Atrioventricular Valve Anomalies Research Articles

Identifying pathogenic variants in the Follistatin-like 1 gene (FSTL1) in patients with skeletal and atrioventricular valve disorders.

BackgroundFollistatin‐like 1 (Fstl1) is a glycoprotein expressed throughout embryonic development. Homozygous loss of Fstl1 in mice results in skeletal and respiratory defects, leading to neonatal death due to a collapse of the trachea. Furthermore, Fstl1 conditional deletion from the endocardial/endothelial lineage results in postnatal death due to heart failure and profound atrioventricular valve defects. Here, we investigated patients with phenotypes similar to the phenotypes observed in the transgenic mice, for variants in FSTL1.MethodsIn total, 69 genetically unresolved patients were selected with the following phenotypes: campomelic dysplasia (12), small patella syndrome (2), BILU (1), and congenital heart disease patients (54), of which 16 also had kyphoscoliosis, and 38 had valve abnormalities as their main diagnosis. Using qPCR, none of 69 patients showed copy number variations in FSTL1. The entire gene body, including microRNA‐198 and three validated microRNA‐binding sites, were analyzed using Sanger sequencing.ResultsNo variants were found in the coding region. However, 8 intronic variants were identified that differed significantly in their minor allele frequency compared to controls. Variant rs2272515 was found to significantly correlate (p < 0.05) with kyphoscoliosis.ConclusionWe conclude that pathogenic variants in FSTL1 are unlikely to be responsible for skeletal or atrioventricular valve anomalies in humans.

Left ventricular apical hypoplasia: a case series and review of the literature

Left ventricular apical hypoplasia (LVAH) is a rare and newly characterized cardiomyopathy. No systemic and detailed case series were reported earlier. We report fi ve patients diagnosed with left ventricular apical hypoplasia at our institute from 2004 to 2011. All the cases underwent clinical examination, eletrocardiography, chest X-ray, transthoracic echocardiography (TTE), and cardiac magnetic resonance imaging (CMRI). We described the clinical presentations, summarized the imaging characteristics of LV apical hypoplasia, and described the associated cardiac malformations. LVAH is characterized by a truncated, spherical left ventricle, without a normal apex; the true apex is occupied by the right ventricle. In addition, the atrioventricular valve anomalies, LV papillary muscle displacement, interventricular and/or interatrial septal bulge aneurysms and patent ductus arteriosus structures coexisted in these patients. LV apical hypoplasia has distinct appearances that can be easily identifi ed on TTE and CMRI. TTE also could accurately defi ne the associated cardiac abnormalities.

Abstract 19140: Targeted Disruption of Endothelial Specific Molecule (ESM)-1 Results in Atrioventricular Valve Malformations Leading to Cardiac Dysfunction

Background: Endothelial cell specific molecule-1 (ESM-1) or Endocan is a circulating dermatan sulphate proteoglycan secreted primarily by the vascular endothelium. Elevated levels of ESM-1 are observed in the plasma of patients during tumor progression and in inflammatory disorders like sepsis suggesting that it could be potential biomarker for endothelial activation or dysfunction. To date there have been no in vivo studies of ESM-1. In this study we investigated the in vivo functional role of ESM-1 by the targeted deletion of the gene in mice. Methods and Results: To determine the critical functions of ESM-1 in vivo, we generated a global ESM-1 knockout mouse by deletion of exon1 of the ESM-1 mouse gene. ESM-1 knockout mice were born at the normal Mendelian ratio but showed 50% perinatal mortality by postnatal day 3 (P3). Pathological analysis of mice that died at P2 revealed dilated atria engorged with blood and thrombi indicative of possible defect in cardiac contractility. Pulmonary and liver congestion were also observed in ESM-1 knockout mice. Furthermore, histopathological studies revealed structural abnormalities in atrioventricular valves (AV) with an ebstenoid tricuspid malformation and parachute mitral valve abnormality suggesting AV valve regurgitation in ESM-1 knockout mice. In contrast, the semilunar valves appeared normal. Fetal genes associated with cardiac stress response including atrial natriuretic peptide (Nppa), brain natriuretic pepetide (Nppb) and beta-myosin heavy chain (Myh7) were significantly up regulated in ESM1 knockout P2 hearts compared to controls. Conclusion: In conclusion, our findings demonstrate for the first time that targeted disruption of ESM-1 results in atrioventricular valve anomalies leading to cardiac dysfuction. Understanding the mechanisms and signaling networks through which ESM-1 regulates valve formation has implications in the field of congenital heart disease research

Real-Time 3-Dimensional Transesophageal Echocardiography of the Atrioventricular Septal Defect

Being able to view the morphological details of the heart malformation in any patient with the diagnosis of atrioventricular septal defect (AVSD) is invaluable in surgical planning, especially in the current era of modified 1-patch versus 2-patch techniques. Real-time 3-dimensional transesophageal echocardiography (RT 3D TEE) is a recently developed technique that allows real-time high-quality images akin to viewing the heart specimen. We present the principal pathomorphological features of AVSD as visualized by RT 3D TEE. The hallmark of AVSD is a common atrioventricular junction guarded by a common atrioventricular valve.1 In the normal heart, when seen from atrial perspective, the aortic valve is wedged between the mitral and tricuspid valve. In AVSD, because of the common AV junction, the aortic valve is in an “unwedged” position (Figure 1). The valve consists of 5 leaflets: the superior and inferior bridging leaflets, each of which overrides the ventricular septum, a left mural leaflet, a right anterior, and a right inferior leaflet (Figure 2). Whether the bridging leaflets are joined together distinguishes the complete form from the partial form. In partial AVSD (also termed “ostium primum ASD”), a tongue of leaflet tissue connects the bridging leaflets and the undersides of these leaflets …

The presence of Down syndrome is not a risk factor in complete atrioventricular septal defect repair

Down syndrome is frequently associated with complete atrioventricular septal defect. The aim of this retrospective study was to evaluate the impact of Down syndrome on morphologic features, surgical management, and perioperative and long-term mortality in patients with complete atrioventricular septal defect. Between October 1974 and March 2005, 476 patients with complete atrioventricular septal defect underwent surgery, 341 (71.6%) of whom had Down syndrome. A total of 336 patients (70.6%) underwent primary repair, 95 patients (20%) underwent palliative surgery on an average of 3.4 +/- 2.9 years before repair, and 45 patients (9.4%) had no subsequent repair. Patients with Down syndrome (group D) exhibited higher preoperative pulmonary artery pressure (P = .012) and resistance (P = .006) compared with patients without Down syndrome (group ND). Rastelli types B and C were more frequent in group D (P = .002), but left atrioventricular valve anomalies were more frequent in group ND (P = .03). No difference was seen regarding operative strategy (P = .117) and timing of repair (P = .32). Thirty-day mortality after complete atrioventricular septal defect repair was 4.9% in group D compared with 5.6% in group ND. Actuarial survival after 20 years is 84% +/- 2.5% (group D) and 75% +/- 5.7% (group ND) (P = .252), and freedom from left atrioventricular valve-related reoperation is 82% +/- 2.9% (group D) and 72% +/- 5.3% (group ND) (P = .004). Reinterventions on the left atrioventricular valve were required significantly more often in patients in group ND. The presence of Down syndrome in patients with complete atrioventricular septal defect is not a risk factor for surgical repair. Because of the early development of pulmonary vascular disease, primary repair should be performed within the first 6 months of life. In the long term, reintervention on the left atrioventricular valve is more often required in children with a normal chromosomal pattern.

Targeted disruption of hesr2 results in atrioventricular valve anomalies that lead to heart dysfunction.

Genes involved in the Notch signaling pathway have been shown to be critical regulators of cardiovascular development. In vitro studies have revealed that the Notch signaling pathway directly regulates transcription of hairy and enhancer of split-related (hesr) genes, encoding basic helix-loop-helix transcription factors. To assess the functional role of hesr genes in cardiovascular development, we generated mice with a targeted disruption of the hesr2 gene and used echocardiography to analyze heart function of the mutant mice. In the early postnatal period, a majority of hesr2 homozygous mice die as a result of congestive heart failure accompanied by pronounced heart enlargement. Transthoracic echocardiography on 5-day-old homozygous mice revealed tricuspid and mitral valve regurgitation and a dilated left ventricular chamber with markedly diminished fractional shortening of the left ventricle. The hemodynamic anomalies were accompanied by morphological changes, such as dysplastic atrioventricular (AV) valves, a perimembranous ventricular septal defect, and a secundum atrial septal defect. AV valve regurgitations attributable to dysplasia of the AV valves were most likely responsible for the heart dysfunction in hesr2 homozygous mice. These observations indicate that the Notch signaling target hesr2 plays an important role in the formation and function of the AV valves. In addition, hesr2 activity may be important for proper development of cardiomyocytes, thereby assuring normal left ventricular contractility. Because of the unique spectrum of cardiac anomalies expressed by hesr2-null mice, they represent a useful model system for elucidating the genetic basis of heart dysfunction.

Criss-cross con discordancia auriculoventricular, acabalgamiento de la válvula auriculoventricular derecha, doble salida del ventrículo derecho y preexcitación

We report the case of a newborn with cyanosis, dyspnea, and supraventricular tachycardia due to reentry with good response to medical therapy. The diagnosis was made by echocardiography. The patient died suddenly at 6 days of follow-up. Necropsy confirmed the following anomaly: criss-cross heart with straddling right atrioventricular valve, and left atrioventricular valve stenosis connected to the anterior trabeculated ventricle giving rise to the pulmonary artery and aorta.Precocious rotation when septal closure is not concluded favors atrioventricular valve anomalies and rhythm disorders.

Correction of complete atrioventricular septal defects with the double-patch technique and cleft closure

Controversy continues to surround determining which is the most beneficial method of complete atrioventricular septal defect repair, eg, one- versus two-patch repair, closure of mitral cleft, and the necessity of annuloplasty. Between January 1988 and November 1995, 120 patients with complete atrioventricular septal defect underwent total correction at the German Heart Institute Berlin. Sixty-nine of the patients were infants and 51 were children or adolescents. Eleven patients had previously undergone pulmonary artery banding. One hundred three patients had Down's syndrome. In all 120 patients complete atrioventricular septal defect repair was performed using the two-patch technique. The mitral cleft was closed with interrupted sutures in 119 cases. Thirty-four patients required aggressive treatment of postoperative pulmonary hypertensive crises (including nitric oxide inhalation). There were 12 hospital deaths (10%). Mortality was highest in patients with persistently high postoperative pulmonary arterial pressure (pulmonary artery pressure/systemic artery pressure > 0.6) (7 of 17 patients died; 41%). Associated atrioventricular valve anomalies, especially dysplastic valve tissue and severe preoperative cardiopulmonary instability necessitating catecholamine support and artificial ventilation, represented other risk factors. There were six late deaths (5%); cumulative mortality was 15%. Four patients suffered a complete heart block and sick sinus node syndrome necessitating pacemaker implantation 1 to 6 months after operation. During the follow-up period (3 to 80 months after operation), 7 patients (6.8% of survivors) were successfully reoperated on after significant mitral valve incompetence due to an open "cleft" (suture failure) developed. Correcting complete atrioventricular septal defect using the two-patch technique, routine cleft closure, and atrial septal incision led to a low incidence of residual mitral valve incompetence. Mortality was primarily influenced by severe cardiopulmonary instability and additional atrioventricular valve anomalies preoperatively and the persistence of high pulmonary arterial hypertension postoperatively.

Cardiovascular anomalies produced by nimustine hydrochloride in the rat fetus.

The cardiovascular teratogenicity of nimustine hydrochloride (ACNU) was studied in rat fetuses. This drug is a nitrosourea derivative anticancer agent and produces alkylation of DNA. Pregnant Donryu rats were treated with single doses of 10, 11 or 13 mg/kg of the teratogen at various stages during gestation. Examination of the hearts was performed by microdissection after sacrificing the animals on the 20th day of gestation. The highest frequency of cardiovascular anomalies was found in the groups treated on the 8th day of gestation, but there was no difference in the rates induced by the three dosages of ACNU administered. The most common cardiovascular anomalies observed were ventricular septal defect (76.8%) and double outlet right ventricle (10.3%). A considerable number of affected fetuses (37/263) showed complex cardiac anomalies with atrioventricular (AV) malalignment and other AV valve anomalies. These anomalies include: double inlet left ventricle, straddling AV valve, atresia or stenosis of the AV valve, and dysplastic AV valve. ACNU appears to be a useful teratogenic agent for inducing complexes of cardiac anomalies which include AV malalignment.