Friday, September 6, 2013

Interpreting and Correlating Abnormal Laboratory Values : Cardiac Function Tests

Diagnosis of Myocardial Infarction (MI) and Acute Coronary Syndrome

Fig. Getting MI attack
Since acute MI (AMI) requires rapid and accurate diagnosis, especially now that new treatment options with thrombolytic agents are available, the clinical laboratory has been called upon to provide serum diagnostic tests that can make this diagnosis at an early stage. Until recently, laboratory diagnosis was based on serial determinations of the MB fraction of creatine phosphokinase (CK-MB); confirmation of the diagnosis was provided by the so-called ‘flipped ratio’ of the isozymes of lactate dehydrogenase (LD) 24-36 hours after the initial acute event and/or by observation of the characteristic time courses for elevations of the three enzymes, CK, aspartate aminotransferase (AST) and LD.

These approaches have been replaced mainly by two other analytes, myoglobin (MY) and especially troponin (Tn), that provide more rapid and specific diagnostic capabilities. MY is an oxygen-binding/transport protein found in both cardiac and skeletal muscle. Its relatively small size and function allow for early release from irreversibly damaged cells. However, current methods of measurement cannot distinguish MY's tissue of origin. Therefore, its use is confined to screening patients for possible AMI; positive results suggest further work-up for AMI.

Troponin is a regulatory protein complex in muscle tissue; it comprises three subunits designated troponin I (TnI), troponin T (TnT), and troponin C (TnC). Different genes encode TnI in skeletal and cardiac muscle, giving rise to isoforms that differ significantly in sequence. In addition, cardiac TnI contains an additional 31 amino acid residues on its N-terminal. Rapid and accurate immunoassays for TnT and cardiac TnI have been developed. In AMI, cardiac TnI becomes elevated 4-8 hours after onset of chest pain, reaches a peak at about 12-16 hours and remains elevated for 5-9 days. Values at or above 1.5 ng/dL are considered to be suggestive of AMI.

Because troponin levels rise relatively rapidly and remain elevated for prolonged times, troponin determinations have replaced the so-called ‘flipped ratio’ of the two isozymes of LDH, LD1 and LD2 (LD2:LD1 ratio rises to > 0.75 and often exceeds 1.0) which occurs only about 36 hours after the onset of symptoms.

TnT does not have tissue-specific sequence differences. Nonetheless, it has proved to be effective in the diagnosis of AMI. One problem with use of TnT is that it may be elevated in patients with renal disease although this does not affect use of TnT in predicting the prognosis of patients with acute coronary syndromes. Overall, both troponin determinations have sensitivities and specificities that exceed 90%, and elevated serum troponin levels 12 hours after the onset of chest pain have 100% sensitivity in diagnosing MI.

It should be noted that CK-MB remains useful in diagnosing AMI. This is an isozyme of creatine phosphokinase (CK), which has three isozymes composed of two chains (called the M and B chains) which are MM, MB and BB. The MB fraction is predominantly found in cardiac muscle. To diagnose AMI from CK-MB serum levels, it is important to show both a rise in the concentration of CK-MB and in the ratio of CK-MB to total CK (also called the cardiac index). Because there is a small amount of CK-MB in skeletal muscle, diseases of skeletal muscle that cause the level of CK-MM to rise to high values will also cause the levels of CK-MB to rise to high absolute concentrations in serum, that can cause false-positive values for CK-MB. In addition, to increase both the sensitivity and specificity of CK-MB in the diagnosis of acute AMI, it has been found necessary to perform serial determinations of MB fraction (at 3- to 4-hour intervals over a 12- to 16-hour period) that show a progressive rise that reaches a peak, followed by a fall to low levels. This pattern is virtually 100% diagnostic of myocardial infarction. Importantly, CK-MB generally rises 4-6 hours, and sometimes only 2 hours, after the onset of chest pain, and peaks within 12 hours. Therefore, MY and CK-MB have been recommended for use as early markers of AMI since both markers are released soon after AMI, with MY, and sometimes CK-MB, increasing as early as 1-2 hours after onset of AMI.

However, elevated TnT and, especially TnI, levels are more specific for cardiac injury than are elevated CK-MB levels. Like CK-MB, they rise within 4-6 hours, and sometimes within 2 hours, after the onset of chest pain. Furthermore, single elevated troponin levels are diagnostic of acute MI and unstable angina and do not require follow-up levels or computation of cardiac indices to confirm these diagnoses, making troponin more effective diagnostically and more cost-effective than CK-MB. As an added bonus, troponin, unlike CK-MB, also serves as a marker for unstable angina. Thus many medical centers use troponin as the preferred marker for MI.

Current protocols for the laboratory diagnosis of AMI vary. In some medical centers TnI or TnT is used exclusively while in other centers, both troponin and CK-MB are used together. Based on earlier recommendations from a conference on standards in laboratory practice concerning laboratory diagnosis of AMI, for patients who present with chest pain and non-diagnostic ECG changes, many centers use both an early marker of myocardial damage, e.g., CK-MB or myoglobin, together with a definitive marker, i.e., troponin (high specificity and sensitivity), for cardiac damage. For patients with diagnostic clinical findings of AMI before treatment is begun, troponin and/or CK-MB may be ordered to document infarction, to monitor the extent of the disease, to detect possible re-infarction and to monitor therapeutic efficacy. In addition, troponin and/or CK-MB can be used to detect perioperative AMI during surgical procedures.

Diagnosis of Congestive Heart Failure

Until recently, this condition was diagnosed strictly on the basis of symptomatology and/or as a result of procedures such as echocardiography. However, a new biomarker has been discovered, B-type natriuretic peptide (BNP), that has been approved as a definitive test for this condition and appears to be an excellent marker for early heart failure; this test may also be both diagnostically and prognostically significant in patients presenting with acute dyspnea and chest pain. The differential diagnosis in these patients includes dyspnea caused by chronic heart failure (signs and symptoms of which are typically nonspecific) versus other causes of acute dyspnea (e.g., pneumonia, carcinoma, effusion, asthma). Normal levels (i.e., a high negative predictive value for this test) appear useful in excluding a cardiac etiology in these patients. Levels of BNP may also be an independent predictor of arrhythmia, stroke, and death.

(Source: McPherson & Pincus: Henry's Clinical Diagnosis and Management by Laboratory Methods,21st ed.)

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