Low grade inflammation and cardiovascular disease Konstantinos Aznaouridis, MD PhD 1 st Department of Cardiology Hippokration Hospital Athens Medical School
Atherosclerosis Start from very young To Old age? 2
Inflammation & atherosclerosis Ross R, NEJM 1999
RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 4
INFLAMMATION CHRONIC ACUTE Subclinical, low-grade Inflammatory diseases
Inflammation & arterial function Inflammatory substances: mediators or only markers Arterial effects of antiinflammatory treatment Clinical significance of inflammation
Inflammation & arterial function
Chronological or vascular age? Thomas Sydenham A man is as old as his arteries
Inflammatory diseases & arterial elastic properties Systemic vasculitis Booth A, Wallace S, McEniery C, et al, Arthr Rheumatism 2004
Inflammatory diseases & arterial elastic properties Correlation with disease duration CRP Controls SLE RA Roman M, Devereux R, Schwartz J, et al, Hypertension 2005
Inflammatory diseases & arterial elastic properties Adamantiades- Behcet Ikonomidis I, Lekakis J, Stamatelopoulos K, et al, JACC 2004
Inflammatory diseases & arterial elastic properties 130 125 120 128 AIx (%) P=0.03 Adamantiades- Behcet 115 114 110 ABD controls Ikonomidis I, Aznaouridis K, Protogerou A et al, J Card Fail 2006 Protogerou A, Lekakis J, Stamatelopoulos K et al, Adv Exp Med Biol 2003
Inflammatory diseases & arterial elastic properties Kawasaki syndrome Kawasaki 20 19 AIx 10 P<0.0001 0 Kawasaki control control -10-9 Senzaki H, Chen C-H, Ishido H, et al, Circulation 2005
Inflammatory diseases & arterial elastic properties HIV infection Schillaci G, et al, Hypertension 2008 Vlachopoulos C, et al. Artery Research 2009
Subclinical inflammation & arterial stiffness General population Higher levels of inflammatory indexes (ie, CRP) correlate with impaired arterial elastic properties Kullo I, et al. Am J Hypertens 2005 Tomiyama et al, Atherosclerosis 2004 Kampus P et al. J Hypertens 2004 Mattace-Raso et al, Atherosclerosis 2004 Yasmin et al, ATVB 2004
Subclinical inflammation & arterial stiffness General population % 60 40 WBC-AIx 20 0-20 2000 4000 6000 8000 10000 12000 /μl Vlachopoulos C, Aznaouridis K, et al, Atherosclerosis 2006
Subclinical infections & arterial stiffness General population H. Pylori seropositivity PWV m/sec 14.5 14.2 13.97 P<0.001 13.9 13.6 13.44 13.3 13 sero (+) sero (-) Occult persistent infections have been related to augmented arterial stiffness, indicating an adverse impact on vascular function Saijo Y, Utsugi M, Yoshioka E, et al. Hypertens Res 2005
Subclinical inflammation & arterial stiffness Diabetes, Metabolic Syndrome In diabetic pts, the level of CRP and other inflammatory markers correlate with stiffness Wakabayashi I, Masuda H. Clin Chim Acta 2006 In patients with MetS, aortic stiffness correlates with the amount of subcutaneous fat, which composes cytokines and other inflammatory mediators Ferreira I, Henry RMA, Twisk JWR, et al. Arch Intern Med 2005
Subclinical inflammation & arterial stiffness Hypercholesterolemia CRP is an independent determinant of c-f PWV in hypercholesterolemic pts Pirro M, Schillaci G, Sayarese G, et al. Eur J Clin Invest 2004
Subclinical inflammation & arterial stiffness Hypertension Mahmud A, Feely J. Hypertension 2005 Pietri P, Vyssoulis G, Vlachopoulos C, et al. J Hypertens 2006
Acute inflammation and arterial function observational studies Charakida M, Donald A, Terese M et al, Circulation 2005
Acute inflammation and arterial function Causal relationship or epiphenomenon? Salmonella Typhi vaccine Vlachopoulos C, Dima I, Aznaouridis K, Stefanadis C. Circulation 2005
Acute inflammation and arterial function Acute inflammation impairs elastic properties and increases levels of inflammatory indexes Vlachopoulos C, Dima I, Aznaouridis K, Stefanadis C. Circulation 2005
Acute inflammation and arterial function Endothelial function Hingorani AD, Cross J, Kharbanda RΚ et al, Circulation 2000 Kharbanda RK, Walton B, Allen M et al, Circulation 2002 Clapp B, Hierschfield G, Storry C et al, Circulation 2005
Inflammatory substances: mediators or only markers
Inflammatory mediators / markers Tousoulis D, et al. Eur Heart J 2016
Predictive value of CRP General population Predicts CV risk independent of LDL-C and FRS Ridker PM, NEJM 2002
Predictive value of inflammatory markers General population The use of contemporary biomarkers (including C-reactive protein) adds only moderately to standard risk factors for risk assessment of individual persons Wang T, et al. NEJM 2006
CRP: a protein causing vascular dysfunction and atherosclerosis?
CRP: a protein causing vascular dysfunction and atherosclerosis? Αm J Med 2004 Αm J Physiol 2003
CRP: a protein causing vascular dysfunction and atherosclerosis? Circulation 2002
CRP: a protein causing vascular dysfunction and atherosclerosis? Clapp B, Hierschfield G, Storry C et al, Circulation 2005 Vlachopoulos C, Dima I, Aznaouridis K,et al. Circulation 2005
CRP: a protein causing vascular dysfunction and atherosclerosis? ΑΤVB 2005
Arterial effects of antiinflammatory treatment
Anti-inflammatory drugs and arterial function Maki-Petaja K, Hall F, Booth A et al, Circulation 2006 Chronic inflammatory diseases Rheumatoid arthritis anti-tnf factors
Anti-inflammatory drugs and arterial function Chronic inflammatory diseases AIx (%) Corticosteroids in Adamantiades- Behcet disease Controls ABD ABD cort + cort - Protogerou A, Lekakis J,Ikonomidis I et al, Am J Hypertens 2006
Anti-inflammatory drugs and arterial function Aspirin in acute inflammation No aspirin pretreatment Aspirin pretreatment Vlachopoulos C, Dima I, Aznaouridis K, Stefanadis C. Circulation 2005
Anti-inflammatory drugs and arterial function COX2 inhibitors: celecoxib FMD PWV % 6.5 5.5 P=NS P<0.05 Baseline m/sec 6 5.6 P=NS P<0.05 4.5 Post-smoking 5.2 3.5 4.8 2.5 4.4 Celecoxib Placebo Celecoxib Placebo Vlachopoulos C, Aznaouridis K, Bratsas A et al, Int J Cardiol 2016
Anti-inflammatory drugs and arterial function Statins in acute inflammation Vlachopoulos C, Aznaouridis K, et al. Eur Heart J 2007
Anti-inflammatory drugs and arterial function ANAKINRA Human recombinant IL-1 receptor antagonist RA patients resistant to dmards Dose: 70-150 mg/d (24 weeks) s.c Side effects: 1.8% infections, local erythema. Has documented anti- proliferative effects in the coronary artery wall after injury AO DIST 14 12 10 8 6 4 2 0 Baseline 3h- post placebo 3h- post anakinra post month Ikonomidis I, Lekakis JP, et al. Circulation. 2008 May 20;117(20):2662-9.
Clinical significance of inflammation
Inflammation & coronary syndromes Stefanadis C, Diamantopoulos L, Vlachopoulos C, et al, Circulation 1999
Clinical value of inflammation in chronic inflammatory disorders TNF- blockers and CV events in RA patients CV events per 1000 pt-year 70 60 50 40 30 20 10 p=0.013 0 no yes treatment with anti-tnf- Swedish national register of TNF- blockers (n=531), and a control cohort of RA patients (n=452) Jacobsson LT, et al. J Rheumatol 2005;32:1213-1218
Clinical value of acute inflammation 5-fold increase of AMI risk and 3-fold increase of stroke risk following an acute respiratory infection Modest but significant increase of risk following an acute urinary tract infection
Clinical value of subclinical inflammation Ridker PM, Lancet 2001
Events/100 Person-Yrs Events/100 Person-Yrs Clinical value of subclinical inflammation JUPITER Trial design: Apparently healthy patients with LDL cholesterol <130 mg/dl and hs-crp 2 mg/dl were randomized to rosuvastatin 20 mg daily or placebo. Clinical outcomes were compared at a median of 1.9 years. 2 1 (p < 0.00001) 0.77 1.36 2 1 (p = 0.02) 1.0 1.25 Results Rosuvastatin associated with a significant in the primary outcome of MI, stroke, unstable angina, revascularization, or cardiovascular death (HR 0.56, 95% CI 0.46-0.69, p < 0.00001) All-cause mortality with rosuvastatin (p = 0.02) 0 Primary outcome 0 All-cause mortality Rosuvastatin was associated with a significant reduction in major cardiovascular events, including death, in patients with LDL <130 mg/dl, but high hs-crp ( 2.0 mg/dl) Rosuvastatin (n = 8,901) Placebo (n = 8,901) Ridker PM, et al. NEJM 2008;359:2195-207
Clinical value of subclinical inflammation CANTOS Trial design: 10,061 patients with previous MI and hs-crp 2 mg/dl were randomized to canakinumab 50, 150 or 300 mg SC every 3 months or placebo. Clinical outcomes were compared at a median of 48 months.
Conclusions - Sufficient data suggest associations between subclinical low grade inflammation (in healthy subjects, general population and subjects with CV risk factors) and clinical inflammation (chronic inflammatory diseases and acute inflammatory disorders) with impaired arterial elastic properties and adverse prognosis. - Evidence suggesting a cause-and-effect relationship is adequate only for acute inflammatory disorders; there are no sufficient data to support a causal association between subclinical low grade inflammation and CV disease in healthy subjects, general population and subjects with CV risk factors but no established CV disease - Data concerning a direct role of CRP in inducing arterial dysfunction are still conflicting - Several anti-inflammatory agents improve arterial performance but further studies are needed to investigate whether this effect is beneficial in terms of prognosis
Conclusions