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HIGH SENSITIVITY C-REACTIVE PROTEIN IN CARDIOVASCULAR DISEASE AND MORTALITY

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HIGH SENSITIVITY C-REACTIVE PROTEIN IN CARDIOVASCULAR DISEASE AND MORTALITY Gary A. Lopez, M.D. Makati Medical Center Asian Hospital and Medical Center – PowerPoint PPT presentation

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Title: HIGH SENSITIVITY C-REACTIVE PROTEIN IN CARDIOVASCULAR DISEASE AND MORTALITY


1
HIGH SENSITIVITY C-REACTIVE PROTEIN IN
CARDIOVASCULAR DISEASE AND MORTALITY
  • Gary A. Lopez, M.D.
  • Makati Medical Center
  • Asian Hospital and Medical Center

2
  • Cardiovascular disease is the most frequent cause
    of mortality in the Philippines , the U.S., and
    many parts of the world.
  • Most events caused by acute coronary events from
    coronary artery disease

3
ATHEROTHROMBOSIS LEADS TO CARDIAC AND VASCULAR
EVENTS
4
COEXISTENCE OF ATHEROSCLEROTIC VASCULAR DISEASE
5
Pathology of Acute Coronary Syndrome
Plaque Rupture
Plaque Erosion
Calcified Nodules
Luminal Thrombosis
Acute Coronary Syndrome
6
Type of Vulnerable Plaque Frequency Pathological Findings
Plaque Rupture 55 60 Numerous neutrophils, Macrophages and monocyte infiltration of thrombus
Plaque Erosion 30 35 Few or absent macrophages and lymphocytes
Calcified Nodule 2 7 Fibrin in between bony spicules along with osteoclasts and inflammatory cells
Virnani et al., JACC vol. 47, no. 8, 2006
7
FORMATION OF THE FIBROFATTY PLAQUE
8
FORMATION OF THE YOUNG ATHEROSCLEROTIC LESION
9
MATURATION OF THE ATHEROSCLEROTIC PLAQUE
10
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12
AVERAGE COMPOSITION OF ADVANCED CORONARY PLAQUE
13
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14
  • High-Risk, Vulnerable and Thrombosis-Prone Plaque
  • - synonyms to describe a plaque that is at
    increased risk of thrombosis and rapid stenosis
    progression
  • Inflamed Thin-cap Fibroatheroma
  • - an inflamed plaque with a thin cap covering
    a lipid-rich, necrotic core. Suspected to be a
    high risk/vulnerable plaque.
  • Vulnerable patient
  • - a patient at high risk (vulnerable/prone) to
    experience a cardiovascular ischemic event due to
    a high atherosclerotic burden, high
    risk/vulnerable plaques, and/or thrombogenic
    blood.

15
NON-INVASIVE TESTS TO IDENTIFY HIGH-RISK CORONARY
DISEASE (gt10 1-YEAR RISK OF CARDIAC EVENTS)
  • 1. MRI of the coronary arteries
  • 2. Multislice (64-slice) CT angiography of the
    coronary arteries with calcium scoring
  • 3. Myocardial perfusion imaging using
    radionuclide techniques.
  • 4. Positive emission tomography.

16
CORONARY ANGIOGRAPHY
  • An invasive cardiac diagnostic procedure using
    catheterization techniques and fluoroscopic
    visualization.
  • Should be performed in asymptomatic high-risk
    patients.
  • Provide risk stratification to alter therapy.

17
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19
C- REACTIVE PROTEIN
  • A circulating pentraxin
  • Produced predominantly in the liver as part of
    the acute phase response
  • Expressed in smooth muscle cells within diseased
    atherosclerotic arteries
  • Plays a major role in human innate immune
    response
  • Provides a stable plasma biomarker for low-grade
    systemic inflammation

20
C-REACTIVE PROTEIN
  • Composed of five 23 kD subunits
  • Has a half-life of 19 hours
  • Neither consumed nor produced during the
    reaction.
  • Ideally 2 assays, averaged, fasting or
    nonfasting, and optimally 2 weeks apart, provide
    a more stable level of this marker.

21
C-REACTIVE PROTEIN
  • Stable for over long periods of time
  • Has no circadian rhythm
  • Not affected by food intake
  • Therefore screening can be done on an outpatient
    basis at the time of cholesterol evaluation.

22
  • Cost of high-sensitivity C-reactive protein at
    Makati Medical Center
  • 925.00 pesos

23
MECHANISMS OF HSCRP ELEVATION IN RELATION TO
ATHEROTHROMBOTIC EVENTS
  • Unknown
  • Theories
  • 1. Inflammation of atherosclerotic plaques
    leading to HSCRP elevation
  • 2. HSCRP may contribute to pathogenesis of
    atherosclerosis due to interaction with lipids,
    lipoproteins, complement and coagulation
  • 3. HSCRP is detected in atherosclerotic
    plaques

24
C-REACTIVE PROTEIN
  • Mechanisms of influencing direct vascular
    vulnerability
  • 1. increased expression of endothelial
    PAI-1.
  • 2. enhanced expression of adhesion molecules
  • 3. reduced endothelial nitric oxide
    bioactivity.
  • 4. altered LDL uptake by macrophages
  • 4. colocalization with complement within
    atherosclerotic lesions.
  • 5. inhibition of intrinsic fibrinolysis

25
THE INFLAMMATORY PATHWAY
26
USES OF ELEVATED HSCRP
  • Neonatal medicine - infection
  • Atherosclerotic and coronary heart disease
  • Osteoarthritis

27
CONDITIONS ASSOCIATED WITH MAJOR ELEVATION OF
SERUM CRP
  • Infections
  • Allergic complications of infection
  • Rheumatic fever
  • Erythema nodosum leprosum
  • Inflammatory disease
  • Rheumatoid arthritis
  • Juvenile chronic arthritis
  • Ankylosing spondylitis
  • Psoriatic arthritis
  • Systemic vasculitis
  • Polymyalgia rheumatica
  • Reiters disease
  • Crohns disease
  • Familial Mediterranean fever
  • Necrosis
  • Myocardial infarction

28
ROLE OF INFECTION IN ATHEROTHROMBOSIS
  • 1. Clamydia , Helicobacter, Herpes simplex virus
    and Cytomegalovirus
  • -- lead to systemic inflammation.
  • -- lead to increased risk of
    cardiovascular events.
  • 2. Clamydia and viral species have been
    identified in atheromatous lesions.

29
  • Need 2-3 weeks to check HSCRP in patients with
    injury or infection due to marked degree of
    inflammation.

30
  • Hormonal replacement therapy
  • may augment levels of HSCRP

Cushman et al, Citculation 100717-7221999
31
NON-PHARMACOLOGIC METHODS TO REDUCE HSCRP
  • 1. WEIGHT REDUCTION
  • 2. EXERCISE

32
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33
VALUE OF HSCRP MEASUREMENTS
  • Conventional CRP assays cannot quantify serum
    proteins less than 5 mg/l.

34
HSCRP gt 2.5 mg/liter
  • Two to five-fold increased risk of suffering a
    coronary event in the future in patients with
    angina or in healthy normal adult population.
  • May predict progression of atherothrombotic
    events in cerebrovascular and peripheral vascular
    disease.

35
HSCRP gt 3 mg/liter
  • Poor outcome in patients with severe unstable
    angina ( increased risk of death, acute
    myocardial infarction, or need for urgent
    revascularization intervention).
  • Predicts early reocclusion in patients undergoing
    PCI.

36
Your blood pressure and cholesterol are fine,
but your hsCRP
37
USE OF HSCRP IN PRIMARY AND SECONDARY PREVENTION
  • More than 24 prospective epidemiologic primary
    prevention studies evaluated the role of hsCRP as
    a determinant of vascular risk all reported
    positive findings.
  • 10 of these studies were powered to evaluate the
    risk prediction role of hsCRP beyond that
    associated with traditional factors included in
    global assessment algorithms such as the
    Framingham Risk Score.

38
HSCRP HAS STRONG PREDICTIVE VALUE IN
  • 1. currently healthy men
  • 2. currently healthy women
  • 3. elderly people
  • 4. high-risk smokers
  • 5. stable and unstable angina
  • 6. prior myocardial infarction

39
ADDITIVE VALUE OF HSCRP AFTER ADJUSTMENT FOR RISK
FACTORS
40
RELATIVE RISKS OF FUTURE CV EVENTS ACCORDING TO
BASELINE LEVELS OF HSCRP
41
PROSPECTIVE STUDIES RELATING BASELINE HSCRP
LEVELS TO THE RISK OF FIRST CV EVENTS
42
ADDITIVE VALUE OF HSCRP OVER TOTAL CHOLESTEROL,
HDL-C AND APO BAPO A RATIO
43
Ridker et al, Womens Health Study , NEJM, 2002
347 1557-65
44
Ridker et al,Clinical application of CRP for CV
disease detection and prevention,Circulation
107363,2003
45
GUSTO IV ACS Trial
46
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47
PROGNOSTIC UTILITY OF HSCRP, TROPONIN, AND BNP IN
ACUTE CORONARY ISCHEMIA
48
  • Baseline levels of HSCRP associate with increased
    risk of developing Type 2 diabetes mellitus.
  • Prediction of vascular events is beyond the
    components of the metabolic syndrome or presence
    of frank diabetes.

49
NATIONAL HEALTH AND NUTRITION EVALUATION SURVEY
(NHANES)
50
Rotterdam Scan Study
  • Higher HSCRP levels are associated with the
    presence and progression of cerebral white matter
    lesions in the periventricular and subcortical
    regions.
  • Data implies small vessel disease progression.

Van Dijk EJ et al, Circulation, 2005112900-5
51
  • Recent observations
  • 1. Statins lower CRP in a manner largely
    independent of LDL-C reduction.
  • 2. Efficacy of statin therapy may be related to
    the underlying level of vascular inflammation as
    detected by HS-CRP.

52
CHOLESTEROL AND RECURRENT EVENTS (CARE) TRIAL
  • Risk reduction with Pravastatin was greater in
    patients with elevated HSCRP
  • Pravastatin significantly reduced elevated HSCRP
    levels over a 5-year period

53
PRAVASTATIN OR ATORVASTATIN EVALUATION AND
INFECTION THERAPY-THROMBOLYSIS IN MYOCARDIAL
INFARCTION 22 TRIAL (PROVE IT-TIMI 22)
  • 1. level of HS-CRP achieved after initiation of
    statin therapy is as important as LDL-C for
    subsequent vascular events.
  • 2. best overall survival was seen not only with
    patients whose LDL-C was lowered to lt70 mg/dl but
    also whose HS-CRP lowered lt 2 mg/l.
  • 3. this result was present regardless of statin
    regimen used.
  • 4. measuring and monitoring of HS-CRP following
    initiation of statin therapy may be required to
    maximize benefit similar to use of LDL-C.

Ridker et al, NEJM, 2005 352 20-8
54
PROVE IT - TIMI 22 CUMULATIVE RATE OF RECURRENT
M.I. OR DEATH AMONG STATIN-TREATED PATIENTS
ACCORDING TO ACHIEVED LEVELS OF LDL-C AND HSCRP
55
PROVE IT - TIMI 22 RATE OF RECURRENT M.I OR
DEATH AMONG STATIN-TREATED PATIENTS ACCORDING TO
LDL-C AND HSCRP AFTER 30 DAYS
56
REVERSAL study
  • Patients were randomized to moderate lipid
    lowering with Pravastatin 40 mg or intensive
    lipid lowering with Atorvastatin 80 mg for 18
    months.
  • Measurement of atherosclerotic burden by IVUS was
    carried out during baseline catheterization and
    at study completion. 502 patients completed the
    trial, 249 on Pravastatin and 253 for
    Atorvastatin. The 2 treatment groups were well
    matched ave. age was 56 yrs, about 70 were
    male, and 20 were diabetic. Baseline
    LDL-cholesterol was 150 mg/dl in both groups,
    triglycerides 197 mg/dl, and C-reactive protein
    (CRP) approximately 3 mg/dl.
  • By the end of the treatment group, LDL-chol was
    significantly lower among patients who had been
    randomized to the Atorvastatin group.

57
REVERSAL STUDY Secondary Endpoints
Endpoints Pravastatin ( n249) Atorvastatin ( n253) P value, Pravastatin vs. Atorvastatin
Change in total Atheroma Volume (mm3) 4.4 -0.9 .02
P value vs baseline .01 .72 --
Change in obstructive Volume () 1.6 0.2 .0002
P value vs baseline .0001 .18 --
Change in hsCRP () -5.2 -36.4
Wilcoxon signed rank test Wilcoxon rank sum
test
58
ASSESSMENT OF THE CLINICAL UTILITY OF NOVEL
MARKERS OF CV RISK
Marker Assay conditions standardized? Prospective studies consistent? Additive to total cholesterol and HDL-C? Additive to Framingham risk?
Lipoprotein (a) - /- /- -
Homocysteine /- -
Tissue plasminogen activator and PAI-1 /- /- -
Lipoprotein density - /- - -
Fibrinogen - -
High-sensitivity CRP
Ridker et al, Risk Factors for Atherothrombotic
Disease, 2005, 939-54
59
ACC/AHA CLASSIFICATIONS
  • Class 1
  • Conditions for which there is evidence
    and/or general agreement that a given procedure
    or treatment is useful and effective.
  • Class II
  • Conditions for which there is conflicting
    evidence and/or a divergence of opinion about the
    usefulness/efficacy of a procedure or treatment.
  • Class IIa Weight of evidence/opinion is in
    favor of usefulness/efficacy
  • Class IIb Usefulness/efficacy is less well
    established by evidence/opinion.
  • Class III
  • Conditions for which there is evidence
    and/or general agreement that a procedure
    /treatment is not useful/effective and in some
    cases may be harmful.

60
ACC/AHA GUIDELINES FOR THE MANAGEMENT OF PATIENTS
WITH UNSTABLE ANGINA AND NON-ST-SEGMENT ELEVATION
MYOCARDIAL INFARCTION Nov, 2002
  • II. Initial evaluation and Management
  • B. Early Risk Stratification Recommendations
  • Class IIb
  • 1. C-reactive protein (CRP) and other markers
    of inflammation should be measured.

61
CENTERS FOR DISEASE CONTROL AND PREVENTION /
AMERICAN HEART ASSOCIATION
  • MARKERS OF INFLAMMATION AND CARDIOVASCULAR
    DISEASE A STATEMENT FOR HEALTHCARE PROFESSIONALS
  • It is reasonable to measure HSCRP as an adjunct
    to the major risk factors to further assess
    absolute risk for coronary disease primary
    prevention optional.
  • HSCRP measurement appears to be best employed to
    detect enhanced absolute risk in persons in whom
    multiple risk factor scoring projects a 10-year
    CHD risk in the range of 10 to 20 -
    intermediate risk.
  • Pearson et al,
  • Circulation, 2003 107449

62
CDC/AHA ISSUES ON HSCRP
  • 1. When and in whom should HSCRP be used?
  • 2. What is the purpose for its measurement and
    the likelihood that further diagnostic and
    therapeutic plans change on the basis of tests
    results?
  • 3. No clinical trials have been completed in
    which a population has been randomly allocated to
    HSCRP screening and both groups followed up
    prospectively to determine the benefits and harms
    of the screening.
  • 4. Few data on the cost-effectiveness of
    screening with HSCRP, taking into account further
    testing and treatment of persons classified as
    being at low risk.

63
CDC/AHA RECOMMENDATIONS
  • 1. HSCRP gt 3.0 mg/L (high risk) may allow
    intensification of medical therapy to further
    reduce the risk and to motivate patients to
    improve their lifestyle or comply with
    medications prescribed to lower their risk.
  • 2. Low risk individuals (lt10 in 10 years) will
    unlikely to have a high risk (gt20) identified
    thru HSCRP testing.
  • 3. High risk individuals (gt20 in 10 years) or
    with established atherosclerotic disease
    generally should be treated intensively
    regardless of their HSCRP levels. (limited use of
    HSCRP in secondary prevention).

64
CDC/AHA RECOMMENDATIONS
  • 4. In patients with stable coronary disease or
    acute coronary syndromes, HSCRP measurement may
    be useful as an independent marker for assessing
    likelihood of recurrent events, including death,
    myocardial infarction, or restenosis after PCI.
  • 5. Secondary preventive interventions with proven
    efficacy should not be dependent on HSCRP levels.
  • 6. Serial testing of HSCRP should not be used to
    monitor effects of treatment.

65
  • The CDC/AHA Workshop identified CRP as the
    current analyte of choice , but do not support
    its use in risk prediction or patient management
    at this point in time.

66
ISSUES ON HS-CRP
  • No firm data to date that lowering CRP levels per
    se will lower vascular risk.
  • It remains controversial whether CRP plays a
    direct causal role in atherogenesis.

67
CONCLUSION
  • Data for high-sensitivity C-reactive protein
    provides evidence that biomarkers beyond those
    taditionally used for vascular risk detection and
    monitoring can play important clinical roles in
    prevention and treatment.

68
  • Thank You
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