Inflammation and CHD Nathan Wong Slide Source Lipids

Inflammation and CHD Nathan Wong Slide Source: Lipids Online www. lipidsonline. org

Thrombosis, Inflammation, and Infection n Many persons experiencing cardiovascular events often do not have well-recognized standard risk factors such as elevated cholesterol or hypertension. n Thrombosis, local or systemic inflammation, and chronic infection may play important roles in the initiation and progression of CHD Slide Source: Lipids Online www. lipidsonline. org

Beyond Cholesterol: Predicting Cardiovascular Risk In the 21 st Century Cardiovascular Risk Lipids HTN Diabetes Behavioral Hemostatic Inflammatory Genetic Thrombotic Slide Source: Lipids Online www. lipidsonline. org

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/d. L 150 CHD 200 250 300 Total Cholesterol (mg/d. L) Slide Source: Lipids Online www. lipidsonline. org

Inflammation and Atherosclerosis n 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 n 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 Slide Source: Lipids Online www. lipidsonline. org

Is there clinical evidence that inflammatory markers predict future coronary events and provide additional predictive information beyond traditional risk factors? Slide Source: Lipids Online www. lipidsonline. org

Evaluating Novel Risk Factors for CAD n Consistency of prospective data n Strength of association n Independence of association n Improve predictive value n Standardized measure n Low variability n High reproducibility n Biologic plausibility n Low cost n Modifiable Slide Source: Lipids Online www. lipidsonline. org

Biomarkers for Venous and Arterial Thrombosis Parameter Venous Arterial Fibrinogen – +++ Factor VII – + v. WF: ag – ++ t. PA: ag – +++ PAI-1: ag – ++ Platelet function – ++ Lp(a) – + hs-CRP / SAA / IL-6 / TNF – +++ Slide Source: Lipids Online www. lipidsonline. org

Biomarkers for Venous and Arterial Thrombosis (cont’d) Parameter Venous Arterial +++ – + – Factor VIII ++ – Anti-thrombin III ++ – Protein C + – Protein S + – Homocysteine ++ ++ D-dimer ++ ++ Factor V Leiden Prothrombin mutation Prothrombin Slide Source: Lipids Online www. lipidsonline. org

Thrombosis and Cardiovascular Risk n Thrombus formation is a crucial factor in the precipitation of unstable angina or myocardial infarction, as well as occlusion during or following angioplasty. n Often preceded by platelet aggregation and activation of the coagulation system. n 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. n Occlusive coronary thrombosis plays a role in over 80% of myocardial infarctions and about 95% of sudden death victims. Slide Source: Lipids Online www. lipidsonline. org

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

Fibrinogen and CHD Risk: Epidemiologic Studies n 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/d. L) n 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. n 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. Slide Source: Lipids Online www. lipidsonline. org

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

Other Thrombotic Factors and CHD n 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. n Endogenous tissue-type plasminogen activator (t. PA) 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 5 th vs. 1 st quintile of t. PA. n Plasminogen activitor inhibitor type 1 (PAI-1) shown associated with increased cardiovascular risk, esp in diabetic patients. Slide Source: Lipids Online www. lipidsonline. org

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

Aspirin and Cardiovascular Risk: Clinical Trial Evidence for Secondary Prevention n 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 n 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 Slide Source: Lipids Online www. lipidsonline. org

Antiplatelet Therapy: AHA Recommendations n Aspirin is clearly recommended in secondary prevention. Provides additional benefit in conjunction with thrombolytic therapy. Clopidogrel may be an option in aspirin-intolerant patients. n Aspirin is not recommended for primary prevention in those free of CHD and younger than 50 years old. n 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. n American Diabetes Association recommends aspirin in diabetics with at least one other CHD risk factor. Slide Source: Lipids Online www. lipidsonline. org

Relative Risks of Future MI among Apparently Healthy Middle-Aged Men: Physician’s Health Study Lipoprotein(a) Homocysteine Total Cholesterol Fibrinogen t. PA Antigen TC: HDL-C hs-CRP + TC/HDL-C 0 1. 0 2. 0 4. 0 Relative Risk for Future MI 6. 0 Slide Source: Lipids Online www. lipidsonline. org

Risk Factors for Future Cardiovascular Events: WHS Lipoprotein(a) Homocysteine IL-6 TC LDL-C s. ICAM-1 SAA Apo B TC: HDL-C hs-CRP + TC: HDL-C 0 1. 0 2. 0 4. 0 6. 0 Relative Risk of Future Cardiovascular Events Slide Source: Lipids Online www. lipidsonline. org

CRP vs hs-CRP n 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. n 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 n 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. Slide Source: Lipids Online www. lipidsonline. org

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

hs-CRP and Risk of Future MI in Apparently Healthy Men Relative Risk of MI P Trend <0. 001 P < 0. 001 3 0. 115– 0. 210 4 >0. 211 P = 0. 03 1 <0. 055 2 0. 056– 0. 114 Quartile of hs-CRP (range, mg/d. L) Slide Source: Lipids Online www. lipidsonline. org

hs-CRP and Risk of Future Stroke in Apparently Healthy Men P Trend <0. 03 P =0. 02 Relative Risk of Ischemic Stroke P =0. 02 1 <0. 055 2 3 0. 056– 0. 114 0. 115– 0. 210 Quartile of hs-CRP (range, mg/d. L) 4 >0. 211 Slide Source: Lipids Online www. lipidsonline. org

hs-CRP (mg/d. L) hs-CRP and Risk of Developing PVD in Apparently Healthy Men None Intermittent Peripheral Artery Claudication Surgery Slide Source: Lipids Online www. lipidsonline. org

hs-CRP and Risk of Future Cardiovascular Events in Apparently Healthy Women P Trend <0. 002 Relative Risk Any Event MI or Stroke 1 <0. 15 2 0. 15– 0. 37 3 0. 37– 0. 73 Quartile of hs-CRP (range, mg/d. L) 4 >0. 73 Slide Source: Lipids Online www. lipidsonline. org

hs-CRP and Risk of Future Cardiovascular Events in Apparently Healthy Women: Low-Risk Subgroups Relative Risk No hypertension No hyperlipidemia No current smoking No diabetes No family history 1 <0. 15 2 0. 15– 0. 37 3 0. 37– 0. 73 Quartile of hs-CRP (range, mg/d. L) 4 >0. 73 Slide Source: Lipids Online www. lipidsonline. org

Rate Ratio (Age Adjusted) hs-CRP and Coronary Heart Disease in Initially Healthy Men: MONICA–Augsburg Cohort 1 <0. 6 2 0. 6– 1. 1 3 1. 1– 2. 2 4 2. 2– 4. 5 Quartile of CRP (mg/d. L) 5 >4. 5 Slide Source: Lipids Online www. lipidsonline. org

hs-CRP as a Risk Factor for Future CVD MRFIT (Kuller 1996) CHD Death PHS (Ridker 1997) MI PHS (Ridker 1997) Stroke CHS/RHPP PHS (Tracy 1997) (Ridker 1998) WHS (Ridker 1998, 2000) CHD PVD CVD MONICA (Koenig 1999) CHD Helsinki (Roivainen 2000) CHD Caerphilly(Mendall 2000) CHD Britain CHD (Danesh 2000) 0 1. 0 2. 0 3. 0 4. 0 5. 0 6. 0 Relative Risk (upper vs lower quartile) Slide Source: Lipids Online www. lipidsonline. org

hs-CRP Adds to the Predictive Value of Total Cholesterol in Determining Risk of First MI Adjusted Relative Risk P = 0. 001 P = 0. 002 P = 0. 02 CRP >75 th percentile – + TC >75 th percentile – – + + Slide Source: Lipids Online www. lipidsonline. org

hs-CRP Adds to Predictive Value of TC: HDL Ratio in Determining Risk of First MI hs-CRP Total Cholesterol: HDL Ratio Slide Source: Lipids Online www. lipidsonline. org

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

Relative Risks for First MI for Baseline s. ICAM-1 >260 ng/d. L Relative Risk 3 2 1 0 0– 1 1– 2 2– 4 Years of Study Follow-up 4– 8 Slide Source: Lipids Online www. lipidsonline. org

Predictivity of Interleukin-6 on CV Risk in Women 4 3 2 1 0 Interleukin-6 High Medium Total cholesterol Low High Medium Slide Source: Lipids Online www. lipidsonline. org