Inflammation and CHD

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
Beyond Cholesterol Predicting Cardiovascular
Risk In the 21st Century
Cardiovascular Risk
4
Total Cholesterol Distribution CHD vs Non-CHD
Population
Framingham Heart Study26-Year Follow-up
No CHD
35 of CHD Occurs in People with TClt200 mg/dL
CHD
150
250
300
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

• Consistency of prospective data
• Strength of association
• Independence of association
• Improve predictive value
• Standardized measure

• Low variability
• High reproducibility
• Biologic plausibility
• Low cost
• Modifiable

8
Biomarkers for Venous and Arterial Thrombosis
9
Biomarkers for Venous and Arterial Thrombosis
(contd)
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--Physicians 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 Physicians Health Study- 22,071 male
  physicians - 44 reduction in MI risk, 13
  nonsignificant increase in risk of stroke
• British Doctors 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 Womens Health Study (n40,000)

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
Relative Risks of Future MI among Apparently
Healthy Middle-Aged Men Physicians Health Study
Relative Risk for Future MI
19
Risk Factors for Future Cardiovascular Events WHS
Lipoprotein(a) Homocysteine IL-6 TC LDL-C sIC
AM-1 SAA Apo B TCHDL-C hs-CRP hs-CRP
TCHDL-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

• 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

22
hs-CRP and Risk of Future MI in Apparently
Healthy Men
P Trend lt0.001
P lt 0.001
P lt 0.001
P 0.03
Relative Risk of MI
1lt0.055
20.0560.114
30.1150.210
4gt0.211
Quartile of hs-CRP (range, mg/dL)
23
hs-CRP and Risk of Future Stroke in Apparently
Healthy Men
P Trend lt0.03
P 0.02
P 0.02
Relative Risk of Ischemic Stroke
1lt0.055
20.0560.114
30.1150.210
4gt0.211
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 lt0.002
Any Event
MI or Stroke
Relative Risk
1lt0.15
20.150.37
30.370.73
4gt0.73
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
1lt0.15
20.150.37
30.370.73
4gt0.73
Quartile of hs-CRP (range, mg/dL)
27
hs-CRP and Coronary Heart Disease in Initially
Healthy Men MONICAAugsburg Cohort
Rate Ratio(Age Adjusted)
1lt0.6
20.61.1
31.12.2
42.24.5
5gt4.5
Quartile of CRP (mg/dL)
28
hs-CRP as a Risk Factor for Future CVD
CHD Death MI Stroke CHD PVD CVD CHD CHD CHD CHD
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)
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 gt75thpercentile




TC gt75thpercentile




30
hs-CRP Adds to Predictive Value of TCHDL Ratio
in Determining Risk of First MI
hs-CRP
Total CholesterolHDL Ratio
31
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
gt260 ng/dL
3 2 1 0
Relative Risk
01
12
24
48
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