Edris A F Mahtab

Leiden University Medical Centre, Leiden, South Holland, Netherlands

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Publications (13)38.46 Total impact

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    ABSTRACT: OBJECTIVES: Borderline left ventricle is the left ventricular morphology at the favorable end of the hypoplastic left heart syndrome. In contrast to the severe end, it is suitable for biventricular repair. Wondering whether it is possible to identify cases suitable for biventricular repair from a developmental viewpoint, we investigated the myocardial histology of borderline and severely hypoplastic left ventricles. METHODS: Postmortem specimens of neonatal, unoperated human hearts with severe hypoplastic left heart syndrome and borderline left ventricle were compared with normal specimens and hearts from patients with transposition of the great arteries. After tissue sampling of the lateral walls of both ventricles, immunohistochemical and immunofluorescence stainings against cardiac troponin I, N-cadherin, and connexin 43, important for proper cardiac differentiation, were done. RESULTS: All severely hypoplastic left hearts (7/7) and most borderline left ventricle hearts (4/6) showed reduced sarcomeric expressions of troponin I in left and right ventricles. N-cadherin and connexin 43 expressions were reduced in intercalated disks. The remaining borderline left ventricle hearts (2/6) were histologically closer to control hearts. CONCLUSIONS: Four of 6 borderline left ventricle hearts showed myocardial histopathology similar to the severely hypoplastic left hearts. The remainder were similar to normal hearts. Our results and knowledge regarding the role of epicardial-derived cells in myocardial differentiation lead us to postulate that an abnormal epicardial-myocardial interaction could explain the observed histopathology. Defining the histopathologic severity with preoperative myocardial biopsy samples of hearts with borderline left ventricle might provide a diagnostic tool for preoperative decision making.
    The Journal of thoracic and cardiovascular surgery 03/2012; · 3.41 Impact Factor
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    ABSTRACT: The inhibitor of differentiation Id2 is expressed in mesoderm of the second heart field, which contributes myocardial and mesenchymal cells to the primary heart tube. The role of Id2 in cardiac development is insufficiently known. Heart development was studied in sequential developmental stages in Id2 wildtype and knockout mouse embryos. Expression patterns of Id2, MLC-2a, Nkx2.5, HCN4, and WT-1 were analyzed. Id2 is expressed in myocardial progenitor cells at the inflow and outflow tract, in the endocardial and epicardial lineage, and in neural crest cells. Id2 knockout embryos show severe cardiac defects including abnormal orientation of systemic and pulmonary drainage, abnormal myocardialization of systemic and pulmonary veins, hypoplasia of the sinoatrial node, large interatrial communications, ventricular septal defects, double outlet right ventricle, and myocardial hypoplasia. Our results indicate a role for Id2 in the second heart field contribution at both the arterial and the venous poles of the heart.
    Developmental Dynamics 11/2011; 240(11):2561-77. · 2.59 Impact Factor
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    ABSTRACT: 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 Ca(2+) 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.
    Journal of Molecular and Cellular Cardiology 10/2010; 49(4):606-16. · 5.15 Impact Factor
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    ABSTRACT: 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.
    Developmental Dynamics 08/2010; 239(8):2307-17. · 2.59 Impact Factor
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    ABSTRACT: Electrical Activity and RhoA in the Embryo. Myocardium at the venous pole (sinus venosus) of the heart has gained clinical interest as arrhythmias can be initiated from this area. During development, sinus venosus myocardium is incorporated to the primary heart tube and expresses different markers than primary myocardium. We aimed to elucidate the development of sinus venosus myocardium, including the sinoatrial node (SAN), by studying expression patterns of RhoA in relation to other markers, and by studying electrical activation patterns of the developing sinus venosus myocardium. 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. 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.
    Journal of Cardiovascular Electrophysiology 04/2010; 21(11):1284-92. · 3.48 Impact Factor
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    ABSTRACT: Neoaortic root dilatation is observed after the arterial switch operation for transposition of the great arteries. Although structural differences in the vessel wall of these patients may be of influence, we hypothesize that a histomorphologic difference in composition and embedding of the fibrous annulus in transposition of the great arteries may play a role in neoaortic root dilatation. Two normal human hearts and two unoperated human hearts with transposition of the great arteries, 1 day postnatal, were studied. Histologic sections stained for collagen, myocardium, and elastin were prepared, and three-dimensional reconstructions of the outflow tracts were made to enable comparison of the morphologic structures between the normal hearts and those with transposition of the great arteries. The amount of collagen in the arterial roots was diminished in hearts with transposition of the great arteries compared with the normal hearts. In addition, the anchorage and embedding of both arterial roots in the myocardium was less extensive in transposition of the great arteries. The changed position of the arteries in the malformed hearts results in less support for the roots from the surrounding atrioventricular myocardium. The combination of the observed histomorphologic differences in amount of collagen and myocardial support may be an explanation for the neoaortic root dilatation observed after the arterial switch operation. The developmental background of the observed deficient fibrous annulus formation may originate from an epicardial problem.
    The Annals of thoracic surgery 10/2009; 88(4):1300-5. · 3.45 Impact Factor
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    ABSTRACT: We investigated the role of podoplanin in development of the sinus venosus myocardium comprising the sinoatrial node, dorsal atrial wall, and primary atrial septum as well as the myocardium of the cardinal and pulmonary veins. We analyzed podoplanin wild-type and knockout mouse embryos between embryonic day 9.5-15.5 using immunohistochemical marker podoplanin; sinoatrial-node marker HCN4; myocardial markers MLC-2a, Nkx2.5, as well as Cx43; coelomic marker WT-1; and epithelial-to-mesenchymal transformation markers E-cadherin and RhoA. Three-dimensional reconstructions were made and myocardial morphometry was performed. Podoplanin mutants showed hypoplasia of the sinoatrial node, primary atrial septum, and dorsal atrial wall. Myocardium lining the wall of the cardinal and pulmonary veins was thin and perforated. Impaired myocardial formation is correlated with abnormal epithelial-to-mesenchymal transformation of the coelomic epithelium due to up-regulated E-cadherin and down-regulated RhoA, which are controlled by podoplanin. Our results demonstrate an important role for podoplanin in development of sinus venosus myocardium.
    Developmental Dynamics 01/2009; 238(1):183-93. · 2.59 Impact Factor
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    ABSTRACT: The developing sinus venosus myocardium, derived from the posterior heart field, contributes to the atrial septum, the posterior atrial wall, the sino-atrial node, and myocardium lining the pulmonary and cardinal veins, all expressing podoplanin, a coelomic and myocardial marker. We compared development and differentiation of the myocardium and vascular wall of the pulmonary veins (PV), left atrial dorsal wall, and atrial septum in wild type with podoplanin knockout mouse embryos (E10.5-E18.5) by 3D reconstruction and immunohistochemistry. Expression of Nkx2.5 in the pulmonary venous myocardium changes from mosaic to positive during development pointing out a high proliferative rate compared with Nkx2.5 negative myocardium of the sino-atrial node and cardinal veins. In mutants, myocardium of the PVs, dorsal atrial wall and atrial septum was hypoplastic. The atrial septum and right-sided wall of the PV almost lacked interposed mesenchyme. Extension of smooth muscle cells into the left atrial body was diminished. We conclude that myocardium of the PVs, dorsal atrial wall, and atrial septum, as well as the smooth muscle cells, are derived from the posterior heart field regulated by podoplanin.
    Pediatric Research 10/2008; 65(1):27-32. · 2.67 Impact Factor
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    ABSTRACT: Epicardium and epicardium-derived cells have been shown to be necessary for myocardial differentiation. To elucidate the function of podoplanin in epicardial development and myocardial differentiation, we analyzed podoplanin knockout mouse embryos between embryonic day (E) 9.5 and E15.5 using immunohistochemical differentiation markers, morphometry, and three-dimensional reconstructions. Podoplanin null mice have an increased embryonic lethality, possibly of cardiac origin. Our study reveals impairment in the development of the proepicardial organ, epicardial adhesion, and spreading and migration of the epicardium-derived cells. Mutant embryos show a hypoplastic and perforated compact and septal myocardium, hypoplastic atrioventricular cushions resulting in atrioventricular valve abnormalities, as well as coronary artery abnormalities. The epicardial pathology is correlated with reduced epithelial-mesenchymal transformation caused by up-regulation of E-cadherin, normally down-regulated by podoplanin. Our results demonstrate a role for podoplanin in normal cardiac development based on epicardial-myocardial interaction. Abnormal epicardial differentiation and reduced epithelial-mesenchymal transformation result in deficient epicardium-derived cells leading to myocardial pathology and cardiac anomalies.
    Developmental Dynamics 04/2008; 237(3):847-57. · 2.59 Impact Factor
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    ABSTRACT: The cardiac conduction system (CCS) encompasses a complex system responsible for the coordinated contraction of the heart. In the developing heart, as well as in the adult heart, tissues of the (putative) CCS are characterized by different properties than the surrounding working myocardium, which can be observed on a histological level, as well as by the expression patterns of several immunohistological and molecular markers. In recent years, many markers have been studied that have helped to elucidate the processes involved in CCS development. It has become clear that multiple genes, cells and their interactions are involved in this complex process. In this article, an overview of the current knowledge of CCS development is supplied. Furthermore, several controversies regarding conduction system development are discussed, as well as the possible significance of embryologic development of the CCS for the development of arrhythmias later in life.
    The Scientific World Journal 02/2008; 8:239-69. · 1.73 Impact Factor
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    ABSTRACT: Mice lacking the zinc finger transcription factor specificity protein 3 (Sp3) die prenatally in the C57BL/6 background. To elucidate the cause of mortality we analyzed the potential role of Sp3 in embryonic heart development. Sp3 null hearts display defective looping at embryonic day 10.5 (E10.5), and at E14.5 the Sp3 null mutants have developed a range of severe cardiac malformations. In an attempt to position Sp3 in the cardiac developmental hierarchy, we analyzed the expression patterns of >15 marker genes in Sp3 null hearts. Expression of cardiac ankyrin repeat protein (Carp) was downregulated prematurely after E12.5, while expression of the other marker genes was not affected. Chromatin immunoprecipitation analysis revealed that Sp3 is bound to the Carp promoter region in vivo. Microarray analysis indicates that small-molecule metabolism and cell-cell interactions are the most significantly affected biological processes in E12.5 Sp3 null myocardium. Since the epicardium showed distension from the myocardium, we studied expression of Wt1, a marker for epicardial cells. Wt1 expression was diminished in epicardium-derived cells in the myocardium of Sp3 null hearts. We conclude that Sp3 is required for normal cardiac development and suggest that it has a crucial role in myocardial differentiation.
    Molecular and cellular biology 12/2007; 27(24):8571-82. · 6.06 Impact Factor
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    ABSTRACT: Recent advances in the study of cardiac development have shown the relevance of addition of myocardium to the primary myocardial heart tube. In wild-type mouse embryos (E9.5-15.5), we have studied the myocardium at the venous pole of the heart using immunohistochemistry and 3D reconstructions of expression patterns of MLC-2a, Nkx2.5, and podoplanin, a novel coelomic and myocardial marker. Podoplanin-positive coelomic epithelium was continuous with adjacent podoplanin- and MLC-2a-positive myocardium that formed a conspicuous band along the left cardinal vein extending through the base of the atrial septum to the posterior myocardium of the atrioventricular canal, the atrioventricular nodal region, and the His-Purkinje system. Later on, podoplanin expression was also found in the myocardium surrounding the pulmonary vein. On the right side, podoplanin-positive cells were seen along the right cardinal vein, which during development persisted in the sinoatrial node and part of the venous valves. In the MLC-2a- and podoplanin-positive myocardium, Nkx2.5 expression was absent in the sinoatrial node and the wall of the cardinal veins. There was a mosaic positivity in the wall of the common pulmonary vein and the atrioventricular conduction system as opposed to the overall Nkx2.5 expression seen in the chamber myocardium. We conclude that we have found podoplanin as a marker that links a novel Nkx2.5-negative sinus venosus myocardial area, which we refer to as the posterior heart field, with the cardiac conduction system.
    The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 02/2007; 290(1):115-22. · 1.34 Impact Factor
  • Wiener klinische Wochenschrift 02/2007; 119(11-12 Suppl 1):13-5. · 0.81 Impact Factor

Publication Stats

158 Citations
38.46 Total Impact Points


  • 2008–2012
    • Leiden University Medical Centre
      • Department of Anatomy and Embryology
      Leiden, South Holland, Netherlands
    • University of Groningen
      • Department of Cardiology
      Groningen, Province of Groningen, Netherlands
  • 2007
    • Erasmus MC
      • Department of Cell Biology
      Rotterdam, South Holland, Netherlands