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Trittmann J.K.,Research Institute at Nationwide Childrens Hospital | Trittmann J.K.,Ohio State University | Peterson E.,Ohio State University | Rogers L.K.,Research Institute at Nationwide Childrens Hospital | And 10 more authors.
Journal of Pediatrics | Year: 2015

Objective To test the hypothesis that levels of the endogenous inhibitor of nitric oxide production, asymmetric dimethylarginine (ADMA), would be greater in preterm infants with bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) than in infants with BPD alone. Study design A case-control study of 23 patients with both BPD and PH (cases) and 95 patients with BPD but no evidence of PH (controls). Levels of ADMA were compared between cases and controls by t test. Results Patients with both BPD and PH had greater plasma levels of ADMA than patients with BPD alone (P =.04). In samples drawn before 28 days of life, greater levels of ADMA were again found in cases compared with controls (P =.02). The plasma arginine-to-ADMA ratio was lower in cases than in controls (P =.03), suggesting a greater likelihood of inhibition of nitric oxide production in patients with both BPD and PH than in patients with BPD alone. Conclusion In this neonatal BPD cohort, ADMA levels are increased in patients with BPD who develop PH. We speculate that ADMA may be both a biomarker and a potential therapeutic target for preterm infants with BPD-associated PH. © 2015 Elsevier Inc. Source


Bosse K.,Center for Cardiovascular and Pulmonary Research | Bosse K.,Heart Center at Nationwide Childrens Hospital | Hans C.P.,Center for Cardiovascular and Pulmonary Research | Hans C.P.,Heart Center at Nationwide Childrens Hospital | And 27 more authors.
Journal of Molecular and Cellular Cardiology | Year: 2013

The mature aortic valve is composed of a structured trilaminar extracellular matrix that is interspersed with aortic valve interstitial cells (AVICs) and covered by endothelium. Dysfunction of the valvular endothelium initiates calcification of neighboring AVICs leading to calcific aortic valve disease (CAVD). The molecular mechanism by which endothelial cells communicate with AVICs and cause disease is not well understood. Using a co-culture assay, we show that endothelial cells secrete a signal to inhibit calcification of AVICs. Gain or loss of nitric oxide (NO) prevents or accelerates calcification of AVICs, respectively, suggesting that the endothelial cell-derived signal is NO. Overexpression of Notch1, which is genetically linked to human CAVD, retards the calcification of AVICs that occurs with NO inhibition. In AVICs, NO regulates the expression of Hey1, a downstream target of Notch1, and alters nuclear localization of Notch1 intracellular domain. Finally, Notch1 and NOS3 (endothelial NO synthase) display an in vivo genetic interaction critical for proper valve morphogenesis and the development of aortic valve disease. Our data suggests that endothelial cell-derived NO is a regulator of Notch1 signaling in AVICs in the development of the aortic valve and adult aortic valve disease. © 2013 Elsevier Ltd. Source


Swier N.L.,Ohio State University | Richards B.,Heart Center at Nationwide Childrens Hospital | Cua C.L.,Heart Center at Nationwide Childrens Hospital | Lynch S.K.,Ohio State University | And 7 more authors.
American Journal of Perinatology | Year: 2016

Objectives Pulmonary vein stenosis (PVS) is a rare, often lethal anomaly associated with poor outcomes. Given the association between bronchopulmonary dysplasia (BPD) and cardiovascular complications, we tested the hypotheses that (1) a subgroup of neonates with severe BPD develop PVS (BPD-PVS) and have worse outcomes than do neonates with severe BPD alone (BPD); (2) among a cohort of neonates with severe BPD-associated pulmonary hypertension (BPD-PH), PVS is an additional risk factor for adverse outcomes and mortality. Study Design We performed a retrospective review of neonates with severe BPD, based on the Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD) criteria, at our institution between June 1, 2009, and June 30, 2013. PVS was determined based on serial review of echocardiograms performed during their hospitalization. Neonates with congenital heart disease or chromosomal anomalies were excluded. Results Of 213 patients with severe BPD, 10 (4.7%) were found to have PVS (BPD-PVS). Neonates with BPD-PVS had lower birth weight (634 ± 178 vs. 767 ± 165 g; p < 0.01) and were more likely to be intrauterine growth restricted (80 vs. 11%; p < 0.01) than neonates with BPD alone. Time on mechanical ventilation and length of hospitalization were longer in the BPD-PVS group than BPD group. Survival was lower in the BPD-PVS group than BPD group (5/10 [50%] vs. 196/203 [97%]; log-rank test p < 0.01). Among a subgroup of neonates with BPD-PH, survival was lower among infants with PVS than those without PVS (5/9 [56%] vs. 26/30 [86%]; log-rank test p = 0.01). Conclusions Compared with neonates with severe BPD alone, those with acquired PVS are at increased risk for worse outcomes, including higher mortality. Evidence-based recommendations regarding screening protocols and surveillance are needed in this high-risk subgroup of BPD neonates. © 2016 by Thieme Medical Publishers, Inc. Source


Moiduddin N.,Heart Center at Nationwide Childrens Hospital | Texter K.M.,Heart Center at Nationwide Childrens Hospital | Cheatham J.P.,Heart Center at Nationwide Childrens Hospital | Chisolm J.L.,Heart Center at Nationwide Childrens Hospital | And 5 more authors.
Congenital Heart Disease | Year: 2012

Introduction. Percutaneous pulmonary valve implantation (PPVI) is an emerging therapy for pulmonary valve dysfunction. Minimal data on the midterm effects of PPVI on ventricular function exist. We describe the effects of PPVI on right and left ventricular (RV, LV) function with speckle tracking echocardiography. Methods. Patients who met the inclusion criteria of the Food and Drug Administration Phase 1 Feasibility Clinical Trial PPVI were identified. Patients were studied with echocardiograms at baseline, post-PPVI (day of discharge), 3 months, and at 6 months. Patients were studied by cardiac magnetic resonance at baseline and at 6 months. Longitudinal strain was measured at the basal, mid, and apical portions of the RV, interventricular septum (IVS), and LV. Global RV and LV strain and strain rates were recorded. Paired t-tests were used for analysis. Results. Ten patients were analyzed: nine patients were a variant of tetralogy of Fallot and one patient had complex LV outflow obstruction requiring a Ross and RV-pulmonary atresia conduit. Mean age was 24.4 ± 7.6 years. Indication for PPVI was pulmonary regurgitation in six patients, stenosis in two patients, and stenosis/regurgitation in two patients. After PPVI, both RV systolic pressure and RV to pulmonary artery pressure gradient significantly decreased. Cardiac magnetic resonance RV end-diastolic volume significantly decreased. IVS-mid, IVS-apical, and LV-global strain significantly increased and RV-basal decreased immediately after PPVI. Global RV a' strain rate significantly increased immediately after PPVI. However, RV, IVS, and LV strain/strain rate values between baseline and the 6 month echocardiographic study were either similar or significantly decreased. Conclusion. Despite improvement in RV hemodynamics, there was a decrease or no improvement in RV and LV function as measured by strain echocardiographic values at midterm follow-up. Larger studies with longer follow-up are needed to determine if these results remain consistent. © 2012 Wiley Periodicals, Inc. Source

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