MARKERS IN CLINICAL DIAGNOSIS AND MONITORING OF CARDIAC DISEASES Flashcards
(32 cards)
Diagnosis of Acute Cardiac Ischaemia and Myocardial Ischaemia has for decades
been based on at least two of the following criteria;
What was the first discovered bio marker?
- History of Chest pain
- ECG changes (Typically ST segment elevation)
- A rise in Biochemical Markers.
The role of Biochemical Markers commenced in the 1950s with the use of AST and
by the 1970s the role of the following biochemical markers was well established; - AST
- CK and CK-MB
- LD-1 (Heart Specific)
- Myoglobin
What are Biomarker and cardiac bio markers?
Biomarkers: cellular, biochemical or molecular alterations that are evaluated as an indicator of a normal biologic process, a pathologic process or a pharmacologic response to a therapeutic intervention.
Cardiac biomarkers: Are protein molecules released into the blood-stream from damaged heart muscles.
They have characteristic rise and fall patterns.
What are the characteristics of anideal cardiac markers of MI?
- It should be abundant in myocytes and low in blood
- It should be released rapidly into the blood at the time of myocardial injury
- There should be a direct relationship between the plasma level of the cardiac marker and the extent of myocardial injury
- The marker should persist in the blood for a sufficient length of time to allow a high rate of diagnosis
- Measurement of the marker should be easy, inexpensive, and rapid.
- Absolutely heart-specific and sensitive
- Able to differentiate irreversible damage from reversible.
- Able to detect re-occlusion and reinfarction.
- Able to monitor reperfusion therapy.
FUNCTIONS OF CARDIAC BIOMARKERS
For risk stratification
Detection of reinfaction
Diagnosis
Prognosis
Monitoring of response to therapy
What is the DEFINITION OF MYOCARDIAL INFARCTION (MI)?
Which specific bio markers represent the cornerstone for the definition of and detection of MI?
What is the rationale for serial sampling of cardiac biomarkers in the diagnosis of myocardial infarction?
MI was defined by a combination of at least two of three characteristics: typical symptoms such as chest discomfort, a rise in biochemical marker levels, and a typical ECG pattern involving the Q waves
The European society of cardiology(ESC) and American college of Cardiology (ACC) 1999 consensus conference decided that cTnI and cTnT represent the cornerstone for the definition of and detection of MI.
The diagnosis of an MI with cardiac markers should not be made on the basis of a single isolated specimen, particularly if the result is negative
ESC/ACC consensus report recommends serial sampling for cardiac markers upon presentation, at 6-9hours,and again at 12-24 hours if the earlier samples were negative and the clinical index of suspicion is high.
What is the CLASSIFICATION OF CARDIAC BIOMARKERS?
- Biomarkers of myocardial injury – Necrosis and Ischemia
- Biomarkers of haemodynamic stress
- Inflammatory and prognostic Biomarkers
CLASSIFICATION OF CARDIAC BIOMARKERS
Biomarkers of myocardial injury – Necrosis and Ischemia
Biomarkers of haemodynamic stress
Inflammatory and prognostic Biomarkers
What are the Markers of myocardial necrosis and myocardial ischemia?
Markers of myocardial necrosis
• Creatine kinase – MB
• Myoglobin
• Cardiac troponins E.T.C.
Markers of myocardial ischemia
* Ischemia Modified Albumin (IMA)
* Heart-type fatty acid binding protein (H-FABP)
Discuss ASPARTATE TRANSAMINASE AST
First cardiac marker.
Widely distributed in many tissues
Highest concentrations are found in cardiac tissue, liver and skeletal muscle.
Clinical utility in hepatocellular disorders and skeletal involvement.
No more useful in diagnosis of AMI
Begins to rise within 6-8 hr.
Makes a peak at 24 hr.
Generally returns to normal within 5 days.
LACTATE DEHYDROGENASE (LDH)
A cytoplasmic enzyme found in skeletal, muscle, liver, heart, kidney and red blood cells.
Hence, low specificity.
5 izoenzymes, composed of 4 subunit peptides of 2 distinct types:M (muscle ), H (heart).
A more sensitive marker of myocardial infarction.
Remains elevated till two weeks post-MI
Increased in cancer and anaemia
MYOGLOBIN
Myoglobin is an early marker .
A rise in myoglobin is detectable in blood as early as 1 to 2 hours after the onset of symptoms and is highly sensitive for MI diagnosis and is effective to rule out MI in the 2 to 6 hour time frame after onset of symptoms
Myoglobin is not cardiac specific, so patients with renal failure , trauma or diseases involving skeletal muscle can have abnormal concentrations in the absence of MI
Also elevated in myoglobin induced renal failure
CREATININE KINASE (CK)/ CK-MB
Creatine kinase (CK/CPK) is an enzyme expressed in a number of tissues.
Function: it catalyses the conversion of creatine to phosphocreatine degrading ATP to ADP
If total CK must be used, it should be combined with more sensitive biomarkers such as the cardiac troponins or CK-MB for accurate clinical diagnosis of MI
•Creatine kinase consists of two protein subunits M and B, which combine to form three isoforms, CK-BB(CK-1),CK-MB (CK-2)and CK-MM(CK-3)
•Usually, 4-6 hours are required after the onset of chest pain before CK-MB becomes elevated in the serum of patients with MI
•It has high diagnostic specificity by 8-12 hours after presentation (peaks at about 12 hours).
•Returns to baseline at 24-36 hours.
•The time course represents the classic temporal sequence of CK-MB changes and is often helpful in distinguishing uncomplicated MI from extension or reinfarction
•CK MB FRACTION- CKMB/ TCK > 2.5 Suggestive of MI
CREATINE KINASE(CK) AND CK ISOENZYMES IN CONDITIONS OTHER THAN MI
•Duchenne muscular dystrophy
•polymyositis
•Rhabdomyolysis
•These increases are in proportion to the degree of muscle fiber regeneration. Skeletal muscle contains CK-MB.
•The actual elevations of total CK observed in serum in skeletal muscle abnormalities are frequently dramatically higher than those observed in MI.
•Cardiac injury for reason other than MI
•Defibrillation
•Blunt chest trauma
•Cocaine abuse
CARDIAC TROPONINS
• Troponin is a complex of three regulatory proteins that is integral to non-smooth muscle contraction in skeletal as well as cardiac muscle
Troponin is attached to the tropomyosin sitting in the groove between actin filaments in muscle tissue
Troponin has three subunits, TnC, TnT, and TnI
•Troponin-C has calcium binding ability and has no diagnostic value
•Troponin-T binds the troponin tropomyosin complex,
•Troponin-I is an inhibitory protein
• Less than 5% in cytosol
•Troponin levels begin to rise 4-6 hours after onset of myocardial injury
•Elevations in Troponin-I and Troponin-T can persist for up to 10 days after MI
•Remember, CK-MB returns to baseline by 48 hours
•Thus far, studies have failed to find a source of Troponin-I outside the heart, but have found some Troponin-T in skeletal muscle
•The release kinetics of both cTnT and cTnI are similar to those of CK-MB after MI
CONDITIONS ASSOCIATED WITH CARDIAC TROPONIN ELEVATION
• Arrhythmias
•Congestive heart failure
•Coronary vasospasm
•Systemic and pulmonary hypertension
•Myocarditis and Pericarditis
•Pulmonary embolism
•Renal failure
•Sepsis/septic shock
•Hypothyroidism
CARDIAC TROPONIN I (CTNI)
•cTnI has a molecular weight of 27kDa.
•cTnI is similar to cTnT in most applications and in the advantage over CK-MB
•cTnI remains elevated 3-7 days after acute MI
•cTnI and CK-MB have the comparable diagnostic sensitivity for MI during the initial 48-72 hours after MI with improved cTnI sensitivities 72 to 96 hours after MI
•cTnI unlike CK-MB and total CK is not elevated in extreme skeletal muscle injury and disorders.
CARDIAC TROPONIN T (CTNT)
• Molecular weight of cTnT is 37KDa
•Once MI has occurred, cTnT increases in serum after 4 hours, achieving an initial peak or plateau at 1 to 6 days
•Two cTnT peaks are observed in some MI patients because cTnT has both cytosolic and structurally bound cTnT pools
•The first peak results from release of the cytosolic pool, the second peak results from the slower release of the bound fraction later in the myocardial necrosis process.
•Using WHO definition of MI, clinical sensitivity of cTnT is similar to that of CK-MB during the first 48hours after the onset of chest pain.
•cTnT is not an early marker of MI showing a clinical sensitivity of 50% to 65% from 0 to 6 hours after chest pain onset
•cTnT like CK-MB is insufficient for effective early diagnosis
•cTnT extended lifetime in serum may provide important diagnostic information about an MI after CK-MB has achieved normal levels
BIOMARKERS OF MYOCARDIAL ISCHAEMIA
• Ischemia-modified albumin
• Glycogen phosphorylase enzyme BB (GPBB)
• Free fatty acids
• Fatty acid binding proteins
• Phospholipase enzymes (A–D)
• Lipoprotein associated phospholipase A2
ISCHEMIA MODIFIED ALBUMIN (IMA)
A novel marker of ischemia, is produced when circulating serum albumin contacts ischemic heart tissues
Mechanism- due to structural change in the amino terminal end of albumin
IMA levels rise within 6 hours
remain elevated for 12 hours
Not specific elevated in stroke, some neoplasms, hepatic cirrhosis, end-stage renal disease)
IMA is levels raised in non- cardiac ischemia
Modification to n- terminal end may also be induced by extracellular hypoxia, acidosis etc,
Multimarker approach using the combination of ECG, the cTnI, and the IMA levels achieve a sensitivity of 95% for ACS
BIOMARKERS OF HEMODYNAMIC STRESS
Function of BIOMARKERS OF HEMODYNAMIC STRESS
ANP and BNP concentrations increase in response to volume expansion and pressure overload of the heart
ANP and BNP have been shown to be physiological antagonists of the effects of:
Angiotensin II on vascular tone
Aldosterone secretion
Renal-tubule sodium reabsorption
Vascular-cell growth
The natriuretic peptides (NP) are a group of structurally similar but genetically distinct peptides.
They are identified as regulatory diuretic-natriuretic substances responsible for salt and water homeostasis and blood pressure
ANP : -atrial natriuretic peptide (28 a.a.)- is released primarily in response to atrial wall stretching and intravascular volume expansion.
BNP : brain natriuretic peptide (32 a.a.)- secreted by the ventricles
CNP : C-type natriuretic peptide (22 a.a)- found predominantly in the brain and also synthesized by vascular endothelial cells
Discuss BNP
Originally isolated from porcine brain but now discovered in human heart
Circulating levels of BNP are raised in patients with cardiovascular or renal disease
More important than ANP in heart failure
Greatest proportion of circulating BNP is thought to come from the ventricles
What are cardiac and non-cardiac Causes For Elevated Natriuretic Peptide Levels
Cardiac:
Heart failure, including RV syndromes
Acute coronary syndrome
Heart muscle disease, including LVH
Valvular heart disease
Pericardial disease
Atrial fibrillation
Myocarditis
Cardiac surgery
Cardioversion
Restrictive cardiomyopathy
Non Cardiac:
Advancing age
Anemia
Renal failure
Pulmonary causes: obstructive sleep apnea, severe pneumonia, pulmonary hypertension
Critical illness
Bacterial sepsis
Severe burns
Toxic-metabolic insults, including cancer chemotherapy and envenomation
