CARDIAC MARKERS IN ACS AND AMI - WordPress.com...three-unit complex called TROPONIN Troponin C ++=...
Transcript of CARDIAC MARKERS IN ACS AND AMI - WordPress.com...three-unit complex called TROPONIN Troponin C ++=...
CARDIAC MARKERS
IN ACS AND AMI
G M KELLERMAN PATHOLOGY NORTH HUNTER SERVICE
TISSUE MARKERS
• Purpose – “What organ is the problem?” “How bad is it?”
• Sensitivity – what proportion of the affected patients do we find?
• Specificity - what proportion of unaffected patients do we identify
correctly?
• Need – high sensitivity (miss very few) and high specificity (not too
many false positive results)
• There are very few tests that fulfil this ideal character
• Second purpose – having identified the organ and the degree of
malfunction, does the test result predict which of the many possible
pathological processes is occurring in the specific patient?
• There are even fewer tests that fulfil this wish
• THERE IS NO MAGIC SOLUTION – YOU MUST CORRELATE
THE CLINICAL PICTURE WITH THE TEST RESULTS
• UNFORTUNATELY MANY DOCTORS BELIEVE IN MAGIC
WHY DO CARDIAC MARKERS?
• ORIGINALLY USED AS A GUIDE TO THE DIAGNOSIS
OF MODERATE TO BIG MYOCARDIAL INFARCTION
• GRADUALLY EXTENDED TO HELP WITH SMALLER
MYOCARDIAL INFARCTS AND DELAYED DIAGNOSIS
• TECHNOLOGY TO MEASURE TROPONINS ENABLED
MUCH SMALLER INFARCTS TO BE IDENTIFIED
• IMPROVING TECHNOLOGY ENABLES RECOGNITION
OF OTHER CAUSES OF TROPONIN LIBERATION
SMALL TROPONIN INCREASES NOW NEED MUCH
THOUGHT AS THEY INDICATE MYOCARDIAL
DAMAGE, BUT DO NOT IDENTIFY CAUSE
OLD MARKERS
• 1950’s – aspartate transaminase (AST). Also found in liver and
skeletal muscle so not specific, and sensitive only for big infarcts
• 1960’s – lactate dehydrogenase (LD). Found in all tissues so very
non specific.
• 1960’s – creatine kinase (CK). Far more in skeletal muscle, small
amounts in other tissues, so not specific.
• 1970’s – creatine kinase cardiac isoenzyme (CK-MB). More specific
as only trace amounts in skeletal muscle and other tissues but
sensitivity limited for small lesions as tests not reliable
• 1980’s – troponins, constituents of the muscle fibre identified and
became measurable. 2 of them have different detailed amino acid
composition in cardiac and skeletal muscle so the condition of tissue
specificity is satisfied.
TROPONINS (1)
All muscle moves by having myosin slide over actin filaments
using the energy of ATP to drive the movement
This has to be controlled to happen only when needed
The control is exerted by allowing Ca++ ions to access the appropriate site on the enzymatic part of the myosin when contraction occurs
The Ca++ binds to a receptor protein (calmodulin) which is part of a three-unit complex called TROPONIN
Troponin C = calmodulin, which binds the Ca++
Troponin I inhibits the myosin ATPase until Ca++ binds to
the Troponin C component, which changes protein interactions
and permits contraction to occur
Troponin T anchors the complex to Tropomyosin
Tropomyosin is a long thin structural protein linked to the actin filaments
MUSCLE CONTRACTION
• A C T I N
• M Y O S I N
• ATPASE
• TROPONIN I
• C Ca++
• T
• ……...T R O P O M Y O S I N………
TROPONINS (2)
The especial value of troponins is that the genetic coding for both
Troponin T and Troponin I is different in heart from other tissues
resulting in differences in their polypeptide chains
It has therefore been possible to manufacture antibodies that are completely specific for cardiac Troponins T or I, thus making
specific immunologically based tests available
The additional advantage is that there is a extremely small
concentration of either of these troponins in normal plasma so that
any significant elevation of cardiac troponin T or I is pathological
Recent research with high sensitivity methods using improved antibodies in the assay shows that there is a minute but measurable
amount of Troponin in plasma of normal people (<16 ng/L in females, <26 ng/L in males)
TROPONINS (3)
The maximum troponin level that I have seen in an untreated patient
who has survived an AMI is of the order of 400,000 ng/L
whereas the normal level is not > 16 ng/L (F) or 26 ng/L (M)
These values are probably very similar for both Troponin T and I
So tiny bits of cardiac myocyte necrosis are detectable (<0.1 g)
In our laboratory we measure Troponin I because Troponin T
requires a special machine for which we have no room!
Quality control is better for Troponin T because Troponin I exists in
several different molecular forms in plasma and breakdown products
occur, so that different brands of reagents give different results
Therefore you must consult the laboratory reference range
However, Troponin I results are probably at least 99% as reliable as
Troponin T in the clinical arena
TIME RELATIONS (1) When and for how long is each test positive?
Cardiac muscle stops contracting about 1 minute after blood flow stops, but it takes about 30 minutes of fatal ischaemia for the muscle to
start dying. This is followed by release of components
Smaller proteins are released earlier than larger ones
It is important to realise that no biochemical test becomes positive under 2-3 hours after onset of severe enough vascular blockage
Revascularisation strategies – thrombolysis or angioplasty – must be started earlier than that to get maximal effect, although some
benefits are found up to about 6 hours post-infarction
So need to rely on clinical features and ECG for early diagnosis
The cardiologist’s motto:
TIME IS MUSCLE (Compare the neurologist treating stroke by thrombolysis – TIME IS BRAIN)
0 1 2 3 4 5 6 7 10 0
5
10
15
20
Multiples of upper
reference limit
Days after onset of AMI
Source: A. H. Wu,
Journal of Clinical Immunoassay (1994) 17, 45-48.
Kinetics of AMI markers
Myoglobin
LD
Troponin T
Troponin I
CKMB
TIME RELATIONS (3)
Note that AST, CK, CK-MB, and both Troponins all
rise at more or less the same time, starting at
about 3-6 hours and peaking at 24-36 hours
Recent work suggests that with the supersensitive new methods, Troponin rise may be reliably detectable in 3
hours if the infarct is of moderate or large extent
After that, CK-MB falls a little faster than CK total, but troponins fall far more slowly, taking up to 2 weeks to
return to baseline, as does H-type LD
So some days after an AMI there is still evidence available to show that it happened in Troponin levels – LD is now
obsolete
IMPORTANCE OF SMALL INFARCTS
Research has shown that the occurrence of further cardiac episodes during the following year or more is much more frequent if there has
been ANY rise in troponin than if there has been no increase
The arbitrary time of 8 hours post onset was the time interval allowed to elapse before the test in these cases, which used to be referred to
as “Unstable Angina Pectoris” or UAP, but financial pressures in ED departments exert pressure to make an earlier decision
This is the basis of risk stratification and of decisions on the intensity of therapy to be instituted in patients in whom an AMI is suspected
(and also valuable in the differential diagnosis of chest pain)
In principle (but doctor’s judgment can override this)
No rise = low risk, can send home on aspirin, return for follow up tests (e.g. stress test, echocardiography, nuclear imaging) as outpatient
Any rise = high risk, admit for at least anticoagulation
WHY DO AMI PATIENTS DIE?
• Sudden death is usually due to cardiac arrest – possibly ventricular asystole
following AV node ischaemia, more often ventricular fibrillation due to
disturbed conduction pathways.
• With large parts of ventricles not contracting, cardiac output falls and the
body is inadequately perfused. If severe, this can lead to death in
“cardiogenic shock” with lactic acidosis, often within hours.
• Less severe output failure is followed by severe sympathetic nerve activity
and vasoconstriction, especially in kidneys and splanchnic region, leading to
necrosis of kidney and/or liver, which may not recover or which may lead to
long and slow convalescence.
• Large dead areas and/or severe remodelling changes following ongoing
inadequate perfusion may lead to ongoing congestive cardiac failure with
inadequate body perfusion, oedema etc and gradual decline and death.
• Finally, where there has been one episode resulting from atherosclerosis,
there can always be a new one – and any clot can always extend.
TROPONINS (4) - SUMMARY
• CAUSES OF TROPONIN RISE • 1. Classical ST elevation MI – much necrosis. Big rise
• 2. Non ST elevation MI – various sizes, with or without ECG changes
• 3. Acute coronary syndrome, no other demonstrable changes, but it has been shown that even a small Troponin rise means a worse prognosis
• 4. Non ischaemic disease of heart – acute failure with large pulmonary embolus viral or other myocarditis
myopathy, e.g. catecholamine or cocaine
renal failure – probably from hypertension
5. Reasonably severe disease elsewhere – e.g. sepsis
6. There is increasing evidence that silent, gradual myocyte death in patients with conditions that lead to reduced myocardial reserve, without any acute symptoms at any time, may also give rise to small irregular increases in Troponin. We find too many such small rises in asymptomatic patients to be explained by the other listed causes. There has recently been some supporting evidence from Sweden, that patients whose “normal healthy” troponin levels are in the upper part of the “normal range” have an increased risk over a 10-year period of follow up
7. Remember that after thrombolysis the washout of Troponin and other cardiac enzymes is rapid and leads to higher values in plasma, often of shorter duration.
8
SUPERSENSITIVE TROPONIN
• IN RECENT YEARS MORE AND MORE SENSITIVE TROPONIN ASSAYS HAVE BEEN DEVELOPED SO THAT WE CAN NOW DETECT TRACES OF TROPONINS IN NORMAL PEOPLE, AND ESSENTIALLY ALL LABORATORIES ARE NOW ADOPTING THESE METHODS
• BY CUSTOM, CURRENT “ABNORMAL” VALUE STARTS AT THE UPPER 99TH PERCENTILE OF NORMAL, ABOUT 16 NG/L (F), 26 NG/L (M)
• ACUTE CORONARY SYNDROME STARTS AT TROPONIN > THIS LEVEL, + APPROPRIATE SYMPTOMS, ± ECG CHANGE, + INCREASE IN TROPONIN OVER NEXT 6-8 HOURS OF > 50%
• THERE IS STILL ARGUMENT ABOUT CUTOFFS!
• THERE IS ALSO A LOT OF ANXIETY IN ED’S AND CARDIOLOGY UNITS ABOUT THE NEED TO ACCEPT THAT SMALL TROPONIN RISES DO NOT EQUATE TO THE ACUTE CORONARY SYNDROME, AND THAT THOUGHT IS ESSENTIAL
BNP (brain natriuretic peptide)
• There is a group of peptides which stimulate the kidney to excrete more Na and
water, to reduce intravascular overload
• ANP – atrial natriuretic peptide – is secreted mainly by atria, when stretched by
excessive blood volume within them
• BNP – brain natriuretic peptide - was first found in pig brain, but it is now known that
there is a lot in the ventricular wall, released when the ventricular muscle is
overstretched (e.g. with increased end-diastolic volume in congestive cardiac failure)
• CNP – no ideas on its real role yet
• BNP is synthesised as a precursor protein, pro-BNP, which loses its N-terminal part
(NTpro-BNP) to release BNP. The inactive other fragment NTpro-BNP is also
released into the circulation and can be measured
• There is no real agreement yet as to whether BNP or NTpro-BNP is the better marker
for disturbance of ventricular function, probably BNP especially in old people
• Our laboratory currently measures BNP, but we must batch it and do it 3 times a
week so it is not available on an urgency basis. This may change if the number of
requests increases
BNP
• In health the plasma level is <100 ng/L
• In severe congestive cardiac failure, levels of several hundred are
found, and >800 ng/L is virtually diagnostic
• Values between 100 ng/L and 800 ng/L must be interpreted in the
clinical scenario, the higher the value the more likely that the
ventricles are in failure
VALUE OF TEST
• To sort out congestive cardiac failure from other causes of dyspnoea
in patients with multiple pathologies especially lung problems
• To monitor the outcome of therapy for congestive failure – if it
decreases significantly and steadily it suggests that the condition is
responding to the treatment
• To date it is not a reimbursable test and is expensive to the patient
C-REACTIVE PROTEIN (CRP)
• A marker of inflammatory processes
• An acute phase reactant whose concentration in plasma is usually somewhere between 0.1 to 10 mg/L (median level about 1.5 mg/L)
• Concentration increases rapidly and manyfold with inflammation (up to > 400 mg/L) depending on intensity and severity
• WHEN ALL OTHER CAUSES OF INFLAMMATION CAN BE EXCLUDED, the risk of cardiac events over the next several years increases with increased baseline CRP levels in the range of about 0.1-4 mg/L
• No value in acute episodes of suspected AMI
• It appears to be an independent risk factor for cardiac disease, additional to Cholesterol and other known risk factors
MY FAVORITE STRESS TEST
• A CLIMB OF 300 METRES IN HEIGHT IN
3 KILOMETRES OF WALKING AT A
BAROMETRIC PRESSURE OF 580-600
mm Hg
• PaO2 approx 60 mm Hg
• CRITERION FOR NORMALITY – NO
ANGINA AND ABILITY TO USE CAMERA