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Inflammation and CHDInflammation and CHD

Nathan Wong


Thrombosis, Inflammation, and InfectionThrombosis, 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


Beyond Cholesterol: Beyond Cholesterol: Predicting Predicting Cardiovascular Risk In the 21Cardiovascular Risk In the 21stst Century Century

Cardiovascular RiskCardiovascular RiskCardiovascular RiskCardiovascular Risk

LipidsLipidsHTNHTN

DiabetesDiabetes

LipidsLipidsHTNHTN

DiabetesDiabetesBehavioralBehavioralBehavioralBehavioral HemostaticHemostatic

ThromboticThromboticHemostaticHemostaticThromboticThrombotic InflammatoryInflammatoryInflammatoryInflammatory GeneticGeneticGeneticGenetic


Total Cholesterol Distribution: Total Cholesterol Distribution: CHD vs Non-CHD PopulationCHD vs Non-CHD Population

35% of CHD 35% of CHD Occurs in People Occurs in People with TC<200 with TC<200 mg/dLmg/dL

150 200

Total Cholesterol (mg/dL)

250 300

No CHD

CHD

Framingham Heart Study—26-Year Follow-up


Inflammation and AtherosclerosisInflammation 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


Is there clinical evidence that Is there clinical evidence that

inflammatory markers predict future inflammatory markers predict future

coronary events and provide additional coronary events and provide additional

predictive information beyond predictive information beyond

traditional risk factors?traditional risk factors?


Evaluating Novel Risk Factors for CADEvaluating 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


Biomarkers for Venous and Arterial Biomarkers for Venous and Arterial ThrombosisThrombosis

+++–hs-CRP / SAA / IL-6 / TNF

+–Lp(a)

++–Platelet function

++–PAI-1: ag

+++–tPA: ag

++–vWF: ag

+–Factor VII

+++–Fibrinogen

ArterialVenousParameter


Biomarkers for Venous and Arterial Biomarkers for Venous and Arterial Thrombosis Thrombosis (cont’d)(cont’d)

++++D-dimer

++++Homocysteine

–+Protein S

–+Protein C

–++Anti-thrombin III

–++Factor VIII

–+Prothrombin

–++Prothrombin mutation

–+++Factor V Leiden

ArterialVenousParameter


Thrombosis and Cardiovascular RiskThrombosis 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.


Fibrinogen and AtherosclerosisFibrinogen 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.


Fibrinogen and CHD Risk: Epidemiologic Fibrinogen and CHD Risk: Epidemiologic StudiesStudies 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.


Fibrinogen and CHD Risk FactorsFibrinogen 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.


Other Thrombotic Factors and CHDOther 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.


Aspirin and Cardiovascular Risk: Clinical Aspirin and Cardiovascular Risk: Clinical Trial Evidence for Primary PreventionTrial 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)


Aspirin and Cardiovascular Risk: Clinical Aspirin and Cardiovascular Risk: Clinical Trial Evidence for Secondary PreventionTrial 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


Antiplatelet Therapy: AHA Antiplatelet Therapy: AHA RecommendationsRecommendations

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.


Relative Risks of Future MI among Apparently Relative Risks of Future MI among Apparently Healthy Middle-Aged Men: Healthy Middle-Aged Men: Physician’s Health StudyPhysician’s Health Study

Relative Risk for Future MI0 1.0 2.0 4.0 6.0

Lipoprotein(a)Homocysteine

FibrinogentPA Antigen

hs-CRPhs-CRP + TC/HDL-C

Total Cholesterol

TC:HDL-C


Risk Factors for Future Cardiovascular Risk Factors for Future Cardiovascular Events: Events: WHSWHS

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-C1.0 2.0 4.0 6.0


CRP vs hs-CRPCRP 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 CRPStandard 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 CRPHigh-sensitivity CRP (hs-CRP) assays (i.e. Dade Behring) detect levels of CRP within the normal range, levels proven to predict future cardiovascular events.


Potential Mechanisms Linking CRP to Potential Mechanisms Linking CRP to AtherothrombosisAtherothrombosis 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


0

1

2

3

hs-CRP and Risk of Future MI in Apparently hs-CRP and Risk of Future MI in Apparently Healthy MenHealthy Men

1<0.055

Rela

tive R

isk

of

MI

P = 0.03

Quartile of hs-CRP (range, mg/dL)

20.056–0.114

30.115–0.210

4>0.211

P < 0.001 P < 0.001

PP Trend <0.001 Trend <0.001


0

1

2

hs-CRP and Risk of Future Stroke in hs-CRP and Risk of Future Stroke in Apparently Healthy MenApparently Healthy Men

1<0.055

Rela

tive R

isk

of

Isch

em

ic S

troke


20.056–0.114

30.115–0.210

4>0.211

P =0.02 P =0.02



0.0

1.0

2.0

hs-CRP and Risk of Developing PVD in hs-CRP and Risk of Developing PVD in Apparently Healthy MenApparently Healthy Men

None

hs-

CR

P (

mg/d

L)

IntermittentClaudication

Peripheral ArterySurgery


0

1

2

3

4

5

6

7

hs-CRP and Risk of Future Cardiovascular hs-CRP and Risk of Future Cardiovascular Events in Apparently Healthy WomenEvents in Apparently Healthy Women

1<0.15

Rela

tive R

isk


20.15–0.37

30.37–0.73

4>0.73


Any Event

MI or Stroke


0

1

2

3

4

5

6

7

hs-CRP and Risk of Future Cardiovascular hs-CRP and Risk of Future Cardiovascular Events in Apparently Healthy Women: Events in Apparently Healthy Women: Low-Risk SubgroupsLow-Risk Subgroups

1<0.15

Rela

tive R

isk


20.15–0.37

30.37–0.73

4>0.73

No hypertension

No hyperlipidemia

No current smoking

No diabetes

No family history


0

1

2

3

4

hs-CRP and Coronary Heart Disease in hs-CRP and Coronary Heart Disease in Initially Healthy Men: Initially Healthy Men: MONICA–Augsburg MONICA–Augsburg CohortCohort

1<0.6

Rate

Rati

o(A

ge A

dju

sted)

Quartile of CRP (mg/dL)

20.6–1.1

31.1–2.2

42.2–4.5

5>4.5


hs-CRP as a Risk Factor for Future CVDhs-CRP as a Risk Factor for Future CVD

1.0 2.0 3.0 4.0 5.0 6.0

Relative Risk (upper vs lower quartile)

CHD Death

MI

Stroke

CHD

PVD

CVD

CHD

CHD

CHD

CHD

0

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

2

3

4

5

6

hs-CRP Adds to the Predictive Value of Total hs-CRP Adds to the Predictive Value of Total Cholesterol in Determining Risk of First MICholesterol in Determining Risk of First MI

Adju

sted

Rela

tive R

isk

CRP >75th

percentile

TC >75th

percentile

– + – +

– +– +

P = 0.02

P = 0.001

P = 0.002


0.0

1.0

2.0

3.0

4.0

5.0

High Medium Low LowMedium

High

hs-CRP Adds to Predictive Value of TC:HDL hs-CRP Adds to Predictive Value of TC:HDL Ratio in Determining Risk of First MIRatio in Determining Risk of First MI

Total Cholesterol:HDL Ratio

hs-CRP


Quartile of TC: Quartile of TC: HDL-CHDL-C

Quartile Quartile of hs-CRP of hs-CRP

43

21 1

23

4

9

8

7

6

5

4

3

2

1

0

hs-CRP, Lipids, and Risk of Future hs-CRP, Lipids, and Risk of Future Coronary Events: Coronary Events: Women's Health Study Women's Health Study (WHS)(WHS)


Relative Risks for First MI for Baseline Relative Risks for First MI for Baseline sICAM-1 >260 ng/dLsICAM-1 >260 ng/dL

Years of Study Follow-up

0–1

3

2

1

0 1–2 2–4 4–8

Rela

tive R

isk


Predictivity of Interleukin-6 on CV Risk Predictivity of Interleukin-6 on CV Risk in Womenin Women

4

3

2

1

0High

Medium

Low

HighMedium

Low

Interleukin-6Interleukin-6

Total cholesterolTotal cholesterol

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