Faculty Bibliography

Background: Analysis of the local unipolar electrogram aids premature ventricular contraction (PVC) localization in catheter ablation of idiopathic, outflow tract PVCs. A unipolar electrogram QS complex may be seen in the region of PVC origin, but the specificity of this finding is low. The unipolar anodal electrode utilized for PVC mapping is typically Wilson central terminal (WCT) or an indifferent electrode placed within the inferior vena cava (IVC). The optimal unipolar electrode selection for unipolar PVC mapping is unknown. Objective: To compare unipolar mapping of idiopathic outflow tract PVCs using WCT to unipolar mapping using an IVC electrode. Methods: PVC mapping and ablation was performed in 20 consecutive patients presenting for first-time ablation of idiopathic, outflow tract PVCs. The unipolar electrode utilized for initial mapping was randomly assigned and blinded to the operator. Mapping was performed using the CARTO 3 mapping system and SmartTouch RF ablation catheter (Biosense Webster, Inc.). Activation mapping and pace-mapping was performed at the discretion of the operator. Locations with a QS complex were annotated on the electroanatomic map. After a complete map was created blinded mapping was repeated with the alternate unipolar electrode prior to RF application. Results: PVCs were localized to the right ventricular outflow tract in 18 patients (90%) and to the left ventricular outflow tract in 2 patients (10%). Complete unipolar mapping could not be completed in 4 of 20 (20%) of cases due to infrequency of PVCs. In the 16 remaining patients, QS complex surface area was significantly larger with WCT than with the IVC electrode (3.11 +/- 1.8 cm² vs. 1.3 +/- 0.8 cm², p < 0.001). The IVC electrode QS area was completely within the WCT QS area in all cases, and the ratio of WCT QS area to IVC electrode QS area was 2.6 +/- 0.8 (range 1.8 to 4.4). The area of RF application at which PVCs were durably suppressed was within the IVC electrode QS area in all patients. Conclusion: Utilization of an indifferent IVC electrode may improve precision and specificity of unipolar mapping in catheter ablation of idiopathic, outflow tract PVCs

Background: Unfavorable outcomes observed with stepwise linear ablation of non-paroxysmal AF (NPAF) in large clinical trials utilizing ablation catheters without contact-force sensing (CFS) may be attributable to pro-arrhythmic effects of incomplete ablation lines. The optimal ablation strategy for catheter ablation of NPAF using a contact force sensing radiofrequency (RF) ablation catheter remains unclear. Objective: To compare catheter ablation outcomes of stepwise linear ablation to left atrial (LA) posterior wall isolation in patients undergoing NPAF ablation using a CFS RF ablation catheter. Methods: We performed pulmonary vein antral isolation (PVAI) followed by isolation of the LA posterior wall in 80 consecutive patients undergoing first-time NPAF ablation between November 2015 and March 2016 (Group 1) and compared clinical outcomes to those of 112 consecutive patients who underwent PVAI followed by step-wise linear ablation for NPAF between May 2014 and November 2015 (Group 2). All ablation procedures were performed using the Carto 3 mapping system and SmartTouch RF ablation catheter (Biosense Webster, Inc.). Arrhythmia recurrence was assessed using 2-week event monitors at 3-month intervals. Arrhythmia-free survival at 12 months was estimated using the Kaplan-Meier method. Results: Baseline characteristics of Group 1 and Group 2 were similar. At 12 months follow-up, arrhythmia-free survival was significantly greater in Group 1 patients compared with Group 2 (81.9% vs. 67.5%, respectively; p=0.0318). There was no significant difference in survival free from AF between group 1 and group 2 (89% vs. 84.1%, respectively; p=0.3431), however group 1 patients developed significantly fewer post-ablation atrial tachycardias (AT) than group 2 patients (8.1% vs 30.1%, respectively; p<0.001). Conclusion: Among patients undergoing NPAF ablation using a contact force sensing RF ablation catheter, LA posterior wall isolation resulted in fewer recurrent atrial arrhythmias than a stepwise linear approach. The reduction in recurrent atrial arrhythmias is driven primarily by a reduction in recurrent AT

The generation and propagation of the cardiac impulse is the central function of the cardiac conduction system (CCS). Impulse initiation occurs in nodal tissues that have high levels of automaticity, but slow conduction properties. Rapid impulse propagation is a feature of the ventricular conduction system, which is essential for synchronized contraction of the ventricular chambers. When functioning properly, the CCS produces ~2.4 billion heartbeats during a human lifetime and orchestrates the flow of cardiac impulses, designed to maximize cardiac output. Abnormal impulse initiation or propagation can result in brady- and tachy-arrhythmias, producing an array of symptoms, including syncope, heart failure or sudden cardiac death. Underlying the functional diversity of the CCS are gene regulatory networks that direct cell fate towards a nodal or a fast conduction gene program. In this review, we will discuss our current understanding of the transcriptional networks that dictate the components of the CCS, the growth factor-dependent signaling pathways that orchestrate some of these transcriptional hierarchies and the effect of aberrant transcription factor expression on mammalian conduction disease.

Rapid impulse propagation in the heart is a defining property of pectinated atrial myocardium (PAM) and the ventricular conduction system (VCS) and is essential for maintaining normal cardiac rhythm and optimal cardiac output. Conduction defects in these tissues produce a disproportionate burden of arrhythmic disease and are major predictors of mortality in heart failure patients. Despite the clinical importance, little is known about the gene regulatory network that dictates the fast conduction phenotype. Here, we have used signal transduction and transcriptional profiling screens to identify a genetic pathway that converges on the NRG1-responsive transcription factor ETV1 as a critical regulator of fast conduction physiology for PAM and VCS cardiomyocytes. Etv1 was highly expressed in murine PAM and VCS cardiomyocytes, where it regulates expression of Nkx2-5, Gja5, and Scn5a, key cardiac genes required for rapid conduction. Mice deficient in Etv1 exhibited marked cardiac conduction defects coupled with developmental abnormalities of the VCS. Loss of Etv1 resulted in a complete disruption of the normal sodium current heterogeneity that exists between atrial, VCS, and ventricular myocytes. Lastly, a phenome-wide association study identified a link between ETV1 and bundle branch block and heart block in humans. Together, these results identify ETV1 as a critical factor in determining fast conduction physiology in the heart.

Fever is a highly conserved systemic response to infection dating back over 600 million years. Although conferring a survival benefit, fever can negatively impact the function of excitable tissues, such as the heart, producing cardiac arrhythmias. Here we show that mice lacking fibroblast growth factor homologous factor 2 (FHF2) have normal cardiac rhythm at baseline, but increasing core body temperature by as little as 3 degrees C causes coved-type ST elevations and progressive conduction failure that is fully reversible upon return to normothermia. FHF2-deficient cardiomyocytes generate action potentials upon current injection at 25 degrees C but are unexcitable at 40 degrees C. The absence of FHF2 accelerates the rate of closed-state and open-state sodium channel inactivation, which synergizes with temperature-dependent enhancement of inactivation rate to severely suppress cardiac sodium currents at elevated temperatures. Our experimental and computational results identify an essential role for FHF2 in dictating myocardial excitability and conduction that safeguards against temperature-sensitive conduction failure.

Introduction: Transcatheter aortic valve replacement (TAVR) is becoming a widely accepted alternative treatment for patients with symptomatic aortic stenosis who are at high risk for surgical aortic valve replacement. A common complication of the procedure is the development of conduction defects requiring permanent pacemaker (PPM) implantation. It has been noted that in some patients, the conduction block is not permanent. Determine the incidence and predictors of resuming intrinsic conduction in patients that receive PPM implantation after TAVR. Methods: A retrospective chart review of patients undergoing TAVR at New York University Langone Medical Center was undertaken. Extracted data included patient demographics, pre-TAVR electrocardiogram, procedural, echocardiographic, catheterization, and device interrogation data. Evaluation of device interrogations done at one month follow-up or earlier to look for resumption of intrinsic conduction. Results: There were a total number of 451 patients who were status-post TAVR in our registry at NYU. Of the 451, 45 patients received a permanent pacemaker placement for complete heart block; 9.9% 45/451. The majority of patients were implanted within 48hrs post TAVR. Device follow-up information at 1 month or earlier was available for 33 of the 45 patients who received PPM. 5 patients who were recently implanted are still pending follow-up. 3 patients expired after implantation and 4 were lost to follow-up. Of the 33 patients, 14 (42%) patients had resumption of AV nodal conduction at 1 month follow-up. 19 patients (57%) remained dependent. Conclusions: 42% of patients who received a permanent pacemaker for complete heart block after TAVR had resumption of conduction. This suggests that many patients may not require long term PPM post TAVR. Patients that remained dependent had a higher incidence of preexisting RBBB and LAFB, however a lack thereof does not preclude an increased risk. These data suggest that waiting longer than 48 hours for resumption of AV nodal conduction would avoid unnecessary implantation in patients who develop complete heart block post TAVR

Introduction: LA ablation for persistent AF that achieves organization to atrial tachycardia (AT) or sinus rhythm (SR) predicts greater long term ablation success. However, extensive LA ablation increases the risks of recurrent AT, adverse atrial remodeling and procedural complications. Preclinical and observational studies suggest that right atrial ablation may reduce AF risk. We hypothesized that CTI ablation may reduce the extent of LA ablation required to achieve organization of persistent AF. Methods: Persistent AF patients (n=107) were randomized to two arms (CTI-first or CTI-last) in a single center, prospective, single blind study. Excluding the CTI ablation, stepwise linear LA ablation was performed in a prespecified order. The primary endpoint was the percentage of patients who organized to AT or SR. The secondary endpoint was number of steps to organization. Results: CTI ablation first versus last during AF ablation did not significantly alter the percentage of patients who organized (Table). Among those who organized, the number of steps to organization did not differ between the two arms. No significant differences were found when patients were stratified by LA size or AF duration. Conclusions: CTI ablation does not alter the extent of LA ablation needed to achieve organization of AF. The utility of right atrial ablation for persistent AF ablation remains unclear. (Table presented)

Introduction: Large clinical trials have recently demonstrated stepwise linear ablation for non-paroxysmal atrial fibrillation (NPAF) to be inferior to pulmonary vein isolation alone. It is unknown whether the unfavorable outcomes observed in these trials can be attributed to the pro-arrhythmic effects of incomplete ablation lines. We hypothesized that improved lesion quality related to use of contact-force sensing (CFS) ablation catheters would improve procedural outcomes. Methods: We prospectively analyzed procedural outcomes of 74 consecutive patients with NPAF undergoing first-time radiofrequency catheter ablation with a CFS catheter (Smart Touch, Biosense Webster) using a step-wise approach (Group 1). The clinical outcomes of these patients were compared with 74 consecutive patients with NPAF who underwent catheter ablation between September 2013 and June 2014 with a non-contact force sense radiofrequency ablation catheter (Group 2) at a single tertiary care medical center. Arrhythmia recurrence was assessed using 2-week event monitors at 3-month intervals following index ablation. Results: Baseline characteristics of Group 1 and Group 2 were similar, although in Group 1 there was a greater prevalence of patients with persistent NPAF lasting for 6-months or longer prior to initial ablation (43% vs 21%, p=0.071). The recurrence rate at 1 year as estimated by the Kaplan-Meier method was not significantly different between Group 1 and Group 2 (25.7% vs 29.7%, p=0.582). The presenting recurrent arrhythmia was most frequently atrial tachycardia (AT) in both groups (Group 1: n=19, AT 68.4% and AF 31.6% vs Group 2: n=22, AT 59.1% and AF 40.9%). A similar proportion of patients in both groups underwent repeat ablation (Group 1: 17.6% vs Group 2: 13.5%, p=0.496). Conclusions: Utilization of a CFS ablation catheter was not associated with improved clinical outcomes for stepwise catheter ablation for NPAF. The optimal strategy for NPAF ablation using a contact-force sensing catheter remains undefined

Tnnt2, encoding thin-filament sarcomeric protein cardiac troponin T, plays critical roles in heart development and function in mammals. To develop an inducible genetic deletion strategy in myocardial cells, we generated a new Tnnt2:MerCreMer (Tnnt2MerCreMer/+ ) knock-in mouse. Rosa26 reporter lines were used to examine the specificity and efficiency of the inducible Cre recombinase. We found that Cre was specifically and robustly expressed in the cardiomyocytes at embryonic and adult stages following tamoxifen induction. The knock-in allele on Tnnt2 locus does not impact cardiac function. These results suggest that this new Tnnt2MerCreMer/+ mouse could be applied towards the temporal genetic deletion of genes of interests in cardiomyocytes with Cre-LoxP technology. The Tnnt2MerCreMer/+ mouse model also provides a useful tool to trace myocardial lineage during development and repair after cardiac injury