Mutation of highly conserved residues in transcription factors may affect protein-protein or protein-DNA interactions, leading to gene network dysregulation and human disease. Human mutations in ...GATA4, a cardiogenic transcription factor, cause cardiac septal defects and cardiomyopathy. Here, iPS-derived cardiomyocytes from subjects with a heterozygous GATA4-G296S missense mutation showed impaired contractility, calcium handling, and metabolic activity. In human cardiomyocytes, GATA4 broadly co-occupied cardiac enhancers with TBX5, another transcription factor that causes septal defects when mutated. The GATA4-G296S mutation disrupted TBX5 recruitment, particularly to cardiac super-enhancers, concomitant with dysregulation of genes related to the phenotypic abnormalities, including cardiac septation. Conversely, the GATA4-G296S mutation led to failure of GATA4 and TBX5-mediated repression at non-cardiac genes and enhanced open chromatin states at endothelial/endocardial promoters. These results reveal how disease-causing missense mutations can disrupt transcriptional cooperativity, leading to aberrant chromatin states and cellular dysfunction, including those related to morphogenetic defects.
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•Systems-level approach reveals GATA4 roles in human cardiac development and function•Heterozygous GATA4 missense mutation impairs cardiac gene program•GATA4 G296S mutation disrupts TBX5 genome occupancy at cardiac super-enhancers•PI3K signaling is a key “hub” in the GATA4 gene regulatory network
A human missense mutation that causes congenital heart defects disrupts the cooperation between transcription factors at cardiac super-enhancers and gives rise to aberrant gene expression.
Objective
Fetuses with complex congenital heart disease have altered physiology, contributing to abnormal neurodevelopment. The effects of altered physiology on brain development have not been well ...studied. We used multi‐modal imaging to study fetal circulatory physiology and brain development in hypoplastic left heart syndrome (HLHS) and d‐transposition of the great arteries (TGA).
Methods
This prospective, cross‐sectional study investigated individuals with fetal congenital heart disease and controls undergoing fetal echocardiography and fetal brain MRI. MRI measured total brain volume and cerebral oxygenation by the MRI quantification method T2*. Indexed cardiac outputs (CCOi) and vascular impedances were calculated by fetal echocardiography. Descriptive statistics assessed MRI and echocardiogram measurement relationships by physiology.
Results
Sixty‐six participants enrolled (control = 20; HLHS = 25; TGA = 21), mean gestational age 33.8 weeks (95% CI: 33.3–34.2). Total brain volume and T2* were significantly lower in fetuses with cardiac disease. CCOi was lower in HLHS, correlating with total brain volume ‐ for every 10% CCOi increase, volume increased 8 mm3 (95% CI: 1.78–14.1; p = 0.012). Echocardiography parameters and cerebral oxygenation showed no correlation. TGA showed no CCOi or aortic output correlation with MRI measures.
Conclusions
In HLHS, lower cardiac output is deleterious to brain development. Our findings provide insight into the role of fetal cardiovascular physiology in brain health.
Key points
What is already known about this topic?
Fetuses with complex congenital heart disease are at risk of abnormal brain development and impaired neurodevelopmental outcomes.
Causes of abnormal brain development in fetuses with congenital heart disease are multi‐factorial including abnormal cardiovascular physiology.
What does this study add?
Lower cardiac output measured by fetal echocardiography is associated with smaller total brain volume in hypoplastic left heart syndrome but not d‐transposition of the great arteries, providing new insight into the relationship between fetal physiology and brain development.
Background Racial/ethnic and socioeconomic disparities exist in outcomes for children with congenital heart disease. We sought to determine the influence of race/ethnicity and mediating socioeconomic ...factors on 1-year outcomes for live-born infants with hypoplastic left heart syndrome and dextro-Transposition of the great arteries. Methods and Results The authors performed a population-based cohort study using the California Office of Statewide Health Planning and Development database. Live-born infants without chromosomal anomalies were included. The outcome was a composite measure of mortality or unexpected hospital readmissions within the first year of life defined as >3 (hypoplastic left heart syndrome) or >1 readmissions (dextro-Transposition of the great arteries). Hispanic ethnicity was compared with non-Hispanic white ethnicity. Mediation analyses determined the percent contribution to outcome for each mediator on the pathway between race/ethnicity and outcome. A total of 1796 patients comprised the cohort (n=964 hypoplastic left heart syndrome, n=832 dextro-Transposition of the great arteries) and 1315 were included in the analysis (n=477 non-Hispanic white, n=838 Hispanic). Hispanic ethnicity was associated with a poor outcome (crude odds ratio, 1.72; 95% confidence interval CI, 1.37-2.17). Higher maternal education (crude odds ratio 0.5; 95% CI , 0.38-0.65) and private insurance (crude odds ratio, 0.65; 95% CI , 0.45-0.71) were protective. In the mediation analysis, maternal education and insurance status explained 33.2% (95% CI , 7-66.4) and 27.6% (95% CI , 6.5-63.1) of the relationship between race/ethnicity and poor outcome, while infant characteristics played a minimal role. Conclusions Socioeconomic factors explain a significant portion of the association between Hispanic ethnicity and poor outcome in neonates with critical congenital heart disease. These findings identify vulnerable populations that would benefit from resources to lessen health disparities.
Pathogenic DNM1L mutations cause a mitochondrial disorder with a highly variable clinical phenotype characterized by developmental delay, hypotonia, seizures, microcephaly, poor feeding, ocular ...abnormalities, and dysarthria. We report the case of an 8‐month‐old female with autosomal dominant, de novo DNM1L c. 1228G>A (p. E410K) mutation and mitochondrial disorder, septo‐optic dysplasia, hypotonia, developmental delay, elevated blood lactate, and severe mitochondrial cardiomyopathy leading to nonischemic congestive heart failure and cardiogenic shock resulting in death. This case suggests that cardiac involvement, previously undescribed, can be a clinically important feature of this syndrome and should be screened for at diagnosis.
Objectives To describe the natural history of pulmonary hypertension (PH) and the risk of death and pulmonary morbidity associated with the persistence of PH through the neonatal hospitalization for ...these infants. Study design We performed a retrospective cohort study of infants with congenital diaphragmatic hernia (CDH) cared for at University of California San Francisco (2002-2012). Infants with other major anomalies or syndromes were excluded (n = 43). Clinical echocardiograms were performed weekly for up to 6 weeks or until PH resolved off respiratory support or until hospital discharge. Echocardiograms were re-read by a blinded reviewer and categorized by severity of elevation in estimated pulmonary arterial pressure. PH was defined as ≥2/3 systemic blood pressure. Severity was determined by a hierarchy of ductus arteriosus level shunt, interventricular septal position, and tricuspid regurgitant jet velocity. Results Of 140 infants with ≥1 echo, 98 resolved their PH prior to death/discharge. Mean time to resolution was 18 days (median 14 days, IQR 8, 21 days). Those with persistence of PH had a higher rate of extracorporeal membrane oxygenation ( P < .001) and death ( P < .001), and fewer ventilator-free days ( P < .001). Persistence of PH at 14 days predicted mortality (area under the receiver operating characteristic curve 0.87) and adverse respiratory outcomes (area under the receiver operating characteristic curve 0.80-0.83). Conclusions The majority of infants with CDH resolve PH between 1 and 3 weeks of life. At 2 weeks of age, severity of PH by echocardiogram strongly predicts short-term pulmonary morbidity and death. Further evaluation of physiological alterations during that time may lead to novel therapies for severe CDH.
Prenatal Detection of Congenital Heart Disease Friedberg, Mark K., MD; Silverman, Norman H., MD, DSc (Med); Moon-Grady, Anita J., MD ...
The Journal of pediatrics,
07/2009, Letnik:
155, Številka:
1
Journal Article
Recenzirano
Objectives To define current frequency of prenatal detection of congenital heart disease (CHD), factors affecting prenatal detection, and its influence on postnatal course. Study design We ...prospectively identified all fetuses and infants ≤6 months of age with major CHD at 3 referral centers in Northern California over 1 year; we obtained prenatal and demographic data, reviewed prenatal ultrasound (US) and postnatal records, and used logistic regression to analyze maternal, fetal, and prenatal-care provider risk factors for prenatal diagnosis. Results Ninety-eight of 309 infants with major CHD had prenatal diagnosis (36% accounting for 27 pregnancy terminations); 185 infant-families participated in the postnatal survey, and although 99% had prenatal US, only 28% were prenatally diagnosed. Anomalous pulmonary venous return (0%), transposition of the great arteries (19%), and left obstructive lesions (23%) had the lowest prenatal detection. Heterotaxy (82%), single ventricle (64%), and HLHS (61%) had the highest. Prenatal diagnosis was higher at university versus community practices ( P = .001). Sociodemographics were not associated with prenatal diagnosis. Infants diagnosed prenatally were less frequently ventilated ( P < .01) or treated with prostaglandin ( P < .05). Conclusions Prenatal detection of major CHD significantly alters postnatal course but remains low despite nearly universal US. CHD type and US practice type are important determinants of prenatal detection.
Objective Congenital diaphragmatic hernia (CDH) results in morbidity and death from lung hypoplasia and persistent pulmonary hypertension (PH). We sought to define the relationship between fetal ...ultrasound markers of severity in CDH and the time to resolution of neonatal PH. Study Design We conducted a retrospective study of fetuses with an antenatal ultrasound scan and left-sided CDH cared for at the University of California San Francisco (2002-2012). Fetal liver position was classified on ultrasound scan as abdominal (entire liver within the abdomen) or thoracic (any portion of the liver within the thorax). Fetal stomach position was classified from least to most aberrant: abdominal, anterior left chest, mid-posterior left chest, or retrocardiac (right chest). Lung-to-head ratio (LHR) was determined from available scans at 20-29 weeks of gestational age (GA). Routine neonatal echocardiograms were performed weekly for up to 6 weeks or until PH resolved or until discharge. PH was assessed by echocardiogram with the use of a hierarchy of ductus arteriosus level shunt, interventricular septal position, and tricuspid regurgitant jet velocity. Days to PH-free survival was defined as the age at which pulmonary artery pressure was estimated to be <2/3 systemic blood pressure. Cox proportional hazards models adjusted for GA at birth, era of birth, fetal surgery, and GA at ultrasound scan (LHR model only), with censoring at 100 days. Results Of 118 patients, the following fetal markers were available: LHR (n = 53), liver position (n = 112), and stomach position (n = 80). Fewer infants experienced resolved PH if they had LHR <1 ( P = .006), thoracic liver position ( P = .001), or more aberrant stomach position ( P < .001). There was also a decreased rate of resolution of PH in infants with LHR <1 (hazard ratio, 0.30; P = .007), thoracic liver position (hazard ratio, 0.38; P < .001), and more aberrant stomach position (hazard ratios, 0.28 P = .002; 0.1 P < .001; and 0.07 P < .001). Conclusion Fetal ultrasound markers of CDH severity are predictive not only of death but also of significant morbidity. LHR <1, thoracic liver, and aberrant stomach position are associated with delayed time to resolution of PH in infants with CDH and may be used to identify fetuses at high risk of persistent PH.
Background Transplacental fetal treatment of immune-mediated fetal heart disease, including third-degree atrioventricular block (AVB III) and endocardial fibroelastosis, is controversial. Methods and ...Results To study the impact of routine transplacental fetal treatment, we reviewed 130 consecutive cases, including 108 with AVB III and 22 with other diagnoses (first-degree/second-degree atrioventricular block n=10; isolated endocardial fibroelastosis n=9; atrial bradycardia n=3). Dexamethasone was started at a median of 22.4 gestational weeks. Additional treatment for AVB III included the use of a β-agonist (n=47) and intravenous immune globulin (n=34). Fetal, neonatal, and 1-year survival rates with AVB III were 95%, 93%, and 89%, respectively. Variables present at diagnosis that were associated with perinatal death included an atrial rate <90 beats per minute (odds ratio OR, 258.4; 95% CI, 11.5-5798.9;
<0.001), endocardial fibroelastosis (OR, 28.9; 95% CI, 1.6-521.7;
<0.001), fetal hydrops (OR, 25.5; 95% CI, 4.4-145.3;
<0.001), ventricular dysfunction (OR, 7.6; 95% CI, 1.5-39.4;
=0.03), and a ventricular rate <45 beats per minute (OR, 12.9; 95% CI, 1.75-95.8;
=0.034). At a median follow-up of 5.9 years, 85 of 100 neonatal survivors were paced, and 1 required a heart transplant for dilated cardiomyopathy. Cotreatment with intravenous immune globulin was used in 16 of 22 fetuses with diagnoses other than AVB III. Neonatal and 1-year survival rates of this cohort were 100% and 95%, respectively. At a median age of 3.1 years, 5 of 21 children were paced, and all had normal ventricular function. Conclusions Our findings reveal a low risk of perinatal mortality and postnatal cardiomyopathy in fetuses that received transplacental dexamethasone±other treatment from the time of a new diagnosis of immune-mediated heart disease.
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