Bio Markers In Acs And Heart Failure

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

30-day mortality 4 relative risk 2

P < 0.001 10

3.5

5.7

6

1.8 1

2 0

0

1

2

3

Elevated cardiac biomarkers (n) n=

67

150

BNP = B-type natriuretic peptide CRP = C-reactive protein

155

78

0

2.1 1 0

1

2

3

Elevated cardiac biomarkers (n) 504

717

324

90

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 Inflammation hs-CRP, CD40L

Hb A1c Accelerated Blood glucose Atherosclerosis

Hemodynamic Stress BNP, NT-proBNP

Vascular Damage

CrCl 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

BNP, pg/mL

Follow up

Pt dev sympto ms (n=14)

P value Pt remain asympto matic (n=29)

Pt dev sympto ms (n=14)

P value Pt remain asympto matic (n=29)

188 (56– 420)

64 (27– 161)

486 (83– 738)

64 (43– 115)

<0.001

<0.001

Circulation. 2004;109:2302-2308