Subclinical inflammation and peripheral artery disease. Luigi M Biasucci, M.D. Institute of Cardiology Catholic University Rome, ITALY

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1 Subclinical inflammation and peripheral artery disease Luigi M Biasucci, M.D. Institute of Cardiology Catholic University Rome, ITALY ESC Congress 2010

2 Conflict of interest Research grants:sanofi-aventis, Behringer-Ingelheim Fees for Presentations: Sanofi, Pfizer Consultant: Sanofi, Pfizer, Siemens Diagnostics

3 Ross Nature 1993

5 Proinflammatory risk factors (oxldl, infectious agents, etc.) Proinflammatory, cytokines ICAM-1 SELECTINS CIRCULATION Libby and Ridker, Circulation 100,1999 IL-6 CRP

6 CLINICAL EVIDENCES HOW LOW MUST INFLAMMATION BE TO BE SAFE? SOURCES OF LOW GRADE INFLAMMATION

7 CLINICAL EVIDENCES HOW LOW MUST INFLAMMATION BE TO BE SAFE? SOURCES OF LOW GRADE INFLAMMATION

8 Diffuse limb artery inflammation by PET Rudd Journ Nuclear Med 2008

9 Relative Risk CRP and Risk of Ischemic Stroke The Framingham Study Rost et al, Stroke 2001;32: Quartile of CRP

10 CRP, Unstable Angina and Carotid Plaques Lombardo, Circulation 2004

11 Echo-lucent peripheral plaques and inflammation Sirico Journ Vascul Surg 2009

12 CLINICAL EVIDENCES HOW LOW MUST INFLAMMATION BE TO BE SAFE? SOURCES OF LOW GRADE INFLAMMATION

13 Cesari Am J Cardiol 2003 Subclinical CV disease and inflammation in elderly

14 CLINICAL EVIDENCES HOW LOW MUST INFLAMMATION BE TO BE SAFE? SOURCES OF LOW GRADE INFLAMMATION

15 Infections?? CP?? HP subclinical inflammation CP CMV cytokine production? endothelial activation platelet activation coagulation thrombosis Liver acute phase proteins (CRP,PAI-1 SAA, fibrinogen, vwf)

16 CRP INDUCES TISSUE FACTOR SYNTHESIS IN HUMAN PERIPHERAL MONOCYTES Cermak, Blood 1993,82;513-20

17 Increased Thrombosis After Arterial Injury in Human CRP-Transgenic Mice Danemberg, Circulation 2003,108:

Percent of MO positive for nuclear p65 Evidence for a

CRP on human monocytes via NF- B activation (by using 3

Nuclei DAPI p65 FITC Nuclei + p65 75% ANOVA P<0.

LPS 10 ng/ml LPS 10 ng/ml + purified CRP 25 mcg/ml 0

18 Percent of MO positive for nuclear p65 Evidence for a direct pro-inflammatory effect of azide and LPS free CRP on human monocytes via NF- B activation (by using 3 different methods: EMSA, ELISA and confocal mycroscopy) Nuclei DAPI p65 FITC Nuclei + p65 75% ANOVA P<0.001 Unstimulated ** 50% purified CRP 25 mcg/ml * 25% LPS 10 ng/ml LPS 10 ng/ml + purified CRP 25 mcg/ml 0 CRP ( g/ml) den LPS (ng/ml) Liuzzo G, JACC 2006

19 IL-6 and IL-8 INDUCE MONOCYTE EXPRESSION OF TISSUE FACTOR Neumann Arteriosclerosis,Thrombosis and Vascular Biology 1997, 17;

20 However the infective hypothesis has lost momentum, because of the clinical trials showing no effects from antibiotic treatment and of the widespread diffusion of infective agents in the plaques, independently from disease statuts.

21 Immunity?? CP?? HP inflammationy subclinical cytokine production Liver? CP CMV endothelial activation platelet activation coagulation thrombosis acute phase proteins (CRP,PAI-1 SAA, fibrinogen, vwf)

22 HSP, Molecular mimicry and atherosclerosis Lamb, Atherosclerosis 2003, 167,

23 Novel acquisitions: Insulin Resistance, Obesity and fat tissue

24 Relative Risks of Future Cardiovascular Events According to CRP & Metabolic Syndrome No Metabolic Syndrome Yes Metabolic Syndrome Ridker et al. Circulation 2003;

25 CRP quartiles CRPquartiles

26 Adjusted RR Abdominal obesity and increased risk of CV events in the HOPE study 1.4 Tertile 1 Tertile 2 Tertile CV death MI All deaths Dagenais GR et al. Am Heart J 2005;149:54-60

27 Loskutoff and Samad ATVB 2008 Biosinthetic activity of lipidladen adipocytes

28 Fantuzzi ATVB 2007 Adipose tissue and atherosclerosis

29 ? ADIPOSE TISSUE Proinflammatory risk factors (oxldl, infectious agents, etc.)? Proinflammatory cytokines (TNF, IL-1) ICAM-1 SELECTINS CIRCULATION IL-6 CRP Libby and Ridker, Circulation 100,1999

30 Is Fat Guilty? Fat is not all the same The paradoxical case of morbid obesity

31 Increased inflammation C C-Reactive Protein D Leptin mg/l 40 p=0.018 p= 0.05 ng/l 100 p<0.001 p< L O MO L O MO Biasucci Am.J.Med.2010

32 Paradoxical Vascular improvement Flow-mediated dilation Maximum carotid IMT % p=0.011 p=0.019 mm p= L O MO L O MO Biasucci Am.J.Med.2010

33 Higher levels of EPCs CD34 + KDR + EPCs % p= L O MO Biasucci Am.J.Med.2010

34 Discrepancy between inflammation and coagulation activation in ACS vs PAD Monaco JACC 2005

35 Microparticles and Atherothrombotic Burden 2000 Extreme values are hidden Extreme values are hidden Apoptotic MP (mp/ul) 300 Endothelial MP (mp/ul) 1500 Platelet MP (mp/ul) Single-Site ACS Multi-site group Biasucci et al Single-Site Multi-site group ACS 0 Single-Site Multi-site group ACS

36 Conclusions1 Low-grade, diffuse inflammation is responsible for initiation and continuation of atherosclerosis, also at the peripheral level. Obesity and metabolic syndrome, and perhaps chronic low-grade infections, may represent the keys of this phenomenon. Their prevention and treatment might reduce the burden of PAD

37 Conclusions 2 However some aspects,as the discrepancy in inflammation and coagulation found between ACS and severe PAD and the paradoxical improved endothelial function in MO claim for more in deep studies on mechanisms and triggers of subclinical inflammation in PAD.

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