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PubMed2026

PIP3 antagonist as a molecular regulator in MSC-derived cardiomyocytes: Potential in vitro therapeutic implications for conotruncal heart defects.

Conotruncal heart defects (CTDs) account for approximately one-third of all congenital heart defects. Elevated levels of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) may contribute to CTD pathogenesis. PIP3 plays a pivotal role in mechanotransduction-based biological processes and remodeling of cardiac cytoskeletal proteins. Here, we aimed to evaluate the efficacy of the 322PESB derivative compound as a molecular regulator that antagonizes PIP3 binding pleckstrin homology (PH) domain of the Akt protein using mesenchymal stem cell-derived cardiomyocyte. Human adipose-derived MSCs (Ad-MSCs) were isolated. Immunophenotypic features of the hAd-MSCs were characterized according to minimal criteria of the international society for cellular therapy (ISCT) including immunophenotyping and trilineage differentiation potential. Subsequently, the differentiated hAd-MSCs were cultured in cardiomyogenesis-inducing medium. Successfully differentiated cardiomyocytes were assessed by measuring the expression levels of cardiomyocyte-specific genes using RT-qPCR. PIP3-primed cardiomyocytes were treated with 10 and 30 μmol/L of a 322PESB derivative molecule. The results showed a typical MSCs with high expression levels of CD73 (77.55%), CD90 (87.59%) and CD105 (91.88%) and that was accompanied by low expression levels of CD34 (0.59%) and CD45 (1.78%). After 21 days of MSC culture, cardiomyocyte-like cells with prominent striations were observed. Subsequent confirmation by RT-qPCR quantification of ADRB1 and MLC2a expression levels showed an average increase of 2.9-fold and 2.1-fold, respectively, in induced cardiomyocytes. Compared with the untreated control, PIP3 ELISA assay showed a significant increase in PIP3 levels in PIP3(10 nmol/L)-primed cardiomyocytes treated with 10 and 30 μmol/L of the 322PESB molecule derivative by 485.804 and 3564.164 ng/mL, respectively. In this study, we conducted the first promising molecular regulator with potential therapeutic implications for CTD patients. Further functional animal model and clinical phase studies are recommended.

Cardiomyocyte↗
PubMed1979

Conotruncal malformation complex: examples of possible monogenic inheritance.

Two families are described in which there is possible monogenic inheritance of congenital cardiac defects within the spectrum of faulty conotruncal septation (CTS). Evidence for a genetic control of conotruncal septation arises from genetic and embryologic studies of similar defects in the Keeshond dog model, the excess of sibship pairs with conotruncal septation defects in sibship pairs with congenital heart diseases, and previously reported pedigrees of families with multiple affected individuals with conotruncal septation defects. It is suggested that in the small number of cases of congenital cardiac defects in which there is a strong family history for CTS defects, a higher recurrence risk should be considered rather than the usual polygenic recurrence risk of 3% that is usually given in such situations.

Adult↗
PubMed1979

[Angiocardiography in the diagnosis of congenital bulboventricular heart defects. Anatomopathological and angiocardiographic correlations].

Current surgical methods enable radical treatment of the most bulboventricular malformations (syn. conotruncal malformations, transposition complex). The defects, which were until now the field of embryologist and pathologist, require accurate and precise clinical diagnosis of the anomaly. The purpose of this analysis was to estimate the ability of angiocardiography for diagnosis of bulboventricular malformations considering the type of essential anomaly, its exact morphology and character of coexisting malformations. The report represents 49 cases with pathological diagnosis of bulboventricular malformations in children, in which during hospitalization angiocardiography has been performed. The cases were selected from 1918 angiocardiographies and also from 987 cases of pathological specimens with congenital heart diseases in the years 1970-1977. There were: 33 cases of TGA, in these 2 with corrected TGA, 3 cases of DORV, 1 case of DOLV , 12 cases of CV. All cases showed the broad spectrum of variants in position of the great arteries and kind of conus apart from type of basic anomaly. Septal defects, pulmonary orifice stenosis or atresia and anomalies of atrio-ventricular orifices particularly in common ventricle were mostly coexisting malformations. To recognize essential anomaly we estimated atrio-ventricular and ventriculo-arterial relation (connection), based on Kirklin classification. The conuses and position of the trunk of the great arteries were treated as pathomorphologic details, that had no influence on essential diagnosis of malformation. Arbitrary accepted definition and nomenclature was based on data from bibliography. Angiocardiography was made using full-size filmchanger AOT with maximal frequency 6 frames/sec. Contrast medium injected mainly into the ventricles. X-rays were performed usually immediately in two projections. Comparison of the angiocardiographic diagnosis with pathology of the hearts showed the correct diagnosis of the essential malformation, by means of angiocardiography, in more than 80% cases. But the diagnosis percentage in particular elements of malformation varied from 2/3 to 1/3 according to the type of malformation. The absence of the correct diagnosis of the essential anomaly, based on type of relations, was the lack of visualization of all heart cavities (in some cases), which was conditioned by the method. On the other hand the correct angiocardiographic diagnosis was sometimes impossible, because of very complicated anatomical situation in malformed hearts.(ABSTRACT TRUNCATED AT 400 WORDS)

Angiocardiography↗
PubMed1978

Aortic aneurysm associated with cardiac defects in theophyline stimulated chick embryos.

Theophylline(1 ml 0.02 M in 0.15 M saline) was administered to embryonic chicks (Hamburger-Hamilton developmental stages 24.27). The drug was topically applied to the surface of the chorioallantoic membrane in the vicinity of the embryonic heart. At necropsy, 63% (44/70) of the theophylline-exposed embryos demonstrated an aneurysm in the ascending aorta. Among the cases exhibiting aortic aneurysm, 48% (21/44) of the embryos demonstrated ventricular septal defects. Four cases of truncus arteriosus were also observed. The morphogenesis and mechanism of theophylline-induced cardiac defects with accompanying aortic aneurysm may be related to the development of the conotruncal region of the heart.

Animals↗
PubMed1979

Complete atrioventricular canal associated with conotruncal malformations: anatomical observations in 13 specimens.

Conotruncal anomalies associated with atrioventricular (AV) canal defects are more common than is generally appreciated on clinical grounds. Among 39 specimens of AV canal malformations, 13 (33%) presented with conotruncal abnormalities: a complete form of AV canal has been observed in all. 5 cases exhibited visceral situs solitus, 5 situs ambiguus with asplenia and 3 situs ambiguus with polysplenia. In the first group, conotruncal anomalies were tetralogy of Fallot in 3 cases, bilateral conus with double outlet right ventricle (DORV) in 2, one with subpulmonary ventricular septal defect (VSD) and the other with doubly commited VSD. Survival in these patients was relatively longer (average 20 mth) and the clinical course was mainly determined by the degree of the pulmonary outflow obstruction: surgical correction should have been feasible in these cases. Patients with situs ambiguus, both with asplenia and polysplenia, had further severe cardiovascular malformations associated with AV canal which led to early death (average survival 12 days): anomalous pulmonary and systemic venous return and univentricular hearts. In the latter patients, tetralogy of Fallot, bilateral conus with DORV and pulmonary atresia were the conotruncal malformation. Retrospectively, in no case of the last category a complete repair had been accomplished. All but one specimen presented the complete form of AV canal with 'free floating anterior leaflet' and hypoplastic anterior tricuspid component. This hypoplasia could be interpreted as missing conal tissue in the development of the anterior tricuspid cusp. For this leaflet a dual embryological origin, both from the dextro-dorsal conal ridge and the right lateral AV cushion, is suggested.

Abnormalities, Multiple↗
PubMed1979

Juxtaposition of the atrial appendages.

Juxtaposition of the atrial appendages is a rare congenital cardiac anomaly almost universally associated with severe conotruncal abnormalities, especially transposition of the aorta. This presentation describes a case of right sided juxtaposition of the atrial appendages without concomitant conotruncal malformations. This finding contradicts previous hypotheses concerning the genesis of juxtaposition.

Ductus Arteriosus, Patent↗
PubMedDate not supplied

The syndrome of absent pulmonary valve and ventricular septal defect--anatomical features and embryological implications.

Four cases of absent pulmonary valve in combination with ventricular septal defect are reported. In this syndrome hypo- and dysplasia of the pulmonary valve is constantly associated with a big ventricular septal defect, formation of a huge pulmonary artery aneurysm and absence of the ductus arteriosus. Presence or absence of a right ventricular outflow tract obstruction is the criteria for classification into two forms. Absence of the pulmonary valve, right ventricular outflow tract obstruction and a malalignment-type ventricular septal defect produced by a conotruncal malseptation process represent the primary complex of malformations. Consecutive intrauterine cardiac failure is most probably prevented by prenatal closure of the ductus arteriosus. Pulmonary artery aneurysm and also dilatation of the right ventricular outflow tract as well as a whole lot of other coexisting deformities can be explained by a cascade of hemodynamical sequelae started by this ductus closure in utero. An embryological scheme explaining the genesis of this syndrome is derived from a morphological analysis of the constituting incoherent-appearing anatomical features.

Angiocardiography↗
PubMed1978

The straddling mitral valve: morphological observations and clinical implications.

The morphological features of 23 patients with straddling or overriding mitral valve are presented. Levocardia was present in 20 of 23; visceroatrial situs solitisu in 20 of 23, with 3 patients, 2 with asplenia and 1 with polysplenia, having visceral heterotaxia. A concordant D-ventricular loop was present in the 20 patients with visceroatrial situs solitus. Six of these had double outlet right ventricle; 2 had asplenia syndrome; 1 had D-transposition of the great arteries, ventricular defect and pulmonary atresia; 1 with tricuspid atresia and double outlet-outlet chamber; 1 with polysplenia syndrome; and 12 had endocardial cushion defect with marked underdevelopment of the left ventricle, and normally related great arteries. Left ventricular size was related to the amount of mitral valve (or left-sided component of a common atrioventricular valve) connected to it. In those patients in whom little effective mitral orifice was connected to the left ventricle, the left ventricle was diminutive. Endocardial fibroelastosis of the left ventricle was noted in only a single patient. Six of the 7 patients with double outlet right ventricle (including one with double outlet bulbus) had subpulmonary obstruction, and in one of these, this was related in part to the straddling mitral valve. In 1 patient with double outlet right ventricle, there was a double orifice mitral valve, and it was the accessory mitral orifice that straddled. The diagnosis of overriding mitral valve should be suspected in any patient with significant conotruncal anomalies and underdeveloped left ventricle, especially the patient with double outlet right ventricle, and in the patient with endocardial cushion defect, hypoplasia of the left ventricle, and obstructive anomalies of the aortic arch. In certain patients, selective left atriography, left ventriculography, and single and two dimensional echocardiography may be diagnostic of this condition.

Abnormalities, Multiple↗
PubMed1979

The spectrum of anomalies of aortopulmonary septation.

Embryologically related defects resulting from abnormal septation of the aortopulmonary trunk in 13 patients were reviewed and grouped according to a new classification system. Seven patients (54 percent) had typical aortopulmonary septal defects or windows (Type I), three (23 percent) had a more cephalad defect between the ascending aorta and the origin of the right pulmonary artery (Type II), and three (23 percent) had anomalous origin of the right pulmonary artery from the ascending aorta (Type III). Type I defects are caused by incomplete septation of the aortopulmonary trunk; Type II and III defects result from unequal partitioning of the aortopulmonary trunk by the conotruncal ridges. Three of six patients survived correction of Type I defects; both patients having correlation of Type II defects and all three patients with Type III defects survived and remain well 2 to 216 months (mean 61 months) postoperatively. The recommended technique for Type I and II defects is transaortic closure of the defect by prosthetic patch with the aid of cardiopulmonary bypass, supplemented by profound hypothermia (20 degrees C.), and circulatory arrest for improved exposure in selected cases. For Type III defects, division of the anomalous connection plus direct implantation of the right pulmonary artery into the main pulmonary artery is the preferred approach.

Angiocardiography↗
PubMed2026

Clinical and Functional Characterization of Gain-of-Function ABL1 Variants Expands the Phenotypic Spectrum of CHDSKM.

Germline gain-of-function (GOF) variants in ABL1 cause congenital heart defects and skeletal malformations syndrome (CHDSKM), a multisystem developmental disorder characterized by congenital heart disease, skeletal abnormalities, dysmorphic features, and variable developmental delay. More recently, biallelic loss-of-function variants and ABL haploinsufficiency have been associated with distinct phenotypes, expanding the allelic spectrum of ABL1-related disorders. We report three individuals with ABL1 variants. A female infant with tetralogy of Fallot, critical pulmonary stenosis, covered omphalocele, and a lethal outcome was found by rapid trio genome sequencing to harbor a de novo likely pathogenic ABL1 variant, NM_007313.2:c.354G>T p.(Trp118Cys). We also provide updated clinical follow-up of a previously reported individual and describe a third individual, both carrying the recurrent p.(Tyr245Cys) variant. Functional studies were performed and support a GOF mechanism. Similar activation was observed for Tyr245Cys despite the differences in clinical severity. Our findings expand the phenotypic spectrum of ABL1-related CHDSKM to include severe conotruncal heart disease and covered omphalocele. The comparison of two biochemically activating ABL1 variants demonstrates substantial clinical variability despite a shared molecular mechanism. Furthermore, the overlap between ventral body wall abnormalities in GOF disease and omphalocele associated with ABL1 haploinsufficiency suggests that precise regulation of ABL1 signaling is critical for normal ventral body wall formation.

ABL1↗