Induced pluripotent stem cell modelling of HLHS underlines the contribution of dysfunctional NOTCH signalling to impaired cardiogenesis.

Hypoplastic left heart syndrome (HLHS) is among the most severe forms of congenital heart disease. Although the consensus view is that reduced flow through the left heart during development is a key factor in the development of the condition, the molecular mechanisms leading to hypoplasia of left heart structures are unknown. We have generated induced pluripotent stem cells (iPSC) from five HLHS patients and two unaffected controls, differentiated these to cardiomyocytes and identified reproducible in vitro cellular and functional correlates of the HLHS phenotype. Our data indicate that HLHS-iPSC have a reduced ability to give rise to mesodermal, cardiac progenitors and mature cardiomyocytes and an enhanced ability to differentiate to smooth muscle cells. HLHS-iPSC-derived cardiomyocytes are characterised by a lower beating rate, disorganised sarcomeres and sarcoplasmic reticulum and a blunted response to isoprenaline. Whole exome sequencing of HLHS fibroblasts identified deleterious variants in NOTCH receptors and other genes involved in the NOTCH signalling pathway. Our data indicate that the expression of NOTCH receptors was significantly downregulated in HLHS-iPSC-derived cardiomyocytes alongside NOTCH target genes confirming downregulation of NOTCH signalling activity. Activation of NOTCH signalling via addition of Jagged peptide ligand during the differentiation of HLHS-iPSC restored their cardiomyocyte differentiation capacity and beating rate and suppressed the smooth muscle cell formation. Together, our data provide firm evidence for involvement of NOTCH signalling in HLHS pathogenesis, reveal novel genetic insights important for HLHS pathology and shed new insights into the role of this pathway during human cardiac development.

Stabilizing an Embolized Pre-stent into the Right Ventricle During MELODY Valve Implantation.

Stent embolization is a complication that usually requires surgical extraction. We report a case where the covered stent used in MELODY valve trans-catheter pulmonary valve placement embolized to the right ventricle after being fully dilated on a 24-m-diameter balloon. After several unsuccessful attempts trying to capture it back or push it forward to the intended landing zone, we succeeded in deploying another stent straddling the embolized stent to anchor both of them in the main pulmonary artery. Two months later, we performed the valve implantation supported by both pre-stents.

Safety of transcatheter patent ductus arteriosus closure in small weight infants.

BACKGROUND: Patent ductus arteriosus (PDA) is a frequent congenital heart disease. Its transcatheter closure has become the treatment of choice in children and adults. However, the device closure of PDA in children with low weight is still challenging with high rate of complications. The aim of this study was to report further experience with trancatheter closure of PDA using the Amplatzer Duct Occluder(ADO) for children weighing less or equal to 8 kg. METHODS: Twenty-two patients (5 male, 17 female) underwent transcatheter closure of a PDA using ADO at a median age of 10 months (range 4 to 26) and a median weight of 7 kg (range 4.3 to 8). Follow-up evaluations were performed with Doppler echocardiography at 24h, and at 6 and 12 months. RESULTS: The device was implanted successfully in all patients. The median fluoroscopy time was 17.25 min (range 10 to 29). Within 24h, color Doppler revealed complete closure in 15 patients (68%), the other patients had a small residual shunt. No deaths were associated with the procedure. Two patients had a slight aortic protrusion of the device without coarctation and in one patient the device encroached partially on the left pulmonary artery without significant acceleration on Doppler echocardiography. All patients were discharged home the next day. All patients completed the 6-month follow-up with complete closure in 18 patients (81%). At the last evaluation in all patients at any time, there has been documentation of complete PDA closure in 20 (91%) of 22 patients. CONCLUSION: In patients weighing less or equal to 8 kg, percutaneous closure of PDA using an ADO is a safe and effective procedure.