Sonali S. Patel

Nongenetic Risk Factors and Congenital Heart Defects

Advances have been made in identifying genetic etiologies of congenital heart defects. Through this knowledge, preventive strategies have been designed and instituted, and prospective parents are counseled regarding their risk of having an affected child. Great strides have been made in genetic variant identification, and genetic susceptibility to environmental exposures has been hypothesized as an etiology for congenital heart defects. Unfortunately, similar advances in understanding have not been made regarding strategies to prevent nongenetic risk factors. Less information is available regarding the potential adverse effect of modifiable risk factors on the fetal heart. This review summarizes the available literature on these modifiable exposures that may alter the risk for congenital heart disease. Information regarding paternal characteristics and conditions, maternal therapeutic drug exposures, parental nontherapeutic drug exposures, and parental environmental exposures are presented. Factors are presented in terms of risk for congenital heart defects as a group. These factors also are broken down by specific defect type. Although additional investigations are needed in this area, many of the discussed risk factors present an opportunity for prevention of potential disease.

Analysis of Selected Maternal Exposures and Non-Syndromic Atrioventricular Septal Defects in the National Birth Defects Prevention Study, 1997–2005

Although the descriptive epidemiology of atrioventricular septal defects (AVSDs), a group of serious congenital heart defects (CHDs), has been recently reported, non‐genetic risk factors have not been consistently identified. Using data (1997–2005) from the National Birth Defects Prevention Study, an ongoing multisite population‐based case–control study, the association between selected non‐genetic factors and non‐syndromic AVSDs was examined. Data on periconceptional exposures to such factors were collected by telephone interview from 187 mothers of AVSD case infants and 6,703 mothers of unaffected infants. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated from logistic regression models. Mothers who reported cigarette smoking during the periconceptional period were more likely to have infants with AVSDs compared with non‐smokers, independent of maternal age, periconceptional alcohol consumption, infant gestational age, family history of CHDs, and study site (aOR 1.5, 95% CI 1.1–2.4). The association was strongest in mothers who smoked more than 25 cigarettes/day. In addition, mothers with periconceptional passive smoke exposure were more likely to have infants with AVSDs than unexposed mothers, independent of maternal age, active periconceptional smoking, infant gestational age, and family history of CHDs (aOR 1.4, 95% CI 1.0–2.0). No associations were observed between AVSDs and maternal history of a urinary tract infection or pelvic inflammatory disease, maternal use of a wide variety of medications, maternal occupational exposure, parental drug use, or maternal alcohol consumption. If the results of this preliminary study can be replicated, minimizing maternal active and passive smoke exposure may decrease the incidence of AVSDs.

The Correction Index: Setting the Standard for Recommending Operative Repair of Pectus Excavatum

BACKGROUND The Haller index, derived from a chest computed tomography scan, remains the standard for determining candidacy for pectus excavatum repair (Haller index≥3.25). However, it has been suggested that this index may not accurately reflect pectus severity in patients with abnormal chest wall morphologies. This study explores a new, more appropriate criteria for recommending repair based on a correction index, while still incorporating the standard set by the Haller index. METHODS A database of 75 patients with pectus excavatum who received computed tomography scans was compiled. For each patient, a staff radiologist calculated the Haller index, a correction index, and an ideal chest index from the computed tomography image with the greatest sternal depression. A correlation was assessed between all Haller and correction indices and separately for those with standard and nonstandard chest dimensions as assessed by an ideal chest index. RESULTS There was a modest correlation between the Haller and correction indices measured in this cohort (r=0.79; p<0.0001). When patients with aberrant ideal chest dimensions were removed from analysis, Haller and correction indices showed a stronger correlation (r=0.86; p<0.0001). CONCLUSIONS The correction index provides an accurate assessment of pectus severity, and by the nature of the measurement, reflects the potential degree of operative repair. The Haller index correlates well with the correction index in pectus patients with standard chest wall dimensions, but is quite discrepant in the nonstandard chest. We recommend operative repair for pectus excavatum with a correction index of 28% or more, because this value correlates with the long-accepted standard (Haller index≥3.25) and this index remains accurate even in nonstandard chest morphologies.

Descriptive Study of Nonsyndromic Atrioventricular Septal Defects in the National Birth Defects Prevention Study, 1997-2005

Nonsyndromic atrioventricular septal defects (AVSDs) are serious congenital heart defects for which information on prevalence and descriptive characteristics based on large, geographically, and ethnically diverse populations has been limited. To describe the birth prevalence and phenotype of nonsyndromic AVSDs, we used data from the National Birth Defects Prevention Study (NBDPS), a multisite, population‐based case–control study aimed at identifying genetic and environmental risk factors for birth defects. For this analysis, infants born during the period 1997–2005 and meeting the NBDPS case definition for AVSDs were included. Infants with an AVSD associated with recognized or strongly suspected chromosomal abnormalities or single‐gene disorders (syndromic case infants) were excluded. We identified 302 infants with a nonsyndromic AVSD for a birth prevalence of 0.83/10,000 livebirths. Over 20% of infants with an AVSD had an additional major birth defect, with gastrointestinal, renal or urinary, and central nervous system defects being the most common. A lower prevalence of AVSDs was seen among infants born to Hispanic mothers compared with those born to non‐Hispanic White mothers [prevalence ratio = 0.63 (95% confidence interval: 0.46–0.86)]. Understanding the prevalence of nonsyndromic AVSDs, demographic factors associated with their occurrence, and associated defects could help guide clinical care, as well as contribute to a better understanding of pathogenesis.

Impact of Pulmonary Hemodynamics and Ventricular Interdependence on Left Ventricular Diastolic Function in Children With Pulmonary Hypertension.

Background—Through ventricular interdependence, pulmonary hypertension (PH) induces left ventricular (LV) dysfunction. We hypothesized that pediatric PH patients have LV diastolic dysfunction, related to adverse pulmonary hemodynamics, leftward septal shift, and prolonged right ventricular systole. Methods and Results—Echocardiography was prospectively performed at 2 institutions in 54 pediatric PH patients during cardiac catheterization and in 54 matched controls. Diastolic LV measures including myocardial deformation were assessed by echocardiography. PH patients had evidence of LV diastolic dysfunction, most consistent with impaired LV relaxation, though some features of reduced ventricular compliance were present. PH patients demonstrated the following: reduced mitral E velocity and inflow duration, mitral E′ and E′/A′, septal E′ and A′, pulmonary vein S and D wave velocities, and LV basal global early diastolic circumferential strain rate and increased mitral E deceleration time, LV isovolumic relaxation time, mitral E/E′, and pulmonary vein A wave duration. PH patients demonstrated leftward septal shift and prolonged right ventricular systole, both known to affect LV diastole. These changes were exacerbated in severe PH. There were no statistically significant differences in diastolic measures between patients with and without a shunt and minimal differences between patients with and without congenital heart disease. Multiple echocardiographic LV diastolic parameters demonstrated weak-to-moderate correlations with invasively determined PH severity, leftward septal shift, and prolonged right ventricular systole. Conclusions—Pediatric PH patients exhibit LV diastolic dysfunction most consistent with impaired relaxation and reduced myocardial deformation, related to invasive hemodynamics, leftward septal shift, and prolonged right ventricular systole.

Left Ventricular Myocardial Function in Children With Pulmonary Hypertension Relation to Right Ventricular Performance and Hemodynamics

Background— Through ventricular interdependence, pulmonary hypertension (PH) induces left ventricular (LV) dysfunction. We hypothesized that LV strain/strain rate, surrogate measures of myocardial contractility, are reduced in pediatric PH and relate to invasive hemodynamics, right ventricular strain, and functional measures of PH. Methods and Results— At 2 institutions, echocardiography was prospectively performed in 54 pediatric PH patients during cardiac catheterization, and in 54 matched controls. Patients with PH had reduced LV global longitudinal strain (LS; −18.8 [−17.3 to −20.4]% versus −20.2 [−19.0 to −20.9]%; P =0.0046) predominantly because of reduced basal (−12.9 [−10.8 to −16.3]% versus −17.9 [−14.5 to −20.7]%; P <0.0001) and mid (−17.5 [−15.5 to −19.0]% versus −21.1 [−19.1 to −23.0]%; P <0.0001) septal strain. Basal global circumferential strain was reduced (−18.7 [−15.7 to −22.1]% versus −20.6 [−19.0 to −22.5]%; P =0.0098), as were septal and free-wall segments. Mid circumferential strain was reduced within the free-wall. Strain rates were reduced in similar patterns. Basal septum LS, the combined average LS of basal and mid interventricular septal segments, correlated strongly with degree of PH ( r =0.66; P <0.0001), pulmonary vascular resistance ( r =0.60; P <0.0001), and right ventricular free-wall LS ( r =0.64; P <0.0001). Brain natriuretic peptide levels correlated moderately with septal LS ( r =0.48; P =0.0038). PH functional class correlated moderately with LV free-wall LS ( r =−0.48; P =0.0051). The septum, shared between ventricles and affected by septal shift, was the most affected LV region in PH. Conclusions— Pediatric PH patients demonstrate reduced LV strain/strain rate, predominantly within the septum, with relationships to invasive hemodynamics, right ventricular strain, and functional PH measures.Background—Through ventricular interdependence, pulmonary hypertension (PH) induces left ventricular (LV) dysfunction. We hypothesized that LV strain/strain rate, surrogate measures of myocardial contractility, are reduced in pediatric PH and relate to invasive hemodynamics, right ventricular strain, and functional measures of PH. Methods and Results—At 2 institutions, echocardiography was prospectively performed in 54 pediatric PH patients during cardiac catheterization, and in 54 matched controls. Patients with PH had reduced LV global longitudinal strain (LS; −18.8 [−17.3 to −20.4]% versus −20.2 [−19.0 to −20.9]%; P=0.0046) predominantly because of reduced basal (−12.9 [−10.8 to −16.3]% versus −17.9 [−14.5 to −20.7]%; P<0.0001) and mid (−17.5 [−15.5 to −19.0]% versus −21.1 [−19.1 to −23.0]%; P<0.0001) septal strain. Basal global circumferential strain was reduced (−18.7 [−15.7 to −22.1]% versus −20.6 [−19.0 to −22.5]%; P=0.0098), as were septal and free-wall segments. Mid circumferential strain was reduced within the free-wall. Strain rates were reduced in similar patterns. Basal septum LS, the combined average LS of basal and mid interventricular septal segments, correlated strongly with degree of PH (r=0.66; P<0.0001), pulmonary vascular resistance (r=0.60; P<0.0001), and right ventricular free-wall LS (r=0.64; P<0.0001). Brain natriuretic peptide levels correlated moderately with septal LS (r=0.48; P=0.0038). PH functional class correlated moderately with LV free-wall LS (r=−0.48; P=0.0051). The septum, shared between ventricles and affected by septal shift, was the most affected LV region in PH. Conclusions—Pediatric PH patients demonstrate reduced LV strain/strain rate, predominantly within the septum, with relationships to invasive hemodynamics, right ventricular strain, and functional PH measures.

Self-instructional CPR training for parents of high risk infants.

OBJECTIVE Premature infants (PRE) and infants with congenital heart disease (CHD) are at high risk for respiratory or cardiac arrest in their first year. Bystander cardiopulmonary resuscitation (CPR) is a major predictor of resuscitation outcome. The purpose of this study was to assess the usefulness of a self-instructional DVD kit (Infant CPRAnytime) for families of high-risk infants. We hypothesized that comfort level of performing CPR would increase, parents would share the kit with others, and review it during the year. METHODS Parents of PRE (<35 weeks or <2500 g) or CHD infants received a self-instructional CPR kit. One parent completed a questionnaire, reviewed the DVD, and practiced CPR before discharge. They were asked to share the kit with other care providers, practice CPR every 3 months, and complete questionnaires at 4 and 12 months. RESULTS We enrolled 311 subjects: 238 PRE and 73 CHD. Comfort level performing CPR increased from 2.8 at baseline to 3.5 at 12 months (p=0.023). The kit was shared with 3.1 additional persons and reviewed by the parent 1.8 times over 12 months. Eight emergency rescue events were reported: choking (3) and CPR (5). All events requiring CPR were in infants with CHD. Six infants survived with reported good or stable neurologic status. CONCLUSIONS Self-instructional tools provide an excellent method of CPR training for parents of high risk infants. Caregiver comfort increased over 12 months and parents continued to review the kit during the first year. An additional 3.1 persons used the kit for CPR training.

Fetal programming alters reactive oxygen species production in sheep cardiac mitochondria.

Exposure to an adverse intrauterine environment is recognized as an important risk factor for the development of cardiovascular disease later in life. Although oxidative stress has been proposed as a mechanism for the fetal programming phenotype, the role of mitochondrial O(2)(*-) (superoxide radical) production has not been explored. To determine whether mitochondrial ROS (reactive oxygen species) production is altered by in utero programming, pregnant ewes were given a 48-h dexamethasone (dexamethasone-exposed, 0.28 mg.kg(-1) of body weight.day(-1)) or saline (control) infusion at 27-28 days gestation (term=145 days). Intact left ventricular mitochondria and freeze-thaw mitochondrial membranes were studied from offspring at 4-months of age. AmplexRed was used to measure H(2)O(2) production. Activities of the antioxidant enzymes Mn-SOD (manganese superoxide dismutase), GPx (glutathione peroxidase) and catalase were measured. Compared with controls, a significant increase in Complex I H(2)O(2) production was found in intact mitochondria from dexamethasone-exposed animals. The treatment differences in Complex I-driven H(2)O(2) production were not seen in mitochondrial membranes. Consistent changes in H(2)O(2) production from Complex III in programmed animals were not found. Despite the increase in H(2)O(2) production in intact mitochondria from programmed animals, dexamethasone exposure significantly increased mitochondrial catalase activity, whereas Mn-SOD and GPx activities were unchanged. The results of the present study point to an increase in the rate of release of H(2)O(2) from programmed mitochondria despite an increase in catalase activity. Greater mitochondrial H(2)O(2) release into the cell may play a role in the development of adult disease following exposure to an adverse intrauterine environment.

Norwood Reconstruction Using Continuous Coronary Perfusion: A Safe and Translatable Technique

BACKGROUND Continuous coronary perfusion during Norwood reconstruction offers the theoretic advantage of less postoperative cardiac dysfunction. The avoidance of a cardiac and circulatory arrest period allows time for a more deliberate aortic reconstruction while the heart remains beating. This single-center study was designed to compare patient results using this method vs standard cardiac arrest for Norwood reconstruction. METHODS A retrospective review was done of 32 patients undergoing Norwood reconstruction from November 2004 to July 2011. The operations in the most recent 16 consecutive patients were performed under deep hypothermia with constant coronary and cerebral perfusion. Continuous coronary perfusion was provided by a cannula inserted into the proximal aorta. The operations in the prior 16 consecutive patients were performed using deep hypothermia, selective cerebral perfusion, and cardioplegic arrest during aortic reconstruction. RESULTS Survival in the beating-heart group was 87.5% (14 of 16) vs 62.5% (10 of 16) in the standard group (p = 0.22). No patients in the beating-heart group required extracorporeal membrane oxygenation vs 3 in the standard group. Postoperative cardiac function was similar for both groups. The beating-heart cohort had lower peak lactate levels (8.2 mEq/L) than the standard group (10.7 mEq/L, p = 0.022). CONCLUSIONS This study presents the largest series of Norwood operations in which the entire aorta is augmented while delivering continuous coronary perfusion. The technique is applicable to any size aorta and represents a safe alternative because outcomes for survival, freedom from extracorporeal membrane oxygenation, postoperative cardiac function, and lactate levels were all noninferior compared with the standard technique.

Three-dimensional Echocardiography of Right Ventricular Function Correlates with Severity of Pediatric Pulmonary Hypertension.

BACKGROUND Right ventricular function and biomarkers of B-type natriuretic peptide (BNP) and N-Terminal pro-BNP (NT pro-BNP) are used to determine the severity of right ventricular failure and outcomes from pulmonary hypertension. Real-time three-dimensional echocardiography (3DE) is a novel quantitative measure of the right ventricle and decreases the geometric assumptions from conventional two-dimensional echocardiography (2DE). We correlated right ventricular functional measures using 2DE and single-beat 3DE with biomarkers and hemodynamics to determine the severity of pediatric pulmonary hypertension. METHODS We retrospectively evaluated 35 patients (mean age 12.67 ± 5.78 years) with established pulmonary hypertension who had echocardiograms and biomarkers on the same day. Ten out of 35 patients had hemodynamic evaluation within 3 days. 2DE evaluation included tricuspid annular plane systolic excursion (TAPSE), right ventricular myocardial performance index from tissue Doppler imaging (RV TDI MPI), and right ventricular fractional area change (FAC). Three-dimensional echocardiography evaluation included right ventricular ejection fraction (EF), end-systolic volume, and end-diastolic volume. The quality of the 3DE was graded as good, fair, or poor. Pearson correlation coefficients were utilized to evaluate between biomarkers and echocardiographic parameters and between hemodynamics and echocardiography. RESULTS Three-dimensional echocardiography and FAC correlated significantly with BNP and NT pro-BNP. TAPSE and RV TDI MPI did not correlate significantly with biomarkers. 3D right ventricular EF correlated significantly with hemodynamics. Two-dimensional echocardiography did not correlate with hemodynamics. CONCLUSIONS Single-beat 3DE is a noninvasive, feasible tool in the quantification of right ventricular function and maybe more accurate than conventional 2DE in evaluating severity of pulmonary hypertension.