Browsing by Author "Hsueh, Chia-Hsiang"

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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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    Cervical vagal nerve stimulation activates the stellate ganglion in ambulatory dogs
    (Synapse, 2015-03-24) Rhee, Kyoung-Suk; Hsueh, Chia-Hsiang; Hellyer, Jessica A.; Park, Hyung Wook; Lee, Young Soo; Garlie, Jason; Onkka, Patrick; Doytchinova, Anisiia T.; Garner, John B.; Patel, Jheel; Chen, Lan S.; Fishbein, Michael C.; Everett 4th, Thomas; Lin, Shien-Fong; Chen, Peng-Sheng; Department of Neurology, IU School of Medicine
    BACKGROUND AND OBJECTIVES: Recent studies showed that, in addition to parasympathetic nerves, cervical vagal nerves contained significant sympathetic nerves. We hypothesized that cervical vagal nerve stimulation (VNS) may capture the sympathetic nerves within the vagal nerve and activate the stellate ganglion. MATERIALS AND METHODS: We recorded left stellate ganglion nerve activity (SGNA), left thoracic vagal nerve activity (VNA), and subcutaneous electrocardiogram in seven dogs during left cervical VNS with 30 seconds on-time and 30 seconds off time. We then compared the SGNA between VNS on and off times. RESULTS: Cervical VNS at moderate (0.75 mA) output induced large SGNA, elevated heart rate (HR), and reduced HR variability, suggesting sympathetic activation. Further increase of the VNS output to >1.5 mA increased SGNA but did not significantly increase the HR, suggesting simultaneous sympathetic and parasympathetic activation. The differences of integrated SGNA and integrated VNA between VNS on and off times (ΔSGNA) increased progressively from 5.2 mV-s {95% confidence interval (CI): 1.25-9.06, p=0.018, n=7} at 1.0 mA to 13.7 mV-s (CI: 5.97-21.43, p=0.005, n=7) at 1.5 mA. The difference in HR (ΔHR, bpm) between on and off times was 5.8 bpm (CI: 0.28-11.29, p=0.042, n=7) at 1.0 mA and 5.3 bpm (CI 1.92 to 12.61, p=0.122, n=7) at 1.5 mA. CONCLUSION: Intermittent cervical VNS may selectively capture the sympathetic components of the vagal nerve and excite the stellate ganglion at moderate output. Increasing the output may result in simultaneously sympathetic and parasympathetic capture.
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    Curve-Fitting the Intracellular Calcium Dynamics
    (Taiwan Society of Cardiology, 2013-07) Lin, Shien-Fong; Hsueh, Chia-Hsiang; Department of Medicine, IU School of Medicine
    "No one believes modeling results except the one who performed the calculation; ...everyone believes the experimental results except the one who did the measurements." P. J. Roache - Computational Physicist.
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    Pathogenesis of Arrhythmias in a Model of CKD
    (American Society of Nephrology (ASN), 2014-12-01) Hsueh, Chia-Hsiang; Chen, Neal X.; Lin, Shien-Fong; Chen, Peng-Sheng; Gattone, Vincent H.; Allen, Matthew R.; Fishbein, Michael C.; Moe, Sharon M.; Department of Medicine, IU School of Medicine
    Patients with CKD have an increased risk of cardiovascular mortality from arrhythmias and sudden cardiac death. We used a rat model of CKD (Cy/+) to study potential mechanisms of increased ventricular arrhythmias. Rats with CKD showed normal ejection fraction but hypertrophic myocardium. Premature ventricular complexes occurred more frequently in CKD rats than normal rats (42% versus 11%, P=0.18). By optical mapping techniques, action potential duration (APD) at 80% of repolarization was longer in CKD rats (78±4ms) than normal rats (63±3 ms, P<0.05) at a 200-ms pacing cycle length. Calcium transient (CaT) duration was comparable. Pacing cycle length thresholds to induce CaT alternans or APD alternans were longer in CKD rats than normal rats (100±7 versus 80±3 ms and 93±6 versus 76±4 ms for CaT and APD alternans, respectively, P<0.05), suggesting increased vulnerability to ventricular arrhythmia. Ventricular fibrillation was induced in 9 of 12 CKD rats and 2 of 9 normal rats (P<0.05); early afterdepolarization occurred in two CKD rats but not normal rats. The mRNA levels of TGF-β, microRNA-21, and sodium calcium-exchanger type 1 were upregulated, whereas the levels of microRNA-29, L-type calcium channel, sarco/endoplasmic reticulum calcium–ATPase type 2a, Kv1.4, and Kv4.3 were downregulated in CKD rats. Cardiac fibrosis was mild and not different between groups. We conclude that cardiac ion channel and calcium handling are abnormal in CKD rats, leading to increased vulnerability to early afterdepolarization, triggered activity, and ventricular arrhythmias.
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    Small conductance calcium-activated potassium current and the mechanism of atrial arrhythmia in mice with dysfunctional melanocyte-like cells
    (Elsevier, 2016-07) Tsai, Wei-Chung; Chan, Yi-Hsin; Hsueh, Chia-Hsiang; Everett, Thomas H., IV; Chang, Po-Cheng; Choi, Eue-Keun; Olaopa, Michael A.; Lin, Shien-Fong; Shen, Changyu; Kudela, Maria Aleksandra; Rubart-von der Lohe, Michael; Chen, Zhenhui; Jadiya, Pooja; Tomar, Dhanendra; Luvison, Emily; Anzalone, Nicholas; Anzalone, Nicholas; Patel, Vickas V.; Chen, Peng-Sheng; Medicine, School of Medicine
    BACKGROUND: The melanin synthesis enzyme dopachrome tautomerase (Dct) regulates intracellular Ca(2+) in melanocytes. Homozygous Dct knockout (Dct(-/-)) adult mice are vulnerable to atrial arrhythmias (AA). OBJECTIVE: The purpose of this study was to determine whether apamin-sensitive small conductance Ca(2+)-activated K(+) (SK) currents are upregulated in Dct(-/-) mice and contribute to AA. METHODS: Optical mapping was used to study the membrane potential of the right atrium in Langendorff perfused Dct(-/-) (n = 9) and Dct(+/-) (n = 9) mice. RESULTS: Apamin prolonged action potential duration (APD) by 18.8 ms (95% confidence interval [CI] 13.4-24.1 ms) in Dct(-/-) mice and by 11.5 ms (95% CI 5.4-17.6 ms) in Dct(+/-) mice at a pacing cycle length of 150 ms (P = .047). The pacing cycle length threshold to induce APD alternans was 48 ms (95% CI 34-62 ms) for Dct(-/-) mice and 21 ms (95% CI 12-29 ms) for Dct(+/-) mice (P = .002) at baseline, and it was 35 ms (95% CI 21-49 ms) for Dct(-/-) mice and 22 ms (95% CI 11-32 ms) for Dct(+/-) mice (P = .025) after apamin administration. Apamin prolonged post-burst pacing APD by 8.9 ms (95% CI 3.9-14.0 ms) in Dct(-/-) mice and by 1.5 ms (95% CI 0.7-2.3 ms) in Dct(+/-) mice (P = .005). Immunoblot and quantitative polymerase chain reaction analyses showed that protein and transcripts levels of SK1 and SK3 were increased in the right atrium of Dct(-/-) mice. AA inducibility (89% vs 11%; P = .003) and duration (281 seconds vs 66 seconds; P = .008) were greater in Dct(-/-) mice than in Dct(+/-) mice at baseline, but not different (22% vs 11%; P = 1.00) after apamin administration. Five of 8 (63%) induced atrial fibrillation episodes in Dct(-/-) mice had focal drivers. CONCLUSION: Apamin-sensitive SK current upregulation in Dct(-/-) mice plays an important role in the mechanism of AA.
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    Utilizing Multiple in Silico Analyses to Identify Putative Causal SCN5A Variants in Brugada Syndrome
    (Springer Nature, 2014-01-27) Juang, Jyh-Ming Jimmy; Lu, Tzu-Pin; Lai, Liang-Chuan; Hsueh, Chia-Hsiang; Liu, Yen-Bin; Tsai, Chia-Ti; Lin, Lian-Yu; Yu, Chih-Chieh; Hwang, Juey-Jen; Chiang, Fu-Tien; Yeh, Sherri Shih-Fan; Chen, Wen-Pin; Chuang, Eric Y.; Lai, Ling-Ping; Lin, Jiunn-Lee; Medicine, School of Medicine
    Brugada syndrome (BrS) is an inheritable sudden cardiac death disease mainly caused by SCN5A mutations. Traditional approaches can be costly and time-consuming if all candidate variants need to be validated through in vitro studies. Therefore, we developed a new approach by combining multiple in silico analyses to predict functional and structural changes of candidate SCN5A variants in BrS before conducting in vitro studies. Five SCN5A non-synonymous variants (1651G>A, 1776C>G, 1673A>G, 3269C>T and 3578G>A) were identified in 14 BrS patients using direct DNA sequencing. Several bioinformatics algorithms were applied and predicted that 1651G>A (A551T) and 1776C>G (N592K) were high-risk SCN5A variants (odds ratio 59.59 and 23.93). The results were validated by Mass spectrometry and in vitro electrophysiological assays. We concluded that integrating sequence-based information and secondary protein structures elements may help select highly potential variants in BrS before conducting time-consuming electrophysiological studies and two novel SCN5A mutations were validated.