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Groningen, Netherlands

Rana M.S.,University of Amsterdam | Sizarov A.,University of Amsterdam | Sizarov A.,Center for Congenital Heart Diseases | Christoffels V.M.,University of Amsterdam | Moorman A.F.M.,University of Amsterdam
American Journal of Medical Genetics, Part A | Year: 2014

Variations and mutations in the human genome, such as 22q11.2 microdeletion, can increase the risk for congenital defects, including aortic arch malformations. Animal models are increasingly expanding our molecular and genetic insights into aortic arch development. However, in order to justify animal-to-human extrapolations, a human morphological, and molecular reference model would be of great value, but is currently lacking. Here, we present interactive three-dimensional reconstructions of the developing human aortic arch system, supplemented with the protein distribution of developmental markers for patterning and growth, including T-box transcription factor TBX1, a major candidate for the phenotypes found in patients with the 22q11.2 microdeletion. These reconstructions and expression data facilitate unbiased interpretations, and reveal previously unappreciated aspects of human aortic arch development. Based on our reconstructions and on reported congenital anomalies of the pulmonary trunk and tributaries, we postulate that the pulmonary arteries originate from the aortic sac, rather than from the sixth pharyngeal arch arteries. Similar to mouse, TBX1 is expressed in pharyngeal mesenchyme and epithelia. The endothelium of the pharyngeal arch arteries is largely negative for TBX1 and family member TBX2 but expresses neural crest marker AP2α, which gradually decreases with ongoing development of vascular smooth muscle. At early stages, the pharyngeal arch arteries, aortic sac, and the dorsal aortae in particular were largely negative for proliferation marker Ki67, potentially an important parameter during aortic arch system remodeling. Together, our data support current animal-to-human extrapolations and future genetic and molecular analyses using animal models of congenital heart disease. © 2013 Wiley Periodicals, Inc. Source

Ploegstra M.-J.,Center for Congenital Heart Diseases | Roofthooft M.T.R.,Center for Congenital Heart Diseases | Douwes J.M.,Center for Congenital Heart Diseases | Bartelds B.,Center for Congenital Heart Diseases | And 4 more authors.
Circulation: Cardiovascular Imaging | Year: 2014

Background: The value of echocardiography in assessing disease severity and predicting outcome in pediatric pulmonary arterial hypertension (PAH) is insufficiently defined. The aim of this study was to describe correlations between echocardiography and disease severity and outcome in pediatric PAH. Methods and Results: Forty-three consecutive children (median age, 8.0 years; range, 0.4-21.5) with idiopathic/ hereditary PAH (n=25) or PAH associated with congenital heart disease (n=18) were enrolled in a prospective singlecenter observational study. Anatomic and right ventricular-functional variables were obtained by two-dimensional echocardiography and Doppler-echocardiography at presentation and at standardized follow-up and were correlated with measures of disease severity (World Health Organization functional class [WHO-FC], N-terminal-pro-B-type natriuretic peptide, hemodynamics) and lung-transplantation-free survival. Right atrial and right ventricular dimensions correlated with WHO-FC and hemodynamics (P<0.05), whereas left ventricular dimensions correlated with hemodynamics and survival (P<0.05). Right-to-left ventricular dimension ratiocorrelated with WHO-FC, hemodynamics and survival (P<0.05). Right ventricular ejection time correlated with hemodynamics and survival (P<0.05) and tended to correlate with WHO-FC (P=0.071). Tricuspid annular plane systolic excursion correlated with WHO-FC, mean right atrial pressure and survival (P<0.05). Conclusions: This early descriptive study shows that echocardiographic chararacteristics of both the right and the left heart correlate with disease severity and outcome in pediatric PAH, both at presentation and during the course of the disease. The preliminary data from this study support the potential value of echocardiography as a tool in guiding management in children with PAH. © 2014 American Heart Association, Inc. Source

Douwes J.M.,Center for Congenital Heart Diseases | Van Loon R.L.E.,Center for Congenital Heart Diseases | Hoendermis E.S.,University of Groningen | Vonk-Noordegraaf A.,VU University Amsterdam | And 4 more authors.
European Heart Journal | Year: 2011

Aims To assess the occurrence and prognostic value of acute vasodilator response (AVR) in paediatric vs. adult pulmonary arterial hypertension, and idiopathic/hereditary pulmonary arterial hypertension (iPAH/HPAH) vs. pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) using three different response criteria. Methods and resultsNinety-nine PAH patients underwent AVR testing (37 children, 62 adults; 70 iPAH/HPAH, 29 PAH-CHD). Three response criteria from clinical practice were used to define AVR. The number of responders was evaluated separately in subgroups based on age, diagnosis, and presence of a non-restrictive post-tricuspid shunt. Numbers of responders varied importantly using the different criteria but were always higher in iPAH/HPAH, compared with PAH-CHD. The number of responders did not differ between paediatric and adult iPAH/HPAH. No responders were identified in patients with a post-tricuspid shunt. Acute vasodilator response was associated with improved survival using all three criteria. Low baseline mean right atrial pressure (mRAP) was associated with improved survival in adults (P< 0.001). High baseline mean pulmonary arterial pressure (mPAP)/mean systemic arterial pressure (mSAP) and pulmonary vascular resistance (PVR)/systemic vascular resistance (SVR) were associated with worse survival, statistically independent from age, diagnosis, and the presence of a post-tricuspid shunt.ConclusionThe proportion of patients with AVR highly depends on the used criteria, but did not differ between paediatric and adult iPAH/HPAH. Current response criteria are not suitable for patients with a post-tricuspid shunt. In both children and adults without post-tricuspid shunts, AVR was associated with improved survival independent of the used criteria. Nevertheless, prognostic value in the individual patient was limited. Baseline mRAP showed a good correlation with survival for adult PAH patients, but not for children. High baseline mPAP/mSAP and PVR/SVR was associated with worse prognosis independent from age, diagnosis, or the presence of a post-tricuspid shunt. Published on behalf of the European Society of Cardiology. © The Author 2011. Source

Gorter T.M.,Center for Congenital Heart Diseases | Van Melle J.P.,University of Groningen | Hillege H.L.,University of Groningen | Pieper P.G.,University of Groningen | And 5 more authors.
Interactive Cardiovascular and Thoracic Surgery | Year: 2014

OBJECTIVES: In patients with severe pulmonary valve regurgitation or stenosis, pulmonary valve replacement (PVR) has a favourable effect on right ventricular (RV) volume and pressure unloading. PVR thereby decreases the progression of RV dilatation and/or hypertrophy. This study investigates RV remodelling patterns after PVR in patients with either pressure, volume or combined volume- and pressure-loaded RVs. METHODS: We evaluated 79 consecutive patients who had undergone PVR, between 1999 and 2012 beyond the age of 14 years. Comparisons were made according to the RV loading condition, i.e. isolated volume-loaded (iPR, n = 53), combined volume- and pressure-loaded (cPR/[PS] pulmonary stenosis, n = 16), and isolated pressure-loaded RVs (iPS n = 10). The main study outcome was the change of the RV end-diastolic diameter (ΔRVEDD) before and after PVR, measured on echocardiography. RESULTS: The majority of patients (65%) had a tetralogy of Fallot. After PVR, the RVEDD decreased with 5.3 mm/m2, body surface area (BSA) (P < 0.001). In addition, the RV end-diastolic volume on cardiac magnetic resonance declines with 40 ml/m2, BSA (P < 0.001). The change in the RVEDD after PVR was different according to the loading condition (i.e. iPR: -6.6, cPR/PS: -4.7 and iPS: +0.4 mm/m2, P < 0.001). In a multivariate regression model, pressure load remained a significant predictor of decreased RVEDD (P = 0.005). CONCLUSIONS: The current data indicate that the type of right ventricular loading (pressure versus volume) before PVR affects the RV remodelling pattern after PVR. Right ventricular pressure load has an adverse effect on early RV remodelling after PVR. © 2014 The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. Source

Borgdorff M.A.J.,Center for Congenital Heart Diseases | Borgdorff M.A.J.,University of Groningen | Koop A.M.C.,Center for Congenital Heart Diseases | Koop A.M.C.,University of Groningen | And 11 more authors.
Journal of Molecular and Cellular Cardiology | Year: 2015

Background: Right ventricular failure (RVF) due to pressure load is a major cause of death in congenital heart diseases and pulmonary hypertension. The mechanisms of RVF are unknown. We used an experimental approach based upon clinical signs of RVF to delineate functional and biological processes associated with RVF. Methods and results: Wistar rats were subjected to a pulmonary artery banding (PAB n. = 12) or sham surgery (CON, n. = 7). After 52. ±. 5. days, 5/12 PAB rats developed clinical symptoms of RVF (inactivity, ruffled fur, dyspnea, ascites) necessitating termination (PAB. +. CF). We compared these to PAB rats with RVF without clinical symptoms (PAB-). PAB resulted in reduced cardiac output, RV stroke volume, TAPSE, and increased end diastolic pressure (all p. <. 0.05 vs. CON) in all rats, but PAB. +. CF rats were significantly more affected than PAB. -, despite similar pressure load (p. = ns). Pressure. -volume analysis showed enhanced contractility (end systolic elastance) in PAB- and PAB. +. CF, but diastolic function (end diastolic elastance, end diastolic pressure) deteriorated especially in PAB. +. CF. In PAB. +. CF capillary density was lower than in PAB. -. Gene-array analysis revealed downregulation of both fatty acid oxidation and carbohydrate metabolism in PAB. +. CF. Conclusion: Chronic PAB led to different degrees of RVF, with half of the rats developing severe clinical symptoms of RVF, associated with progressive deterioration of diastolic function, hypoxia-prone myocardium, increased response to oxidative stress and suppressed myocardial metabolism. This model represents clinical RVF and allows for unraveling of mechanisms involved in the progression from RV adaptation to RV failure and the effect of intervention on these mechanisms. © 2014 Elsevier Ltd. Source

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