Browsing by Author "Hsieh, Yu-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
;
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.
Gap junction modifier rotigaptide decreases the susceptibility to ventricular arrhythmia by enhancing conduction velocity and suppressing discordant alternans during therapeutic hypothermia in isolated rabbit hearts
(2016-01-01)
Hsieh, Yu-Cheng
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Lin, Jiunn-Cherng
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Hung, Chen-Ying
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Li, Cheng-Hung
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Lin, Shien-Fong
BACKGROUND Therapeutic hypothermia (TH) may increase the susceptibility to ventricular arrhythmias by decreasing ventricular conduction velocity (CV) and facilitating arrhythmogenic spatially discordant alternans (SDA). OBJECTIVE The purpose of this study was to test the hypothesis that rotigaptide, a gap junction enhancer, can increase ventricular CV, delay the onset of SDA, and decrease the susceptibility to pacing-induced ventricular fibrillation (PIVF) during TH. METHODS Langendorff-perfused isolated rabbit hearts were subjected to 30-minute moderate hypothermia (33 degrees C) followed by 20-minute treatment with rotigaptide (300 nM, n = 8) or vehicle (n = 5). The same protocol was also performed at severe hypothermia (30 degrees C; n = 8 for rotigaptide, n = 5 for vehicle). Using an optical mapping system, epicardial CV and SDA threshold were evaluated by Si pacing. Ventricular fibrillation inducibility was evaluated by burst pacing for 30 seconds at the shortest pacing cycle length (PCL) that achieved 1:1 ventricular capture. RESULTS Rotigaptide increased ventricular CV during 33 degrees C (PCL 300 ms, from 76 +/- 6 cm/s to 84 +/- 7 cm/s, P =.039) and 30 degrees C (PCL 300 ms, from 62 +/- 6 cm/s to 68 +/- 4 cm/s, P =.008). Rotigaptide decreased action potential duration dispersion at 33 degrees C (P =.01) and 30 degrees C (P =.035). During 30 degrees C, SDA thresholds (P =.042) and incidence of premature ventricular complexes (P =.025) were decreased by rotigaptide. PIVF inducibility was decreased by rotigaptide at 33 degrees C (P =.039) and 30 degrees C (P =.042). Rotigaptide did not change connexin43 expressions and distributions during hypothermia. CONCLUSION Rotigaptide protects the hearts against ventricular arrhythmias by increasing ventricular CV, delaying the onset of SDA, and reducing repolarization heterogeneity during TH. Enhancing cell-to-cell coupling by rotigaptide might be a novel approach to prevent ventricular arrhythmias during TH.
Interleukin-17 enhances cardiac ventricular remodeling via activating MAPK pathway in ischemic heart failure
(2018-09-01)
Chang, Shih-Lin
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Hsiao, Ya-Wen
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Tsai, Yung-Nan
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Lin, Shien-Fong
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Liu, Shuen-Hsin
Background: We aimed to investigate the impact of interleukin (IL)-17 on ventricular remodeling and the genesis of ventricular arrhythmia (VA) in an ischemic heart failure (HF) model. The expression of the proinflammatory cytokine IL-17 is upregulated during myocardial ischemia and plays a fundamental role in post-infarct inflammation. However, the influence of IL-17 on the genesis of VA has not yet been studied. Methods and results: The level of inflammation and Th17 cell (CD4(+)IL-17(+)) expression in the rabbit model of ischemic HF were studied by flow cytometry, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay (ELISA). The effect of IL-17 on VA induction following acute and chronic administration of IL-17 was determined using electrophysiological techniques and optical mapping. The expression of IL-17 target genes and related cytokines and chemokines in vivo and in vitro were measured using qPCR, ELISA, and immunoblotting. Th17 cells were markedly increased in the ischemic HF rabbit model. IL-17 directly induced VA in vivo and in vitro in a dose-dependent manner. IL-17 decreased conduction velocity, lengthened action potential duration, and increased the slope of the left ventricle (LV) restitution curve. IL-17 treatment led to fibrosis, collagen production and apoptosis in the LV. Furthermore, increased IL-17 signaling activated mitogen-activated protein kinase and increased the expression of downstream target genes, IL-6, TNF, CCL20, and CXCL1. An anti IL -17 neutralizing antibody abolished the effects of IL-17. Conclusions: The expression of IL-17 and its downstream target genes may play fundamental roles in inducing VA in ischemic HF.
Moderate Hypothermia (33 degrees C) Decreases the Susceptibility to Pacing-Induced Ventricular Fibrillation Compared with Severe Hypothermia (30 degrees C) by Attenuating Spatially Discordant Alternans in Isolated Rabbit Hearts
(2014-09-01)
Hsieh, Yu-Cheng
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Lin, Shien-Fong
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Huang, Jin-Long
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Hung, Chen-Ying
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Lin, Jiunn-Cherng
Background: Severe hypothermia (SH, 30 degrees C) increases the risk of pacing-induced ventricular fibrillation (PIVF) by enhancing spatially discordant alternans (SDA). Whether moderate hypothermia (MH, 33 degrees C), which is clinically used for therapeutic hypothermia, also facilitates SDA remains unclear. We hypothesized that MH attenuates SDA occurrence compared with that achieved by SH, and decreases the susceptibility of PIVF. Methods: Using an optical mapping system, action potential duration (APD)/conduction velocity restitutions and thresholds of APD alternans were determined by Si pacing in Langendorff-perfused isolated rabbit hearts. In the MH group (n = 7), S-1 pacing was performed at baseline (37 degrees C), after 5-min MH, and after 5-min rewarming (37 degrees C). In the SH group (n = 9), pacing was also performed at baseline (37 degrees C), after 5-min SH, and after 5-min rewarming (37 degrees C). The thresholds of APD alternans were defined as the longest Si pacing cycle length at which APD alternans were detected. Results: Although the thresholds of APD alternans were not different between the MH (273 +/- 46 ms) and the SH (300 +/- 35 ms) (p = 0.281) groups, SDA threshold was shorter (at a faster heart rate) during MH (228 +/- 33 ms) than that during SH (289 +/- 42 ms) (p = 0.028). At APD alternans threshold, SH hearts showed more SDA than that during MH (SH: 7 hearts, MH: 2 hearts, p = 0.049). SDA could be induced in all 9 SH hearts (100%), while only 4 MH hearts (57%) had SDA (p = 0.029). The PIVF inducibility during SH (44 +/- 53%) was higher than that during MH (0%) (p = 0.043). Conclusions: Compared with SH, the MH group showed greater attenuation of SDA and decreased the susceptibility of PIVF. Therefore, MH is safer as a procedural guideline for use in clinical therapeutic hypothermia than SH.
Role of Apamin-Sensitive Calcium-Activated Small-Conductance Potassium Currents on the Mechanisms of Ventricular Fibrillation in Pacing-Induced Failing Rabbit Hearts
(2017-02-01)
Yin, Dechun
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Hsieh, Yu-Cheng
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Tsai, Wei-Chung
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Wu, Adonis Zhi-Yang
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Jiang, Zhaolei
Background-Ventricular fibrillation (VF) during heart failure is characterized by stable reentrant spiral waves (rotors). Apamin-sensitive small-conductance calcium-activated potassium currents (I-KAS) are heterogeneously upregulated in failing hearts. We hypothesized that I-KAS influences the location and stability of rotors during VF. Methods and Results-Optical mapping was performed on 9 rabbit hearts with pacing-induced heart failure. The epicardial right ventricular and left ventricular surfaces were simultaneously mapped in a Langendorff preparation. At baseline and after apamin (100 nmol/L) infusion, the action potential duration (APD(80)) was determined, and VF was induced. Areas with a >50% increase in the maximum action potential duration (Delta APD) after apamin infusion were considered to have a high I-KAS distribution. At baseline, the distribution density of phase singularities during VF in high I-KAS distribution areas was higher than in other areas (0.0035 +/- 0.0011 versus 0.0014 +/- 0.0010 phase singularities/pixel; P=0.004). In addition, high dominant frequencies also colocalized to high I-KAS distribution areas (26.0 versus 17.9 Hz; P=0.003). These correlations were eliminated during VF after apamin infusion, as the number of phase singularities (17.2 versus 11.0; P=0.009) and dominant frequencies (22.1 versus 16.2 Hz; P=0.022) were all significantly decreased. In addition, reentrant spiral waves became unstable after apamin infusion, and the duration of VF decreased. Conclusions-The I-KAS current influences the mechanism of VF in failing hearts as phase singularities, high dominant frequencies, and reentrant spiral waves all correlated to areas of high I-KAS. Apamin eliminated this relationship and reduced VF vulnerability.
Ventricular divergence correlates with epicardial wavebreaks and predicts ventricular arrhythmia in isolated rabbit hearts during therapeutic hypothermia
(2020-02-21)
Hsieh, Yu-Cheng
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Hsieh, Wan-Hsin
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Li, Cheng-Hung
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Liao, Ying-Chieh
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Lin, Jiunn-Cherng
Introduction High beat-to-beat morphological variation (divergence) on the ventricular electrogram during programmed ventricular stimulation (PVS) is associated with increased risk of ventricular fibrillation (VF), with unclear mechanisms. We hypothesized that ventricular divergence is associated with epicardial wavebreaks during PVS, and that it predicts VF occurrence. Method and results Langendorff-perfused rabbit hearts (n = 10) underwent 30-min therapeutic hypothermia (TH, 30 degrees C), followed by a 20-min treatment with rotigaptide (300 nM), a gap junction modifier. VF inducibility was tested using burst ventricular pacing at the shortest pacing cycle length achieving 1:1 ventricular capture. Pseudo-ECG (p-ECG) and epicardial activation maps were simultaneously recorded for divergence and wavebreaks analysis, respectively. A total of 112 optical and p-ECG recordings (62 at TH, 50 at TH treated with rotigaptide) were analyzed. Adding rotigaptide reduced ventricular divergence, from 0.13 +/- 0.10 at TH to 0.09 +/- 0.07 (p = 0.018). Similarly, rotigaptide reduced the number of epicardial wavebreaks, from 0.59 +/- 0.73 at TH to 0.30 +/- 0.49 (p = 0.036). VF inducibility decreased, from 48 +/- 31% at TH to 22 +/- 32% after rotigaptide infusion (p = 0.032). Linear regression models showed that ventricular divergence correlated with epicardial wavebreaks during TH (p<0.001). Conclusion Ventricular divergence correlated with, and might be predictive of epicardial wavebreaks during PVS at TH. Rotigaptide decreased both the ventricular divergence and epicardial wavebreaks, and reduced the probability of pacing-induced VF during TH.