Perfluoroalkyl substances (PFAS) and lead (Pb) as "cardiovascular disruptors" in 9-11-year-old children living in Syracuse, New York, United States.

OBJECTIVE: Per- and polyfluoro-alkyl substances (PFAS) and lead (Pb) are ubiquitous environmental toxicants with apparent impact on cardiovascular disease (CVD) risk. As one possible mechanism for this increased risk, we have previously demonstrated an association between Pb exposure and heightened cardiovascular reactivity to acute psychological stress, a CVD risk factor. The present study expands this approach and considers both PFAS and Pb exposures (and the possible interaction). METHODS: We assessed 14 serum PFAS and whole blood Pb concentrations in a sample of 9-11 year-old children (N = 291; 43.2% White, 56.8% Black; 53.5% female). We measured cardiovascular functioning at rest and during psychological stress as well as multiple indicators of subclinical CVD including resting blood pressure (BP), carotid-femoral pulse wave velocity (cfPWV), carotid intima-media thickness (cIMT), and left ventricular mass (LVM). Data analysis included general linear modeling as well as a non-parametric approach to study metal mixtures, specifically Bayesian Kernel Machine Regression (BKMR). RESULTS: Significant interactions between different PFAS and with Pb suggest the importance of considering toxicant mixtures when assessing potential disruption of the cardiovascular system. The pattern of findings suggests that greater "vascular reactivity" (elevated BP and vascular resistance during acute psychological stress) was associated with higher concentrations of perfluorononanoic acid (PFNA), perfluorohexane sulfonate (PFHxS), and Pb, but only when perfluorooctanoic acid (PFOA) was concurrently elevated. With respect to subclinical outcomes, increasing perfluorodecanoic acid (PFDA) was associated with greater cIMT (ß = 0.21, p = 0.010). CONCLUSION: To our knowledge this is the first study to consider how PFAS exposures might affect cardiovascular functioning and subclinical disease. Although a complex pattern of associations emerged, it does appear that PFAS and Pb can be classified as "cardiovascular disruptors" in children. Further research is needed to replicate these novel findings and determine whether these disruptions produce future cardiovascular disease.

Exposure to Arsenic and Subclinical Cardiovascular Disease in 9- to 11-Year-Old Children, Syracuse, New York.

Importance: Studies in adults have demonstrated associations between arsenic exposure and clinical and subclinical cardiovascular disease (CVD). No studies to date have considered potential associations in children. Objective: To examine the association between total urinary arsenic levels in children and subclinical indicators of CVD. Design, Setting, and Participants: This cross-sectional study considered 245 children, a subset from the Environmental Exposures and Child Health Outcomes (EECHO) cohort. Children from the Syracuse, New York, metropolitan area were recruited from August 1, 2013, until November 30, 2017, with enrollment throughout the year. Statistical analysis was performed from January 1, 2022, to February 28, 2023. Exposures: Total urinary arsenic was measured using inductively coupled plasma mass spectrometry. Creatinine concentration was used to adjust for urinary dilution. In addition, potential exposure routes (eg, diet) were measured. Main Outcomes and Measures: Three indicators of subclinical CVD were assessed: carotid-femoral pulse wave velocity, carotid intima media thickness, and echocardiographic measures of cardiac remodeling. Results: The study sample included 245 children aged 9 to 11 years (mean [SD] age, 10.52 [0.93] years; 133 [54.3%] female). The geometric mean of the creatinine-adjusted total arsenic level in the population was 7.76 µg/g creatinine. After adjustment for covariates, elevated total arsenic levels were associated with significantly greater carotid intima media thickness (ß = 0.21; 95% CI, 0.08-0.33; P = .001). In addition, echocardiography revealed that elevated total arsenic was significantly higher for children with concentric hypertrophy (indicated by greater left ventricular mass and greater relative wall thickness; geometric mean, 16.77 µg/g creatinine; 95% CI, 9.87-28.79 µg/g) relative to the reference group (geometric mean, 7.39 µg/g creatinine; 95% CI, 6.36-8.58 µg/g). With respect to exposure source, significant geographic clustering of total arsenic was found in 1 urban area of Syracuse, New York. Conclusions and Relevance: These findings suggest a significant association between arsenic exposure and subclinical CVD in children. Elevated total arsenic levels were found in an area of Syracuse with known elevations of toxic metals from industrial waste, suggesting historical pollution as a possible source. Given the novelty and potential importance of this association, further research is needed to confirm our findings. Any potential effect of urinary arsenic exposure in childhood on actual clinical CVD outcomes in adulthood remains to be determined.

Airborne levels of cadmium are correlated with urinary cadmium concentrations among young children living in the New York state city of Syracuse, USA.

Air pollution is a serious public health issue with early childhood exposure being of high concern because of the greater risk that children might experience negative health outcomes. Industrial sources in and near communities are one potential path of exposure that children might face with greater levels of air pollution correlating with higher levels of toxicants detected in children. We compare estimated ambient air concentrations of Cadmium (Cd) to a cohort (n = 281) of 9 to 11-year old children during their early childhood years (0-5 years of age) in a mid-size city in Upstate New York. Levels of Cd air pollution are compared to children's urine-Cd levels. Urine has been shown to be a superior biomarker to blood for Cd exposure particularly for longer-term exposures. We find that participants who reside in households that faced greater Cd air pollution during the child's early years have higher urine-Cd levels. This association is stable and stronger than previously presented associations for blood-Cd. Findings support expanded use of air modelling data for risk screening to reduce the potential health burden that industrial pollution can have.

Pulmonary Venous Gradients in Healthy Controls and Following the Repair of Total Anomalous Pulmonary Venous Return.

The percent of children who can achieve a normal and physiologic pulmonary venous gradient and flow following the repair of Total Anomalous Pulmonary Venous Return (TAPVR) is not known. Pulmonary venous confluence gradients from infants with supra-, infra-, or mixed TAPVR, repaired using a direct anastomotic connection were measured. Data from age, weight, and gender-matched controls established the normal pulmonary venous gradient range (0.30-0.94 mmHg). TAPVR subjects were divided into three groups: (I) pulmonary venous gradient < 2 × normal with multiphasic flow (II) pulmonary venous gradient > 2 × normal with multiphasic flow, and (III) pulmonary venous gradient > 2 × normal with monophasic flow. From 63 children following TAPVR repair and 63 matched controls, pulmonary venous gradients were significantly lower [0.5 mmHg (IQR:0.4, 0.6) vs 1.6 mmHg (IQR:1.0, 2.4); p < 0.001], and multiphasic flow more frequent (100 vs. 84.1%; p = 0.001) within the control group. There were 38 children (60.3%) in group I, 15 (23.8%) in group II, and 10 (15.8%) in group III. Children in Group I were significantly older at the time of repair, had shorter cardiopulmonary bypass times, and did not utilize deep hypothermic circulatory arrest (DHCA). Multivariate analysis confirmed that avoiding DHCA [Odds Ratio 0.931 (0.913,0.994; p = 0.002)] and shorter cardiopulmonary bypass times [Odds Ratio 0.962 (0.861,0.968; p = 0.02)] during repair were associated with the lowest pulmonary venous gradients and multiphasic flow. Following TAPVR repair with a direct anastomosis, the majority of children can achieve a gradient two times normal or less with multiphasic pulmonary venous flow.

A modified approach in the repair of type I and II truncus arteriosus to promote branch pulmonary arterial growth and limit early reoperation.

Objective: Maintaining adequate branch pulmonary arterial growth is critical in preventing early (<3 years) right ventricular outflow tract reoperation after the repair of truncus arteriosus. We hypothesized that a modified truncus arteriosus repair keeping the branch pulmonary arteries in situ would promote branch pulmonary arterial growth and limit early right ventricular outflow tract reoperation. Methods: For infants requiring repair for type I and II truncus arteriosus, the truncal root was septated through a hockey stick incision keeping the branch pulmonary arteries in situ, the ventricular septal defect was closed, and a short aortic homograft was used to reconstruct the right ventricular outflow tract. Echocardiograms measured preoperative and follow-up branch pulmonary artery diameter. Results: Between 1998 and 2020, 41 infants were repaired using the modified approach (type I, 28; type II, 13). With a median follow-up of 11.6 (interquartile range, 3.1-15.5) years, there was no significant change between preoperative left pulmonary artery and right pulmonary artery Z-scores and their corresponding follow-up measurement (left pulmonary artery: 0.97, interquartile range, 0.6-1.6 vs left pulmonary artery: 1.4, interquartile range, -0.3 to 1.9) (right pulmonary artery: 0.6, interquartile range, -0.4 to 1.7 vs right pulmonary artery: 0.3 interquartile range, 0.5-0.9). Only 7.3% (n = 2) of follow-up right pulmonary artery Z-scores were less than 2.5 Z-scores below preoperative measurements. Four children (9.8%) required early right ventricular outflow tract reoperation. On multivariable analysis, larger conduit Z-scores were associated with greater time to right ventricular outflow tract reoperation (hazard ratio, 0.55, confidence interval, 0.307-0.984; P = .043). Conclusions: Maintaining the branch pulmonary arteries in situ at initial truncus arteriosus repair allows for branch pulmonary arterial growth, limiting early right ventricular outflow tract reoperation.

Factors Associated With an Abnormal Blood Pressure Response During Exercise After Coarctation Repair.

BACKGROUND: Although resting blood pressures following aortic arch repair or the extended end-to-end anastomosis (EEA) repair for coarctation can be physiologic, factors associated with an abnormal blood pressure response after exercise are unknown. We measured blood pressure gradients following exercise in children who had undergone previous repair in accordance with a surgical selection algorithm and sought to identify factors associated with an abnormal blood pressure response. METHODS: In accordance with our practice's surgical algorithm for repair of coarctation, infants were stratified to aortic arch repair when the distal transverse arch-to-left carotid artery ratio (DTA:LCA) ≤ 1.0, or when a brachiocephalic trunk or intra-cardiac lesion requiring repair was present. A thoracotomy and EEA were otherwise used. A follow-up exercise stress test (EST) measured the arm:leg blood pressure gradient after exercise, and a gradient ≥ 20 mm Hg was defined as an abnormal blood pressure response. RESULTS: Thirty-seven infants who had previously undergone coarctation repair (aortic arch repair-19, EEA-18) completed an EST at 12.3 ± 2.2 years of age. Thirteen (35%) children (aortic arch repair-5, EEA-8; p = .3) exhibited an abnormal blood pressure response. Factors associated with an abnormal blood pressure response included: smaller DTA:LCA ratios prior to repair (1.0 ± .2 vs. 1.2 ± .3; p = .04) and greater body weight at the time of EST (57.5 ± 19.1 vs. 40.9 ± 15.6 kg; p = .03). CONCLUSION: An abnormal blood pressure response following exercise is associated with smaller DTA:LCA ratios at the time of repair and increased weight during follow-up suggesting that patients with these factors warrant close observation.

Association of Sleep Quality With Greater Left Ventricular Mass in Children Aged 9 to 11 Years.

OBJECTIVE: Research has consistently found associations between sleep characteristics and cardiovascular disease risk in children, adolescents, and adults. Although primarily investigated in clinical samples (e.g., in those with sleep disorders), greater left ventricular mass is associated with poor sleep quality in nonclinical adult populations as well; however, this has not been evaluated in children or adolescents. Our study aim was to consider the relationship between objectively measured sleep characteristics and left ventricular mass in children. METHODS: We assessed sleep and cardiac structure in a biracial sample of 9- to 11-year-old children (n = 176; 41% White, 59% Black; 50% female). Sleep was assessed with actigraphy for five nights. Cardiac dimensions were assessed using echocardiography. RESULTS: After adjusting for covariates, we found that poor sleep quality was associated with significantly greater left ventricular mass (ß = 0.13, t(167) = 2.14, p = .034, Cohen d = 0.16, for activity during sleep; ß = 0.15, t(167) = 2.43, p = .016, Cohen d = 0.18, for sleep fragmentation). Other cardiac dimensions (namely, relative wall thickness and right ventricular dimension) were also significantly associated with sleep characteristics. Notably, associations did not differ as a function of sex or race. CONCLUSIONS: The present findings are novel and unique because no prior reports have systematically documented the association between poor sleep quality with potentially detrimental cardiac remodeling in a nonclinical sample of children. However, the novelty and importance of these findings require additional research for confirmation.

Linking metal (Pb, Hg, Cd) industrial air pollution risk to blood metal levels and cardiovascular functioning and structure among children in Syracuse, NY.

BACKGROUND: Exposure to air pollution has been linked to individual health effects in occupational environments and communities proximate to air pollution sources. Use of estimated chemical concentrations from the Risk Screening Environmental Indicators (RSEI) model, derived from the Toxics Release Inventory, can help approximate some contributions to individual lifetime exposure to risk from air pollution and holds potential for linkages with specific health outcome data. OBJECTIVES: Our objectives were: (1) use regression modeling to test for associations between observed blood metal concentrations in children and RSEI total air concentrations of the same metals released from proximate manufacturing facilities; (2) determine the relative contribution of RSEI air pollution to blood metal concentrations; and (3) examine associations between chronic metal exposure and cardiovascular functioning and structure in study participants. METHODS: Using data synthesis methods and regression modeling we linked individual blood-based levels of lead, mercury, and cadmium(Pb, Hg, Cd) and cardiovascular functioning and structure to proximate industrial releases of the same metals captured by the Environmental Protection Agency's (EPA) RSEI geographic microdata. RESULTS: We found that RSEI-derived ground-level ambient air concentrations of Hg and Cd were a significant predictor of blood metal levels, when controlling for covariates and other exposure variables. In addition to associations with blood metal findings, RSEI concentrations also predicted cardiovascular dysfunction and risk including changes in left-ventricular mass, blood pressure, and heart rate. DISCUSSION: Right-to-know data, such as EPA's RSEI, can be linked to objective health outcomes, rather than simply serving as a non-specific risk estimate. These data can serve as a proxy for hazard exposure and should be used more widely to understand the dynamics of environmental exposure. Furthermore, since these data are both a product of and contribute to regulatory decision making, they could serve as an important link between disease risk and translation-orientated national environmental health policy.

Racial Differences in Left Ventricular Mass and Wave Reflection Intensity in Children.

The burden of heart failure is disproportionately higher in African Americans, with a higher prevalence seen at an early age. Examination of racial differences in left ventricular mass (LVM) in childhood may offer insight into risk for cardiac target organ damage (cTOD) in adulthood. Central hemodynamic load, a harbinger of cTOD in adults, is higher in African Americans. The purpose of this study was to examine racial differences in central hemodynamic load and LVM in African American and non-Hispanic white (NHW) children. Two hundred sixty-nine children participated in this study (age, 10 ± 1 years; n = 149 female, n = 154 African American). Carotid pulse wave velocity (PWV), forward wave intensity (W1) and reflected wave intensity (negative area, NA) was assessed from simultaneously acquired distension and flow velocity waveforms using wave intensity analysis (WIA). Wave reflection magnitude was calculated as NA/W1. LVM was assessed using standard 2D echocardiography and indexed to height as LVM/[height (2.16) + 0.09]. A cutoff of 45 g/m (2.16) was used to define left ventricular hypertrophy (LVH). LVM was higher in African American vs. NHW children (39.2 ± 8.0 vs. 37.2 ± 6.7 g/m (2.16), adjusted for age, sex, carotid systolic pressure and socioeconomic status; p < 0.05). The proportion of LVH was higher in African American vs. NHW children (25 vs. 12 %, p < 0.05). African American and NHW children did not differ in carotid PWV (3.5 ± 4.9 vs. 3.3 ± 1.3 m/s; p > 0.05). NA/W1 was higher in African American vs. NHW children (8.5 ± 5.3 vs. 6.7 ± 2.9; p < 0.05). Adjusting for NA/W1 attenuated racial differences in LVM (38.8 ± 8.0 vs. 37.6 ± 7.0 g/m (2.16); p = 0.19). In conclusion, racial differences in central hemodynamic load and cTOD are present in childhood. African American children have greater wave intensity from reflected waves and higher LVMI compared to NHW children. WIA offers novel insight into early life origins of racial differences in central hemodynamic load and cTOD.

Neurodevelopmental Delay After the Neonatal Repair of Coarctation and Arch Obstruction.

BACKGROUND: Although single ventricle physiology and cyanosis are known risk factors for neurodevelopmental delay (NDD), the impacts of isolated coarctation (Iso CoA) repair or arch reconstruction (AR) are less understood. METHODS: The Vineland Adaptive Behavior Scales, third edition, prospectively evaluated children without a genetic syndrome. An overall composite score, normalized to age and sex, was generated from individual domain scores. NDD was defined as a composite or domain score at least 1 SD less than the established mean. Iso CoA was repaired using a left thoracotomy, whereas AR was performed using a sternotomy and cardiopulmonary bypass. Children with a structurally normal heart and without previous surgery were used as control patients. RESULTS: Of 60 children, 50 required neonatal repair (12 for Iso CoA, 38 for AR), and 10 were control patients. From the entire cohort of children who required neonatal coarctation repair (Iso CoA + AR) composite (93.9 ± 15.9 vs 105.0 ± 7.4; P = .004) and all domain scores were significantly lower than control patients. NDD was present in 25 of 50 children after repair and in 0 of 10 control patients (P = .003). Similarly, the prevalence of NDD was significantly greater after Iso CoA repair (58.3% vs 0%; P = .005) and AR (47.3% vs 0%; P = .007) than in the control population, but no significant difference was found between the Iso CoA and AR groups (P = .74). CONCLUSIONS: In this small cohort, half of the neonates who required either Iso CoA repair or AR exhibit NDD at an intermediate-term follow-up.

Serial Follow-Up of Two Surgical Strategies for the Repair of Tetralogy of Fallot.

Adverse events following tetralogy of Fallot repair include arrhythmia, reoperation, and death. While limiting the right ventriculotomy mitigates these events over the short and intermediate term, the impact over the long term is unknown. Children requiring tetralogy of Fallot repair were divided into 2 groups: extended right ventriculotomy vs limited right ventriculotomy with transatrial ventricular septal defect closure. Follow-up office ECGs and Holter monitoring, exercise stress tests, and echocardiograms were obtained in the first, second, and third postoperative decades. The primary outcome was cumulative events defined as reoperation, arrhythmia, or death. The extended and limited right ventriculotomy techniques were used in 21 and 17 children, respectively. Cumulative survival was 93.6% at 30 years and was not different between groups. While 10-year (42.9% vs 5.9%, P = 0.02) event rates favored the limited ventriculotomy technique, there were no significant differences at 20 or 25 years. Cox proportional hazard analysis demonstrated that the limited ventriculotomy technique was independently associated with lower events at 10 years (hazard ratio 0.03, 95% confidence interval 0.0016, 0.5697, P = 0.01). The limited ventriculotomy group had greater exercise capacity in the second decade but not the third. Right ventricular end-diastolic diameter Z score was not different at 10 or 20 years, but was significantly smaller in the limited ventriculotomy group at 30 years (5.55 ± 1.69 vs 4.14 ± 0.63, P = 0.03). Limiting the right ventriculotomy during tetralogy of Fallot repair limits 10-year events, improves exercise capacity at 20 years, and attenuates late right ventricular dilation.

Modified Repair of Type I and II Truncus Arteriosus Limits Early Right Ventricular Outflow Tract Reoperation.

Repair of truncus arteriosus often requires early right ventricular outflow tract (RVOT) reoperation. Using a modified repair, the branch pulmonary arteries are left in situ, which may avoid earlier RVOT reoperation. We hypothesized that our modified repair for type I and II truncus arteriosus would extend the time to RVOT reoperation. Infants with truncus arteriosus were divided into 2 groups: (1) traditional technique where the branch pulmonary arteries are excised from the truncal root, or (2) modified repair where the branch pulmonary arteries are left in situ and septated from the truncal root. Regardless of the approach, a bioprosthetic conduit or homograft was used to establish right ventricular to pulmonary artery continuity. Follow-up pulmonary artery angiograms were used to assess for branch pulmonary artery stenosis. From 54 infants (modified repair: 33, traditional technique: 21), there were no significant differences in age at repair, gender, or type of truncus arteriosus. With 100% follow-up, use of the modified repair resulted in a lower rate of branch pulmonary artery stenosis, and greater freedom from surgical branch pulmonary arterioplasty. Five- and 10-year freedom from RVOT reoperation (5 years: modified-81.5% vs traditional-30.5%, P = 0.004; 10 years: modified-53.3% vs traditional-30.5%, P = 0.01) favored the modified repair. Cox regression analysis demonstrated that the modified repair was associated with an independently lower risk for RVOT reoperation (hazard ratio: 0.08, confidence interval: 0.01, 0.75, P = 0.02). Thus, maintaining the branch pulmonary artery architecture resulted in greater freedom from RVOT reoperation.

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.

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.

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.

Regression of left ventricular hypertrophy in children following the Ross procedure.

OBJECTIVES: Left ventricular hypertrophy (LVH) frequently accompanies the progression of aortic valve disease in children. The extent of LVH regression following surgical relief of aortic valve disease in children has not been clearly elucidated. We hypothesized that significant regression of LVH will occur in children following the Ross procedure. METHODS: We examined LVH over time in children <18 years of age who underwent the Ross procedure. Left ventricular mass index (LVMI) and corresponding z scores were calculated based on height, age and gender. Left ventricular hypertrophy was defined as an LVMI of > 39 g/m(2.7) and a z score of >1.6. RESULTS: Twenty-five children underwent the Ross procedure. The left ventricular mass increased proportionally with the growth of the child from baseline to the latest follow-up at 7.3 ± 2.9 years (121.1 ± 81.5 vs 133.1 ± 79.8 g, P = 0.4). However, 96% (24/25) of children demonstrated LVMI regression from baseline. Mean LVMI decreased from 70.8 ± 31.2 to 41.8 ± 16.6 g/m(2.7) (P < 0.001). Similarly, LVMI z scores decreased from 2.2 ± 1.2 to 0.2 ± 1.9 (P < 0.001). Freedom from LVH was 83% at 10 years. Examination of LVMI and z scores over time demonstrated that the largest decrease occurred after the first year, with continued gradual decline over 10 years of follow-up. CONCLUSIONS: The Ross procedure is effective in reversing LVH in children with aortic valve disease.

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.

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-ß, 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-ß (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.

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.