Browsing by Author "Qu, Zhilin"

Now showing 1 - 7 of 7
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    Concomitant SK current activation and sodium current inhibition cause J wave syndrome
    (American Society for Clinical Investigation, 2018-11-15) Chen, Mu; Xu, Dong-Zhu; Wu, Adonis Z.; Guo, Shuai; Wan, Juyi; Yin, Dechun; Lin, Shien-Fong; Chen, Zhenhui; Rubart-von der Lohe, Michael; Everett, Thomas H., IV; Qu, Zhilin; Weiss, James N.; Chen, Peng-Sheng; Medicine, School of Medicine
    The mechanisms of J wave syndrome (JWS) are incompletely understood. Here, we showed that the concomitant activation of small-conductance calcium-activated potassium (SK) current (IKAS) and inhibition of sodium current by cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) recapitulate the phenotypes of JWS in Langendorff-perfused rabbit hearts. CyPPA induced significant J wave elevation and frequent spontaneous ventricular fibrillation (SVF), as well as sinus bradycardia, atrioventricular block, and intraventricular conduction delay. IKAS activation by CyPPA resulted in heterogeneous shortening of action potential (AP) duration (APD) and repolarization alternans. CyPPA inhibited cardiac sodium current (INa) and decelerated AP upstroke and intracellular calcium transient. SVFs were typically triggered by short-coupled premature ventricular contractions, initiated with phase 2 reentry and originated more frequently from the right than the left ventricles. Subsequent IKAS blockade by apamin reduced J wave elevation and eliminated SVF. β-Adrenergic stimulation was antiarrhythmic in CyPPA-induced electrical storm. Like CyPPA, hypothermia (32.0°C) also induced J wave elevation and SVF. It facilitated negative calcium-voltage coupling and phase 2 repolarization alternans with spatial and electromechanical discordance, which were ameliorated by apamin. These findings suggest that IKAS activation contributes to the development of JWS in rabbit ventricles.
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    Loss of function of hNav1.5 by a ZASP1 mutation associated with intraventricular conduction disturbances in left ventricular noncompaction
    (Ovid Technologies Wolters Kluwer -American Heart Association, 2012-10) Xi, Yutao; Ai, Tomohiko; De Lange, Enno; Li, Zhaohui; Wu, Geru; Brunelli, Luca; Kyle, W. Buck; Turker, Isik; Cheng, Jie; Ackerman, Michael J.; Kimura, Akinori; Weiss, James N.; Qu, Zhilin; Kim, Jeffrey J.; Faulkner, Georgine; Vatta, Matteo; Department of Medicine, IU School of Medicine
    BACKGROUND: Defects of cytoarchitectural proteins can cause left ventricular noncompaction, which is often associated with conduction system diseases. We have previously identified a p.D117N mutation in the LIM domain-binding protein 3-encoding Z-band alternatively spliced PDZ motif gene (ZASP) in a patient with left ventricular noncompaction and conduction disturbances. We sought to investigate the role of p.D117N mutation in the LBD3 NM_001080114.1 isoform (ZASP1-D117N) for the regulation of cardiac sodium channel (Na(v)1.5) that plays an important role in the cardiac conduction system. METHODS AND RESULTS: Effects of ZASP1-wild-type and ZASP1-D117N on Na(v)1.5 were studied in human embryonic kidney-293 cells and neonatal rat cardiomyocytes. Patch-clamp study demonstrated that ZASP1-D117N significantly attenuated I(Na) by 27% in human embryonic kidney-293 cells and by 32% in neonatal rat cardiomyocytes. In addition, ZASP1-D117N rightward shifted the voltage-dependent activation and inactivation in both systems. In silico simulation using Luo-Rudy phase 1 model demonstrated that altered Na(v)1.5 function can reduce cardiac conduction velocity by 28% compared with control. Pull-down assays showed that both wild-type and ZASP1-D117N can complex with Na(v)1.5 and telethonin/T-Cap, which required intact PDZ domains. Immunohistochemical staining in neonatal rat cardiomyocytes demonstrates that ZASP1-D117N did not significantly disturb the Z-line structure. Disruption of cytoskeletal networks with 5-iodonaphthalene-1-sulfonyl homopiperazine and cytochalasin D abolished the effects of ZASP1-D117N on Na(v)1.5. CONCLUSIONS: ZASP1 can form protein complex with telethonin/T-Cap and Na(v)1.5. The left ventricular noncompaction-specific ZASP1 mutation can cause loss of function of Na(v)1.5, without significant alteration of the cytoskeletal protein complex. Our study suggests that electric remodeling can occur in left ventricular noncompaction subject because of a direct effect of mutant ZASP on Na(v)1.5.
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    Perspective: a dynamics-based classification of ventricular arrhythmias
    (Elsevier, 2015-05) Weiss, James N.; Garfinkel, Alan; Karagueuzian, Hrayr S.; Nguyen, Thao P.; Olcese, Riccardo; Chen, Peng-Sheng; Qu, Zhilin; Department of Medicine, IU School of Medicine
    Despite key advances in the clinical management of life-threatening ventricular arrhythmias, culminating with the development of implantable cardioverter-defibrillators and catheter ablation techniques, pharmacologic/biologic therapeutics have lagged behind. The fundamental issue is that biological targets are molecular factors. Diseases, however, represent emergent properties at the scale of the organism that result from dynamic interactions between multiple constantly changing molecular factors. For a pharmacologic/biologic therapy to be effective, it must target the dynamic processes that underlie the disease. Here we propose a classification of ventricular arrhythmias that is based on our current understanding of the dynamics occurring at the subcellular, cellular, tissue and organism scales, which cause arrhythmias by simultaneously generating arrhythmia triggers and exacerbating tissue vulnerability. The goal is to create a framework that systematically links these key dynamic factors together with fixed factors (structural and electrophysiological heterogeneity) synergistically promoting electrical dispersion and increased arrhythmia risk to molecular factors that can serve as biological targets. We classify ventricular arrhythmias into three primary dynamic categories related generally to unstable Ca cycling, reduced repolarization, and excess repolarization, respectively. The clinical syndromes, arrhythmia mechanisms, dynamic factors and what is known about their molecular counterparts are discussed. Based on this framework, we propose a computational-experimental strategy for exploring the links between molecular factors, fixed factors and dynamic factors that underlie life-threatening ventricular arrhythmias. The ultimate objective is to facilitate drug development by creating an in silico platform to evaluate and predict comprehensively how molecular interventions affect not only a single targeted arrhythmia, but all primary arrhythmia dynamics categories as well as normal cardiac excitation-contraction coupling.
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    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 Medicine
    Background: 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.
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    Simultaneous activation of the small conductance calcium-activated potassium current by acetylcholine and inhibition of sodium current by ajmaline cause J-wave syndrome in Langendorff-perfused rabbit ventricles
    (Elsevier, 2021) Fei, Yu-Dong; Chen, Mu; Guo, Shuai; Ueoka, Akira; Chen, Zhenhui; Rubart-von der Lohe, Michael; Everett, Thomas H., IV.; Qu, Zhilin; Weiss, James N.; Chen, Peng-Sheng; Medicine, School of Medicine
    Background: Concomitant apamin-sensitive small conductance calcium-activated potassium current (IKAS) activation and sodium current inhibition induce J-wave syndrome (JWS) in rabbit hearts. Sudden death in JWS occurs predominantly in men at night when parasympathetic tone is strong. Objective: The purpose of this study was to test the hypotheses that acetylcholine (ACh), the parasympathetic transmitter, activates IKAS and causes JWS in the presence of ajmaline. Methods: We performed optical mapping in Langendorff-perfused rabbit hearts and whole-cell voltage clamp to determine IKAS in isolated ventricular cardiomyocytes. Results: ACh (1 μM) + ajmaline (2 μM) induced J-point elevations in all (6 male and 6 female) hearts from 0.01± 0.01 to 0.31 ± 0.05 mV (P<.001), which were reduced by apamin (specific IKAS inhibitor, 100 nM) to 0.14 ± 0.02 mV (P<.001). More J-point elevation was noted in male than in female hearts (P=.037). Patch clamp studies showed that ACh significantly (P<.001) activated IKAS in isolated male but not in female ventricular myocytes (n=8). Optical mapping studies showed that ACh induced action potential duration (APD) heterogeneity, which was more significant in right than in left ventricles. Apamin in the presence of ACh prolonged both APD at the level of 25% (P<.001) and APD at the level of 80% (P<.001) and attenuated APD heterogeneity. Ajmaline further increased APD heterogeneity induced by ACh. Ventricular arrhythmias were induced in 6 of 6 male and 1 of 6 female hearts (P=.015) in the presence of ACh and ajmaline, which was significantly suppressed by apamin in the former. Conclusion: ACh activates ventricular IKAS. ACh and ajmaline induce JWS and facilitate the induction of ventricular arrhythmias more in male than in female ventricles.
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    The Small Conductance Calcium Activated Potassium Current Modulates the Ventricular Escape Rhythm in Normal Rabbit Hearts
    (Elsevier, 2018) Wan, Juyi; Chen, Mu; Wang, Zhuo; Everett, Thomas H., IV; Rubart-von der Lohe, Michael; Shen, Changyu; Qu, Zhilin; Weiss, James N.; Boyden, Penelope A.; Chen, Peng-Sheng; Medicine, School of Medicine
    Background The apamin-sensitive small-conductance calcium-activated K (SK) current (IKAS) modulates automaticity of the sinus node; IKAS blockade by apamin causes sinus bradycardia. Objective To test the hypothesis that IKAS modulates ventricular automaticity. Methods We tested the effects of apamin (100 nM) on ventricular escape rhythms in Langendorff perfused rabbit ventricles with atrioventricular (AV) block (Protocol 1) and on recorded transmembrane action potential (TMP) of pseudotendons of superfused right ventricular (RV) endocardial preparations (Protocol 2). Results All preparations exhibited spontaneous ventricular escape rhythms. In Protocol 1, apamin decreased the atrial rate from 186.2±18.0 bpm to 163.8±18.7 bpm (N=6, p=0.006) but accelerated the ventricular escape rate from 51.5±10.7 to 98.2±25.4 bpm (p=0.031). Three preparations exhibited bursts of nonsustained ventricular tachycardia (NSVT) and pauses, resulting in repeated burst-termination pattern. In Protocol 2, apamin increased the ventricular escape rate from 70.2±13.1 to 110.1±2.2 bpm (p=0.035). Spontaneous phase 4 depolarization was recorded from the pseudotendons in 6 of 10 preparations at baseline and in 3 in the presence of apamin. There were no changes of phase 4 slope (18.37±3.55 vs. 18.93±3.26 mV/s, p=0.231, N=3), but the threshold of phase 0 activation (mV) reduced from -67.97±1.53 to -75.26±0.28 (p=0.034). Addition of JTV-519, a ryanodine receptor 2 (RyR2) stabilizer, in 5 preparations reduced escape rate back to baseline. Conclusions Contrary to its bradycardic effect in the sinus node, IKAS blockade by apamin accelerates ventricular automaticity and causes repeated NSVT in normal ventricles. RyR2 blockade reversed the apamin effects on ventricular automaticity.
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    Small-conductance Ca2+-activated K+ channels promote J-wave syndrome and phase-2 reentry
    (Elsevier, 2020-09) Landaw, Julian; Zhang, Zhaoyang; Song, Zhen; Liu, Michael B.; Olcese, Riccardo; Chen, Peng-Sheng; Weiss, James N.; Qu, Zhilin; Medicine, School of Medicine
    Background: Small-conductance Ca2+-activated potassium (SK) channels play complex roles in cardiac arrhythmogenesis. SK channels colocalize with L-type Ca2+ channels, yet how this colocalization affects cardiac arrhythmogenesis is unknown. Objective: The purpose of this study was to investigate the role of colocalization of SK channels with L-type Ca2+ channels in promoting J-wave syndrome and ventricular arrhythmias. Methods: We carried out computer simulations of single-cell and tissue models. SK channels in the model were assigned to preferentially sense Ca2+ in the bulk cytosol, subsarcolemmal space, or junctional cleft. Results: When SK channels sense Ca2+ in the bulk cytosol, the SK current (ISK) rises and decays slowly during an action potential, the action potential duration (APD) decreases as the maximum conductance increases, no complex APD dynamics and phase 2 reentry can be induced by ISK. When SK channels sense Ca2+ in the subsarcolemmal space or junctional cleft, ISK can rise and decay rapidly during an action potential in a spike-like pattern because of spiky Ca2+ transients in these compartments, which can cause spike-and-dome action potential morphology, APD alternans, J-wave elevation, and phase 2 reentry. Our results can account for the experimental finding that activation of ISK induced J-wave syndrome and phase 2 reentry in rabbit hearts. Conclusion: Colocalization of SK channels with L-type Ca2+ channels so that they preferentially sense Ca2+ in the subsarcolemmal or junctional space may result in a spiky ISK, which can functionally play a similar role of the transient outward K+ current in promoting J-wave syndrome and ventricular arrhythmias.