Podoplanin and the posterior heart field : epicardial-myocardial interaction

This thesis introduces the posterior heart field contributing to the venous pole of the heart by epithelial-mesenchymal-transformation of the coelomic epithelium. Based on studying of podoplanin and Sp3 (novel genes in cardiogenesis) wildtype and knockout mouse embryos between stages 9.5-18.5, we postulate that the posterior heart field contributes through mesenchymal and myocardial cell populations. The mesenchymal population is involved in the formation of the proepicardial organ, epicardium and epicardium-derived cells. The hypoplastic proepicardial organ and impaired epicardial-myocardial interaction result from altered mesenchymal contribution of the posterior heart field by lack of podoplanin and SP3 leading to hypoplasia of the chamber myocardium and coronary arterial vascular wall as well as (atrioventricular) septal defects. Myocardial contribution concerns myocardium of the sinus venosus including the sinoatrial node, venous valves, primary atrial septum and the left atrial dorsal wall as well as the wall of the pulmonary and cardinal veins. Development of smooth-muscle-cells of the wall of the pulmonary vein is also related to the posterior heart field. Moreover, we have reported formation of a transient left-sided sinoatrial node which persists during development in 10% of the cases. Podoplanin mutants show cardiac malformations including a hypoplastic sinoatrial node. This thesis contributes to the understanding of the mechanism underlying the mentioned cardiac malformations and arrhythmias originating in the sinus venosus region.Nederlandse Hartstichting J.E. Jurriaanse Stichting Sanofi-aventis Netherlands B.V. Datascope Bristol-Myers SquibbUBL - phd migration 201

Current and future applications of virtual reality technology for cardiac interventions

Virtual reality is a fast-evolving technology that already has several promising applications in medicine. In this Clinical Outlook, we discuss the current evidence and the future challenges for virtual reality applications in cardiac interventions. The incorporation of virtual reality in daily practice will inevitably make clinical care more robust, patient-centred and safe

Disturbed myocardial connexin 43 and N-cadherin expressions in hypoplastic left heart syndrome and borderline left ventricle

Cardiolog

Noot bij: HvJ EU 6 maart 2014, JB, 2014, 77 (Toepassingsgebied van het EU-Handvest van de Grondrechten)

Platelet-derived growth factor receptor alpha (Pdgfralpha) identifies cardiac progenitor cells in the posterior part of the second heart field. We aim to elucidate the role of Pdgfralpha in this region. Hearts of Pdgfralpha-deficient mouse embryos (E9.5-E14.5) showed cardiac malformations consisting of atrial and sinus venosus myocardium hypoplasia, including venous valves and sinoatrial node. In vivo staining for Nkx2.5 showed increased myocardial expression in Pdgfralpha mutants, confirmed by Western blot analysis. Due to hypoplasia of the primary atrial septum, mesenchymal cap, and dorsal mesenchymal protrusion, the atrioventricular septal complex failed to fuse. Impaired epicardial development and severe blebbing coincided with diminished migration of epicardium-derived cells and myocardial thinning, which could be linked to increased WT1 and altered alpha4-integrin expression. Our data provide novel insight for a possible role for Pdgfralpha in transduction pathways that lead to repression of Nkx2.5 and WT1 during development of posterior heart field-derived cardiac structures.Stem cells & developmental biolog

Epicardium-derived cells enhance proliferation, cellular maturation and alignment of cardiomyocytes

During heart development, cells from the proepicardial organ spread over the naked heart tube to form the epicardium. From here, epicardium-derived cells (EPDCs) migrate into the myocardium. EPDCs proved to be indispensable for the formation of the ventricular compact zone and myocardial maturation, by largely unknown mechanisms. In this study we investigated in vitro how EPDCs affect cardiomyocyte proliferation, cellular alignment and contraction, as well as the expression and cellular distribution of proteins involved in myocardial maturation. Embryonic quail EPDCs induced proliferation of neonatal mouse cardiomyocytes. This required cell-cell interactions, as proliferation was not observed in transwell cocultures. Western blot analysis showed elevated levels of electrical and mechanical junctions (connexin43, N-cadherin), sarcomeric proteins (Troponin-I, alpha-actinin), extracellular matrix (collagen I and periostin) in cocultures of EPDCs and cardiomyocytes. Immunohistochemistry indicated more membrane-bound expression of Cx43, N-cadherin, the mechanotransduction molecule focal adhesion kinase, and higher expression of the sarcoplasmic reticulum Ca2+ ATPase (SERCA2a). Newly developed software for analysis of directionality in immunofluorescent stainings showed a quantitatively determined enhanced cellular alignment of cardiomyocytes. This was functionally related to increased contraction. The in vitro effects of EPDCs on cardiomyocytes were confirmed in three reciprocal in vivo models for EPDC-depletion (chicken and mice) in which downregulation of myocardial N-cadherin, Cx43, and FAK were observed. In conclusion, direct interaction of EPDCs with cardiomyocytes induced proliferation, correct mechanical and electrical coupling of cardiomyocytes. ECM-deposition and concurrent establishment of cellular array. These findings implicate that EPDCs are ideal candidates as adjuvant cells for cardiomyocyte integration during cardiac (stem) cell therapy. (c) 2010 Elsevier Ltd. All rights reserved.Stem cells & developmental biolog

Electrical Activation of Sinus Venosus Myocardium and Expression Patterns of RhoA and Isl-1 in the Chick Embryo

Methods and Results: Expression of RhoA, myocardial markers cTnI and Nkx2.5, transcription factors Isl-1 and Tbx18, and cation channel HCN4 were examined in sequential stages in chick embryos. Electrical activation patterns were studied using microelectrodes and optical mapping. Embryonic sinus venosus myocardium is cTnI and HCN4 positive, Nkx2.5 negative, complemented by distinct patterns of Isl-1 and Tbx18. During development, initial myocardium-wide expression of RhoA becomes restricted to right-sided sinus venosus myocardium, comprising the SAN. Electrophysiological measurements revealed initial capacity of both atria to show electrical activity that in time shifts to a right-sided dominance, coinciding with persistence of RhoA, Tbx18, and HCN4 and absence of Nkx2.5 expression in the definitive SAN. Conclusion: Results show an initially bilateral electrical potential of sinus venosus myocardium evolving into a right-sided activation pattern during development, and suggest a role for RhoA in conduction system development. We hypothesize an initial sinus venosus-wide capacity to generate pacemaker signals, becoming confined to the definitive SAN. Lack of differentiation toward a chamber phenotype would explain ectopic pacemaker foci. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1284-1292, November 2010).Stem cells & developmental biolog

A nationwide population-based cohort study of surgical care for patients with superior sulcus tumors

Objectives: Data on national patterns of care for patients with superior sulcus tumors (SST) is currently lacking. We investigated the distribution of surgical care and outcome for patients with SST in the Netherlands. Material and methods: Data was retrieved from the Dutch Lung Cancer Audit for Surgery (DLCA-S) for all patients undergoing resection for clinical stage IIB-IV SST from 2012 to 2019. Because DLCA-S is not linked to survival data, survival for a separate cohort (2015–2017) was obtained from the Netherlands Cancer Registry (NCR). Results: In the study period, 181 patients had SST surgery, representing 1.03% (181/17488) of all lung cancer pulmonary resections. For 2015–2017, the SST resection rate was 14.4% (79/549), and patients with stage IIB/III SST treated with trimodality had a 3-year overall survival of 67.4%. 63.5% of patients were male, and median age was 60 years. Almost 3/4 of tumors were right sided. Surgery was performed in 20 hospitals, with average number of annual resections ranging from ≤ 1 (n = 17) to 9 (n = 1). 39.8% of resections were performed in 1 center and 63.5% in the 3 most active centers. 12.7% of resections were extended (e.g. vertebral resection). 85.1% of resections were complete (R0). Morbidity and 30-day mortality were 51.4% and 3.3% respectively. Despite treating patients with a higher ECOG performance score and more extended resections, the highest volume center had rates of morbidity/mortality, and length of hospital stay that were comparable to those of the medium volume (n = 2) and low-volume centers (n = 1). Conclusion: In the Netherlands, surgery for SST accounts for about 1% of all lung cancer pulmonary resections, the number of SST resections/hospital/year varies widely, with most centers performing an average of ≤ 1/year. Morbidity and mortality are acceptable and survival compares favourably with the literature. Although further centralisation is possible, it is unknown whether this will improve outcomes.</p