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2. Donor characteristics and their impact on kidney transplantation outcomes: Results from two nationwide instrumental variable analyses based on outcomes of donor kidney pairs accepted for transplantation

Author

Schaapherder, Alexander F., Kaisar, Maria, Mumford, Lisa, Robb, Matthew, Johnson, Rachel, de Kok, Michèle J.C., Bemelman, Frederike J., van de Wetering, Jacqueline, van Zuilen, Arjan D., Christiaans, Maarten H.L., Baas, Marije C., Nurmohamed, Azam S., Berger, Stefan P., Bastiaannet, Esther, de Vries, Aiko P.J., Sharples, Edward, Ploeg, Rutger J., and Lindeman, Jan H.N.

Published
2022
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5. Identifying Women at High Risk of 90 Day Death after Elective Open Abdominal Aortic Aneurysm Repair: A Multicentre Case Control Study

Author

Akkersdijk, G.P., Boer, G.J., Bouwman, L.H., Diks, J., Elshof, J.W., Geelkerken, R.H., Ho, G.H., Hoed, P.T. den, Keller, B.P., Klunder, J.W., Koning, O.H., Kruse, R.R., Lardenoye, J.H., Lemson, M.S., Leeuwerke, S.J.G., van der Linden, F.T., Pierie, M.E., Sant, H.P. van ’t, Schouten, O., Schreuder, S.M., The, R.M., van Silfhout, L., van Tongeren, R.B., Vriens, P.W., Wiersema, A.M., Wiersma, A., Zeebregts, C.J., Tedjawirja, Victoria N., Bulder, Ruth M.A., Lindeman, Jan H.N., Hamming, Jaap F., van Dieren, Susan, Balm, Ron, and Koelemay, Mark J.W.

Published
2022
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7. Red blood cells as oxygen carrier during normothermic machine perfusion of kidney grafts:Friend or foe?

Author

Arykbaeva, Asel S., Lerink, Lente J.S., Vos, Jaël, Engelse, Marten A., van Kooten, Cees, de Korte, Dirk, Lagerberg, Johan W.M., Klei, Thomas R.L., Mulder, Aat A., Minnee, Robert C., Ploeg, Rutger J., Moers, Cyril, Pol, Robert A., Alwayn, Ian P.J., de Vries, Dorottya K., Lindeman, Jan H.N., Arykbaeva, Asel S., Lerink, Lente J.S., Vos, Jaël, Engelse, Marten A., van Kooten, Cees, de Korte, Dirk, Lagerberg, Johan W.M., Klei, Thomas R.L., Mulder, Aat A., Minnee, Robert C., Ploeg, Rutger J., Moers, Cyril, Pol, Robert A., Alwayn, Ian P.J., de Vries, Dorottya K., and Lindeman, Jan H.N.

Abstract

Renal ex vivo normothermic machine perfusion (NMP) is under development as an assessment tool for high-risk kidney grafts and as a means of achieving more physiologically accurate organ preservation. On-going hemolysis has been reported during NMP, as this technique relies on red blood cells for oxygen delivery. In this study, we confirm the occurrence of progressive hemolysis during 6-hour kidney NMP. NMP-associated erythrostasis in the glomeruli and in peri-glomerular vascular networks points to an interaction between the red blood cells and the graft. Continuous hemolysis resulted in prooxidative changes in the perfusate, which could be quenched by addition of fresh frozen plasma. In a cell-based system, this hemolysis induced redox stress and exhibited toxic effects at high concentrations. These findings highlight the need for a more refined oxygen carrier in the context of renal NMP.

Published
2024

9. Equivalent Long-term Transplantation Outcomes for Kidneys Donated After Brain Death and Cardiac Death: Conclusions From a Nationwide Evaluation

Author

Schaapherder, Alexander, Wijermars, Leonie G.M., de Vries, Dorottya K., de Vries, Aiko P.J., Bemelman, Frederike J., van de Wetering, Jacqueline, van Zuilen, Arjan D., Christiaans, Maarten H.L., Hilbrands, Luuk H., Baas, Marije C., Nurmohamed, Azam S., Berger, Stefan P., Alwayn, Ian P., Bastiaannet, Esther, and Lindeman, Jan H.N.

Published
2018
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11. Plaque Evaluation by Ultrasound and Transcriptomics Reveals BCLAF1 as a Regulator of Smooth Muscle Cell Lipid Transdifferentiation in Atherosclerosis

Author

Rykaczewska, Urszula, primary, Zhao, Quanyi, additional, Saliba-Gustafsson, Peter, additional, Lengquist, Mariette, additional, Kronqvist, Malin, additional, Bergman, Otto, additional, Huang, Zhiqiang, additional, Lund, Kent, additional, Waden, Katarina, additional, Pons Vila, Zara, additional, Caidahl, Kenneth, additional, Skogsberg, Josefin, additional, Vukojevic, Vladana, additional, Lindeman, Jan H.N., additional, Roy, Joy, additional, Hansson, Göran K., additional, Treuter, Eckardt, additional, Leeper, Nicholas J., additional, Eriksson, Per, additional, Ehrenborg, Ewa, additional, Razuvaev, Anton, additional, Hedin, Ulf, additional, and Matic, Ljubica, additional

Published
2022
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13. Donor characteristics and their impact on kidney transplantation outcomes:Results from two nationwide instrumental variable analyses based on outcomes of donor kidney pairs accepted for transplantation

Author

Schaapherder, Alexander F., Kaisar, Maria, Mumford, Lisa, Robb, Matthew, Johnson, Rachel, de Kok, Michèle J.C., Bemelman, Frederike J., van de Wetering, Jacqueline, van Zuilen, Arjan D., Christiaans, Maarten H.L., Baas, Marije C., Nurmohamed, Azam S., Berger, Stefan P., Bastiaannet, Esther, de Vries, Aiko P.J., Sharples, Edward, Ploeg, Rutger J., Lindeman, Jan H.N., Schaapherder, Alexander F., Kaisar, Maria, Mumford, Lisa, Robb, Matthew, Johnson, Rachel, de Kok, Michèle J.C., Bemelman, Frederike J., van de Wetering, Jacqueline, van Zuilen, Arjan D., Christiaans, Maarten H.L., Baas, Marije C., Nurmohamed, Azam S., Berger, Stefan P., Bastiaannet, Esther, de Vries, Aiko P.J., Sharples, Edward, Ploeg, Rutger J., and Lindeman, Jan H.N.

Abstract

Background: Donor-characteristics and donor characteristics-based decision algorithms are being progressively used in the decision process whether or not to accept an available donor kidney graft for transplantation. While this may improve outcomes, the performance characteristics of the algorithms remains moderate. To estimate the impact of donor factors of grafts accepted for transplantation on transplant outcomes, and to test whether implementation of donor-characteristics-based algorithms in clinical decision-making is justified, we applied an instrumental variable analysis to outcomes for kidney donor pairs transplanted in different individuals. Methods: This analysis used (dis)congruent outcomes of kidney donor pairs as an instrument and was based on national transplantation registry data for all donor kidney pairs transplanted in separate individuals in the Netherlands (1990-2018, 2,845 donor pairs), and the United Kingdom (UK, 2000-2018, 11,450 pairs). Incident early graft loss (EGL) was used as the primary discriminatory factor. It was reasoned that a scenario with a dominant impact of donor variables on transplantation outcomes would result in high concordance of EGL in both recipients, whilst dominance of asymmetrical outcomes could indicate a more complex scenario, involving an interaction of donor, procedural and recipient factors. Findings: Incidences of congruent EGL (Netherlands: 1·2%, UK: 0·7%) were slightly lower than the arithmetical (stochastic) incidences, suggesting that once a graft has been accepted for transplantation, donor factors minimally contribute to incident EGL. A long-term impact of donor factors was explored by comparing outcomes for functional grafts from donor pairs with asymmetrical vs. symmetrical outcomes. Recipient survival was similar for both groups, but a slightly compromised graft survival was observed for grafts with asymmetrical outcomes in the UK cohort: (10-years Hazard Ratio for graft loss: 1·18 [1·03-1·35] p<0

Published
2022

15. Athero-occlusive Disease Appears to be Associated with Slower Abdominal Aortic Aneurysm Growth: An Exploratory Analysis of the TEDY Trial

Author

Matthews, Evan O., primary, Moxon, Joseph V., additional, Singh, Tejas P., additional, Thanigaimani, Shivshankar, additional, Jones, Rhondda E., additional, Gasser, Thomas C., additional, Fitridge, Robert, additional, Lindeman, Jan H.N., additional, Dalman, Ronald L., additional, and Golledge, Jonathan, additional

Published
2022
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16. Identifying Women at High Risk of 90 Day Death after Elective Open Abdominal Aortic Aneurysm Repair: A Multicentre Case Control Study

Author

Tedjawirja, Victoria N., primary, Bulder, Ruth M.A., additional, Lindeman, Jan H.N., additional, Hamming, Jaap F., additional, van Dieren, Susan, additional, Balm, Ron, additional, Koelemay, Mark J.W., additional, Akkersdijk, G.P., additional, Boer, G.J., additional, Bouwman, L.H., additional, Diks, J., additional, Elshof, J.W., additional, Geelkerken, R.H., additional, Ho, G.H., additional, Hoed, P.T. den, additional, Keller, B.P., additional, Klunder, J.W., additional, Koning, O.H., additional, Kruse, R.R., additional, Lardenoye, J.H., additional, Lemson, M.S., additional, Leeuwerke, S.J.G., additional, van der Linden, F.T., additional, Pierie, M.E., additional, Sant, H.P. van ’t, additional, Schouten, O., additional, Schreuder, S.M., additional, The, R.M., additional, van Silfhout, L., additional, van Tongeren, R.B., additional, Vriens, P.W., additional, Wiersema, A.M., additional, Wiersma, A., additional, and Zeebregts, C.J., additional

Published
2022
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18. Distinct defects in collagen microarchitecture underlie vessel-wall failure in advanced abdominal aneurysms and aneurysms in Marfan syndrome

Author

Lindeman, Jan H.N., Ashcroft, Brian A., Beenakker, Jan-Willem M., van Es, Maarten, Koekkoek, Nico B.R., Prins, Frans A., Tielemans, Jarl F., Abdul-Hussien, Hazem, Bank, Ruud A., and Oosterkamp, Tjerk H.

Subjects
Aortic aneurysms -- Risk factors, Aortic aneurysms -- Research, Aortic aneurysms -- Diagnosis, Collagen -- Physiological aspects, Collagen -- Research, Science and technology
Abstract

An aneurysm of the aorta is a common pathology characterized by segmental weakening of the artery. Although it is generally accepted that the vessel-wall weakening is caused by an impaired collagen metabolism, a clear association has been demonstrated only for rare syndromes such as the vascular type Ehlers--Danlos syndrome. Here we show that vessel-wall failure in growing aneurysms of patients who have aortic abdominal aneurysm (AAA) or Marfan syndrome is not related to a collagen defect at the molecular level. On the contrary our findings indicate similar (Marfan) or even higher collagen concentrations (AAA) and increased collagen cross-linking in the aneurysms. Using 3D confocal imaging we show that the two conditions are associated with profound defects in collagen microarchitecture. Reconstructions of normal vessel wall show that adventitial collagen fibers are organized in a loose braiding of collagen ribbons. These ribbons encage the vessel, allowing the vessel to dilate easily but preventing overstretching. AAA and aneurysms in Marfan syndrome show dramatically altered collagen architectures with loss of the collagen knitting. Evaluations of the functional characteristics by atomic force microscopy showed that the wall has lost its ability to stretch easily and revealed a second defect: although vascular collagen in normal aortic wall behaves as a coherent network, in AAA and Marfan tissues it does not. As result, mechanical forces loaded on individual fibers are not distributed over the tissue. These studies demonstrate that the mechanical properties of tissue are strongly influenced by collagen microarchitecture and that perturbations in the collagen networks may lead to mechanical failure. www.pnas.org/cgi/doi/10.1073/pnas.0910312107

Published
2010
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19. Improving outcomes for donation after circulatory death kidney transplantation: Science of the times

Author

Kok, Michele J.C. de, Schaapherder, Alexander F.M., Alwayn, Ian P.J., Bemelman, Frederike J., Wetering, Jacqueline van de, Zuilen, Arjan D. van, Baas, M.C., Vries, Aiko P.J. de, Lindeman, Jan H.N., Kok, Michele J.C. de, Schaapherder, Alexander F.M., Alwayn, Ian P.J., Bemelman, Frederike J., Wetering, Jacqueline van de, Zuilen, Arjan D. van, Baas, M.C., Vries, Aiko P.J. de, and Lindeman, Jan H.N.

Abstract

Contains fulltext : 221518.pdf (publisher's version ) (Open Access)

Published
2020

20. Transcriptomic profiling of experimental arterial injury reveals new mechanisms and temporal dynamics in vascular healing response

Author

Röhl, Samuel, Rykaczewska, Urszula, Seime, Till, Suur, Bianca E., Diez, Maria Gonzalez, Gådin, Jesper R., Gainullina, Anastasiia, Sergushichev, Alexey A., Wirka, Robert, Lengquist, Mariette, Kronqvist, Malin, Bergman, Otto, Odeberg, Jacob, Lindeman, Jan H.N., Quertermous, Thomas, Hamsten, Anders, Eriksson, Per, Hedin, Ulf, Razuvaev, Anton, Matic, Ljubica Perisic, Röhl, Samuel, Rykaczewska, Urszula, Seime, Till, Suur, Bianca E., Diez, Maria Gonzalez, Gådin, Jesper R., Gainullina, Anastasiia, Sergushichev, Alexey A., Wirka, Robert, Lengquist, Mariette, Kronqvist, Malin, Bergman, Otto, Odeberg, Jacob, Lindeman, Jan H.N., Quertermous, Thomas, Hamsten, Anders, Eriksson, Per, Hedin, Ulf, Razuvaev, Anton, and Matic, Ljubica Perisic

Abstract

Objective: Endovascular interventions cause arterial injury and induce a healing response to restore vessel wall homeostasis. Complications of defective or excessive healing are common and result in increased morbidity and repeated interventions. Experimental models of intimal hyperplasia are vital for understanding the vascular healing mechanisms and resolving the clinical problems of restenosis, vein graft stenosis, and dialysis access failure. Our aim was to systematically investigate the transcriptional, histologic, and systemic reaction to vascular injury during a prolonged time. Methods: Balloon injury of the left common carotid artery was performed in male rats. Animals (n = 69) were euthanized before or after injury, either directly or after 2 hours, 20 hours, 2 days, 5 days, 2 weeks, 6 weeks, and 12 weeks. Both injured and contralateral arteries were subjected to microarray profiling, followed by bioinformatic exploration, histologic characterization of the biopsy specimens, and plasma lipid analyses. Results: Immune activation and coagulation were key mechanisms in the early response, followed by cytokine release, tissue remodeling, and smooth muscle cell modulation several days after injury, with reacquisition of contractile features in later phases. Novel pathways related to clonal expansion, inflammatory transformation, and chondro-osteogenic differentiation were identified and immunolocalized to neointimal smooth muscle cells. Analysis of uninjured arteries revealed a systemic component of the reaction after local injury, underlined by altered endothelial signaling, changes in overall tissue bioenergy metabolism, and plasma high-density lipoprotein levels. Conclusions: We demonstrate that vascular injury induces dynamic transcriptional landscape and metabolic changes identifiable as early, intermediate, and late response phases, reaching homeostasis after several weeks. This study provides a temporal “roadmap” of vascular healing as a publicly availabl, QC 20230718

Published
2020
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21. Transcriptomic profiling of experimental arterial injury reveals new mechanisms and temporal dynamics in vascular healing response

Author

Röhl, Samuel, primary, Rykaczewska, Urszula, additional, Seime, Till, additional, Suur, Bianca E., additional, Diez, Maria Gonzalez, additional, Gådin, Jesper R., additional, Gainullina, Anastasiia, additional, Sergushichev, Alexey A., additional, Wirka, Robert, additional, Lengquist, Mariette, additional, Kronqvist, Malin, additional, Bergman, Otto, additional, Odeberg, Jacob, additional, Lindeman, Jan H.N., additional, Quertermous, Thomas, additional, Hamsten, Anders, additional, Eriksson, Per, additional, Hedin, Ulf, additional, Razuvaev, Anton, additional, and Matic, Ljubica Perisic, additional

Published
2020
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26. Oncostatin M reduces atherosclerosis development in APOE3Leiden.CETP mice and is associated with increased survival probability in humans

Author

van Keulen, Danielle, Pouwer, Marianne G., Emilsson, Valur, Matic, Ljubica Perisic, Pieterman, Elsbet J., Hedin, Ulf, Gudnason, Vilmundur, Jennings, Lori L., Holmstrøm, Kim, Nielsen, Boye Schnack, Pasterkamp, Gerard, Lindeman, Jan H.N., van Gool, Alain J., Sollewijn Gelpke, Maarten D., Princen, Hans M.G., Tempel, Dennie, van Keulen, Danielle, Pouwer, Marianne G., Emilsson, Valur, Matic, Ljubica Perisic, Pieterman, Elsbet J., Hedin, Ulf, Gudnason, Vilmundur, Jennings, Lori L., Holmstrøm, Kim, Nielsen, Boye Schnack, Pasterkamp, Gerard, Lindeman, Jan H.N., van Gool, Alain J., Sollewijn Gelpke, Maarten D., Princen, Hans M.G., and Tempel, Dennie

Published
2019

27. Oncostatin M reduces atherosclerosis development in APOE3Leiden.CETP mice and is associated with increased survival probability in humans

Author

CDL Onderzoek Pasterkamp, Other research (not in main researchprogram), dLAB Afdelingen, Circulatory Health, Divisie LAB, Divisie Biomedische Genetica, van Keulen, Danielle, Pouwer, Marianne G., Emilsson, Valur, Matic, Ljubica Perisic, Pieterman, Elsbet J., Hedin, Ulf, Gudnason, Vilmundur, Jennings, Lori L., Holmstrøm, Kim, Nielsen, Boye Schnack, Pasterkamp, Gerard, Lindeman, Jan H.N., van Gool, Alain J., Sollewijn Gelpke, Maarten D., Princen, Hans M.G., Tempel, Dennie, CDL Onderzoek Pasterkamp, Other research (not in main researchprogram), dLAB Afdelingen, Circulatory Health, Divisie LAB, Divisie Biomedische Genetica, van Keulen, Danielle, Pouwer, Marianne G., Emilsson, Valur, Matic, Ljubica Perisic, Pieterman, Elsbet J., Hedin, Ulf, Gudnason, Vilmundur, Jennings, Lori L., Holmstrøm, Kim, Nielsen, Boye Schnack, Pasterkamp, Gerard, Lindeman, Jan H.N., van Gool, Alain J., Sollewijn Gelpke, Maarten D., Princen, Hans M.G., and Tempel, Dennie

Published
2019

29. CXCL8 hyper-signaling in the aortic abdominal aneurysm

Author

Kokje, Vivianne B.C., Gäbel, Gabor, Dalman, Ron L., Koole, Dave, Northoff, Bernd H., Holdt, Lesca M., Hamming, Jaap F., Lindeman, Jan H.N., Kokje, Vivianne B.C., Gäbel, Gabor, Dalman, Ron L., Koole, Dave, Northoff, Bernd H., Holdt, Lesca M., Hamming, Jaap F., and Lindeman, Jan H.N.

Published
2018

30. Integrated Human Evaluation of the Lysophosphatidic Acid Pathway as a Novel Therapeutic Target in Atherosclerosis

Author

Aldi, Silvia, primary, Matic, Ljubica Perisic, additional, Hamm, Gregory, additional, van Keulen, Daniëlle, additional, Tempel, Dennie, additional, Holmstrøm, Kim, additional, Szwajda, Agnieszka, additional, Nielsen, Boye Schnack, additional, Emilsson, Valur, additional, Ait-Belkacem, Rima, additional, Lengquist, Mariette, additional, Paulsson-Berne, Gabrielle, additional, Eriksson, Per, additional, Lindeman, Jan H.N., additional, Gool, Alain J., additional, Stauber, Jonathan, additional, Hedin, Ulf, additional, and Hurt-Camejo, Eva, additional

Published
2018
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34. Defective postreperfusion metabolic recovery directly associates with incident delayed graft function

Author

Wijermars, Leonie G.M., primary, Schaapherder, Alexander F., additional, de Vries, Dorottya K., additional, Verschuren, Lars, additional, Wüst, Rob C.I., additional, Kostidis, Sarantos, additional, Mayboroda, Oleg A., additional, Prins, Frans, additional, Ringers, Jan, additional, Bierau, Jörgen, additional, Bakker, Jaap A., additional, Kooistra, Teake, additional, and Lindeman, Jan H.N., additional

Published
2016
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35. Collagen Degradation in the Abdominal Aneurysm : A Conspiracy of Matrix Metalloproteinase and Cysteine Collagenases

Author

Abdul-Hussien, Hazem, Soekhoe, Ratna G.V., Weber, Ekkehard, von der Thüsen, Jan H., Kleemann, Robert, Mulder, Adri, van Bockel, J. Hajo, Hanemaaijer, Roeland, and Lindeman, Jan H.N.

Subjects
Male, Reverse Transcriptase Polymerase Chain Reaction, Blotting, Western, macromolecular substances, Immunohistochemistry, Matrix Metalloproteinases, cardiovascular system, Humans, Female, Protease Inhibitors, Collagen, Collagenases, Cysteine, RNA, Messenger, Regular Articles, Aged, Aortic Aneurysm, Abdominal
Abstract

Growth and rupture of abdominal aortic aneurysms (AAAs) result from increased collagen turnover. Collagen turnover critically depends on specific collagenases that cleave the triple helical region of fibrillar collagen. As yet, the collagenases responsible for collagen degradation in AAAs have not been identified. Increased type I collagen degradation products confirmed collagen turnover in AAAs (median values: 80%). We found indications that this secondary deficiency relates to cystatin C degradation by (neutrophil-derived) proteases.

Published
2007

37. Correction

Author

Beenakker, Jan-Willem M., primary, Ashcroft, Brian A., additional, Lindeman, Jan H.N., additional, and Oosterkamp, Tjerk H., additional

Published
2012
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41. Expression of Vascular Endothelial Growth Factor, Stromal Cell-Derived Factor-1, and CXCR4 in Human Limb Muscle With Acute and Chronic Ischemia

Author

van Weel, Vincent, primary, Seghers, Leonard, additional, de Vries, Margreet R., additional, Kuiper, Esther J., additional, Schlingemann, Reinier O., additional, Bajema, Ingeborg M., additional, Lindeman, Jan H.N., additional, Delis-van Diemen, Pien M., additional, van Hinsbergh, Victor W.M., additional, van Bockel, J. Hajo, additional, and Quax, Paul H.A., additional

Published
2007
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42. Collagen Degradation in the Abdominal Aneurysm

Author

Abdul-Hussien, Hazem, primary, Soekhoe, Ratna G.V., additional, Weber, Ekkehard, additional, von der Thüsen, Jan H., additional, Kleemann, Robert, additional, Mulder, Adri, additional, van Bockel, J. Hajo, additional, Hanemaaijer, Roeland, additional, and Lindeman, Jan H.N., additional

Published
2007
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45. Phenotypic Modulation of Smooth Muscle Cells in Atherosclerosis Is Associated With Downregulation of LMOD1, SYNPO2, PDLIM7, PLN, and SYNM

Author

Perisic Matic, Ljubica, Rykaczewska, Urszula, Razuvaev, Anton, Sabater-Lleal, Maria, Lengquist, Mariette, Miller, Clint L., Ericsson, Ida, Röhl, Samuel, Kronqvist, Malin, Aldi, Silvia, Magné, Joelle, Paloschi, Valentina, Vesterlund, Mattias, Li, Yuhuang, Jin, Hong, Diez, Maria Gonzalez, Roy, Joy, Baldassarre, Damiano, Veglia, Fabrizio, Humphries, Steve E., de Faire, Ulf, Tremoli, Elena, Odeberg, Jacob, Vukojević, Vladana, Lehtiö, Janne, Maegdefessel, Lars, Ehrenborg, Ewa, Paulsson-Berne, Gabrielle, Hansson, Göran K., Lindeman, Jan H.N., Eriksson, Per, Quertermous, Thomas, Hamsten, Anders, and Hedin, Ulf

Abstract

Supplemental Digital Content is available in the text.

Published
2016
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46. Correction

Author

Beenakker, Jan-Willem M., Ashcroft, Brian A., Lindeman, Jan H.N., and Oosterkamp, Tjerk H.

Subjects
Biophysics, Correction
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47. No prominent role for terminal complement activation in the early myocardial reperfusion phase following cardiac surgery.

Author

Kortekaas, Kirsten A., van der Pol, Pieter, Lindeman, Jan H.N., Baan, Carla C., van Kooten, Cees, and Klautz, Robert J.M.

Subjects
*MYOCARDIAL reperfusion, *CARDIAC surgery, *HEART failure patients, *COMPLEMENT activation, *CLINICAL trials, *HEART pathophysiology, *HOMOGRAFTS, *IMMUNOLOGY
Abstract

OBJECTIVES Complement activation is considered an important mediator of myocardial ischaemia/reperfusion (I/R) injury. Although complement inhibitors are highly effective in animals, clinical trials fail to show a substantial benefit in humans. This raises questions on the role of complement activation in human myocardial I/R injury. METHODS Soluble C5b-9, i.e. terminal complement complex, and C5a were assessed in patients with non-ischaemic (n = 10) and ischaemic heart failure (n = 10), and patients without heart failure (n = 10) undergoing cardiac surgery. To study the pathophysiology of human I/R injury, a model of arteriovenous measurements over the reperfused heart was applied at consecutive time points during the early reperfusion phase. Furthermore, C3d and C5b-9 depositions in pre-reperfusion myocardial and endomyocardial tissue were evaluated and compared to pre-transplantation tissue from myocardial allografts. RESULTS Simultaneous assessment of soluble C5b-9 and C5a in systemical and myocardial venous blood samples revealed the absence of net release from the reperfused heart in all three patient groups. Biopsies of patients with non-ischaemic heart failure showed the most abundant myocardial depositions of C3d and C5b-9: 4.8 times more C3d (P = 0.008) and 4.7 times more C5b-9 (P = 0.004) than donor tissue. Also C3d was abundantly present in endomyocardial tissue of both heart failure groups compared to donors (both P = 0.02). CONCLUSIONS No evidence was obtained that terminal complement activation is involved in the acute phase following myocardial reperfusion. Since complement deposition was already present before reperfusion, human complement inhibition might be more beneficial in the preoperative phase than during reperfusion. [ABSTRACT FROM AUTHOR]

Published
2012
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