Slide Source: Lipids Online Inflammation and CHD Inflammation and CHD Nathan Wong

Slide Source: Lipids Online 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

Slide Source: Lipids Online Beyond Cholesterol: Predicting Cardiovascular Risk In the 21 st Century Cardiovascular Risk Lipids HTN Diabetes BehavioralBehavioral Hemostatic Thrombotic InflammatoryInflammatoryGeneticGenetic

Slide Source: Lipids Online Total Cholesterol Distribution: CHD vs Non-CHD Population 35% of CHD Occurs in People with TC<200 mg/dL Total Cholesterol (mg/dL) No CHD CHD Framingham Heart Study—26-Year Follow-up

Slide Source: Lipids Online 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

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

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

Slide Source: Lipids Online Biomarkers for Venous and Arterial Thrombosis +++– hs-CRP / SAA / IL-6 / TNF +–Lp(a) ++–Platelet function ++–PAI-1: ag +++–tPA: ag ++–vWF: ag +–Factor VII +++–Fibrinogen ArterialVenousParameter

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

Slide Source: Lipids Online 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.

Slide Source: Lipids Online 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.

Slide Source: Lipids Online 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 ) comparing the highest vs lowest tertile of fibrinogen levels (mean.35 vs..25 g/dL) ARIC study in 14,477 adults aged 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 for coronary death and all-cause mortality.

Slide Source: Lipids Online 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.

Slide Source: Lipids Online 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.

Slide Source: Lipids Online 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)

Slide Source: Lipids Online 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

Slide Source: Lipids Online 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.

Slide Source: Lipids Online Relative Risks of Future MI among Apparently Healthy Middle-Aged Men: Physician’s Health Study Relative Risk for Future MI Lipoprotein(a) Homocysteine Fibrinogen tPA Antigen hs-CRP hs-CRP + TC/HDL-C Total Cholesterol TC:HDL-C

Slide Source: Lipids Online Risk Factors for Future Cardiovascular Events: WHS Relative Risk of Future Cardiovascular Events 0 Lipoprotein(a) Homocysteine IL-6 TC LDL-C sICAM-1 SAA Apo B TC:HDL-C hs-CRP hs-CRP + TC:HDL-C

Slide Source: Lipids Online 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 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 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 Potential Mechanisms Linking CRP to Atherothrombosis 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 Marker for subclinical atherosclerosis - EBCT / IMT / ABI Marker for insulin resistance/ obesity Marker for endothelial dysfunction Marker for dysmetabolic syndrome Marker for plaque vulnerability

Slide Source: Lipids Online hs-CRP and Risk of Future MI in Apparently Healthy Men 1 <0.055 Relative Risk of MI P = 0.03 Quartile of hs-CRP (range, mg/dL) – – >0.211 P < P Trend <0.001

Slide Source: Lipids Online hs-CRP and Risk of Future Stroke in Apparently Healthy Men 1 <0.055 Relative Risk of Ischemic Stroke Quartile of hs-CRP (range, mg/dL) – – >0.211 P =0.02 P Trend <0.03

Slide Source: Lipids Online hs-CRP and Risk of Developing PVD in Apparently Healthy Men None hs-CRP (mg/dL) Intermittent Claudication Peripheral Artery Surgery

Slide Source: Lipids Online hs-CRP and Risk of Future Cardiovascular Events in Apparently Healthy Women 1 <0.15 Relative Risk Quartile of hs-CRP (range, mg/dL) – – >0.73 P Trend <0.002 Any Event MI or Stroke

Slide Source: Lipids Online hs-CRP and Risk of Future Cardiovascular Events in Apparently Healthy Women: Low-Risk Subgroups 1 <0.15 Relative Risk Quartile of hs-CRP (range, mg/dL) – – >0.73 No hypertension No hyperlipidemia No current smoking No diabetes No family history

Slide Source: Lipids Online hs-CRP and Coronary Heart Disease in Initially Healthy Men: MONICA–Augsburg Cohort 1 <0.6 Rate Ratio (Age Adjusted) Quartile of CRP (mg/dL) 2 0.6– – –4.5 5 >4.5

Slide Source: Lipids Online hs-CRP as a Risk Factor for Future CVD Relative Risk (upper vs lower quartile) CHD Death MI Stroke CHD PVD CVD CHD 0 MRFIT ( Kuller 1996) 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)

Slide Source: Lipids Online hs-CRP Adds to the Predictive Value of Total Cholesterol in Determining Risk of First MI Adjusted Relative Risk CRP >75 th percentile TC >75 th percentile –+–+ –+–+ P = 0.02 P = P = 0.002

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

Slide Source: Lipids Online Quartile of TC: HDL-C Quartile of hs-CRP hs-CRP, Lipids, and Risk of Future Coronary Events: Women's Health Study (WHS)

Slide Source: Lipids Online Relative Risks for First MI for Baseline sICAM-1 >260 ng/dL Years of Study Follow-up 0– –22–44–8 Relative Risk

Slide Source: Lipids Online Predictivity of Interleukin-6 on CV Risk in Women High Medium Low High Medium Low Interleukin-6 Total cholesterol