cardiac biomarkers:. history 1950’s: clinical reports that transaminases released from dying...

CARDIAC BIOMARKERS:

History

1950’s: Clinical reports that transaminases released from dying myocytes could be detected via laboratory testing, aiding in the diagnosis of myocardial infarction1

The race to define clinical markers to aid in the diagnosis, prognosis, and risk stratification of patients with potential cardiovascular disease begins

1 Circulation 108:250-252

History

Initial serum markers included AST, LDH, total CK and α-hydroxybutyrate

These enzymes are all released in varying amounts by dying myocytes

Lack of sensitivity and specificity for cardiac muscle necrosis fuels continued research

History: CK and Isoenzymes

CK known to be released during muscle necrosis (including cardiac)

Quantitative assays were cumbersome and difficult to perform

Total CK designed as a fast, reproducible spectrophotometric assay in the late 1960’s


CK isoenzymes are subsequently described

MM, MB and BB fractions

1970’s: MB fraction noted to be elevated in and highly specific for acute MI1

1 Clinical Chemistry 50(11): 2205-2213


CKMB now measured via a highly sensitive monoclonal antibody assay

It was felt for a time that quantitative CKMB determination could be used to enzymatically measure the size of an infarct

This has been complicated by release of additional enzymes during reperfusion


As CK-MB assays become more sensitive, researchers come to the paradoxical realization that it too is not totally cardiac specific

The MB fraction is determined to be expressed in skeletal muscle, particularly during the process of muscle regeneration

The search for cardiac specificity continues…

Clinical Chemistry 50(11): 2205-2213

History

Research turns towards isolation of and development of assays for sarcomeric proteins

Myosin light chains were originally isolated and then subsequently abandoned because of specificity issues

History: Troponin

Troponin I first described as a biomarker specific for AMI in 19871; Troponin T in 19892

Now the biochemical “gold standard” for the diagnosis of acute myocardial infarction via consensus of ESC/ACC

1 Am Heart J 113: 1333-442 J Mol Cell Cardiol 21: 1349-53

History

This work encourages development of other clinical assays for diagnosis and prognosis of a wide spectrum of cardiac diseases

Notable examples: BNP (FDA approved in November 2000 for

diagnosis of CHF) C-reactive protein

MARKERS OF CARDIAC NECROSIS

What is Myocardial Infarction?

Myocardial ischemia results from the reduction of coronary blood flow to an extent that leads to insufficiency of oxygen supply to myocardial tissue

When this ischemia is prolonged & irreversible, myocardial cell death & necrosis occurs ---this is defined as:

myocardial infarction

Biochemical Changes in Acute Myocardial Infarction(mechanism of release of myocardial markers)

ischemia to myocardial muscles (with low O2 supply)

anaerobic glycolysis

increased accumulation of Lactate

decrease in pH

activate lysosomal enzymes

disintegration of myocardial proteins

cell death & necrosis

release of intracellular contents to bloodBIOCHEMICAL

MARKERS

clinical manifestations (chest pain)

ECG changes

Diagnosis of Myocardial Infarction

SHOULD depend on THREE items

(as recommended by WHO)

1- Clinical Manifestations 2- ECG

3- Biochemical Markers

Markers of Cardiac Necrosis

Cardiac biomarkers an integral part of the most recent joint ACC/ESC consensus statement on the definition of acute or recent MI:

“Perfect” Cardiac Marker

Early appearance

Accurate, specific, precise

Readily available, fast results

Cost-effective


Typical rise and gradual fall (troponin) or more rapid rise and fall (CK-MB) of biochemical markers of myocardial necrosis with at least (1) of the following:

Ischemic symptomsDevelopment of pathologic Q wavesST segment elevation or depressionCoronary artery intervention

Troponins

Troponin T (cTnT) and troponin I (cTnI) control the calcium-mediated interaction of actin and myosin

cTnI completely specific for the heart cTnT released in small amounts by

skeletal muscles, though clinical assays do not detect skeletal TnT

Troponins

Troponins

4-6 hours to rise post-infarct, similar to CKMB

6-9 hours to detect pathologic elevations in all patients with infarct

Elevated levels can persist in blood for weeks; the cardiac specificity of troponins thus make them the ideal marker for retrospective diagnosis of infarction

CK-MB

High specificity for cardiac tissue The preferred marker for cardiac injury for

many years Begins to rise 4-6 hours after infarction

but can take up to 12 hours to become elevated in all patients with infarction

Elevations return to baseline within 36-48 hours, in contrast to troponins

CK-MB is the marker of choice for diagnosis of reinfarction after CABG because of rapid washout

CK and CK-MB

CK-MB: Shortcomings

Concomitant skeletal muscle damage can confuse the issue of diagnosis: CPR and defibrillation Cardiac and non-cardiac procedures Blunt chest trauma Cocaine abuse

CK:CK-MB Ratio

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

Myoglobin

Heme protein rapidly released from damaged muscle

Elevations can be seen as early as one hour post-infarct

Much less cardiac specific; meant to be used as a marker protein for early diagnosis in conjunction with troponins

NATRIURETIC PEPTIDES

Natriuretic Peptides

Present in two forms, atrial (ANP) and brain (BNP)

Both ANP and BNP have diuretic, natriuretic and hypotensive effects

Both inhibit the renin-angiotensin system and renal sympathetic activity

BNP is released from the cardiac ventricles in response to volume expansion and wall stress

BNP Assay

Approved by the FDA for diagnosis of cardiac causes of dysnpea

Currently measured via a rapid, bedside immunofluorescence assay taking 10 minutes

Especially useful in ruling out heart failure as a cause of dyspnea given its excellent negative predictive value

BNP

Came to market in 2000 based on data from many studies, primarily the Breathing Not Properly (BNP) study

Prospective study of 1586 patients presenting to the ER with acute dyspnea

The predictive value of BNP much superior to previous standards including radiographic, clinical exam, or Framingham Criteria

BNP

BNP has also shown utility as a prognostic marker in acute coronary syndrome

It is associated with increased risk of death at 10 months as concentration at 40 hours post-infarct increased

Also associated with increased risk for new or recurrent MI

PROGNOSTIC MARKERS AND MARKERS OF RISK STRATIFICATION

Prognostic Markers and Markers of Risk Stratification

C-reactive protein Myeloperoxidase Homocysteine Glomerular filtration rate

C-Reactive Protein

Multiple roles in cardiovascular disease have been examined Screening for cardiovascular risk in

otherwise “healthy” men and women Predictive value of CRP levels for disease

severity in pre-existing CAD Prognostic value in ACS

C-Reactive Protein

Pentameric structure consisting of five 23-kDa identical subunits

Produced primarily in hepatocytes Plasma levels can increase rapidly to

1000x baseline levels in response to acute inflammation

“Positive acute phase reactant”

C-Reactive Protein

Binds to multiple ligands, including many found in bacterial cell walls

Once ligand-bound, CRP can: Activate the classical compliment pathway Stimulate phagocytosis Bind to immunoglobulin receptors

C-Reactive Protein:Risk Factor or Risk Marker?

CRP previously known to be a marker of high risk in cardiovascular disease

More recent data may implicate CRP as an actual mediator of atherogenesis

Multiple hypotheses for the mechanism of CRP-mediated atherogenesis: Endothelial dysfunction via ↑ NO synthesis ↑LDL deposition in plaque by CRP-

stimulated macrophages

CRP and CV Risk

Elevated levels predictive of: Long-term risk of first MI Ischemic stroke All-cause mortality

Myeloperoxidase

Released by activated leukocytes at elevated levels in vulnerable plaques

Predicts cardiac risk independently of other markers of inflammation

May be useful in triage of ACS (levels elevate in the 1st two hours)

Also identifies patients at increased risk of CV event in the 6 months following a negative troponin

NEJM 349: 1595-1604

Homocysteine

Intermediary amino acid formed by the conversion of methionine to cysteine

Moderate hyperhomocysteinemia occurs in 5-7% of the population

Recognized as an independent risk factor for the development of atherosclerotic vascular disease and venous thrombosis

Can result from genetic defects, drugs, vitamin deficiencies, or smoking

Homocysteine

Homocysteine implicated directly in vascular injury including: Intimal thickening Disruption of elastic lamina Smooth muscle hypertrophy Platelet aggregation

Vascular injury induced by leukocyte recruitment, foam cell formation, and inhibition of NO synthesis

Homocysteine

Elevated levels appear to be an independent risk factor, though less important than the classic CV risk factors

Screening recommended in patients with premature CV disease (or unexplained DVT) and absence of other risk factors

Treatment includes supplementation with folate, B6 and B12

Glomerular Filtration Rate

The relationship between chronic kidney disease and cardiovascular risk is longstanding

Is this the result of multiple comorbid conditions (such as diabetes and hypertension), or is there an independent relationship?


Recent studies have sought to identify whether creatinine clearance itself is inversely related to increased cardiovascular risk, independent of comorbid conditions


Go, et al performed a cohort analysis of 1.12 million adults in California with CKD that were not yet dialysis-dependent

Their hypothesis was that GFR was an independent predictor of cardiovascular morbidity and mortality

They noted a strong independent association between the two

NEJM 351: 1296-1305


Reduced GFR has been associated with: Increased inflammatory factors Abnormal lipoprotein levels Elevated plasma homocysteine Anemia Arterial stiffness Endothelial dysfunction

cardiac biomarkers:. history 1950’s: clinical reports that transaminases released from dying...

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