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A six-fold increase in congenital heart defects (CHD) exists among monochorionic (MC) twins compared to singleton or dichorionic twin pregnancies. Though MC twins share an identical genotype, discordant phenotypes related to CHD and other malformations have been described, with reported rates of concordance for various congenital anomalies at less than 20%. Our objective was to characterize the frequency and spectrum of CHD in a contemporary cohort of MC twins, coupled with genetic and clinical variables to provide insight into risk factors and pathophysiology of discordant CHD in MC twins. Retrospective analysis of all twins receiving prenatal fetal echocardiography at a single institution from January 2010 -March 2020 (N = 163) yielded 23 MC twin pairs (46 neonates) with CHD (n = 5 concordant CHD, n = 18 discordant CHD). The most common lesions were septal defects (60% and 45.5% in concordant and discordant cohorts, respectively) and right heart lesions (40% and 18.2% in concordant and discordant cohorts, respectively). Diagnostic genetic testing was abnormal for 20% of the concordant and 5.6% of the discordant pairs, with no difference in rate of abnormal genetic results between the groups (p = 0.395). No significant association was found between clinical risk factors and development of discordant CHD (p>0.05). This data demonstrates the possibility of environmental and epigenetic influences versus genotypic factors in the development of discordant CHD in monochorionic twins., Competing Interests: The authors have declared that no competing interests exist.

Background: Surgical repair is the standard treatment for complete atrioventricular septal defect. At our institution, this repair is performed by single patch, modified single patch or two patch techniques, according to the surgeon preferences and the surgical anatomy of the defect. The goal of this study was to evaluate our results from the last twelve years., Methods: From June 2006 to June 2018, 81 children with complete atrioventricular septal defect (without tetralogy of Fallot or unbalanced ventricles) were submitted to surgical repair at our institution. Data from all patients was retrospectively collected and evaluated., Results: The average age was 6.9 ± 13.7 months and 84% had Down syndrome. Eighty percent were symptomatic and 6 patients were previously submitted to pulmonary artery banding. No more that mild left atrioventricular valve insufficiency was found in 84% and 89% of the patients, at discharge and follow-up, respectively. Small residual septal defects were present in 27% at discharge; during follow-up, 41% of these closed spontaneously. Pulmonary hypertension at discharge and follow-up appeared in 3.7% and 1.3%, respectively. Permanente pacemaker was implanted in 3 patients. Left ventricle outflow tract obstruction was found in 3 patients and 2 needed surgical correction. At follow-up (40 ± 38 months), 90% of the patients presented NYHA functional class I. No significant differences in the main repair outcomes were found between techniques, with the exception of small residual septal defects, although the groups were unmatched., Conclusions: Overall and regardless of the technique used for the repair of complete AVSD, good early and midterm outcomes were achieved.

Purpose of Review: In the last 40 years, with a better understanding of cardiac defects, and with the improved results of cardiac surgery, the life expectancy of persons with Down syndrome has significantly increased. This review article reports on advances in knowledge of cardiac defects and cardiovascular system of persons with trisomy 21., Recent Findings: New insights into the genetics of this syndrome have improved our understanding of the pathogenetic mechanisms of cardiac defects. Recent changes in neonatal prevalence of Down syndrome suggest a growing number of children with cardiac malformations, in particular with simple types of defects. Ethnic and sex differences of the prevalence of specific types of congenital heart disease (CHD) have also been underlined. A recent study confirmed that subclinical morphologic anomalies are present in children with trisomy 21, also in the absence of cardiac defects, representing an internal stigma of Down syndrome. The results of cardiac surgery are significantly improved in terms of immediate and long-term outcomes, but specific treatments are indicated in relation to pulmonary hypertension. Particular aspects of the cardiovascular system have been described, clarifying a reduced sympathetic response to stress but also a 'protection' from atherosclerosis and arterial hypertension in these patients., Summary: Continuing dedication to clinical and basic research studies is essential to further improve survival and the quality of life from childhood to adulthood of patients with trisomy 21.

Background: The pattern and risk factors for congenital heart diseases (CHD) in children with Down syndrome (DS) vary over time., Objectives: To update knowledge of the prevalence, types, trends and associated factors for CHD in children with DS in the Egyptian Delta., Design: A retrospective hospital record-based descriptive study., Setting: A tertiary care center in Mansoura, Egypt during a period of 14 years from 2003 up to 2016., Patients and Methods: We studied children with genetically proven DS. Relevant sociodemographic factors, medical history, clinical examination, karyotype and echocardiographic data were statistically analyzed., Main Outcome Measures: Prevalence, types and risk factors of CHD in DS., Results: The prevalence of overall, isolated and multiple CHD in 1720 children with DS were 36.9%, 29% and 8%, respectively. Isolated defects accounted for 78.4% of all CHD. Ventricular septal defect, atrioventricular septal defect and atrial septal defect were the most frequent isolated defects. There was a downward trend in the prevalence of overall CHD (from 56.2% to 25.0%) and isolated CHD (from 56.2% to 19.8%). The logistic regression model predicted 65.7% of CHD and revealed that passive maternal smoking, lack of folic acid/multivitamin supplementation and parental consanguinity were the independent predictors of CHD in children with DS with adjusted odds ratios of 1.9, 1.8 and 1.9, respectively., Conclusion: More than one-third of children with DS have CHD with ventricular septal defect, which is the most common. Avoidance of passive maternal smoking and consanguineous marriage together with maternal folic acid supplementation could contribute to further reduction of CHD in children with DS., Limitations: Single-center study and retrospective.

A 4 year-old male presented with effort dyspnea, and was diagnosed as atrioventricular canal defects. This finding was confirmed by open heart surgery, and a congenital double orifice mitral valve was discovered. The septal defect was closed but the double orifice mitral valve was respected because of the absence of hemodynamic disturbance. We report this case with review of literature.

The goal of this study was to identify the contribution of common genetic variants to Down syndrome-associated atrioventricular septal defect, a severe heart abnormality. Compared with the euploid population, infants with Down syndrome, or trisomy 21, have a 2000-fold increased risk of presenting with atrioventricular septal defects. The cause of this increased risk remains elusive. Here we present data from the largest heart study conducted to date on a trisomic background by using a carefully characterized collection of individuals from extreme ends of the phenotypic spectrum. We performed a genome-wide association study using logistic regression analysis on 452 individuals with Down syndrome, consisting of 210 cases with complete atrioventricular septal defects and 242 controls with structurally normal hearts. No individual variant achieved genome-wide significance. We identified four disomic regions (1p36.3, 5p15.31, 8q22.3, and 17q22) and two trisomic regions on chromosome 21 (around PDXK and KCNJ6 genes) that merit further investigation in large replication studies. Our data show that a few common genetic variants of large effect size (odds ratio >2.0) do not account for the elevated risk of Down syndrome-associated atrioventricular septal defects. Instead, multiple variants of low-to-moderate effect sizes may contribute to this elevated risk, highlighting the complex genetic architecture of atrioventricular septal defects even in the highly susceptible Down syndrome population., (Copyright © 2015 Ramachandran et al.)

Cardiac septal overgrowth complicates 10-40% of births from diabetic mothers, but perplexingly hyperglycemia markers during pregnancy are not reliably predictive. We thus tested whether fetal exposure to hyperglycemia is sufficient to induce fetal cardiac septal overgrowth even in the absence of systemic maternal diabetes. To isolate the effects of hyperglycemia, we infused glucose into the blood supply of the left but not right uterine horn in nondiabetic pregnant rats starting on gestational day 19. After 24 h infusion, right-sided fetuses and dams remained euglycemic while left-sided fetuses were moderately hyperglycemic. Echocardiograms in utero demonstrated a thickened cardiac septum among left-sided (glucose-exposed, 0.592 ± 0.016 mm) compared to right-sided (control, 0.482 ± 0.016 mm) fetuses. Myocardial proliferation was increased 1.5 ± 0.2-fold among left-sided compared to right-sided fetuses. Transcriptional markers of glucose-derived anabolism were not different between sides. However, left-sided fetuses exhibited higher serum insulin and greater JNK phosphorylation compared to controls. These results show that hyperglycemic exposure is sufficient to rapidly induce septal overgrowth even in the absence of the myriad other factors of maternal diabetes. This suggests that even transient spikes in glucose may incite cardiac overgrowth, perhaps explaining the poor clinical correlation of septal hypertrophy with chronic hyperglycemia.

Background: Congenital anomalies are a leading cause of infant morbidity and mortality. Studies suggest associations between environmental contaminants and some anomalies, although evidence is limited., Methods: We used data from the California Center of the National Birth Defects Prevention Study and the Children's Health and Air Pollution Study to estimate the odds of 27 congenital heart defects with respect to quartiles of seven ambient air pollutant and traffic exposures in California during the first 2 months of pregnancy, 1997-2006 (n = 822 cases and n = 849 controls)., Results: Particulate matter < 10 microns (PM10 ) was associated with pulmonary valve stenosis [adjusted odds ratio (aOR)Fourth Quartile  = 2.6] [95% confidence intervals (CI) 1.2, 5.7] and perimembranous ventricular septal defects (aORThird Quartile  = 2.1) [95% CI 1.1, 3.9] after adjusting for maternal race/ethnicity, education and multivitamin use. PM2.5 was associated with transposition of the great arteries (aORThird Quartile  = 2.6) [95% CI 1.1, 6.5] and inversely associated with perimembranous ventricular septal defects (aORFourth Quartile  = 0.5) [95% CI 0.2, 0.9]. Secundum atrial septal defects were inversely associated with carbon monoxide (aORFourth Quartile  = 0.4) [95% CI 0.2, 0.8] and PM2.5 (aORFourth Quartile  = 0.5) [95% CI 0.3, 0.8]. Traffic density was associated with muscular ventricular septal defects (aORFourth Quartile  = 3.0) [95% CI 1.2, 7.8] and perimembranous ventricular septal defects (aORThird Quartile  = 2.4) [95% CI 1.3, 4.6], and inversely associated with transposition of the great arteries (aORFourth Quartile  = 0.3) [95% CI 0.1, 0.8]., Conclusions: PM10 and traffic density may contribute to the occurrence of pulmonary valve stenosis and ventricular septal defects, respectively. The results were mixed for other pollutants and had little consistency with previous studies., (© 2013 John Wiley & Sons Ltd.)

Background: Maternal smoking during pregnancy has been consistently associated with an increased risk of congenital heart defects (CHDs). However, few studies have reported the association between paternal smoking during pregnancy and CHDs among offspring. This report presents the first case-control study to investigate the possible association between periconceptional paternal smoking and CHDs in China., Methods: From February 2010 through October 2011, 284 case fetuses with nonsyndromic CHDs and 422 control fetuses with no birth defects were recruited. The mothers of cases and controls were interviewed regarding whether the fathers of fetuses smoked and avoided the mothers while smoking during the periconceptional period. An unconditional logistic regression was used to calculate the adjusted odds ratios (AORs) and 95% confidence intervals (CIs) while controlling for potential confounders., Results: Light paternal smoking increased the risk of isolated conotruncal heart defects (AOR, 2.23; 95% CI, 1.05, 4.73). Medium paternal smoking seemed to be associated with septal defects (AOR, 2.04; 95% CI, 1.05, 3.98) and left ventricular outflow tract obstructions (AOR, 2.48; 95% CI, 1.04, 5.95). Heavy paternal smoking was also associated with isolated conotruncal heart defects (AOR, 8.16; 95% CI, 1.13, 58.84) and left ventricular outflow tract obstructions (AOR, 13.12; 95% CI, 2.55, 67.39). Paternal smoking with no avoidance behavior was associated with an increased risk of these CHDs subtypes., Conclusions: Periconceptional paternal smoking increased the risk of isolated conotruncal heart defects, septal defects and left ventricular outflow tract obstructions. The avoidance behavior of paternal smokers may decrease the risk of selected CHDs., (Copyright © 2013 Wiley Periodicals, Inc.)

Gerbode defect is a rare type of left ventricle to right atrium shunt. It is usually congenital in origin, but acquired cases are also described, mainly following infective endocarditis, valve replacement, trauma or acute myocardial infarction. We report a case of a 50-year-old man who suffered an extensive and complex infective endocarditis involving a bicuspid aortic valve, the mitral-aortic intervalvular fibrosa and the anterior leaflet of the mitral valve. After dual valve replacement and annular reconstruction, a shunt between the left ventricle and the right atrium--Gerbode defect, and a severe leak of the mitral prosthesis were detected. Reintervention was performed with successful shunt closure with an autologous pericardial patch and paravalvular leak correction. No major complications occurred denying the immediate post-surgery period and the follow-up at the first year was uneventful.

Background: Cardiac abnormalities, including atrioventricular (AV) septal defects (AVSDs), are the most common birth defects in diabetic embryopathy. The AV septum is derived from the endocardial cushions, which undergo development and remodeling during septation. The impact of maternal diabetes on these processes needs to be identified. Maternal diabetes disturbs the function of the endoplasmic reticulum (ER). The role of ER stress in cardiac malformation remains to be delineated to gain information for developing therapy., Methods: Female mice were induced diabetic via intravenous injection of streptozotocin. Pregnant mice were made hyperglycemic at desired embryonic (E) days. AVSDs were examined histologically at E15.5. ER stress-associated factors were examined and quantified using immunohistochemical and immunoblot assays at E10.5. The role of ER stress in endocardial cell migration was investigated by treating endocardial cushion explants that were cultured in high glucose with an organic chaperone molecule, sodium 4-phenylbutyrate., Results: The rate of AVSDs in the embryos that were exposed to maternal hyperglycemia during the period of endocardial cushion development was significantly higher than that in those during endocardial cushion remodeling. ER stress was increased in the hearts. Amelioration of ER stress restored endocardial cell migration under hyperglycemic conditions., Conclusions: The development, rather than remodeling, of the endocardial cushions is the cardiomorphogenic process that is susceptible to the insult of maternal hyperglycemia in the formation of AVSDs. Maternal diabetes increases ER stress in the developing heart. ER stress plays an essential role in mediating the effect of hyperglycemia on endocardial cell migration., (© 2011 Wiley-Liss, Inc.)

Very-long-chain acyl-coenzyme A (CoA) dehydrogenase deficiency (VLCADD) (OMIM #201475) is an autosomal recessive disorder of fatty acid oxidation. Major phenotypic expressions are hypoketotic hypoglycemia, hepatomegaly, cardiomyopathy, myopathy, rhabdomyolysis, elevated creatinine kinase, and lipid infiltration of liver and muscle. At the same time, it is a rare cause of Sudden Infant Death Syndrome (SIDS) or unexplained death in the neonatal period [1-4]. We report a patient with VLCADD whose parents were investigated for infanticide because her three previous siblings had suddenly died after normal deliveries., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Situs inversus totalis (SIT) is a congenital disorder characterized by mirror reversal of the thoracic and abdominal organs. The underlying cardiovascular malpositions complicate transseptal catheterization. In the present report, we present the case of a patient with SIT, where access in the morphologic left atrium was gained with conventional fluoroscopic approach without the use of intracardiac imaging modalities.

Infantile spinal muscular atrophy (SMA) caused by homozygous SMN1 gene deletions/mutations is characterized by neuronal loss and axonopathy of motor neurons. We report two unrelated patients with severe SMA type I who had only one SMN2 copy and developed ulcerations and necroses of the fingers and toes. Sural nerve biopsy was normal in patient 1, whose affected skin displayed necroses and thrombotic occlusions of small vessels. Corresponding to a mouse model and other patients with similar findings, we believe that severe survival motor neuron (SMN) deficiency may present as vasculopathy.

Hyaluronan is a major carbohydrate component of the extracellular matrix. Besides its structural role, it also appears to regulate cell transformation and migration during embryogenesis in vertebrates. Hyaluronan is synthesized by hyaluronan synthetases, transmembrane proteins expressed at several embryonic stages, as early as gastrulation. Inactivation or upregulation of hyaluronan synthetases elicits cardiac or skeletal development anomalies (atrioventricular septal defects caused by abnormal endocardial cushion formation, impaired chondrogenesis). Hyaluronidases degrade hyaluronan and interact with cell surface receptors involved in cell activation. Hyluronan binds not only extracellular matrix glycoproteins, but also cell surface receptors (CD44, RHAMM) also involved in cell signalling, differentiation and proliferation pathways. It facilitates migration and transformation and decreases contact inhibition. Hence, hyaluronan has a central regulating role during embryogenesis., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)

Left ventricular (LV) to right atrial (RA) communication, also known as Gerbode defect, is very rare, usually congenital but sometimes also acquired. Cases of Gerbode defect have been reported after left valve surgery, usually valve replacement. We describe the first case of LV-RA communication following a tricuspid annuloplasty not combined to a left valve surgery. The case we report concerns a 73-year-old woman who underwent a double-valve surgery (pulmonary valve replacement and tricuspid annuloplasty) for symptomatic severe right heart failure due to post-endocarditis pulmonary valve regurgitation. A LV-RA shunt was discovered 1 year after surgery. This case report confirms the responsibility of a tricuspid annuloplasty in an acquired LV-RA shunt.

The Gerbode defect is a congenital shunt from the left ventricle to the right atrium. The type I defect (2) results in a direct shunt through a portion of the membranous septum, while a type II (indirect) defect occurs if the membranous septal defect lies below the attachment of the septal leaflet of the tricuspid valve. The shunt is directed towards the right atrium through a cleft or perforations of the septal leaflet. Acquired Gerbode defects have been identified in endocarditis, after mitral or aortic valve surgery, or may be post-traumatic. The case is presented of a 69-year-old woman with a postoperative Gerbode defect in association with aortic prosthetic endocarditis caused by non-typhoid Salmonella.

Trauma inflicted by sharp penetrating objects can cause unusual and complex injuries to the heart. We present a case where penetrating trauma caused an unusual ventricular laceration that filleted the ventricular septum into two separate sections creating an artificial chamber in between. The ventricular septal defect was clearly displayed with echocardiography and required special cardiac surgical intervention.

Objective: We evaluated the prevalence of myocardial perfusion defects using myocardial perfusion imaging (MPI) after chemoradiation or radiation therapy (CRT/RT) in lung cancer patients and described their patterns in relation to tumor location., Methods: MPI in 44 patients who received RT for lung cancer and 44 control patients were compared. The two groups were comparable in risk factors for coronary artery disease. Data regarding tumor stage and location, interval between CRT/RT and MPI, and mean radiation dose to the heart was collected. The level of radiation delivered to the affected segments of the left ventricle versus the normal segments was compared using the isodose lines on the simulation computed tomography., Results: Considering all tumor locations, 8 patients (18%) demonstrated MPI defects after CRT/RT versus 9 (20%) in the controls. However, 7 of 18 patients (39%) with centrally located tumors in the CRT/RT group versus only 1 of 15 patients (7%) in the control group demonstrated MPI defect (p= 0.04). The defects in the CRT/RT group were in the anterior and septal segments while the defects were in different segments in the controls. The median interval between end of RT and MPI was 12.3 months. The affected segments in the CRT/RT group received a mean radiation dose of 39.6 versus 11.4 Gy (p = 0.003) to the normal segments., Conclusions: CRT/RT to centrally located lung tumors tends to cause anterior/septal MPI defects. Abnormal MPI segments in the CRT/RT group have received significantly higher radiation than normal segments.

A 71-year-old woman was admitted for examination of a heart murmur and anemia. She had a history of mitral valve replacement and tricuspid ring annuloplasty 8 months prior to admission. A new systolic murmur was heard, and echocardiography showed a high-velocity jet originating from the left ventricular outflow tract to the right atrium and a small defect between the left ventricle and the right atrium. No periprosthetic leaks were detected in the mitral position. At operation, a communication just beneath the detached prosthetic ring at the anterior-septal commissure of the tricuspid valve, and a jet of bright red blood entering the right atrium through the defect at the atrial septum just cephalad to the commissure, were found. After removing the ring, the defect was closed using a mattress suture. In this case, the tricuspid annuloplasty ring was probably placed on the atrio-ventricular portion of the membranous septum, rather than the tricuspid annulus, at the antero-septal commissure of the tricuspid valve in the previous operation, and its dehiscence may have created a tear in the atrio-ventricular membranous septum, leading to left ventricular-right atrial communication.

Objectives: We evaluated patients who underwent complete or partial surgical correction for atrioventricular septal defect (AVSD) with regard to surgical techniques and early and midterm results., Study Design: Forty-six patients were treated for complete (n=28) or partial (n=18) AVSD between 2000 and 2007. There were nine boys and 19 girls (mean age 5.5 months; range 1.5 to 11 months) with complete AVSD. Of these, 17 patients underwent total repair, while 11 patients underwent palliative procedures. Five males and 13 females (mean age 11 years; range 1 to 50 years) with partial AVSD were treated with total repair. Down syndrome was seen in nine patients (32.1%) and one patient (5.6%) in complete and partial AVSD groups, respectively. Twenty-one patients (75%) and 14 patients (77.8%) could be followed-up for a mean of 26.3 months (range 1-72) and 21.8 months (range 2 to 71) in the two groups, respectively., Results: Total repair of partial AVSD resulted in no mortality or significant morbidity. Early postoperative mortality occurred in three cases (10.7%) after repair of complete AVSD, one of which had Down syndrome. Six patients required prolonged mechanical ventilation beyond one week. Two patients without Down syndrome underwent reoperation due to severe atrioventricular (AV) valve insufficiency in the early postoperative period. None of the patients required permanent pacemaker implantation. Clinical and echocardiographic monitoring showed moderate left AV valve insufficiency in three patients in each group, while the remaining patients had no or minimal insufficiency., Conclusion: Total repair of complete AVSD should be the procedure of choice in early infancy. Left AV valve insufficiency continues to be the most important cause of postoperative morbidity in these cases.

On a first anatomical series of 52 hearts of trisomic 21 fetuses, published in June 2002, we described a new minor cardiac anomaly, belonging to the atrioventricular septal defect, with a linear insertion of the atrioventricular valves without defect. We want to confirm these data, on a larger series of 213 new hearts of trisomic 21 fetuses by adding a complementary section to the standard examination; 100% of controls have shown a normal insertion with an offsetting of the atrioventricular valves. On 113 out of these 213 hearts of trisomic 21 fetuses, with a so called "normal" heart at the standard examination showing no defect, the complementary section has shown that only 37.2% of these hearts have a normal insertion, whereas 62.83% show a linear insertion, without offsetting and without any septal defect. This linear insertion has been observed in all the different types of atrioventricular septal defect as a good hallmark for trisomy 21; but, since then, they have always been described associated with a septal defect, atrial or ventricular. Our hypothesis is that the linear insertion of the atrioventricular valves without defect is the minor form of the atrioventricular septal defect spectrum, taking place between the prior described partial types of atrioventricular septal defect, in which there is always a defect (ostium primum type atrial septal defect or inflow type ventricular septal defect), and the real normal heart. A precise description of the level of the complementary section and of the anatomic peculiarities of the linear insertion of the atrioventricular valves without defect would help its screening in fetal ultrasonography.

Controversy over patients with complete atrioventricular septal defect (CAVSD) and coarctation of the aorta (CoA) continues: whether they should be treated with a primary total correction or a staged approach utilizing initial pulmonary artery banding during neonatal period. A 17-day-old neonate with Down's syndrome underwent definitive repair of CAVSD and CoA. With the postoperative course uneventful, he was discharged from the hospital on 19th postoperative day. Single-stage repair of CAVSD and CoA appears to offer a good prognosis provided that valve morphology is amenable to repair.

Williams syndrome is a genetic disorder associated with characteristic facies, supravalvar aortic stenosis, peripheral pulmonary stenosis, mental retardation, hypertension, premature aging of skin, and congenital cardiac defects. Many cardiac defects such as bicuspid aortic valve, mitral valve regurgitation, coarctation of the aorta, and ventricular or atrial septal defects are linked to the syndrome. Complete atrioventricular septal defect has rarely been associated with Williams syndrome and only one necropsy case has been reported in the literature. The long term follow up of Williams syndrome associated with complete atrioventricular septal defect is reported. During a 10 year follow up period, the pressure gradient in the ascending aorta did not increase despite narrowing of the ascending aorta as identified on an aortogram.

BMP-2 and BMP-4 are known to be involved in the early events which specify the cardiac lineage. Their later patterns of expression in the developing mouse and chick heart, in the myocardium overlying the atrioventricular canal (AV) and outflow tract (OFT) cushions, also suggest that they may play a role in valvoseptal development. In this study, we have used a recombinant retrovirus expressing noggin to inhibit the function of BMP-2/4 in the developing chick heart. This procedure resulted in abnormal development of the OFT and the ventricular septum. A spectrum of abnormalities was seen ranging from common arterial trunk to double outlet right ventricle. In hearts infected with noggin virus, where the neural crest cells have been labelled, the results show that BMP-2/4 function is required for the migration of neural crest cells into the developing OFT to form the aortopulmonary septum. Prior to septation, misexpression of noggin also leads to a decrease in the number of proliferating mesenchymal cells within the proximal cushions of the outflow tract. These results suggest that BMP-2/4 function may mediate several key events during cardiac development., (Copyright 2001 Academic Press.)

The authors describe, in a case report, an isolated defect of the ventricular septum developing due to a stab injury to the heart not requiring an emergency surgical intervention. Two months after the injury, the authors performed primary surgical correction of the defect.

Chemokines and their receptors are important in cell migration during inflammation, in the establishment of functional lymphoid microenvironments, and in organogenesis. The chemokine receptor CXCR4 is broadly expressed in cells of both the immune and the central nervous systems and can mediate migration of resting leukocytes and haematopoietic progenitors in response to its ligand, SDF-1. CXCR4 is also a major receptor for strains of human immunodeficiency virus-1 (HIV-1) that arise during progression to immunodeficiency and AIDS dementia. Here we show that mice lacking CXCR4 exhibit haematopoietic and cardiac defects identical to those of SDF-1-deficient mice, indicating that CXCR4 may be the only receptor for SDF-1. Furthermore, fetal cerebellar development in mutant animals is markedly different from that in wild-type animals, with many proliferating granule cells invading the cerebellar anlage. This is, to our knowledge, the first demonstration of the involvement of a G-protein-coupled chemokine receptor in neuronal cell migration and patterning in the central nervous system. These results may be important for designing strategies to block HIV entry into cells and for understanding mechanisms of pathogenesis in AIDS dementia.

FKBP12, a cis-trans prolyl isomerase that binds the immunosuppressants FK506 and rapamycin, is ubiquitously expressed and interacts with proteins in several intracellular signal transduction systems. Although FKBP12 interacts with the cytoplasmic domains of type I receptors of the transforming growth factor-beta (TGF-beta) superfamily in vitro, the function of FKBP12 in TGF-beta superfamily signalling is controversial. FKBP12 also physically interacts stoichiometrically with multiple intracellular calcium release channels including the tetrameric skeletal muscle ryanodine receptor (RyR1). In contrast, the cardiac ryanodine receptor, RyR2, appears to bind selectively the FKBP12 homologue, FKBP12.6. To define the functions of FKBP12 in vivo, we generated mutant mice deficient in FKBP12 using embryonic stem (ES) cell technology. FKBP12-deficient mice have normal skeletal muscle but have severe dilated cardiomyopathy and ventricular septal defects that mimic a human congenital heart disorder, noncompaction of left ventricular myocardium. About 9% of the mutants exhibit exencephaly secondary to a defect in neural tube closure. Physiological studies demonstrate that FKBP12 is dispensable for TGF-beta-mediated signalling, but modulates the calcium release activity of both skeletal and cardiac ryanodine receptors.

Objective: To describe a modification of a surgical technique for relief of subaortic stenosis in patients with atrioventricular canal., Material and Methods: We report an etiology-oriented modified technique of repair of subaortic stenosis after previous repair of atrioventricular canal, without (N = 2) or with (N = 1) a restrictive interventricular communication., Results: In addition to a generous myectomy of the left ventricular septum, the technique consists of complete detachment of the left and right atrioventricular valves from the ventricular crest, patch augmentation of the concavity of the ventricular crest, and attachment of both atrioventricular valves at the superior aspect of the ventricular septal patch; thus, the septal leaflet of the left atrioventricular valve--in particular, its superior component--is lifted away from the elongated left ventricular outflow tract., Conclusion: This modification (as opposed to detachment of only the superior component of the septal leaflet of the left atrioventricular valve, as performed in previously proposed techniques) may be a valuable adjunctive technique to relieve subaortic obstruction associated with atrioventricular canal. In addition, this modification allows a secure anchoring of the patch to the right of the ventricular septum and therefore is associated with minimal risk of damaging the conduction tissue and of causing regurgitation of the left atrioventricular valve.

The association of tuberous sclerosis with Down syndrome is exceedingly rare. An infant with this unusual association is reported with a description of brain and ocular abnormalities which were referable to both conditions. There was anteroposterior foreshortening of the brain and Brushfield spots in the iris, which are described in Down syndrome. The infant, who suffered from a seizure disorder, manifested multiple tubers and subependymal candle gutterings in the brain as well as bilateral retinal astrocytic hamartomas.

A case of massive pulmonary embolism resulting in marked pulmonary to systemic shunting in a patient with a previously clinically inapparent ventricular or atrial septal defect is presented. The various types of unrecognized intracardiac shunts and their prevalence in the adult population are discussed.

Objective: Our purpose was to determine the incidence of cardiac septal defects in fetuses with trisomy 21 diagnosed by increased nuchal translucency thickness at 10 to 13 weeks' gestation., Study Design: Pathologic examination of the fetal heart was performed in 36 fetuses with trisomy 21 after suction termination of pregnancy at 12 to 15 weeks' gestation. The diagnosis of trisomy 21 was made by chorion villus sampling because of increased (> or = 3 mm) fetal nuchal translucency thickness detected at routine first-trimester ultrasonographic examination., Results: Perimembranous ventricular and atrioventricular septal defects were detected in 20 of 36 fetal hearts. A septal defect was observed in 1 of the 11 fetuses with nuchal translucency thickness of 3 mm and in 19 of the 25 with translucency > or = 4 mm (p < 0.001)., Conclusion: The incidence of ventricular and atrioventricular septal defects is much higher in fetuses with trisomy 21 and increased nuchal translucency thickness at 10 to 13 weeks' gestation than in live-born infants with this chromosomal abnormality. The incidence of cardiac septal defects increases with nuchal translucency thickness.

Left ventricular-right atrial communication may be a congenital defect or can result from trauma, endocarditis, or valve replacement. Traditionally the preoperative diagnosis of this entity was made during cardiac catheterization, but recent advances in echocardiography, particularly color Doppler imaging, have greatly facilitated the noninvasive diagnosis of left ventricular-right atrial communication. We present four cases of left ventricular-right atrial communication, each identified by two-dimensional and color Doppler imaging. One case is a congenital defect, two were identified years after cardiac surgery, and one presents as an unusual complication of myocardial infarction. Optimal views for identifying this defect are discussed along with clues to quantifying its hemodynamic significance.

Children with phenylketonuria (PKU) detected in the neonatal period and who have received the appropriate diet develop normally whatever their sex. However, female PKU patients who, before becoming pregnant, do not take the precaution to follow a diet bringing phenylalanine to "normal levels" (2 to 5 mg in 100 ml of blood) give birth to children presenting with severe embryofoetal damage (e.g. intrauterine growth retardation, microcephaly, mental retardation, various malformations) directly due to their hyperphenylalaninaemia (20 mg or more in 100 ml of blood under a free diet). It is important to know these facts, since the benefits of systematic neonatal PKU detection may be cancelled by this late complication. The therapeutic approach in such cases is a follows: 1. Young women with known PKU must be informed of this risk and how it can be avoided by a preconception therapeutic diet. This means that they must permanently reside in the same geographical area, receive an adequate information at the end of puberty, use and effective contraception method and program their pregnancies preceded by a return to low phenylalanine diet. 2. Doctors must remember that because PKU detection has not become systematic until 1978, PKU girls of child-bearing are remain undetected, that they are not always mentally debilitated and can normally five birth to children with embryofoetal damage. In case of e.g. unexplained intrauterine growth retardation or microcephaly, it is necessary to perform a Guthrie test on the woman, since a prenatal diagnosis may lead to therapeutic abortion, and a postnatal diagnosis to a genetic counselling which will avoid recurrences.(ABSTRACT TRUNCATED AT 250 WORDS)

Microbiological and morphological methods were used to study abnormalities in the greater microcirculation in acyanotic heart disease. The bulbar conjunctiva (patients), greater omentum and cardiac serous membranes (autopsy material) were used as test objects. The most marked changes were revealed in the metabolic link of the microcirculatory system. They were characterized by progressive reduction in intrinsic capillaries and an increase in the modulus of microcirculation of microvessels (capillaries) of the great (exchange-shunting) type. The alternations in the structure of the microcirculatory system were accompanied by centralization of tissue blood flow and its decreased metabolic efficiency, which were clinically manifested by tissue capillary trophic tissue failure with the occurrence of a number of severe common symptoms of the disease and various organ lesions in children. Analyzing the results of the study enabled the author to be the first to reveal in the above cardiac pathology specific tissue blood circulatory disorders which are interpreted as a phenomenon of centralized microhemodynamics. The important results of the study is also the morphofunctional rationale for the concept "capillary trophic incompetence".

We have investigated the reasons why female patients with Down's syndrome prevail in our out-patient clinic for Paediatric Cardiology compared to the higher incidence of Down's syndrome among live born male children. We reviewed 277 cases of Down's syndrome, 119 males (42.96%) and 158 females (57.04%) from 1970 to 1987. A final diagnosis of the type of the congenital heart disease was accomplished among 210 cases, 85 males (40.47%) and 125 females (59.38%). This different distribution between the sexes was significant (P less than 0.01) when compared to that of the general population with congenital heart disease (4150 patients, 2108 males and 2042 females). The dominant lesion was atrioventricular septal defect, (130 cases; 46 males [54.11%] and 84 females [67.20%]). We found an identical incidence of this lesion among patients without Down's syndrome. In the studied population, we did not find any of the congenital heart diseases usually prevalent in males, such as aortic coarctation or stenosis and complete transposition. The molecular determinants of Down's syndrome seem to influence the preponderance of atrioventricular septal defect in females, increasing its incidence, while seeming to act in a negative way concerning congenital heart diseases usually showing male prevalence.

Foetal macrosomia is arbitrarily defined as an excessive weight for the gestational age, was found to be present in 36 p. 100 of 43 diabetic pregnancies. This finding may indicate incomplete normalization of maternal metabolic control despite the use of new forms of insulin delivery systems, such as insulin pumps. However, in our series the macrosomia was usually moderate and without consequences on the foetal outcome. The levels of insulin, but not those of the insulin-like growth factor (IgF1), were increased in the umbilical cord blood of macrosomic newborns of diabetic mothers. Cardiac septum hypertrophy correlated with maternal glycosylated haemoglobin levels better than with macrosomia. We therefore suggest that in all diabetic pregnancies the cardiac septum thickness should be measured in utero by sonocardiography.

Echocardiography was used to determine the incidence and severity of cardiac lesions in 20 patients with progressive systemic sclerosis. Abnormal findings were recorded in 14 (70%) patients. These included pericardial effusion in five, increased right ventricular diameter in five, increased left ventricular posterior wall thickness in four with no systemic hypertension, decreased diastolic closure of anterior mitral leaflet in five, and abnormal septal features in four patients. Dilatation of aortic root was found in two patients and moderated thickening of the anterior mitral valve in one patient. Clinical evidence of scleroderma heart was found in one of the 20 patients. Abnormal ECG changes were found in 12 (60%) of the patients. These included LVH, simulating MI pattern, conduction disturbances and P wave changes. Echocardiography proved to be an important non-invasive diagnostic tool which decreases the discrepancy between the relatively few clinical findings and rich cardiac pathology. Furthermore, this study confirms the usefulness of the method in the evaluation of the "asymptomatic" cardiac patient.

The destructive intracardiac complications of infective endocarditis present a continuing problem even though the mortality from the disease is decreasing. Osler in 1885 correctly described it as a malignant process. Tissue necrosis secondary to infection can cause destruction of valve leaflets and abscess formation in the valve annulus; the process may extend into adjacent parts of the heart and may even perforate into the pericardial cavity. For surgery to succeed it is necessary to excise all necrotic tissue, to replace the valve, and repair annular or other defects and suture the prosthesis to healthy tissue. The technical considerations in achieving a successful surgical result are illustrated and discussed in relation to a patient suffering from severe aortic valve regurgitation and a ventricular septal defect due to active infective endocarditis.

Up to 50% of the neonates operated during the first hours of life for a congenital diaphragmatic hernia die. The presence of a severe lung hypoplasia, which is at the origin of hypoxia, acidosis, increased pulmonary vascular resistance and right to left shunt, explains the poor clinical results, in spite of surgical success and intensive therapy. A modern approach to the problem includes treatment with pulmonary vasodilator drugs, whose effects are still discussed. Perhaps the prenatal recognition of the defect could improve prognosis. Lots of experience are needed to know more on the subject. This could be obtained with an experimental approach on newborn animals with a CDH. The article relates authors experience in the creation of a CDH in a foetus of sheep, by means of a surgical intervention during its intrauterine life.

Left ventricular to right atrial (LV-RA) communications are rare septal defects. The majority of them are congenital in origin and acquired defects are exceedingly rare. The causes of acquired LV-RA communications include chest trauma, infective endocarditis, and valvar replacement. This report describes a case of direct LV-RA and interventricular communications occurring three months after excision of a subaortic shelf.