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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
History: CK and Isoenzymes
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
History: CK and Isoenzymes
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
History: CK and Isoenzymes
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
Markers of Cardiac Necrosis
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
Markers of Cardiac Necrosis
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?
Glomerular Filtration Rate
Recent studies have sought to identify whether creatinine clearance itself is inversely related to increased cardiovascular risk, independent of comorbid conditions
Glomerular Filtration Rate
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
Glomerular Filtration Rate
Reduced GFR has been associated with: Increased inflammatory factors Abnormal lipoprotein levels Elevated plasma homocysteine Anemia Arterial stiffness Endothelial dysfunction