The Experts below are selected from a list of 2529 Experts worldwide ranked by ideXlab platform
Christopher L.-h. Huang - One of the best experts on this subject based on the ideXlab platform.
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sodium channel haploinsufficiency and structural change in Ventricular Arrhythmogenesis
Acta Physiologica, 2016Co-Authors: Andrew A Grace, Kamalan Jeevaratnam, Laila Guzadhur, Yong Meng Goh, Christopher L.-h. HuangAbstract:Normal cardiac excitation involves orderly conduction of electrical activation and recovery dependent upon surface membrane, voltage-gated, sodium (Na(+) ) channel α-subunits (Nav 1.5). We summarize experimental studies of physiological and clinical consequences of loss-of-function Na(+) channel mutations. Of these conditions, Brugada syndrome (BrS) and progressive cardiac conduction defect (PCCD) are associated with sudden, often fatal, Ventricular tachycardia (VT) or fibrillation. Mouse Scn5a(+/-) hearts replicate important clinical phenotypes modelling these human conditions. The arrhythmic phenotype is associated not only with the primary biophysical change but also with additional, anatomical abnormalities, in turn dependent upon age and sex, each themselves exerting arrhythmic effects. Available evidence suggests a unified binary scheme for the development of arrhythmia in both BrS and PCCD. Previous biophysical studies suggested that Nav 1.5 deficiency produces a background electrophysiological defect compromising conduction, thereby producing an arrhythmic substrate unmasked by flecainide or ajmaline challenge. More recent reports further suggest a progressive decline in conduction velocity and increase in its dispersion particularly in ageing male Nav 1.5 haploinsufficient compared to WT hearts. This appears to involve a selective appearance of slow conduction at the expense of rapidly conducting pathways with changes in their frequency distributions. These changes were related to increased cardiac fibrosis. It is thus the combination of the structural and biophysical changes both accentuating arrhythmic substrate that may produce arrhythmic tendency. This binary scheme explains the combined requirement for separate, biophysical and structural changes, particularly occurring in ageing Nav 1.5 haploinsufficient males in producing clinical arrhythmia.
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Ca2+ Signaling and Heart Rhythm
Frontiers Media SA, 2016Co-Authors: John R Solaro, Christopher L.-h. Huang, Ming LeiAbstract:Ca2+ is a key second messenger in the intricate workings of the heart. In cardiac myocytes, Ca2+ signaling controls or modulates electrophysiological function, excitation-contraction coupling, contractile function, energy balance, cell death, and gene transcription. Thus, diverse Ca2+-dependent regulatory processes occur simultaneously within a cell. Yet, distinct signals can be resolved by local Ca2+ sensitive protein complexes and differential Ca2+ signal integration. In addition to its importance to normal cardiac function, such regulation is also crucial in disease conditions. Ca2+ is likely involved in ectopic cardiac rhythms in both atrial and Ventricular tissues through generating triggered activity often appearing as delayed afterdepolarisations, particularly following cellular Ca overloading. Recent studies also implicate Ca2+ in Na+ channel expression and properties with consequences for conduction velocity and therefore arrhythmic substrate. At the cellular level, such regulation involves control of the activity of membrane ion channels and Ca2+ handling proteins. These in turn involve multiple extra- and intracellular signaling pathways. This e-book assembles review and original articles from experts in this field. It summarises major recent progress bearing on roles of Ca2+ in cardiac electrophysiological function encompassing both normal and abnormal cardiac function. These extend from physiological roles of Ca2+ signaling in pacemaker function, in particular generation of sino-atrial pacemaker potentials, to pathological roles of abnormal Ca2+ signaling in both atrial and Ventricular Arrhythmogenesis. It also seeks to bridge the gap between advances in basic science and development of new therapies
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Ventricular Arrhythmogenesis following slowed conduction in heptanol-treated, Langendorff-perfused mouse hearts
The Journal of Physiological Sciences, 2012Co-Authors: Gary Tse, Andrew A Grace, Sandeep S. Hothi, Christopher L.-h. HuangAbstract:Arrhythmogenic effects of slowed action potential conduction produced by the gap junction and sodium-channel inhibitor heptanol (0.1–2 m M ) were explored in Langendorff-perfused mouse hearts. Monophasic action potential recordings showed that 2 m M heptanol induced Ventricular tachycardia in the absence of triggered activity arising from early or after-depolarizations during regular 8 Hz pacing and programmed electrical stimulation (PES). It also increased activation latencies and Ventricular effective refractory periods (VERPs), but did not alter action potential duration (APD), thereby reducing local critical intervals for re-excitation given by APD_90 − VERP. Bipolar electrogram recordings showed that 2 m M heptanol increased electrogram duration (EGD) and ratios of EGDs obtained at the longest to those obtained at the shortest S1S2 intervals studied during PES, suggesting increased dispersion of conduction velocities. These findings show, for the first time in the mouse heart, that slowed conduction induces reversible arrhythmogenic effects despite repolarization abnormalities expected to reduce arrhythmogenicity.
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Epac activation, altered calcium homeostasis and Ventricular Arrhythmogenesis in the murine heart
Pflügers Archiv - European Journal of Physiology, 2008Co-Authors: Sandeep S. Hothi, Iman S Gurung, Andrew A Grace, Yanmin Zhang, Jennifer C. Heathcote, Stephen W. Booth, Jeremy N. Skepper, Christopher L.-h. HuangAbstract:The recently described exchange protein directly activated by cAMP (Epac) has been implicated in distinct protein kinase A-independent cellular signalling pathways. We investigated the role of Epac activation in adrenergically mediated Ventricular Arrhythmogenesis. In contrast to observations in control conditions ( n = 20), monophasic action potentials recorded in 2 of 10 intrinsically beating and 5 of 20 extrinsically paced Langendorff-perfused wild-type murine hearts perfused with the Epac activator 8-pCPT-2′-O-Me-cAMP (8-CPT, 1 μM) showed spontaneous triggered activity. Three of 20 such extrinsically paced hearts showed spontaneous Ventricular tachycardia (VT). Programmed electrical stimulation provoked VT in 10 of 20 similarly treated hearts ( P 0.05) in left Ventricular epicardial (40.7 ± 1.2 versus 44.0 ± 1.7 ms; n = 10) or endocardial action potential durations (APD_90; 51.8 ± 2.3 versus 51.9 ± 2.2 ms; n = 10), transmural (ΔAPD_90) (11.1 ± 2.6 versus 7.9 ± 2.8 ms; n = 10) or apico-basal repolarisation gradients, Ventricular effective refractory periods (29.1 ± 1.7 versus 31.2 ± 2.4 ms in control and 8-CPT-treated hearts, respectively; n = 10) and APD_90 restitution characteristics. Nevertheless, fluorescence imaging of cytosolic Ca^2+ levels demonstrated abnormal Ca^2+ homeostasis in paced and resting isolated Ventricular myocytes. Epac activation using isoproterenol in the presence of H-89 was also arrhythmogenic and similarly altered cellular Ca^2+ homeostasis. Epac-dependent effects were reduced by Ca^2+/calmodulin-dependent protein kinase II (CaMKII) inhibition with 1 μM KN-93. These findings associate VT in an intact cardiac preparation with altered cellular Ca^2+ homeostasis and Epac activation for the first time, in the absence of altered repolarisation gradients previously implicated in reentrant arrhythmias through a mechanism dependent on CaMKII activity.
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dispersions of repolarization and Ventricular Arrhythmogenesis lessons from animal models
Progress in Biophysics & Molecular Biology, 2008Co-Authors: Matthew J Killeen, Andrew A Grace, Ian N Sabir, Christopher L.-h. HuangAbstract:Sudden cardiac death resulting from Ventricular Arrhythmogenesis is a leading cause of mortality in the developed world, accounting for up to 400,000 deaths per year in the US alone. Within the past forty years we have taken considerable leaps forward in our understanding of the causes and mechanisms underlying cardiac arrhythmias, particularly in the setting of inherited and acquired dysfunctions in ionic currents which constitute human long QT syndrome (LQTS). Impaired repolarization seen in LQTS commonly gives rise to an altered dispersion of repolarization, which is considered to provide the functional substrate necessary for the perpetuation of lethal arrhythmias. This review examines the bases for arrhythmias arising from repolarization heterogeneities and explores the applicability of the genetically amenable mouse for the study of arrhythmias arising from such mechanisms.
Andrew A Grace - One of the best experts on this subject based on the ideXlab platform.
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sodium channel haploinsufficiency and structural change in Ventricular Arrhythmogenesis
Acta Physiologica, 2016Co-Authors: Andrew A Grace, Kamalan Jeevaratnam, Laila Guzadhur, Yong Meng Goh, Christopher L.-h. HuangAbstract:Normal cardiac excitation involves orderly conduction of electrical activation and recovery dependent upon surface membrane, voltage-gated, sodium (Na(+) ) channel α-subunits (Nav 1.5). We summarize experimental studies of physiological and clinical consequences of loss-of-function Na(+) channel mutations. Of these conditions, Brugada syndrome (BrS) and progressive cardiac conduction defect (PCCD) are associated with sudden, often fatal, Ventricular tachycardia (VT) or fibrillation. Mouse Scn5a(+/-) hearts replicate important clinical phenotypes modelling these human conditions. The arrhythmic phenotype is associated not only with the primary biophysical change but also with additional, anatomical abnormalities, in turn dependent upon age and sex, each themselves exerting arrhythmic effects. Available evidence suggests a unified binary scheme for the development of arrhythmia in both BrS and PCCD. Previous biophysical studies suggested that Nav 1.5 deficiency produces a background electrophysiological defect compromising conduction, thereby producing an arrhythmic substrate unmasked by flecainide or ajmaline challenge. More recent reports further suggest a progressive decline in conduction velocity and increase in its dispersion particularly in ageing male Nav 1.5 haploinsufficient compared to WT hearts. This appears to involve a selective appearance of slow conduction at the expense of rapidly conducting pathways with changes in their frequency distributions. These changes were related to increased cardiac fibrosis. It is thus the combination of the structural and biophysical changes both accentuating arrhythmic substrate that may produce arrhythmic tendency. This binary scheme explains the combined requirement for separate, biophysical and structural changes, particularly occurring in ageing Nav 1.5 haploinsufficient males in producing clinical arrhythmia.
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Ventricular Arrhythmogenesis following slowed conduction in heptanol-treated, Langendorff-perfused mouse hearts
The Journal of Physiological Sciences, 2012Co-Authors: Gary Tse, Andrew A Grace, Sandeep S. Hothi, Christopher L.-h. HuangAbstract:Arrhythmogenic effects of slowed action potential conduction produced by the gap junction and sodium-channel inhibitor heptanol (0.1–2 m M ) were explored in Langendorff-perfused mouse hearts. Monophasic action potential recordings showed that 2 m M heptanol induced Ventricular tachycardia in the absence of triggered activity arising from early or after-depolarizations during regular 8 Hz pacing and programmed electrical stimulation (PES). It also increased activation latencies and Ventricular effective refractory periods (VERPs), but did not alter action potential duration (APD), thereby reducing local critical intervals for re-excitation given by APD_90 − VERP. Bipolar electrogram recordings showed that 2 m M heptanol increased electrogram duration (EGD) and ratios of EGDs obtained at the longest to those obtained at the shortest S1S2 intervals studied during PES, suggesting increased dispersion of conduction velocities. These findings show, for the first time in the mouse heart, that slowed conduction induces reversible arrhythmogenic effects despite repolarization abnormalities expected to reduce arrhythmogenicity.
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Epac activation, altered calcium homeostasis and Ventricular Arrhythmogenesis in the murine heart
Pflügers Archiv - European Journal of Physiology, 2008Co-Authors: Sandeep S. Hothi, Iman S Gurung, Andrew A Grace, Yanmin Zhang, Jennifer C. Heathcote, Stephen W. Booth, Jeremy N. Skepper, Christopher L.-h. HuangAbstract:The recently described exchange protein directly activated by cAMP (Epac) has been implicated in distinct protein kinase A-independent cellular signalling pathways. We investigated the role of Epac activation in adrenergically mediated Ventricular Arrhythmogenesis. In contrast to observations in control conditions ( n = 20), monophasic action potentials recorded in 2 of 10 intrinsically beating and 5 of 20 extrinsically paced Langendorff-perfused wild-type murine hearts perfused with the Epac activator 8-pCPT-2′-O-Me-cAMP (8-CPT, 1 μM) showed spontaneous triggered activity. Three of 20 such extrinsically paced hearts showed spontaneous Ventricular tachycardia (VT). Programmed electrical stimulation provoked VT in 10 of 20 similarly treated hearts ( P 0.05) in left Ventricular epicardial (40.7 ± 1.2 versus 44.0 ± 1.7 ms; n = 10) or endocardial action potential durations (APD_90; 51.8 ± 2.3 versus 51.9 ± 2.2 ms; n = 10), transmural (ΔAPD_90) (11.1 ± 2.6 versus 7.9 ± 2.8 ms; n = 10) or apico-basal repolarisation gradients, Ventricular effective refractory periods (29.1 ± 1.7 versus 31.2 ± 2.4 ms in control and 8-CPT-treated hearts, respectively; n = 10) and APD_90 restitution characteristics. Nevertheless, fluorescence imaging of cytosolic Ca^2+ levels demonstrated abnormal Ca^2+ homeostasis in paced and resting isolated Ventricular myocytes. Epac activation using isoproterenol in the presence of H-89 was also arrhythmogenic and similarly altered cellular Ca^2+ homeostasis. Epac-dependent effects were reduced by Ca^2+/calmodulin-dependent protein kinase II (CaMKII) inhibition with 1 μM KN-93. These findings associate VT in an intact cardiac preparation with altered cellular Ca^2+ homeostasis and Epac activation for the first time, in the absence of altered repolarisation gradients previously implicated in reentrant arrhythmias through a mechanism dependent on CaMKII activity.
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dispersions of repolarization and Ventricular Arrhythmogenesis lessons from animal models
Progress in Biophysics & Molecular Biology, 2008Co-Authors: Matthew J Killeen, Andrew A Grace, Ian N Sabir, Christopher L.-h. HuangAbstract:Sudden cardiac death resulting from Ventricular Arrhythmogenesis is a leading cause of mortality in the developed world, accounting for up to 400,000 deaths per year in the US alone. Within the past forty years we have taken considerable leaps forward in our understanding of the causes and mechanisms underlying cardiac arrhythmias, particularly in the setting of inherited and acquired dysfunctions in ionic currents which constitute human long QT syndrome (LQTS). Impaired repolarization seen in LQTS commonly gives rise to an altered dispersion of repolarization, which is considered to provide the functional substrate necessary for the perpetuation of lethal arrhythmias. This review examines the bases for arrhythmias arising from repolarization heterogeneities and explores the applicability of the genetically amenable mouse for the study of arrhythmias arising from such mechanisms.
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Ventricular Arrhythmogenesis insights from murine models
Progress in Biophysics & Molecular Biology, 2008Co-Authors: Ian N Sabir, Matthew J Killeen, Andrew A Grace, Christopher L.-h. HuangAbstract:Ventricular arrhythmias are the key underlying cause of sudden cardiac death, a common cause of mortality and a significant public health burden. Insights into the electrophysiological basis of such phenomena have been obtained using a wide range of recording techniques and a diversity of experimental models. As in other fields of biology, the murine system presents both a wealth of opportunities and important challenges when employed to model the human case. This article begins by reviewing the extent to which the murine heart is representative of that of the human. It then presents a novel physiological classification of mechanisms of Arrhythmogenesis, critically assessing the extent to which the study of murine hearts has offered worthwhile insights.
Michael C Wadman - One of the best experts on this subject based on the ideXlab platform.
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macrophage depletion in stellate ganglia alleviates cardiac sympathetic overactivation and Ventricular Arrhythmogenesis by attenuating neuroinflammation in heart failure
Basic Research in Cardiology, 2021Co-Authors: Dongze Zhang, Bryan T Hackfort, Bin Duan, Wanfen Xiong, Michael C WadmanAbstract:Cardiac sympathetic overactivation is involved in Arrhythmogenesis in patients with chronic heart failure (CHF). Inflammatory infiltration in the stellate ganglion (SG) is a critical factor for cardiac sympathoexcitation in patients with Ventricular arrhythmias. This study aims to investigate if macrophage depletion in SGs decreases cardiac sympathetic overactivation and Ventricular Arrhythmogenesis in CHF. Surgical ligation of the coronary artery was used for induction of CHF. Clodronate liposomes were microinjected into bilateral SGs of CHF rats for macrophage depletion. Using cytokine array, immunofluorescence staining, and Western blot analysis, we found that macrophage expansion and expression of TNFα and IL-1β in SGs were markedly increased in CHF rats. Flow cytometry data confirmed that the percentage of macrophages in SGs was higher in CHF rats than that in sham rats. Clodronate liposomes significantly reduced CHF-elevated proinflammatory cytokine levels and macrophage expansion in SGs. Clodronate liposomes also reduced CHF-increased N-type Ca2+ currents and excitability of cardiac sympathetic postganglionic neurons and inhibited CHF-enhanced cardiac sympathetic nerve activity. ECG data from 24-h, continuous telemetry recording in conscious rats demonstrated that clodronate liposomes not only restored CHF-induced heterogeneity of Ventricular electrical activities, but also decreased the incidence and duration of Ventricular tachycardia/fibrillation in CHF. Macrophage depletion with clodronate liposomes attenuated CHF-induced cardiac sympathetic overactivation and Ventricular arrhythmias through reduction of macrophage expansion and neuroinflammation in SGs.
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inhibition of n type calcium channels in cardiac sympathetic neurons attenuates Ventricular Arrhythmogenesis in heart failure
Cardiovascular Research, 2021Co-Authors: Dongze Zhang, Robert L Muelleman, Chaojun Wang, Liang Cao, Bryan T Hackfort, Michael C WadmanAbstract:Aims Cardiac sympathetic overactivation is an important trigger of Ventricular arrhythmias in patients with chronic heart failure (CHF). Our previous study demonstrated that N-type calcium (Cav2.2) currents in cardiac sympathetic post-ganglionic (CSP) neurons were increased in CHF. This study investigated the contribution of Cav2.2 channels in cardiac sympathetic overactivation and Ventricular Arrhythmogenesis in CHF. Methods and results Rat CHF was induced by surgical ligation of the left coronary artery. Lentiviral Cav2.2-α shRNA or scrambled shRNA was transfected in vivo into stellate ganglia (SG) in CHF rats. Final experiments were performed at 14 weeks after coronary artery ligation. Real-time polymerase chain reaction and western blot data showed that in vivo transfection of Cav2.2-α shRNA reduced the expression of Cav2.2-α mRNA and protein in the SG in CHF rats. Cav2.2-α shRNA also reduced Cav2.2 currents and cell excitability of CSP neurons and attenuated cardiac sympathetic nerve activities (CSNA) in CHF rats. The power spectral analysis of heart rate variability (HRV) further revealed that transfection of Cav2.2-α shRNA in the SG normalized CHF-caused cardiac sympathetic overactivation in conscious rats. Twenty-four-hour continuous telemetry electrocardiogram recording revealed that this Cav2.2-α shRNA not only decreased incidence and duration of Ventricular tachycardia/Ventricular fibrillation but also improved CHF-induced heterogeneity of Ventricular electrical activity in conscious CHF rats. Cav2.2-α shRNA also decreased susceptibility to Ventricular arrhythmias in anaesthetized CHF rats. However, Cav2.2-α shRNA failed to improve CHF-induced cardiac contractile dysfunction. Scrambled shRNA did not affect Cav2.2 currents and cell excitability of CSP neurons, CSNA, HRV, and Ventricular Arrhythmogenesis in CHF rats. Conclusions Overactivation of Cav2.2 channels in CSP neurons contributes to cardiac sympathetic hyperactivation and Ventricular Arrhythmogenesis in CHF. This suggests that discovering purely selective and potent small-molecule Cav2.2 channel blockers could be a potential therapeutic strategy to decrease fatal Ventricular arrhythmias in CHF.
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reduced n type ca2 channels in atrioVentricular ganglion neurons are involved in Ventricular Arrhythmogenesis
Journal of the American Heart Association, 2018Co-Authors: Dongze Zhang, Hong Zheng, Robert L Muelleman, Liang Cao, Michael C WadmanAbstract:Background Attenuated cardiac vagal activity is associated with Ventricular Arrhythmogenesis and related mortality in patients with chronic heart failure. Our recent study has shown that expression of N‐type Ca 2+ channel α‐subunits (Ca v 2.2‐α) and N‐type Ca 2+ currents are reduced in intracardiac ganglion neurons from rats with chronic heart failure. Rat intracardiac ganglia are divided into the atrioVentricular ganglion (AVG) and sinoatrial ganglion. Ventricular myocardium receives projection of neuronal terminals only from the AVG. In this study we tested whether a decrease in N‐type Ca 2+ channels in AVG neurons contributes to Ventricular Arrhythmogenesis. Methods and Results Lentiviral Ca v 2.2‐α shRNA (2 μL, 2×10 7 pfu/mL) or scrambled shRNA was in vivo transfected into rat AVG neurons. Nontransfected sham rats served as controls. Using real‐time single‐cell polymerase chain reaction and reverse‐phase protein array, we found that in vivo transfection of Ca v 2.2‐α shRNA decreased expression of Ca v 2.2‐α mRNA and protein in rat AVG neurons. Whole‐cell patch‐clamp data showed that Ca v 2.2‐α shRNA reduced N‐type Ca 2+ currents and cell excitability in AVG neurons. The data from telemetry electrocardiographic recording demonstrated that 83% (5 out of 6) of conscious rats with Ca v 2.2‐α shRNA transfection had premature Ventricular contractions ( P v 2.2‐α shRNA transfection compared with nontransfected sham rats and scrambled shRNA‐transfected rats. Conclusions A decrease in N‐type Ca 2+ channels in AVG neurons attenuates vagal control of Ventricular myocardium, thereby initiating Ventricular arrhythmias.
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abstract 14004 overactivation of n type calcium channels in stellate ganglia and Ventricular Arrhythmogenesis in chronic heart faiulre
Circulation, 2017Co-Authors: Dongze Zhang, Robert L Muelleman, Chaojun Wang, Michael C WadmanAbstract:Ventricular arrhythmia is a leading cause of sudden cardiac death in patients with chronic heart failure (CHF). Cardiac sympathetic overactivation is an important trigger for onset of Ventricular a...
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correlation of Ventricular Arrhythmogenesis with neuronal remodeling of cardiac postganglionic parasympathetic neurons in the late stage of heart failure after myocardial infarction
Frontiers in Neuroscience, 2017Co-Authors: Dongze Zhang, Robert L Muelleman, Chaojun Wang, Liang Cao, Michael C WadmanAbstract:Introduction: Ventricular arrhythmia is a major cause of sudden cardiac death in patients with chronic heart failure (CHF). Our recent study demonstrates that N-type Ca2+ currents in intracardiac ganglionic neurons are reduced in the late stage of CHF rats. Rat intracardiac ganglia are divided into the atrioVentricular ganglion (AVG) and sinoatrial ganglion. Only AVG nerve terminals innervate the Ventricular myocardium. In this study, we tested the correlation of electrical remodeling in AVG neurons with Ventricular Arrhythmogenesis in CHF rats. Methods and results: CHF was induced in male Sprague-Dawley rats by surgical ligation of the left coronary artery. The data from 24-hour continuous radiotelemetry ECG recording in conscious rats showed that Ventricular tachycardia/fibrillation (VT/VF) occurred in 3-week and 14-week CHF rats but not 8-week CHF rats. Additionally, as an index for vagal control of Ventricular function, changes of left Ventricular systolic pressure (LVSP) and the maximum rate of left Ventricular pressure rise (LV dP/dtmax) in response to vagal efferent nerve stimulation were blunted in 14-week CHF rats but not 3-week or 8-week CHF rats. Results from whole-cell patch clamp recording demonstrated that N-type Ca2+ currents in AVG neurons began to decrease in 8-week CHF rats, and that there was also a significant decrease in 14-week CHF rats. Correlation analysis revealed that N-type Ca2+ currents in AVG neurons negatively correlated with the cumulative duration of VT/VF in 14-week CHF rats, whereas there was no correlation between N-type Ca2+ currents in AVG neurons and the cumulative duration of VT/VF in 3-week CHF. Conclusion: Malignant Ventricular arrhythmias mainly occur in the early and late stages of CHF. Electrical remodeling of AVG neurons highly correlates with the occurrence of Ventricular arrhythmias in the late stage of CHF.
Dongze Zhang - One of the best experts on this subject based on the ideXlab platform.
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macrophage depletion in stellate ganglia alleviates cardiac sympathetic overactivation and Ventricular Arrhythmogenesis by attenuating neuroinflammation in heart failure
Basic Research in Cardiology, 2021Co-Authors: Dongze Zhang, Bryan T Hackfort, Bin Duan, Wanfen Xiong, Michael C WadmanAbstract:Cardiac sympathetic overactivation is involved in Arrhythmogenesis in patients with chronic heart failure (CHF). Inflammatory infiltration in the stellate ganglion (SG) is a critical factor for cardiac sympathoexcitation in patients with Ventricular arrhythmias. This study aims to investigate if macrophage depletion in SGs decreases cardiac sympathetic overactivation and Ventricular Arrhythmogenesis in CHF. Surgical ligation of the coronary artery was used for induction of CHF. Clodronate liposomes were microinjected into bilateral SGs of CHF rats for macrophage depletion. Using cytokine array, immunofluorescence staining, and Western blot analysis, we found that macrophage expansion and expression of TNFα and IL-1β in SGs were markedly increased in CHF rats. Flow cytometry data confirmed that the percentage of macrophages in SGs was higher in CHF rats than that in sham rats. Clodronate liposomes significantly reduced CHF-elevated proinflammatory cytokine levels and macrophage expansion in SGs. Clodronate liposomes also reduced CHF-increased N-type Ca2+ currents and excitability of cardiac sympathetic postganglionic neurons and inhibited CHF-enhanced cardiac sympathetic nerve activity. ECG data from 24-h, continuous telemetry recording in conscious rats demonstrated that clodronate liposomes not only restored CHF-induced heterogeneity of Ventricular electrical activities, but also decreased the incidence and duration of Ventricular tachycardia/fibrillation in CHF. Macrophage depletion with clodronate liposomes attenuated CHF-induced cardiac sympathetic overactivation and Ventricular arrhythmias through reduction of macrophage expansion and neuroinflammation in SGs.
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inhibition of n type calcium channels in cardiac sympathetic neurons attenuates Ventricular Arrhythmogenesis in heart failure
Cardiovascular Research, 2021Co-Authors: Dongze Zhang, Robert L Muelleman, Chaojun Wang, Liang Cao, Bryan T Hackfort, Michael C WadmanAbstract:Aims Cardiac sympathetic overactivation is an important trigger of Ventricular arrhythmias in patients with chronic heart failure (CHF). Our previous study demonstrated that N-type calcium (Cav2.2) currents in cardiac sympathetic post-ganglionic (CSP) neurons were increased in CHF. This study investigated the contribution of Cav2.2 channels in cardiac sympathetic overactivation and Ventricular Arrhythmogenesis in CHF. Methods and results Rat CHF was induced by surgical ligation of the left coronary artery. Lentiviral Cav2.2-α shRNA or scrambled shRNA was transfected in vivo into stellate ganglia (SG) in CHF rats. Final experiments were performed at 14 weeks after coronary artery ligation. Real-time polymerase chain reaction and western blot data showed that in vivo transfection of Cav2.2-α shRNA reduced the expression of Cav2.2-α mRNA and protein in the SG in CHF rats. Cav2.2-α shRNA also reduced Cav2.2 currents and cell excitability of CSP neurons and attenuated cardiac sympathetic nerve activities (CSNA) in CHF rats. The power spectral analysis of heart rate variability (HRV) further revealed that transfection of Cav2.2-α shRNA in the SG normalized CHF-caused cardiac sympathetic overactivation in conscious rats. Twenty-four-hour continuous telemetry electrocardiogram recording revealed that this Cav2.2-α shRNA not only decreased incidence and duration of Ventricular tachycardia/Ventricular fibrillation but also improved CHF-induced heterogeneity of Ventricular electrical activity in conscious CHF rats. Cav2.2-α shRNA also decreased susceptibility to Ventricular arrhythmias in anaesthetized CHF rats. However, Cav2.2-α shRNA failed to improve CHF-induced cardiac contractile dysfunction. Scrambled shRNA did not affect Cav2.2 currents and cell excitability of CSP neurons, CSNA, HRV, and Ventricular Arrhythmogenesis in CHF rats. Conclusions Overactivation of Cav2.2 channels in CSP neurons contributes to cardiac sympathetic hyperactivation and Ventricular Arrhythmogenesis in CHF. This suggests that discovering purely selective and potent small-molecule Cav2.2 channel blockers could be a potential therapeutic strategy to decrease fatal Ventricular arrhythmias in CHF.
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reduced n type ca2 channels in atrioVentricular ganglion neurons are involved in Ventricular Arrhythmogenesis
Journal of the American Heart Association, 2018Co-Authors: Dongze Zhang, Hong Zheng, Robert L Muelleman, Liang Cao, Michael C WadmanAbstract:Background Attenuated cardiac vagal activity is associated with Ventricular Arrhythmogenesis and related mortality in patients with chronic heart failure. Our recent study has shown that expression of N‐type Ca 2+ channel α‐subunits (Ca v 2.2‐α) and N‐type Ca 2+ currents are reduced in intracardiac ganglion neurons from rats with chronic heart failure. Rat intracardiac ganglia are divided into the atrioVentricular ganglion (AVG) and sinoatrial ganglion. Ventricular myocardium receives projection of neuronal terminals only from the AVG. In this study we tested whether a decrease in N‐type Ca 2+ channels in AVG neurons contributes to Ventricular Arrhythmogenesis. Methods and Results Lentiviral Ca v 2.2‐α shRNA (2 μL, 2×10 7 pfu/mL) or scrambled shRNA was in vivo transfected into rat AVG neurons. Nontransfected sham rats served as controls. Using real‐time single‐cell polymerase chain reaction and reverse‐phase protein array, we found that in vivo transfection of Ca v 2.2‐α shRNA decreased expression of Ca v 2.2‐α mRNA and protein in rat AVG neurons. Whole‐cell patch‐clamp data showed that Ca v 2.2‐α shRNA reduced N‐type Ca 2+ currents and cell excitability in AVG neurons. The data from telemetry electrocardiographic recording demonstrated that 83% (5 out of 6) of conscious rats with Ca v 2.2‐α shRNA transfection had premature Ventricular contractions ( P v 2.2‐α shRNA transfection compared with nontransfected sham rats and scrambled shRNA‐transfected rats. Conclusions A decrease in N‐type Ca 2+ channels in AVG neurons attenuates vagal control of Ventricular myocardium, thereby initiating Ventricular arrhythmias.
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abstract 14004 overactivation of n type calcium channels in stellate ganglia and Ventricular Arrhythmogenesis in chronic heart faiulre
Circulation, 2017Co-Authors: Dongze Zhang, Robert L Muelleman, Chaojun Wang, Michael C WadmanAbstract:Ventricular arrhythmia is a leading cause of sudden cardiac death in patients with chronic heart failure (CHF). Cardiac sympathetic overactivation is an important trigger for onset of Ventricular a...
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correlation of Ventricular Arrhythmogenesis with neuronal remodeling of cardiac postganglionic parasympathetic neurons in the late stage of heart failure after myocardial infarction
Frontiers in Neuroscience, 2017Co-Authors: Dongze Zhang, Robert L Muelleman, Chaojun Wang, Liang Cao, Michael C WadmanAbstract:Introduction: Ventricular arrhythmia is a major cause of sudden cardiac death in patients with chronic heart failure (CHF). Our recent study demonstrates that N-type Ca2+ currents in intracardiac ganglionic neurons are reduced in the late stage of CHF rats. Rat intracardiac ganglia are divided into the atrioVentricular ganglion (AVG) and sinoatrial ganglion. Only AVG nerve terminals innervate the Ventricular myocardium. In this study, we tested the correlation of electrical remodeling in AVG neurons with Ventricular Arrhythmogenesis in CHF rats. Methods and results: CHF was induced in male Sprague-Dawley rats by surgical ligation of the left coronary artery. The data from 24-hour continuous radiotelemetry ECG recording in conscious rats showed that Ventricular tachycardia/fibrillation (VT/VF) occurred in 3-week and 14-week CHF rats but not 8-week CHF rats. Additionally, as an index for vagal control of Ventricular function, changes of left Ventricular systolic pressure (LVSP) and the maximum rate of left Ventricular pressure rise (LV dP/dtmax) in response to vagal efferent nerve stimulation were blunted in 14-week CHF rats but not 3-week or 8-week CHF rats. Results from whole-cell patch clamp recording demonstrated that N-type Ca2+ currents in AVG neurons began to decrease in 8-week CHF rats, and that there was also a significant decrease in 14-week CHF rats. Correlation analysis revealed that N-type Ca2+ currents in AVG neurons negatively correlated with the cumulative duration of VT/VF in 14-week CHF rats, whereas there was no correlation between N-type Ca2+ currents in AVG neurons and the cumulative duration of VT/VF in 3-week CHF. Conclusion: Malignant Ventricular arrhythmias mainly occur in the early and late stages of CHF. Electrical remodeling of AVG neurons highly correlates with the occurrence of Ventricular arrhythmias in the late stage of CHF.
Robert L Muelleman - One of the best experts on this subject based on the ideXlab platform.
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inhibition of n type calcium channels in cardiac sympathetic neurons attenuates Ventricular Arrhythmogenesis in heart failure
Cardiovascular Research, 2021Co-Authors: Dongze Zhang, Robert L Muelleman, Chaojun Wang, Liang Cao, Bryan T Hackfort, Michael C WadmanAbstract:Aims Cardiac sympathetic overactivation is an important trigger of Ventricular arrhythmias in patients with chronic heart failure (CHF). Our previous study demonstrated that N-type calcium (Cav2.2) currents in cardiac sympathetic post-ganglionic (CSP) neurons were increased in CHF. This study investigated the contribution of Cav2.2 channels in cardiac sympathetic overactivation and Ventricular Arrhythmogenesis in CHF. Methods and results Rat CHF was induced by surgical ligation of the left coronary artery. Lentiviral Cav2.2-α shRNA or scrambled shRNA was transfected in vivo into stellate ganglia (SG) in CHF rats. Final experiments were performed at 14 weeks after coronary artery ligation. Real-time polymerase chain reaction and western blot data showed that in vivo transfection of Cav2.2-α shRNA reduced the expression of Cav2.2-α mRNA and protein in the SG in CHF rats. Cav2.2-α shRNA also reduced Cav2.2 currents and cell excitability of CSP neurons and attenuated cardiac sympathetic nerve activities (CSNA) in CHF rats. The power spectral analysis of heart rate variability (HRV) further revealed that transfection of Cav2.2-α shRNA in the SG normalized CHF-caused cardiac sympathetic overactivation in conscious rats. Twenty-four-hour continuous telemetry electrocardiogram recording revealed that this Cav2.2-α shRNA not only decreased incidence and duration of Ventricular tachycardia/Ventricular fibrillation but also improved CHF-induced heterogeneity of Ventricular electrical activity in conscious CHF rats. Cav2.2-α shRNA also decreased susceptibility to Ventricular arrhythmias in anaesthetized CHF rats. However, Cav2.2-α shRNA failed to improve CHF-induced cardiac contractile dysfunction. Scrambled shRNA did not affect Cav2.2 currents and cell excitability of CSP neurons, CSNA, HRV, and Ventricular Arrhythmogenesis in CHF rats. Conclusions Overactivation of Cav2.2 channels in CSP neurons contributes to cardiac sympathetic hyperactivation and Ventricular Arrhythmogenesis in CHF. This suggests that discovering purely selective and potent small-molecule Cav2.2 channel blockers could be a potential therapeutic strategy to decrease fatal Ventricular arrhythmias in CHF.
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reduced n type ca2 channels in atrioVentricular ganglion neurons are involved in Ventricular Arrhythmogenesis
Journal of the American Heart Association, 2018Co-Authors: Dongze Zhang, Hong Zheng, Robert L Muelleman, Liang Cao, Michael C WadmanAbstract:Background Attenuated cardiac vagal activity is associated with Ventricular Arrhythmogenesis and related mortality in patients with chronic heart failure. Our recent study has shown that expression of N‐type Ca 2+ channel α‐subunits (Ca v 2.2‐α) and N‐type Ca 2+ currents are reduced in intracardiac ganglion neurons from rats with chronic heart failure. Rat intracardiac ganglia are divided into the atrioVentricular ganglion (AVG) and sinoatrial ganglion. Ventricular myocardium receives projection of neuronal terminals only from the AVG. In this study we tested whether a decrease in N‐type Ca 2+ channels in AVG neurons contributes to Ventricular Arrhythmogenesis. Methods and Results Lentiviral Ca v 2.2‐α shRNA (2 μL, 2×10 7 pfu/mL) or scrambled shRNA was in vivo transfected into rat AVG neurons. Nontransfected sham rats served as controls. Using real‐time single‐cell polymerase chain reaction and reverse‐phase protein array, we found that in vivo transfection of Ca v 2.2‐α shRNA decreased expression of Ca v 2.2‐α mRNA and protein in rat AVG neurons. Whole‐cell patch‐clamp data showed that Ca v 2.2‐α shRNA reduced N‐type Ca 2+ currents and cell excitability in AVG neurons. The data from telemetry electrocardiographic recording demonstrated that 83% (5 out of 6) of conscious rats with Ca v 2.2‐α shRNA transfection had premature Ventricular contractions ( P v 2.2‐α shRNA transfection compared with nontransfected sham rats and scrambled shRNA‐transfected rats. Conclusions A decrease in N‐type Ca 2+ channels in AVG neurons attenuates vagal control of Ventricular myocardium, thereby initiating Ventricular arrhythmias.
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abstract 14004 overactivation of n type calcium channels in stellate ganglia and Ventricular Arrhythmogenesis in chronic heart faiulre
Circulation, 2017Co-Authors: Dongze Zhang, Robert L Muelleman, Chaojun Wang, Michael C WadmanAbstract:Ventricular arrhythmia is a leading cause of sudden cardiac death in patients with chronic heart failure (CHF). Cardiac sympathetic overactivation is an important trigger for onset of Ventricular a...
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correlation of Ventricular Arrhythmogenesis with neuronal remodeling of cardiac postganglionic parasympathetic neurons in the late stage of heart failure after myocardial infarction
Frontiers in Neuroscience, 2017Co-Authors: Dongze Zhang, Robert L Muelleman, Chaojun Wang, Liang Cao, Michael C WadmanAbstract:Introduction: Ventricular arrhythmia is a major cause of sudden cardiac death in patients with chronic heart failure (CHF). Our recent study demonstrates that N-type Ca2+ currents in intracardiac ganglionic neurons are reduced in the late stage of CHF rats. Rat intracardiac ganglia are divided into the atrioVentricular ganglion (AVG) and sinoatrial ganglion. Only AVG nerve terminals innervate the Ventricular myocardium. In this study, we tested the correlation of electrical remodeling in AVG neurons with Ventricular Arrhythmogenesis in CHF rats. Methods and results: CHF was induced in male Sprague-Dawley rats by surgical ligation of the left coronary artery. The data from 24-hour continuous radiotelemetry ECG recording in conscious rats showed that Ventricular tachycardia/fibrillation (VT/VF) occurred in 3-week and 14-week CHF rats but not 8-week CHF rats. Additionally, as an index for vagal control of Ventricular function, changes of left Ventricular systolic pressure (LVSP) and the maximum rate of left Ventricular pressure rise (LV dP/dtmax) in response to vagal efferent nerve stimulation were blunted in 14-week CHF rats but not 3-week or 8-week CHF rats. Results from whole-cell patch clamp recording demonstrated that N-type Ca2+ currents in AVG neurons began to decrease in 8-week CHF rats, and that there was also a significant decrease in 14-week CHF rats. Correlation analysis revealed that N-type Ca2+ currents in AVG neurons negatively correlated with the cumulative duration of VT/VF in 14-week CHF rats, whereas there was no correlation between N-type Ca2+ currents in AVG neurons and the cumulative duration of VT/VF in 3-week CHF. Conclusion: Malignant Ventricular arrhythmias mainly occur in the early and late stages of CHF. Electrical remodeling of AVG neurons highly correlates with the occurrence of Ventricular arrhythmias in the late stage of CHF.
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abstract 11882 reduced n type calcium channels in Ventricular vagal neurons and Ventricular Arrhythmogenesis
Circulation, 2016Co-Authors: Dongze Zhang, Hong Zheng, Robert L MuellemanAbstract:Attenuated cardiac vagal activity is linked to Ventricular Arrhythmogenesis, and is associated with mortality in patients with chronic heart failure (CHF). However, the sites and mechanisms responsible for decreased cardiac vagal activity are still poorly understood. Our previous studies showed that expression of N-type Ca++ channel α-subunits (Cav2.2-α) and N-type Ca++ currents were reduced in intracardiac ganglion neurons from coronary artery ligation-induced CHF rats. Rat intracardiac ganglia are divided into the atrioVentricular ganglion (AVG) and sinoatrial ganglion. Ventricular myocardium only receives projection of neuronal terminals from the AVG. Here, we tested the hypothesis that reducing N-type Ca++ channels in AVG neurons contributes to Ventricular Arrhythmogenesis. Lentiviral Cav2.2-α shRNA (2 μl, 1x106 pfu/ml) or scrambled shRNA was in-vivo transfected into rat AVG neurons. Non-transfected sham rats served as control. Using real-time single-cell PCR and reverse-phase protein array, we found ...
