bio markers in acs and heart failure

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



T. Multimarker strategy using troponin, crp and BNP improve prognostic information

B. Troponin is useful in diagnosis of reinfarction within two weeks




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 =




F. Troponin is useful in diagnosis of reinfarction within one week




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




F. Troponin is useful in diagnosis of reinfarction within two weeks

F. Myoglobulins rise steadily one hour after myocardial infarct



Myoglobulin

• Small molecule

• Release rapidly upon myocardial injury

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






F. Biomarkers result should be obtained before starting thrombolytic therapy in acute ST elevation 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

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


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




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




T. The peak level of troponin correlate with the extent of myocardial infarct



Response of cardiac markers to reperfusion





T. Troponin level provide prognostic information in Non ST elevation myocardial infarct


Troponin as a prognostic tool





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


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



× 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.



CKD patients with falsely raised troponin have worse cardiovascular outcome



× 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



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


A. Can be used for prognosis in patient with heart failure.



F. BNP rose with atrial dilatation due to cardiac disorders.


Natriuretic Peptide

http://bmj.bmjjournals.com/content/vol320/issue7228/images/large/heart03.f2.jpeg

Question 8


T. Can be used for prognosis in patient with heart failure.





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



T. BNP level reduced with successful treatment of heart failure.

C. Level of BNP correlates with NYHA classification.



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



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



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




T. Level of BNP correlate with NYHA classification.



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




T. Level of BNP correlate with NYHA classification.



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


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


Indicates increased ventricular volume and/or wall stress

B. Is not affected by renal function


D. BNP level is higher in obese patient


Non cardiac influences on secretion/clearanceNon cardiac influences on secretion/clearance

AgeAge

GenderGender

Renal FunctionRenal Function

ObesityObesity

Question 9



× Is not affected by renal function




Renal function and BNP

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

Question 9




× Is elevated in only systolic, but not diastolic heart failure



BNP is also raised in diastolic dysfunction

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

Question 9





× BNP level is higher in obese patient


Question 9





× 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

bio markers in acs and heart failure

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