Browsing by Author "Yeh, Hung-I"

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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
;
Lin, Jiunn-Cherng
;
Hung, Chen-Ying
;
Li, Cheng-Hung
;
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.
Pleiotropic Effects of Myocardial MMP-9 Inhibition to Prevent Ventricular Arrhythmia
(2016-12-14)
Weng, Ching-Hui
;
Chung, Fa-Po
;
Chen, Yao-Chang
;
Lin, Shien-Fong
;
Huang, Po-Hsun
Observational studies have established a strong association between matrix metalloproteinase-9 (MMP-9) and ventricular arrhythmia. However, whether MMP-9 has a causal link to ventricular arrhythmia, as well as the underlying mechanism, remains unclear. Here, we investigated the mechanistic involvement of myocardial MMP-9 in the pathophysiology of ventricular arrhythmia. Increased levels of myocardial MMP-9 are linked to ventricular arrhythmia attacks after angiotensin II (Ang II) treatment. MMP-9-deficient mice were protected from ventricular arrhythmia. Increased expressions of protein kinase A (PKA) and ryanodine receptor phosphorylation at serine 2808 (pS2808) were correlated with inducible ventricular arrhythmia. MMP-9 deficiency consistently prevented PKA and pS2808 increases after Ang II treatment and reduced ventricular arrhythmia. Calcium dynamics were examined via confocal imaging in isolated murine cardiomyocytes. MMP-9 inhibition prevents calcium leakage from the sarcoplasmic reticulum and reduces arrhythmia-like irregular calcium transients via protein kinase A and ryanodine receptor phosphorylation. Human induced pluripotent stem cell-derived cardiomyocytes similarly show that MMP-9 inhibition prevents abnormal calcium leakage. Myocardial MMP-9 inhibition prevents ventricular arrhythmia through pleiotropic effects, including the modulation of calcium homeostasis and reduced calcium leakage.