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Biomarkers in ACS and Heart FailureDr Chee Kok HanUniversity of Malaya Medical Centre
Question 1Which 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 1Which 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
OPUS-TIMI 16
Sabatine MS et al. Circulation. 2002;105:1760-3.
TACTICS TIMI-18
11.8
3.5
6
12.1
5.7
13
1 2 301 2 30
14
10
6
2
BNP = B-type natriuretic peptideCRP = 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 =
Question 1Which 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 1Which 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 1Which 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 1Which 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
STRIVETM
Future of Biomarkers in ACS: Toward a Multimarker Strategy
Adapted with permission from Morrow DA, Braunwald E. Circulation. 2003;108:250-252.
Myocyte Necrosis
Inflammation
Troponin
Accelerated Atherosclerosis
Vascular Damage
HemodynamicStress
hs-CRP, CD40L
Hb A1cBlood glucose
CrClMicroalbuminuria
Biomarker profile in acute coronary syndromes. hs-CRP indicates high-sensitivity CRP; CrCl, creatinine clearance; and Hb A1c, hemoglobin A 1c.
BNP, NT-proBNP
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 3TroponinsA. Regulate the calcium-mediated interactions of actin and
myosin in cardiac muscle contraction.B. Is not present in skeletal muscleC. Troponin complex consists of troponin C, T and I
subunits.D. Hypocalcemia will impair the release of the troponin into
systemic circulationE. Raised troponin is one of the diagnostic criteria of acute
myocardial infarct
Question 3Troponins
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 3Troponins
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 4Cardiac 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 4Cardiac 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 4Cardiac 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 4Cardiac 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 4Cardiac 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 5Cardiac troponin may be raise inA. Non ST elevation myocardial infarctB. Septicemic shockC. Acute pulmonary embolismD. HypothyroidismE. Rheumatic feverF. Amyloidosis of the heartG. RhabdomyolysisH. After electrical cardioversion of fast atrial fibrillation
Question 5Cardiac troponin may be raise in
Non ST elevation myocardial infarctSepticemic shockAcute pulmonary embolismHypothyroidismRheumatic feverAmyloidosis of the heartRhabdomyolysisAfter 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 6Cardiac 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 6Cardiac troponin in chronic kidney disease (CKD)
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/mLin 40 (38%) patients
Circulation, Oct 2000; 102: 1964 - 1969.
Question 6Cardiac troponin in chronic kidney disease (CKD)
Troponin may falsely raised in patients with chronic kidney disease with no myocardial necrosis
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
Dierkes, J. et al. Circulation 2000;102:1964-1969
Estimated survival rate among 102 patients with ESRD according to cTNT concentrations
Question 6Cardiac troponin in chronic kidney disease (CKD)
Troponin may falsely raised in patients with chronic kidney disease with no myocardial necrosis
CKD patients with falsely raised troponin have worse cardiovascular outcome
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/IIIainhibitor
Question 7
Troponin and acute coronary syndrome
Raised troponin = higher incidence of left ventricular failure
Raised troponin = more benefit for early intervention
Raised troponin = more benefit for low molecular weight heparin
Raised troponin = higher risk of death
Raised troponin = more benefit from glycoprotein IIb/IIIainhibitor
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
Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply.
Jourdain, P. et al. J Am Coll Cardiol 2007;49:1733-1739
Event-Free (Hospital Stay for Heart Failure or Death Related to Heart Failure) Survival in the 2 Groups
Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply.
Jourdain, P. et al. J Am Coll Cardiol 2007;49:1733-1739
Plasma BNP Level in BNP Group During Titration Phase and % of Patients Reaching Target BNP Value
Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply.
Jourdain, P. et al. J Am Coll Cardiol 2007;49:1733-1739
Number of Changes in Medical Therapy During the First 3 Months
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 CHFBNP and Severity of CHF
BNP BNP ↑↑ with NYHA Classwith NYHA Class
And with And with ↓↓ LV functionLV function–– 153 patients referred 153 patients referred
for RNVGfor RNVG–– BNP (RIA)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)
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/clearanceNon cardiac influences on secretion/clearance
AgeAge
GenderGender
Renal FunctionRenal Function
ObesityObesity
Question 9
B-natriuretic peptide (BNP)
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)
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)
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
Copyright ©2005 American Heart Association
Das, S. R. et al. Circulation 2005;112:2163-2168
Natriuretic peptide levels stratified by sex and BMI category
Question 9
B-natriuretic peptide (BNP)
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
Is elevated in both symptomatic and asymptomatic heart failure
Question 10Higher BNP level suggest poorer outcome in the
following condition(s)A. Acute decompensated heart failureB. Chronic heart failureC. Acute Non ST elevation myocardial infarctD. Stable anginaE. Mitral regurgitaionF. Pulmonary hypertensionG. Aortic stenosis
Question 10Higher BNP level suggest poorer outcome in the
following condition(s)Acute decompensated heart failureChronic heart failureAcute Non ST elevation myocardial infarctStable anginaMitral regurgitaionPulmonary hypertensionAortic stenosis
BNP in aortic stenosis
Baseline Follow upPt dev symptoms (n=14)
Pt remain asymptomatic (n=29)
P value Pt dev symptoms (n=14)
Pt remain asymptomatic (n=29)
P value
BNP, pg/mL
188 (56–420)
64 (27–161)
<0.001 486 (83–738)
64 (43–115)
<0.001
Circulation. 2004;109:2302-2308