Obesity is related to a higher inflammatory responsive state of circulating cells after stimulation of toll like receptor 2 and 4.

Transcription

1 Toll Like Receptor Response and traditional risk factors for atherosclerosis: Obesity is related to a higher inflammatory responsive state of circulating cells after stimulation of toll like receptor 2 and 4. V.P.W. Scholtes Experimental Laboratory Cardiology University Medical Center Utrecht The Netherlands ESC Congress, Stockholm 21 Adipose tissue and inflammation

2 Atherosclerosis and inflammation Adapted from Obesity, inflammation, and atherosclerosis Viviane Z. Rocha and Peter Libby Nat. Rev. Cardiol. 6, (29)

3 Toll Like Receptor and inflammation Ligand Toll Like Receptor TNF-α IL-6 NF-κB DNA transcription

4 Toll like Receptor Response 1 μl of blood + 1 μl of LPS 1 μl of blood + 1 μl of P3C TLR4 monocyte monocyte TLR2 cytokines ELISA: TNF-alpha

5 TLR response: clinical perspective (1) Enhanced response of blood monocytes to in vitro LPS challenge in patients with recurrent unstable angina, Liuzzo Circulation 21;13;

6 TLR response: clinical perspective (2) Monocyte toll-like receptor 2 and 4 responses and expression following PCI. Asocation with lesion stenosis and fractional flow reserve D Versteeg Heart 28 94:

7 Research question Are traditional risk factors and obesity associated with an altered Toll Like Receptor response?

8 Obesity and inflammation Inflammatory disorder Adapted from Obesity, inflammation, and atherosclerosis Viviane Z. Rocha and Peter Libby Nat. Rev. Cardiol. 6, (29)

9 Methods Cohort 1 (PCI cohort) 1 Patients scheduled for Percutaneous Coronary Intervention Cohort 2 (CEA cohort) 113 Patients scheduled for Carotid Artery Endarterectomy Exclusion of: patients with an acute Myocardial infarction patients with a chronic inflammatory disease (corticosteroid use)

10 Clinical Characteristics PCI cohort CEA cohort parameter 78 patients 15 patients sex / 56 / / 35 age median [IQR] 62,5 [53 7] 7,7 [63 78] BMI median [IQR] 26.9 [ ] 26.4 [ ] BMI > 25 n (%) 41(73%) 14(64%) 45(66%) 23(68%) smoking n (%) 5 (6%) 27 (25%) hypertension n (%) 52 (67%) 88 (84%) diabetes n (%) 16 (21%) 21 (2%) hypercholesteremia n (%) 72 (92%) 84 (8%) family history of CVD n (%) 41 (53%) 28 (27%)

11 TNF-alpha ng/ml TNF-alpha ng/ml Risk factors and TLR response CEA cohort PCI cohort 1 8 TLR yes (52) no (26) yes (88) no (17) yes (16) no (62) yes (21) no (84) Hypertension Diabetes

12 TNF-alpha ng/ml TNF-alpha ng/ml Risk factors and TLR response PCI cohort CEA cohort 1 8 TLR yes (72) no (6) yes (84) no (21) Hypercholesterolemia yes (41) no (37) yes (28) no (59) Family History of CVD

13 TNF-alpha pg/ml TNF-alpha pg/ml Smoking and TLR response PCI cohort CEA cohort 1 TLR 2 1 p =.13 TLR no (73) yes (5) no (79) yes (26) no (73) yes (5) no (79) yes (26)

14 TNF-alpha pg/ml TNF-alpha pg/ml BMI and TLR response PCI cohort CEA cohort p =.4 TLR 2 1 p =.41 TLR 4 1 p =.254 p = < 25 (37) > 25 (68) < 25 (23) > 25 (55) < 25 (37) > 25 (68) < 25 (23) > 25 (55)

15 cd11b expression (mean fluorescence) cd11b expression (mean fluorescence) BMI and inflammation: Cd11b expression on monocytes 8 Study 1 p =.6 3 p =.72 Study cd11b < 25 (13) 25-3 (21) > 3 (9) BMI group cd11b < 25 (24) 25-3 (29) > 3 (11) BMI group

16 hscrp serum level mg/l BMI and inflammation: hscrp levels (study 1) 15 Study 1 p = < 25 (23) 25-3 (31) > 3 (24) hscrp BMI group

17 Conclusion Obesity was the only risk factor for CVD that was positively associated with an altered TLR response We observed a trend towards lower levels of TNF-alpha for patients who were active smokers The enhanced systemic inflammatory state in obese patients was also reflected in: - elevated levels of hscrp - and increased expression of the activation marker cd11b on monocytes.

18 Acknowledgements Experimental Laboratory Cardiology Prof. G. Pasterkamp Prof DPV de Kleijn dr I Hoefer dr JK van Keulen dr DIK Versteeg EHAM Elsenberg Department of Cardiology Prof DA Doevedans dr PR Stella Department of Vascular Surgery Prof FL Moll dr GJ de Borst dr J.A. van Herwaarden dr R.J. Toorop Department of Vascular Surgery dr JPPM de Vries dr H.D.W.M. Van de Pavoordt dr J. Wille drs R.H. van de Mortel dr B.A.N. Verhoeven Department of Microbiology dr G.T. Rijkers mail: vscholt2@umcutrecht.nl

19 Extra figures

20 Smoking and Attenuation of TLR response Tobacco Smoking Inhibits Expression of Proinflammatory Cytokines and Activation of IL-1R-Associated Kinase, p38, and NF- {kappa}b in Alveolar Macrophages Stimulated with TLR2 and TLR4 Agonists Haiyan Chen, Mark J. Cowan, Jeffrey D. Hasday, Stefanie N. Vogel and Andrei E. Medvedev J. Immunol. 27;179;

21 cd11b expression (mean fluorescence) cd11b expression (mean fluorescence) Very obese patients and lower TLR responsiveness 8 Study 1 p =.6 3 p =.72 Study cd11b < 25 (13) 25-3 (21) > 3 (9) BMI group cd11b < 25 (24) 25-3 (29) > 3 (11) BMI group

22 TNF-alpha pg/ml TNF-alpha pg/ml TNF-alpha pg/ml TNF-alpha pg/ml Very obese patients have a lower TLR response 15 Study 1 6A p =.6 1 Study 1 6B p = < 25 (23) 25-3 (31) > 3 (24) P3C5 (TLR2) Study 2 6C BMI group p =.6 6 < 25 (23) 25-3 (31) > 3 (24) LPS1 (TLR4) Study 2 6D BMI group p = < 25 (37) 25-3 (44) > 3 (24) P3C5 (TLR2) BMI group < 25 (37) 25-3 (44) > 3 (24) LPS1 BMI group

23 TNF-alpha pg/ml TNF-alpha pg/ml BMI and TLR response 2 study 1 1 study BMI BMI

24 PCI cohort CEA cohort TLR2 stimulation present not present present not present Hypertension (26) 11 [3 35] (52) 18 [8 5] (88) 12 [6 22] (17) 14 [7 25] Diabetes (16) 1 [ 26] (62) 14 [6 44] (21) 12 [7 2] (84) 12 [6 25] Hypercholesterolemia (72) 12 [4 42] (6) 23 [8 4] (84) 11 [6 21] (21) 15 [9 32] Family history of heart disease < 6 years (41) 15 [6 46] (37) 11 [3 36] (28) 11 [7 32] (59) 12 [6 19] BMI ( BMI < 25 / BMI > 25) (55) 17 [8 49] (23) 7 [2 19] (37) 9 [6 16] (68) 14 [7 28] Smoking (yes / no) (5) 8 [2 22] (73) 13 [5 43] (26) 11 [6 2] (79) 12 [7 25] TLR4 stimulation present not present present not present Hypertension (26) 355 [ ] (52) 246 [18 582] (88) 173 [99-296] (17) 245 [ ] Diabetes (16) 246 [ ] (62) 363 [ ] (21) 196 [ ] (84) 185 [13 315] Hypercholesterolemia (72) 36 [ ] (6) 35 [27 694] (84) 185 [13 3] (21) 22 [ ] Family history of heart disease < 6 years (41) 273 [ ] (37) 359 [22 578] (28) 216 [95 336] (59) 165 [18 297] BMI ( BMI < 25 / BMI > 25) (55) 364 [ ] (23) 219 [ ] (37) 154 [15 261] (68) 29 [ ] Smoking (yes / no) (5) 15 [7 231] (73) 353 [ ] (26) 26 [ ] (79) 181 [18-3]