Biomechanical and Molecular Aspects of Pulmonary Vascular Disease in Children with Congenital Heart Disease

Pulmonary hypertension and increased pulmonary blood flow both lead to functional and structural changes in the pulmonary vasculature. Pulnlollary vascular disease constitutes an ongoing threat to children with congenital heart disease. Without .early surgical repair, an estimated 30% of patients with congenital heart disease will develop signitlcant pulmonary vascular disease. Pulmonary hypertension and pulmonary vascular disease arc important causes of morbidity and mortality in patients with congenital heart disease. Pulmonary plexogenic arteriopathy is a eharactetistic form of pulmonary vascular disease and is most frequently associated with congenital heart defects. The combination of increased pulmoluu')' blood t10w with elevated pulmonary artery pressure, causes a rapid progression of the pulmonary vascular remodeling process that may progress to irreversibility and, then, precludes curative therapy or both the heart- and the vascular disease. Although the time course in which pulmonary arteriopathy progresses towards this stage is highly variable in different patients and different heart defects, our current knowledge, mainly based on empiricism, has lead to management strategies in pediatric cardiology Owt aims at surgical interventions early in life. On the other hand, at present, surgical corrections of complex congenital heart diseases may be delayed because of a staged approach. In addition, earlier and potentially reversible stages of plexogenic arteriopathy can jeopardize the outcome of surgical procedures because of acute pulmonary hypertensive crises perioperativcly. This aspect is of special importance in dIe management of patients with a univentricular heart, who will undergo Norwood- or Fontan procedures. These procedures are being performed in a rapidly increasing frequency in the current era and create a circulation, in which no ventricular force faces the pulmonary vasculaturc. In such a condition, already early stages of pulmonary vascular disease may be detrimental to surgical outcome and prognosis

Vascular rings: A rare cause of common respiratory symptoms

Upper airway symptoms or dysphagia may be caused by vascular anomalies, forming a ring around the trachea, oesophagus or both. To analyse the clinical presentation, use of various diagnostic techniques, treatment and follow-up we carried out a retrospective study of 38 children who had been diagnosed with a vascular ting between 1981 and 1996. We found 74% of the vascular tings to be symptomatic, with inspiratory stridor and wheezing as the main complaints. The delay between the onset of symptoms and diagnosis of a vascular ting in patients without associated anomalies ranged from 1 to 84 mo. Associated anomalies were found in 53% of cases and 80% of these anomalies consisted of associated cardiovascular malformations. Oesophagography proved to be a valuable diagnostic technique when a vascular ting was suspected. Echocardiography appeared to be of little value for the diagnosis of a vascular ring, but was essential to exclude associated cardiovascular malformations. Although angiography has always been considered to be the gold standard in the determination of the exact anatomy of vascular tings, increasing evidence is available that CT scan or MRI may replace this role. Mortality was related to co-existent tracheal deformities in 5/6 cases. Of the remaining, preoperatively symptomatic patients, relief of symptoms was achieved immediately after surgery in 43% and within 4y after surgery in 57%. Prolonged and recurrent respiratory complaints or dysphagia in infancy or childhood should alert the paediatrician to the possibility of a vascular ring

Pulmonary arterial wall distensibility assessed by intravascular ultrasound in children with congenital heart disease: an indicator for pulmonary vascular disease?

BACKGROUND: Both pulmonary hypertension and pulmonary overflow are associated with functional and structural changes of the pulmonary arterial wall. Current techniques to evaluate the pulmonary vasculature neglect the pulsatile nature of pulmonary flow. STUDY OBJECTIVES: To determine whether the dynamic properties of the pulmonary arterial wall are altered in patients with abnormal pulmonary hemodynamics due to congenital heart defects, and whether these changes are associated with the progression of pulmonary vascular disease (PVD). PATIENTS AND METHODS: In 43 children with PVD due to congenital heart defects and 12 control subjects, pulmonary arterial pulsatility (the relative increase in vessel area during the cardiac cycle) and distensibility (the inverse of the stress/strain elastic modulus) were determined with intravascular ultrasound. Results were correlated with clinical and hemodynamic parameters. RESULTS: Pulsatility correlated with pulmonary pulse pressure (p < 0.001), pulmonary-to-systemic vascular resistance ratio (PVR/SVR) [p = 0.001], and hemoglobin concentration (p = 0.01). However, when corrected for these variables, pulsatility did not differ between patients and control subjects. In contrast, arterial wall distensibility decreased with the severity of PVD and correlated independently with pulmonary-to-systemic arterial pressure ratio (p < 0.001) and PVR/SVR (p = 0.03), and with hemoglobin concentration (p < 0.01). Adjusted for hemodynamic variables, distensibility was still decreased in patients with PVD compared to control subjects. CONCLUSIONS: These results demonstrate that pulmonary arterial wall distensibility is progressively decreased in PVD; moreover, this decreased distensibility is, in part, related to increased distending pressure as a result of pulmonary hypertension but also, in part, to stiffening of the arterial wall during the disease process. Arterial wall distensibility may be of additional value in the evaluation of pulmonary vasculature and ventricular workload

Autoimmune lymphoproliferative syndrome (ALPS) in a child from consanguineous parents: a dominant or recessive disease?

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by autoimmune features and lymphoproliferations and is generally caused by defective Fas-mediated apoptosis. This report describes a child with clinical features of ALPS without detectable Fas expression on freshly isolated blood leukocytes. Detection of FAS transcripts via real-time quantitative PCR made a severe transcriptional defect unlikely. Sequencing of the FAS gene revealed a 20-nucleotide duplication in the last exon affecting the cytoplasmic signaling domain. The patient was homozygous for this mutation, whereas the consanguineous parents and the siblings were heterozygous. The patient reported here is a human homologue of the Fas-null mouse, inasmuch as she carries an autosomal homozygous mutation in the FAS gene and she shows the severe and accelerated ALPS phenotype. The heterozygous family members did not have the ALPS phenotype, indicating that the disease-causing FAS mutation in this family is autosomal recessive

Inhibition of the prolyl isomerase Pin1 improves endothelial function and attenuates vascular remodelling in pulmonary hypertension by inhibiting TGF-beta signalling

Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by obstructive pulmonary vascular remodelling ultimately leading to right ventricular (RV) failure and death. Disturbed transforming growth factor-beta (TGF-beta)/bone morphogenetic protein (BMP) signalling, endothelial cell dysfunction, increased proliferation of smooth muscle cells and fibroblasts, and inflammation contribute to this abnormal remodelling. Peptidyl-prolyl isomerase Pin1 has been identified as a critical driver of proliferation and inflammation in vascular cells, but its role in the disturbed TGF-beta/BMP signalling, endothelial cell dysfunction, and vascular remodelling in PAH is unknown. Here, we report that Pin1 expression is increased in cultured pulmonary microvascular endothelial cells (MVECs) and lung tissue of PAH patients. Pin1 inhibitor, juglone significantly decreased TGF-beta signalling, increased BMP signalling, normalized their hyper-proliferative, and inflammatory phenotype. Juglone treatment reversed vascular remodelling through reducing TGF-beta signalling in monocrotaline + shunt-PAH rat model. Juglone treatment decreased Fulton index, but did not affect or harm cardiac function and remodelling in rats with RV pressure load induced by pulmonary artery banding. Our study demonstrates that inhibition of Pin1 reversed the PAH phenotype in PAH MVECs in vitro and in PAH rats in vivo, potentially through modulation of TGF-beta/BMP signalling pathways. Selective inhibition of Pin1 could be a novel therapeutic option for the treatment of PAH.Cancer Signaling networks and Molecular Therapeutic

Common arterial trunk and ventricular non-compaction in Lrp2 knockout mice indicate a crucial role of LRP2 in cardiac development

Lipoprotein-related receptor protein 2 (LRP2) is important for development of the embryonic neural crest and brain in both mice and humans. Although a role in cardiovascular development can be expected, the hearts of Lrp2 knockout (KO) mice have not yet been investigated. We studied the cardiovascular development of Lrp2 KO mice between embryonic day 10.5 (E10.5) and E15.5, applying morphometry and immunohistochemistry, using antibodies against Tfap2α (neural crest cells), Nkx2.5 (second heart field), WT1 (epicardium derived cells), tropomyosin (myocardium) and LRP2. The Lrp2 KO mice display a range of severe cardiovascular abnormalities, including aortic arch anomalies, common arterial trunk (persistent truncus arteriosus) with coronary artery anomalies, ventricular septal defects, overriding of the tricuspid valve and marked thinning of the ventricular myocardium. Both the neural crest cells and second heart field, which are essential for the lengthening and growth of the right ventricular outflow tract, are abnormally positioned in the Lrp2 KO. T hi s explains the absence of the aorto-pulmonary septum, which leads to common arterial trunk and ventricular septal defects. Severe blebbing of the epicardial cells covering the ventricles is seen. Epithelial-mesenchymal transition does occur; however, there are fewer WT1-positive epicardium-derived cells in the ventricular wall as compared to normal, coinciding with the myocardial thinning and deep intertrabecular spaces. LRP2 plays a crucial role in cardiovascular development in mice. This corroborates findings of cardiac anomalies in humans with LRP2 mutations. Future studies should reveal the underlying signaling mechanisms in which LRP2 is involved during cardiogenesis

Volume load-induced right ventricular failure in rats is not associated with myocardial fibrosis

Background Right ventricular (RV) function and failure are key determinants of morbidity and mortality in various cardiovascular diseases. Myocardial fibrosis is regarded as a contributing factor to heart failure, but its importance in RV failure has been challenged. This study aims to assess whether myocardial fibrosis drives the transition from compensated to decompensated volume load-induced RV dysfunction.MethodsWistar rats were subjected to aorto-caval shunt (ACS, n = 23) or sham (control, n = 15) surgery, and sacrificed after 1 month, 3 months, or 6 months. Echocardiography, RV pressure-volume analysis, assessment of gene expression and cardiac histology were performed.ResultsAt 6 months, 6/8 ACS-rats (75%) showed clinical signs of RV failure (pleural effusion, ascites and/or liver edema), whereas at 1 month and 3 months, no signs of RV failure had developed yet. Cardiac output has increased two- to threefold and biventricular dilatation occurred, while LV ejection fraction gradually decreased. At 1 month and 3 months, RV end-systolic elastance (Ees) remained unaltered, but at 6 months, RV Ees had decreased substantially. In the RV, no oxidative stress, inflammation, pro-fibrotic signaling (TGF beta 1 and pSMAD2/3), or fibrosis were present at any time point.ConclusionsIn the ACS rat model, long-term volume load was initially well tolerated at 1 month and 3 months, but induced overt clinical signs of end-stage RV failure at 6 months. However, no myocardial fibrosis or increased pro-fibrotic signaling had developed. These findings indicate that myocardial fibrosis is not involved in the transition from compensated to decompensated RV dysfunction in this model.Therapeutic cell differentiatio

First genotype-phenotype study in TBX4 syndrome : gain-of-function mutations causative for lung disease

Rationale: Despite the increased recognition of TBX4-associated pulmonary arterial hypertension (PAH), genotype-phenotype associations are lacking and may provide important insights. Methods: We assembled a multi-center cohort of 137 patients harboring monoallelic TBX4 variants and assessed the pathogenicity of missense variation (n = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. We sought genotype-phenotype correlations and undertook a comparative analysis with PAH patients with BMPR2 causal variants (n = 162) or no identified variants in PAH-associated genes (n = 741) genotyped via the NIHR BioResource - Rare Diseases (NBR). Results: Functional assessment of TBX4 missense variants led to the novel finding of gain-of-function effects associated with older age at diagnosis of lung disease compared to loss-of-function (p = 0.038). Variants located in the T-BOX and nuclear localization domains were associated with earlier presentation (p = 0.005) and increased incidence of interstitial lung disease (p = 0.003). Event-free survival (death or transplantation) was shorter in the T-BOX group (p = 0.022) although age had a significant effect in the hazard model (p = 0.0461). Carriers of TBX4 variants were diagnosed at a younger age (p < 0.001) and had worse baseline lung function (FEV1, FVC) (p = 0.009) compared to the BMPR2 and no identified causal variant groups. Conclusions: We demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain-of-function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains