Identifizierung genetischer und epigenetischer Biomarker für die Thrombozytenfunktion und thrombozytenvermittelte inflammatorische Prozesse in einer etablierten prospektiven kardiologischen Patientenkohorte

• Antragsteller: Professor Dr. Tobias Geisler; Professor Dr. Matthias Schwab
• Fachliche Zuordnung: Kardiologie, Angiologie
• Förderung: Förderung von 2011 bis 2018
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 190538538

Zusammenfassung der Projektergebnisse

Epigenetic changes, such as DNA-methylation und miRNAs play an important role in various cardiovascular diseases like coronary artery disease and chronic heart failure. In addition to circulating miRNAs in the blood, endogenous metabolite levels were shown to be important biomarkers for the prognosis/prediction of cardiovascular diseases. The importance of these metabolites and circulating miRNAs for the function of platelets and platelet-induced processes such as inflammation, apoptosis and angiogenesis has not been examined extensively up to date. Therefore diagnostic, prognostic and therapeutic importance of epigenetic factors (e.g. circulating miRNAs) and endogenous metabolite levels should be examined additionally to previously investigated genetic factors of selected candidate genes in past funding periods. In order to be able to validly examine the clinical relevance of potential molecular biomarkers, an analysis of a prospectively identified cardiologic cohort is necessary, so additional influencing factors (age, diabetes mellitus, concomitant medication and dietary habits) can be evaluated. The prospective patient cohort with associated biobank and exact phenotypic characterization under standardized conditions established during the first and second funding period allowed for systematic analyses of epigenetic markers, such as e.g. circulating miRNAs and metabolite levels in vivo and for verification of their relevance for platelet function as well as platelet-induced inflammatory and regenerative processes. Another objective was to evaluate particular targets form other projects in connection with the newly identified biomarkers, to validate the basic research findings of those projects in the established patient cohort at an early stage.

Projektbezogene Publikationen (Auswahl)

• CXCL16 is a novel diagnostic marker and predictor of mortality in inflammatory cardiomyopathy and heart failure. Int J Cardiol. 2014 Oct 20;176(3):896-903
  Borst O, Schaub M, Walker B, Sauter M, Muenzer P, Gramlich M, Mueller K, Geisler T, Lang F, Klingel K, Kandolf R, Bigalke B, Gawaz M, Zuern CS
  (Siehe online unter https://doi.org/10.1016/j.ijcard.2014.08.033)
• Impact of counterbalance between macrophage migration inhibitory factor and its inhibitor Gremlin-1 in patients with coronary artery disease. Atherosclerosis. 2014 Dec;237(2):426-32
  Müller II, Müller KA, Karathanos A, Schönleber H, Rath D, Vogel S, Chatterjee M, Schmid M, Haas M, Seizer P, Langer H, Schaeffeler E, Schwab M, Gawaz M, Geisler T
  (Siehe online unter https://doi.org/10.1016/j.atherosclerosis.2014.09.010)
• Platelet expression of transforming growth factor beta 1 is enhanced and associated with cardiovascular prognosis in patients with acute coronary syndrome. Atherosclerosis. 2014 Dec;237(2):754-9
  Rath D, Chatterjee M, Müller I, Müller K, Böckmann C, Droppa M, Stimpfle F, Karathanos A, Borst O, Seizer P, Langer H, Schwab M, Gawaz M, Geisler T
  (Siehe online unter https://doi.org/10.1016/j.atherosclerosis.2014.10.021)
• Endomyocardial expression of SDF-1 predicts mortality in patients with suspected myocarditis. Clin Res Cardiol. 2015 Dec;104(12):1033-43
  Zuern CS, Walker B, Sauter M, Schaub M, Chatterjee M, Mueller K, Rath D, Vogel S, Tegtmeyer R, Seizer P, Geisler T, Kandolf R, Lang F, Klingel K, Gawaz M, Borst O
  (Siehe online unter https://doi.org/10.1007/s00392-015-0871-y)
• Enzymatically Modified Low-Density Lipoprotein Is Present in All Stages of Aortic Valve Sclerosis. Implications for Pathogenesis of the Disease. J Am Heart Assoc 4 (10), e002156
  Twardowski, L.; Cheng, F.; Michaelsen, J.; Winter, S.; Hofmann, U.; Schaeffeler, E. et al.
  (Siehe online unter https://doi.org/10.1161/jaha.115.002156)
• Evaluation of clinical risk factors to predict high on-treatment platelet reactivity and outcome in patients with stable coronary artery disease (PREDICT-STABLE). PLoS One. 2015 Mar 23;10(3):e0121620
  Droppa M, Tschernow D, Müller KA, Tavlaki E, Karathanos A, Stimpfle F, Schaeffeler E, Schwab M, Tolios A, Siller- Matula JM, Gawaz M, Geisler T
  (Siehe online unter https://doi.org/10.1371/journal.pone.0121620)
• Expression of anaphylatoxin receptors on platelets in patients with coronary heart disease. Atherosclerosis. 2015 Feb;238(2):289-95
  Patzelt J, Mueller KA, Breuning S, Karathanos A, Schleicher R, Seizer P, Gawaz M, Langer HF, Geisler T
  (Siehe online unter https://doi.org/10.1016/j.atherosclerosis.2014.12.002)
• Impact of the serum- and glucocorticoid-inducible kinase 1 on platelet dense granule biogenesis and secretion. J Thromb. Haemost. 13 (7), S. 1325–1334
  Walker, B.; Schmid, E.; Russo, A.; Schmidt, E. M.; Burk, O.; Munzer, P. et al.
  (Siehe online unter https://doi.org/10.1111/jth.12998)
• Platelet surface expression of stromal cell-derived factor-1 receptors CXCR4 and CXCR7 is associated with clinical outcomes in patients with coronary artery disease. J Thromb. Haemost. 13 (5), S. 719–728
  Rath, D.; Chatterjee, M.; Borst, O.; Muller, K.; Langer, H.; Mack, A. F. et al.
  (Siehe online unter https://doi.org/10.1111/jth.12870)
• PDK1 Determines Collagen-Dependent Platelet Ca2+ Signaling and Is Critical to Development of Ischemic Stroke In Vivo. Arterioscler. Thromb. Vasc. Biol 36 (8), S. 1507–1516, 2016
  Munzer, P.; Walker-Allgaier, B.; Geue, S.; Geuss, E.; Hron, G.; Rath, D. et al.
  (Siehe online unter https://doi.org/10.1161/atvbaha.115.307105)
• Periprocedural platelet inhibition with cangrelor in P2Y12-inhibitor naïve patients with acute coronary syndromes - A matched-control pharmacodynamic comparison in real-world patients. Int J Cardiol. 2016 Nov 15;223:848-851
  Droppa M, Spahn P, Takhgiriev K, Müller KA, Alboji A, Straub A, Rath D, Jeong YH, Gawaz M, Geisler T
  (Siehe online unter https://doi.org/10.1016/j.ijcard.2016.08.270)
• SDF1 Polymorphisms Influence Outcome in Patients with Symptomatic Cardiovascular Disease. PLoS One. 2016 Sep 8;11(9):e0161933
  Rath D, Schaeffeler E, Winter S, Hewer J, Müller K, Droppa M, Stimpfle F, Gawaz M, Schwab M, Geisler T
  (Siehe online unter https://doi.org/10.1371/journal.pone.0161933)
• Vascular risk levels affect the predictive value of platelet reactivity for the occurrence of MACE in patients on clopidogrel. Systematic review and meta-analysis of individual patient data. Thromb Haemost. 2016 Apr;115(4):844-55
  Reny JL, Fontana P, Hochholzer W, Neumann FJ, Ten Berg J, Janssen PW, Geisler T, Gawaz M, Marcucci R, Gori AM, Cuisset T, Alessi MC, Berdagué P, Gurbel PA, Yong G, Angiolillo DJ, Aradi D, Beigel R, Campo G, Combescure C
  (Siehe online unter https://doi.org/10.1160/th15-09-0742)
• Regulation of oxidized platelet lipidome: implications for coronary artery disease. Eur Heart J. 2017 Jul 1;38(25):1993-2005
  Chatterjee M, Rath D, Schlotterbeck J, Rheinlaender J, Walker-Allgaier B, Alnaggar N, Zdanyte M, Müller I, Borst O, Geisler T, Schäffer TE, Lämmerhofer M, Gawaz M
  (Siehe online unter https://doi.org/10.1093/eurheartj/ehx146)
• Functional Relevance of the Anaphylatoxin Receptor C3aR for Platelet Function and Arterial Thrombus Formation Marks an Intersection Point Between Innate Immunity and Thrombosis. Circulation. 2018 Oct 16;138(16):1720-1735
  Sauter RJ, Sauter M, Reis ES, Emschermann FN, Nording H, Ebenhöch S, Kraft P, Münzer P, Mauler M, Rheinlaender J, Madlung J, Edlich F, Schäffer TE, Meuth SG, Dürschmied D, Geisler T, Borst O, Gawaz M, Kleinschnitz C, Lambris JD, Langer HF
  (Siehe online unter https://doi.org/10.1161/circulationaha.118.034600)
• Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical endpoints - Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC). Am Heart J. 2018;198:152-159
  Bergmeijer To, ..., Shuldiner AR for the ICPC Investigators
  (Siehe online unter https://doi.org/10.1016/j.ahj.2017.12.010)
• Genotype-Phenotype Association and Impact on Outcomes following Guided De-Escalation of Anti- Platelet Treatment in Acute Coronary Syndrome Patients: The TROPICAL-ACS Genotyping Substudy. Thromb Haemost. 2018 Sep;118(9):1656-166
  Gross L, Trenk D, Jacobshagen C, Krieg A, Gawaz M, Massberg S, Baylacher M, Aradi D, Stimpfle F, Hromek J, Vogelgesang A, Hadamitzky M, Sibbing D, Geisler T
  (Siehe online unter https://doi.org/10.1055/s-0038-1667337)
• Inhibitory mechanisms of very low-dose rivaroxaban in non-ST-elevation myocardial infarction. Blood Adv. 2018 Mar 27;2(6):715-730
  Borst O, Münzer P, Alnaggar N, Geue S, Tegtmeyer R, Rath D, Droppa M, Seizer P, Heitmeier S, Heemskerk JWM, Jennings LK, Storey RF, Angiolillo DJ, Rocca B, Spronk H, Ten Cate H, Gawaz M, Geisler T
  (Siehe online unter https://doi.org/10.1182/bloodadvances.2017013573)
• Myocardial expression of the anaphylatoxin receptor C3aR is associated with cardiac inflammation and prognosis in patients with non-ischaemic heart failure. ESC Heart Fail. 2018 Oct;5(5):846-857
  Mueller KAL, Patzelt J, Sauter M, Maier P, Gekeler S, Klingel K, Kandolf R, Seizer P, Gawaz M, Geisler T, Langer HF
  (Siehe online unter https://doi.org/10.1002/ehf2.12298)
• Relative survival potential of platelets is associated with platelet CXCR4/CXCR7 surface exposure and functional recovery following STEMI. Atherosclerosis. 2018 Nov;278:269-277
  Rath D, Chatterjee M, Meyer L, Tekath N, Olma C, Krumm P, Adams C, Borst O, Müller K, Droppa M, Nikolaou K, Riethmüller J, Gawaz M, Geisler T
  (Siehe online unter https://doi.org/10.1016/j.atherosclerosis.2018.10.008)