Cardiovascular Disease Biomarkers PDF

CARDIOVASCULAR DISEASE BIOMARKERS 8/15/23 1  Cardiovascular disease (or CVD) includes heart and blood vessel diseases — diseases that affect the circulatory system. These include: Coronary heart disease (heart attack) Cerebrovascula...

CARDIOVASCULAR DISEASE BIOMARKERS 8/15/23 1  Cardiovascular disease (or CVD) includes heart and blood vessel diseases — diseases that affect the circulatory system. These include: Coronary heart disease (heart attack) Cerebrovascular disease (stroke) High blood pressure Congestive heart failure Congenital cardiovascular defects Peripheral vascular disease 8/15/23 2  CARDIAC BIOMARKERS A cardiac biomarker is defined as a clinical laboratory test useful for detecting acute myocardial infarction (AMI) or minor myocardial injury. Cardiac markers are most useful when patients have nondiagnostic ECG tracings. 8/15/23 3  EVOLVING DEFINITIONS OF MI The criteria for the definition of MI have evolved over the years, in part due to the improvement in detection technologies, in particular biomarkers. 8/15/23 4  EVOLVING DEFINITIONS OF MI 8/15/23 5  (old) Diagnosis of AMI Based on 2 out of 3 of WHO criteria (1979) Symptoms of ischemia (prolonged chest pain) ECG changes Cardiac biomarker concentrations (enzymes) 8/15/23 6  DEFINITION OF AMI Based on the American College of Cardiology and European Society of Cardiology, the criteria for AMI to be predicated on documenting an increase in cardiac troponin or CK-MB mass (total CK, AST, and LD not recommended) in the context of myocardial ischemia. 8/15/23 7  ESC/ACC redefinition (2018) Typical rise and gradual fall (troponin) or more rapid rise and fall of biochemical markers of myocardial necrosis with at least one of the following: ischemic symptoms development of pathologic Q waves ECG changes indicative of ischemia Identification of a coronary thrombus by angiography, including intracoronary imaging or by autopsy. 8/15/23 8  Stages of Atherosclerosis 8/15/23 9  Patients with AMI can be categorized into four groups: 1. Patients who present early to the emergency department within 0 to 4 hours after the onset of chest pain, without diagnostic ECG evidence of AMI. For laboratory test to be clinically useful, markers of MI must be released rapidly from the heart into the circulation to provide sensitive and specific diagnostic information. 8/15/23 10  Further the analytical assays must be rapid and sensitive enough to distinguish small changes within the reference interval in serum. 2. The second group of patients are those presenting 4 to 48 hours after the onset of chest pain, without evidence of AMI on ECG. In this group of patients, the diagnosis of AMI requires serial monitoring of both cardiac markers and ECG changes. 8/15/23 11 3 In the third group are patients who present more than 48 hours after the onset chest pain with nonspecific ECG changes. The ideal marker of myocardial injury in this group would persist in the circulation for several days to provide a late diagnostic time window. The shortfall of such a marker might be inability to distinguish recurrent injury from old injury. 8/15/23 12 4 The fourth group of patients are those who present to the emergency department at any time after the onset of chest pain with clear ECG evidence of AMI. In this group, detection with serum markers of myocardial injury is not necessary. Numerous biomarkers have been monitored to assess myocardial injury. 8/15/23 13  Ideal Marker to Detect AMI High concentration in myocardium Absence from non-myocardial tissues High sen & spec in circulation Rapid release into blood following myocardial injury Remains in blood several days to allow detection Blood levels correlate with extent of myocardial injury & prognosis Rapid, simple & automated commercial assays available 8/15/23 14  Numerous biomarkers have been monitored to assess myocardial injury. Most are myocardial proteins and differ in their: location within myocyte release kinetics after damage clearance from circulation 8/15/23 15  Troponins Regulatory proteins in striated muscle Responsible for calcium-modulated interaction Exist in a number of isoforms Cardiac specific forms immunologically separable Troponin T (TpnT) Troponin I (TpnI) 8/15/23 16  This complex regulates the interaction of actin and myosin filaments during muscular contraction.. Both troponin T and I have amino acid sequences that differ between adult skeletal and cardiac muscle. Troponin C has no potential as a cardiac specific marker because its amino acid sequence is identical in skeletal and cardiac muscle. 8/15/23 17  Troponins T and I contrasted Troponin T Troponin I Molecular weight 37 kDa 22.5 kDa Nature of protein Structural Catalytic Kinetics of Biphasic Only a single release peak Duration of Upto 14 days 5-7days elevation 8/15/23 18  Negligible concentrations of TnI are present in the plasma of healthy adults. Therefore, reference ranges are very low and slight elevations usually indicate myocardial damage. Following myocardial damage, TnI levels are elevated within 3 to 12 hours and reach concentrations that are 5 to 50 fold higher than the upper limit of normal. TnI appears in the blood at about the same time as CK-MB. 8/15/23 19  Troponin Release Kinetics Pattern of release in MI is BIPHASIC. Detectable in blood 3-12 h, similar to CKMB Peaks 12-38 h Remains elevated for 5-10 days 8/15/23 20  TnI remains elevated longer than CK-MB due to ongoing release of the myofibril bound fraction. For example, TnI is detectable for 5 to 9 days, compared to 24 to 72 hours for CK-MB. Because it remains elevated for such a long time, TnI is beneficial in detecting infarctions in late presenting patients. The use of TnI eliminates the need for AST, LD or LD isoenzymes. 8/15/23 21  TIMING OF RELEASE OF BIOMARKERS 8/15/23 22  CKMB & Tpn I profiles in AMI 8/15/23 23  Elevated TnI is found in 30 to 40% of patients with unstable angina. It appears to be a better risk indicator in angina than CK-MB. Patients with unstable angina who have normal CK- MB and increased TnI have a 30% likelihood of ischemic complications such as acute MI or cardiac death. Serial monitoring of TnI over 8 to 12 hours is becoming common practice in many well-developed institutions. 8/15/23 24  To rule out an acute myocardial infarction, many centers are ordering CK-MB and TnI on admission and again at either 8 or 12 hours. Two normal TnI levels indicate a dischargeable patient. Elevated TnI and normal CK-MB suggest either unstable angina or late admission after an acute infarction. Normal TnI and elevated CK-MB usually indicate skeletal muscle injury. 8/15/23 25  An increase in plasma troponin concentration is indicative of myocardial injury, but is not synonymous with MI The most common non-ischemic causes of elevated plasma TnI concentration include: Congestive heart failure Hypertension Circulatory shock Pulmonary embolism Covid-19 8/15/23 26  Mechanical injury Cardiac contusion Cardiotrophic viral infections Chemotherapy Renal failure GI bleed The cutoff for acute myocardial infarction is 0.5 ng/mL. Troponin results performed on a Beckman Coulter DXi analyzer can be interpreted as follows: 8/15/23 27 8/15/23 28 8/15/23 29 8/15/23 30 8/15/23 31  Case Study A 66-year-old man had experienced central chest pain on exertion for some months, but in the afternoon of the day prior to admission he had had a particularly severe episode of the pain, which came on without any exertion and lasted for about an hour. On admission there were no abnormalities on examination and the ECG was normal. The troponin was clearly detectable. Comment on these results. Has he suffered a myocardial infarction? 8/15/23 32  Case Study A 52-year-old man presented at the Accident and Emergency department with severe chest pain which had been present for the past hour. He had previously attended the chest pain clinic and had a 2-year history of angina of effort. What would you do? What specific tests would you request from the biochemistry laboratory? 8/15/23 33  Case Study 8/15/23 34  Case Study QUESTIONS 1. Do the symptoms and the personal history of the patient suggest acute MI? 2. Based on the preceding laboratory data, would this diagnosis be acute MI? 3. Why or why not? 8/15/23 35  Case Study A well-trained marathon runner collapsed as he was approaching the finishing line. An ECG was normal but CK was elevated at 9500 U/L (reference range 30–200 U/L), and the CK-MB was 14% of the total CK (normally