Biomarkers in ACS

and Heart Failure

Dr Chee Kok Han
University of Malaya Medical Centre
Question 1
Which of the following statement(s) is/are true about biomarkers
in acute coronary syndrome?
A. Multimarker strategy using troponin, crp and BNP improve
prognostic information
B. Troponin is useful in diagnosis of reinfarction within two weeks
C. Myoglobulins rise steadily one hour after myocardial infarct
D. Biomarkers result should be obtained before starting thrombolytic
therapy in acute ST elevation myocardial infarct
E. CK-CKMB ratio of more than 2.5 improve sensitivity of diagnosis in
acute ST elevation myocardial infarct
Question 1
Which of the following statement(s) is/are true about biomarkers
in acute coronary syndrome?
T. Multimarker strategy using troponin, crp and BNP improve
prognostic information
B. Troponin is useful in diagnosis of reinfarction within two weeks
C. Myoglobulins rise steadily one hour after myocardial infarct
D. Biomarkers result should be obtained before starting thrombolytic
therapy in acute ST elevation myocardial infarct
E. CK-CKMB ratio of more than 2.5 improve sensitivity of diagnosis in
acute ST elevation myocardial infarct
Acute Coronary Syndrome
Multimarker strategy improve diagnosis

Circulation 2001;103:1832–1837
Multimarker strategy: Identifying high-risk
patients by troponin I, CRP, and BNP

OPUS-TIMI 16 TACTICS TIMI-18

6
6 14 13

P = 0.014 P < 0.001

30-day 10
mortality 4 3.5
relative
risk 6 5.7
2 1.8
1 2.1
2 1
0 0
0 1 2 3 0 1 2 3
Elevated cardiac biomarkers (n) Elevated cardiac biomarkers (n)
n= 67 150 155 78 504 717 324 90
BNP = B-type natriuretic peptide
CRP = C-reactive protein Sabatine MS et al. Circulation. 2002;105:1760-3.
Question 1
Which of the following statement(s) is/are true about biomarkers
in acute coronary syndrome?
T. Multimarker strategy using troponin, crp and BNP improve
prognostic information
F. Troponin is useful in diagnosis of reinfarction within one week
C. Myoglobulins rise steadily one hour after myocardial infarct
D. Biomarkers result should be obtained before starting thrombolytic
therapy in acute ST elevation myocardial infarct
E. CK-CKMB ratio of more than 2.5 improve sensitivity of diagnosis in
acute ST elevation myocardial infarct
Cardiac Enzymes in ACS
Cardiac Enzymes in ACS

Test Onset Peak Duration

Myoglobulin 1-4 hours 6-7 hours 24 hours

Troponin 3-12 hours 18-24 hours Up to 10 days

CK-MB 3-12 hours 18-24 hours 36-48 hours

LDH 6-12 hours 24-48 hours 6-8 days

CK-MB and Reinfarction
• CK-MB is the marker of choice for diagnosis of
reinfarction after STEMI, PCI, or CABG because of rapid
washout
• The ACC/AHA definition of re-infarction includes both
– re-elevation of CK-MB
– supporting criteria including ECG changes, pain or
hemodynamic instability
Question 1
Which of the following statement(s) is/are true about biomarkers
in acute coronary syndrome?
T. Multimarker strategy using troponin, crp and BNP improve
prognostic information
F. Troponin is useful in diagnosis of reinfarction within two weeks
F. Myoglobulins rise steadily one hour after myocardial infarct
D. Biomarkers result should be obtained before starting thrombolytic
therapy in acute ST elevation myocardial infarct
E. CK-CKMB ratio of more than 2.5 improve sensitivity of diagnosis in
acute ST elevation myocardial infarct
Myoglobulin
• Small molecule
• Release rapidly upon myocardial injury
Cardiac Enzymes in ACS
Myoglobulin: Limitation
• “Stacatto” pattern of release
• Lacks specificity for heart
• In muscular injury
• In renal impairment
Myoglobulin
• “Stacatto” pattern of release

Am J Med 1977
Question 1
Which of the following statement(s) is/are true about biomarkers
in acute coronary syndrome?
T. Multimarker strategy using troponin, crp and BNP improve
prognostic information
F. Troponin is useful in diagnosis of reinfarction within two weeks
F. Myoglobulins rise steadily one hour after myocardial infarct
F. Biomarkers result should be obtained before starting thrombolytic
therapy in acute ST elevation myocardial infarct
E. CK-CKMB ratio of more than 2.5 improve sensitivity of diagnosis in
acute ST elevation myocardial infarct
Question 1
Which of the following statement(s) is/are true about biomarkers
in acute coronary syndrome?
T. Multimarker strategy using troponin, crp and BNP improve
prognostic information
F. Troponin is useful in diagnosis of reinfarction within two weeks
F. Myoglobulins rise steadily one hour after myocardial infarct
F. Biomarkers result should be obtained before starting thrombolytic
therapy in acute ST elevation myocardial infarct
T. CK-CKMB ratio of more than 2.5 improve sensitivity of diagnosis in
acute ST elevation myocardial infarct
CK:CK-MB Ratio
• CK-MB index = 100% (CK-MB/Total CK)
• Proposed to improve specificity for use in diagnosis of
AMI
• Ratios 2.5-5 have been proposed
• Significantly reduces sensitivity in patients with both
skeletal muscle and cardiac injury
• Also known to be misleading in the setting of
hypothyroidism, renal failure, and chronic skeletal
muscle diseases
Question 2
The following biomarker(s) rise as a result of
myocardial necrosis in acute ST elevation
myocardial infarct:
A. B-natriuretic peptide
B. Myoglobulin
C. Troponin
D. hs-C reactive protein
E. Haemoglobulin A1c
Question 2
The following biomarker(s) rise as a result of
myocardial necrosis in acute ST elevation
myocardial infarct:
A. B-natriuretic peptide
B. Myoglobulin
C. Troponin
D. hs-C reactive protein
E. Haemoglobulin A1c
 Future of Biomarkers in ACS:
Toward a Multimarker Strategy
Myocyte Necrosis
Troponin

Hemodynamic
Inflammation
Stress
hs-CRP, CD40L
BNP, NT-proBNP

Hb A1c Accelerated Vascular CrCl

Blood glucose Atherosclerosis Damage Microalbuminuria

Biomarker profile in acute coronary syndromes. hs-CRP indicates high-sensitivity

CRP; CrCl, creatinine clearance; and Hb A1c, hemoglobin A 1c.

Adapted with permission from Morrow DA, Braunwald E. Circulation. 2003;108:250-252. STRIVE TM
Question 2
The following biomarker(s) rise as a result of
myocardial necrosis in acute ST elevation
myocardial infarct:
A. B-natriuretic peptide ×
B. Myoglobulin √
C. Troponin √
D. hs-C reactive protein ×
E. Haemoglobulin A1c ×
Question 3
Troponins
A. Regulate the calcium-mediated interactions of actin and
myosin in cardiac muscle contraction.
B. Is not present in skeletal muscle
C. Troponin complex consists of troponin C, T and I
subunits.
D. Hypocalcemia will impair the release of the troponin into
systemic circulation
E. Raised troponin is one of the diagnostic criteria of acute
myocardial infarct
Question 3
Troponins
A. Regulate the calcium-mediated interactions of actin and √
myosin in cardiac muscle contraction.
B. Is not present in skeletal muscle
C. Troponin complex consists of troponin C, T and I
subunits.
D. Hypocalcemia will impair the release of the troponin into
systemic circulation
E. Raised troponin is one of the diagnostic criteria of acute
myocardial infarct
Troponins

Troponins and tropomyosin are protein complex that

regulate the calcium-mediated interactions of actin and
myosin in cardiac and skeletal muscle contraction.
Question 3
Troponins
A. Regulate the calcium-mediated interactions of actin and √
myosin in cardiac muscle contraction.
B. Is not present in skeletal muscle ×
C. Troponin complex consists of troponin C, T and I √
subunits.
D. Hypocalcemia will impair the release of the troponin into ×
systemic circulation
E. Raised troponin is one of the diagnostic criteria of acute √
myocardial infarct
Definition of AMI 1999
• Typical rise and gradual fall (troponin) or more rapid rise
and fall (CK-MB) of biochemical markers of myocardial
necrosis with at least one of the following:
– ischemic symptoms;
– development of pathologic Q waves on the ECG;
– ECG changes indicative of ischemia (ST segment elevation or
depression); or
– coronary artery intervention (e.g., coronary angioplasty).

• Pathologic findings of an acute MI.

Question 4
Cardiac troponin during acute coronary syndrome
A. Troponin will be raised within two hours of onset of the Acute ST
elevation myocardial infarct
B. Troponin will be detectable up to 10 days after acute myocardial
infarct
C. The peak level of troponin correlate with the extent of myocardial
infarct
D. Troponin level provide prognostic information in Non ST elevation
myocardial infarct
E. Creatinine kinase MB (CKMB) but not troponin will be raised in blunt
chest trauma
Question 4
Cardiac troponin during acute coronary syndrome
F. Troponin will be raised within two hours of onset of the Acute ST
elevation myocardial infarct
T. Troponin will be detectable up to 10 days after acute myocardial
infarct
C. The peak level of troponin correlate with the extent of myocardial
infarct
D. Troponin level provide prognostic information in Non ST elevation
myocardial infarct
E. Creatinine kinase MB (CKMB) but not troponin will be raised in blunt
chest trauma
Cardiac Enzymes in ACS

Test Onset Peak Duration

Myoglobulin 1-4 hours 6-7 hours 24 hours

Troponin 3-12 hours 18-24 hours Up to 10 days

CK-MB 3-12 hours 18-24 hours 36-48 hours

LDH 6-12 hours 24-48 hours 6-8 days

Question 4
Cardiac troponin during acute coronary syndrome
F. Troponin will be raised within two hours of onset of the Acute ST
elevation myocardial infarct
T. Troponin will be detectable up to 10 days after acute myocardial
infarct
T. The peak level of troponin correlate with the extent of myocardial
infarct
D. Troponin level provide prognostic information in Non ST elevation
myocardial infarct
E. Creatinine kinase MB (CKMB) but not troponin will be raised in blunt
chest trauma
Cardiac Enzymes in ACS
Response of cardiac markers to
reperfusion
Question 4
Cardiac troponin during acute coronary syndrome
F. Troponin will be raised within two hours of onset of the Acute ST
elevation myocardial infarct
T. Troponin will be detectable up to 10 days after acute myocardial
infarct
T. The peak level of troponin correlate with the extent of myocardial
infarct
T. Troponin level provide prognostic information in Non ST elevation
myocardial infarct
E. Creatinine kinase MB (CKMB) but not troponin will be raised in blunt
chest trauma
Troponin as a prognostic tool
Question 4
Cardiac troponin during acute coronary syndrome
F. Troponin will be raised within two hours of onset of the Acute ST
elevation myocardial infarct
T. Troponin will be detectable up to 10 days after acute myocardial
infarct
T. The peak level of troponin correlate with the extent of myocardial
infarct
T. Troponin level provide prognostic information in Non ST elevation
myocardial infarct
T. Creatinine kinase MB (CKMB) but not troponin will be raised in blunt
chest trauma
CK-MB and troponin raise in
• Myocardial injury after cardiopulmonary resuscitation
• Cardioversion
• Defibrillation
• Cardiac and non-cardiac surgical procedures
• Blunt chest trauma with possible cardiac contusion
• Cocaine abuse
Question 5
Cardiac troponin may be raise in
A. Non ST elevation myocardial infarct
B. Septicemic shock
C. Acute pulmonary embolism
D. Hypothyroidism
E. Rheumatic fever
F. Amyloidosis of the heart
G. Rhabdomyolysis
H. After electrical cardioversion of fast atrial fibrillation
Question 5
Cardiac troponin may be raise in
9 Non ST elevation myocardial infarct
9 Septicemic shock
9 Acute pulmonary embolism
9 Hypothyroidism
9 Rheumatic fever
9 Amyloidosis of the heart
9 Rhabdomyolysis
9 After electrical cardioversion of fast atrial fibrillation
Troponins
• release into the bloodstream when there is some type of
damage to cardiac myocyte cell-wall integrity.
Troponin also rise in ….

Of note:
Sepsis
Heart failure
Pulmonary embolism
Chest wall trauma
Stroke
Question 6
Cardiac troponin in chronic kidney disease (CKD)
A. Troponin may falsely raised in patients with chronic kidney disease
with no myocardial necrosis
B. CKD patients with falsely raised troponin have worse cardiovascular
outcome
C. Troponin I assays appears to be much less likely to be associated
with false positives in the CKD population than Troponin T assay
D. Repeated troponin measurements is not useful in CKD patients
suspected to have acute coronary syndrome
E. Troponin is falsely positive is less than half of the CKD patients
Question 6
Cardiac troponin in chronic kidney disease (CKD)
9 Troponin may falsely raised in patients with chronic kidney disease
with no myocardial necrosis
B. CKD patients with falsely raised troponin have worse cardiovascular
outcome
C. Troponin I assays appears to be much less likely to be associated
with false positives in the CKD population than Troponin T assay
D. Repeated troponin measurements is not useful in CKD patients
suspected to have acute coronary syndrome
× Troponin is falsely positive in less than half of the CKD patients
Troponin in renal failure
• In a study on 102 asymptomatic ESRF patients who
were on dialysis
• cTNT was above the limit of detection in 85 (83%)
patients and was above the reference limit of 0.04 ng/mL
in 40 (38%) patients

Circulation, Oct 2000; 102: 1964 - 1969.

Question 6
Cardiac troponin in chronic kidney disease (CKD)
9 Troponin may falsely raised in patients with chronic kidney disease
with no myocardial necrosis
9 CKD patients with falsely raised troponin have worse cardiovascular
outcome
C. Troponin I assays appears to be much less likely to be associated
with false positives in the CKD population than Troponin T assay
D. Repeated troponin measurements is not useful in CKD patients
suspected to have acute coronary syndrome
× Troponin is falsely positive is less than half of the CKD patients
Estimated survival rate among 102 patients with ESRD according to cTNT concentrations

Dierkes, J. et al. Circulation 2000;102:1964-1969

Question 6
Cardiac troponin in chronic kidney disease (CKD)
9 Troponin may falsely raised in patients with chronic kidney disease
with no myocardial necrosis
9 CKD patients with falsely raised troponin have worse cardiovascular
outcome
9 Troponin I assays appears to be much less likely to be associated
with false positives in the CKD population than Troponin T assay
× Repeated troponin measurements is not useful in CKD patients
suspected to have acute coronary syndrome
× Troponin is falsely positive is less than half of the CKD patients
CKD and Elevated Troponins
• Serial measurements are helpful in the setting of
possible ACS

• cTnI appears to be much less likely to be associated with

false positives in the CKD population than cTnT, making
it the preferred biomarker in this setting
Question 7
Troponin and acute coronary syndrome
A. Raised troponin = higher incidence of left ventricular
failure
B. Raised troponin = more benefit for early intervention
C. Raised troponin = more benefit for low molecular weight
heparin
D. Raised troponin = higher risk of death
E. Raised troponin = more benefit from glycoprotein IIb/IIIa
inhibitor
Question 7
Troponin and acute coronary syndrome
9 Raised troponin = higher incidence of left ventricular
failure
9 Raised troponin = more benefit for early intervention
9 Raised troponin = more benefit for low molecular weight
heparin
9 Raised troponin = higher risk of death
9 Raised troponin = more benefit from glycoprotein IIb/IIIa
inhibitor
Troponin and benefit of glycoprotein
IIb/IIIa inhibitor
Troponin and benefit of early invasive
strategy
Troponin as a prognostic marker

Data from Hamm, CW, Braunwald, E, Circulation 2000; 102:118.

Question 8
B-natriuretic peptide (BNP)
A. Can be used for prognosis in patient with heart failure.
B. BNP level reduced with successful treatment of heart
failure.
C. Level of BNP correlates with NYHA classification
D. BNP rose with atrial dilatation due to cardiac disorders.
E. In acute coronary syndrome, patients with raised BNP
have worse outcome
Question 8
B-natriuretic peptide (BNP)
A. Can be used for prognosis in patient with heart failure.
B. BNP level reduced with successful treatment of heart
failure.
C. Level of BNP correlates with NYHA classification
F. BNP rose with atrial dilatation due to cardiac disorders.
E. In acute coronary syndrome, patients with raised BNP
have worse outcome
Natriuretic Peptide
Question 8
B-natriuretic peptide (BNP)
T. Can be used for prognosis in patient with heart failure.
B. BNP level reduced with successful treatment of heart
failure.
C. Level of BNP correlates with NYHA classification
F. BNP rose with atrial dilatation due to cardiac disorders.
E. In acute coronary syndrome, patients with raised BNP
have worse outcome
Level of BNP correlate with survival in
chronic heart failure

Circulation 2003; 107:1278.

Level of admission BNP predict mortality
in acute heart failure

J Am Coll Cardiol 2007;49:1943–50

Question 8
B-natriuretic peptide (BNP)
T. Can be used for prognosis in patient with heart failure.
T. BNP level reduced with successful treatment of heart
failure.
C. Level of BNP correlates with NYHA classification.
F. BNP rose with atrial dilatation due to cardiac disorders.
E. In acute coronary syndrome, patients with raised BNP
have worse outcome
STARS-BNP Multicenter Study
• 220 NYHA II to III patients considered optimally treated
with ACEIs, BBs, and diuretics
• Randomized to either
– current guidelines (clinical group) or
– a goal of decreasing BNP plasma levels <100 pg/ml (BNP
group).

• The primary combined end point was CHF-related death

or hospital stay for CHF
 Event-Free (Hospital Stay for Heart Failure or Death Related to Heart Failure)
Survival in the 2 Groups

Jourdain, P. et al. J Am Coll Cardiol 2007;49:1733-1739

Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply.

 Plasma BNP Level in BNP Group During Titration Phase and % of Patients Reaching
Target BNP Value

Jourdain, P. et al. J Am Coll Cardiol 2007;49:1733-1739

Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply.

 Number of Changes in Medical Therapy During the First 3 Months

Jourdain, P. et al. J Am Coll Cardiol 2007;49:1733-1739

Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply.

STARS-BNP Multicentre study
• In optimally treated CHF patients, a BNP-guided strategy
reduced the risk of CHF-related death or hospital stay for
CHF. The result was mainly obtained through an
increase in ACEI and beta-blocker dosages.
Question 8
B-natriuretic peptide (BNP)
T. Can be used for prognosis in patient with heart failure.
T. BNP level reduced with successful treatment of heart
failure.
T. Level of BNP correlate with NYHA classification.
F. BNP rose with atrial dilatation due to cardiac disorders.
E. In acute coronary syndrome, patients with raised BNP
have worse outcome
B-Natriuretic Peptide
B-Natriuretic Peptide
 BNP and Severity of CHF

„ BNP ↑ with NYHA Class

„ And with ↓ LV function

– 153 patients referred
for RNVG
– BNP (RIA)

Valli et al Clin Chim Acta 2001;306:19

Question 8
B-natriuretic peptide (BNP)
T. Can be used for prognosis in patient with heart failure.
T. BNP level reduced with successful treatment of heart
failure.
T. Level of BNP correlate with NYHA classification.
F. BNP rose with atrial dilatation due to cardiac disorders.
E. In acute coronary syndrome, patients with raised BNP
have worse outcome
BNP in ACS
• 2525 patients in OPUS-TIMI 16 (825 STEMI, 565
NSTEMI, 1133 UAP, 2 unspecified). Baseline
sample within 72 h of presentation
• No consistent relationship between time of onset of
symptoms and BNP level
Kaplan–Meier Curves Showing the Cumulative Incidence of Death at 10 Months,
According to the Quartile of B-Type Natriuretic Peptide Level at Enrollment.
de Lemos et al NEJM 2001;345:1014-21
Post acute MI
• 666 patients
• Samples 24-96 hours from symptom onset
• NTpBNP and BNP measured
• Survival curves for BNP and NTproBNP above or below
the median value
Richards AM et al Circulation 2003; 107: 2786-92
Post acute MI
Question 9
B-natriuretic peptide (BNP)
A. Indicates increased ventricular volume and/or wall
stress
B. Is not affected by renal function
C. Is elevated in only systolic, but not diastolic heart failure
D. Will always be elevated in heart failure
E. Is elevated in both symptomatic and asymptomatic
heart failure
Question 9
B-natriuretic peptide (BNP)
9 Indicates increased ventricular volume and/or wall
stress
B. Is not affected by renal function
C. Is elevated in only systolic, but not diastolic heart failure
D. BNP level is higher in obese patient
E. Is elevated in both symptomatic and asymptomatic
heart failure
Non cardiac influences on secretion/clearance

„ Age

„ Gender

„ Renal Function

„ Obesity
Question 9
B-natriuretic peptide (BNP)
9 Indicates increased ventricular volume and/or wall
stress
× Is not affected by renal function
C. Is elevated in only systolic, but not diastolic heart failure
D. BNP level is higher in obese patient
E. Is elevated in both symptomatic and asymptomatic
heart failure
Renal function and BNP

JACC 2006 Jan 3;47(1):91-7

Question 9
B-natriuretic peptide (BNP)
9 Indicates increased ventricular volume and/or wall
stress
× Is not affected by renal function
× Is elevated in only systolic, but not diastolic heart failure
D. BNP level is higher in obese patient
E. Is elevated in both symptomatic and asymptomatic
heart failure
BNP is also raised in diastolic
dysfunction

Am J Med 2001 Sep;111(4):274-9

Question 9
B-natriuretic peptide (BNP)
9 Indicates increased ventricular volume and/or wall
stress
× Is not affected by renal function
× Is elevated in only systolic, but not diastolic heart failure
× BNP level is higher in obese patient
E. Is elevated in both symptomatic and asymptomatic
heart failure
 Natriuretic peptide levels stratified by sex and BMI category

Das, S. R. et al. Circulation 2005;112:2163-2168

Copyright ©2005 American Heart Association

Question 9
B-natriuretic peptide (BNP)
9 Indicates increased ventricular volume and/or wall
stress
× Is not affected by renal function
× Is elevated in only systolic, but not diastolic heart failure
× BNP level is higher in obese patient
9 Is elevated in both symptomatic and asymptomatic
heart failure
Question 10
Higher BNP level suggest poorer outcome in the
following condition(s)
A. Acute decompensated heart failure
B. Chronic heart failure
C. Acute Non ST elevation myocardial infarct
D. Stable angina
E. Mitral regurgitaion
F. Pulmonary hypertension
G. Aortic stenosis
Question 10
Higher BNP level suggest poorer outcome in the
following condition(s)
9 Acute decompensated heart failure
9 Chronic heart failure
9 Acute Non ST elevation myocardial infarct
9 Stable angina
9 Mitral regurgitaion
9 Pulmonary hypertension
9 Aortic stenosis
BNP in aortic stenosis

Baseline Follow up
Pt dev Pt P value Pt dev Pt P value
sympto remain sympto remain
ms asympto ms asympto
(n=14) matic (n=14) matic
(n=29) (n=29)
BNP, 188 64 (27– <0.001 486 64 (43– <0.001
pg/mL (56– 161) (83– 115)
420) 738)

Circulation. 2004;109:2302-2308