Howard S. Seiden

De novo mutations in histone-modifying genes in congenital heart disease.

Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent–offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left–right organizer. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes ‘poised’ promoters and enhancers, which regulate expression of key developmental genes. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10% of severe CHD.

Acute Kidney Injury After Surgery for Congenital Heart Disease

BACKGROUND The RIFLE criteria (risk, injury, failure, loss, and end-stage kidney disease) have been used to assess acute kidney injury (AKI) in various populations of critically ill children. There are limited reports of AKI using RIFLE criteria in large pediatric populations undergoing congenital heart disease surgery. METHODS Records of patients 18 years and younger who underwent surgery for congenital heart disease between January 2006 and November 2009 were reviewed. The RIFLE score was determined for each patient postoperatively. Multivariate logistic regression analyses were performed to determine risk factors for AKI and the association with clinical outcomes, with subanalyses of patients 1 month of age or younger. RESULTS Data for 458 patients (median age, 7.6 months) were collected and analyzed. Evidence of AKI was demonstrated in 234 patients (51%), the vast majority of whom recovered within 48 hours. Younger age, higher RACHS-1 (risk-adjusted classification for congenital heart surgery) category, and longer cardiopulmonary bypass time were associated with development of AKI. Acute kidney injury was associated with longer duration of ventilation and lengths of intensive care unit and hospital stay. Incidence of AKI in patients 1 month of age or younger was 60.9%, of which more than half required greater than 72 hours to recover. In patients 1 month of age or younger, use of cardiopulmonary bypass, lower preoperative serum creatinine, and higher preoperative blood urea nitrogen were associated with AKI, and AKI was the only factor associated with longer intensive care unit and hospital lengths of stay. CONCLUSIONS Incidence of AKI based on RIFLE criteria in patients undergoing congenital heart disease surgery is higher than previously reported. Risk factors include age 1 month or younger and use of cardiopulmonary bypass. Acute kidney injury is associated with longer lengths of stay.

The Congenital Heart Disease Genetic Network Study Rationale, Design, and Early Results

Congenital heart defects (CHD) are the leading cause of infant mortality among birth defects, and later morbidities and premature mortality remain problematic. Although genetic factors contribute significantly to cause CHD, specific genetic lesions are unknown for most patients. The National Heart, Lung, and Blood Institute-funded Pediatric Cardiac Genomics Consortium established the Congenital Heart Disease Genetic Network Study to investigate relationships between genetic factors, clinical features, and outcomes in CHD. The Pediatric Cardiac Genomics Consortium comprises 6 main and 4 satellite sites at which subjects are recruited, and medical data and biospecimens (blood, saliva, cardiovascular tissue) are collected. Core infrastructure includes an administrative/data-coordinating center, biorepository, data hub, and core laboratories (genotyping, whole-exome sequencing, candidate gene evaluation, and variant confirmation). Eligibility includes all forms of CHD. Annual follow-up is obtained for probands <1-year-old. Parents are enrolled whenever available. Enrollment from December 2010 to June 2012 comprised 3772 probands. One or both parents were enrolled for 72% of probands. Proband median age is 5.5 years. The one third enrolled at age <1 year are contacted annually for follow-up information. The distribution of CHD favors more complex lesions. Approximately, 11% of probands have a genetic diagnosis. Adequate DNA is available from 97% and 91% of blood and saliva samples, respectively. Genomic analyses of probands with heterotaxy, atrial septal defects, conotruncal, and left ventricular outflow tract obstructive lesions are underway. The scientific community’s use of Pediatric Cardiac Genomics Consortium resources is welcome.

Web-Based Survey of Current Trends in Hemodynamic Monitoring After Congenital Heart Surgery

Strategies for monitoring patients recovering after congenital heart surgery have evolved considerably as technology continues to progress. Monitoring techniques traditionally centered around the comprehensive physical examination have been replaced by a number of revolutionary technologies developed to objectively evaluate various components of the cardiovascular system. Despite scant evidence that these methodologies actually improve outcomes, some have been embraced by clinicians. We developed an Internet survey designed to describe current practices of clinicians who care for patients after congenital heart surgery. There were 162 respondents to our survey with the majority from the United States. The views of cardiologists, intensivists, those dual trained in both cardiology and critical care medicine, and surgeons are all robustly represented in the results. Serial lactate monitoring was the strategy that was utilized most often by respondents (94%), followed by multisite near-infrared spectrometry (NIRS, 67%). There were 78% who utilized the combination of serial lactate and NIRS monitoring. Serial lactate monitoring was the technique that was thought to best represent cardiovascular well-being after heart surgery (40%). The results of this survey suggest that despite the paucity of evidence that clinical outcomes of patients recovering after congenital heart surgery are improved by any of these monitoring techniques, there is almost universal acceptance to monitor patients with serial lactate monitoring, NIRS monitoring, or a combination of these techniques.

Brain injury with systemic inflammation in newborns with congenital heart disease undergoing heart surgery

The potential role of systemic inflammation on brain injury in newborns with congenital heart disease (CHD) was assessed by measuring levels of central nervous system (CNS)-derived proteins in serum prior to and following cardiac surgery. A total of 23 newborns (gestational age, 39±1 weeks) with a diagnosis of CHD that required cardiac surgery with cardiopulmonary bypass (CPB) were enrolled in the current study. Serum samples were collected immediately prior to surgery and 2, 24 and 48 h following CPB, and serum levels of phosphorylated neurofilament-heavy subunit (pNF-H), neuron-specific enolase (NSE) and S100B were analyzed. Systemic inflammation was assessed by measuring serum concentrations of complement C5a and complement sC5b9, and the following cytokines: Interleukin (IL)-1β, IL-6, IL-8, IL-10, IL12p70, interferon γ and tumor necrosis factor (TNF)-α. Analysis of cord blood from normal term deliveries (n=26) provided surrogate normative values for newborns. pNF-H and S100B were 2.4- to 2.8-fold higher (P<0.0001) in patient sera than in cord blood prior to surgery and remained elevated following CPB. Pre-surgical serum pNF-H and S100B levels directly correlated with interleukin (IL)-12p70 (ρ=0.442, P<0.05). pNF-H was inversely correlated with arterial pO2 prior to surgery (ρ=−0.493, P=0.01) and directly correlated with arterial pCO2 post-CPB (ρ=0.426, P<0.05), suggesting that tissue hypoxia and inflammation contribute to blood brain barrier (BBB) dysfunction and neuronal injury. Serum IL12p70, IL-6, IL-8, IL-10 and TNF-α levels were significantly higher in patients than in normal cord blood and levels of these cytokines increased following CPB (P<0.001). Activation of complement was observed in all patients prior to surgery, and serum C5a and sC5b9 remained elevated up to 48 h post-surgery. Furthermore, they were correlated (P<0.05) with low arterial pO2, high pCO2 and elevated arterial pressure in the postoperative period. Length of mechanical ventilation was associated directly with post-surgery serum IL-12p70 and IL-8 concentrations (P<0.05). Elevated serum concentrations of pNF-H and S100B in neonates with CHD suggest BBB dysfunction and CNS injury, with concurrent hypoxemia and an activated inflammatory response potentiating this effect.

Increased Prevalence of Congenital Heart Disease in Children With Diamond Blackfan Anemia Suggests Unrecognized Diamond Blackfan Anemia as a Cause of Congenital Heart Disease in the General Population: A Report of the Diamond Blackfan Anemia Registry

Congenital heart disease (CHD) is one of the most commonly occurring congenital anomalies in the general population. In patients with Diamond Blackfan anemia (DBA)—a rare inherited bone marrow failure syndrome—CHD represents ≈30% of all congenital anomalies.1 Affected individuals within multiplex families may have hematologic manifestations with or without CHD or have CHD alone. To support a link between these 2 conditions, we hypothesized that because CHD is common in the Diamond Blackfan Anemia Registry (DBAR) cohort, there are patients with occult DBA in the general CHD population. This study could reveal new knowledge regarding the pathogenesis of nonsyndromic CHD. DBA, characterized by hypoproliferative, proapoptotic erythropoiesis and red cell failure, birth defects, growth failure, and cancer predisposition, presents with hypoplastic anemia; median age, 2 months. Inactivating mutations in large or small subunit-associated RP (ribosomal protein) genes are found in 65% to 70% of cases. RP-associated DBA has autosomal dominant inheritance with variable penetrance or presents as sporadic new dominant mutations. A few cases are not RP associated.1,2 The DBAR of North America, established in 1991, captures patients in a nonbiased fashion.1 In the DBAR (n=744), 111 patients have CHD, representing a significantly greater prevalence of CHD in patients with DBA (n=111 of 744; prevalence, 1491.9/10 000; 14.9%) compared with the general population3 (n=3240 of 398 140; prevalence, 81.4/10 000; <1%; P <0.0001 [χ2]). The relative distribution of CHD in DBA is similar to the general population (Figure). Figure. Congenital heart disease (CHD) in Diamond Blackfan anemia (DBA). A , The CHD anomalies in the Diamond Blackfan …

Endothelial function evaluation in patients with anorexia nervosa

Introduction: This study evaluated endothelial function in patients with anorexia nervosa (AN) using Endothelial Pulse Amplitude Testing (Endo-PAT) and correlated findings with the patients’ history and biochemical data. Method: Twenty-one patients age 13-21 years diagnosed with AN by the Division of Adolescent Medicine at Cohen Children’s Medical Center of New York between 6/1/2012 and 5/31/2013 were studied along with 19 healthy controls similar in age and gender distribution. Digital pulse amplitude was examined using Endo-PAT. Raw data were automatically transferred into a reactive hyperemia index (RHI) and the natural log transformation of RHI (LnRHI). Subjects’ and controls’ electrocardiograms and biochemical markers were obtained. Results: AN and controls had similar RHI (P=0.7542) and LnRHI (P=0.9497). AN had lower mean weight (P<0.0001), height (P=0.0207), BMI (P<0.0001), resting HR (P<0.0001), systolic (P<0.0001) and diastolic BP (P=0.0141). AN also had lower mean HR during EndoPAT testing (P<0.0001), triiodothyronine (T3) (P<0.0001), luteinizing hormone (LH) (P=0.0055) and estradiol (E2) (P=0.0052). Total cholesterol (Chol) (P=0.0004) was higher in AN subjects. No correlation was observed between RHI and other parameters. Conclusion: No significant differences in RHI or LnRHI were found between the two groups. There were significantly higher Chol and lower HR, T3, LH and E2 levels in the AN group compared to controls. There were no correlations of these parameters to RHI. Abbreviations: AN: anorexia nervosa; BMI: body mass index; Chol: total cholesterol; DBP: diastolic blood pressure; E2: estradiol; ECG: electrocardiogram; Endo-PAT: Endothelial Pulse Amplitude Testing; FSH: follicle-stimulating hormone; Hcy: homocysteine; HDL: high-density lipoprotein; LDL: low-density lipoprotein; LH: luteinizing hormone; LnRHI: natural logarithm transformation of Reactive Hyperemia Index; ln(Lp(a)): natural logarithm transformation of lipoprotein A; Lp(a): lipoprotein A; PAT: Peripheral Arterial Tone; PRL: prolactin; RHI: Reactive Hyperemia Index; SBP: systemic blood pressure; T3: triiodothyronine; TG: triglyceride; TSH: thyroid stimulating hormone