objective: To test the hypothesis that amiodarone inhibits I KAS in human embryonic kidney 293 (HEK-293) cells. Methods: We used the patch-clamp technique to study I KAS in HEK-293 cells transiently expressing human SK2 before and after amiodarone administration. Results: Amiodarone inhibited IKAS in a dose-dependent manner (IC50, 2.67 ± 0.25 µM with 1 µM intrapipette Ca(2+)). Maximal inhibition was observed with 50 µM amiodarone which inhibited 85.6 ± 3.1% of IKAS induced with 1 µM intrapipette Ca(2+) (n = 3). IKAS inhibition by amiodarone was not voltage-dependent, but was Ca(2+)-dependent: 30 µM amiodarone inhibited 81.5±1.9% of I KAS induced with 1 µM Ca(2+) (n = 4), and 16.4±4.9% with 250 nM Ca(2+) (n = 5). Desethylamiodarone, a major metabolite of amiodarone, also exerts voltage-independent but Ca(2+) dependent inhibition of I KAS. Conclusion: Both amiodarone and desethylamiodarone inhibit I KAS at therapeutic concentrations. The inhibition is independent of time and voltage, but is dependent on the intracellular Ca(2+) concentration. SK2 current inhibition may in part underlie amiodarone's effects in preventing electrical storm in failing ventricles.
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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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    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 Medicine
    Background 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.
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    Apamin Does Not Inhibit Human Cardiac Na+ Current, L-type Ca2+ Current or Other Major K+ Currents
    (Public Library of Science, 2014-05-05) Yu, Chih-Chieh; Ai, Tomohiko; Weiss, James N.; Chen, Peng-Sheng; Medicine, School of Medicine
    Background: Apamin is commonly used as a small-conductance Ca2+-activated K+ (SK) current inhibitor. However, the specificity of apamin in cardiac tissues remains unclear. Objective: To test the hypothesis that apamin does not inhibit any major cardiac ion currents. Methods: We studied human embryonic kidney (HEK) 293 cells that expressed human voltage-gated Na+, K+ and Ca2+ currents and isolated rabbit ventricular myocytes. Whole-cell patch clamp techniques were used to determine ionic current densities before and after apamin administration. Results: Ca2+ currents (CACNA1c+CACNB2b) were not affected by apamin (500 nM) (data are presented as median [25th percentile;75th percentile] (from -16 [-20;-10] to -17 [-19;-13] pA/pF, P = NS), but were reduced by nifedipine to -1.6 [-3.2;-1.3] pA/pF (p = 0.008). Na+ currents (SCN5A) were not affected by apamin (from -261 [-282;-145] to -268 [-379;-132] pA/pF, P = NS), but were reduced by flecainide to -57 [-70;-47] pA/pF (p = 0.018). None of the major K+ currents (IKs, IKr, IK1 and Ito) were inhibited by 500 nM of apamin (KCNQ1+KCNE1, from 28 [20]; [37] to 23 [18]; [32] pA/pF; KCNH2+KCNE2, from 28 [24]; [30] to 27 [24]; [29] pA/pF; KCNJ2, from -46 [-48;-40] to -46 [-51;-35] pA/pF; KCND3, from 608 [505;748] to 606 [454;684]). Apamin did not inhibit the INa or ICaL in isolated rabbit ventricular myocytes (INa, from -67 [-75;-59] to -68 [-71;-59] pA/pF; ICaL, from -16 [-17;-14] to -14 [-15;-13] pA/pF, P = NS for both). Conclusions: Apamin does not inhibit human cardiac Na+ currents, L-type Ca2+ currents or other major K+ currents. These findings indicate that apamin is a specific SK current inhibitor in hearts as well as in other organs.
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    Apamin Induces Early Afterdepolarizations and Torsades de Pointes Ventricular Arrhythmia From Failing Rabbit Ventricles Exhibiting Secondary Rises in Intracellular Calcium
    (Elsevier, 2013) Chang, Po-Cheng; Hsieh, Yu-Cheng; Hsueh, Chia-Hsiang; Weiss, James N.; Lin, Shien-Fong; Chen, Peng-Sheng; Medicine, School of Medicine
    Background: A secondary rise of intracellular Ca(2+) (Cai) and an upregulation of apamin-sensitive K(+) current (I(KAS)) are characteristic findings of failing ventricular myocytes. We hypothesize that apamin, a specific I(KAS) blocker, may induce torsades de pointes (TdP) ventricular arrhythmia from failing ventricles exhibiting secondary rises of Cai. Objective: To test the hypothesis that small conductance Ca(2+) activated IKAS maintains repolarization reserve and prevents ventricular arrhythmia in a rabbit model of heart failure (HF). Methods: We performed Langendorff perfusion and optical mapping studies in 7 hearts with pacing-induced HF and in 5 normal control rabbit hearts. Atrioventricular block was created by cryoablation to allow pacing at slow rates. Results: The left ventricular ejection fraction reduced from 69.1% [95% confidence interval 62.3%-76.0%] before pacing to 30.4% [26.8%-34.0%] (N = 7; P < .001) after pacing. The corrected QT interval in failing ventricles was 337 [313-360] ms at baseline and 410 [381-439] ms after applying 100 nmol/L of apamin (P = .01). Apamin induced early afterdepolarizations (EADs) in 6 ventricles, premature ventricular beats (PVBs) in 7 ventricles, and polymorphic ventricular tachycardia consistent with TdP in 4 ventricles. The earliest activation site of EADs and PVBs always occurred at the site with long action potential duration and large amplitude of the secondary rises of Ca(i). Apamin induced secondary rises of Ca(i) in 1 nonfailing ventricle, but no EAD or TdP were observed. Conclusions: In HF ventricles, apamin induces EADs, PVBs, and TdP from areas with secondary rises of Ca(i). I(KAS) is important in maintaining repolarization reserve and preventing TdP in HF ventricles.
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    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 Medicine
    Introduction 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.
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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.
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    Atrial fibrillation and electrophysiology in transgenic mice with cardiac-restricted overexpression of FKBP12
    (American Physiological Society, 2019-02-01) Pan, Zhenwei; Ai, Tomohiko; Chang, Po-Cheng; Liu, Ying; Liu, Jijia; Maruyama, Mitsunori; Homsi, Mohamed; Fishbein, Michael C.; Rubart, Michael; Lin, Shien-Fong; Xiao, Deyong; Chen, Hanying; Chen, Peng-Sheng; Shou, Weinian; Li, Bai-Yan; Medicine, School of Medicine
    Cardiomyocyte-restricted overexpression of FK506-binding protein 12 transgenic (αMyHC-FKBP12) mice develop spontaneous atrial fibrillation (AF). The aim of the present study is to explore the mechanisms underlying the occurrence of AF in αMyHC-FKBP12 mice. Spontaneous AF was documented by telemetry in vivo and Langendorff-perfused hearts of αMyHC-FKBP12 and littermate control mice in vitro. Atrial conduction velocity was evaluated by optical mapping. The patch-clamp technique was applied to determine the potentially altered electrophysiology in atrial myocytes. Channel protein expression levels were evaluated by Western blot analyses. Spontaneous AF was recorded in four of seven αMyHC-FKBP12 mice but in none of eight nontransgenic (NTG) controls. Atrial conduction velocity was significantly reduced in αMyHC-FKBP12 hearts compared with NTG hearts. Interestingly, the mean action potential duration at 50% but not 90% was significantly prolonged in αMyHC-FKBP12 atrial myocytes compared with their NTG counterparts. Consistent with decreased conduction velocity, average peak Na+ current ( INa) density was dramatically reduced and the INa inactivation curve was shifted by approximately +7 mV in αMyHC-FKBP12 atrial myocytes, whereas the activation and recovery curves were unaltered. The Nav1.5 expression level was significantly reduced in αMyHC-FKBP12 atria. Furthermore, we found increases in atrial Cav1.2 protein levels and peak L-type Ca2+ current density and increased levels of fibrosis in αMyHC-FKBP12 atria. In summary, cardiomyocyte-restricted overexpression of FKBP12 reduces the atrial Nav1.5 expression level and mean peak INa, which is associated with increased peak L-type Ca2+ current and interstitial fibrosis in atria. The combined electrophysiological and structural changes facilitated the development of local conduction block and altered action potential duration and spontaneous AF. NEW & NOTEWORTHY This study addresses a long-standing riddle regarding the role of FK506-binding protein 12 in cardiac physiology. The work provides further evidence that FK506-binding protein 12 is a critical component for regulating voltage-gated sodium current and in so doing has an important role in arrhythmogenic physiology, such as atrial fibrillation.
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    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 Medicine
    Background 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.