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Xuwen Peng - One of the best experts on this subject based on the ideXlab platform.
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short long heart rate variation increases dispersion of action potential duration in long qt type 2 Transgenic Rabbit model
Scientific Reports, 2019Co-Authors: Paul Jeng, Gideon Koren, Jungmin Hwang, Xuwen Peng, Leroy L Cooper, Zachary Pfeiffer, Divyang Patel, Konstantinos Kossidas, Jason Centracchio, Zhilin QuAbstract:The initiation of polymorphic ventricular tachycardia in long QT syndrome type 2 (LQT2) has been associated with a characteristic ECG pattern of short-long RR intervals. We hypothesize that this characteristic pattern increases APD dispersion in LQT2, thereby promoting arrhythmia. We investigated APD dispersion and its dependence on two previous cycle lengths (CLs) in Transgenic Rabbit models of LQT2, LQT1, and their littermate controls (LMC) using random stimulation protocols. The results show that the short-long RR pattern was associated with a larger APD dispersion in LQT2 but not in LQT1 Rabbits. The multivariate analyses of APD as a function of two previous CLs (APDn = C + α1CLn−1 + α2CLn−2) showed that α1 (APD restitution slope) is largest and heterogeneous in LQT2 but uniform in LQT1, enhancing APD dispersion under long CLn−1 in LQT2. The α2 (short-term memory) was negative in LQT2 while positive in LQT1, and the spatial pattern of α1 was inversely correlated to α2 in LQT2, which explains why a short-long combination causes a larger APD dispersion in LQT2 but not in LQT1 Rabbits. In conclusion, short-long RR pattern increased APD dispersion only in LQT2 Rabbits through heterogeneous APD restitution and the short-term memory, underscoring the genotype-specific triggering of arrhythmias in LQT syndrome.
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transient outward k current ito underlies the right ventricular initiation of polymorphic ventricular tachycardia in a Transgenic Rabbit model of long qt syndrome type 1
Circulation-arrhythmia and Electrophysiology, 2018Co-Authors: Bumrak Choi, Tae Yun Kim, Dmitry Terentyev, Mingwang Zhong, Anatoli Y Kabakov, Colin M Rees, Radmila Terentyeva, Xuwen Peng, Alain Karma, Gideon KorenAbstract:Background:Sudden death in long-QT syndrome type 1 (LQT1), an inherited disease caused by loss-of-function mutations in KCNQ1, is triggered by early afterdepolarizations (EADs) that initiate polymo...
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transient outward k current underlies heterogeneity of action potential duration and early afterdepolarization from right ventricle in Transgenic Rabbit model of long qt type 1
Biophysical Journal, 2015Co-Authors: Bumrak Choi, Zhilin Qu, Dmitry Terentyev, Colin M Rees, Xuwen Peng, Alain Karma, Weiyan Li, Radmila Terentieva, Gideon KorenAbstract:Introduction: Long QT syndrome type 1 (LQT1) is a congenital disease lacking slowly activating K+ channel (IKs), associated with polymorphic VT (pVT) and sudden cardiac death. Tissue heterogeneity has been proposed as an important factor to trigger and maintain pVT. We investigated ionic mechanisms that underlie regional differences in the formation of early afterdepolarization (EAD) using Transgenic Rabbit model of LQT1.Methods: The initiation of pVT under isoproterenol was mapped using optical mapping and myocytes isolated from RV and septum were studied using voltage clamp and confocal calcium imaging.Results: Optical mapping of LQT1 hearts showed pVT preferentially originating from right ventricle (RV) (16 of 18 pVTs), which was changed after perfusing transient outward K channel (Ito) blocker, 0.5 mM 4-aminopyridine (only 1 of 5 pVTs from RV, n=5 hearts). Myocytes isolated from RV demonstrated higher incidence of EADs under 50 nM isoproterenol (8 of 12 cells from RV vs. 2 of 11 cells from septum). Voltage clamp study highlighted regional differences of Ito (4.7 ± 0.5 in RV vs. 2.9 ± 0.7 pA/pF in septum at 0 mV) but other currents such as ICaL, IKr and RyR-mediated Ca2+ leak and SERCA-mediated Ca2+ uptake were same between RV and septum. Computer modeling study of Rabbit action potential lacking IKs exhibit frequent EADs but reduction of Ito prevented EAD formation, verifying that Ito plays a major role in EAD formation by providing repolarizing currents during the plateau phase to maintain the membrane potential lower enough to re-activate ICa window current to form EADs.Conclusion: Regional differences of Ito in LQT1 Rabbits underlie frequent pVTs originating mostly from RV myocytes with high incidence of EADs.
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hyperphosphorylation of ryrs underlies triggered activity in Transgenic Rabbit model of lqt2 syndrome
Circulation Research, 2014Co-Authors: Dmitry Terentyev, Hitesh K. Jindal, Colin M Rees, Radmila Terentyeva, Xuwen Peng, Katja E Odening, Leroy L Cooper, Jean M Daley, Kamana Bist, Bumrak ChoiAbstract:Rationale:Loss-of-function mutations in human ether go-go (HERG) potassium channels underlie long QT syndrome type 2 (LQT2) and are associated with fatal ventricular tachyarrhythmia. Previously, most studies focused on plasma membrane–related pathways involved in arrhythmogenesis in long QT syndrome, whereas proarrhythmic changes in intracellular Ca2+ handling remained unexplored. Objective:We investigated the remodeling of Ca2+ homeostasis in ventricular cardiomyocytes derived from Transgenic Rabbit model of LQT2 to determine whether these changes contribute to triggered activity in the form of early after depolarizations (EADs). Methods and Results:Confocal Ca2+ imaging revealed decrease in amplitude of Ca2+ transients and sarcoplasmic reticulum Ca2+ content in LQT2 myocytes. Experiments using sarcoplasmic reticulum–entrapped Ca2+ indicator demonstrated enhanced ryanodine receptor (RyR)–mediated sarcoplasmic reticulum Ca2+ leak in LQT2 cells. Western blot analyses showed increased phosphorylation of RyR...
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ttx converts polymorphic vt to monomorphic vt in Transgenic Rabbit model of lqt1
Biophysical Journal, 2013Co-Authors: Zachary Pfeiffer, Gideon Koren, Jungmin Hwang, Tae Yun Kim, Xuwen Peng, Brijesh Patel, Bumrak ChoiAbstract:Long QT syndrome Type 1 (LQT1) is a congenital disease defined by loss of function mutations in KCNQ1, and associated with syncope and sudden death preceded by polymorphic ventricular tachycardia (pVT). We hypothesized that inhibition of sodium channel function suppresses pVT formation. using a Transgenic Rabbit model of LQT1 (n=4), we simultaneously mapped activation patterns from a voltage sensitive dye and microelectrode. The AV node was ablated to slow intrinsic heart rate, isoproterenol (140nM) was injected to mimic sympathetic stimulation, and pVTs were subsequently observed (avg = 3-10 s). The associated activation patterns revealed multifocal activities and complex waveform propagation varying in spatial origin and direction. Subsequent perfusion of a sodium channel blocker, TTX (2 μM), notably converted pVTs toward monomorphic activation patterns. We also report evidence of fully rotating spiral waves, and their role in maintaining monomorphic VTs. Taken together, these results strongly suggest that 1) early afterdepolarizations (EADs) play an important role in maintaining pVTs complexity, 2) sodium currents significantly influence EAD regeneration by their continuous firing during pVTs, 3) sodium channel inhibition by TTX reduces EAD generation and stabilizes reentry into monomorphic VTs.View Large Image | View Hi-Res Image | Download PowerPoint Slide
Gideon Koren - One of the best experts on this subject based on the ideXlab platform.
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Transgenic Rabbit models for cardiac disease research
British Journal of Pharmacology, 2021Co-Authors: Gideon Koren, Tibor Hornyik, Marina Rieder, Alessandro Castiglione, P Major, Istvan Baczko, Michael Brunner, Katja E OdeningAbstract:To study the pathophysiology of human cardiac diseases and to develop novel treatment strategies, complex interactions of cardiac cells on cellular, tissue and on level of the whole heart need to be considered. As in vitro cell-based models do not depict the complexity of the human heart, animal models are used to obtain insights that can be translated to human diseases. Mice are the most commonly used animals in cardiac research. However, differences in electrophysiological and mechanical cardiac function and a different composition of electrical and contractile proteins limit the transferability of the knowledge gained. Moreover, the small heart size and fast heart rate are major disadvantages. In contrast to rodents, electrophysiological, mechanical and structural cardiac characteristics of Rabbits resemble the human heart more closely, making them particularly suitable as an animal model for cardiac disease research. In this review, various methodological approaches for the generation of Transgenic Rabbits for cardiac disease research, such as pronuclear microinjection, the sleeping beauty transposon system and novel genome-editing methods (ZFN and CRISPR/Cas9)will be discussed. In the second section, we will introduce the different currently available Transgenic Rabbit models for monogenic cardiac diseases (such as long QT syndrome, short-QT syndrome and hypertrophic cardiomyopathy) in detail, especially in regard to their utility to increase the understanding of pathophysiological disease mechanisms and novel treatment options.
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short long heart rate variation increases dispersion of action potential duration in long qt type 2 Transgenic Rabbit model
Scientific Reports, 2019Co-Authors: Paul Jeng, Gideon Koren, Jungmin Hwang, Xuwen Peng, Leroy L Cooper, Zachary Pfeiffer, Divyang Patel, Konstantinos Kossidas, Jason Centracchio, Zhilin QuAbstract:The initiation of polymorphic ventricular tachycardia in long QT syndrome type 2 (LQT2) has been associated with a characteristic ECG pattern of short-long RR intervals. We hypothesize that this characteristic pattern increases APD dispersion in LQT2, thereby promoting arrhythmia. We investigated APD dispersion and its dependence on two previous cycle lengths (CLs) in Transgenic Rabbit models of LQT2, LQT1, and their littermate controls (LMC) using random stimulation protocols. The results show that the short-long RR pattern was associated with a larger APD dispersion in LQT2 but not in LQT1 Rabbits. The multivariate analyses of APD as a function of two previous CLs (APDn = C + α1CLn−1 + α2CLn−2) showed that α1 (APD restitution slope) is largest and heterogeneous in LQT2 but uniform in LQT1, enhancing APD dispersion under long CLn−1 in LQT2. The α2 (short-term memory) was negative in LQT2 while positive in LQT1, and the spatial pattern of α1 was inversely correlated to α2 in LQT2, which explains why a short-long combination causes a larger APD dispersion in LQT2 but not in LQT1 Rabbits. In conclusion, short-long RR pattern increased APD dispersion only in LQT2 Rabbits through heterogeneous APD restitution and the short-term memory, underscoring the genotype-specific triggering of arrhythmias in LQT syndrome.
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transient outward k current ito underlies the right ventricular initiation of polymorphic ventricular tachycardia in a Transgenic Rabbit model of long qt syndrome type 1
Circulation-arrhythmia and Electrophysiology, 2018Co-Authors: Bumrak Choi, Tae Yun Kim, Dmitry Terentyev, Mingwang Zhong, Anatoli Y Kabakov, Colin M Rees, Radmila Terentyeva, Xuwen Peng, Alain Karma, Gideon KorenAbstract:Background:Sudden death in long-QT syndrome type 1 (LQT1), an inherited disease caused by loss-of-function mutations in KCNQ1, is triggered by early afterdepolarizations (EADs) that initiate polymo...
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mechanisms linking t wave alternans to spontaneous initiation of ventricular arrhythmias in Rabbit models of long qt syndrome
The Journal of Physiology, 2018Co-Authors: Xiaodong Huang, Gideon Koren, Bumrak Choi, Zhilin QuAbstract:KEY POINTS: T-wave alternans (TWA) and T-wave lability (TWL) are precursors of ventricular arrhythmias in long QT syndrome; however, the mechanistic link remains to be clarified. Computer simulations show that action potential duration (APD) prolongation and slowed heart rates promote APD alternans and chaos, manifesting as TWA and TWL, respectively. Regional APD alternans and chaos can exacerbate pre-existing or induce de novo APD dispersion, which combines with enhanced ICa,L to result in premature ventricular complexes (PVCs) originating from the APD gradient region. These PVCs can directly degenerate into re-entrant arrhythmias without the need for an additional tissue substrate or further exacerbate the APD dispersion to cause spontaneous initiation of ventricular arrhythmias. Experiments conducted in Transgenic long QT Rabbits show that PVC alternans occurs at slow heart rates, preceding spontaneous intuition of ventricular arrhythmias. ABSTRACT: T-wave alternans (TWA) and irregular beat-to-beat T-wave variability or T-wave lability (TWL), the ECG manifestations of action potential duration (APD) alternans and variability, are precursors of ventricular arrhythmias in long QT syndromes. TWA and TWL in patients tend to occur at normal heart rates and are usually potentiated by bradycardia. Whether or how TWA and TWL at normal or slow heart rates are causally linked to arrhythmogenesis remains unknown. In the present study, we used computer simulations and experiments of a Transgenic Rabbit model of long QT syndrome to investigate the underlying mechanisms. Computer simulations showed that APD prolongation and slowed heart rates caused early afterdepolarization-mediated APD alternans and chaos, manifesting as TWA and TWL, respectively. Regional APD alternans and chaos exacerbated pre-existing APD dispersion and, in addition, APD chaos could also induce APD dispersion de novo via chaos desynchronization. Increased APD dispersion, combined with substantially enhanced ICa,L , resulted in a tissue-scale dynamical instability that gave rise to the spontaneous occurrence of unidirectionally propagating premature ventricular complexes (PVCs) originating from the APD gradient region. These PVCs could directly degenerate into re-entrant arrhythmias without the need for an additional tissue substrate or could block the following sinus beat to result in a longer RR interval, which further exacerbated the APD dispersion giving rise to the spontaneous occurrence of ventricular arrhythmias. Slow heart rate-induced PVC alternans was observed in experiments of Transgenic LQT2 Rabbits under isoproterenol, which was associated with increased APD dispersion and spontaneous occurrence of ventricular arrhythmias, in agreement with the theoretical predictions.
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Transgenic Rabbit models to investigate the cardiac ion channel disease long qt syndrome
Progress in Biophysics & Molecular Biology, 2016Co-Authors: Corinna N Lang, Gideon Koren, Katja E OdeningAbstract:Long QT syndrome (LQTS) is a rare inherited channelopathy caused mainly by different mutations in genes encoding for cardiac K(+) or Na(+) channels, but can also be caused by commonly used ion-channel-blocking and QT-prolonging drugs, thus affecting a much larger population. To develop novel diagnostic and therapeutic strategies to improve the clinical management of these patients, a thorough understanding of the pathophysiological mechanisms of arrhythmogenesis and potential pharmacological targets is needed. Drug-induced and genetic animal models of various species have been generated and have been instrumental for identifying pro-arrhythmic triggers and important characteristics of the arrhythmogenic substrate in LQTS. However, due to species differences in features of cardiac electrical function, these different models do not entirely recapitulate all aspects of the human disease. In this review, we summarize advantages and shortcomings of different drug-induced and genetically mediated LQTS animal models - focusing on mouse and Rabbit models since these represent the most commonly used small animal models for LQTS that can be subjected to genetic manipulation. In particular, we highlight the different aspects of arrhythmogenic mechanisms, pro-arrhythmic triggering factors, anti-arrhythmic agents, and electro-mechanical dysfunction investigated in Transgenic LQTS Rabbit models and their translational application for the clinical management of LQTS patients in detail. Transgenic LQTS Rabbits have been instrumental to increase our understanding of the role of spatial and temporal dispersion of repolarization to provide an arrhythmogenic substrate, genotype-differences in the mechanisms for early afterdepolarization formation and arrhythmia maintenance, mechanisms of hormonal modification of arrhythmogenesis and regional heterogeneities in electro-mechanical dysfunction in LQTS.
Bumrak Choi - One of the best experts on this subject based on the ideXlab platform.
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transient outward k current ito underlies the right ventricular initiation of polymorphic ventricular tachycardia in a Transgenic Rabbit model of long qt syndrome type 1
Circulation-arrhythmia and Electrophysiology, 2018Co-Authors: Bumrak Choi, Tae Yun Kim, Dmitry Terentyev, Mingwang Zhong, Anatoli Y Kabakov, Colin M Rees, Radmila Terentyeva, Xuwen Peng, Alain Karma, Gideon KorenAbstract:Background:Sudden death in long-QT syndrome type 1 (LQT1), an inherited disease caused by loss-of-function mutations in KCNQ1, is triggered by early afterdepolarizations (EADs) that initiate polymo...
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transient outward k current underlies heterogeneity of action potential duration and early afterdepolarization from right ventricle in Transgenic Rabbit model of long qt type 1
Biophysical Journal, 2015Co-Authors: Bumrak Choi, Zhilin Qu, Dmitry Terentyev, Colin M Rees, Xuwen Peng, Alain Karma, Weiyan Li, Radmila Terentieva, Gideon KorenAbstract:Introduction: Long QT syndrome type 1 (LQT1) is a congenital disease lacking slowly activating K+ channel (IKs), associated with polymorphic VT (pVT) and sudden cardiac death. Tissue heterogeneity has been proposed as an important factor to trigger and maintain pVT. We investigated ionic mechanisms that underlie regional differences in the formation of early afterdepolarization (EAD) using Transgenic Rabbit model of LQT1.Methods: The initiation of pVT under isoproterenol was mapped using optical mapping and myocytes isolated from RV and septum were studied using voltage clamp and confocal calcium imaging.Results: Optical mapping of LQT1 hearts showed pVT preferentially originating from right ventricle (RV) (16 of 18 pVTs), which was changed after perfusing transient outward K channel (Ito) blocker, 0.5 mM 4-aminopyridine (only 1 of 5 pVTs from RV, n=5 hearts). Myocytes isolated from RV demonstrated higher incidence of EADs under 50 nM isoproterenol (8 of 12 cells from RV vs. 2 of 11 cells from septum). Voltage clamp study highlighted regional differences of Ito (4.7 ± 0.5 in RV vs. 2.9 ± 0.7 pA/pF in septum at 0 mV) but other currents such as ICaL, IKr and RyR-mediated Ca2+ leak and SERCA-mediated Ca2+ uptake were same between RV and septum. Computer modeling study of Rabbit action potential lacking IKs exhibit frequent EADs but reduction of Ito prevented EAD formation, verifying that Ito plays a major role in EAD formation by providing repolarizing currents during the plateau phase to maintain the membrane potential lower enough to re-activate ICa window current to form EADs.Conclusion: Regional differences of Ito in LQT1 Rabbits underlie frequent pVTs originating mostly from RV myocytes with high incidence of EADs.
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hyperphosphorylation of ryrs underlies triggered activity in Transgenic Rabbit model of lqt2 syndrome
Circulation Research, 2014Co-Authors: Dmitry Terentyev, Hitesh K. Jindal, Colin M Rees, Radmila Terentyeva, Xuwen Peng, Katja E Odening, Leroy L Cooper, Jean M Daley, Kamana Bist, Bumrak ChoiAbstract:Rationale:Loss-of-function mutations in human ether go-go (HERG) potassium channels underlie long QT syndrome type 2 (LQT2) and are associated with fatal ventricular tachyarrhythmia. Previously, most studies focused on plasma membrane–related pathways involved in arrhythmogenesis in long QT syndrome, whereas proarrhythmic changes in intracellular Ca2+ handling remained unexplored. Objective:We investigated the remodeling of Ca2+ homeostasis in ventricular cardiomyocytes derived from Transgenic Rabbit model of LQT2 to determine whether these changes contribute to triggered activity in the form of early after depolarizations (EADs). Methods and Results:Confocal Ca2+ imaging revealed decrease in amplitude of Ca2+ transients and sarcoplasmic reticulum Ca2+ content in LQT2 myocytes. Experiments using sarcoplasmic reticulum–entrapped Ca2+ indicator demonstrated enhanced ryanodine receptor (RyR)–mediated sarcoplasmic reticulum Ca2+ leak in LQT2 cells. Western blot analyses showed increased phosphorylation of RyR...
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ttx converts polymorphic vt to monomorphic vt in Transgenic Rabbit model of lqt1
Biophysical Journal, 2013Co-Authors: Zachary Pfeiffer, Gideon Koren, Jungmin Hwang, Tae Yun Kim, Xuwen Peng, Brijesh Patel, Bumrak ChoiAbstract:Long QT syndrome Type 1 (LQT1) is a congenital disease defined by loss of function mutations in KCNQ1, and associated with syncope and sudden death preceded by polymorphic ventricular tachycardia (pVT). We hypothesized that inhibition of sodium channel function suppresses pVT formation. using a Transgenic Rabbit model of LQT1 (n=4), we simultaneously mapped activation patterns from a voltage sensitive dye and microelectrode. The AV node was ablated to slow intrinsic heart rate, isoproterenol (140nM) was injected to mimic sympathetic stimulation, and pVTs were subsequently observed (avg = 3-10 s). The associated activation patterns revealed multifocal activities and complex waveform propagation varying in spatial origin and direction. Subsequent perfusion of a sodium channel blocker, TTX (2 μM), notably converted pVTs toward monomorphic activation patterns. We also report evidence of fully rotating spiral waves, and their role in maintaining monomorphic VTs. Taken together, these results strongly suggest that 1) early afterdepolarizations (EADs) play an important role in maintaining pVTs complexity, 2) sodium currents significantly influence EAD regeneration by their continuous firing during pVTs, 3) sodium channel inhibition by TTX reduces EAD generation and stabilizes reentry into monomorphic VTs.View Large Image | View Hi-Res Image | Download PowerPoint Slide
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different ventricular fibrillation vf dynamics in long qt syndrome type 1 vs 2 in a Transgenic Rabbit model
Biophysical Journal, 2013Co-Authors: Tae Yun Kim, Gideon Koren, Jungmin Hwang, Xuwen Peng, Zachary Pfeiffer, Yukiko Kunitomo, Bumrak ChoiAbstract:Long QT syndrome (LQTS) is a congenital disease characterized by APD prolongation and associated with sudden cardiac death. LQT1 and LQT2, the most common types of LQTS, lack delayed rectifying potassium currents, IKs and IKr, respectively. We hypothesize that the differential kinetic properties of IKs and IKr can influence vulnerability to ventricular fibrillation (VF) through genotype-specific enhancement of VF maintenance. We investigated VF dynamics in Transgenic Rabbit models of LQT1, LQT2, and littermate controls (LMC) with optical mapping (n=6). VF frequency (VFF) analysis showed wave propagation to be slowest in LQT2 in line with APD gradient in groups (LQT2=7.06Hz, LQT1=11.72Hz, LMC=12.14Hz). Despite low frequency in LQT2, complexity of VFs was comparable to LMC. Further pattern analysis revealed that LQT2 exhibited higher incidence of wave breaks per wave while LQT1 shows even lower than LMC (LQT2=0.374 vs. LQT1=0.234, LMC=0.320). These results highlight role of IKr vs. IKs in VF maintenance, suggesting that VFs in LQT1 and 2 are maintained by different mechanisms such as wave breaks and re-initiation of reentry vs. triggered activity.View Large Image | View Hi-Res Image | Download PowerPoint Slide
Jungmin Hwang - One of the best experts on this subject based on the ideXlab platform.
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late ina blocker gs967 supresses polymorphic ventricular tachycardia in a Transgenic Rabbit model of long qt type 2
Circulation-arrhythmia and Electrophysiology, 2020Co-Authors: Luiz Belardinelli, Jungmin Hwang, Tae Yun Kim, Dmitry Terentyev, Mingwang Zhong, Anatoli Y Kabakov, Peter Bronk, Karuppiah Arunachalam, Sridharan RajamaniAbstract:Background: Long QT syndrome has been associated with sudden cardiac death likely caused by early afterdepolarizations (EADs) and polymorphic ventricular tachycardias (PVTs). Suppressing the late s...
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short long heart rate variation increases dispersion of action potential duration in long qt type 2 Transgenic Rabbit model
Scientific Reports, 2019Co-Authors: Paul Jeng, Gideon Koren, Jungmin Hwang, Xuwen Peng, Leroy L Cooper, Zachary Pfeiffer, Divyang Patel, Konstantinos Kossidas, Jason Centracchio, Zhilin QuAbstract:The initiation of polymorphic ventricular tachycardia in long QT syndrome type 2 (LQT2) has been associated with a characteristic ECG pattern of short-long RR intervals. We hypothesize that this characteristic pattern increases APD dispersion in LQT2, thereby promoting arrhythmia. We investigated APD dispersion and its dependence on two previous cycle lengths (CLs) in Transgenic Rabbit models of LQT2, LQT1, and their littermate controls (LMC) using random stimulation protocols. The results show that the short-long RR pattern was associated with a larger APD dispersion in LQT2 but not in LQT1 Rabbits. The multivariate analyses of APD as a function of two previous CLs (APDn = C + α1CLn−1 + α2CLn−2) showed that α1 (APD restitution slope) is largest and heterogeneous in LQT2 but uniform in LQT1, enhancing APD dispersion under long CLn−1 in LQT2. The α2 (short-term memory) was negative in LQT2 while positive in LQT1, and the spatial pattern of α1 was inversely correlated to α2 in LQT2, which explains why a short-long combination causes a larger APD dispersion in LQT2 but not in LQT1 Rabbits. In conclusion, short-long RR pattern increased APD dispersion only in LQT2 Rabbits through heterogeneous APD restitution and the short-term memory, underscoring the genotype-specific triggering of arrhythmias in LQT syndrome.
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complex excitation dynamics underlie polymorphic ventricular tachycardia in a Transgenic Rabbit model of long qt syndrome type 1
Heart Rhythm, 2015Co-Authors: Tae Yun Kim, Jungmin Hwang, Zachary Pfeiffer, Brijesh Patel, Yukiko Kunitomo, Paul Jeng, Divyang Patel, Kathryn Harrison, Ohad ZivAbstract:Background Long QT syndrome type 1 (LQT1) is a congenital disease arising from a loss of function in the slowly activating delayed potassium current I Ks , which causes early afterdepolarizations (EADs) and polymorphic ventricular tachycardia (pVT). Objective The purpose of this study was to investigate the mechanisms underlying pVT using a Transgenic Rabbit model of LQT1. Methods Hearts were perfused retrogradely, and action potentials were recorded using a voltage-sensitive dye and CMOS cameras. Results Bolus injection of isoproterenol (140 nM) induced pVT initiated by focal excitations from the right ventricle (RV; n=16 of 18 pVTs). After the pVT was initiated, complex focal excitations occurred in both the RV and the left ventricle, which caused oscillations of the QRS complexes on ECG, consistent with the recent proposal of multiple shifting foci caused by EAD chaos. Moreover, the action potential upstroke in pVT showed a bimodal distribution, demonstrating the coexistence of 2 types of excitation that interacted to produce complex pVT: Na + current (I Na )-mediated fast conduction and L-type Ca 2+ current (I Ca )-mediated slow conduction coexist, manifesting as pVT. Addition of 2 μM tetrodotoxin to reduce I Na converted pVT into monomorphic VT. Reducing late I Na in computer simulation converted pVT into a single dominant reentry, agreeing with experimental results. Conclusion Our study demonstrates that pVT in LQT1 Rabbits is initiated by focal excitations from the RV and is maintained by multiple shifting foci in both ventricles. Moreover, wave conduction in pVT exhibits bi-excitability, that is, fast wavefronts driven by I Na and slow wavefronts driven by I Ca co-exist during pVT.
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ttx converts polymorphic vt to monomorphic vt in Transgenic Rabbit model of lqt1
Biophysical Journal, 2013Co-Authors: Zachary Pfeiffer, Gideon Koren, Jungmin Hwang, Tae Yun Kim, Xuwen Peng, Brijesh Patel, Bumrak ChoiAbstract:Long QT syndrome Type 1 (LQT1) is a congenital disease defined by loss of function mutations in KCNQ1, and associated with syncope and sudden death preceded by polymorphic ventricular tachycardia (pVT). We hypothesized that inhibition of sodium channel function suppresses pVT formation. using a Transgenic Rabbit model of LQT1 (n=4), we simultaneously mapped activation patterns from a voltage sensitive dye and microelectrode. The AV node was ablated to slow intrinsic heart rate, isoproterenol (140nM) was injected to mimic sympathetic stimulation, and pVTs were subsequently observed (avg = 3-10 s). The associated activation patterns revealed multifocal activities and complex waveform propagation varying in spatial origin and direction. Subsequent perfusion of a sodium channel blocker, TTX (2 μM), notably converted pVTs toward monomorphic activation patterns. We also report evidence of fully rotating spiral waves, and their role in maintaining monomorphic VTs. Taken together, these results strongly suggest that 1) early afterdepolarizations (EADs) play an important role in maintaining pVTs complexity, 2) sodium currents significantly influence EAD regeneration by their continuous firing during pVTs, 3) sodium channel inhibition by TTX reduces EAD generation and stabilizes reentry into monomorphic VTs.View Large Image | View Hi-Res Image | Download PowerPoint Slide
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different ventricular fibrillation vf dynamics in long qt syndrome type 1 vs 2 in a Transgenic Rabbit model
Biophysical Journal, 2013Co-Authors: Tae Yun Kim, Gideon Koren, Jungmin Hwang, Xuwen Peng, Zachary Pfeiffer, Yukiko Kunitomo, Bumrak ChoiAbstract:Long QT syndrome (LQTS) is a congenital disease characterized by APD prolongation and associated with sudden cardiac death. LQT1 and LQT2, the most common types of LQTS, lack delayed rectifying potassium currents, IKs and IKr, respectively. We hypothesize that the differential kinetic properties of IKs and IKr can influence vulnerability to ventricular fibrillation (VF) through genotype-specific enhancement of VF maintenance. We investigated VF dynamics in Transgenic Rabbit models of LQT1, LQT2, and littermate controls (LMC) with optical mapping (n=6). VF frequency (VFF) analysis showed wave propagation to be slowest in LQT2 in line with APD gradient in groups (LQT2=7.06Hz, LQT1=11.72Hz, LMC=12.14Hz). Despite low frequency in LQT2, complexity of VFs was comparable to LMC. Further pattern analysis revealed that LQT2 exhibited higher incidence of wave breaks per wave while LQT1 shows even lower than LMC (LQT2=0.374 vs. LQT1=0.234, LMC=0.320). These results highlight role of IKr vs. IKs in VF maintenance, suggesting that VFs in LQT1 and 2 are maintained by different mechanisms such as wave breaks and re-initiation of reentry vs. triggered activity.View Large Image | View Hi-Res Image | Download PowerPoint Slide
Neil D Christensen - One of the best experts on this subject based on the ideXlab platform.
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Rabbit genetics and Transgenic models
The Laboratory Rabbit Guinea Pig Hamster and Other Rodents, 2012Co-Authors: Neil D Christensen, Xuwen PengAbstract:Publisher Summary Researchers using Rabbit models to study diverse projects such as infectious diseases, atherosclerosis, antiviral treatments, toxicology, diabetes, transplantation, eye diseases (both inherited and infectious), milk production, breed sizes, quantitative traits, immunology, and Transgenics will all benefit from the upcoming newly compiled Oryctolagus cuniculus genomic sequence. The Broad Institute's Rabbit Genome Project was designed to encompass a deep full coverage that will be both a comprehensive and powerful resource for Rabbit researchers and the Rabbit industry alike. Comparative genomics, disease traits, and the selection for resistance/susceptibility to important human pathogens are likely to benefit from this new database. In addition, the domestic Rabbit is an important research tool to study other genetic predispositions including inherited hyperlipidemia, atherosclerosis, glaucoma, and diabetes, and for the production of polyclonal antibodies and biopharmaceuticals via Transgenics. Transgenic Rabbit models for studying the genetics of specific diseases continue to expand the knowledge of these processes in humans and provide excellent preclinical models for therapeutic treatments. Rabbits also are excellent models to study immune responses to various pathogens and are used extensively to make specialized antibody reagents for the research community.
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vaccine generated immunity targets an hpv16 e7 hla a2 1 restricted cd8 t cell epitope relocated to an early gene or a late gene of the cottontail Rabbit papillomavirus crpv genome in hla a2 1 Transgenic Rabbits
Vaccine, 2011Co-Authors: Callie E Bounds, Nancy M Cladel, Karla K Balogh, Neil D ChristensenAbstract:The newly established HLA-A2.1 Transgenic Rabbit model has proven useful for testing the immunogenicity of well known and computer-predicted A2-restricted epitopes. In the current study we compared the protective immunity induced to a preferred HPV16 E7 A2-restricted epitope that has been relocated to positions within the CRPV E7 gene and the CRPV L2 gene. Epitope expression from both the E7 protein and the L2 protein resulted in increased protection against viral DNA challenge of the HLA-A2.1 Transgenic Rabbits as compared to control-vaccinated Rabbit groups. These data indicate that proteins expressed at both early and late time points during a natural papillomavirus infection can be targeted by epitope-specific immunity and indicate this immunity is increased to early rather than late expressed proteins of papillomaviruses. This study also highlights the broad utility of the HLAA2.1 Transgenic Rabbit model for testing numerous immunological factors involved in vaccine generated protective immunity.
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using hla a2 1 Transgenic Rabbit model to screen and characterize new hla a2 1 restricted epitope dna vaccines
Journal of Vaccines and Vaccination, 2010Co-Authors: Todd D Schell, Xuwen Peng, Nancy M Cladel, Karla K Balogh, Neil D ChristensenAbstract:We have established an HLA-A2.1 Transgenic Rabbit /cottontail Rabbit papillomavirus (CRPV) infection model. Using this novel Transgenic animal model, we reported earlier that a multivalent epitope DNA vaccine (CRPVE1ep1-5) containing five HLA-A2.1 restricted epitopes from CRPVE1 (42-50, 149-157, 161-169, 245-253 and 303-311) was successful in providing strong and specific protective and therapeutic immunity. Among these five epitopes, two (161- 169 and 303-311) have been proven to stimulate strong immunity in both HLA-A2.1 Transgenic mouse and Rabbit models. In the current study, we further identified the remaining three epitopes (CRPVE1/42-50,149-157, 245-253) in both animal models. CRPVE1/149-157 was able to induce specific CTL responses in HLA-A2.1 Transgenic mice by DNA immunization but undetectable by peptide immunization. CRPVE1/42-50 and 245-253 failed to respond in HLA-A2.1 Transgenic mice either by peptide or DNA immunization. All the three epitopes when administrated as DNA vaccines, however, were able to stimulate strong protective immunity in HLA-A2.1 Transgenic Rabbits in a dose dependent manner. Among the five epitopes, two (CRPVE1/ 303-311and CRPVE1/149-157) DNA vaccines also showed specific therapeutic effects in CRPV-infected HLA-A2.1 Transgenic Rabbits. Taken together, the HLA-A2.1 Transgenic Rabbit model recognized more epitopes than did the HLA-A2.1 Transgenic mouse model. Our data demonstrate that the HLA-A2.1 Transgenic Rabbit model can complement the HLA-A2.1 Transgenic mouse model for the development and testing of new HLA-A2.1 restricted prophylactic and therapeutic T cell based DNA vaccines.
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a novel hla hla a 0201 Transgenic Rabbit model for preclinical evaluation of human cd8 t cell epitope based vaccines against ocular herpes
Journal of Immunology, 2010Co-Authors: Aziz Alami Chentoufi, Neil D Christensen, Anthony B Nesburn, Steven L Wechsler, Gargi Dasgupta, Zareen S Choudhury, Arfan Azeem, James V Jester, Lbachir BenmohamedAbstract:We introduced a novel humanized HLA-A*0201 Transgenic (HLA Tg) Rabbit model to assess the protective efficacy of a human CD8+ T cell epitope-based vaccine against primary ocular herpes infection and disease. Each of the three immunodominant human CD8+ T cell peptide epitopes from HSV-1 glycoprotein D (gD53–61, gD70–78, and gD278–286) were joined with a promiscuous human CD4+ T cell peptide epitope (gD49–82) to construct three separate pairs of CD4–CD8 peptides. Each CD4–CD8 peptide pair was then covalently linked to an Ne-palmitoyl–lysine residue via a functional base lysine amino group to construct CD4–CD8 lipopeptides. HLA Tg Rabbits were immunized s.c. with a mixture of the three CD4–CD8 HSV-1 gD lipopeptides. The HSV-gD–specific T cell responses induced by the mixture of CD4–CD8 lipopeptide vaccine and the protective efficacy against acute virus replication and ocular disease were determined. Immunization induced HSV-gD49–82–specific CD4+ T cells in draining lymph node (DLN); induced HLA-restricted HSV-gD53–61, gD70–78, and gD278–286–specific CD8+ T cells in DLN, conjunctiva, and trigeminal ganglia and reduced HSV-1 replication in tears and corneal eye disease after ocular HSV-1 challenge. In addition, the HSV-1 epitope-specific CD8+ T cells induced in DLNs, conjunctiva, and the trigeminal ganglia were inversely proportional with corneal disease. The humanized HLA Tg Rabbits appeared to be a useful preclinical animal model for investigating the immunogenicity and protective efficacy of human CD8+ T cell epitope-based prophylactic vaccines against ocular herpes. The relevance of HLA Tg Rabbits for future investigation of human CD4–CD8 epitope-based therapeutic vaccines against recurrent HSV-1 is discussed.
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protective immunity with an e1 multivalent epitope dna vaccine against cottontail Rabbit papillomavirus crpv infection in an hla a2 1 Transgenic Rabbit model
Vaccine, 2008Co-Authors: Nancy M Cladel, Xuwen Peng, Karla K Balogh, Neil D ChristensenAbstract:Cottontail Rabbit papillomavirus (CRPV)/Rabbit model is widely used to study pathogenesis of papillomavirus infections and malignant tumor progression. Recently, we established HLA-A2.1 Transgenic Rabbit lines and demonstrated efficacy for the testing of immunogenicity of a well-known A2-resticted epitope (HPV16E7/82-90) [Hu J, Peng X, Schell TD, Budgeon LR, Cladel NM, Christensen ND. An HLA-A2.1-Transgenic Rabbit model to study immunity to papillomavirus infection. J Immunol 2006;177(11):8037-45]. In the present study, we screened five HLA-A2.1 restricted epitopes from CRPVE1 (selected using online MHCI epitope prediction software) and constructed a multivalent epitope DNA vaccine (CRPVE1ep1-5). CRPVE1ep1-5 and a control DNA vaccine (Ub3) were then delivered intracutaneously onto normal and HLA-A2.1 Transgenic Rabbits, respectively, by a helium-driven gene-gun delivery system. One, two or three immunizations were given to different groups of animals from both New Zealand White outbred and EIII/JC inbred genetic background. Two and three immunizations with CRPVE1ep1-5 DNA vaccine provided complete protection against viral DNA infection of HLA-A2.1 Transgenic Rabbits from both genetic backgrounds but not in the control-vaccinated groups. One immunization, however, failed to protect HLA-A2.1 Transgenic Rabbits against viral DNA infection. This study further demonstrated that the HLA-A2.1 Transgenic Rabbits can be used to test the immunogenicity of HLA-A2.1 restricted epitopes identified by MHCI epitope predication software.