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Heart Diseases and Cardiac
Markers
Prof. Dr. Serdar ÖZTEZCAN
Heart Disease
 Heart disease is a common and debilitating condition that effect
millions of patient each year; however obtaining an accurate and
timely diagnosis remain difficult
 During the 20th century, heart disease become the leading
cause of morbidity and mortality in developed nations
 Technology has had a causal role,
 allowing people to live longer
 enabling a sedentary and consumptive life style
 It is important to differentiate patients
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need further procedures, such as bypass grafting,
angioplasty or thrombolytic therapy
can safely be managed medically
Angina Pectoris
 Angina (acute myocardial ischemia) is chest pain due
to insufficient blood supply to the heart muscle that
results from coronary artery disease
 Angina can be described as a discomfort, heaviness,
pressure, aching, burning, fullness, squeezing or
painful feeling in your chest
 It can be mistaken for indigestion or heartburn
 Angina is usually felt in the chest, but may also be felt
in the shoulders, arms, neck, throat, jaw or back
Angina Pectoris
 Atypical pain is the rule rather than the exception
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Up to 22% of patients with AMI describe their
symptoms as sharp, stabbing in nature
Atypical chest pain is more common in women than
men
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Chest pain at rest but not during exercise does not
decrease the likelihood of disease in women as it does
men
Patients predisposed to sensory impairment due to
diabetes, advanced age, or altered mental status are
especially likely to present in atypical ways
Up to 1/3 of AMIs may be silent
Why?
 Because of wide spinal cord distribution of
the cardiac pain fibers, the cerebral cortex
often misinterprets the location and origin of
the pain.Therefore, myocardial ischemia is
easily confused with pain from other
structures in the chest
Acut Coronary Syndrome
 The most important disease affecting the heart is
coronary artery disease (CHD/CAD) which can lead
to an acute blockage of coronary blood flow known
as an acute coronary sendrom (ACS)
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ACS with frank necrosis of any amount of myocardium
is known as myocardial infarction (MI)
When the blockage is not complete, irrevesible muscle
damage may be avoided, but the patient will
experience severe angina at rest. This syndrome is
known as unstable angina (UA)
Myocardial Infarction
Diagnosis of ACS
 Patients who have symptoms of acute myocardial
ischemia may or may not have an ST elevation (ECG)
 Most patients who have ST-segment elevation will
ultimately develop a Q-wave acute myocardial
infarction (1)
 Patients who have ischemic discomfort without an STsegment elevation are having either
 unstable angina (2) or
 non-ST-segment elevation myocardial infarction
that usually leads to a non-Q-wave myocardial
infarction (3)
ECG
ST segment
ST elevation
Q wave
ACS
Numbers (from The U.S.)
 5 Million patients present annually to the Emergency
Department (ED) complaining of chest pain (approx. 5 % of all
annual ED visits)
 Acute Myocardial Infarction (AMI) and ACS are missed at a rate
of 2% -5%
 Mortality in mistakenly discharged patients is twice that of
admitted patients with similar risk
 20% of malpractice dollars in emergency medicine are related to
missed acute MI
 The conservative practice of hospital admission for the most
patients with suspected ACS spends billions of dollars
unnecessarily, because two-thirds of these patients turn out not
to have ACS
Risk Factors for Coronary Artery
Disease
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Male > 35
Female > 45, postmenopausal
Hypercholesterolemia
Hypertension
Family History
Diabetes
Smoking
Truncal Obesity
Sedentary Lifestyle
Response to stress

aggressive, ambitious, compulsive persons have almost twice the
risk for coronory disease as person who do not express these
characteristics
Diagnosis of AMI
 Previously, the diagnosis of AMI estabilished by the WHO
required at least two of the following criteria;
 History of chest pain
 Evolving changes on the ECG
 Elevation of serial cardiac markers
 In 2000, Joint European Society of Cardiology/American
College of Cardiology (ESC/ACC) codified the role of
biomarkers
 The quidelines recognized the reality that
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neither the clinical presentation (atypical symtoms)
nor the ECG (the initial ECG may be negative/non-diagnostic in
> 40%) had adequate sensitivity and spesifity
 Not: an ECG still remains the most specific diagnostic tool in evaluating
the ED patient with chest pain
Diagnosis of AMI
 Guidelines: Either one of the following criteria satisfies the
diagnosis for an acute, evolving or recent MI
 Typical rise and gradual fall (troponin) or more rapid rise
and fall (CK-MB) of biochemical markers with at least
one of the following;
 Ischemic symptoms
 Development of pathological Q waves on the ECG
 ECG changes indicative of ischemia (ST segment
elevation or depression)
 Coronary artery intervention (e.g. Coronary
angioplasty)
 Pathological findings of an AMI
An Ideal Marker for Myocardial Injury
Would Be
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Found in high concentrations in myocardium
Released rapidly after the onset of pain
Not be found in other tissues even in trace amounts
Have a convenient diagnostic time window
Reflect as much as possible the evaluation of
myocardial damage
 The perfect cardiac marker test, with a 100% early
sensitivity and 100% specificity does not exist

different cardiac markers are used in varying
combinations
Serum Cardiac Markers of the Past
 Aspartate Aminotransferase Activity (AST)
 Total CK Activity (CK)
 Lactate Dehydrogenase Activity (LD)
 LD1/LD2 Ratio
Current Cardiac Markers
 CK-MB
 Myoglobin
 Troponin I and T
Creatin Kinase
 Role in muscular contraction

Creatine + ATP
ADP + Phosphocreatine
 the most commonly utilized cardiac enzyme test
 Dimer composed of 2 monomers:
 M (43,000 Da)
 B (44,500 Da)
 three different iso-enzymes of CK exist
 CK BB
 CK MB
 CK MM
CK-MB
 Skeletal muscle
 CK-MM (99%)
 CK-MB (1%)
 Cardiac muscle
 80% CK-MM
 20% CK-MB
 Even if total plasma CK is eleveted (trauma, severe
exercises), presence of more than about 5% of total as
CK-MB suggests cardiac muscle damage
 CK-BB is found primarily in the brain and contributes very
little to the serum TCK level
 Most of the serum CK is derived from skeletal muscle and
the serum level reflects the total body muscle mass
CK-MB After AMI
 Increase 4-6 Hours
 Peak 10-24 Hours
 Return to Normal 48-72 Hours
 During recent years, CK-MB activity assays have been
increasingly replaced by CK-MB mass assays that measure the
protein concentration of CK-MB rather than its catalyitic activity
(a more rapid and more sensitive test)
Diagnostic performance of CK-MB in
AMI
 Admission
 2 Hr
 4 Hr
 6 Hr
Sensitivity
31
68
80
96
Specificity
94
92
91
94
 an elevated serum CK-MB is usually highly specific for an AMI,
although rare false-positives exist (mainly from skeletal muscle
release and renal failure)
Limitations of CKMB in AMI
 Elevated CKMB levels can be observed in:
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Skeletal Muscle Involvement
Duchenne Muscular Dystrophy
Polymyositis
Alcohol Myopathy
Thermal or Electrical Burn Patients
Carcinomas

Colon, Lung, Prostate, Endometrial
CK isoforms
C-terminal lysine
 CK-MB2 (tissue)
CK-MB1 (circulating)
Plasma carboxypeptidase
 normal serum CK-MB2/CK-MB1 ratio (about 1.0) is
increased in patients with an AMI (1.5 within six hours)
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Advantages:
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Early detection of AMI (1-2 hours)
Methodology Limitations
 Labor Intensive
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Requires careful interpretation of CK patterns
Results not available in a timely fashion
Myoglobin
 Definition:
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Oxygen-binding protein
MW=17,800 kd
Cytoplasmic
Heart and Skeletal Muscle Tissue
Myoglobin
 The most sensitive early marker of
myocardial injury (arguably)
 Increase 2-4 Hours
 Peak 5-9 Hours
 Return to Normal 12-24 Hours
 very low specificity with many false positive
test results

exhaustive exercise, trauma, rhabdomyolysis,
surgery, shock, renal failure
Myoglobin
 Increase Hrs
 Peak Hrs
 Return to Normal
Myoglobin
2-4
5-9
12-24
CKMB
4-6
10-24
48-72
Myoglobin
 Advantages:
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Early Indicator of AMI
Methodology – Automated
Results Available in <60 Minutes
 Disadvantages:
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Not Cardiac Specific
Troponins
 Regulatory proteins in cardiac muscle that modulate
the interaction between actin and myosin
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Troponin C (18 kd)
Troponin I (26.5 kd)
Troponin T (39 kd)
Troponins
Tissue specificity of Troponin Subunits
 Troponin C is the same in all muscle tissue
 Troponins I and T have cardiac-specific forms
cTnI and cTnT
 Circulating concentrations of cTnI and cTnT are very
low
 cTnI and cTnT remain elevated for several days
 Troponins would seem to have
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better specificity than CK-MB
the long-term sensitivity of LD-1
Troponins After AMI
Troponin I
Increase Hrs
4-6
Peak Hrs
14-24
Return to Normal (Days) 5-7
TroponinT
3-6
10-24
6-10
CKMB
4-6
10-24
2-3
Diagnostic Performance of Troponin I
and Troponin T for AMI
Admission
1 hr
2 hr
6 hr
12-24 hr
Sensitivity %
Troponin I
Troponin T
6
15
25
38
70
74
96
97
96
99
Specificity %
Troponin I Troponin T
100
97
100
96
100
93
99
93
99
93
Kinetics of cardiac markers
Use of Biochemical Markers
for Detecting Myocardial Necrosis
 ESC/ACC Recommendations
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Tn – at least 1 value > cutoff in first 24 hrs
CK-MB – 2 successive samples > cutoff or
1 sample 2x cutoff
CK, AST, LDH – not recommended
 Testing Protocol
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On admission, 6 – 9 hrs, and 12 – 24 hrs
 JACC, 2000; 36:959-69
ACS
Other markers for ACS
 Carbonic anhydrase III
 Gylcogen phosphorylase isoenzyme BB
 Heart fatty acid binding protein
 Myosin
 Ischemia modified albumin
Markers of Coronary Risk
 Hs-CRP
 Homocystein
 Fibrinogen
 D-dimer
Hs-CRP (High sensitive C-reactive protein)
 CRP is a member of the class of acute phase
reactants
 Its levels rise dramatically during
inflammatory processes occurring in the body
 Recent research suggests that patients with
elevated basal levels of CRP are at an
increased risk of diabetes, hypertension and
cardiovascular disease
Homocystein
 Homocysteine is a homologue of the
naturally-occurring amino acid cysteine
 A high level of homocysteine is a powerful
risk factor for cardiovascular disease by
promoting plaque formation
 Deficiencies of the vitamins folic acid (B9),
pyridoxine (B6), or cyanocobalamin (B12) can
lead to high homocysteine levels
Fibrinogen
 Fibrinogen is a soluble glycoprotein produced
in the liver and involved in platelet agregation
and coagulation
 It is also an acute phase protein produced in
response to inflammation
 A relationship has been estabilished between
elevated levels of fibrinogen and risk of CVD
and may serve as a marker of long-term
prognosis
D-dimer
 D-dimer is the end product of the ongoing process of
thrombus formation and dissolution that occurs at the
site of active plaques
 Because this process precedes myocardial cell
damage and release of protein contents, it can be
used for early detection
 Elevations of D-dimer have been shown to be useful
in predicting risk for future cardiac events
 D-dimer lacks specifity for cardiac damage as it is
increased in other conditions that cause thrombosis
Markers of Congestive Heart Failure
 B-type Natriuretic peptid (BNP)
 The Human Heart
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functions as a Pump
functions as an Endocrine Organ
 Cardiomyocytes secrete a family of related
peptide hormones, called natriuretic peptides
(B-Type)
 Secreted by the ventricles of the heart in
response to excessive stretching of heart
muscle cells
BNP
BNP
 Cleavage of the 108-amino acid precursor of
BNP (proBNP) produces two molecules:
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BNP, the active C-terminal, 77 to 108-amino
acid molecule
N-terminal proBNP (NT-proBNP), the inactive
1 to 76-amino acid molecule
 Studies indicate that NT-proBNP testing has
the same clinical utility as BNP
BNP / NT-proBNP
BNP
 Strong negative predictive value (>98%) allows BNP
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and proBNP to rule out CHF
Help triage possible CHF patients by determining
whether symptoms such as dyspnea, edema, and
fatigue are due to heart or lung disease
Can detect asymptomatic left ventricular dysfunction
in post-MI patients
Help optimize treatment in individuals with heart
failure
Aid in the prognosis of existing CHF patients - BNP
and proBNP levels increase proportionally with
severity of disease