Faculty Bibliography

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: 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

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.

A mouse model that mediates temporal, specific, and efficient myocardial deletion with Cre-LoxP technology will be a valuable tool to determine the function of genes during heart formation. Mhy6 encodes a cardiac muscle specific protein: alpha-myosin heavy chain. Here, we generated a new Myh6-MerCreMer (Myh6MerCreMer/+) inducible Cre knock-in mouse by inserting a MerCreMer cassette into the Myh6 start codon. By crossing knock-in mice with Rosa26 reporter lines, we found the Myh6MerCreMer/+ mice mediate complete Cre-LoxP recombination in cardiomyocytes after tamoxifen induction. X-gal staining and immunohistochemistry analysis revealed that Myh6-driven Cre recombinase was specifically activated in cardiomyocytes at embryonic and adult stages. Furthermore, echocardiography showed that Myh6MerCreMer/+ mice maintained normal cardiac structure and function before and after tamoxifen administration. These results suggest that the new Myh6MerCreMer/+ mouse can serve as a robust tool to dissect the roles of genes in heart development and function. Additionally, myocardial progeny during heart development and after cardiac injury can be traced using this mouse line.

The bone marrow niche is thought to act as a permissive microenvironment required for emergence or progression of hematologic cancers. We hypothesized that osteoblasts, components of the niche involved in hematopoietic stem cell (HSC) function, influence the fate of leukemic blasts. We show that osteoblast numbers decrease by 55% in myelodysplasia and acute myeloid leukemia patients. Further, genetic depletion of osteoblasts in mouse models of acute leukemia increased circulating blasts and tumor engraftment in the marrow and spleen leading to higher tumor burden and shorter survival. Myelopoiesis increased and was coupled with a reduction in B lymphopoiesis and compromised erythropoiesis, suggesting that hematopoietic lineage/progression was altered. Treatment of mice with acute myeloid or lymphoblastic leukemia with a pharmacologic inhibitor of the synthesis of duodenal serotonin, a hormone suppressing osteoblast numbers, inhibited loss of osteoblasts. Maintenance of the osteoblast pool restored normal marrow function, reduced tumor burden, and prolonged survival. Leukemia prevention was attributable to maintenance of osteoblast numbers because inhibition of serotonin receptors alone in leukemic blasts did not affect leukemia progression. These results suggest that osteoblasts play a fundamental role in propagating leukemia in the marrow and may be a therapeutic target to induce hostility of the niche to leukemia blasts.

PURPOSE: Transesophageal echocardiography (TEE) is routinely used to assess for thrombus in the left atrium (LA) and left atrial appendage (LAA) in patients undergoing atrial fibrillation (AF) ablation. However, little is known about the outcome of AF ablation in patients with documented LAA sludge. We hypothesize that AF ablation can be performed safely in a proportion of patients with sludge in the LAA and may have a significant benefit for these patients. METHODS: We performed a retrospective analysis of all patients undergoing AF ablation at New York University Langone Medical Center (NYULMC) from January 1st 2011 to June 30, 2013. Patients with sludge found on their TEE immediately prior to AF ablation were identified and followed for stroke, AF recurrence, procedural complications, major bleeding, or death. RESULTS: Among 1,076 patients who underwent AF ablation, 8 patients (mean age 69 +/- 13 years; 75 % men) with sludge were identified. Patients with sludge in their LAA had no incidence of early or late occurrence of stroke during mean follow-up of 10 months. One patient had a left groin hematoma, and two patients had atrial tachycardias that needed a repeat ablation. TEE at the time of repeat ablation demonstrated the presence of spontaneous echo contrast (smoke) and resolution of sludge. There were no deaths. CONCLUSION: In a cohort of eight patients with LAA sludge who underwent AF ablation, no significant thromboembolic events occurred during or after the procedure. AF ablation can be performed safely and may be beneficial in these patients. Larger studies are warranted to better determine the most appropriate management route.