Nader Atallah-Yunes

A role for the aryl hydrocarbon receptor in cardiac physiology and function as demonstrated by AhR knockout mice.

The aryl hydrocarbon receptor (AhR), a ligand activated transcription factor, is the receptor for the polycyclic aromatic hydrocarbons found in tobacco smoke, polychlorinated biphenyls, and the environmental pollutant, dioxin. To better understand the role of the AhR in the heart, echocardiography, invasive measurements of aortic and left ventricular pressures, isolated working heart preparations, as well as morphological and molecular analysis were used to investigate the impact of AhR inactivation on the mouse heart using the AhR knockout as a model. Cardiac hypertrophy is an early phenotypic manifestation of the AhR knockout. Although the knockout animals were not hypertensive at the ages examined, cardiomyopathy accompanied by diminished cardiac output developed. Despite the structural left ventricular remodeling, the hearts of these animals exhibit minimal fibrosis and do not have the expected increases in surrogate molecular markers of cardiac hypertrophy. The anatomic remodeling without typical features of molecular remodeling is not consistent with hypertrophic growth secondary to pressure or volume overload, suggesting that increased cardiomyocyte size may be a direct consequence of the absence of the AhR in this cell type.

Decreased Incidence of Supravalvar Pulmonary Stenosis After Arterial Switch Operation

Background— Supravalvar pulmonary stenosis (SVPS) is frequently observed after arterial switch. Traditionally the coronary arteries are removed from the neopulmonic root by excising the entire sinus of Valsalva. As a result, reconstruction of the neopulmonic root requires a pericardial patch encompassing two-thirds of the anastomosis between the neopulmonic root and pulmonary artery. We present a technique where the coronary arteries are removed as limited buttons of sinus tissue, leaving the transected edge of the neopulmonic root intact. We hypothesize that maintaining native arterial tissue in the anastomosis between the neopulmonic root and the pulmonary artery bifurcation reduces postoperative SVPS. Methods and Results— We performed a retrospective review of neonates with D-transposition of the great arteries undergoing arterial switch procedure from 1996 to 2009. Charts were reviewed, and clinical outcomes recorded for each patient. Most recent echocardiograms were evaluated for right ventricular outflow tract obstruction. A total of 120 patients received arterial switch using this technique. There was 99% survival and no injuries to the coronary arteries regardless of anatomy. Total follow-up was 564 patient-years. Mean follow-up at last clinical visit was 66±46 months. Evaluation of the most recent outpatient echocardiogram revealed an average peak instantaneous gradient across the neopulmonic root of 22.5±5 mm Hg. Only 7 (5%) patients required reintervention (balloon dilation, n=5; surgery, n=2). Conclusions— Our technique of removing the coronary arteries as limited buttons, and anastomosis of the pulmonary artery using only native arterial tissue provides excellent midterm results with minimal SVPS.

Surgical Strategy for Aortic Coarctation Repair Resulting in Physiologic Arm and Leg Blood Pressures

OBJECTIVE The goal of aortic coarctation repair is laminar aortic blood flow resulting in a negative or absent arm:leg blood pressure (BP) gradient. Despite satisfactory relief of coarctation, associated arch hypoplasia can result in residual obstruction and postoperative upper body hypertension. INTERVENTION We devised a surgical strategy to create a tension-free anastomosis with a diameter as large as both the adjacent proximal and distal aorta using a radically extended end-to-end anastomosis via sternotomy and/or thoracotomy. Sternotomy is chosen when there is significant transverse arch hypoplasia defined as a distal transverse arch ≤ diameter of the left carotid artery, presence of a common brachiocephalic trunk, or coexisting intracardiac lesion requiring repair. Thoracotomy is used in all other cases. RESULTS From 2000 to 2008, 95 consecutive patients were repaired using this approach, 35 with sternotomy and 60 with thoracotomy. At a mean follow-up of 50 ± 23 months, mean systolic BP was 94 ± 10 mm Hg, and 84% of patients had no residual arm:leg BP gradient. Mean arm:leg BP gradient was not statistically different between groups (-8.5 ± 15 sternotomy and -7.0 ± 10 mm Hg thoracotomy, P= .7). With Doppler echocardiography, 96% of patients demonstrated normal early diastolic reversal of blood flow in the descending thoracic aorta. CONCLUSIONS For aortic coarctation repair in infancy, a strategy designed to directly address aortic arch hypoplasia results in excellent intermediate-term results with normal BP, physiologic arm:leg BP relationship, and near normal descending aortic blood flow velocities by Doppler.

Hypertensive Changes Within the Aortic Arch of Infants and Children With Isolated Coarctation

BACKGROUND Despite repair, a significant proportion of patients with coarctation of the aorta (CoA) present with late hypertension. Increased gene expression of aortic wall collagen and vascular smooth muscle cell markers occurs in the presence of hypertension. Before repair, a patent ductus arteriosus (PDA) limits hypertension proximal to the coarctation. We hypothesize that preoperative collagen and vascular smooth muscle expression from the aortic arch in children is variable, depending on the presence or absence of a PDA. METHODS We analyzed the expression patterns of collagen and vascular smooth muscle cell markers in 25 children with CoA using a quantitative polymerase chain reaction. Aortic arch tissue proximal to the CoA was normalized to descending aortic tissue distal to the coarctation. Collagen-I, transforming growth factor-β, elastin, and calponin were analyzed. RESULTS At repair, 19 patients were aged younger than 3 months (14 with a PDA, 5 with a ligamentum arteriosum), and the remaining 6 were older than 1 year. There was no difference in age or weight between infants with or without a PDA. Infants without a PDA had the greatest difference in collagen-I expression compared with infants with a PDA (7.0 ± 1.6-fold vs 0.8 ± 1.1-fold, p = 0.01). Expression of transforming growth factor-β (4.3 ± 1.4 vs 2.6 ± 2.3, p = 0.01) and calponin (3.7 ± 0.7 vs 0.6 ± 1.1, p = 0.05) was lower from infants with vs without a PDA. CONCLUSIONS Our findings provide evidence of preoperative changes in the aortic arch before repair, particularly in the absence of a PDA.

Racial Differences in Aortic Stiffness in Children

Objective To investigate racial differences in central blood pressure and vascular structure/function as subclinical markers of atherosclerotic cardiovascular disease in children. Study design This cross‐sectional study recruited 54 African American children (18 female, 36 male; age 10.5 ± 0.9 years) and 54 white children (27 female, 26 male; age 10.8 ± 0.9 years) from the Syracuse City community as part of the Environmental Exposures and Child Health Outcomes study. Participants underwent blood lipid and vascular testing on 2 separate days. Carotid artery intima‐media thickness and aortic stiffness were measured by ultrasonography and carotid‐femoral pulse wave velocity, respectively. Blood pressure was assessed at the brachial artery and estimated in the carotid artery using applanation tonometry. Results African American children had significantly higher pulse wave velocity (4.8 ± 0.8 m/s) compared with white children (4.2 ± 0.7 m/s; P < .05), which remained significant after adjustment for confounding variables including socioeconomic status. African American children had significantly higher intima‐media thickness (African American 0.41 ± 0.06, white 0.39 ± 0.05 mm), and carotid systolic blood pressure (African American 106 ± 11, white 102 ± 8 mm Hg; P < .05) compared with white children, although these racial differences were no longer present after covariate adjustments for height. Conclusions Racial differences in aortic stiffness are present in childhood. Our findings suggest that racial differences in subclinical cardiovascular disease occur earlier than previously recognized.

Risk Factors for a Positive Neoaortic Arch Gradient After Stage I Palliation for Hypoplastic Left Heart Syndrome

BACKGROUND Providing unobstructed systemic blood flow is one goal of stage I palliation for hypoplastic left heart syndrome. Although clinically significant obstruction is defined when the arch gradient exceeds 15 mm Hg, any positive gradient constitutes obstruction, which may impair ventricular function. We sought to identify risk factors before stage I palliation that result in a positive neoaortic arch gradient before bidirectional Glenn. METHODS Reviewed were 51 neonates who underwent stage I palliation and subsequent bidirectional cavopulmonary anastomosis procedures for hypoplastic left heart syndrome. Echocardiograms before stage I palliation were reviewed for aortic dimensions. Cardiac catheterization before bidirectional cavopulmonary anastomosis determined the aortic arch gradient and degree of right ventricular dysfunction. RESULTS Of the 51 patients, 24 (47%) had a negative or absent arch gradient. Patients with a positive gradient had a median gradient of 5 mm Hg (range, 1 to 60 mm Hg). The diameter of the ascending aorta and proximal transverse arch indexed to the descending thoracic aorta (0.5 ± 0.2 vs 0.7 ± 0.4 and 0.4 ± 0.2 vs 0.6 ± 0.2 mm, p = 0.02 and p = 0.01) and lower birth weight (3.1 ± 0.5 vs 3.4 ± 0.4 kg, p = 0.03) were risk factors of a positive neoaortic arch gradient. Further, the degree of arch obstruction was inversely related to the degree of right ventricular function (odds ratio, 1.08; p < 0.01). CONCLUSIONS Lower birth weight and a smaller aortic diameter confer a higher risk of developing a positive neoaortic arch gradient, resulting in reduced right ventricular function.

Sustained Improvement in Right Ventricular Chamber Dimensions 10 Years Following Xenograft Pulmonary Valve Replacement

Background: The goals following pulmonary valve replacement (PVR) are to optimize right ventricular hemodynamics and minimize the need for subsequent reoperations on the right ventricular outflow tract. We hypothesized PVR using a xenograft valved conduit would result in superior freedom from reoperation with sustained improvement in right ventricular chamber dimensions. Methods: Xenograft valved conduits placed in patients aged >16 years were reviewed from 2000 to 2010 to allow for a 5-year minimum follow-up. Preoperative, one-year, and the most recent echocardiograms quantified right ventricular chamber dimensions, corresponding Z scores, and prosthetic valve function. Magnetic resonance imaging (MRI) studies compared preoperative and follow-up right ventricular volumes. Results: A total of 100 patients underwent PVR at 24 (19-34) years. Freedom from reintervention was 100% at 10 years. At most recent follow-up, only one patient had greater than mild pulmonary insufficiency. The one-year (17.3 ± 7.2 mm Hg; P < .01) and most recent follow-up (18.6 ± 9.8 mm Hg; P < .01) Doppler-derived right ventricular outflow tract gradients remained significantly lower than preoperative measurements (36.7 ± 27.0 mm Hg). Similarly, right ventricular basal diameter, basal longitudinal diameter, and the corresponding Z scores remained lower at one year and follow-up from preoperative measurements. From 34 MRI studies, the right ventricular end-diastolic indexed volume (161.7 ± 58.5 vs 102.9 ± 38.3; P < .01) and pulmonary regurgitant fraction (38.0% ± 15.9% vs 0.8% ± 3.3%; P < .01) were significantly lower at 7.1 ± 3.4 years compared to the preoperative levels. Conclusion: Use of a xenograft valved conduit for PVR results in excellent freedom from reoperation with sustained improvement in right ventricular dimensions at an intermediate-term follow-up.

Distal Transverse Arch to Left Carotid Artery Ratio Helps to Identify Infants With Aortic Arch Hypoplasia

BACKGROUND Aortic coarctation (CoA) with concomitant aortic arch hypoplasia (AAH) is associated with an increased risk of hypertension after surgical repair. The differentiation of CoA with or without AAH may be critical to delineate the ideal surgical approach that best ameliorates postoperative hypertension. Since 2000, we have defined CoA with AAH when the diameter of the distal transverse aortic arch is equal to or less than the diameter of the left carotid artery. We hypothesized that, based on our definition, aortic tissue from infants having CoA with AAH would demonstrate distinct genetic expression patterns as compared with infants having CoA alone. METHODS From 6 infants (AAH, 3; CoA, 3), an Affymetrix 1.0 genome array identified genes in the coarctation/arch region that were differentially expressed between infants having CoA with AAH versus CoA alone. Reverse transcription polymerase chain reaction validated genetic differences from a cohort of 21 infants (CoA with AAH, 10; CoA, 11). To evaluate the clinical outcomes based on our definition of CoA with AAH, we reviewed infants repaired using this algorithm from 2000 to 2010. RESULTS Microarray data demonstrated genes differentially expressed between groups. Reverse transcription polymerase chain reaction confirmed that CoA with AAH was associated with an increased expression of genes involved in cardiac and vascular development and growth, including hepsin, fibroblast growth factor-18, and T-box 2. The clinical outcomes of 79 infants (AAH, 26; CoA, 53) demonstrated that 90.1% were free of hypertension at 13 years when managed with this surgical strategy. CONCLUSIONS These findings provide evidence that the ratio of the diameter of the distal transverse arch to the left carotid artery may be helpful to identify CoA with AAH and, when used to delineate the surgical approach, may minimize hypertension.

Acute Cardiopulmonary and Echocardiographic Responses to Inhaled Nitric Oxide (INO) in Infants with Persistent Pulmonary Hypertension of the Newborn (PPHN)

Acute Cardiopulmonary and Echocardiographic Responses to Inhaled Nitric Oxide (INO) in Infants with Persistent Pulmonary Hypertension of the Newborn (PPHN)