Atrioventricular septal defect : advanced imaging from early development to long-term follow-up

The aim of this thesis is to review the current knowledge on atrioventricular septal defect (AVSD) (Part 1), to study the pathogenesis of AVSD (Part 2) and finally to analyze cardiac outcome long-term after AVSD correction (Part 3). Studies are performed with novel imaging techniques. In part 2 it is made plausible that AVSD is a sliding scale and that patients with Down syndrome without AVSD also have abnormalities of the membranous septum and atrioventricular valves. High frequency ultrasound in mouse embryos shows to be a promising technique to study cardiovascular flow in early stages of heart development. In a mouse model with disturbed VEGF signalling, the heart rate is reduced and the sinoatrial node develops abnormally. Finally, in part 3 of this thesis, 4DFlow MRI data reveals that patients with an abnormal left atrioventricular valve (LAVV) after AVSD correction have aberrant intra-cardiac flow patterns. During diastole the inflow into the left ventricle is directed more towards the lateral wall, more towards the apex and vortex formation is abnormal. During systole the dynamic and eccentric regurgitation of the LAVV disturbs the normal recirculating flow patterns in the left atrium.4DFlow MRI can be used to reliably quantify flow over the LAVV.UBL - phd migration 201

Echocardiographic Assessment of Embryonic and Fetal Mouse Heart Development: A Focus on Haemodynamics and Morphology

Background. Heart development is a complex process, and abnormal development may result in congenital heart disease (CHD). Currently, studies on animal models mainly focus on cardiac morphology and the availability of hemodynamic data, especially of the right heart half, is limited. Here we aimed to assess the morphological and hemodynamic parameters of normal developing mouse embryos/fetuses by using a high-frequency ultrasound system. Methods. A timed breeding program was initiated with a WT mouse line (Swiss/129Sv background). All recordings were performed transabdominally, in isoflurane sedated pregnant mice, in hearts of sequential developmental stages: 12.5, 14.5, and 17.5 days after conception (n=105). Results. Along development the heart rate increased significantly from 125 ± 9.5 to 219 ± 8.3 beats per minute. Reliable flow measurements could be performed across the developing mitral and tricuspid valves and outflow tract. M-mode measurements could be obtained of all cardiac compartments. An overall increase of cardiac systolic and diastolic function with embryonic/fetal development was observed. Conclusion. High-frequency echocardiography is a promising and useful imaging modality for structural and hemodynamic analysis of embryonic/fetal mouse hearts

Atrioventricular septal defect : advanced imaging from early development to long-term follow-up

The aim of this thesis is to review the current knowledge on atrioventricular septal defect (AVSD) (Part 1), to study the pathogenesis of AVSD (Part 2) and finally to analyze cardiac outcome long-term after AVSD correction (Part 3). Studies are performed with novel imaging techniques. In part 2 it is made plausible that AVSD is a sliding scale and that patients with Down syndrome without AVSD also have abnormalities of the membranous septum and atrioventricular valves. High frequency ultrasound in mouse embryos shows to be a promising technique to study cardiovascular flow in early stages of heart development. In a mouse model with disturbed VEGF signalling, the heart rate is reduced and the sinoatrial node develops abnormally. Finally, in part 3 of this thesis, 4DFlow MRI data reveals that patients with an abnormal left atrioventricular valve (LAVV) after AVSD correction have aberrant intra-cardiac flow patterns. During diastole the inflow into the left ventricle is directed more towards the lateral wall, more towards the apex and vortex formation is abnormal. During systole the dynamic and eccentric regurgitation of the LAVV disturbs the normal recirculating flow patterns in the left atrium.4DFlow MRI can be used to reliably quantify flow over the LAVV

Disturbed Intracardiac Flow Organization After Atrioventricular Septal Defect Correction as Assessed With 4D Flow Magnetic Resonance Imaging and Quantitative Particle Tracing

Objectives Four-dimensional (3 spatial directions and time) velocity-encoded flow magnetic resonance imaging with quantitative particle tracing analysis allows assessment of left ventricular (LV) blood flow organization. Corrected atrioventricular septal defect (AVSD) patients have an abnormal left atrioventricular valve shape. We aimed to analyze flow organization in corrected AVSD patients and healthy controls. Methods A total of 32 patients (age, 25 14 years), 21 after partial AVSD correction and 11 after complete/intermediate AVSD correction, and 30 healthy volunteers (26 12 years) underwent whole-heart four-dimensional velocity-encoded flow magnetic resonance imaging. Particle tracing in the 16-segment LV cavity model was used to quantitatively evaluate blood flow organization discriminating multiple components. Results Patients showed a smaller percentage of direct flow compared with controls (30% +/- 9% vs 44% +/- 11%; P <0.001). In patients, more inflow was observed in the basal inferior segment (22% +/- 11% vs controls, 17% +/- 5%; P = 0.005), with less direct but more retained inflow (ie, part of inflow that is not ejected from LV in subsequent systole). In patients, more inflow reached the midventricular level (68% +/- 13% vs controls, 58% +/- 9%; P <0.001), most notably as retained inflow in the lateral segments. Subsequently, in patients, more (mostly retained) inflow reached the apex (23% +/- 13% vs 14% +/- 7%; P <0.001), which correlated with early peak filling velocity (r = 0.637, P <0.001). Patients with a corrected complete or intermediate AVSD presented with less direct flow (24% +/- 8% vs 33% +/- 8%; P = 0.003) and more apical inflow (30% +/- 14% vs 18% +/- 12%; P = 0.014) compared with a corrected partial AVSD. Conclusion Multicomponent particle tracing combined with 16-segment analysis quantitatively demonstrated altered LV flow organization after AVSD correction, with less direct and more retained inflow in apical and lateral LV cavity segments, which may contribute to decreased cardiac pumping efficienc

Abnormal sinoatrial node development resulting from disturbed vascular endothelial growth factor signaling

Background: Sinus node dysfunction is frequently observed in patients with congenital heart disease (CHD). Variants in the Vascular Endothelial Growth Factor-A (VEGF) pathway are associated with CHD. In Vegf(120/120) mice, over-expressing VEGF(120), a reduced sinoatrial node (SAN) volume was suggested. Aim of the study is to assess the effect of VEGF over-expression on SAN development and function. Methods: Heart rate was measured in Vegf(120/120) and wildtype (WT) embryos during high frequency ultrasound studies at embryonic day (E) 12.5, 14.5 and 17.5 and by optical mapping at E12.5. Morphology was studied with several antibodies. SAN volume estimations were performed, and qualitative-PCR was used to quantify expression of genes in SAN tissues of WT and Vegf(120/120) embryos. Results: Heart rate was reduced in Vegf(120/120) compared with WT embryos during embryonic echocardiography (52 +/- 17 versus 125 +/- 31 beats per minute (bpm) at E12.5, p <0.001; 123 +/- 37 vs 160 +/- 29 bmp at E14.5, p = 0.024; and 177 +/- 30 vs 217 +/- 34 bmp, at E17.5 p = 0.017) and optical mapping (81 +/- 5 vs 116 +/- 8 bpm at E12.5; p = 0.003). The SAN of mutant embryos was smaller and more vascularized, and showed increased expression of the fast conducting gap junction protein, Connexin43. Conclusions: Over-expression of VEGF(120) results in reduced heart rate and a smaller, less compact and hypervascularized SAN with increased expression of Connexin43. This indicates that VEGF is necessary for normal SAN development and function. (C) 2014 Elsevier Ireland Ltd. All rights reserve