Faculty Bibliography

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

OBJECTIVES/OBJECTIVE:This study aimed to evaluate the cumulative effect of treatment of obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) on atrial fibrillation (AF) recurrence. BACKGROUND:OSA is a known predictor for onset and recurrence of AF. The effect of treatment with CPAP on AF recurrence has been evaluated in small studies with varied outcomes. METHODS:We searched MEDLINE, EMBASE, CINAHL, Google Scholar, Cochrane Database of Systematic Reviews, and Cochrane Trials Register for relevant studies. Evaluation of AF recurrence in CPAP users and nonusers in patients with OSA was the primary outcome evaluated in this study. The secondary outcome was evaluation of AF recurrence in CPAP users and nonusers after pulmonary vein isolation (PVI). RESULTS: = 0%). The beneficial effect of CPAP use was statistically significant in both groups of patients: those who underwent catheter ablation with PVI and those who did not undergo ablation and were managed medically. No other study covariates had any significant association with these outcomes of AF reduction. CONCLUSIONS:The use of CPAP is associated with significant reduction in recurrence of AF in patients with OSA. This effect remains consistent and similar across patient populations irrespective of whether they undergo PVI.

SCN5A encodes the alpha subunit of the major cardiac sodium channel NaV1.5. Mutations in SCN5A are associated with conduction disease and ventricular fibrillation (VF); however, the mechanisms that link loss of sodium channel function to arrhythmic instability remain unresolved. Here, we generated a large-animal model of a human cardiac sodium channelopathy in pigs, which have cardiac structure and function similar to humans, to better define the arrhythmic substrate. We introduced a nonsense mutation originally identified in a child with Brugada syndrome into the orthologous position (E558X) in the pig SCN5A gene. SCN5AE558X/+ pigs exhibited conduction abnormalities in the absence of cardiac structural defects. Sudden cardiac death was not observed in young pigs; however, Langendorff-perfused SCN5AE558X/+ hearts had an increased propensity for pacing-induced or spontaneous VF initiated by short-coupled ventricular premature beats. Optical mapping during VF showed that activity often began as an organized focal source or broad wavefront on the right ventricular (RV) free wall. Together, the results from this study demonstrate that the SCN5AE558X/+ pig model accurately phenocopies many aspects of human cardiac sodium channelopathy, including conduction slowing and increased susceptibility to ventricular arrhythmias.