Cause Of Congenital Heart Disease Research Articles

Peri-conceptual and antenatal parental factors and neonatal congenital heart disease: a case-control study

Background: Our understanding of the causes of congenital heart disease (CHD), a leading cause of infant death in developed countries is poor. This study is aimed to explore the relationship between the occurrence of CHD in neonates and parental environmental exposures during peri-conceptual period. Methods: A case-control study was conducted at 9 maternity hospitals in eastern China. Cases comprised of neonates with CHD diagnosed by cardiac ultrasound. The controls were healthy infants who were born in the same center at the same period and in similar conditions. The neonates’ parents completed a questionnaire for collecting pre-conceptual environmental exposures including smoking, alcohol, supplementation of vitamins and folic acid, herbal medications, and medications during peri-conceptual period. Results: A total of 199 CHD cases and 262 controls were recruited without difference in gender and maternal age. Multivariable logistic regression analysis showed that maternal vitamin supplements (OR 0.57; 95% CI: 0.35–0.94) and folic acid-supplements (OR 0.64; 95% CI: 0.42–0.97) in the first trimester of pregnancy decreased the risk of CHD. Paternal smoking (OR 1.86; 95% CI: 1.22–2.85) and Chinese herbal medication intake (OR 3.46; 95% CI: 0.98–12.19) may increase the risk of CHD. Conclusions: The supplements of vitamin and folic acid in the early gestation would be important to decrease the risk of the occurrence of CHD. While the exposure to smoke may be a risk factor.

Fluid forces shape the embryonic heart: Insights from zebrafish.

Heart formation involves a complex series of tissue rearrangements, during which regions of the developing organ expand, bend, converge, and protrude in order to create the specific shapes of important cardiac components. Much of this morphogenesis takes place while cardiac function is underway, with blood flowing through the rapidly contracting chambers. Fluid forces are therefore likely to influence the regulation of cardiac morphogenesis, but it is not yet clear how these biomechanical cues direct specific cellular behaviors. In recent years, the optical accessibility and genetic amenability of zebrafish embryos have facilitated unique opportunities to integrate the analysis of flow parameters with the molecular and cellular dynamics underlying cardiogenesis. Consequently, we are making progress toward a comprehensive view of the biomechanical regulation of cardiac chamber emergence, atrioventricular canal differentiation, and ventricular trabeculation. In this review, we highlight a series of studies in zebrafish that have provided new insight into how cardiac function can shape cardiac morphology, with a particular focus on how hemodynamics can impact cardiac cell behavior. Over the long-term, this knowledge will undoubtedly guide our consideration of the potential causes of congenital heart disease.

In vitro comparison of endothelialisation process and biocompatibility of 3 percutaneous atrial septal defect devices using human endothelial cells

The first cause of congenital heart disease is atrial septal defect (ASD). Several devices were developed to close secundum ASD but complications can occur (thromboembolic, infectious…). Providers claim different coatings supposed to improve device haemocompatibility. To study, in vitro, the ability of 3 devices to be endothelialized by endothelial cells derived from circulating human endothelial progenitors cells (EPCs), to induce platelet or complement activations or coagulation intrinsic pathway activation. EPCs from umbilical cord blood were extracted, cultured and characterized (CD31, VE-cadherin and von Willebrand factor). Devices were seeded with 100,000 cells/cm 2 . EPC adhesion, at 3 and 24 hours, was investigated (biological activity of N acetyl β-D-hexosaminidase). EPC proliferation was monitored with Alamar blue® test which allowed a longitudinal follow-up (Days1, 3, 6, 8, 10 and 12). C3a assay was performed after blood-contacting devices (standard ASTM F1984). Thereafter, platelet activation (via Pselectin and GPIIBIIA) and blood coagulation on biomaterials (standard ASTM F2888, F2382) were explored. With regard to EPCs adhesion and proliferation, no statistically significant differences were found between 3 devices. There was a significant EPC proliferation on each device as a function of time appearing at Day 8 for devices 2 and 3 and Day10 for device 1. No complement activation was detected by the C3a assay (device 1: 3584 ± 978 ng/mL, device 2: 3386 ± 1092 ng/mL and device 3: 4612 ± 1657 ng/mL). No platelet activation occurred within 15 min of contact with devices. However, there was a minimal activation of coagulation for 3 devices (mean time for PTT test on device 1: 183 ± 23.3 s, device 2: 170.7 ± 22.2 s and device 3: 167 ± 22.6 s). Despite different coatings, the haemocompatibility of 3 devices was comparable. The benefit of effective anticoagulation should be confirmed by future clinical studies.

Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart Association.

This review provides an updated summary of the state of our knowledge of the genetic contributions to the pathogenesis of congenital heart disease. Since 2007, when the initial American Heart Association scientific statement on the genetic basis of congenital heart disease was published, new genomic techniques have become widely available that have dramatically changed our understanding of the causes of congenital heart disease and, clinically, have allowed more accurate definition of the pathogeneses of congenital heart disease in patients of all ages and even prenatally. Information is presented on new molecular testing techniques and their application to congenital heart disease, both isolated and associated with other congenital anomalies or syndromes. Recent advances in the understanding of copy number variants, syndromes, RASopathies, and heterotaxy/ciliopathies are provided. Insights into new research with congenital heart disease models, including genetically manipulated animals such as mice, chicks, and zebrafish, as well as human induced pluripotent stem cell-based approaches are provided to allow an understanding of how future research breakthroughs for congenital heart disease are likely to happen. It is anticipated that this review will provide a large range of health care-related personnel, including pediatric cardiologists, pediatricians, adult cardiologists, thoracic surgeons, obstetricians, geneticists, genetic counselors, and other related clinicians, timely information on the genetic aspects of congenital heart disease. The objective is to provide a comprehensive basis for interdisciplinary care for those with congenital heart disease.

In vitro comparison of endothelialisation process and biocompatibility of 3 percutaneous atrial septal defect devices using human endothelial cells

The first cause of congenital heart disease is atrial septal defect (ASD). Several devices were developed to close secundum ASD but complications can occur (thromboembolic, infectious…) [1] , [2] , [3] . Providers claim different coatings supposed to improve device haemocompatibility. To study, in vitro, the ability of 3 devices to be endothelialized by endothelial cells derived from circulating human endothelial progenitors cells (EPCs), to induce platelet or complement activations or coagulation intrinsic pathway activation. EPCs from umbilical cord blood were extracted, cultured and characterized (CD31, VE-cadherin and von Willebrand factor). Devices were seeded with 100,000 cells/cm 2 . EPC adhesion, at 3 and 24 hours, was investigated (biological activity of N acetyl β-D-hexosaminidase). EPC proliferation was monitored with Alamar blue ® test which allowed a longitudinal follow-up (Days 1, 3, 6, 8, 10 and 12). C3a assay was performed after blood-contacting devices (standard ASTM F1984) [4] . Thereafter, platelet activation (via Pselectin and GPIIBIIA) and blood coagulation on biomaterials (standard ASTM F2888, F2382) [5] , [6] were explored. With regard to EPCs adhesion and proliferation ( Fig. 1 , Fig. 2 ), no statistically significant differences were found between 3 devices. There was a significant EPC proliferation on each device as a function of time appearing at Day 8 for devices 2 and 3 and Day 10 for device 1. No complement activation was detected by the C3a assay (device 1: 3584 ± 978 ng/mL, device 2: 3386 ± 1092 ng/mL and device 3: 4612 ± 1657 ng/mL) ( Fig. 3 ). No platelet activation occurred within 15 min of contact with devices (Figs 4 and 5). However, there was a minimal activation of coagulation for 3 devices (Mean time for PTT test on device 1: 183 ± 23.3 s, device 2: 170.7 ± 22.2 s and device 3: 167 ± 22.6 s). Despite different coatings, the haemocompatibility of three devices was comparable. The benefit of effective anticoagulation should be confirmed by future clinical studies.

Genome-wide compound heterozygosity analysis highlighted 4 novel susceptibility loci for congenital heart disease in Chinese population.

Genome-wide association studies (GWASs) have achieved great success in deciphering the genetic cause of congenital heart disease (CHD). However, the heritability of CHD remains to be clarified, and numerous genetic factors responsible for occurrence of CHD are yet unclear. In this study, we performed a genome-wide search for relaxed forms of compound heterozygosity (CH) in association with CHD using our existing GWAS data including 2265 individuals (957 CHD cases and 1308 controls). CollapsABEL was used to iteratively test the association between the CH genotype and the CHD phenotype in a sliding window manner. We highlighted 17 genetic loci showing suggestive CH-like associations with CHD (P < 5 × 10-8 ), among which 4 genetic loci had expression quantitative trait loci (eQTL) effects in blood (PeQTL < 0.01). After conditional association analysis, each loci had only 1 independently effective signal reaching the significance threshold (rs2071477/rs3129299 at 6p21.32, P = 2.47 × 10-10 ; rs10773097/rs2880921 at 12q24.31, P = 3.30 × 10-8 ; rs73032040/rs7259476 at 19q13.11, P = 1.14 × 10-8 ; rs10416386/rs4239517 at 19q13.31, P = 1.15 × 10-9 ), together explained 7.83% of the CHD variance. Among these 4 associated loci, outstanding candidates for CHD-associated genes included UBC, CFM2, ZNF302, LYPD3 and CADM4. Although replication studies with larger sample size are warranted, the first CH GWAS of CHD may extend our current knowledge of the genetic contributions to CHD in the Han Chinese population.

Septation of the Intrapericardial Arterial Trunks in the Early Human Embryonic Heart.

Background:Outflow tract (OFT) septation defects are a common cause of congenital heart disease. Numerous studies have focused on the septation mechanism of the OFT, but have reported inconsistent conclusions. This study, therefore, aimed to investigate the septation of the aortic sac and the OFT in the early embryonic human heart.Methods:Serial sections of 27 human embryonic hearts from Carnegie stage (CS) 10 to CS19 were immunohistochemically stained with antibodies against α-smooth muscle actin (α-SMA) and myosin heavy chain.Results:At CS10–CS11, the OFT wall was an exclusively myocardial structure that was continuous with the aortic sac at the margin of the pericardial cavity. From CS13 onward, the OFT was divided into nonmyocardial and myocardial portions. The cushion formed gradually, and its distal border with the OFT myocardium was consistently maintained. The aortic sac between the fourth and sixth aortic arch arteries was degenerated. At CS16, the α-SMA-positive aortopulmonary septum formed and fused with the two OFT cushions, thus septating the nonmyocardial portion of the OFT into two arteries. At this stage, the cushions were not fused. At CS19, the bilateral cushions were fused to septate the myocardial portion of the OFT.Conclusions:Data suggest that the OFT cushion is formed before the aortopulmonary septum is formed. Thus, the OFT cushion is not derived from the aortopulmonary septum. In addition, the nonmyocardial part of the OFT is septated into the aorta and pulmonary trunk by the aortopulmonary septum, while the main part of the cushion fuses and septates the myocardial portion of the OFT.

Assessment of interaction between maternal polycyclic aromatic hydrocarbons exposure and genetic polymorphisms on the risk of congenital heart diseases

The major causes of congenital heart diseases (CHDs) are the interactions of genetic and environmental factors. We conducted a case–control study in 357 mothers of CHDs fetuses and 270 control mothers to investigate the association of maternal PAHs exposure, AHR, CYP1A1, CYP1A2, CYP1B1 and CYP2E polymorphisms, the interaction between PAHs exposure and genetic variants with the risk of CHDs. The higher level PAHs exposure was associated with the risk of CHDs (aOR = 2.029, 95% CI: 1.266, 3.251) or subtypes. The haplotypes of AHR or CYP1A2 were associated with the risk of CHDs: AHR: C-G-A-C: aOR = 0.765; T-A-G-A: aOR = 1.33; CYP1A2: A-T:aOR = 1.75; C-C: aOR = 0.706. When exposed to higher level PAHs, the risk of CHDs among the mothers carrying rs2158041 “C/T or T/T” genotype or rs7811989 “G/A or A/A” genotype in AHR was 1.724 (χ2 = 7.209, P = 0.007) or 1.735 (χ2 = 7.364, P = 0.007) times greater than the aOR in the mothers carrying wild genotype. The multiplicative-scale interactions between PAHs exposure and polymorphisms of CYP1A2 rs4646425 (P = 0.03) or CYP2E1 rs915908 (P = 0.0238) on the risk of CHDs were observed. Our study suggests that maternal AHR polymorphisms may modify the association of PAHs exposure with CHDs, CYP1A2 or CYP2E1 polymorphisms significantly interact with PAHs exposure on CHDs.

Identification of a novel non-sense mutation in TBX5 gene in pediatric patients with congenital heart defects

Introduction: Congenital heart diseases (CHDs) are structural cardiovascular malformations that arise from abnormal development of the heart during the prenatal life. Mutations in the TBX5 gene, encoding T-box transcription factor, are a major cause of CHD. To evaluate the TBX5 mutations in hotspot exons in sporadic pediatric patients with CHD phenotypes, analytical case/control study performed in an Iranian cohort of unrelated patients with clinical diagnosis of congenital heart malformations. Methods: We investigated TBX5 coding exons 4, 5, 6 and 7 in 95 sporadic patients with CHD phenotypes and compared to 82 healthy controls using PCR-SSCP and DNA sequencing approaches. Results: We report here on a novel and heterozygote Non-sense mutation in exon 5 of TBX5, E128X (G14742T), in two Iranian children. This mutation locates inside the T-box and both of pediatric patients carrying this novel mutation suffer from severe heart malformations. The G14742T mutation leads to the substitution of glutamic acid (E) by stop codon (X) at residue 128, an evolutionarily conserved position in T-box as well as in other species. The non-sense mutation of E128X was predicted to be pathogenic by Mutation Taster and Polyphen software programs. Conclusion: TBX5 E128X mutation results in a translational premature stop. This type of mutation results in a shortened protein that may function improperly and which cannot bind to other transcription factors; therefore, haploinsufficiency of TBX5 protein is presumably causing the severe cardiac malformations in these patients.

Genetic contribution to neurodevelopmental outcomes in congenital heart disease: are some patients predetermined to have developmental delay?

Neurodevelopmental impairment is common in children with moderate to severe congenital heart disease (CHD). As children live longer and healthier lives, research has focused on identifying causes of neurodevelopmental morbidity that significantly impact long-term quality of life. This review will address the role of genetic factors in predicting neurodevelopmental outcome in CHD. A robust literature suggests that among children with various forms of CHD, those with known genetic/extracardiac anomalies are at highest risk of neurodevelopmental impairment. Advances in genetic technology have identified genetic causes of CHD in an increasing percentage of patients. Further, emerging data suggest substantial overlap between mutations in children with CHD and those that have previously been associated with neurodevelopmental disorders. Innate and patient factors appear to be more important in predicting neurodevelopmental outcome than medical/surgical variables. Future research is needed to establish a broader understanding of the mutations that contribute to neurodevelopmental disorders and the variations in expressivity and penetrance.

The genetics of congenital heart disease… understanding and improving long-term outcomes in congenital heart disease: a review for the general cardiologist and primary care physician.

This review has two purposes: to provide an updated review of the genetic causes of congenital heart disease (CHD) and the clinical implications of these genetic mutations, and to provide a clinical algorithm for clinicians considering a genetics evaluation of a CHD patient. A large portion of congenital heart disease is thought to have a significant genetic contribution, and at this time a genetic cause can be identified in approximately 35% of patients. Through the advances made possible by next generation sequencing, many of the comorbidities that are frequently seen in patients with genetic congenital heart disease patients can be attributed to the genetic mutation that caused the congenital heart disease. These comorbidities are both cardiac and noncardiac and include: neurodevelopmental disability, pulmonary disease, heart failure, renal dysfunction, arrhythmia and an increased risk of malignancy. Identification of the genetic cause of congenital heart disease helps reduce patient morbidity and mortality by improving preventive and early intervention therapies to address these comorbidities. Through an understanding of the clinical implications of the genetic underpinning of congenital heart disease, clinicians can provide care tailored to an individual patient and continue to improve the outcomes of congenital heart disease patients.

Disruption of spatiotemporal hypoxic signaling causes congenital heart disease in mice.

Congenital heart disease (CHD) represents the most prevalent inborn anomaly. Only a minority of CHD cases are attributed to genetic causes, suggesting a major role of environmental factors. Nonphysiological hypoxia during early pregnancy induces CHD, but the underlying reasons are unknown. Here, we have demonstrated that cells in the mouse heart tube are hypoxic, while cardiac progenitor cells (CPCs) expressing islet 1 (ISL1) in the secondary heart field (SHF) are normoxic. In ISL1+ CPCs, induction of hypoxic responses caused CHD by repressing Isl1 and activating NK2 homeobox 5 (Nkx2.5), resulting in decreased cell proliferation and enhanced cardiomyocyte specification. We found that HIF1α formed a complex with the Notch effector hes family bHLH transcription factor 1 (HES1) and the protein deacetylase sirtuin 1 (SIRT1) at the Isl1 gene. This complex repressed Isl1 in the hypoxic heart tube or following induction of ectopic hypoxic responses. Subsequently, reduced Isl1 expression abrogated ISL1-dependent recruitment of histone deacetylases HDAC1/5, inhibiting Nkx2.5 expression. Inactivation of Sirt1 in ISL1+ CPCs blocked Isl1 suppression via the HIF1α/HES1/SIRT1 complex and prevented CHDs induced by pathological hypoxia. Our results indicate that spatial differences in oxygenation of the developing heart serve as signals to control CPC expansion and cardiac morphogenesis. We propose that physiological hypoxia coordinates homeostasis of CPCs, providing mechanistic explanations for some nongenetic causes of CHD.

Point mutations in murine Nkx2-5 phenocopy human congenital heart disease and induce pathogenic Wnt signaling.

Mutations in the Nkx2-5 gene are a main cause of congenital heart disease. Several studies have addressed the phenotypic consequences of disrupting the Nkx2-5 gene locus, although animal models to date failed to recapitulate the full spectrum of the human disease. Here, we describe a new Nkx2-5 point mutation murine model, akin to its human counterpart disease-generating mutation. Our model fully reproduces the morphological and physiological clinical presentations of the disease and reveals an understudied aspect of Nkx2-5-driven pathology, a primary right ventricular dysfunction. We further describe the molecular consequences of disrupting the transcriptional network regulated by Nkx2-5 in the heart and show that Nkx2-5-dependent perturbation of the Wnt signaling pathway promotes heart dysfunction through alteration of cardiomyocyte metabolism. Our data provide mechanistic insights on how Nkx2-5 regulates heart function and metabolism, a link in the study of congenital heart disease, and confirms that our models are the first murine genetic models to our knowledge to present all spectra of clinically relevant adult congenital heart disease phenotypes generated by NKX2-5 mutations in patients.

Understanding the epigenetic origins of congenital heart disease may lead to its control

Congenital heart disease (CHD), which occurs in about 1 per 100 live births, remains the leading life-threatening abnormality present at birth. It is reasonable to assume that most, if not all, CHD stems from errors or disruptions in the genetic control of heart development, and that a more thorough knowledge of these controlling molecular mechanisms may lead to a better understanding of the origins of CHD. With understanding comes the potential for prevention, and possibly early repair. Our operational research in the Western Cape has identifi ed a severe epidemiological shortfall between the theoretical number of newborns that should present to us with severe CHD and those who actually do - we are referred only 50% of the children that (epidemiologically) should receive heart surgery. Even if we could identify all the missing children, our services would be unable to contend with the consequent demand. This stark dilemma plays itself out in most resource-constrained cardiac health services. It is therefore of utmost importance that the origins of CHD that may be under environmental infl uences - “the epigenetic causes of CHD” - are prioritised in our quest to reduce heart defects. I will outline these infl uences and show how an understanding of them may begin to reduce an enormous health burden.

Gata4 potentiates second heart field proliferation and Hedgehog signaling for cardiac septation

GATA4, an essential cardiogenic transcription factor, provides a model for dominant transcription factor mutations in human disease. Dominant GATA4 mutations cause congenital heart disease (CHD), specifically atrial and atrioventricular septal defects (ASDs and AVSDs). We found that second heart field (SHF)-specific Gata4 heterozygote embryos recapitulated the AVSDs observed in germline Gata4 heterozygote embryos. A proliferation defect of SHF atrial septum progenitors and hypoplasia of the dorsal mesenchymal protrusion, rather than anlage of the atrioventricular septum, were observed in this model. Knockdown of the cell-cycle repressor phosphatase and tensin homolog (Pten) restored cell-cycle progression and rescued the AVSDs. Gata4 mutants also demonstrated Hedgehog (Hh) signaling defects. Gata4 acts directly upstream of Hh components: Gata4 activated a cis-regulatory element at Gli1 in vitro and occupied the element in vivo. Remarkably, SHF-specific constitutive Hh signaling activation rescued AVSDs in Gata4 SHF-specific heterozygous knockout embryos. Pten expression was unchanged in Smoothened mutants, and Hh pathway genes were unchanged in Pten mutants, suggesting pathway independence. Thus, both the cell-cycle and Hh-signaling defects caused by dominant Gata4 mutations were required for CHD pathogenesis, suggesting a combinatorial model of disease causation by transcription factor haploinsufficiency.

TBX20 loss-of-function mutation responsible for familial tetralogy of Fallot or sporadic persistent truncus arteriosus.

Congenital heart disease (CHD), the most common form of developmental abnormality in humans, remains a leading cause of morbidity and mortality in neonates. Genetic defects have been recognized as the predominant causes of CHD. Nevertheless, CHD is of substantial genetic heterogeneity and the genetic defects underlying CHD in most cases remain unclear. In the current study, the coding regions and splicing junction sites of the TBX20 gene, which encodes a T-box transcription factor key to cardiovascular morphogenesis, were sequenced in 175 unrelated patients with CHD, and a novel heterozygous TBX20 mutation, p.K274X, was identified in an index patient with tetralogy of Fallot (TOF). Genetic analysis of the proband's available family members showed that his father, elder brother and son had also TOF. In addition, his father and elder brother had also atrial septal defect, and his niece had persistent truncus arteriosus and ventricular septal defect. Analysis of the pedigree revealed that the mutation co-segregated with CHD transmitted in an autosomal dominant fashion, with complete penetrance. The nonsense mutation, which was absent in the 800 control chromosomes, was predicted to produce a truncated protein with only the amino terminus and partial T-box domain left. Functional analyses by using a dual-luciferase reporter assay system showed that the mutant TBX20 lost the ability to transactivate the target gene ANF. Furthermore, the mutation reduced the synergistic activation between TBX20 and NKX2.5 as well as GATA4, two other transcriptional factors previously associated with various CHD, encompassing TOF. This study firstly links TBX20 loss-of-function mutation to familial TOF or sporadic persistent truncus arteriosus, providing novel insight into the molecular pathogenesis of CHD.

Alcohol Exposure Causes Overexpression of Heart Development-Related Genes by Affecting the Histone H3 Acetylation via BMP Signaling Pathway in Cardiomyoblast Cells.

Abusive alcohol utilization of pregnant woman may cause congenital heart disease (CHD) of fetus, where alcohol ignites histone H3 hyperacetylation leading to abnormal development of heart morphogenesis and associated genes. Knowledge about the regularized upstream genes is little, but bone morphogenetic protein (BMP) signaling may actively and prominently take part in alteration in acetylation of histone H3. The supreme objective of this study was to unearth the involvement of BMP signaling pathway in alcohol-driven hyperacetylation of histone H3 in cardiomyoblast cells. Cardiomyoblast cells (H9c2 cells) were addicted with alcohol (100mM) for 24hours. Dorsomorphin (5μM) was used for the inhibition of BMP signaling pathway. We detected the phosphorylation activity of SMAD1/5/8, mRNA expression, histone acetyltransferases (HAT)/histone deacetylase (HDAC) activity, and acetylation of histone H3. Following alcohol exposure, phosphorylation of SMAD1/5/8 and HAT activities was increased to a significant extent, while histone H3 acetylation and expression of heart development-related genes were also increased. The said phenomenon influenced by alcohol was reverted upon dorsomorphin treatment to the cells without effecting HDAC activity. The data clearly identified that BMP-mediated histone H3 acetylation of heart development-related genes might be one of the possible cellular mechanisms to control alcohol-induced expression of heart development-related genes. Dorsomorphin, on the other hand, may modulate alcohol-induced hyperacetylation of histone H3 throughBMP targeting, which could be a potential way to block CHD.

Genetic and flow anomalies in congenital heart disease.

Congenital heart defects are the most common malformations in humans, affecting approximately 1% of newborn babies. While genetic causes of congenital heart disease have been studied, only less than 20% of human cases are clearly linked to genetic anomalies. The cause for the majority of the cases remains unknown. Heart formation is a finely orchestrated developmental process and slight disruptions of it can lead to severe malformations. Dysregulation of developmental processes leading to heart malformations are caused by genetic anomalies but also environmental factors including blood flow. Intra-cardiac blood flow dynamics plays a significant role regulating heart development and perturbations of blood flow lead to congenital heart defects in animal models. Defects that result from hemodynamic alterations, however, recapitulate those observed in human babies, even those due to genetic anomalies and toxic teratogen exposure. Because important cardiac developmental events, such as valve formation and septation, occur under blood flow conditions while the heart is pumping, blood flow regulation of cardiac formation might be a critical factor determining cardiac phenotype. The contribution of flow to cardiac phenotype, however, is frequently ignored. More research is needed to determine how blood flow influences cardiac development and the extent to which flow may determine cardiac phenotype.

Gestational stress induces the unfolded protein response, resulting in heart defects.

Congenital heart disease (CHD) is an enigma. It is the most common human birth defect and yet, even with the application of modern genetic and genomic technologies, only a minority of cases can be explained genetically. This is because environmental stressors also cause CHD. Here we propose a plausible non-genetic mechanism for induction of CHD by environmental stressors. We show that exposure of mouse embryos to short-term gestational hypoxia induces the most common types of heart defect. This is mediated by the rapid induction of the unfolded protein response (UPR), which profoundly reduces FGF signaling in cardiac progenitor cells of the second heart field. Thus, UPR activation during human pregnancy might be a common cause of CHD. Our findings have far-reaching consequences because the UPR is activated by a myriad of environmental or pathophysiological conditions. Ultimately, our discovery could lead to preventative strategies to reduce the incidence of human CHD.

Rebalancing gene haploinsufficiency in vivo by targeting chromatin.

Congenital heart disease (CHD) affects eight out of 1,000 live births and is a major social and health-care burden. A common genetic cause of CHD is the 22q11.2 deletion, which is the basis of the homonymous deletion syndrome (22q11.2DS), also known as DiGeorge syndrome. Most of its clinical spectrum is caused by haploinsufficiency of Tbx1, a gene encoding a T-box transcription factor. Here we show that Tbx1 positively regulates monomethylation of histone 3 lysine 4 (H3K4me1) through interaction with and recruitment of histone methyltransferases. Treatment of cells with tranylcypromine (TCP), an inhibitor of histone demethylases, rebalances the loss of H3K4me1 and rescues the expression of approximately one-third of the genes dysregulated by Tbx1 suppression. In Tbx1 mouse mutants, TCP treatment ameliorates substantially the cardiovascular phenotype. These data suggest that epigenetic drugs may represent a potential therapeutic strategy for rescue of gene haploinsufficiency phenotypes, including structural defects.