Die Bedeutung der peripheren arteriellen Verschlusskrankheit ist durch ihre hohe Prävalenz in den Industrienationen, durch den demografischen Wandel und durch eine höhere Inaktivität der Menschen allgegenwärtig. Im Alter von 70 Jahren leidet ca. jeder fünfte Deutsche an einer pAVK. (Criqui, M.H., Fronek, A., et al., 1985) Erste asymptomatische Gefäßwandveränderungen können bereits im frühen Erwachsenenalter entstehen und werden durch Risikofaktoren, wie Hypertonus, Nikotinabusus, Diabetes mellitus, Bewegungsmangel und Hyperlipidämie weiter vorangetrieben.
Der klinische Verlauf der Erkrankung ist schwierig abzuschätzen und Biomarker könnten dabei helfen ein Voranschreiten der Erkrankung frühzeitig zu detektieren, um mögliche Komplikationen zu vermeiden und die Therapie frühzeitig zu optimieren. Aus einem stabilen klinischen Erkrankungsverlauf der pAVK kann sich durch viele Einflussfaktoren eine plötzliche Krankheitsverschlechterung, gemessen an den Stadien der pAVK, entwickeln. Im Rahmen der Evaluierung von Biomarkern für die pAVK ist es dabei primär wichtig zu überprüfen, ob sich die potenziellen Marker überhaupt in den Stadien, bzw.
Schweregrad der Erkrankung unterscheiden.
In dieser Studie konnte erstmals gezeigt werden, dass es signifikante Unterschiede in der Verteilung der Proportionen der einzelnen Monozytensubpopulationen bei den verschiedenen Rutherfordstadien gibt. Die „intermediären“
𝐶𝐷14++𝐶𝐷16++Monozyten zeigten in unserer Arbeit die stärkste Assoziation mit dem Schweregrad der pAVK. Zusätzlich zeigten sich phänotypische Unterschiede in der Expression von CD106, MPO und CD162. Die „intermediären“
𝐶𝐷14++𝐶𝐷16++ Monozyten zeigten zusätzlich eine erhöhte Expression der proatherogenen Marker CD162/PSGL-1 und MPO bei Patienten mit höherem Rutherfordstadium.
Neben ihrer Rolle als potenzielle Biomarker könnten die Monozytensubpopulationen sowie spezifische phänotypische Marker auch als Zielstrukturen neuer zellulärer bzw. molekularer Therapien dienen, um den Grad
der vaskulären Inflammation in höheren Erkrankungsstadien der pAVK zu reduzieren.
8. Danksagung
An erster Stelle möchte ich mich bei meiner Forschungsgruppe für die gute Zusammenarbeit bedanken.
Besonderer Dank gilt meiner Familie, die den ganzen langen Weg, mit mir gegangen ist. Danke Mama, Danke Papa, Danke Max, Danke Oma.
9. Abbildungsverzeichnis
ABBILDUNG 1ABIWERTE ZUR ABSCHÄTZUNG DES SCHWEREGRADS DER PAVK ...14
ABBILDUNG 2KLASSIFIKATIONEN DER ARTERIELLEN VERSCHLUSSKRANKHEIT ...17
ABBILDUNG 3STADIENGERECHTE BEHANDLUNG DER PAVK IN ABHÄNGIGKEIT DER FONTAINE KLASSIFIKATION...20
ABBILDUNG 4STUDIENDESIGN ...35
ABBILDUNG 5DEMOGRAFISCHE DATEN ...43
ABBILDUNG 6FACSANALYSE;DARSTELLUNG MIT FLOWJO V.8.5.2 ...45
ABBILDUNG 7LEUKOZYTEN (TOTAL) IN DEN RUTHERFORDSTADIEN ...46
ABBILDUNG 8MONOZYTEN (TOTAL) IN DEN RUHTERFORDSATDIEN ...47
ABBILDUNG 9MONOZYTEN (%) IN DEN RUTHERFORDSTADIEN ...47
ABBILDUNG 10MONOZYTENSUBPOPULATIONEN (%) IN DEN RUTHERFORDSTADIEN ...49
ABBILDUNG 11MONOZYTENSUBPOPULATIONEN (TOTAL) IN DEN RUTHERFORDSTADIEN ...51
ABBILDUNG 12CX3CR1(%) UND (MFI) IN DEN RUTHERFORDSTADIEN ...53
ABBILDUNG 13CCR2(%) UND (MFI) IN DEN RUTHERFORDSTADIEN ...55
ABBILDUNG 14CD11B (%) UND (MFI) IN DEN RUTHERFORDSTADIEN ...57
ABBILDUNG 15CD106(%) UND (MFI) IN DEN RUTHERFORDSTADIEN ...59
ABBILDUNG 16CD162(%) UND (MFI) IN DEN RUTHERFORDSTADIEN ...61
ABBILDUNG 17MPO(%) UND (MFI) IN DEN RUTHERFORDSTADIEN ...63
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Journal of vascular surgery. 44 (2006) 510-517
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Effect of time, temperature, and anticoagulant on flow cytometry and hematological values.
Annals of the New York Academy of Sciences. 677 (1993) 440-443
Poitou, C., Dalmas, E., Renovato, M., Benhamo, V., Hajduch, F., Abdennour, M., Kahn, J.F., Veyrie, N., Rizkalla, S., Fridman, W.H., Sautes-Fridman, C., Clement, K., Cremer, I.
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Analysis of the cilostazol safety database.
The American journal of cardiology. 87 (2001) 28D-33D
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The American journal of pathology. 138 (1991) 385-393 Robben, P.M., LaRegina, M., Kuziel, W.A., Sibley, L.D.
Recruitment of Gr-1+ monocytes is essential for control of acute toxoplasmosis.
The Journal of experimental medicine. 201 (2005) 1761-1769
Rogacev, K.S., Cremers, B., Zawada, A.M., Seiler, S., Binder, N., Ege, P., Grosse-Dunker, G., Heisel, I., Hornof, F., Jeken, J., Rebling, N.M., Ulrich, C., Scheller, B., Bohm, M., Fliser, D., Heine, G.H.
CD14++CD16+ monocytes independently predict cardiovascular events: a cohort study of 951 patients referred for elective coronary angiography.
Ibid.60 (2012) 1512-1520
Rosenfeld, M.E., Yla-Herttuala, S., Lipton, B.A., Ord, V.A., Witztum, J.L., Steinberg, D.
Macrophage colony-stimulating factor mRNA and protein in atherosclerotic lesions of rabbits and humans.
The American journal of pathology. 140 (1992) 291-300 Saederup, N., Chan, L., Lira, S.A., Charo, I.F.
Fractalkine deficiency markedly reduces macrophage accumulation and atherosclerotic lesion formation in CCR2-/- mice: evidence for independent chemokine functions in atherogenesis.
Circulation. 117 (2008) 1642-1648
Said, E.A., Dupuy, F.P., Trautmann, L., Zhang, Y., Shi, Y., El-Far, M., Hill, B.J., Noto, A., Ancuta, P., Peretz, Y., Fonseca, S.G., Van Grevenynghe, J., Boulassel, M.R., Bruneau, J., Shoukry, N.H., Routy, J.P., Douek, D.C., Haddad, E.K., Sekaly, R.P.
Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection.
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Schirmer, S.H., Millenaar, D.N., Werner, C., Schuh, L., Degen, A., Bettink, S.I., Lipp, P., van Rooijen, N., Meyer, T., Bohm, M., Laufs, U.
Exercise promotes collateral artery growth mediated by monocytic nitric oxide.
Ibid. 1862-1871
Schlitt, A., Heine, G.H., Blankenberg, S., Espinola-Klein, C., Dopheide, J.F., Bickel, C., Lackner, K.J., Iz, M., Meyer, J., Darius, H., Rupprecht, H.J.
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Senti, M., Nogues, X., Pedro-Botet, J., Rubies-Prat, J., Vidal-Barraquer, F.
Lipoprotein profile in men with peripheral vascular disease. Role of intermediate density lipoproteins and apoprotein E phenotypes.
Circulation. 85 (1992) 30-36
Serbina, N.V., Jia, T., Hohl, T.M., Pamer, E.G.
Monocyte-mediated defense against microbial pathogens.
Annual review of immunology. 26 (2008) 421-452 Serbina, N.V., Pamer, E.G.
Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2.
Nature immunology. 7 (2006) 311-317
Serbina, N.V., Salazar-Mather, T.P., Biron, C.A., Kuziel, W.A., Pamer, E.G.
TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection.
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Shahin, Y., Cockcroft, J.R., Chetter, I.C.
Randomized clinical trial of angiotensin-converting enzyme inhibitor, ramipril, in patients with intermittent claudication.
The British journal of surgery. 100 (2013) 1154-1163
Shantsila, E., Tapp, L.D., Wrigley, B.J., Montoro-Garcia, S., Lip, G.Y.
Receptors to interleukin-6 and adhesion molecules on circulating monocyte subsets in acute myocardial infarction.
Thrombosis and haemostasis. 110 (2013) 340-348
Soder, H.K., Manninen, H.I., Jaakkola, P., Matsi, P.J., Rasanen, H.T., Kaukanen, E., Loponen, P., Soimakallio, S.
Prospective trial of infrapopliteal artery balloon angioplasty for critical limb ischemia:
angiographic and clinical results.
Journal of vascular and interventional radiology : JVIR. 11 (2000) 1021-1031 Spronk, S., den Hoed, P.T., de Jonge, L.C., van Dijk, L.C., Pattynama, P.M.
Value of the duplex waveform at the common femoral artery for diagnosing obstructive aortoiliac disease.
Journal of vascular surgery. 42 (2005) 236-242; discussion 242 Strauss-Ayali, D., Conrad, S.M., Mosser, D.M.
Monocyte subpopulations and their differentiation patterns during infection.
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Sugiyama, S., Okada, Y., Sukhova, G.K., Virmani, R., Heinecke, J.W., Libby, P.
Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes.
The American journal of pathology. 158 (2001) 879-891
Swirski, F.K., Pittet, M.J., Kircher, M.F., Aikawa, E., Jaffer, F.A., Libby, P., Weissleder, R.
Swirski, F.K., Pittet, M.J., Kircher, M.F., Aikawa, E., Jaffer, F.A., Libby, P., Weissleder, R.