Sungha Park M.D

Division of Cardiology

Yonsei Cardiovascular Center

Yonsei University College of Medicine

Clinical utility of Novel

biomarkers

Agenda

• Identifying high risk patients(Primary

prevention)

• Accurate diagnosis of coronary artery disease in

the ER

• Prognostic factor for future cardiovascular

events(Secondary prevention)

Biomarkers in ACS patients: vascular inflammation to

plaque rupture to ischemia to cell death to myocardial

dysfunction

Clinical Chemistry 2005;51:5 810–824

Prerequisite requirement

for useful biomarker

• Standardized assay

• Very specific for cardiovascular system

• Established reference value

• Strongly correlates with CVD while showing poor correlation with traditional risk factors

• Ability to improve prediction beyond traditional risk factors

• Acceptable cost

Prevalence of Risk Factors in Patients with Coronary Heart Disease

Khot, et al. JAMA 2003;290:898-904

0

5

10

15

20

25

30

35

40

45P

erc

en

t

0 1 2 3 4Risk Factors

Women

Men

Does CRP provide predictive

information beyond existing

global predictors?

CRP and Risk of MI: Rotterdam Study

van der Meer, et al Arch Intern Med 2003;164:1323-8

Rotterdam Study: Prospective trial of 7093

apparently healthy men and women, age > 55,

in which 157 with myocardial infarction were

compared with 500 selected controls were

compared in nested case control analysis based

on baseline CRP levels.

CRP compared with Framingham Risk Score (FRS):

Receiver operating characteristic curve was not

improved when hs-CRP was added FRS:

•AUC FRS: 0.745

•AUC FRS + CRP = 0.748

P Trend = 0.50

00.5

11.5

22.5

33.5

44.5

5

Od

ds R

ati

o f

or

Myo

card

ial

Infa

rcti

on

1 2 3 4

CRP Quartile

Folsom AR et al Arch Intern Med 2006;166:1368-1373Folsom AR et al Arch Intern Med 2006;166:1368-1373

CRP and Framingham Risk Score

Ridker PM et al NEJM 2002;347:1557-1565

27939 subjects in the Women’s Health Study

Variability of CRP

according to ethnicity

Arnand SS et al ATVB 2004;24:1509-1515

AHA/CDC Consensus Panel

Class I: None

Class IIa:

• In primary prevention, CRP measurement may be

useful in those at intermediate risk (10-20% 10-year

CHD risk), to help direct further evaluation and

treatment.

• In patients with stable CAD or ACS, CRP may be

useful as an independent marker of recurrent events,

including death, MI and restenosis following PCI.

Circulation 2003;107:499-511

Hs-CRP Recommendations

Agenda

• Identifying high risk patients(Primary prevention)

• Accurate diagnosis of coronary artery

disease in the ER

• Prognostic factor for future cardiovascular

events(Secondary prevention)

Clinical dilemma in diagnosing

troponin negative

acute coronary syndrome

• Absence of biomarkers that are specific for the heart except troponin

• Absence of biomarkers that has the ability to improve prediction beyond traditional risk factors

Sensitivity of IMA for diagnosis of ACS

Sinha MK et al.Emerg Med J 2004;21:29–34

IMA for diagnosis of CAD

Change of IMA during exercise40 consecutive pts with known CAD

Sbarouni E et al J Am Coll Cardiol 2006;48:2482-2484

Ischemia modified albumin in the

clinical practice

• Period: from Nov.2005 to Aug. 2007

• Patients: 500 patients with chest pain who arrived at the emergency department or outpatient clinic

• Method:

Blood sampling for IMA at the time of the hospital arrival.

Echocardiography, coronary angiography, TMT,or MIBI

Comparison of IMA levels between patients with

atypical chest pain and ischemic heart disease

Atypical

chest pain(N=236)IHD (N=264) p

Age 57.8 +/- 15.8 66.3 +/- 45.6 0.007

Sex, M/F 55.9/44.1 70.1/29.9 0.001

Diabetes 12.70% 24.20% 0.001

Hypertension 33.10% 52.70%

sensitivity specificitypositive

predictivenegative predictive

IMA>90 84.1 14.4 52.4 44.7

IMA>95 67.8 34.3 53.6 48.8

IMA>98 51.9 42.8 50.4 44.3

IMA>105 30.7 64.4 49.1 45.4

IMA>110 23.1 78.8 55 47.8

ROC curve comparing sensitivity

and specificity of IMA levels

YUMC data

AUC=0.52

Agenda

• Identifying high risk patients(Primary prevention)

• Accurate diagnosis of coronary artery disease in

the ER

• Prognostic factor for future cardiovascular

events(Secondary prevention)

Early Risk Stratification - cTn

In patients with a clinical syndrome consistent with ACS, a maximal (peak) concentration exceeding the 99th percentile of values for a reference control group should be considered indicative of increased risk of death and recurrent ischemic events

Class I, Level of Evidence A

Antman EM et al. JAMA. 2000;284:835-42.n = 1957 ACS patients

Risk factors

(n)

0

45

35

25

15

5

0/1 2 3 4 5 6/7

Death/MI/

severe ischemia

at 14 days

(%)

4.7

8.3

13.2

19.9

26.2

40.9

TIMI risk score in UA/NSTEMI

Risk of death in patients with NSTEAC syndrome stratified by quartile of

concentration of NT-proBNP (Elecsys 2010, Roche Diagnostics) at baseline

James SK et al. Circiculation 2003;108:275-81.

Westerhout CM et al. J Am Coll Cardiol 2006;48:939-947

1. Screening of the population as a whole is NOT recommended

2. Application of secondary prevention measures should not depend upon hs-CRP results

3. Application of management guidelines for acute coronary syndromes should not be dependent upon hs-CRP level

4. Serial CRP levels should not be used to monitor effects of treatment

Circulation 2003;107:499-511

AHA/CDC Consensus PanelHs-CRP Recommendations

Comparison of novel biomarkers

Standardized Specific Established

Reference

Independent

from traditional

risk factors

Improve prediction

beyond traditional

risk factors

hsCRP Yes No Yes No Weak

CD40L No No No Yes NA

PAPPA No No No No NA

IMA No No Yes Yes NA

Myeloperoxidase No No No No NA

Non of the biomarkers have proven to be

better than hsCRP: Why use it?

Yonsei Cardiovascular Hospital

Yonsei University College of Medicine

Class IIa:

• Measurement should be done twice (two weeks apart)

and results averaged.

• If level > 10 mg/L, test should be repeated and patient

examined for sources of infection or inflammation

• Classify risk as follows:

Low < 1 mg/L

Average 1.0 – 3.0 mg/L

High: > 3.0 mg/L

Circulation 2003;107:499-511

AHA/CDC Consensus Panel

Hs-CRP Recommendations

CRP Limitations

• Most studies limited to North American and

European population -- limited ability to

extrapolate to Native American, African and

South Asian

• Not good indicator of extent of disease burden

• Most studies have not adjusted for body-mass-

index

• Strength of association lessoned in some

studies when adjusting for other risk factors

C-reactive Protein

• Circulating acute phase reactant

• Many-fold increase with injury & infection

• Synthesized in liver, induced primarily by

interleukin-6 (IL-6)

• Stable levels in circulation, not affected by

meals, no circadian levels

• Level – within normal range – predicts

CVD risk

*Family history of CAD, hypertension, elevated

cholesterol, diabetes, current smoker†Creatine-kinase MB and/or cardiac troponins Antman EM et al. JAMA. 2000;284:835-42.

TIMI risk score for UA/NSTEMI

• Age ≥65 years

• ≥3 CAD risk factors*

• Significant coronary stenosis

• ST-segment deviation

• Severe angina (≥2 anginal events in last 24

hours)

• Daily use of aspirin in prior 7 days

• Elevated serum cardiac markers†

CRP and Cardiovascular Risk

• MI

• Stroke

• Peripheral arterial disease

• Sudden cardiac death

• Recurrent ischemia and death in:

• Unstable Angina

• Myocardial Infarction

• Percutaneous intervention

CRP will Predict:

Early Risk Stratification

hsCRP and BNP/NTproBNP

… may be useful, in addition to a cardiac

troponin…

The benefits of therapy based on this strategy

remain uncertain!

Class IIa, Level of Evidence A

Ischemia-Modified Albumin

• The amino terminal end (N-terminal) of the albumin molecule is a binding site for transitional metals such as cobalt, copper and nickel.

• Possibly as the result of hypoxia, acidosis, free-radical injury and energy dependent membrane disruption, the N-terminal undergoes a decrease in binding capacity in the presence of ischemia.

This alteration can be measured: a set amount of cobalt is added to the patient’s serum, after which a colorimetric assay, the albumin–cobalt binding assay, is used to determine the amount of cobalt that remains unbound.

Bar-Or D et al. Am Heart J 2001;141:985-91.

OPUS-TIMI 16

Sabatine MS et al. Circulation. 2002;105:1760-3.

TACTICS-TIMI 18

1

1.8

3.5

6

12.1

5.7

13

1 2 301 2 30

14

10

6

2

BNP = B-type natriuretic peptide

CRP = C-reactive protein

6

4

2

0

30-day

mortality

relative

risk

Elevated cardiac biomarkers (n) Elevated cardiac biomarkers (n)

P = 0.014 P < 0.001

67 150 155 78 504 717 324 90

0

Multimarker strategy: Identifying high-risk

patients by troponin I, CRP, and BNP

n =