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Evaluation of Cardiac Injury and
Function
Introduction
• CHD,
– The most important disease affecting the heart is
coronary heart disease
• ACS,
– CHD, can lead to an acute blockage of coronary
blood flow known as an acute coronary syndrome
• MI,
– ACS with frank necrosis of any amount of
myocardium is known as myocardial infarction
Background
• Ischemia
– the lack of an adequate blood supply
• Atherosclerosis
– a chronic process involving damage to
endothelium and the build-up of vessel occluding
lesions called plaque.
• angina pectoris (exertional angina)
– Once the diameter of a coronary artery is reduced
to less than 10-20% of its original size
Background
• Myocardial infarction (MI)
– Complete blockage of blood flow
• Irreversible ischemic damage
• Unstable angina (UA)
– When the blockage is not complete
– irreversible muscle damage may be avoided
– experience severe angina, even at rest
Diagnosis of Cardiac diseases
(Outline)
• Cardiac diseases discussed in this session
– Coronary heart disease (CHD)
– Heart failure (HF)
• Diagnosis of Cardiac diseases
– Clinical (non laboratory) examination
• e.g, Clinical history, ECG, angiography, echocardiography
– Biochemical markers
• Markers of Myocardial Damage
• Risk factors associated with the development and
progression of CHD.
ECG;ElectroCardioGraphy
Heart Disease Statistics for the US
Markers of Myocardial Damage
• Cardiac enzymes
– Transaminases (SGOT,SGPT)
– Lactate dehydrogenase (LD)
– Creatine kinase (CK)
• Improved cardiac specificity
– with separation of isoenzymes.
• LD1 is relatively abundant in cardiac muscle
– Flipped LD, where the normal finding LD2> LD1] is
reversed.
• In normal heart, 15-20% of the CK is CK-MB
• Changes in LD observable for a much longer
time than changes in CK.
• The isoenzyme analyses were relatively
lengthy & tedious
– Could only be performed about once per day
• CK-MB Mass Assay
– Can be performed rapidly
Kinetics of several cardiac markers following an MI
Cardiac Troponin
• The most important laboratory test for cardiac
diagnosis.
• TnT (tropomyosin-binding subunit, 37 kDa)
• Tnl (inhibitory subunit, 24 kDa),
• TnC (calcium-binding subunit, 18 kDa).
Cardiac Troponin
• Tnl has a cardiospecific form (cTnl)
• TnT also has distinct forms in myocardium
(cTnT)
– Also, Fetal skeletal muscle and diseased skeletal
muscle.
• post-translational modifications cause detectable
differences
Cardiac Troponin
• Bound form
– released slowly over the course of 1-2 weeks following
myocardial infarction.
• Free form
– time frame similar to that of CK-MB, with cTn reaching
a peak at about 24 h following MI
• cTnT and cTnl are nearly absent from normal
serum
• Small elevations
– pericarditis, myocarditis, pulmonary embolism, renal
failure, sepsis, and other critical illness
• The high sensitivity and specificity of cTn
• Patients with ischemic symptoms who also
have elevations in cTn receive greater benefit
from therapies with various antiplatelet and
anti thrombotic agents
Myoglobin
• Lacking cardiac specificity,
• more rapidly than other proteins
• Within 2-3 h following onset of MI, earlier
than with troponin or other markers
• myoglobin peaks about 6 h after MI and
returns to baseline after 24
• half-life,approximately 4 hours, but is longer if
renal function is impaired.
Myoglobin
• Muscle mass and muscle activity
– Higher in men
• increases with increasing age
• Day-to-day variation is about 10-15%
• offers fairly high clinical specificity (> 95%) when
patients with renal failure or suspected injury to
skeletal muscle are excluded.
• Sensitivity can be enhanced
– δ Mb
Other Markers
• Carbonic Anhydrase III(CA III)
– present in skeletal but not cardiac muscle,
• Negative cardiac marker.
• Creatine Kinase Isoforms
– a high ratio of MB2/MB1 suggests that a recent
release of enzyme has occurred.
– in the first 3-4 hours following symptom onset,
improved sensitivity for MI detection
Limitations
• cTn
– is a highly heterogeneous analyte.
– Reference ranges and decision points have been a
matter of some confusion
Diagnosis of ACS
• Biochemical markers play a secondary role in
the initial management of patients with
suspected ACS.
• The earliest decision-making, which should
ideally take place within 10 min of the
patient's arrival in the ED, is based on history,
physical examination, and 12-lead ECG
• Likely to be negative at this early time.
ACS: acute coronary syndrome. ED: emergency department
• Choice of markers and time points
– cTn (either I or T) is the preferred marker for
definitive diagnosis
• Also for early diagnosis,
– Myoglobin but possibly CK isoforms, at the 0 and
1- to 4-h time points.
• noninvasive indicator that reperfusion has
occurred,
– Myoglobin was found to perform better than CKMB or cTn
• early reinfarction
– CK-MB appears to be superior to cTn because of
its more rapid decline following MI
– myoglobin is also useful.
• Diagnosis of MI following surgical procedures
– cTn is clearly the marker of choice in this situation,
Markers of Coronary Risk
• Laboratory tests
– Serum cholesterol
• LDL
• HDL, a negative risk factor
• Triglyceride
• C-Reactive Protein (CRP)
– In acute illness, cytokines, chiefly interleukin-6,
stimulate hepatic production of CRP
Clinical (non laboratory) risk factors for CHD
Markers of Coronary Risk
• the usefulness of the hsCRP test in individual
patients has been controversial.
– the variations in quantitative risk estimates,
– the unclear role of CRP in pathogenesis of vascular
disease,
– the lack of specific treatment for high CRP,
Markers of Coronary Risk
• epidemiology studies
– confirm a correlation between moderate Hey levels and
CHD.
• Homocysteine (Hey)
– total homocysteine (tHcy):
• free sulfhydryl group,
• as a disulfide (homocystine),
• as a mixed disulfide,
– linked to a plasma protein via one of its cysteine residues.
• Excessive levels of circulating Hcy
– Enzyme defect
• Cystathionine-β-synthase
Chemical structure of homocysteine and related compounds.
Markers of Coronary Risk
• Clinical manifestations
– thromboembolic disease, including CHD
• The basis of the damaging effects of Hcy is
uncertain.
– Oxidant stress and inhibition of transmethylation
reactions are likely
• Measurment
– Chromatographic
– Enzymatic
Clinical algorithm for treating patients
presenting to an emergency department with symptoms suggesting ACS.
Markers of Congestive Heart Failure
• Cardiac Natriuretic Peptides
– brain natriuretic peptide (BNP) produced mainly in
the cardiac ventricle
– Secretion enhanced by ventricular wall stretch and
volume overload, as occurs in HF
– Circulating half-life is approximately 22 minutes.
– (N-terminal fragment)N-BNP is considerably
longer (60-120 min)
Markers of Congestive Heart Failure
• Applications of BNP testing
– The best-established application
• For diagnosing acutely ill patients presenting to emergency
service with shortness of breath.
• At a decision point of 100 pg/mL, the BNP test
had the following characteristics for diagnosis of
HF:
–
–
–
–
Sensitivity 90%,
Specificity 76%,
Positive predictive value 79%,
Negative predictive value 89%
Markers of Congestive Heart Failure
• Other applications of BNP testing
– Monitoring the course and treatment of patients
with HF
– Risk stratification of patients with ACS
– Monitoring disease severity in patients with
stable CHD
– Screening for ventricular dysfunction
– Testing for drug cardiotoxicity
Markers of Congestive Heart Failure
• The major limitation of BNP
– Decision point
• a wide range of values is observed in patients with and
without HF
– Patients with symptomatic HF especially when it is
chronic and stable, can have 'normal' levels
• So,
– the most appropriate use of the BNP test is as an
adjunctive test to rule out HF in the acute setting.
Markers of Congestive Heart Failure
• BNP has natriuretic, vasodilatory, and other
effects that are ameliorative for the syndrome,
and is in fact available as the drug nesiritide
(Natrecor) for treatment of HF