Browsing by Author "Chang, Po-Cheng"

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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.
LCZ696 Therapy Reduces Ventricular Tachyarrhythmia Inducibility in a Myocardial Infarction-Induced Heart Failure Rat Model
(2019-01-01)
Chang, Po-Cheng
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Lin, Shien-Fong
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Chu, Yen
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Wo, Hung-Ta
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Lee, Hui-Ling
Background. LCZ696 (valsartan/sacubitril) therapy significantly reduced mortality in patients with heart failure (HF). Although a clinical trial (PARADISE-MI Trial) has been ongoing to examine the effects of LCZ696 in myocardial infarction (MI) patients, the effects of LCZ696 on remodeling of cardiac electrophysiology in animal models remain largely unclear. Methods. We performed coronary artery ligation to create MI in Sprague-Dawley rats. Echocardiography was performed one week after MI to confirm the development of HF with left ventricular ejection fraction <= 40%. MI rats were randomly assigned to receive medical therapy for 4 weeks: LCZ696, enalapril, or vehicle. The sham-operation rats received sham operation without MI creation. In vivo electrophysiological exams were performed under general anesthesia. Western blot analyses were conducted to quantify ion channel proteins. Results. The HF-vehicle group did not show significant changes in LVEF. Both enalapril and LCZ696 therapy significantly improved LVEF. The HF-vehicle group had higher ventricular arrhythmia (VA) inducibility than the sham group. As compared with the HF-vehicle group, LCZ696 therapy significantly reduced VA inducibility, but enalapril therapy did not. Western blot analyses showed significant downregulation of NaV1.5, ERG, KCNE1, and KCNE2 channel proteins in the HF vehicle group compared with the sham group. LCZ696 therapy upregulated protein expression of ERG, KCNE1, and KCNE2. Conclusion. As compared with enalapril therapy, LCZ696 therapy led to improvement of LVEF, reduced VA inducibility, and upregulated expression of K+ channel proteins.
Paradoxical Effects of Sodium-Calcium Exchanger Inhibition on Torsade de Pointes and Early Afterdepolarization in a Heart Failure Rabbit Model
(2018-08-01)
Chang, Po-Cheng
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Lu, Yu-Ying
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Lee, Hui-Ling
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Lin, Shien-Fong
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Chu, Yen
Calcium homeostasis plays an important role in development of early afterdepolarizations (EADs) and torsade de pointes (TdP). The role of sodium-calcium exchanger (NCX) inhibition in genesis of secondary Ca2+ rise and EAD-TdP is still debated. Dual voltage and intracellular Ca2+ optical mapping were conducted in 6 control and 9 failing rabbit hearts. After baseline electrophysiological and optical mapping studies, E4031 was given to simulate long QT syndrome. ORM-10103 was then administrated to examine the electrophysiological effects on EAD-TdP development. E4031 enhanced secondary Ca2+ rise, EADs development, and TdP inducibility in both control and failing hearts. The results showed that ORM-10103 reduced premature ventricular beats but was unable to suppress the inducibility of TdP or EADs. The electrophysiological effects of ORM-10103 included prolongation of action potential duration (APD) and increased APD heterogeneity in failing hearts. ORM-10103 had a neutral effect on the amplitude of secondary Ca-1 rise in control and heart failure groups. In this model, most EADs generated from long-short APD junction area. In conclusion, highly selective NCX inhibition with ORM-10103 reduced premature ventricular beat burden but was unable to suppress secondary Ca2+ rise, EADs development, or inducibility of TdP. The possible electrophysiological mechanisms include APD prolongation and increased APD heterogeneity.
Role of Sarcoplasmic Reticulum Calcium in Development of Secondary Calcium Rise and Early Afterdepolarizations in Long QT Syndrome Rabbit Model
(2015-04-13)
Chang, Po-Cheng
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Wo, Hung-Ta
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Lee, Hui-Ling
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Lin, Shien-Fong
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Wen, Ming-Shien
Background L-type calcium current reactivation plays an important role in development of early afterdepolarizations (EADs) and torsades de pointes (TdP). Secondary intracellular calcium (Ca-i) rise is associated with initiation of EADs. Objective To test whether inhibition of sarcoplasmic reticulum (SR) Ca2+ cycling suppresses secondary Ca-i rise and genesis of EADs. Methods Langendorff perfusion and dual voltage and Cai optical mapping were conducted in 10 rabbit hearts. Atrioventricular block (AVB) was created by radiofrequency ablation. After baseline studies, E4031, SR Ca2+ cycling inhibitors (ryanodine plus thapsigargin) and nifedipine were then administrated subsequently, and the protocols were repeated. Results At baseline, there was no spontaneous or pacing-induced TdP. After E4031 administration, action potential duration (APD) was significantly prolonged and the amplitude of secondary Cai rise was enhanced, and 7 (70%) rabbits developed spontaneous or pacing-induced TdP. In the presence of ryanodine plus thapsigargin, TdP inducibility was significantly reduced (2 hearts, 20%, p = 0.03). Although APD was significantly prolonged (from 298 +/- 30 ms to 457 +/- 75 ms at pacing cycle length of 1000 m, p = 0.007) by ryanodine plus thapsigargin, the secondary Ca-i rise was suppressed ( from 8.8 +/- 2.6% to 1.2 +/- 0.9%, p = 0.02). Nifedipine inhibited TdP inducibility in all rabbit hearts. Conclusion In this AVB and long QT rabbit model, inhibition of SR Ca2+ cycyling reduces the inducibility of TdP. The mechanism might be suppression of secondary Ca-i rise and genesis of EADs.
Roles of impaired intracellular calcium cycling in arrhythmogenicity of diabetic mouse model
(2017-10-01)
Chou, Chung-Chuan
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Ho, Chien-Te
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Lee, Hui-Ling
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Chu, Yen
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Yen, Tzung-Hai
BackgroundDiabetes mellitus is associated an increased risk of ventricular arrhythmias (VAs), but the underlying electrophysiological mechanisms are not fully explored. This study was aimed to test whether dynamic factors and Ca-i handling play roles in arrhythmogenesis of a diabetic animal model. Methods: We used 26 db/db type 2 diabetes mice and 28 control mice in this study. VA inducibility was evaluated in vivo under isoflurane general anesthesia. The intracellular Ca2+ (Ca-i) and membrane voltage (V-m) signals of the Langendorff-perfused mouse hearts were simultaneously recorded using the optical mapping technique. Action potential duration (APD), Ca-i dynamics conduction velocity (CV), and arrhythmogenic alternans were analyzed. Western blot was conducted to examine expressions of calcium handling and associated ion channels proteins. Results: The diabetic db/db mice showed significantly increased VA inducibility and severity. Longer APD and Ca-i transient duration and slower Ca-i decay and CV in the db/db mice than these in the control ones were observed. Dynamic pacing showed increased incidence of spatially discordant alternans leading to more VA inducibility in the db/db mice. Western blot analyses revealed increased phosphorylated-Ca2+/calmodulin-dependent protein kinase II protein expression and decreased ryanodine receptor protein expression, which probably underlay the molecular mechanisms of enhanced arrhythmogenicity in db/db mice. Conclusions: The type 2 diabetic mouse hearts show impaired repolarization, Ca-i handling homeostasis, and cardiac conduction reserve, leading to vulnerability of spatially discordant alternans development and induction of VA. Altered Ca-i-handling protein expressions probably underlie the molecular mechanisms of arrhythmogenicity in the type 2 diabetes animal model.
Sacubitril/Valsartan Therapy Ameliorates Ventricular Tachyarrhythmia Inducibility in a Rabbit Myocardial Infarction Model
(2020-06-01)
Chang, Po-Cheng
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Wo, Hung-Ta
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Lee, Hui-Ling
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Lin, Shien-Fong
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Chu, Yen
Background: Coronary artery disease is the most common cause of heart failure (HF) in developed countries. The aim of this study was to elucidate the mechanisms of reduction of arrhythmias after sacubitril/valsartan (LCZ696) therapy in a myocardial infarction (MI)-HF rabbit model. Methods and Results: Chronic MI in rabbits with HF were divided into 3 groups: placebo control, valsartan 30 mg/day and LCZ696 60 mg/day. After 4 weeks of therapy, an electrophysiologic study and a dual voltage-calcium optical mapping study were performed. The LCZ696 group had significantly better left ventricular ejection fraction and lower ventricular tachyarrhythmia inducibility than the valsartan and placebo groups. The most common ventricular tachyarrhythmia pattern was 1 or 2 ectopic beats originating from the peri-infarct areas, followed by re-entrant beats surrounding phase singularity points. Compared to the valsartan and placebo groups, the LCZ696 group had significantly shorter action-potential duration, shorter intracellular calcium tau constant, faster conduction velocity, and shorter pacing cycle length to induce arrhythmogenic alternans. LCZ696 therapy reduced the phosphorylated calmodulin-dependent protein kinase II (CaMKII-p) expression. Conclusions: In a rabbit model with chronic MI and HF, LCZ696 therapy ameliorated postinfarct heart function impairment and electrophysiologic remodeling and altered CaMKII-p expression, leading to reduced ventricular tachyarrhythmia inducibility.
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
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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.
Small-Conductance Calcium-Activated Potassium Current Is Activated During Hypokalemia and Masks Short-Term Cardiac Memory Induced by Ventricular Pacing
(2015-10-13)
Chan, Yi-Hsin
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Tsai, Wei-Chung
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Ko, Jum-Suk
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Yin, Dechun
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Chang, Po-Cheng
Background-Hypokalemia increases the vulnerability to ventricular fibrillation. We hypothesize that the apamin-sensitive small-conductance calcium-activated potassium current (I-KAS) is activated during hypokalemia and that I-KAS blockade is proarrhythmic. Methods and Results-Optical mapping was performed in 23 Langendorff-perfused rabbit ventricles with atrioventricular block and either right or left ventricular pacing during normokalemia or hypokalemia. Apamin prolonged the action potential duration (APD) measured to 80% repolarization (APD(80)) by 26 milliseconds (95% confidence interval [CI], 14-37) during normokalemia and by 54 milliseconds (95% CI, 40-68) during hypokalemia (P=0.01) at a 1000-millisecond pacing cycle length. In hypokalemic ventricles, apamin increased the maximal slope of APD restitution, the pacing cycle length threshold of APD alternans, the pacing cycle length for wave-break induction, and the area of spatially discordant APD alternans. Apamin significantly facilitated the induction of sustained ventricular fibrillation (from 3 of 9 hearts to 9 of 9 hearts; P=0.009). Short-term cardiac memory was assessed by the slope of APD(80) versus activation time. The slope increased from 0.01 (95% CI, -0.09 to 0.12) at baseline to 0.34 (95% CI, 0.23-0.44) after apamin (P<0.001) during right ventricular pacing and from 0.07 (95% CI, -0.05 to 0.20) to 0.54 (95% CI, 0.06-1.03) after apamin infusion (P=0.045) during left ventricular pacing. Patch-clamp studies confirmed increased I-KAS in isolated rabbit ventricular myocytes during hypokalemia (P=0.038). Conclusions-Hypokalemia activates I-KAS to shorten APD and maintain repolarization reserve at late activation sites during ventricular pacing. I-KAS blockade prominently lengthens the APD at late activation sites and facilitates ventricular fibrillation induction.