Transcript HIGH SENSITIVITY C

HIGH SENSITIVITY
C-REACTIVE PROTEIN IN
CARDIOVASCULAR
DISEASE AND MORTALITY
Gary A. Lopez, M.D.
Makati Medical Center
Asian Hospital and Medical Center
 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
ATHEROTHROMBOSIS LEADS TO CARDIAC AND VASCULAR EVENTS
COEXISTENCE OF ATHEROSCLEROTIC VASCULAR DISEASE
Pathology of Acute Coronary Syndrome
Plaque
Rupture
Plaque
Erosion
Luminal
Thrombosis
Acute Coronary
Syndrome
Calcified
Nodules
Type of
Vulnerable
Plaque
Frequency
Plaque Rupture
55 – 60%
Plaque Erosion
30 – 35%
Calcified Nodule
2 – 7%
Pathological Findings
Numerous neutrophils,
Macrophages and monocyte
infiltration of thrombus
Few or absent macrophages
and lymphocytes
Fibrin in between bony
spicules along with
osteoclasts and inflammatory
cells
Virnani et al., JACC vol. 47, no. 8, 2006
FORMATION OF THE FIBROFATTY PLAQUE
FORMATION OF THE YOUNG ATHEROSCLEROTIC LESION
MATURATION OF THE ATHEROSCLEROTIC PLAQUE
AVERAGE COMPOSITION OF ADVANCED CORONARY PLAQUE



High-Risk, Vulnerable and ThrombosisProne 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.
NON-INVASIVE TESTS TO IDENTIFY HIGH-RISK
CORONARY DISEASE (>10% 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.
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.
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
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.
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.
Cost of high-sensitivity C-reactive
protein at Makati Medical Center
= 925.00 pesos
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
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
THE INFLAMMATORY PATHWAY
USES OF ELEVATED HSCRP

Neonatal medicine - infection

Atherosclerotic and coronary heart disease

Osteoarthritis
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
Reiter’s disease
Crohn’s disease
Familial Mediterranean fever
Necrosis
Myocardial infarction
Tumour embolization
Acute pancreatitis
Trauma
Surgery
Burns
Fracrures
Malignant neoplasia
Lymphoma, Hodgkin’s disease
Carcinoma, sarcoma
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.

Need 2-3 weeks to check HSCRP in
patients with injury or infection due to
marked degree of inflammation.
Hormonal replacement therapy
may augment levels of HSCRP
Cushman et al, Citculation 100:717-722;1999
NON-PHARMACOLOGIC METHODS TO REDUCE
HSCRP
1. WEIGHT REDUCTION
2. EXERCISE
VALUE OF HSCRP
MEASUREMENTS

Conventional CRP assays cannot quantify serum proteins
less than 5 mg/l.
HSCRP > 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.
HSCRP > 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.
“Your blood pressure and cholesterol are fine,
but your hsCRP… “
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.
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
ADDITIVE VALUE OF HSCRP AFTER ADJUSTMENT FOR RISK FACTORS
RELATIVE RISKS OF FUTURE CV EVENTS ACCORDING TO BASELINE LEVELS OF HSCRP
PROSPECTIVE STUDIES RELATING BASELINE HSCRP LEVELS TO THE RISK OF FIRST CV EVENTS
ADDITIVE VALUE OF HSCRP OVER TOTAL CHOLESTEROL, HDL-C AND APO B:APO A RATIO
Ridker et al, Women’s Health Study , NEJM, 2002; 347; 1557-65
Ridker et al,Clinical application of CRP for CV disease detection and prevention,Circulation 107:363,2003
GUSTO IV ACS Trial
PROGNOSTIC UTILITY OF HSCRP, TROPONIN, AND BNP IN ACUTE CORONARY ISCHEMIA


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.
NATIONAL HEALTH AND NUTRITION EVALUATION SURVEY (NHANES)
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, 2005;112:900-5
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.
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
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 <70 mg/dl but also whose HS-CRP
lowered < 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
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
PROVE IT - TIMI 22 – RATE OF RECURRENT M.I OR DEATH AMONG STATIN-TREATED
PATIENTS ACCORDING TO LDL-C AND HSCRP AFTER 30 DAYS
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 LDLcholesterol 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.
REVERSAL STUDY : Secondary Endpoints
Endpoints
Pravastatin
( n=249)
Atorvastatin
( n=253)
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
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
-
+
+
-
Highsensitivity
CRP
+
+
+
+
Ridker et al, Risk Factors for Atherothrombotic Disease, 2005, 939-54
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.
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.
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; 107:449
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.
CDC/AHA RECOMMENDATIONS
1. HSCRP > 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 (<10% in 10 years) will unlikely to have a
high risk (>20%) identified thru HSCRP testing.
3. High risk individuals (>20% 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).
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.

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.
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.
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.
Thank You