Molecular Pathways and Animal Models of Tricuspid Atresia and Univentricular Heart.

The process of valve formation is a complex process that involves intricate interplay between various pathways at precise times. Although we have not completely elucidated the molecular pathways that lead to normal valve formation, we have identified a few major players in this process. We are now able to implicate TGF-ß, BMP, and NOTCH as suspects in tricuspid atresia (TA), as well as their downstream targets: NKX2-5, TBX5, NFATC1, GATA4, and SOX9. We know that the TGF-ß and the BMP pathways converge on the SMAD4 molecule, and we believe that this molecule plays a very important role to tie both pathways to TA. Similarly, we look at the NOTCH pathway and identify the HEY2 as a potential link between this pathway and TA. Another transcription factor that has been implicated in TA is NFATC1. While several mouse models exist that include part of the TA abnormality as their phenotype, no true mouse model can be said to represent TA. Bridging this gap will surely shed light on this complex molecular pathway and allow for better understanding of the disease process.

Canonical wnt signaling regulates atrioventricular junction programming and electrophysiological properties.

RATIONALE: Proper patterning of the atrioventricular canal (AVC) is essential for delay of electrical impulses between atria and ventricles, and defects in AVC maturation can result in congenital heart disease. OBJECTIVE: To determine the role of canonical Wnt signaling in the myocardium during AVC development. METHODS AND RESULTS: We used a novel allele of ß-catenin that preserves ß-catenin's cell adhesive functions but disrupts canonical Wnt signaling, allowing us to probe the effects of Wnt loss of function independently. We show that the loss of canonical Wnt signaling in the myocardium results in tricuspid atresia with hypoplastic right ventricle associated with the loss of AVC myocardium. In contrast, ectopic activation of Wnt signaling was sufficient to induce formation of ectopic AV junction-like tissue as assessed by morphology, gene expression, and electrophysiological criteria. Aberrant AVC development can lead to ventricular pre-excitation, a characteristic feature of Wolff-Parkinson-White syndrome. We demonstrate that postnatal activation of Notch signaling downregulates canonical Wnt targets within the AV junction. Stabilization of ß-catenin protein levels can rescue Notch-mediated ventricular pre-excitation and dysregulated ion channel gene expression. CONCLUSIONS: Our data demonstrate that myocardial canonical Wnt signaling is an important regulator of AVC maturation and electric programming upstream of Tbx3. Our data further suggest that ventricular pre-excitation may require both morphological patterning defects, as well as myocardial lineage reprogramming, to allow robust conduction across accessory pathway tissue.

Oxygen supply to the fetal cerebral circulation in hypoplastic left heart syndrome: a simulation study based on the theoretical models of fetal circulation.

Hypoxia due to congenital heart diseases (CHDs) adversely affects brain development during the fetal period. Head circumference at birth is closely associated with neuropsychiatric development, and it is considerably smaller in newborns with hypoplastic left heart syndrome (HLHS) than in normal newborns. We performed simulation studies on newborns with CHD to evaluate the cerebral circulation during the fetal period. The oxygen saturation of cerebral blood flow in newborns with CHD was simulated according to a model for normal fetal circulation in late pregnancy. We compared the oxygen saturation of cerebral blood flow between newborns with tricuspid atresia (TA; a disease showing univentricular circulation and hypoplasia of the right ventricle), those with transposition of the great arteries (TGA; a disease showing abnormal mixing of arterial and venous blood), and those with HLHS. The oxygen saturation of cerebral blood flow in newborns with normal circulation was 75.7 %, whereas it was low (49.5 %) in both newborns with HLHS and those with TA. Although the oxygen level is affected by the blood flow through the foramen ovale, the oxygen saturation in newborns with TGA was even lower (43.2 %). These data, together with previous reports, suggest that the cerebral blood flow rate is decreased in newborns with HLHS, and the main cause was strongly suspected to be retrograde cerebral perfusion through a patent ductus arteriosus. This study provides important information about the neurodevelopmental prognosis of newborns with HLHS and suggests the need to identify strategies to resolve this unfavorable cerebral circulatory state in utero.

[Functional properties of smooth muscle cells in ascending aortic aneurysm].

Thoracic aortic aneurism (TAA) develops as a result of complex series of events that dynamically alter the structure and composition of the aortic vascular extracellular matrix (ECM). The main elements that alter the composition of aortic wall are smooth muscle cells (SMC). The purpose of the present work was to study alteration of smooth muscle cell functions derived from the patients with TAA and from healthy donors. As it is supposed that TAA associated with bicuspid aortic valve (BAV) and with tricuspid aortic valve (TAV) differ in their pathogenesis, we compared the SMC and tissues samples from BAV-, TAV-patients and healthy donors. We compared TAA patients' derived tissues and SMC to healthy donors' ones in several parameters: SMC growth, migration and apoptotic dynamics; metalloproteinase MMP2 and MMP9 activity (zymography) and elastin, collagen and fibrillin content (Western blot) in both tissue samples and cultured SMC. Proliferation ability of both BAV and TAV SMC was decreased comparing to donors cells; migration ability in scratch tests was increased in TAV-derived SMC comparing to donor cells. BAV-cells migration ability was not changed comparing to donor-SMC. Elastin content was decreased in TAA SMC comparing to donor cells whereas the content of fibrillin and collagen was not altered. At the same time elastin and collagen protein level was significantly higher in tissue samples of TAA patients comparing to donor-derived samples. SMS proliferation and migration ability is differently affected in TAV and BAV-associated TAA that supports the idea of different nature of these two groups of TAA. Also our data show that SMC functional properties are altered in TAA patients and these alterations could play a significant role in the disease pathogenesis.