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Inflammation and CHD

Inflammation and CHD. Nathan Wong. Thrombosis, Inflammation, and Infection. Many persons experiencing cardiovascular events often do not have well-recognized standard risk factors such as elevated cholesterol or hypertension.

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Inflammation and CHD

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  1. Inflammation and CHD Nathan Wong

  2. Thrombosis, Inflammation, and Infection • Many persons experiencing cardiovascular events often do not have well-recognized standard risk factors such as elevated cholesterol or hypertension. • Thrombosis, local or systemic inflammation, and chronic infection may play important roles in the initiation and progression of CHD

  3. LipidsHTNDiabetes Behavioral HemostaticThrombotic Inflammatory Genetic Beyond Cholesterol: Predicting Cardiovascular Risk In the 21st Century Cardiovascular Risk

  4. Total Cholesterol Distribution: CHD vs Non-CHD Population Framingham Heart Study—26-Year Follow-up No CHD 35% of CHD Occurs in People with TC<200 mg/dL CHD 150 300 250 200 Total Cholesterol (mg/dL)

  5. Inflammation and Atherosclerosis • Inflammation may determine plaque stability - Unstable plaques have increased leukocytic infiltrates - T cells, macrophages predominate rupture sites - Cytokines and metalloproteinases influence both stability and degradation of the fibrous cap • Lipid lowering may reduce plaque inflammation - Decreased macrophage number - Decreased expression of collagenolytic enzymes (MMP-1) - Increased interstitial collagen - Decreased expression of E-selectin - Reduced calcium deposition

  6. Is there clinical evidence that inflammatory markers predict future coronary events and provide additional predictive information beyond traditional risk factors?

  7. Evaluating Novel Risk Factors for CAD • Low variability • High reproducibility • Biologic plausibility • Low cost • Modifiable • Consistency of prospective data • Strength of association • Independence of association • Improve predictive value • Standardized measure

  8. Parameter Venous Arterial Fibrinogen – +++ Factor VII – + vWF: ag – ++ tPA: ag – +++ PAI-1: ag – ++ Platelet function – ++ Lp(a) – + hs-CRP / SAA / IL-6 / TNF – +++ Biomarkers for Venous and Arterial Thrombosis

  9. Parameter Venous Arterial Factor V Leiden +++ – Prothrombin mutation ++ – Prothrombin + – Factor VIII ++ – Anti-thrombin III ++ – Protein C + – Protein S + – Homocysteine ++ ++ D-dimer ++ ++ Biomarkers for Venous and Arterial Thrombosis (cont’d)

  10. Thrombosis and Cardiovascular Risk • Thrombus formation is a crucial factor in the precipitation of unstable angina or myocardial infarction, as well as occlusion during or following angioplasty. • Often preceded by platelet aggregation and activation of the coagulation system. • A thrombus may develop at sites of only mild to moderate coronary stenosis. The majority of coronary events occur where there is less than 70% stenosis. • Occlusive coronary thrombosis plays a role in over 80% of myocardial infarctions and about 95% of sudden death victims.

  11. Fibrinogen and Atherosclerosis • Promotes atherosclerosis • Essential component of platelet aggregation • Relates to fibrin deposited and the size of the clot • Increases plasma viscosity • May also have a proinflammatory role • Measurement of fibrinogen, incl. Test variability, remains difficult. • No known therapies to selectively lower fibrinogen levels in order to test efficacy in CHD risk reduction via clinical trials.

  12. Fibrinogen and CHD Risk: Epidemiologic Studies • Recent meta-analysis of 18 studies involving 4018 CHD cases showed a relative risk of CHD of 1.8 (95% CI 1.6-2.0) comparing the highest vs lowest tertile of fibrinogen levels (mean .35 vs. .25 g/dL) • ARIC study in 14,477 adults aged 45-64 showed relative risks of 1.8 in men and 1.5 in women, attenuated to 1.5 and 1.2 after risk factor adjustment. • Scottish Heart Health Study of 5095 men and 4860 women showed fibrinogen to be an independent risk factor for new events--RRs 2.2-3.4 for coronary death and all-cause mortality.

  13. Fibrinogen and CHD Risk Factors • Fibrinogen levels increase with age and body mass index, and higher cholesterol levels • Smoking can reversibly elevated fibrinogen levels, and cessation of smoking can lower fibrinogen. • Those who exercise, eat vegetarian diets, and consume alcohol have lower levels. Exercise may also lower fibrinogen and plasma viscosity. • Studies also show statin-fibrate combinations (simvastatin-ciprofibrate) and estrogen therapy to lower fibrinogen.

  14. Other Thrombotic Factors and CHD • Mixed reports of coagulation factor VIIc in cardiovascular disease. PROCAM study showed no association with CHD events, CHS also showed no relation to subclinical CVD. • Endogenous tissue-type plasminogen activator (tPA) shown in some studies to relate to increased cardiovascular risk--Physician’s Health Study showed RR for MI 2.8, stroke 3.5 in those in 5th vs. 1st quintile of tPA. • Plasminogen activitor inhibitor type 1 (PAI-1) shown associated with increased cardiovascular risk, esp in diabetic patients.

  15. Aspirin and Cardiovascular Risk: Clinical Trial Evidence for Primary Prevention • US Physician’s Health Study- 22,071 male physicians - 44% reduction in MI risk, 13% nonsignificant increase in risk of stroke • British Doctor’s Study of 5139 male physicians showed nonsignificant 3% reduction in MI risk,13% nonsignificant increase in stroke • Hypertension Optimal Treatment (HOT) study among 18,790 pts w/htn showed 15% reduction in CVD events, 36% reduction in MI • Ongoing Women’s Health Study (n=40,000)

  16. Aspirin and Cardiovascular Risk: Clinical Trial Evidence for Secondary Prevention • Antiplatelet Trialists Collaboration of 54,000 patients with cardiovascular disease (10 trials post-MI) showed 31% reduction in MI, 42% reduction in stroke, 13% reduction in total vascular mortality • International Study of Infarct Survival of 17,187 pts w/evolving MI showed 49% reduction in reinfarction, 26% reduction in nonfatal stroke, and 23% reduction in total vascular mortality

  17. Antiplatelet Therapy: AHA Recommendations • Aspirin is clearly recommended in secondary prevention. Provides additional benefit in conjunction with thrombolytic therapy. Clopidogrel may be an option in aspirin-intolerant patients. • Aspirin is not recommended for primary prevention in those free of CHD and younger than 50 years old. • Aspirin may be considered in those over age 50 with additional risk factors, free of contraindications, and may benefit those with hypertension, diabetes, and cigarette smoking. • American Diabetes Association recommends aspirin in diabetics with at least one other CHD risk factor.

  18. Lipoprotein(a) Homocysteine Total Cholesterol Fibrinogen tPA Antigen TC:HDL-C hs-CRP hs-CRP + TC/HDL-C 1.0 2.0 4.0 6.0 0 Relative Risks of Future MI among Apparently Healthy Middle-Aged Men: Physician’s Health Study Relative Risk for Future MI

  19. Risk Factors for Future Cardiovascular Events: WHS Lipoprotein(a) Homocysteine IL-6 TC LDL-C sICAM-1 SAA Apo B TC:HDL-C hs-CRP hs-CRP + TC:HDL-C 0 1.0 2.0 4.0 6.0 Relative Risk of Future Cardiovascular Events

  20. CRP vs hs-CRP • CRP is an acute-phase protein produced by the liver in response to cytokine production (IL-6, IL-1, tumor necrosis factor) during tissue injury, inflammation, or infection. • Standard CRP tests determine levels which are increased up to 1,000-fold in response to infection or tissue destruction, but cannot adequately assess the normal range • High-sensitivity CRP (hs-CRP) assays (i.e. Dade Behring) detect levels of CRP within the normal range, levels proven to predict future cardiovascular events.

  21. Potential Mechanisms Linking CRP to Atherothrombosis • Marker for subclinical atherosclerosis- EBCT / IMT / ABI • Marker for insulin resistance/ obesity • Marker for endothelial dysfunction • Marker for dysmetabolic syndrome • Marker for plaque vulnerability • Confounding by cigarette consumption • Innocent bystander- Acute phase response • Cytokine surrogate- IL-6, TNF-, IL-1 • Direct effects of CRP- Innate immunity- Complement activation- CAM induction • Prior infection- Chlamydia, H pylori, CMV

  22. hs-CRP and Risk of Future MI in Apparently Healthy Men P Trend <0.001 P < 0.001 P < 0.001 P = 0.03 Relative Risk of MI 1<0.055 20.056–0.114 30.115–0.210 4>0.211 Quartile of hs-CRP (range, mg/dL)

  23. hs-CRP and Risk of Future Stroke in Apparently Healthy Men P Trend <0.03 P =0.02 P =0.02 Relative Risk of Ischemic Stroke 1<0.055 20.056–0.114 30.115–0.210 4>0.211 Quartile of hs-CRP (range, mg/dL)

  24. hs-CRP and Risk of Developing PVD in Apparently Healthy Men hs-CRP (mg/dL) IntermittentClaudication Peripheral ArterySurgery None

  25. hs-CRP and Risk of Future Cardiovascular Events in Apparently Healthy Women P Trend <0.002 Any Event MI or Stroke Relative Risk 1<0.15 20.15–0.37 30.37–0.73 4>0.73 Quartile of hs-CRP (range, mg/dL)

  26. hs-CRP and Risk of Future Cardiovascular Events in Apparently Healthy Women: Low-Risk Subgroups No hypertension No hyperlipidemia No current smoking No diabetes No family history Relative Risk 1<0.15 20.15–0.37 30.37–0.73 4>0.73 Quartile of hs-CRP (range, mg/dL)

  27. hs-CRP and Coronary Heart Disease in Initially Healthy Men: MONICA–Augsburg Cohort Rate Ratio(Age Adjusted) 1<0.6 20.6–1.1 31.1–2.2 42.2–4.5 5>4.5 Quartile of CRP (mg/dL)

  28. hs-CRP as a Risk Factor for Future CVD MRFIT (Kuller 1996) PHS (Ridker 1997) PHS (Ridker 1997) CHS/RHPP (Tracy 1997) PHS (Ridker 1998) WHS (Ridker 1998, 2000) MONICA (Koenig 1999) Helsinki (Roivainen 2000) Caerphilly(Mendall 2000) Britain (Danesh 2000) CHD Death MI Stroke CHD PVD CVD CHD CHD CHD CHD 0 1.0 2.0 3.0 4.0 5.0 6.0 Relative Risk (upper vs lower quartile)

  29. hs-CRP Adds to the Predictive Value of Total Cholesterol in Determining Risk of First MI P = 0.001 Adjusted Relative Risk P = 0.002 P = 0.02 CRP >75thpercentile – + – + TC >75thpercentile – – + +

  30. hs-CRP Adds to Predictive Value of TC:HDL Ratio in Determining Risk of First MI hs-CRP Total Cholesterol:HDL Ratio

  31. 9 8 7 6 5 4 3 2 1 0 4 4 3 3 2 2 1 1 hs-CRP, Lipids, and Risk of Future Coronary Events: Women's Health Study (WHS) Quartile of hs-CRP Quartile of TC: HDL-C

  32. Relative Risks for First MI for Baseline sICAM-1 >260 ng/dL 3 2 1 0 Relative Risk 0–1 1–2 2–4 4–8 Years of Study Follow-up

  33. Predictivity of Interleukin-6 on CV Risk in Women 4 3 2 1 0 Interleukin-6 High High Medium Medium Low Total cholesterol Low

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