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Item Moderate Hypothermia (33 °C) Decreases the Susceptibility to Pacing-Induced Ventricular Fibrillation Compared with Severe Hypothermia (30 °C) by Attenuating Spatially Discordant Alternans in Isolated Rabbit Hearts(Taiwan Society of Cardiology, 2014-09) Hsieh, Yu-Cheng; Lin, Shien-Fong; Huang, Jin-Long; Hung, Chen-Ying; Lin, Jiunn-Cherng; Liao, Ying-Chieh; Lo, Chu-Pin; Wang, Kuo-Yang; Wu, Tsu-Juey; Department of Medicine, IU School of MedicineBackground Severe hypothermia (SH, 30 °C) increases the risk of pacing-induced ventricular fibrillation (PIVF) by enhancing spatially discordant alternans (SDA). Whether moderate hypothermia (MH, 33 °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 S1 pacing in Langendorff-perfused isolated rabbit hearts. In the MH group (n = 7), S1 pacing was performed at baseline (37 °C), after 5-min MH, and after 5-min rewarming (37 °C). In the SH group (n = 9), pacing was also performed at baseline (37 °C), after 5-min SH, and after 5-min rewarming (37 °C). The thresholds of APD alternans were defined as the longest S1 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.Item Neonatal Deletion of Hand1 and Hand2 within Murine Cardiac Conduction System Reveals a Novel Role for HAND2 in Rhythm Homeostasis(MDPI, 2022-07-04) George, Rajani M.; Guo, Shuai; Firulli, Beth A.; Rubart, Michael; Firulli, Anthony B.; Pediatrics, School of MedicineThe cardiac conduction system, a network of specialized cells, is required for the functioning of the heart. The basic helix loop helix factors Hand1 and Hand2 are required for cardiac morphogenesis and have been implicated in cardiac conduction system development and maintenance. Here we use embryonic and post-natal specific Cre lines to interrogate the role of Hand1 and Hand2 in the function of the murine cardiac conduction system. Results demonstrate that loss of HAND1 in the post-natal conduction system does not result in any change in electrocardiogram parameters or within the ventricular conduction system as determined by optical voltage mapping. Deletion of Hand2 within the post-natal conduction system results in sex-dependent reduction in PR interval duration in these mice, suggesting a novel role for HAND2 in regulating the atrioventricular conduction. Surprisingly, results show that loss of both HAND factors within the post-natal conduction system does not cause any consistent changes in cardiac conduction system function. Deletion of Hand2 in the embryonic left ventricle results in inconsistent prolongation of PR interval and susceptibility to atrial arrhythmias. Thus, these results suggest a novel role for HAND2 in homeostasis of the murine cardiac conduction system and that HAND1 loss potentially rescues the shortened HAND2 PR phenotype.Item Sex-specific IKAS activation in rabbit ventricles with drug-induced QT prolongation(Elsevier, 2021) Wu, Adonis Z.; Chen, Mu; Yin, Dechun; Everett, Thomas H., IV.; Chen, Zhenhui; Rubart, Michael; Weiss, James N.; Qu, Zhilin; Chen, Peng-Sheng; Medicine, School of MedicineBackground: Female sex is a known risk factor for drug-induced long QT syndrome (diLQTS). We recently demonstrated a sex difference in apamin-sensitive small-conductance Ca2+-activated K+ current (IKAS) activation during β-adrenergic stimulation. Objective: The purpose of this study was to test the hypothesis that there is a sex difference in IKAS in the rabbit models of diLQTS. Methods: We evaluated the sex difference in ventricular repolarization in 15 male and 22 female Langendorff-perfused rabbit hearts with optical mapping techniques during atrial pacing. HMR1556 (slowly activating delayed rectifier K+ current [IKs] blocker), E4031 (rapidly activating delayed rectifier K+ current [IKr] blocker) and sea anemone toxin (ATX-II, late Na+ current [INaL] activator) were used to simulate types 1-3 long QT syndrome, respectively. Apamin, an IKAS blocker, was then added to determine the magnitude of further QT prolongation. Results: HMR1556, E4031, and ATX-II led to the prolongation of action potential duration at 80% repolarization (APD80) in both male and female ventricles at pacing cycle lengths of 300-400 ms. Apamin further prolonged APD80 (pacing cycle length 350 ms) from 187.8±4.3 to 206.9±7.1 (P=.014) in HMR1556-treated, from 209.9±7.8 to 224.9±7.8 (P=.003) in E4031-treated, and from 174.3±3.3 to 188.1±3.0 (P=.0002) in ATX-II-treated female hearts. Apamin did not further prolong the APD80 in male hearts. The Cai transient duration (CaiTD) was significantly longer in diLQTS than baseline but without sex differences. Apamin did not change CaiTD. Conclusion: We conclude that IKAS is abundantly increased in female but not in male ventricles with diLQTS. Increased IKAS helps preserve the repolarization reserve in female ventricles treated with IKs and IKr blockers or INaL activators.Item 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 MedicineBACKGROUND: 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.Item Testosterone does not shorten action potential duration in Langendorff perfused rabbit ventricles(Elsevier, 2023-10) Ueoka, Akira; Sung, Yen-Ling; Liu, Xiao; Rosenberg, Carine; Chen, Zhenhui; Everett, Thomas H, IV; Rubart, Michael; Tisdale, James E.; Chen, Peng-Sheng; Pediatrics, School of MedicineBackground: Women have longer baseline QT intervals than men. Because previous studies showed that testosterone and 5α-dihydrotestosterone shorten the ventricular action potential duration (APD) in animal models, differential testosterone concentrations may account for the sex differences in QT interval. Objective: The purpose of this study was to test the hypothesis that testosterone shortens the APD in Langendorff-perfused rabbit ventricles. Methods: We performed optical mapping studies in hearts with or without testosterone administration. Acute studies included 26 hearts using 2 different protocols, including 17 without and 9 with atrioventricular (AV) block. For chronic studies, we implanted testosterone pellets subcutaneously in 7 female rabbits for 2-3 weeks before optical mapping studies during complete AV block. Six rabbits without pellet implantation served as controls. Results: The hearts in the acute studies were paced with a pacing cycle length (PCL) of 200-300 ms and mapped at baseline and after administration of 1 nM, 10 nM, 100 nM, and 3 μM of testosterone. There was no shortening of APD80 at any PCL. Instead, a lengthening of APD80 was noted at higher concentrations. There were no sex differences in testosterone responses. In chronic studies, heart rates were 136 ± 5 bpm before and 148 ± 9 bpm after (P = .10) while QTc intervals were 314 ± 9 ms before and 317 ± 99 ms after (P = .69) testosterone pellet implantation, respectively. Overall, ventricular APD80 in the pellet group was longer than in the control group at 300- to 700-ms PCL. Conclusion: Testosterone does not shorten ventricular repolarization in rabbit hearts.Item Testosterone does not shorten action potential duration in Langendorff-perfused rabbit ventricles(Elsevier, 2022-11) Ueoka, Akira; Sung, Yen-Ling; Liu , Xiao; Rosenberg, Carine; Chen, Zhenhui; Everett, Thomas H., IV; Rubart , Michael; Tisdale, James E.; Chen, Peng-Sheng; Medicine, School of MedicineBackground Women have longer baseline QT intervals than men. Because previous studies showed that testosterone and 5α-dihydrotestosterone shorten the ventricular action potential duration (APD) in animal models, differential testosterone concentrations may account for the sex differences in QT interval. Objective The purpose of this study was to test the hypothesis that testosterone shortens the APD in Langendorff-perfused rabbit ventricles. Methods We performed optical mapping studies in hearts with or without testosterone administration. Acute studies included 26 hearts using 2 different protocols, including 17 without and 9 with atrioventricular (AV) block. For chronic studies, we implanted testosterone pellets subcutaneously in 7 female rabbits for 2–3 weeks before optical mapping studies during complete AV block. Six rabbits without pellet implantation served as controls. Results The hearts in the acute studies were paced with a pacing cycle length (PCL) of 200–300 ms and mapped at baseline and after administration of 1 nM, 10 nM, 100 nM, and 3 μM of testosterone. There was no shortening of APD80 at any PCL. Instead, a lengthening of APD80 was noted at higher concentrations. There were no sex differences in testosterone responses. In chronic studies, heart rates were 136 ± 5 bpm before and 148 ± 9 bpm after (P = .10) while QTc intervals were 314 ± 9 ms before and 317 ± 99 ms after (P = .69) testosterone pellet implantation, respectively. Overall, ventricular APD80 in the pellet group was longer than in the control group at 300- to 700-ms PCL. Conclusion Testosterone does not shorten ventricular repolarization in rabbit hearts.