Faculty Bibliography

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.

Genome-wide association studies (GWAS) have implicated SCN10A, which encodes a nociceptor-associated voltage-gated sodium channel subunit, as a modulator of cardiac conduction; however, this role has traditionally been ascribed to SCN5A, which is highly expressed in cardiac muscle. SCN10A is believed to affect cardiac conduction either directly through cardiomyocytes or indirectly via intracardiac neurons. In this issue of the JCI, van den Boogaard and colleagues introduce a third possibility: that the SCN10A locus acts as an enhancer of SCN5A gene expression. The authors demonstrate that SCN10A expression is negligible within human and murine hearts, and that a T-box enhancer within the SCN10A locus drives SCN5A expression within cardiomyocytes. This work reasserts SCN5A as the key determinant of cardiac conduction and highlights the importance of deciphering the functionality of coding versus noncoding regions when interpreting GWAS data.

MicroRNA cluster miR-17-92 has been implicated in cardiovascular development and function, yet its precise mechanisms of action in these contexts are uncertain. This study aimed to investigate the role of miR-17-92 in morphogenesis and function of cardiac and smooth muscle tissues. To do so, a mouse model of conditional overexpression of miR-17-92 in cardiac and smooth muscle tissues was generated. Extensive cardiac functional studies identified a dose-dependent induction of dilated, hypertrophic cardiomyopathy, and arrhythmia inducibility in transgenic animals, which correlated with premature mortality (98.3+/-42.5 d, P<0.0001). Expression analyses revealed the abundance of Pten transcript, a known miR-17-92 target, to be inversely correlated with miR-17-92 expression levels and heart size. In addition, we demonstrated through 3'-UTR luciferase assays and expression analyses that Connexin43 (Cx43) is a novel direct target of miR-19a/b and its expression is suppressed in transgenic hearts. Taken together, these data demonstrate that dysregulated expression of miR-17-92 during cardiovascular morphogenesis results in a lethal cardiomyopathy, possibly in part through direct repression of Pten and Cx43. This study highlights the importance of miR-17-92 in both normal and pathological functions of the heart, and provides a model that may serve as a useful platform to test novel antiarrhythmic therapeutics.-Danielson, L. S., Park, D. S., Rotllan, N., Chamorro-Jorganes, A., Guijarro, M. V., Fernandez-Hernando, C., Fishman, G. I., Phoon, C. K. L., Hernando, E. Cardiovascular dysregulation of miR-17-92 causes a lethal hypertrophic cardiomyopathy and arrhythmogenesis.