Outflow Tract Region Research Articles

Abstract 13269: Clinical and Electrophysiological Features of New Onset Ventricular Arrythmias Following Catheter Ablation of Atrial Fibrillation

Introduction: Data on new onset ventricular arrhythmias (VAs) following catheter ablation of atrial fibrillation (AF) is sparse. Hypothesis: We aimed to assess the incidence of new onset VA post AF RFA. Methods: We conducted a retrospective study of all patients at our institution that underwent AF ablation who also developed symptomatic high burden premature ventricular complexes (PVCs) requiring catheter ablation within 1 year of the index AF ablation procedure. All patients underwent post AF ablation monitoring with either 48 hr Holter monitors or implantable cardiac monitors. New onset VA was defined as symptomatic new onset PVC with >5% burden. Data on PVC morphology and successful ablation sites was analyzed. Results: Out of 175 patients that underwent AF ablation during the study period, 2.8 % (n=5) patients developed new onset high burden PVCs requiring catheter ablation therapy within 1 year of AF ablation. Mean age was 68.6 + 11 years and all patients were male. Mean baseline LVEF was 56 + 9.6% and mean PVC burden was 10.3 + 8.8 %. A total of 9 PVCs were mapped in 5 patients. The number of VA morphology was 1 in 2 (40%) patients, 2 in 2 (40%) and 3 in 1 (20%) patient. Site of origin for the PVCs was in the left ventricle in all patients, with majority (55%) localizing to the LV outflow tract and summit region (table). Average time from AF RFA to PVC ablation was 4 + 2.9 months. PVC ablation was successful in all patients except one where ablation was deferred due to proximity to the conduction system. Conclusions: New onset VAs following catheter ablation of AF tend to localize to the LV outflow tract and areas of bipolar voltage abnormality. Potential mechanisms of new onset PVCs could include altered sympathetic tone due to ablation of cardiac ganglia, unmasking of PVCs due to regularization of ventricular rate and withdrawal of anti-arrhythmic medications. Further prospective studies are needed to understand true incidence of new onset VAs following AF ablation.

Abstract 17188: Electrocardiographic Algorithms for Localization Ventricular Ectopy From the Ventricular Outflow Tracts Demonstrate Poor Accuracy and Agreement

Background: Premature ventricular contractions (PVCs) and ventricular tachycardia (VT) commonly arise from the outflow tracts of the left and right ventricles and can be treated with catheter ablation when symptomatic or associated with cardiomyopathy. Accurate localization of these ectopic sources aids procedural planning. Several different electrocardiographic (ECG) algorithms have been published, but their relative performance has not been assessed. Objective: Compare the accuracy and agreement of three ECG algorithms for PVC localization. Methods: ECGs from patients who underwent catheter ablation for PVCs or VT originating the outflow tract region were analyzed using three published PVC localization algorithms. The predictions from these algorithms were then compared to the site of successful catheter ablation (right ventricular outflow tract [RVOT], left ventricular outflow tract [LVOT], or epicardium). The accuracy and agreement of the three algorithms were compared. Results: A total of 43 patients were evaluated and ectopy was suppressed via ablation from a single chamber in 37 (86%) of patients. VT/PVCs originated from the RVOT (N=10), LVOT (N=26), and epicardium (N=1). The three studied algorithms demonstrated accuracy rates of 46-70%. The algorithms disagreed on the predicted ectopy location for 19 (51%) patients. When all algorithms agreed (N=18), the prediction was accurate for only 11 patients (61%). Conclusion: Rules-based ECG algorithms demonstrate poor performance and use of different published algorithms frequently result in disparate results. More accurate and consistent methods incorporating individualized electroanatomic variation may improve accuracy and periprocedural management for PVC and VT ablation.

PO-05-067 THE USE OF THE HIS BUNDLE LOCAL ACTIVATION TIME IN OUTFLOW TRACT PREMATURE VENTRICULAR CONTRACTIONS TO ASSIST IN LOCALIZATION

Localization of premature ventricular contractions (PVCs) from the outflow tract regions based upon ECG localization criteria may prove challenging based upon cardiac rotation and surface lead placement. Multiple studies describe ECG parameters based upon axis and precordial R wave transition for distinction of left (LVOT) vs right ventricular outflow tract (RVOT) site of origin. No previous studies describe intracardiac fiducial points to assist in site discrimination for PVC origin between LVOT, RVOT, and intramyocardial sites. Assessment of PVC timing at the His bundle region (HB) as a predictor for area of origin of a premature ventricular contraction. Timing at the area of the HB could help discriminate LVOT, RVOT, and intramural PVCs and guide ablation strategy. We performed retrospective analysis of 30 consecutive patients who underwent a PVC ablation from July 2021 until present day. During index mapping, placement of a multipolar catheter in the HB yielded local activation timing (LAT) for PVCs, and the HB was marked on the mapping system . The timing of a PVC was recorded as well as the area of successful ablation. Of the 30 patients 10 were female and 20 male with an average age of 60 years. The average EF was 52%. 10 patients had coronary artery disease 9 had ICDs. 10 Patients with successful LVOT ablation had HB LAT average of -6 msec +/- 12msec. 8 Patients with successful RVOT ablation had HB LAT average of 32 msec +/-11msec. 12 patients with successful intramyocardial ablation had HB LAT of 45 msec +- 8 msec. The difference between LVOT HB LAT and RVOT HB LAT was statically significant P<0.001. The difference between LVOT HB LAT and intramyocardial HB LAT was statistically significant P<0.001. The difference between RVOT HB LAT and intramyocardial HB LAT was statistically significant P<0.0062. Use of the HB as an intracardiac fiducial point for LAT assists with accurate localization and successful ablation of PVCs originating from the outflow tracts.

Ablation of Focal Intramural Outflow Tract Ventricular Arrhythmias.

Most idiopathic ventricular arrhythmias (VAs) originate from the outflow tract (OT) region and can be targeted with ablation either from the endocardial aspect of the right and left ventricular outflow tracts or from the aortic sinuses of Valsalva. It is important to exclude scar in patients with OT VAs. In some patients, the site of origin may be intramural. Ablation of intramural OT VAs can be challenging to map and ablate due to deep intramural sites of origin. The coronary venous branches may permit mapping and ablation of intramural OT VAs.

En Face Endocardial Cushion Preparation for Planar Morphogenesis Analysis in Mouse Embryos.

The study of the cellular and molecular mechanisms underlying the development of the mammalian heart is essential to address human congenital heart disease. The development of the primitive cardiac valves involves the epithelial-to-mesenchymal transition (EMT) of endocardial cells from the atrioventricular canal (AVC) and outflow tract (OFT) regions of the heart in response to local inductive myocardial and endocardial signals. Once the cells delaminate and invade the extracellular matrix (cardiac jelly) located between the endocardium and the myocardium, the primitive endocardial cushions (EC) are formed. This process implies that the endocardium has to fill the gaps left by the delaminated cells and has to reorganize itself to converge (narrow) or extend (lengthen) along an axis. Current research has implicated the planar cell polarity (PCP) pathway in regulating the subcellular localization of the factors involved in this process. Classically, the initial phases of cardiac valve development have been studied in cross-sections of embryonic hearts or in ex vivo AVC or OFT explants cultured on collagen gels. These approaches allow the analysis of apico-basal polarity but do not allow the analysis of cell behavior within the plane of the epithelium or of the morphological changes of migrating cells. Here, we show an experimental approach that allows the visualization of the endocardium at valvulogenic regions as a planar field of cells. This experimental approach provides the opportunity to study PCP, planar topology, and intercellular communication within the endocardium of the OFT and AVC during valve development. Deciphering new cellular mechanisms involved in cardiac valve morphogenesis may contribute to understanding congenital heart disease associated with endocardial cushion defects.

Long-term outcomes of non-contact multi-electrode balloon catheter mapping-guided ablation of ventricular arrhythmias originating from the outflow tract

IntroductionThe outflow tract (OT) regions of the ventricles are a common location of origin for idiopathic ventricular arrhythmias (VA). Non-contact mapping (NCM) with a multi-electrode balloon catheter Ensite-Array enables three-dimensional reconstruction of the geometry of the cardiac chambers and accurate mapping of the propagation map, based on a single beat analysis, facilitating the ablation and contributing procedure success. ObjectiveAssessment of the feasibility and long-term outcomes following NCM-guided OT VA ablation. MethodsSingle center retrospective analysis of patients admitted for symptomatic OT VA ablation. Demographic and clinical characteristics of patients, procedure data and long-term outcomes were assessed. ResultsFifty-eight patients (79.3% female, age 43.9±17.6 years) were considered, 89.7% without structural heart disease. In 85.7% of the cases left ventricle ejection fraction (LVEF) was preserved (LVEF≥50%), 8.6% had mild systolic dysfunction (LVEF 40%-49%) and 5.7% had moderate systolic dysfunction (LVEF 30%-39%). Twenty-four-hour Holter recording documented sustained VA episodes in 12.1% of the patients, non-sustained VA in 31.0%, and >10 000 premature ventricular complex (PVC)/24 h in 56.9%, with an ECG suggesting right ventricular OT origin in 84.5%. There was total elimination of PVC in 87.9% cases and a significant reduction in 3.4%. During a mean follow-up of 5.5 years, 87.9% patients remained asymptomatic without medication, 12.1% underwent re-ablation due to symptomatic PVC recurrence, and two cases underwent a third successful intervention. ConclusionNon-contact mapping-guided multi-electrode balloon catheter VA ablation is a highly effective and safe procedure, with a low rate of long-term recurrence.

Empiric ablation of polymorphic ventricular tachycardia/fibrillation in the absence of a mappable trigger: Prospective feasibility and efficacy of pacemap matching to defibrillator electrograms.

Catheter ablation strategies for ventricular fibrillation (VF) and polymorphic ventricular tachycardia (PMVT) are not established when spontaneous triggers are rare or absent. The purpose of this study was to report the feasibility and efficacy of a novel empiric ablation strategy of pacemapping to stored implantable cardioverter-defibrillator (ICD) template electrograms (SITE) of the clinical premature ventricular contraction (PVC) trigger. Fifteen patients with drug-refractory VF/PMVT receiving defibrillator shocks without identifiable and mappable PVC triggers were prospectively analyzed. The protocol incorporated systematic pacemapping from known arrhythmogenic sites (moderator band/right ventricular [RV] papillary muscles, left conduction system/Purkinje network, outflow tracts) with real-time comparison between the paced ICD electrogram (EGM) morphology and SITE. Regions within the left Purkinje network yielded the best pacemap match for the SITE of the clinical PVC trigger in 55% of ablation targets (left posterior fascicle 6, left septal fascicle 1, left anterior fascicle 5), followed by the RV moderator band region in 14% (n = 3), RV papillary muscles in 13% (n = 3), periaortic region in 14% (n = 3), and left ventricular anterolateral papillary muscle in 4% (n = 1). Freedom from ICD therapies off antiarrhythmic drug (AAD) was 64% at 6 months and 48% at 12 months. Shock burden was reduced from 4 (2-6) to 0 (0-1) (P = .001), and use of AADs was reduced from 2 (1-2) to 0 (0-1) (P = .001). In the absence of a mappable trigger, an empiric strategy of interrogating the Purkinje network, papillary muscles, and outflow tract regions by pacemap matching with SITE of the clinical PVC is feasible to guide ablation. A significant reduction in VF/PMVT therapy burden and AAD utilization was observed after a single procedure.

Utility of Prolonged Duration EndocardialAblation for Ventricular Arrhythmias Originating From the Left Ventricular Summit.

This study sought to explore whether prolonged duration (PD) radiofrequency ablation (RFA) from adjacent endocardial locations can improve catheter ablation (CA) outcomes of left ventricular summit (LVS) ventricular arrhythmias (Vas). CA of VAs originating from the LVS region can be challenging. Patients undergoing CA of LVS VAs from January 1, 2015, to December 31, 2019, were included. Standard RFA approach involved incremental power titration (20-45 W) over 60-120 seconds with irrigated tip catheter to achieve 10%-12% impedance drop. Prolonged duration RFA involved similar power titration; however, lesion application was extended beyond 120 seconds (maximum 5minutes). Lesions were confined to lowest aspect of aortic cusps and/or subvalvular LV outflow tract region (≤0.5cm from the valve). Procedural success was defined as suppression of VA≥30minutes postablation and clinical success as no arrhythmia symptoms on follow-up and >80% reduction of VA burden on postprocedure monitor. This study included 102 patients (60±14 years old, 62% male): standard RFA in 80 and PD RFA in 38. Procedural success was achieved in 54 patients with standard and 32 patients with PD RFA (68% vs 84%; P = 0.05). Short-term clinical success was achieved in 48 patients (60%) with standard and 30 patients (79%) with PD RFA (P=0.04). Two pericardial effusions occurred (1 in each group) and no steam pops were noted. Patients in whom standard RFA was successful were more likely to have R/S ratio >1 or absence of qS in lead I (odds ratio: 3.35; 95%CI: 1.20-9.35; P = 0.03). Prolonged duration RFA from adjacent endocardial locations is a safe and effective technique for successfully targeting challenging LVS VAs that fail standard RFA.

Symptomatic Premature Ventricular Contractions in Vasovagal Syncope Patients: Autonomic Modulation and Catheter Ablation.

IntroductionThere has been limited reports about the comorbid premature ventricular contractions (PVCs) and vasovagal syncope (VVS). Deceleration capacity (DC) was demonstrated to be a quantitative evaluation to assess the cardiac vagal activity. This study sought to report the impact of autonomic modulation on symptomatic PVCs in VVS patients.Methods and ResultsTwenty-six VVS patients with symptomatic idiopathic PVCs were consecutively enrolled. Identification and catheter ablation of left atrial ganglionated plexi (GP) and PVCs were performed in 26 and 20 patients, respectively. Holter 24 h-electrocardiograms were performed before and after the procedure to evaluate DC and PVCs occurrence. Eighteen patients were subtyped as DC-dependent PVCs (D-PVCs) and eight as DC-independent PVCs groups (I-PVCs). In D-PVCs group, circadian rhythm of hourly PVCs was positively correlated with hourly DC (P < 0.05) while there was no correlation in I-PVCs group (P > 0.05). Fifty-three GPs with positive vagal response were successfully elicited (2.0 ± 0.8 per patient). PVCs failed to occur spontaneously nor to be induced in six patients. In the remaining 20 patients, PVCs foci identified were all located in the ventricular outflow tract region. Post-ablation DC decreased significantly from baseline (P < 0.05). During mean follow-up of 10.64 ± 6.84 months, syncope recurred in one patient and PVCs recurred in another. PVCs burden of the six patients in whom neither catheter ablation nor antiarrhythmic drugs were applied demonstrated a significant decrease during follow-up (P = 0.037).ConclusionAutonomic activities were involved in the occurrence of symptomatic idiopathic PVCs in some VVS patients. D-PVCs might be facilitated by increased vagal activities. Catheter ablation of GP and PVCs foci may be an effective, safe treatment in patients with concomitant VVS and idiopathic PVCs.

Msx1 upregulates p27 expression to control cellular proliferation during valvuloseptal endocardial cushion formation in the chick embryonic heart.

Cushion tissues, the primordia of valves and septa of the adult heart, are formed in the atrioventricular (AV) and outflow tract (OFT) regions of the embryonic heart. The cushion tissues are generated by the endothelial-mesenchymal transition (EMT), involving many soluble factors, extracellular matrix, and transcription factors. Moreover, neural crest-derived mesenchymal cells also migrate into the OFT cushion. The transcription factor Msx1 is known to be expressed in the endothelial and mesenchymal cells during cushion tissue formation. However, its exact role in EMT during cushion tissue formation is still unknown. In this study, we investigated the expression patterns of Msx1 mRNA and protein during chick heart development. Msx1 mRNA was localized in endothelial cells of the AV region at Stage 14, and its protein was first detected at Stage 15. Thereafter, Msx1 mRNA and protein were observed in the endothelial and mesenchymal cells of the OFT and AV regions. in vitro assays showed that ectopic Msx1 expression in endothelial cells induced p27, a cell-cycle inhibitor, expression and inhibited fibroblast growth factor 4 (FGF4)-induced cell proliferation. Although the FGF signal reduced the EMT-inducing activities of transforming growth factor β (TGFβ), ectopic Msx1 expression in endothelial cells enhanced TGFβ signaling-induced αSMA, an EMT marker, expression. These results suggest that Msx1 may support the transformation of endothelial cells due to a TGFβ signal in EMT during cushion tissue formation.

Catheter ablation in highly symptomatic Brugada patients: a Dutch case series.

In the past few years, promising results were described in targeting the arrhythmogenic substrate of the epicardial right ventricular outflow tract (RVOT) region in patients with Brugada syndrome (BrS). In this report, we describe our experience with endo- and epicardial substrate mapping and ablation in a series of highly symptomatic BrS patients. This case series consists of seven patients with clinical BrS diagnosis who underwent catheter ablation in two Dutch hospitals (Isala hospital Zwolle; and Amsterdam University Medical Centre, location AMC, Amsterdam) and Hamad Heart Hospital in Qatar between 2013 and 2017. All patients had an ICD and recurrent ventricular arrhythmia (VA) episodes. All patients underwent endo-and epicardial mapping of the RVOT region. Elimination of all abnormal potentials and disappearance of BrS ECG pattern during the ablation procedure was the aimed endpoint. The study group consisted of seven patients with mean age 45.6 ± 16.9years. Five patients had SCN5A mutations. One patient was excluded from analysis, since ablation could not be performed due to a very large low-voltage area and was later diagnosed with arrhythmogenic right ventricular cardiomyopathy, associated with an SCN5A mutation. One patient underwent both endo- and epicardial ablation to eliminate VA. During a mean follow-up of 3.6 ± 1.5years, 5/6 patients remained VA free with two patients continuing quinidine. In patients with BrS and drug-refractory VA, ablation of the arrhythmogenic substrate in the RVOT region was associated with excellent long-term VA-free survival. The majority of these highly symptomatic BrS patients had an SCN5A mutation and also low-voltage areas epicardially.

Long term follow-up after ventricular tachycardia ablation in patients with congenital heart disease.

Ventricular tachycardia (VT) is frequently encountered in patients with repaired and unrepaired congenital heart disease (CHD), causing significant morbidity and sudden cardiac death. Data regarding underlying VT mechanisms and optimal ablation strategies in these patients remain limited. To describe the electrophysiologic mechanisms, ablation strategies, and long-term outcomes in patients with CHD undergoing VT ablation. Forty-eight patients (mean age 41.3 ± 13.3 years, 77.1% male) with CHD underwent a total of 57 VT ablation procedures at two centers from 2000 to 2017. Electrophysiologic and follow-up data were analyzed. Of the 77 different VTs induced at initial or repeat ablation, the underlying mechanism in 62 (81.0%) was due to scar-related re-entry; the remaining included four His-Purkinje system-related macrore-entry VTs and focal VTs mainly originating from the outflow tract region (8 of 11, 72.7%). VT-free survival after a single procedure was 72.9% (35 of 48) at a median follow-up of 53 months. VT-free survival after multiple procedures was 85.4% (41 of 48) at a median follow-up of 52 months. There were no major complications. Three patients died during the follow-up period from nonarrhythmic causes, including heart failure and cardiac surgery complication. While scar-related re-entry is the most common VT mechanism in patients with CHD, importantly, nonscar-related VT may also be present. In experienced tertiary care centers, ablation of both scar-related and nonscar-related VT in patients with CHD is safe, feasible, and effective over long-term follow-up.

Idiopathic Outflow Tract Ventricular Arrhythmia Ablation: Pearls and Pitfalls.

Idiopathic outflow tract ventricular arrhythmias (VAs) occur typically in patients without structural heart disease. They are often symptomatic and can sometimes lead to left ventricular systolic dysfunction. Both activation and pace mapping are utilised for successful ablation of these arrhythmias. Pace mapping is particularly helpful when the VA is infrequent and/or cannot be elucidated during the ablation procedure. VAs originating from different sites in the outflow tract region have distinct QRS patterns on the 12-lead ECG and careful analysis of the latter can help predict the site of origin of these arrhythmias. Successful ablation of these VAs requires understanding of the detailed anatomy of the OT region, which can be accomplished through electroanatomic mapping tools and intracardiac echocardiography.

Role of Semaphorin Signaling During Cardiovascular Development.

Semaphorins are a family of secreted and membrane‐bound molecules that play critical functions in diverse biological processes.[1][1], [2][2], [3][3], [4][4], [5][5], [6][6], [7][7], [8][8], [9][9] SEMA1A/Fasciclin IV is the founding member of the semaphorin family and was first reported in 1992

Utility of Conventional Electrocardiographic Criteria in Patients With Idiopathic VentricularTachycardia.

This study sought to determine the ability of conventional electrocardiographic (ECG) criteria to correctly differentiate idiopathic ventricular tachycardia (VT) from supraventricular tachycardia (SVT) with aberrancy. Previously reported VT ECG criteria were developed from cohorts of patients with structural heart disease and have not been applied to patients with idiopathic VT. ECGs of 115 idiopathic VTs, 101 post-myocardial infarction (MI) VTs, and 111 wide QRS SVTs were analyzed using standard criteria. VT was diagnosed in patients when at least 1 criterion was met, SVT when no criteria were met, and indeterminate when there were conflicting criteria. Standard ECG criteria more frequently diagnosed VT in the post-MI group than the idiopathic group (95% vs. 82%, respectively; p< 0.01). Diagnosis in only 12 of the 111 SVT patients (11%) met the criteria for VT. All patients in the idiopathic VT group with right branch bundle block morphology who did not meet VT criteria demonstrated an rsR' pattern in V1 (consistent with SVT). Among idiopathic VT patients, Purkinje-associated VT had the lowest sensitivity for correct VT diagnosis in 13 of 23 patients (57%), septal sites of origin were correctly diagnosed in only 56 of 76 patients (74%), whereas nonseptal sites had a high sensitivity in 35 of 35 patients (100%; p< 0.005). Conventional ECG criteria have reduced sensitivity to distinguish VT from SVT with aberrancy in patients with idiopathic VT. This is most pronounced in VT originating from septal sites, particularly Purkinje sites and the septal outflow tract regions. Clinicians should be aware that application of conventional ECG criteria in idiopathic VT may underdiagnose VT.

Distribution and Prognostic Significance of Fragmented QRS in Patients With Brugada Syndrome.

Fragmented QRS complexes (fQRS) in the right precordial leads are associated with occurrence of ventricular fibrillation (VF) in Brugada syndrome. Recently, epicardial mapping has revealed abnormal electrograms at the right ventricular (RV) outflow tract and inferior region of the right ventricle. fQRS may reflect the extent of the area of abnormal potentials, but whether the distribution of fQRS has prognostic value is not known. We evaluated the existence of fQRS in 456 patients with Brugada syndrome, including 117 patients with syncope and 23 patients with VF. The region of fQRS was defined as inferior (II, III, and aVF), lateral (I, aVL, and V5 and V6), anterior (V3 and V4), RV (V1 and V2), and RV outflow tract (V1 and V2 at the third intercostal space). fQRS were present in 229 patients (RV outflow tract in 175, inferior in 135, RV in 90, and lateral in 16 patients). During follow-up (mean 91 months), 39 patients experienced VF. In univariable analyses, fQRS in any distribution and fQRS in each region excluding the RV were associated with VF. Multivariable analysis showed that fQRS in the inferior (hazard ratio, 3.9; confidence interval, 1.9-8.5), lateral (hazard ratio, 3.5; confidence interval, 1.2-8.2), and RV outflow tract (hazard ratio, 2.5; confidence interval, 1.2-5.6) were associated with VF events. The presence of multiple regions of fQRS was associated with worse prognosis. The distribution of fQRS is associated with prognosis in Brugada syndrome, further supporting the association of fQRS and arrhythmia substrate.

Hypothetical "anatomy" of Brugada phenomenon: "Long QT sine Long QT" syndrome implicating morphologically undefined specific "Brugada's myocells".

The Brugada syndrome (BrS) is associated with increased risk of ventricular arrhythmias and sudden cardiac death. It generates genetically mediated arrhythmias posing a true pathophysiological challenge. In search of the similarities between BrS and long QT syndrome some novel insights are suggested. In patients with BrS the duration of QT interval is usually normal. Some investigators have found prolonged QT interval in the syndrome's natural course or the duration of QT segment have been extended by provocative tests unmasking BrS. Thus, BrS might be characterized as "long QT sine long QT" syndrome. The existence of two functional types of myocites is suspected. Regarding structure and function the majority of ventricular myocardium is probably mostly healthy. The rest of myocardium (preferably the subepicardium of right ventricular outflow tract) due to its genotypic peculiarities demonstrates no negative influence on ventricular performance until early adulthood is reached and/or other unstable preconditions are fulfilled (nocturnal time, fever, specific drugs, etc.). Based on published findings of positive outcomes, following the epicardial ablation of the right ventricular outflow tract region, a new hypothetical concept suggesting the presence of specific, genetically affected "Brugada's myocells" is proposed. These cells as a suitable arrhythmogenic substrate reside intramurally within the subepicardial region of the outflow tract of right ventricle. In the daytime these cells likely are dormant but at rest their nocturnal proarrhythmic behavior is activated occasionally. Presumptions regarding the pathophysiology of BrS might be the focus of further discussion.

Scn2b Deletion in Mice Results in Ventricular and Atrial Arrhythmias.

Mutations in SCN2B, encoding voltage-gated sodium channel β2-subunits, are associated with human cardiac arrhythmias, including atrial fibrillation and Brugada syndrome. Because of this, we propose that β2-subunits play critical roles in the establishment or maintenance of normal cardiac electric activity in vivo. To understand the pathophysiological roles of β2 in the heart, we investigated the cardiac phenotype of Scn2b null mice. We observed reduced sodium and potassium current densities in ventricular myocytes, as well as conduction slowing in the right ventricular outflow tract region. Functional reentry, resulting from the interplay between slowed conduction, prolonged repolarization, and increased incidence of premature ventricular complexes, was found to underlie the mechanism of spontaneous polymorphic ventricular tachycardia. Scn5a transcript levels were similar in Scn2b null and wild-type ventricles, as were levels of Nav1.5 protein, suggesting that similar to the previous work in neurons, the major function of β2-subunits in the ventricle is to chaperone voltage-gated sodium channel α-subunits to the plasma membrane. Interestingly, Scn2b deletion resulted in region-specific effects in the heart. Scn2b null atria had normal levels of sodium current density compared with wild type. Scn2b null hearts were more susceptible to atrial fibrillation, had increased levels of fibrosis, and higher repolarization dispersion than wild-type littermates. Genetic deletion of Scn2b in mice results in ventricular and atrial arrhythmias, consistent with reported SCN2B mutations in human patients.

Effect of Outflow Tract Banding on Embryonic Cardiac Hemodynamics.

We analyzed heart wall motion and blood flow dynamics in chicken embryos using in vivo optical coherence tomography (OCT) imaging and computational fluid dynamics (CFD) embryo-specific modeling. We focused on the heart outflow tract (OFT) region of day 3 embryos, and compared normal (control) conditions to conditions after performing an OFT banding intervention, which alters hemodynamics in the embryonic heart and vasculature. We found that hemodynamics and cardiac wall motion in the OFT are affected by banding in ways that might not be intuitive a priori. In addition to the expected increase in ventricular blood pressure, and increase blood flow velocity and, thus, wall shear stress (WSS) at the band site, the characteristic peristaltic-like motion of the OFT was altered, further affecting flow and WSS. Myocardial contractility, however, was affected only close to the band site due to the physical restriction on wall motion imposed by the band. WSS were heterogeneously distributed in both normal and banded OFTs. Our results show how banding affects cardiac mechanics and can lead, in the future, to a better understanding of mechanisms by which altered blood flow conditions affect cardiac development leading to congenital heart disease.

Determinants of ventricular arrhythmias in human explanted hearts with dilated cardiomyopathy.

The molecular and cellular determinants of ventricular tachycardia (VT) in patients with nonischaemic dilated cardiomyopathy (NIDCM) remain poorly defined. We examined 20 NIDCM hearts where VT was reported in 10 cases and VT was absent in 10 cases, using a double-blinded case-control study design, and assessed the molecular and cellular features of the adverse myocardial remodelling. Explanted hearts from patients with VT showed greater hypertrophic changes based on cardiomyocyte cross-sectional area and expression of disease markers, and increased myocardial fibrosis which extended into the left ventricular and right ventricular outflow tract regions. The VT group also showed increased oxidative stress with reduction in reduced glutathione levels. Connexin 43 levels in the intercalated discs showed increased levels in the VT group with reduced phosphorylation. Microarray mRNA analysis of gene expression in the left ventricle (LV) free wall revealed several families of genes which were differentially upregulated or downregulated in hearts with documented VT compared to hearts without VT. Notably, we identified reduced expression of the Ca(2+) -activated K(+) channel (KCNN2) and increased expression of the transient receptor potential cation channel 7 (TRPM7) and intracellular chloride channel 3. Western blot analysis on LV membrane fractions showed reduced KCNN2 and increased TRPM7 levels in hearts with VT. In explanted human hearts with NIDCM, VT is associated with greater hypertrophy, oxidative stress and myocardial fibrosis, differential gene expression, and altered ion channel levels indicative of a distinctive adverse myocardial remodelling process associated with clinically significant VT.