Inducible Ventricular Arrhythmias Research Articles

Clinical efficacy of open-irrigated electrode cooled with half-normal saline for initially failed radiofrequency ablation of idiopathic outflow tract ventricular arrhythmias.

Acute failure of radiofrequency ablation (RFA) of ventricular arrhythmias (VAs) occur in 10%-20% of patients and is partly attributed to inadequate lesion depth acquired with standard ablation protocols. Half-normal saline (HNS)-irrigation is a promising strategy to improve the success rate of VA ablation. This study investigated the efficacy of HNS-irrigated ablation after a failed standard plain normal saline solution (PNSS)-irrigated ablation on idiopathic outflow tract ventricular arrhythmia (OT-VA). This is a prospective observational study of consecutive patients undergoing RFA of idiopathic OT-VA comparing the efficacy of additional HNS-irrigated ablation for failed standard PNSS-irrigated ablation. Acute failure was defined as persistence of spontaneous VA or persistent inducibility of the clinical VA. Out of 160 OT-VA cases (51 ± 15-year-old, 62 males), 31 underwent HNS irrigation after a failed standard PNSS-irrigated ablation. The HNS group had a significantly longer procedure time (60.06 ± 43.83 vs 37.51 ± 33.40 minutes; P = .013) and higher radiation exposure (31.45 ± 20.24 vs 17.22 ± 15.25 minutes; P = .001) than the PNSS group but provided an additional acute success in 21 of 31 (67.7%) patients. Over a follow-up duration of 7.8 ± 4.6 months, 24 recurrences were identified, including 8 (25.8%) in the HNS and 16 (12.4%) in the PNSS group, with lower freedom from recurrence in the HNS group (log rank P = .009). No major complication was observed. HNS-irrigated ablation after failed standard PNSS-irrigated ablation is safe and additionally improves acute ablation success by 67.7% for idiopathic OT-VA but with a higher rate of recurrence on follow-up. Whether the application of HNS as initial irrigant could result in better outcome requires further investigation.

Light-emitting diode therapy protects against ventricular arrhythmias by neuro-immune modulation in myocardial ischemia and reperfusion rat model

BackgroundSympathetic overactivation and inflammation are two major mediators to post-myocardial ischemia-reperfusion (I/R)-induced ventricular arrhythmia (VA). The vicious cycle between microglia and sympathetic activation plays an important role in sympathetic hyperactivity related to cardiovascular diseases. Recently, studies have shown that microglial activation might be attenuated by light-emitting diode (LED) therapy. Therefore, we hypothesized that LED therapy might protect against myocardial I/R-induced VAs by attenuating microglial and sympathetic activation.MethodsThirty-six male anesthetized rats were randomized into four groups: control group (n = 6), LED group (n = 6), I/R group (n = 12), and LED+I/R group (n = 12). I/R was generated by left anterior descending artery occlusion for 30 min followed by 3 h reperfusion. ECG and left stellate ganglion (LSG) neural activity were recorded continuously. After 3 h reperfusion, a programmed stimulation protocol was conducted to test the inducibility of VA. Furthermore, we extracted the brain tissue to examine the microglial activation, and the peri-ischemic myocardium to examine the expression of NGF and inflammatory cytokines (IL-1β, IL-18, IL-6, and TNF-α).ResultsAs compared to the I/R group, LED illumination significantly inhibited the LSG neural activity (P < 0.01) and reduced the inducibility of VAs (arrhythmia score 4.417 ± 0.358 vs. 3 ± 0.3257, P < 0.01) in the LED+I/R group. Furthermore, LED significantly attenuated microglial activation and downregulated the expression of inflammatory cytokines and NGF in the peri-infarct myocardium.ConclusionsLED therapy may protect against myocardial I/R-induced VAs by central and peripheral neuro-immune regulation.

Ethnic differences in patients with Brugada syndrome and arrhythmic events: New insights from Survey on Arrhythmic Events in Brugada Syndrome

There is limited information on ethnic differences between patients with Brugada syndrome (BrS) and arrhythmic events (AEs). The purpose of this study was to compare clinical, electrocardiographic (ECG), electrophysiological, and genetic characteristics between white and Asian patients with BrS and AEs. The Survey on Arrhythmic Events in Brugada Syndrome is a multicenter survey from Western and Asian countries, gathering 678 patients with BrS and first documented AE. After excluding patients with other (n = 14 [2.1%]) or unknown (n = 30 [4.4%]) ethnicity, 364 (53.7%) whites and 270 (39.8%) Asians comprised the study group. There was no difference in AE age onset (41.3 ± 16.1 years in whites vs 43.3 ± 12.3 years in Asians; P = .285). Higher proportions of whites were observed in pediatric and elderly populations. Asians were predominantly men (98.1% vs 85.7% in whites; P < .001) and frequently presented with aborted cardiac arrest (71.1% vs 56%; P < .001). Asians tended to display more spontaneous type 1 BrS-ECG pattern (71.5% vs 64.3%; P = .068). A family history of sudden cardiac death was noted more in whites (29.1% vs 11.5%; P < .001), with a higher rate of SCN5A mutation carriers (40.1% vs 13.2% in Asians; P < .001), as well as more fever-related AEs (8.5% vs 2.9%; P = .011). No difference was observed between the 2 groups regarding history of syncope and ventricular arrhythmia inducibility. There are important differences between Asian and white patients with BrS. Asian patients present almost exclusively as male adults, more often with aborted cardiac arrest and spontaneous type 1 BrS-ECG. However, they have less family history of sudden cardiac death and markedly lower SCN5A mutation rates. The striking difference in SCN5A mutation rates should be tested in future studies.

Electrophysiologic effects and outcomes of sympatholysis in patients with recurrent ventricular arrhythmia and structural heart disease.

Autonomic modulation has been used as a therapy to control recurrent ventricular arrhythmia (VA). This study was to explore stellate ganglion block (SGB) effect on cardiac electrophysiologic properties and evaluate the long-term outcome of cardiac sympathetic denervation (CSD) for patients with recurrent VA and structural heart disease (SHD). Patients who had recurrent VA due to SHD were enrolled prospectively. Electrophysiologic study and ventricular tachycardia (VT) induction were performed before and after left and right SGB. VA burden and long-term outcomes were assessed for a separate patient group who underwent left or bilateral CSD for drug-refractory VA due to SHD. Electrophysiologic study of nine patients showed that baseline mean (SD) corrected sinus node recovery time (cSNRT) increased from 320.4 (73.3) ms to 402.9 (114.2) ms after left and 482.4 (95.7) ms after bilateral SGB (P = .03). SGB did not significantly change P-R, QRS, and Q-T intervals and ventricular effective refractory period, nor did the inducibility of VA. Nineteen patients underwent left (n = 14) or bilateral (n = 5) CSD. CSD reduced VA burden and appropriate ICD therapies from a median (interquartile range) of 2.5 (0.4-11.6) episodes weekly to 0.1 (0.0-2.4) episodes weekly at 6-month follow-up (P = .002). Three-year freedom from orthotopic heart transplant (OHT) and death was 52.6%. New York Heart Association functional class III/IV and VT rate less than 160 beats per minute were predictors of recurrent VA, OHT, and death. SGB increased cSNRT without changing heart rate. CSD was more beneficial for patients with mild-to-moderate heart failure and faster VA.

LCZ696 Therapy Reduces Ventricular Tachyarrhythmia Inducibility in a Myocardial Infarction-Induced Heart Failure Rat Model

Background LCZ696 (valsartan/sacubitril) therapy significantly reduced mortality in patients with heart failure (HF). Although a clinical trial (PARADISE-MI Trial) has been ongoing to examine the effects of LCZ696 in myocardial infarction (MI) patients, the effects of LCZ696 on remodeling of cardiac electrophysiology in animal models remain largely unclear. Methods We performed coronary artery ligation to create MI in Sprague-Dawley rats. Echocardiography was performed one week after MI to confirm the development of HF with left ventricular ejection fraction ≤ 40%. MI rats were randomly assigned to receive medical therapy for 4 weeks: LCZ696, enalapril, or vehicle. The sham-operation rats received sham operation without MI creation. In vivo electrophysiological exams were performed under general anesthesia. Western blot analyses were conducted to quantify ion channel proteins. Results The HF-vehicle group did not show significant changes in LVEF. Both enalapril and LCZ696 therapy significantly improved LVEF. The HF-vehicle group had higher ventricular arrhythmia (VA) inducibility than the sham group. As compared with the HF-vehicle group, LCZ696 therapy significantly reduced VA inducibility, but enalapril therapy did not. Western blot analyses showed significant downregulation of NaV1.5, ERG, KCNE1, and KCNE2 channel proteins in the HF vehicle group compared with the sham group. LCZ696 therapy upregulated protein expression of ERG, KCNE1, and KCNE2. Conclusion As compared with enalapril therapy, LCZ696 therapy led to improvement of LVEF, reduced VA inducibility, and upregulated expression of K+ channel proteins.

Epicardial ganglionated plexi ablation increases the inducibility of ventricular tachyarrhythmias in a canine postmyocardial infarction model.

Previous studies have shown that epicardial ganglionated plexi ablation (EGPA) could increase the risk of ventricular arrhythmias induced by acute myocardial ischemia. However, the long-term effect of EGPA in a canine postmyocardial infarction (MI) model is not well established. Twenty mongrel dogs were randomly divided into two groups: an MI group (n = 10) and an EGPA group (EGPA plus MI, n = 10). EGPA was achieved by ablation of four major ganglion plexi and the ligament of Marshall. The electrocardiograph (ECG) parameters, ventricular effective refractory period (ERP), inducibility of tachyarrhythmias, and ventricular fibrillation threshold (VFT) were measured at baseline and after 8 weeks. Tyrosine hydroxylase (TH) and nerve growth factor (NGF) expression levels in the peri-infarcted zone were also determined by immunohistochemistry in both groups at the end of the study. No significant differences were found in electrophysiological parameters at the baseline between the two groups. At the end of the 8-week follow-up, however, the EGPA group was associated with a longer QT interval, corrected QT (QTc) interval and ventricular ERP, larger dispersion of QT, QTc, and ERP, and higher inducibility of tachyarrhythmia and VFT when compared to the MI group. In addition, the density of TH and NGF in the peri-infarcted zone was also significantly increased in the EGPA group in comparison to the MI group. After the 8-week follow-up, EGPA increased the ventricular arrhythmia inducibility in the canine post-MI model, likely by increasing ventricular electrophysiological instability and promoting ventricular sympathetic remodeling.

Treatment with mononuclear cell populations improves post-infarction cardiac function but does not reduce arrhythmia susceptibility.

BackgroundClinical and experimental data give evidence that transplantation of stem and progenitor cells in myocardial infarction could be beneficial, although the underlying mechanism has remained elusive. Ventricular tachyarrhythmia is the most frequent and potentially lethal complication of myocardial infarction, but the impact of mono nuclear cells on the incidence of ventricular arrhythmia is still not clear.ObjectiveWe aimed to characterize the influence of splenic mononuclear cell populations on ventricular arrhythmia after myocardial infarction.MethodsWe assessed electrical vulnerability in vivo in mice with left ventricular cryoinfarction 14 days after injury and intramyocardial injection of specific subpopulations of mononuclear cells (MNCs) (CD11b-positive cells, Sca-1-positive cells, early endothelial progenitor cells (eEPCs)). As positive control group we used embryonic cardiomyocytes (eCMs). Epicardial mapping was performed for analysing conduction velocities in the border zone. Left ventricular function was quantified by echocardiography and left heart catheterization.ResultsIn vivo pacing protocols induced ventricular tachycardia (VT) in 30% of non-infarcted mice. In contrast, monomorphic or polymorphic VT could be evoked in 94% of infarcted and vehicle-injected mice (p<0.01). Only transplantation of eCMs prevented post-infarction VT and improved conduction velocities in the border zone in accordance to increased expression of connexin 43. Cryoinfarction resulted in a broad aggravation of left ventricular function. All transplanted cell types augmented left ventricular function to a similar extent.ConclusionsTransplantation of different MNC populations after myocardial infarction improves left ventricular function similar to effects of eCMs. Prevention of inducible ventricular arrhythmia is only seen after transplantation of eCMs.

The Role of Myofibroblast Senescence in Arrhythmogenesis of the Aged Infarcted Heart

Aging increases risk of Sudden Cardiac Death (SCD) by more than 10-20 fold. Prior myocardial infarction (MI) increases short- and long-term SCD risk. Cellular senescence is an irreversible cell cycle arrest process which regulates tumor suppression and wound healing, however, accumulation of senescent cells in various tissues is thought to drive aging pathology. We hypothesize that with age, persistent cardiac myofibroblast (CMF) senescence promotes persistent inflammation in the scar and thereby facilitating arrhythmogenesis. Our laboratory has established that the infarcted New Zealand White rabbit model of cardiac aging recapitulates pathology observed in aging humans, namely cardiac fibrosis, abnormal conduction, ryanodine receptor oxidation, and spontaneous and inducible ventricular arrhythmias post-MI. Here, we show that aged infarcted rabbits display increased peri-procedural arrhythmic death, prolonged action potential duration and slowed conduction at the IBZ compared to young, which correlates with anchoring of higher frequency ventricular fibrillation in the IBZ of aged rabbits. We show no change in scar geometry between young and aged rabbits in the first 3 weeks post-MI. However, we observed delayed and persistent CMF senescence in the aged scar, even until 12 weeks post-MI. We also demonstrate increased expression of senescence-associated markers in the aged IBZ and scar compared to young, and colocalization of senescent CMFs and inflammatory macrophages in the aged scar and IBZ. In conclusion, we demonstrate the infarcted aged heart heals differently than young, including delayed and persistent scar CMF senescence, increased VT/VF, and electrophysiological remodeling. Our data support our hypothesis that altered CMF senescence with age induces pathological tissue remodeling post-MI, underlying the increased risk of SCD.

Three-dimensional cardiac fibre disorganization as a novel parameter for ventricular arrhythmia stratification after myocardial infarction.

AimsMyocardial infarction (MI) alters cardiac fibre organization with unknown consequences on ventricular arrhythmia. We used diffusion tensor imaging (DTI) of three-dimensional (3D) cardiac fibres and scar reconstructions to identify the main parameters associated with ventricular arrhythmia inducibility and ventricular tachycardia (VT) features after MI.Methods and resultsTwelve pigs with established MI and three controls underwent invasive electrophysiological characterization of ventricular arrhythmia inducibility and VT features. Animal-specific 3D scar and myocardial fibre distribution were obtained from ex vivo high-resolution contrast-enhanced T1 mapping and DTI sequences. Diffusion tensor imaging-derived parameters significantly different between healthy and scarring myocardium, scar volumes, and left ventricular ejection fraction (LVEF) were included for arrhythmia risk stratification and correlation analyses with VT features. Ventricular fibrillation (VF) was the only inducible arrhythmia in 4 out of 12 infarcted pigs and all controls. Ventricular tachycardia was also inducible in the remaining eight pigs during programmed ventricular stimulation. A DTI-based 3D fibre disorganization index (FDI) showed higher disorganization within dense scar regions of VF-only inducible pigs compared with VT inducible animals (FDI: 0.36; 0.36–0.37 vs. 0.32; 0.26–0.33, respectively, P = 0.0485). Ventricular fibrillation induction required lower programmed stimulation aggressiveness in VF-only inducible pigs than VT inducible and control animals. Neither LVEF nor scar volumes differentiated between VF and VT inducible animals. Re-entrant VT circuits were localized within areas of highly disorganized fibres. Moreover, the FDI within heterogeneous scar regions was associated with the median VT cycle length per animal (R2 = 0.5320).ConclusionThe amount of scar-related cardiac fibre disorganization in DTI sequences is a promising approach for ventricular arrhythmia stratification after MI.

Modulation of Cardiac Ventricular Excitability by GLP-1 (Glucagon-Like Peptide-1).

BackgroundGlucagon-like peptide-1 receptor (GLP-1R) agonists improve cardiovascular outcomes in patients with type 2 diabetes mellitus. However, systemic actions of these agents cause sympathetic activation, which is generally considered to be detrimental in cardiovascular disease. Despite significant research interest in cardiovascular biology of GLP-1, the presence of GLP-1R in ventricular cardiomyocytes remains a controversial issue, and the effects of this peptide on the electrical properties of intact ventricular myocardium are unknown. We sought to determine the effects of GLP-1R agonist exendin-4 (Ex4) on ventricular action potential duration (APD) and susceptibility to ventricular arrhythmia in the rat heart in vivo and ex vivo.MethodsVentricular monophasic action potentials were recorded in anaesthetized (urethane) rats in vivo and isolated perfused rat hearts during sinus rhythm and ventricular pacing.ResultsIn vivo, systemic administration of Ex4 (5 μg/kg intravenously) increased heart rate, and this effect was abolished by β-adrenoceptor blockade. Despite causing sympathetic activation, Ex4 increased APD at 90% repolarization during ventricular pacing by 7% (P=0.044; n=6) and reversed the effect of β-adrenoceptor agonist dobutamine on APD at 90% repolarization. In isolated perfused hearts, Ex4 (3 nmol/L) increased APD at 90% repolarization by 14% (P=0.015; n=6) with no effect on heart rate. Ex4 also reduced ventricular arrhythmia inducibility in conditions of β-adrenoceptor stimulation with isoproterenol. Ex4 effects on APD and ventricular arrhythmia susceptibility were prevented in conditions of muscarinic receptor blockade or inhibition of nitric oxide synthase.ConclusionsThese data demonstrate that GLP-1R activation effectively opposes the effects of β-adrenoceptor stimulation on cardiac ventricular excitability and reduces ventricular arrhythmic potential. The effect of GLP-1R activation on the ventricular myocardium is indirect, mediated by acetylcholine and nitric oxide and, therefore, can be explained by stimulation of cardiac parasympathetic (vagal) neurons.

A modified approach for programmed electrical stimulation in mice: Inducibility of ventricular arrhythmias.

BackgroundElectrophysiological studies in mice, the prevailing model organism in the field of basic cardiovascular research, are impeded by the low yield of programmed electrical stimulation (PES).ObjectiveTo investigate a modified approach for ventricular arrhythmia (VA) induction and a novel scoring system in mice.MethodA systematic review of literature on current methods for PES in mice searching the PubMed database revealed that VA inducibility was low and ranged widely (4.6 ± 10.7%). Based on this literature review, a modified PES protocol with 3 to 10 extrastimuli was developed and tested in comparison to the conventional PES protocol using up to 3 extrastimuli in anesthetized wildtype mice (C57BL/6J, n = 12). Induced VA, classified according to the Lambeth Convention, were assessed by established arrhythmia scores as well as a novel arrhythmia score based on VA duration.ResultsPES with the modified approach raised both the occurrence and the duration of VA compared to conventional PES (0% vs 50%; novel VA score p = 0.0002). Particularly, coupling of >6 extrastimuli raised the induction of VA. Predominantly, premature ventricular complexes (n = 6) and ventricular tachycardia <1s (n = 4) were observed. Repeated PES after adrenergic stimulation using isoprenaline resulted in enhanced induction of ventricular tachycardia <1s in both protocols.ConclusionOur findings suggest that the presented approach of modified PES enables effective induction and quantification of VA in wildtype mice and may well be suited to document and evaluate detailed VA characteristics in mice.

Neuropilin 1 ameliorates electrical remodeling at infarct border zones in rats after myocardial infarction.

Electrical remodeling at infarct border zone (IBZ) has been shown to contribute to the occurrence of ventricular arrhythmias after myocardial infarction (MI). Sema3A has been demonstrated to reduce the inducibility of ventricular arrhythmias. Neuropilin 1 (NRP1) is the receptor of Sema3A. In the present study, we investigated whether treatment with NRP1 can ameliorate electrical remodeling at IBZ after MI. Wistar rats underwent sham operation (n = 20), the ligation of left coronary artery (MI group, n = 30), MI with control adenovirus (Ad group, n = 30), and MI with NRP1 adenovirus (NRP1 group, n = 30). Eight weeks after treatment, electrophysiological properties including heart rate variability (HRV), monophasic action potential duration (MAPD), effective refractory period (ERP) and the inducibility of ventricular arrhythmias and the expression of arrhythmia-related ion channel proteins including Kv4.2, Kv4.3, KChIP2 and Kir2.1 at the IBZ of the left ventricle were examined. Compared with the MI or Ad group, NRP1 significantly increased HRV and shortened MAPD and ERP (all P < 0.05). Inducibility of VT by electrophysiological study was significantly lower in the NRP1 group than in the MI or Ad group (P < 0.05). The expression levels of Kv4.2, Kv4.3, KChIP2 and Kir2.1 proteins were significantly decreased in MI group and Ad group. In contrast, the expression levels of these proteins were restored in NRP1 group, which may represent the molecular basis of the NRP1-mediated inhibition of electrical remodeling. NRP1 can ameliorate electrical remodeling at IBZ after MI.

Interleukin-17 enhances cardiac ventricular remodeling via activating MAPK pathway in ischemic heart failure

BackgroundWe aimed to investigate the impact of interleukin (IL)-17 on ventricular remodeling and the genesis of ventricular arrhythmia (VA) in an ischemic heart failure (HF) model. The expression of the proinflammatory cytokine IL-17 is upregulated during myocardial ischemia and plays a fundamental role in post-infarct inflammation. However, the influence of IL-17 on the genesis of VA has not yet been studied. Methods and resultsThe level of inflammation and Th17 cell (CD4+IL-17+) expression in the rabbit model of ischemic HF were studied by flow cytometry, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay (ELISA). The effect of IL-17 on VA induction following acute and chronic administration of IL-17 was determined using electrophysiological techniques and optical mapping. The expression of IL-17 target genes and related cytokines and chemokines in vivo and in vitro were measured using qPCR, ELISA, and immunoblotting. Th17 cells were markedly increased in the ischemic HF rabbit model. IL-17 directly induced VA in vivo and in vitro in a dose-dependent manner. IL-17 decreased conduction velocity, lengthened action potential duration, and increased the slope of the left ventricle (LV) restitution curve. IL-17 treatment led to fibrosis, collagen production and apoptosis in the LV. Furthermore, increased IL-17 signaling activated mitogen-activated protein kinase and increased the expression of downstream target genes, IL-6, TNF, CCL20, and CXCL1. An anti-IL-17 neutralizing antibody abolished the effects of IL-17. ConclusionsThe expression of IL-17 and its downstream target genes may play fundamental roles in inducing VA in ischemic HF.

Myocardial Fibrosis in Patients With Primary Mitral Regurgitation With and Without Prolapse

BackgroundRecent studies reported left ventricular (LV) fibrosis in patients with primary mitral regurgitation (MR) thought to be principally due to mitral valve prolapse (MVP). ObjectivesThis study sought to evaluate the prevalence, characteristics, and prognostic implications of LV fibrosis in a large cohort of primary MR patients with and without MVP using cardiovascular magnetic resonance (CMR). MethodsPatients referred for contrast CMR assessment of chronic primary MR were enrolled and underwent comprehensive assessment of cardiac remodeling, severity of MR, and LV replacement fibrosis. Primary MR patients were stratified into: an MVP group if there was >2 mm mitral leaflet displacement on cine-CMR, or a non-MVP group. Patients were followed for arrhythmic events (sudden cardiac death, aborted sudden cardiac arrest, and sustained or inducible ventricular arrhythmia). ResultsA total of 356 primary MR patients (177 MVP and 179 non-MVP) were enrolled. LV fibrosis was more prevalent in the MVP group than the non-MVP group (36.7% vs. 6.7%; p < 0.001). The presence of MVP had the strongest association (odds ratio: 6.82; p < 0.001) with LV fibrosis even after adjustment for clinical variables, measures of cardiac remodeling, and MR severity. During follow-up (median 1,354 days), MVP patients with LV fibrosis had the highest event rate for arrhythmic events. ConclusionsIn primary MR patients, LV fibrosis is more prevalent in MVP than non-MVP, suggesting a unique pathophysiology beyond volume overload in MVP. LV fibrosis in primary MR may represent a risk marker of arrhythmic events.

Targeted regulation of sympathetic activity in paraventricular nucleus reduces inducible ventricular arrhythmias in rats after myocardial infarction

BackgroundThe hypothalamic paraventricular nucleus (PVN) is the center of the regulation of autonomic nervous system functions and cardiovascular activity. Phosphoinositide-3 kinase (PI3K)-AKT pathway in PVN contributes to mediate sympathetic nerve activity and is activated in spontaneously hypertensive rats. Overactivation of the sympathetic output was considered as an important mechanism of the arrhythmias. In the present study, we aimed to explore whether targeted regulation of sympathetic activity in PVN could reduce the peripheral sympathoexcitatory and attenuate the ventricular arrhythmias (VAs) in myocardial infarction (MI) rats via PI3K-AKT pathway. MethodsA stainless steel gauge guide cannula was stereotaxically implanted into the PVN, and 7 days later, rats were randomly divided into the following 4 groups: group A, control+dimethyl sulfoxide (DMSO); group B, control+LY294002; group C, MI surgery+DMSO; and group D, MI surgery+LY294002. Studies were conducted seven days post-MI. Myocardial function, infarct size, inducible VAs by programmed electrical stimulation, renal sympathetic nerve activity (RSNA), and protein level of PI3K and AKT were measured. ResultsMI increased the protein ratios of p-PI3K-to-total-PI3K and p-AKT-to-total-AKT in PVN but can be reduced by LY294002 treatment. Inhibition of sympathetic nerve activity in PVN led to a reversion in plasma norepinephrine, RSNA and inducible VAs in MI rats. ConclusionsPI3K-AKT pathway in the PVN was a main mechanism in regulating sympathetic activity and arrhythmias in MI rats. Targeted inhibition of sympathetic activity in PVN may be a potential treatment for the VAs via PI3K-AKT pathway.

Analysis on the factors related to the immediate success rate of radiofrequency catheter ablation on patients with idiopathic right ventricular outflow tract ventricular arrhythmia

Objective: To analyze the clinical characteristics of patients with idiopathic right ventricular outflow tract (RVOT) ventricular arrhythmias (VA) and factors related to the immediate success rate of radiofrequency ablation. Methods: Patients diagnosed as idiopathic RVOT arrhythmia in Fuwai Hospital from February 2009 to January 2013 were retrospectively screened. Patients with structural heart disease or inherited arrhythmia were excluded. All patients underwent endocardial electrophysiological study and radiofrequency catheter ablation. Baseline clinical and operation records were collected and analyzed. Immediate success rate was defined as no inducible ventricular arrhythmia by isoprinosine and electrophysiological induction at the end of ablation. The origins of idiopathic RVOT were classified as septal, anterior, posterior, free wall site, epicardial and RVOT-aorta root site. Results: A total of 468 patients were finally included, and the age was (40.4±13.3) years old and 60.5%(283/468) patients were female. Immediate radiofrequency success rate was 89.3%(418/468). Patients were divided into ablation success group (n=418) and ablation failure group (n=50). Percent of female patients and patients with interventricular septal origin was significantly higher in the ablation success group than in ablation failure group (261(62.4%) vs. 22 (44.0%) , P=0.01, and 233(55.7%) vs. 18(36.0%), P=0.005), while percent of patients with epicardial origin was significantly lower in the ablation success group than in ablation failure group (17(4.1%) vs. 11(22.0%), P<0.001). Immediate success rate was the highest for patients with the septal origin and the lowest for patients with epicardial origin (92.8%(233/251) vs. 60.7%(17/28), P<0.05). Multivariate analysis showed that the origin site of VAs was the most important independent factor related to the success rate of ablation. Compared with the septal origin patients, patients with RVOT-aorta root and epicardial origin VAs faced with 1.82-fold and 8.26-fold increased risk of failed ablation, respectively (OR=2.82, 95%CI 1.05-7.57, and OR=9.26, 95%CI 3.60-23.86). Sex category was not the independent risk factor for failed ablation(OR=1.76, 95%CI 0.93-3.33, P=0.08) . Conclusions: The immediate success rate of radiofrequency catheter ablation for idiopathic RVOT ventricular arrhythmia is relative high, however, immediate success rate of radiofrequency catheter ablation is relatively low for patients with epicardial and RVOT-aorta root origin arrhythmia and VAs origin is an independent risk factor of immediate ablation success rate.

Oxidized CaMKII (Ca2+/Calmodulin-Dependent Protein Kinase II) Is Essential for Ventricular Arrhythmia in a Mouse Model of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy patients are prone to ventricular arrhythmias, which may be caused by abnormal calcium (Ca2+) homeostasis and elevated reactive oxygen species. CaMKII (Ca2+/calmodulin-dependent protein kinase II) is vital for normal Ca2+ homeostasis, but excessive CaMKII activity contributes to abnormal Ca2+ homeostasis and arrhythmias in cardiomyocytes. Reactive oxygen species induce CaMKII to become autonomously active. We hypothesized that genetic inhibition of CaMKII oxidation (ox-CaMKII) in a mouse model of Duchenne muscular dystrophy can alleviate abnormal Ca2+ homeostasis, thus, preventing ventricular arrhythmia. The objective of this study was to test if selective loss of ox-CaMKII affects ventricular arrhythmias in the mdx mouse model of Duchenne muscular dystrophy. 5-(6)-Chloromethyl-2,7-dichlorodihydrofluorescein diacetate staining revealed increased reactive oxygen species production in ventricular myocytes isolated from mdx mice, which coincides with elevated ventricular ox-CaMKII demonstrated by Western blotting. Genetic inhibition of ox-CaMKII by knockin replacement of the regulatory domain methionines with valines (MM-VV [CaMKII M281/282V]) prevented ventricular tachycardia in mdx mice. Confocal calcium imaging of ventricular myocytes isolated from mdx:MM-VV mice revealed normalization of intracellular Ca2+ release events compared with cardiomyocytes from mdx mice. Abnormal action potentials assessed by optical mapping in mdx mice were also alleviated by genetic inhibition of ox-CaMKII. Knockout of the NADPH oxidase regulatory subunit p47 phox normalized elevated ox-CaMKII, repaired intracellular Ca2+ homeostasis, and rescued inducible ventricular arrhythmias in mdx mice. Inhibition of reactive oxygen species or ox-CaMKII protects against proarrhythmic intracellular Ca2+ handling and prevents ventricular arrhythmia in a mouse model of Duchenne muscular dystrophy.

DL-3-n-butylphthalide improves ventricular function, and prevents ventricular remodeling and arrhythmias in post-MI rats.

DL-3-n-butylphthalide (NBP) is used in the treatment of ischemic stroke. It was demonstrated NBP also has a cardioprotective effect in acute myocardial infarction (MI) model. However, the chronic effects of NBP on ventricular function, remodeling, and arrhythmias in post-MI stage are unknown. This study was to investigate the effect of NBP on reducing ventricular remodeling and arrhythmias in post-MI stage. Post-MI rats were randomly treated with 100mg/kg NBP daily (n = 21) or vehicle (n = 21) for 5weeks. Sham-operated rats were treated with the same dose vehicle (n = 18). Echocardiographic assessment, ventricular arrhythmias inducibility test, morphological and collagen analysis, immunohistochemistry, and western blot were studied. NBP significantly improved cardiac function, inhibited the severity and inducibility of ventricular arrhythmias, reduced cardiac index, fibrosis and hypertrophy, improved the protein expression and distribution of Cx43 gap junction, and upregulated PI3k/Akt/Nrf2 pathway and the downstream antioxidant response elements (ARE), including heme oxygenase-1, Glutathione, Cu-Zn superoxide dismutase, and Fe/Mn superoxide dismutase. These results suggest NBP improves LV function and reduces ventricular arrhythmias by mitigating LV fibrosis, hypertrophy, and Cx43 gap junction remodeling. PI3k/Akt/Nrf2/ARE signaling pathway may contribute to its anti-ventricular remodeling effects.

Reduced N-Type Ca2+ Channels in Atrioventricular Ganglion Neurons Are Involved in Ventricular Arrhythmogenesis.

BackgroundAttenuated 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 Ca2+ channel α‐subunits (Cav2.2‐α) and N‐type Ca2+ 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 Ca2+ channels in AVG neurons contributes to ventricular arrhythmogenesis.Methods and ResultsLentiviral Cav2.2‐α shRNA (2 μL, 2×107 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 Cav2.2‐α shRNA decreased expression of Cav2.2‐α mRNA and protein in rat AVG neurons. Whole‐cell patch‐clamp data showed that Cav2.2‐α shRNA reduced N‐type Ca2+ currents and cell excitability in AVG neurons. The data from telemetry electrocardiographic recording demonstrated that 83% (5 out of 6) of conscious rats with Cav2.2‐α shRNA transfection had premature ventricular contractions (P<0.05 versus 0% of nontransfected sham rats or scrambled shRNA‐transfected rats). Additionally, an index of susceptibility to ventricular arrhythmias, inducibility of ventricular arrhythmias evoked by programmed electrical stimulation, was higher in rats with Cav2.2‐α shRNA transfection compared with nontransfected sham rats and scrambled shRNA‐transfected rats.ConclusionsA decrease in N‐type Ca2+ channels in AVG neurons attenuates vagal control of ventricular myocardium, thereby initiating ventricular arrhythmias.

Abstract 23071: Hydroquinidine Abolishes Life-threatening Arrhythmic Events in Patients With Short QT Syndrome

Background: Short QT Syndrome (SQTS) is one of the rarest and most lethal inherited arrhythmogenic syndromes. Preliminary data have shown that hydroquinidine (HQ) is effective in prolonging the duration of QT interval and in preventing the induction of ventricular arrhythmias during programmed electrical stimulation in SQTS patients. No data exist regarding the efficacy of HQ in reducing cardiac events in SQTS patients. Objective: To determine whether HQ reduces the occurrence of Life-threatening Arrhythmic Events (LAE), defined as aborted cardiac arrest and sudden cardiac death, in SQTS patients. Methods: Cohort study on consecutive SQTS patients referred to our center and treated with HQ. The endpoint was to evaluate the antiarrhythmic efficacy of HQ, by comparing the percentage of patients with LAE, the number of LAE per patient and the annual rate of LAE before and after the beginning of therapy with HQ (mean duration of therapy 6±1 years). Results: The study population was comprised of 17 SQTS patients with the following characteristics: 13 (76%) males, age at beginning of therapy with HQ 29±3 years, QTc interval before treatment 331±3 ms. Therapy with HQ was ceased in 2 cases (12%) after 1 week due to gastrointestinal intolerance, while in the remaining 15 patients HQ was administered continuously for 6±1 years, at an average dose of 528±42 mg per day (7±0.6 mg/kg/day). HQ significantly prolonged the QTc interval in all patients, by a mean of 60±6 ms (p&lt;0.001). HQ reduced to zero the percentage of patients with LAE (from 40% to 0%, p=0.03), the mean number of LAE per patient (from 0.73±0.3 to 0, p=0.026) and the annual rate of LAE (from 12.2% to 0%, p=0.028). Conclusions: We showed for the first time that HQ, besides normalizing the duration of the QT interval, is associated with a major reduction of life-threatening arrhythmic events in SQTS patients, thus representing an efficacious therapeutic approach in this group of individuals. Early discontinuation due to gastrointestinal intolerance occurred in 12% of patients.