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
(2013-10-01)
Chang, Po-Cheng
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Hsieh, Yu-Cheng
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Hsueh, Chia-Hsiang
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Weiss, James N.
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Lin, Shien-Fong
BACKGROUND A secondary rise of intracellular Ca2+ (Ca) and an upregulation of apamin-sensitive K+ current (I-KAs) are characteristic findings of failing ventricular myocytes. We hypothesize that apamin, a specific IKAs Mocker, may induce torsades de pointes (TdP) ventricular arrhythmia from failing ventricles exhibiting secondary rises of Ca,. OBJECTIVE To test the hypothesis that small conductance Ca2+ activated Los 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,. Apamin induced secondary rises of Ca, 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,. IKAs is important in maintaining repolarization reserve and preventing TdP in HF ventricles.
Differential effects of SKCa blockade on arrhythmogenesis in normal and remodeled hearts
(2015-01-01)
Hsueh, Chia-Hsiang
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Chen, Peng-Sheng
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Lin, Shien-Fong
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分子醫學與生物工程研究所
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Institute of Molecular Medicine and Bioengineering
Small conductance calcium-activated potassium current and the mechanism of atrial arrhythmia in mice with dysfunctional melanocyte-like cells
(2016-07)
Tsai, Wei-Chung
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Chan, Yi-Hsin
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Hsueh, Chia-Hsiang
;
Everett, Thomas H.
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Chang, Po-Cheng
BACKGROUND The melanin synthesis enzyme dopachrome tautomerase (Dct) regulates intracellular Ca2+ 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 Ca2+-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.