Heart Transplantation

Introduction

Research focused on heart failure and heart transplantation (HTx) has a long-standing tradition in the Department of Pathology. Research is performed in close collaboration with the Department of Heart and Lung/Cardiology and Cardiosurgery at the UMC Utrecht.

Heart Transplantation

The first heart transplantation in Utrecht was performed in 1984 and research on acute rejection screening after heart transplantation started around 1985. In early studies, in close collaboration with the department of Immunology at the UMC-Utrecht, Dr. Peter Wijngaard analysed the possibility to replace the invasive rejection screening by endomyocardial biopsies by cytoimmunologic monitoring after HTx.
Subsequent studies focused on T-cells in acute rejection episodes. Donor-specific non-responsiveness was shown to develop in the first 6 months after HTx in cytotoxic T-cells. Dr. Hu Huaizhong demonstrated in cloned graft infiltrating T-cells that this non-responsiveness coincides with a change in T-Cell Receptor-Vβ repertoire. This non-responsiveness was not observed in T-helper cells. However, dr. Els van Hoffen showed in elegant studies using in situ hybridisation in combination with Immunohistochemistry (IHC) and confocal laser scan microscopy (CLSM) that a large proportion of infiltrating lymphocytes are apoptotic. An observation confirmed in later years in many other organ transplant situations. Her studies on cytokines revealed that a high frequency of IL-4 producing lymphocytes correlated with a reduced incidence of graft rejection. The studies on the role of cytokines were expanded by analyzing the influence of single nucleotide-polymorphisms (SNP) in TGF-β, TNF-α, IL-4 and IL-4R in graft rejection. Also these molecular biological studies by dr. Femke Bijlsma showed a prominent role of Th2-cells, and especially IL-4 in preventing graft rejection


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Figure 1. Cardiac Allograft Vasculopathy (CAV)
1. Neo-intima Luminal Layer (met mononuclear cell (MNC) infiltrates), 2. Neo-intima Smooth Muscle cell Layer, 3. Media, 4. Adventitia, 5. MNC accumulations extravascular.

As immunosuppressive regiments improved, and the number of acute rejections reduced considerably, we started studies on chronic rejection. Coronary arteries of heart transplants are obtained at autopsy and analyzed for the presence of cardiac allograft vasculopathy (CAV). Morphologically, it was determined that CAV is not primarily due to immigrating smooth muscle cells (SMC) in the intima (as generally described), but due to an increase of a loose connective tissue in the inner part of the neo-intima (Luminal Layer; figure 1). In this Luminal Layer a large infiltrate of mononuclear cells (MNC) was observed. By IHC the presence and localization of various lymphocyte and macrophage markers, chemokines and chemokine receptors was analyzed. Furthermore, on mRNA isolated from the coronary arteries the expression of these markers was analyzed by quantitative PCR. These studies (by Van Loosdregt and Hagemeijer) indicated that the majority of infiltrating T-cells in the arterial wall are activated memory T-cells producing γ-interferon. More detailed characterization of the mnc infiltrate by double IHC staining and in situ hybridisation revealed that next to the activated Th1-population a small but distinct population of Th2-cells is present in the arterial wall. By Q-PCR (Low Density Array) on mRNA isolated from micro-dissected layers of CAV arteries (figure 2), it was shown that Th17-cells were not active, but a distinct population of M2-macrophages could be responsible for the pro-fibrotic response. This pro-fibrotic response is presently the main subject of research in CAV in human HTx and animal studies.

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Figure 2 Laser micro-dissection of the various layers of the wall of a coronary artery with CAV

Most of the earlier studies on CAV were performed on coronary arteries from patients transplanted less than 2 years earlier. Coronary arteries of HTx patients that were transplanted for more than 5 years often show a more collagen rich fibrosis. Drs. Manon Huibers recently started her Ph.D. studies and will reevaluate the morphology of CAV arteries at various times after HTx. She will also analyse the fibrotic response in the arterial wall in more detail in a human-mouse model, that is set up in collaboration with Prof.dr. G. Tellides (New Haven, USA) and dr. Jan-Luuk Hillebrands (UMC-Groningen). In this mouse model, SCID-Beige mice are transplanted with human arterial grafts. Under influence of allogeneic human blood lymphocytes, these grafts develop a characteristic intima proliferation, comparable to CAV. This model will enable us to study the role of various cells and cytokines/growth factors in this proliferative response.
In another series of experiments Manon Huibers with Heleen Vromans are analysing the role of microRNAs (miR) in serum of HTx patients and the neointima of Human CAV arteries. The role of these miR as biomarkers and possible therapeutic targets for CAV is investigated.

To analyse whether patient cells enter the donor graft and (re)populate the donor tissues, we analysed in male-female heart and bone marrow transplantations the capacity of bone marrow derived stem cells to produce male cardiomyocytes in the female heart by Y-chromosome in situ hybridization. This indicated that only few male cardiomyocytes (1% or less) were present in the female hearts of these gender mismatched transplantations.

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Figure 3. Infiltration of recipient cells in donor heart
One Y-chromosome positive cardiomyocytes in a female heart after heart transplantation in a male individual (yellow arrow). Bottom picture is view in Z-direction at the level of the 2 white arrows.

Heart Failure and Left Ventricular Mechanical Support

In 1993 the first left ventricular assist device (LVAD) was implanted in Utrecht. This initiated studies on the changes in the heart after pulsatile LVAD support, by comparing the pre-LVAD heart tissue (heart apex) with the explanted heart tissue (at HTx; post-LVAD). Studies by dr. Nicolaas de Jonge showed an improved exercise performance in LVAD-patients. Morphologically, the size of the cardiomyocytes decreased but immunohistochemical studies on the heart tissues indicated persistent structural myocyte damage. The number of apoptotic cardiomyocytes was low both pre- as well as post-LVAD.
Follow-up studies were dedicated to the changes in the extra cellular matrix (ECM) during LVAD support. Annette Gijsbers-Bruggink studied the changes in collagens and the role of matrix metalloproteinases by immunohistochemistry, zymography (gel and in situ), biochemically, Q-PCR and cardiomyocyte cultures. The ECM changes in a biphasic pattern. Initially the ECM increases in size but after 100-150 days the ECM reduces in time to almost normal levels. Prominent changes were also observed in collagen IV content of the basement membranes. This ECM analysis also included characterization of the fibrils by electron microscopy. For these studies in 2005 Annette Gijsbers-Bruggink was nominated for the Caves Award of the ISHLT in Philadelphia (US) and received the Young Investigator Award of the European Society of Heart Failure (ECS) in Lisbon.
Subsequently, dr. M. Van Oosterhout (supported by a Dekker Grant of the Dutch Heart Foundation; 2006-2008) studied the changes in mRNA (by Q-PCR in Low Density Array analysis) in the myocardium during LVAD support. Next to these human studies, he also studied the effects of unloading on cardiomyocytes, by analysing the effect of stretching on neonatal rat cardiomyocytes in vitro in close collaboration with Prof. dr. A. van de Laarse (Dept of Cardiology at the Leiden University Medical Centre). In these studies the role of integrins and ECM components on stretching was determined.
At present, drs. Marguerite Schipper (pathologist) studies the changes in the protein content and composition in pre- and post LVAD biopsies of (pulsatile) LVAD patients by 2 D electroforesis and mass spectrometry (proteomics; in collaboration with dr. N. Bovenschen, head of Laboratory of Proteomics in UMC-U). Observed changes in integrins and osteopontin are studied in more detail. For this work Petra van der Weide was nominated for the Caves awards at the ISHLT in Chicago (2010). Dr. Schipper was the first that described changes in regulatory miRNAs in heart tissue after LVAD support.
Studies on the changes in the myocardium of LVAD supported patients is shifted from patients supported by a pulsatile LVAD to patients that are supported by a continuous flow LVAD. Drs. Sjoukje Lok has recently started her Ph.D studies analysing changes in pro- and anti-fibrotic biomarkers both in the myocardium and the serum of LVAD supported patients. These changes will be linked to changes in miRNAs also both in the myocardium and the plasma of LVAD patients. In collaboration with the Group of Prof.dr. Leon de Windt, that showed that miRNA inhibitors (antagomirs) can inhibit heart failure in mice, it was shown that the same target miRNAs are present in the myocardium of heart failure patients.


The Heart Failure Transplantation Study Group UMC Utrecht

Department of Pathology
Department of Pathology
dr. Roel De Weger, Immunologist/Exp Pathologist
dr. Marguerite Schipper, Pathologist
dr. Hub Dullens, Exp Pathologist/Animal studies
dr. Niels Bovenschen, Biochemist in proteomics

Mrs. Patricia Bachmann – Plomp, Management Assistant

Ph.D students:
Sjoukje Lok: Myocardial Changes during continuous flow LVAD support.
Manon Huibers : Chronic Allograft Vasculopathy in man and hu-mice.

Technicians:
Dick Van Wichen, Immunohistochemistry and animal surgery
Joyce Van Kuik, Q-PCR, High resolution Melting, miRNA and Western Blotting
Erica Sierra - de Koning, Laser tissue microdissection and proteomics
Petra Van Der Weide, Western Blotting and proteomics


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Figure 4. Pathology HF & HTx-group.
(ltr Erica Siera-de Koning, Joyce van Kuik, Dianne Hamerpagt, Manon Huibers, Heleen Vroman, Sjoukje Lok, Fay Nous, Petra van der Weide, Roel de Weger, Hub Dullens and Dick van Wichen)

Undergraduate students (MSc; 2010-2011):
Dianne Hamerpagt (2010)
Heleen Vroman (2010-2011)
Fay Nous (2010-2011)
Maartje Geerlings (2011)
Ankie van Geffen (2011)

Division of Heart and Lung (DHL)
dr. Nicolaas De Jonge, Cardiologist
dr. Hans Kirkels, Cardiologist
dr. Corinne Klopping, Cardiologist
Prof.dr. Jaap Lahpor, Cardiosurgereon
Collaboration in the UMC Utrecht
Prof.dr. Marc A. Vos, Department of Physiology (LVAD and heart failure studies)
Prof.dr. Gerard Pasterkamp and dr. Aryan Vink, Department of Cardiology and Pathology (Atherosclerose)

Collaboration outside UMC Utrecht
Several studies are performed in close collaboration with the Heart-Transplantation study group in Rotterdam, The Netherlands: Prof.dr. Willem Weimar and dr. Carla Baan.
Studies on miRNA are performed in close collaboration with Prof.dr. L.J. de Windt and dr. Paula da Costa Martins in Department of Cardiology, University of Maastricht.
Animal studies are set-up in collaboration with Prof.dr. G. Tellides in New Haven, USA, and dr. Jan Luuk Hillebrand in the Department of Pathology at the UMC-Groningen.


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Figure 5. Heleen Vroman and Manon Huibers and their posters at the Cardiovascular Conference in Noordwijkerhout (april 2011)

PUBLICATIONS

  1. Wijngaard, P.L.J., J.A. Gimpel, H.J. Schuurman, A. van der Meulen, F.H.J. Gmelig-Meyling, and G. Jambroes. Rejection monitoring after heart transplantation: Cytoimmunologic monitoring on blood cells and quantitative birefringence measurements on endomyocardial specimens. J. Clin Pathology 43, 137-142, 1990. 
  2. W.B. Tuijnman, F.H.J. Gmelig-Meyling, G. Jambroes, and H.J. Schuurman. Endomyocardial biopsies after heart transplantation: presence of markers indicative of activation. Transplantation 55, 103-107, 1993. 
  3. Hu, H.Z., R.A. De Weger, K. Bosboom-Kalsbeek, M.G.J. Tilanus, J. Rozing, and H.-J. Schuurman. T-cell receptor Vß variable gene family expression in human peripheral blood lymphocytes at the mRNA and membrane protein level. Clin. Exp. Immunol. 88, 335-340, 1992. 
  4. Hu, H.Z., M.R. Queiro, M.G.J. Tilanus, R.A. De Weger, and H.-J. Schuurman. Expression of T-cell receptor alpha and beta variable genes in normal and malignant human T cells. British Journal of Haematology 84, 39-48, 1993. 
  5. Hu, H.Z., N. de Jonge, H. Doornewaard, F.H.J. Gmelig-Meyling, M.G.J. Tilanus, K. Bosboom, M. Robertus, S. Plomp, F. Van Reijsen, H.-J. Schuurman and R.A. De Weger. Cytotoxic T-lymphocytes infiltrating the human heart allograft show a restriction in T-cell receptor Vß gene usage: A study on serial biopsy and blood specimens. Journal of Heart and Lung Transplantation 13, 1058-1071, 1994. 
  6. Hu, H.Z., M. Robertus, N. de Jonge, F.H.J. Gmelig-Meyling, A. Van Der Meulen, H.-J. Schuurman,H. Doornewaard, H.C. Van Prooijen and R.A. De Weger. Reduction of donor-specific T-lymphocyte precursors in peripheral blood of allografted heart recipients. Transplantation 58, 1263-1268, 1994. 
  7. Klein, S., J.G. Golverdingen, A.G.M. Bouwens, M.G.J. Tilanus, and R.A. De Weger. Two alternatively spliced IL4 isoforms in lymphoid cells. Immunogenetics 41, 57, 1995. 
  8. Klein, S., D.F. Van Wichen, J. Golverdingen, K.C. Jacobse, R. Broekhuizen, and R.A. De Weger. An improved, sensitive non radioactive in situ hybridization method for the detection of cytokine mRNAs. APMIS 103, 345-353, 1995. 
  9. Van Prooijen, H.C., M.I. Aarts-Riemens, W.R. Van Oostendorp, R.J. Hené, F.H.J. Gmelig-Meyling and R.A. de Weger. Prevention of donor-specific T-cell unresponsiveness after buffy coat-depleted blood transfusion. British Journal of Heamatology 91, 219-223, 1995. 
  10. Van Hoffen, E., D. Van Wichen, I. Stuij, N. De Jonge, C. Klöpping, J. Laphor, J. Van Den Tweel, F. Gmelig-Meyling, and R.A. De Weger. In situ expression of cytokines in human allografts. .American Journal of Pathology 149, 1991-2003, 1996. 
  11. Van Hoffen, E., F.H.J. Gmelig-Meyling, E.C. Bosboom-Kalsbeek, H. Hu, N. De Jonge, M.G.J. Tilanus, J.R. Laphor, and R.A. De Weger. Cytokine mRNA-expression by donor-specific cytotoxic T-cell clones after allogeneic heart transplantation. The Journal of Heart and Lung Tansplantation 16, 216-221, 1997. 
  12. De Weger, R.A., E. Van Hoffen, D.F. Van Wichen, R. Broekhuizen, J. Parker, J.J. Bredée, and F.H.J. Gmelig-Meyling. Cytokine receptor clinical studies: Expression of cytokine receptors in acute rejection of human heart allografts. In: Leucocyte Typing VI, White cell differentiation antigens (Eds: T. Kishimoto, H. Kikutani, A.E.G.Kr. Von Dem Borne, S.M. Goyert, D.Y. Mason, M. Miyasaka, L. Moretta, K. Okumura, S. Shaw, T.A. Springer, K. Sugamura, and H. Zola). Garland Publishing, Inc. New York, pp. 920-922, 1998. 
  13. Van Hoffen, E., D.F. van Wichen, J.C. Leemans, R.A.F. Broekhuizen, A.H. Bruggink, M. De Boer, N. De Jonge, H. Kirkels, P.J. Slootweg, F. H.J. Gmelig-Meyling and R.A. De Weger. T- Cell Apoptosis in Human Heart Allografts. Association with lack of co-stimulation? American Jounal of Pathology, 153, 1813-1824, 1998. 
  14. Van Wichen, D.F. E. Van Hoffen, F. Veninga, F.H.J. Gmelig-Meyling, J. Lahpor, and R.A. De Weger. Intracardial dendritic cells and expression of co-stimulatory molecules after heart transplantation. Transplantation Proceedings 30, 913-915, 1998. 
  15. Slootweg, P.J. and R.A. De Weger. Cardiac transplantation pathology: an update. Current Diagnostic Pathology 5, 198-203, 1998. 
  16. Van Hoffen, E., E. Polen, M. Robertus-Teunissen, N. de Jonge, J.R. Lahpor, F.H.J. Gmelig-Meyling, R.A.De Weger. High frequency of IL-4 producing helper T lymfocytes associated with a reduced incidence of heart allograft rejection. Transplant International, 13 (suppl 1), S216-S224, 2000. 
  17. Vos, I.H.C., R. Govers, H-J. Gröne, L. Kleij, M. Schurink, R.A. De Weger, R. Goldschmeding and T.J. Rabelink. F6B decoy oligodeoxynucleotides reduce monocyte infiltration in renal allografts. The FASEB Journal 14, 815-822, 2000. 
  18. Bijlsma F.J., A.H. Bruggink , M. Hartman , F.H.J. Gmelig-Meyling, M.G.J. Tilanus, N. de Jonge, R.A. De Weger.. No association between IL-10 promoter gene polymorphism and heart failure or rejection following cardiac transplantation. Tissue Antigens 57; 151-153, 2001. 
  19. Bijlsma, F.J., J. Van Kuik, N. De Jonge, M. Tilanus, E. Rozemuller, F.H. Gmelig-Meyling, R.A. De Weger. Donor interleukin-4 promotor gene polymorphism influences allograft rejection after heart transplantation. J.Heart and Lung transplant 21, 340-346, 2002. 
  20. Bijlsma, F.J., J. Van Kuik, E. Van Hoffen, N. De Jonge, F.H. Gmelig-Meyling, and R.A. De Weger. Acute cardiac transplant rejection is associated with low frequencies of IL-4 producing helper T-lymphocytes rather than with IL-4 promotor or splice variants. Human Immunology 63, 317-323, 2002. 
  21. De Jonge, N, H. Kirkels, J.R. Lahpor, C. Klopping, E. J. Hulzebos, A. Brutel de la Riviere, E. O. Robles de Medina. Exercise performance in patients with end-stage heart failure after implantation of a left ventricular assist device and after heart transplantation; an outlook for permanent assisting? J. Am Coll Cardiol 37, 1794-1799, 2001. 
  22. De Jonge, N., D.F. Van Wichen, M.E.I. Schipper, J.R. Lahpor, F.H.J. Gmelig-Meyling, E.O. Robles de Medina, R.A. De Weger. Left ventricular assist in end-stage heart failure: persistence of structural myocyte damage after unloading. An immunohistochemical analysis of the contractile myofilaments. J. Am. Coll, Cardiol. 39, 963-969, 2002. 
  23. Van Rijen, M.M.L., M.L. Kuijf, H.J. Metselaar, H.W. Tilanus, G.J. Bouma, R.A. De Weger, M. Jonker, and J. Kwekkeboom. CD 154 is expressed during treatment with calcineurin inhibitors after organ transplantation. Transplantation 73, 1666-1672, 2002. 
  24. Bijlsma, F.J., A.A. Van Der Horst, M.G.J. Tilanus, E. Rozemuller, N. De Jonge, F.H. Gmelig-Meyling, and R.A. De Weger. No association between transforming growth factor b1 gene polymorphism and acute allograft rejectionafter cardiac transplantation. Transplant Immunology, 10, 43-47, 2002. 
  25. De Weger, R.A., M.G.J. Tilanus, E. Rozemuller. DNA polymorphisms and mutation analysis; Some applications in the pathology practice. Histopathology; 41 suppl 1, 1-11, 2002. 
  26. Bijlsma, F.J., A.H. Bruggink, F.H.J. Gmelig-Meyling, and R.A. De Weger. Cytokine gene polymorphism in heart transplantation: a review. Current Genomics 4, 205-215, 2003. 
  27. De Jonge, N. MD, D.F. van Wichen, J. van Kuik, H. Kirkels MD, J.R. Lahpor MD, F.H.J. Gmelig-Meyling PhD, J.G. van den Tweel MD, R.A. de Weger PhD. Cardiomyocyte cell death in patients with end-stage heart failure before and after support with a left ventricular assist device: low incidence of apoptosis despite ubiquitours mediators. J. Heart and Lung Transplantation 22, 1028-1036, 2003. 
  28. Van Rijn, R.S., E.R. Simonetti, A. Hagenbeek, M.C. Hogenes, R.A. De Weger, M.R. Canninga-Van Dijk, K. Weijer, H. Spits, G. Storm, L. Van Bloois, G. Rijkers, A.C. Martens and S.B. Ebeling. A new xenograft model for graft versus host disease by intravenous transfer of human peripheral blood mononuclear cells in RAG2 -/- γc -/- double mutant mice. Blood 102, 2522-2531, 2003.
  29. Bijlsma, F.J., A.H. Bruggink, F.H.J. Gmelig-Meyling, and R.A. De Weger. Cytokine gene polymorphism in heart transplantation: a review. Current Genomics 4, 205-215, 2003. 
  30. De Jonge, N. MD, D.F. van Wichen, J. van Kuik, H. Kirkels MD, J.R. Lahpor MD, F.H.J. Gmelig-Meyling PhD, J.G. van den Tweel MD, R.A. de Weger PhD. Cardiomyocyte cell death in patients with end-stage heart failure before and after support with a left ventricular assist device: low incidence of apoptosis despite ubiquitous mediators. J. Heart and Lung Transplantation 22, 1028-1036, 2003. 
  31. Weijtens M., A. van Spronsen, A. Hagenbeek, R.A. de Weger, A. Martens. Ganciclovir-mediated elimination of HSV-Tk+ T cells and cure of graft-vs-host disease in an allogeneic bone marrow transplantation model in the rat. Experimental Hematology 32, 962-969, 2004. 
  32. Groot-Kruseman, C.C. Baan, P.E. Zondervan, R.A. De Weger, H.G.M. Niesters, A.H.M.M. Balk, and W. Weimar. Apoptotic death of infiltrating cells in human cardiac allografts is regulated by IL-2, FAS-L, and FLIP. Transplantation Proceedings 36, 3143-3148, 2004. 
  33. De Jonge, N., J.R. Lahpor, D.F. Van Wichen, H. Kirkels, F.H.J. Gmelig-Meyling, J.G. van den Tweel, P.A. Doevendans, and R. A. de Weger. Similar left and right ventricular sarcomere structure after support with a left ventricular assist device suggests the utility of right ventricular biopsies to monitor left ventricular reverse remodeling. International Journal of Cardiology 98, 465-470, 2005.
  34. De Vries, W.B., M.P. Bal, P. Homoet-Van der Kraak, P.J.G.H. Kamphuis, F.R. Van der Leij, J. Baan, P. Steendijk, R.A. De Weger, F. Van Bel, M.F.M. Van Oosterhout. Suppression of physiological cardiomyocyte proliferation in the rat pup after neonatal glucocorticosteroid treatment. Basic and Research Cardiology 1001, 36-42, 2006.
  35. Bruggink, A.H., N. de Jonge, M.F.M. van Oosterhout, D.F. Wichen, E. de Koning, J.R. Lahpor, H. Kemperman, F.H.K. Gmelig-Meyling, R.A. de Weger. Brain Natriuretic Peptide is produced both by cardiomyocytes, and cells infiltrating the heart in patients with severe heart failure supported by a Left Ventricular Assist Device. Journal of Heart and Lung Transplantation 25, 174-180, 2006. 
  36. Bruggink, A.H., M.F.M. van Oosterhout, N. De Jonge, B. Ivangh, J. Van Kuik, R.H.A.M. Voorbij, J.P.M. Cleutjens, F.H.J. Gmelig-Meyling, and R.A. De Weger. Reverse remodeling of the myocardial extracellular matrix after prolonged left ventricular assist device support follows a biphasic pattern. Journal of Heart and Lung Transplantation 25, 1091-1098, 2006. 
  37. Van Loosdregt, J., M.F.M. Van Oosterhout, A.H. Bruggink, D.F. van Wichem, J. Van Kuik, E. De Koning, C.C. Baan, N. De Jonge, F.H.J. Gmelig-Meyling, and R.A. De Weger. The chemokine and chemokine receptor profile of infiltrating cells in the wall of arteries with cardiac allograft vasculopathy is indicative of a memory T-helper 1 Response. Circulation 114, 1599-1607, 2006. 
  38. Roepman, P., E. de Koning, D. van Leenen, R.A. de Weger, J. A. Kummer, P.J. Slootweg and Frank Holstege. Dissection of a metastatic gene expression signature into distinct components. Genome Biology 7, R117-12, 2006. 
  39. Bruggink, A.H. M.F.M. van Oosterhout, N. De Jonge, J.P.M. Cleutjens, D.F. Van Wichen, J. Van Kuik, M.G.J. Tilanus, F.H.J. Gmelig-Meyling, J.G. Van Den Tweel and R.A. De Weger. TypeIV collagen degradation in the myocardial basement membrane after unloading of the failing heart by a left ventricular assist device. Laboratory Investigation 87, 1125-1137, 2007 
  40. De Weger, R.A., I. Verbrugge, A.H. Bruggink, M.F.M.Van Oosterhout, Y de Souza, D.F. Van Wichen , F. H.J. Gmelig Meyling, N.De Jonge, and L.F. Verdonck. Stem cell derived cardiomyocytes after bone marrow and heart transplantation. Bone Marrow Transplantation 41, 563-569, 2008. 
  41. Van Kuik, J., E. De Koning, D.F. Van Wichen, M.F.M. Van Oosterhout, F.H.J. Gmelig-Meyling, N. De Jonge, and R.A. de Weger. The IL-23/IL-17 axis in human cardiac allograft vasculopathy. Journal Heart and Lung Transplantation 26, S113, 2007. 
  42. De Koning, E., J. Van Kuik, D.F. Van Wichen, M.F.M. Van Oosterhout, F.H.J. Gmelig-Meyling, N. De Jonge, and R.A. de Weger. M2 macrophages, key players in the fibro-proliferative response in cardiac allograft vasculopathy. Journal Heart and Lung Transplantation 26, S145, 2007. 
  43.  Van Rhijn, I, R. Spiering, M. Smits, M.T.M. Van Blokland, R. De Weger, W. van Eden, V.P.M.G. Rutten, A.P. Koets. Highly diverse TCR delta chain repertoire in bovine tissues due to the use of up to four D segments per delta chain. Molecular Immunology 44, 3155-3161, 2007. 
  44. Post, S, Peeters, W., E. Busser, D. Lamers, J.P.G. Sluijter, M.-J. Goumans, R.A. De Weger, F.L. Moll, P.A. Doevendans, G. Pasterkamp and A. Vink. Balance between Angiopoietin-1 and angiopoietin-2 is in favour of angiopoietin-2 in atherosclerotic plaques with high microvessel density. J Vascular Research 45, 244-250, 2008. 


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    Figure 6: Joyce van Kuik presents data during the ISHLT in Paris 2009


  45. Hagemeijer, M.C., M.F.M. Van Oosterhout, D.F. Van Wichen, J. Van Kuik, E. Siera-de Koning, F.H.J. Gmelig-Meyling, M.E.I. Schipper, N. De Jonge, and R.A. De Weger. T-cells in cardiac allograft vasculopathy are skewed to memory Th-1 cells in the presence of a distinct Th-2 population. American Journal of Transplantation 8, 1040-1050, 2008. Editorial: M.L. Rose. A closer look at T-cells in the artery wall. Am. J. Transplantation 8, 915-916, 2008. 
  46. Bruggink, A.H., M.F.M. van Oosterhout, N. De Jonge, F.H.J. Gmelig-Meyling, and R.A. De Weger. TNFα in patients with end-stage heart failure on medical therapy or supported by a left ventricular assist device. Transplant Immunology 19, 64-68, 2008. 
  47. Vink, A., M.H. Bender, G. Schep, D.F. van Wichen, R.A. de Weger, G. Pasterkamp, and F.L. Moll. Histopathological comparison between endofibrosis of the high-performance athlete and atherosclerosis in the external iliac artery. Journal of Vascular Surgery 48, 1458-1463, 2008. 
  48. Schipper, M.E.I., J. Van Kuik, N. De Jonge, H.F.J. Dullens en R.A. De Weger. Changes in regulatory microRNA expression in myocardium of heart failure patients on left ventricular assist device support. Journal of Heart and Lung Transplantation 27, 1282-1285, 2008. 
  49. J-L Hillebrand, J.-L., R.A. de Weger, and J. Rozing. Transplant Arteriosclerosis. In: Encyclopedia of Molecular Mechanisms of Disease. Eds C. Senthikumaran. pp pp 20099-2100, 2009. 
  50. Van Kuik, J, D.F. Van Wichen, E. Siera-de Koning, N. de Jonge, H.F.J. Dullens, F.H.J. Gmelig Meyling, and R.A. de Weger. T-cells producing both IFN-y and TGF-b induce cardiac allograft vasulopathy. J. Heart and Lung Transplantation 28, S76, 2009. 
  51. De Weger, R.A. and N. De Jonge. Editorial comment and Editorial introductions. Current Opinion in Organ Transplantation 14, 552-553, 2009.

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    Figure 7: Heleen Vroman and Fay Nous on their way to present their poster at the Dutch Transplantation Congress in Amsterdam 2011


  52. De Vries, W., P. van der Borne, R. Goldschmeding, R. de Weger, M.P. Bal, F. van Bel en M.F. Van Oosterhout. Neonatal dexamethasone treatment in the rat leads to kidney damage in adulthood. Pediatric Res 67, 72-76, 2010. 
  53. Da Costa Martins P.A., K. Salic, M.M.Gladka, A.-S. Armand, S. Leptidis, H. el Azzouzi, A. Hansen, C.J. Coenen-de Roo, M.F. Bierhuizen, Roel van der Nagel, J. van Kuik, R. de Weger, A. de Bruin, G. Condorelli, M.L. Arbones, T. Eschenhagen and L. De Windt. MicroRNA-199b targets the nuclear kinase Dyrk1a in an auto-amplification loop promoting calcineurin/NFAT signaling. Nature Cell Biology 12 (12), 1220-1227, 2010. 
  54. De Weger, R.A., M.E.I. Schipper, E.S. Koning, P. van der Weide, M.F. van Oosterhout, R. Quadir, H. Steenbergen-Nakken, J.R. Lahpor, N. de Jonge, and N. Bovenschen. Proteomic profiling of the human failing heart after left ventricular assist device support. J Heart Lung Transplant. In press 2011. 
  55. Schipper, M.E.I., M.R. Scheenstra, J. Van Kuik, D.F. Van Wichen, P. van der Weide, H.F.J. Dullens, J.R. Lahpor, N. de Jonge, and R.A. De Weger. Osteopontin: A potential biomarker for heart failuyre and reverse remodeling after LVAD support. J Heart Lung Transplant. In press 2011. 
  56. Schipper, M.E.I., M.R. Scheenstra, J. Van Kuik, D.F. Van Wichen, P. van der Weide, H.F.J. Dullens, J.R. Lahpor, N. de Jonge, and R.A. De Weger. Osteopontin: A potential biomarker for heart failuyre and reverse remodeling after LVAD support. J Heart Lung Transplant. In press 2011. 

    figure8hearttransplantation1











    Figure 8: Sjoukje Lok presents her data at the ISHLT in San Diego (2011)


  57. Schipper, M.E.I., S.I. Lok, H.Dullens, J. Van Kuik, F.H.J. Gmelig-Meyling, J.R. Lahpor, M.A. Vos, A. Van Der Laarse, N. de Jonge, M.F.M. Van Oosterhout, and R.A. De Weger. Altered expression of mRNA and miRNA during mechanical support of the failing human heart. Intech Open Acess publisher in press.

Recently published abstracts

  1. Van der Weide, P., A.H. Bruggink, D.F. Van Wichen, J. Van Kuik, N. De Jonge, J.R. Lahpor, M.E.I. Schipper, and R.A. de Weger. The role of cathepsin K in extra cellular matrix remodeling in patients with end stage heart failure. The Journal of heart and Lung Transplantation 29, S65, 2010. 
  2. Van Kuik, J., M.E.I. Schipper, H. Dullens, L. De Windt, P.A. Da Costa Martins, N. De Jonge, and R.A. De Weger. Localization and distribution of micro-RNAs in the myocardium of heart failure patients before and after LVAD support. The Journal of Heart and Lung Transplantation 29, S177, 2010. 
  3. Lok, S., M.E.I. Schipper, J. Van Kuk, J. Lahpor, P.A.F. Doevendans, R.A. De Weger, and N. De Jonge. Changes in regulatory miRNA’s during continuous flow LVAD support in failing human heart. European Heart Journal 31, 66-67, 2010. 
  4. S.I. Lok, . Bovenschen, R. Quadir, J. van Kuik,, B, Winkens, M.E.I. Schipper, P.A.F. Doevendans, n. De Jonger, and R.A. de Weger. Anti-1-chymotrypsin: A new player in reverse remodeling of the human heart. Circulerende biomarkers gedurende LVAD ondersteuning. The Journal of Heart and Lung Transplantation 30, 4S, S173, 2011. 
  5. S.I. Lok, P. Van Der weide, J. Kuik, B. Winkems, M.E.I. Schipper, H. Kemperman, P.A.F. Doevendans, R.A. de Weger, and N. de Jonge. Circulating biomarkers of reverse remodeling during support of a continuous flow LVAD. The Journal of Heart and Lung Transplantation 30, 4S, S212, 2011
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