scholarly journals Stereoselectivity of Propafenone RyR2 Channel Block and Prevention of Ventricular Arrhythmia In Vivo

2011 ◽  
Vol 100 (3) ◽  
pp. 180a
Author(s):  
Michela Faggione ◽  
Hyun Seok Hwang ◽  
Bjorn C. Knollmann
Keyword(s):  
Ventricular Arrhythmia ◽  
Channel Block ◽  
Ryr2 Channel

scholarly journals RYR2 Channel Inhibition Is the Principal Mechanism 0f Flecainide Action in CPVT

2020 ◽  
Author(s):  
Dmytro O Kryshtal ◽  
Daniel Blackwell ◽  
Christian Egly ◽  
Abigail N Smith ◽  
Suzanne M Batiste ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Sodium Channel ◽  
Sodium Channels ◽  
Antiarrhythmic Action ◽  
Channel Block ◽  
Principal Mechanism ◽  
Channel Inhibition ◽  
Ryr2 Channel ◽  
Cardiac Sodium Channels

Rationale: The class Ic antiarrhythmic drug flecainide prevents ventricular tachyarrhythmia in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease caused by hyperactive cardiac ryanodine receptor (RyR2) calcium (Ca) release. Although flecainide inhibits single RyR2 channels in vitro, reports have claimed that RyR2 inhibition by flecainide is not relevant for its mechanism of antiarrhythmic action and concluded that sodium channel block alone is responsible for flecainide's efficacy in CPVT. Objective: To determine whether RyR2 block independently contributes to flecainide's efficacy for suppressing spontaneous sarcoplasmic reticulum (SR) Ca release and for preventing ventricular tachycardia in vivo. Methods and Results: We synthesized N-methylated flecainide analogues (QX-FL and NM-FL) and showed that N-methylation reduces flecainide's inhibitory potency on RyR2 channels incorporated into artificial lipid bilayers. N-Methylation did not alter flecainide's inhibitory activity on human cardiac sodium channels expressed in HEK293T cells. Antiarrhythmic efficacy was tested utilizing a calsequestrin knockout (Casq2-/-) CPVT mouse model. In membrane-permeabilized Casq2-/- cardiomyocytes — lacking intact sarcolemma and devoid of sodium channel contribution — flecainide, but not its analogues, suppressed RyR2-mediated Ca release at clinically relevant concentrations. In voltage-clamped, intact Casq2-/- cardiomyocytes pretreated with tetrodotoxin (TTX) to inhibit sodium channels and isolate the effect of flecainide on RyR2, flecainide significantly reduced the frequency of spontaneous SR Ca release, while QX-FL and NM-FL did not. In vivo, flecainide effectively suppressed catecholamine-induced ventricular tachyarrhythmias in Casq2-/- mice, whereas NM-FL had no significant effect on arrhythmia burden, despite comparable sodium channel block. Conclusions: Flecainide remains an effective inhibitor of RyR2-mediated arrhythmogenic Ca release even when cardiac sodium channels are blocked. In mice with CPVT, sodium channel block alone did not prevent ventricular tachycardia. Hence, RyR2 channel inhibition likely constitutes the principal mechanism of antiarrhythmic action of flecainide in CPVT.

Abstract 15420: Resolving a Controversy: Inhibition of Cardiac Ryanodine Receptors is the Principal Mechanism of Antiarrhythmic Action of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Dmytro O Kryshtal ◽  
Daniel J Blackwell ◽  
Christian L Egly ◽  
Abigail N Smith ◽  
Suzanne M Batiste ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Sodium Channel ◽  
Sodium Channels ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Antiarrhythmic Action ◽  
Channel Block ◽  
Principal Mechanism ◽  
Cardiac Sodium Channels

Rationale: The class Ic antiarrhythmic drug flecainide prevents ventricular tachyarrhythmia in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease caused by hyperactive cardiac ryanodine receptor (RyR2) calcium (Ca) release. Although flecainide inhibits single RyR2 channels in vitro , reports have claimed that RyR2 inhibition by flecainide is not relevant for its mechanism of antiarrhythmic action and concluded that sodium channel block alone is responsible for flecainide’s efficacy in CPVT. Objective: To determine whether RyR2 block independently contributes to flecainide’s efficacy for suppressing spontaneous sarcoplasmic reticulum (SR) Ca release and for preventing ventricular tachycardia in vivo . Methods and Results: We synthesized N -methyl flecainide analogues (QX-FL and NM-FL) and showed that N -methylation reduces flecainide’s inhibitory potency on RyR2 channels but not on cardiac sodium channels. Antiarrhythmic efficacy was tested utilizing a calsequestrin knockout (Casq2-/-) CPVT mouse model. In membrane-permeabilized Casq2-/- cardiomyocytes — lacking intact sarcolemma and devoid of sodium channel contribution — flecainide, but not its analogues, suppressed RyR2-mediated Ca release at clinically relevant concentrations. In voltage-clamped, intact Casq2-/- cardiomyocytes pretreated with tetrodotoxin (TTX) to inhibit sodium channels and isolate the effect of flecainide on RyR2, flecainide significantly reduced the frequency of spontaneous SR Ca release, while QX-FL and NM-FL did not. In vivo , flecainide effectively suppressed catecholamine-induced ventricular tachyarrhythmias in Casq2-/- mice, whereas NM-FL did not, despite comparable sodium channel block. Conclusions: Flecainide remains an effective inhibitor of RyR2-mediated arrhythmogenic Ca release even when cardiac sodium channels are blocked. In mice with CPVT, sodium channel block alone was not enough to prevent arrhythmias. Hence, RyR2 inhibition by flecainide is critical for its mechanism of antiarrhythmic action.

Increased ventricular repolarization heterogeneity in patients with ventricular arrhythmia vulnerability and cardiomyopathy: a human in vivo study

2006 ◽  
Vol 290 (1) ◽  
pp. H79-H86 ◽  
Author(s):  
Vijay S. Chauhan ◽  
Eugene Downar ◽  
Kumaraswamy Nanthakumar ◽  
John D. Parker ◽  
Heather J. Ross ◽  
...  
Keyword(s):  
Ventricular Arrhythmia ◽  
Ventricular Arrhythmias ◽  
Conduction Block ◽  
Left Ventricular ◽  
Ventricular Repolarization ◽  
Similar Patient ◽  
T Wave Alternans ◽  
Activation Times ◽  
Unipolar Electrograms

Increased repolarization heterogeneity can provide the substrate for reentrant ventricular arrhythmias in animal models of cardiomyopathy. We hypothesized that ventricular repolarization heterogeneity is also greater in patients with cardiomyopathy and ventricular arrhythmia vulnerability (inducible ventricular tachycardia or positive microvolt T wave alternans, VT/TWA) compared with a similar patient population without ventricular arrhythmia vulnerability (no VT/TWA). Endocardial and epicardial repolarization heterogeneity was measured in patients with ( n = 12) and without ( n = 10) VT/TWA by using transvenous 26-electrode catheters placed along the anteroseptal right ventricular endocardium and left ventricular epicardium. Local activation times (AT), activation-recovery intervals (ARI), and repolarization times (RT) were measured from unipolar electrograms. Endocardial RT dispersion along the apicobasal ventricle was greater ( P < 0.005) in patients with VT/TWA than in those without VT/TWA because of greater ARI dispersion ( P < 0.005). AT dispersion was similar between the two groups. Epicardial RT dispersion along the apicobasal ventricle was greater ( P < 0.05) in patients with VT/TWA than in those without VT/TWA because of greater ARI dispersion ( P < 0.05). AT dispersion was similar between the two groups. A plot of AT as a function of ARI revealed an inverse linear relationship for no VT/TWA such that progressively later activation was associated with progressively shorter ARI. The AT-ARI relationship was nonlinear in VT/TWA. In conclusion, patients with cardiomyopathy and VT/TWA have greater endocardial and epicardial repolarization heterogeneity than those without VT/TWA without associated conduction slowing. The steep repolarization gradients in VT/TWA may provide the substrate for functional conduction block and reentrant ventricular arrhythmias.

scholarly journals Slow Diffusion Across Cell Membrane Delays Onset of RyR2-Channel Block and Ca Wave Suppression by Flecainide in Intact Myocytes

2011 ◽  
Vol 100 (3) ◽  
pp. 416a
Author(s):  
Hyun Seok Hwang ◽  
Eleonora S. Galimberti ◽  
Bjorn C. Knollmann
Keyword(s):  
Cell Membrane ◽  
Channel Block ◽  
Slow Diffusion ◽  
Ryr2 Channel

Abstract 297: Development of Molecular Targeted Therapy Against Right Ventricular Failure: Involvement in a Network of Immunocompetent Cells

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Shogo Ito ◽  
Shinsuke Yuasa ◽  
Jin Komuro ◽  
Mai Kimura ◽  
Dai Kusumoto ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ventricular Arrhythmia ◽  
Right Ventricular ◽  
Microarray Analysis ◽  
Pathway Analysis ◽  
Therapeutic Target ◽  
Immunocompetent Cells ◽  
Wild Type ◽  
Novel Therapeutic

Backgrounds: Right ventricular (RV) failure plays a critical role in right heart failure and left heart failure. However, there is no specific therapy developed for RV failure. To elucidate a novel therapeutic target against RV failure, we focus on RV specific genes to develop novel therapeutics for RV failure. Methods: Microarray analysis using several parts of adult murine heart was conducted and differentially expressed genes (DEGs) were applied to pathway analysis. Molecular mechanism was examined by using neonatal rat ventricular cardiomyocyte (NRVM) in vitro. To understand the function of target molecule in vivo, we induced RV failure by pulmonary artery constriction (PAC) in mice and inhibition experiments were performed using RV failure model. Results: In microarray analysis for RV, left ventricle and ventricular septum, 995 genes were extracted as DEGs in RV. Pathway analysis showed that alternative complement pathway-related genes were significantly up-regulated in RV. Moreover, complement factor D (Cfd) and C3a was a potential upstream factor attributable to unique feature of RV. Administration of C3a recombinant protein to NRVM phosphorylated several MAP kinases. In vivo, in C3KO PAC mice, RV dysfunction was significantly suppressed, and histological study showed that RV fibrosis was significantly suppressed. In wild type mice with PAC, administration of C3a receptor antagonist dramatically improved RV dysfunction and reduced RV fibrosis. Additionally, in vivo electrophysiological study revealed that the inducibility of ventricular arrhythmia was increased in wild type PAC mice, but ventricular arrhythmia was significantly attenuated in C3KO PAC mice. Furthermore, the expression of chemokine Ccl5 was enhanced in RV of wild type PAC mice, while Ccl5 was significantly attenuated in C3KO PAC mice. Conclusion: We revealed that complement C3a was highly produced in RV and chemical or genetical blockade of C3a ameliorates RV dysfunction and RV fibrosis in PAC mice. C3a was to be a potent bioactive protein for immunocompetent cells that played an important role in modulating cardiac function. Accordingly, we demonstrated that the blockade of C3a had a potential role for novel therapeutic target to RV failure.

scholarly journals Binding of LncRNA-DACH1 to dystrophin impairs the membrane trafficking of Nav1.5 protein and increases ventricular arrhythmia susceptibility

2021 ◽  
Author(s):  
Zhenwei Pan ◽  
Gen-Long Xue ◽  
Yang Zhang ◽  
Jiming Yang ◽  
Ying Yang ◽  
...  
Keyword(s):  
Ventricular Arrhythmia ◽  
Membrane Trafficking ◽  
Ex Vivo ◽  
Conditional Knockout ◽  
Human Homologue ◽  
Interacting Protein ◽  
Membrane Anchoring ◽  
Ventricular Arrhythmogenesis

Abstract Dystrophin is a critical interacting protein of Nav1.5 that determines its membrane anchoring in cardiomyocytes. The study aims to explore whether lncRNA-DACH1(lncDACH1) can regulate the distribution of Nav1.5 by binding to dystrophin and participate in ventricular arrhythmogenesis. LncDACH1 was confirmed to bind to dystrophin. Cardiomyocyte-specific transgenic overexpression of lncDACH1(lncDACH1-TG) reduced the membrane distribution of dystrophin and Nav1.5 in cardiomyocytes. The opposite data were collected from lncDACH1 cardiomyocyte conditional knockout (lncDACH1-CKO) mice. Moreover, increased ventricular arrhythmia susceptibility was observed in lncDACH1-TG mice in vivo and ex vivo. The conservative fragment of lncDACH1 inhibited membrane distribution of dystrophin and Nav1.5 and promoted the inducibility of ventricular arrhythmia. Upregulation of dystrophin in lncDACH1-TG mice rescued the impaired membrane distribution of dystrophin and Nav1.5. The human homologue of lncDACH1 inhibited the membrane distribution of Nav1.5 in human iPS-differentiated cardiomyocytes. Collectively, lncDACH1 regulates Nav1.5 membrane distribution by binding to dystrophin and participates in ventricular arrhythmogenesis.

Translation of L-type calcium channel block: From in vitro assays to in vivo models

2013 ◽  
Vol 68 (1) ◽  
pp. e48-e49
Author(s):  
Sunny Z. Sun ◽  
David Ramirez ◽  
William P. Gorczyca ◽  
Stephen C. Foote ◽  
Michelle D. Hemkens ◽  
...  
Keyword(s):  
Calcium Channel ◽  
In Vitro Assays ◽  
Channel Block ◽  
In Vivo Models

scholarly journals Interaction between Endothelin-1 and Left Stellate Ganglion Activation: A Potential Mechanism of Malignant Ventricular Arrhythmia during Myocardial Ischemia

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Zhenya Wang ◽  
Shuyan Li ◽  
Huanzhu Lai ◽  
Liping Zhou ◽  
Guannan Meng ◽  
...  
Keyword(s):  
Ventricular Arrhythmia ◽  
Proinflammatory Cytokines ◽  
Stellate Ganglion ◽  
Saline Control ◽  
Control Group ◽  
Endothelin 1 ◽  
Left Stellate Ganglion ◽  
Cardiac Sympathetic Afferent Reflex ◽  
Malignant Ventricular Arrhythmia

Endothelin-1 (ET-1) is synthesized primarily by endothelial cells. ET-1 administration in vivo enhances the cardiac sympathetic afferent reflex and sympathetic activity. Previous studies have shown that sympathetic hyperactivity promotes malignant ventricular arrhythmia (VA). The aim of this study was to investigate whether ET-1 could activate the left stellate ganglion (LSG) and promote malignant VA. Twelve male beagle dogs who received local microinjections of saline (control, n=6) and ET-1 into the LSG (n=6) were included. The ventricular effective refractory period (ERP), LSG function, and LSG activity were measured at different time points. VA was continuously recorded for 1 h after left anterior descending occlusion (LADO), and LSG tissues were then collected for molecular detection. Compared to that of the control group, local ET-1 microinjection significantly decreased the ERP and increased the occurrence of VA. In addition, local microinjection of ET-1 increased the function and activity of the LSG in the normal and ischemic hearts. The expression levels of proinflammatory cytokines and the protein expression of c-fos and nerve growth factor (NGF) in the LSG were also increased. More importantly, endothelin A receptor (ETA-R) expression was found in the LSG, and its signaling was significantly activated in the ET-1 group. LSG activation induced by local ET-1 microinjection aggravates LADO-induced VA. Activated ETA-R signaling and the upregulation of proinflammatory cytokines in the LSG may be responsible for these effects.

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