Inflammation and CHD
Nathan Wong
Slide Source: Lipids Online www.lipidsonline.org
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 www.lipidsonline.org
Beyond Cholesterol: Predicting Cardiovascular Risk In the 21st 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/dL
CHD
150
200
250
300
Total Cholesterol (mg/dL)
Slide Source: Lipids Online www.lipidsonline.org
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 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
Consistency of
prospective data
Strength of
Low variability High
association
Independence of
reproducibility
Biologic
association
Improve predictive
plausibility
Low cost
value
Standardized measure
Modifiable
Slide Source: Lipids Online www.lipidsonline.org
Biomarkers for Venous and Arterial Thrombosis
Parameter
Fibrinogen Factor VII vWF: ag tPA: ag PAI-1: ag Platelet function
Lp(a)
hs-CRP / SAA / IL-6 / TNF
Venous
– – – – – –
– –
Arterial
+++ + ++ +++ ++ ++
+ +++
Slide Source: Lipids Online www.lipidsonline.org
Biomarkers for Venous and Arterial Thrombosis (cont’d)
Parameter
Factor V Leiden Prothrombin mutation Prothrombin Factor VIII Anti-thrombin III Protein C Protein S Homocysteine D-dimer
Venous
+++ ++ + ++ ++ + + ++ ++
Arterial
– – – – – – – ++ ++
Slide Source: Lipids Online www.lipidsonline.org
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 www.lipidsonline.org
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 www.lipidsonline.org
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.
Slide Source: Lipids Online www.lipidsonline.org
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 www.lipidsonline.org
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 www.lipidsonline.org
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 www.lipidsonline.org
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 www.lipidsonline.org
Aspirin is clearly recommended in secondary
Antiplatelet Therapy: AHA Recommendations
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 www.lipidsonline.org
Relative Risks of Future MI among Apparently Healthy Middle-Aged Men: Physician’s Health Study
Lipoprotein(a) Homocysteine Total Cholesterol Fibrinogen tPA Antigen TC:HDL-C hs-CRP 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 sICAM-1
SAA Apo B
TC:HDL-C hs-CRP hs-CRP + TC:HDL-C
0
1.0
2.0
4.0
6.0
Lipids Online www.lipidsonline.org
Relative Risk of Future Cardiovascular Events Slide Source:
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. increased up to 1,000-fold in response to infection or tissue destruction, but cannot adequately assess the normal range
Standard CRP tests determine levels which are
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
Confounding by cigarette Marker for subclinical
consumption
Innocent bystander
atherosclerosis - EBCT / IMT / ABI
Marker for insulin
- Acute phase response
Cytokine surrogate
resistance/ obesity
Marker for endothelial
- IL-6, TNF-, IL-1
Direct effects of CRP
dysfunction
Marker for dysmetabolic
- Innate immunity - Complement activation - CAM induction
Prior infection
syndrome
Marker for plaque
vulnerability
Slide Source: Lipids Online www.lipidsonline.org
- Chlamydia, H pylori, CMV
hs-CRP and Risk of Future MI in Apparently Healthy Men
3
Relative Risk of MI
P Trend <0.001
P < 0.001 P = 0.03
P < 0.001
2
1
0
<0.055
1
0.056–0.114
2
0.115–0.210
3
>0.211
Slide Source: Lipids Online www.lipidsonline.org
4
Quartile of hs-CRP (range, mg/dL)
hs-CRP and Risk of Future Stroke in Apparently Healthy Men
2
Relative Risk of Ischemic Stroke
P Trend <0.03
P =0.02 P =0.02
1
0
<0.055
1
0.056–0.114 0.115–0.210
2
3
>0.211
Slide Source: Lipids Online www.lipidsonline.org
4
Quartile of hs-CRP (range, mg/dL)
hs-CRP and Risk of Developing PVD in Apparently Healthy Men
2.0
hs-CRP (mg/dL)
1.0
0.0
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
7 6
Relative Risk
P Trend <0.002
Any Event MI or Stroke
5 4 3 2 1 0
1 <0.15
2 0.15–0.37
3 0.37–0.73
4 >0.73
Slide Source: Lipids Online www.lipidsonline.org
Quartile of hs-CRP (range, mg/dL)
hs-CRP and Risk of Future Cardiovascular Events in Apparently Healthy Women: Low-Risk Subgroups
7 6
Relative Risk
No hypertension No hyperlipidemia No current smoking
No diabetes No family history
5 4 3 2 1 0
1 <0.15
2 0.15–0.37
3 0.37–0.73
4 >0.73
Slide Source: Lipids Online www.lipidsonline.org
Quartile of hs-CRP (range, mg/dL)
hs-CRP and Coronary Heart Disease in Initially Healthy Men: MONICA–Augsburg Cohort
4
Rate Ratio (Age Adjusted)
3 2 1 0
1 <0.6
2 0.6–1.1
3 1.1–2.2
4 2.2–4.5
5 >4.5
Slide Source: Lipids Online www.lipidsonline.org
Quartile of CRP (mg/dL)
hs-CRP as a Risk Factor for Future CVD
MRFIT (Kuller 1996) CHD Death
PHS PHS PHS
(Ridker 1997) (Ridker 1997) (Tracy 1997)
MI Stroke CHD PVD CVD CHD CHD CHD CHD
0
CHS/RHPP WHS
(Ridker 1998) (Ridker 1998, 2000) (Koenig 1999) (Roivainen 2000) 2000)
MONICA Helsinki Britain
Caerphilly(Mendall
(Danesh 2000)
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
6
Adjusted Relative Risk
5 4 3 2 1
P = 0.02
P = 0.002
P = 0.001
0 CRP >75th percentile
TC >75th percentile
– –
+ –
– +
+ +
Slide Source: Lipids Online www.lipidsonline.org
hs-CRP Adds to Predictive Value of TC:HDL Ratio in Determining Risk of First MI
5.0 4.0 3.0 2.0 1.0 0.0 Medium High Medium Low Low High
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 sICAM-1 >260 ng/dL
3
Relative Risk
2
1
0
0–1
1–2
2–4
4–8
Slide Source: Lipids Online www.lipidsonline.org
Years of Study Follow-up
Predictivity of Interleukin-6 on CV Risk in Women
4 3
2
1
0 High Medium Total cholesterol Low Low
Interleukin-6
High Medium
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