Cardiac muscle injury, biomarkers

Diagnosis of cardiac muscle injury relies on the detection of biomarkers such as troponin I (Tnl), troponin C (TnC), myoglobin, fatty acid binding protein (FABP), glycogen phosporylase isoenzyeme BB (GPBB), C-reactive protein (CP), urinary albumin, creatine kinase myocardial band (CK-MB), and brain (B-type) natriuretic peptide in blood and urine [28-30]. 

The lack of tissue specificity of the total serum CK assay and the reliance on histopathology to definitively diagnose drug-induced skeletal muscle injury in preclinical drug development have highlighted the need to identily better biomarkers. Beyond the characteristics desired in all safety biomarkers (reviewed in Robinson et al. (2008)), the ideal skeletal muscle injury biomarker should have a number of specific characteristics. First, it should be specific for skeletal muscle tissue injury and, most importantly, allow the discrimination between cardiac and skeletal muscle... 

Whereas CK and LD isozymes have been quite successful as cardiac biomarkers in humans, their use in animals has been limited by the need to exclude muscle injury (O Brien et al. 1997a). This is clearly more difficult in animals because symptoms of myopathy are more difficult to detect and because of a greater background incidence of effects on skeletal muscle associated with handling and stress. The mildly greater concentration of specific isoenzymes in cardiac versus skeletal muscle that confers diagnostic relevance may be offset by the much larger amount of muscle mass. 

Fatty acid binding protein (FABP3) is a cytosolic protein recently reported to be more sensitive for detection of cardiac injury in humans with myocardial infarct or congestive heart failure (Mion et al. 2007 Niizeki et al. 2007). Flowever, FABP3 is also found, although in much lower concentrations, in muscle, brain, and kidney. As for CK and LD, its occurrence in skeletal muscle substantially diminishes its value as a cardiac biomarker because of the higher and variable background of mild skeletal muscle injury in laboratory animals. Its use as a cardiac biomarker would require exclusion of muscle injury and renal disease. 

Although CK and LD isozymes and myoglobin are sensitive biomarkers of skeletal muscle injury, they are also found in cardiac muscle and thus are not tissue specific. Cardiotoxicity must be excluded in order to use them effectively as biomarkers. Injured muscle releases other enzymes in significant amounts, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and aldolase however, these also lack tissue specificity. 

Troponin is the regulatory complex of three proteins of the thin filament of myocytes. Troponin T binds to tropomyosin, troponin I is an inhibitory protein, and troponin C binds to calcium needed for muscle contraction. Following irreversible myocyte damage, unbound troponin subunits are initially released into blood from the cytosolic pools. This is followed by a sustained release of the tri-troponin complex due to the breakdown of the myocyte itself. Once in blood, the complex is further degraded into the binary troponin I-C complex, and frees troponin T. Figure 92.1 shows the kinetics of troponin subunit release. Troponin is superior to the other biomarkers for cardiac injury for two... 

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