Troponin release--reversible or irreversible injury? Should we care?

Controversies concerning whether cardiac biomarkers can be released in the absence of cell death have existed for years. The initial observations were made with lactate dehydrogenase (LDH), the 134-kDa enzyme that was found to be released from cells or organs in response to tissue injury in the absence of overt cell death (1 ). Similar issues arose with creatine kinase (CK) and CK isoenzyme MB (CK-MB). Heyndrickx et al. (2 ), who found increases in CK in response to brief (5–15 min) coronary occlusions thought to be insufficient to induce cardiac injury, argued that the release was due to ischemia and not cell death; however, pathologic confirmation of this finding was not demonstrated. Subsequently, Ishikawa et al. attempted to cause CK release in animals in the absence of cell death by creating small, graded coronary occlusions (3 ). Whenever they found CK release in the circulation, they observed cells that appeared severely damaged and necrotic, according to electron microscopy results and extensive evaluations of the potentially ischemic area. These findings were supported by the absence of mitochondrial CK in the blood, a biomarker that would provide clear evidence of irreversible cell death. For these reasons, this group argued that the release of CK (86 kDa) was due to cell death. The discussion has been extensive regarding this controversial issue of whether biomarkers can be released from cells in the absence of cell death. Initially, it was thought that regeneration of cardiac myocytes did not occur. That led to a real concern that if the release of biomarkers was due to cell death, one could in essence run out of heart tissue over time. That possibility is no longer a concern, because we now know that cardiomyocytes can regenerate and repair the heart (4 ). This controversy became topical again with the advent of cardiac troponin assays. Increases in cardiac troponins are far more sensitive as biomarkers of cell damage than CK-MB, with larger -fold increases produced relative to the upper reference limit. This fact has led to speculation that all of the cardiac troponin found in blood might not be due to cell death (5 ). This speculation has been supported by cardiac troponin release kinetics in certain clinical situations, which has led to the argument that perhaps cardiac troponin is released after reversible injury. The argument goes as follows: An early-releasable cytosolic pool of cardiac troponin (although whether this pool resides exclusively in the cytosol is not clear) appears to be responsible for the early release of cardiac troponin. Cardiac troponin concentrations are similar to those of CK-MB if one includes only this pool. Thus, the greater clinical sensitivity of cardiac troponin reflects the fact that a greater percentage of this pool reaches the blood after cell injury. Subsequent cardiac troponin release from a structural pool over time explains the prolonged persistence of cardiac troponin in the circulation despite the quite short half-life of the protein (observed in animal studies in which purified cardiac troponin was injected). Release from the structural pool was postulated to be synonymous with cell death, and perhaps release from the cytosolic pool could be due to either reversible or irreversible injury. Initially, prolonged cardiac troponin release was not observed in patients with pulmonary embolism, a finding that led to the idea that pulmonary embolism was a pathology in which release came only from the releasable pool and therefore could be indicative of reversible injury and not cell death (5 ). Unfortunately, we now know that most of those studies were done with inadequately sensitive cardiac troponin assays. Indeed, resolving the question of whether sustained release occurs in patients with pulmonary embolism or in individuals after extreme exercise will require a study to determine whether sustained minor increases in cardiac troponins occur. On the basis of one published study in this area conducted with a high-sensitivity cardiac troponin T (hs-cTnT) assay, it appears that 72 h are required for all values to return to normal (6 ). Because high-sensitivity assays are now available, new studies are needed to sort out the data that originally led to the speculation that cardiac troponin was released in response to reversible injury. Mechanistic studies have shown that necrosis is not essential for cardiac troponin release, but, in fact, 1 Mayo Clinic and Medical School, Rochester, MN; 2 University of San Francisco School of Medicine, San Francisco, CA. * Address correspondence to this author at: Mayo Clinic, Gonda Building 5th Floor, 200 First St. S.W., Rochester, MN 55905. Fax 507-266-0228; e-mail [email protected]. Received September 16, 2011; accepted October 7, 2011. Previously published online at DOI: 10.1373/clinchem.2011.173070 3 Nonstandard abbreviations: LDH, lactate dehydrogenase; CK, creatine kinase; CK-MB, CK isoenzyme MB; hs-cTnT, high-sensitivity cardiac troponin T. Clinical Chemistry 58:1 148–150 (2012) Opinions