Rapid Cardiac Troponin Release After Transient Ischemia

Abstract

Article, see p 1095 Immunoassays for cardiac troponin (cTn) I and T have been the cornerstone of the diagnosis of myocardial infarction (MI) for 20 years, since they were recommended in the first Universal Definition of Myocardial Infarction. 1 In addition, measurable cTn levels, below the diagnostic threshold for MI, identified individuals with acute coronary syndromes who benefited from therapies, such as early revascularization, even in the absence of ST-segment elevation. 2 With this recognition of potential therapeutic benefit, assay manufacturers developed high-sensitivity assays that could accurately detect levels 10 to 100 times lower than the assays used 20 years ago. Today, high-sensitivity assays can measure cTn levels in most healthy individuals and identify small changes in the absence of MI. 3 Elevated cTn levels are considered synonymous with cardiomyocyte cell death, irrespective of the mechanism, with a rising or falling pattern accompanying signs or symptoms of ischemia diagnostic of MI. The work by Árnadóttir et al 4 in this issue of Circulation exploits the analytic precision at low levels of several high-sensitivity cTn (hs-cTn) assays to provide insights that challenge these assumptions. The authors use a model of myocardial ischemia involving transient balloon occlusion of the left anterior descending artery in patients undergoing elective cardiac catheterization who were free from coronary artery disease. They randomly assigned 34 patients to a control arm or 1 of 3 arms with balloon occlusion for 30, 60, or 90 s, followed by blood sampling over the next 4 hours. There were several important observations. 4 First, with only 30 s of occlusive balloon inflation, a 6-fold increase in cTn levels was measurable by 3 hours, and with 90 s of balloon inflation, a duration in which all subjects experienced chest pain, levels of cardiac troponin I (cTnI) had risen by almost 50% within 15 minutes. Second, there were marked differences in the rate of rise and peak concentrations of the 3 hs-cTn assays. Third, copeptin, which has been considered an early marker of MI in some studies, did not change from baseline following ischemia. Cellular Mechanisms of Cardiac Troponin Release Is it plausible that only 30 s of ischemia could result in cardiomyocyte cell death? In a porcine model where the left anterior descending artery was transiently occluded for 10 minutes, cTn levels increased within an hour. 5 This was associated with apoptosis of individual dispersed myocytes, but no evidence of myocardial necrosis or infarction. Although the majority of cTn is tightly bound to the actin-myosin contractile apparatus and is released slowly after cell death, a small proportion is less tightly bound or is free in the cytoplasm. Could the rapid release of this smaller pool account for the early increases in cTn observed here? Alternative hypotheses have been proposed to explain cTn release in the absence of infarction, including changes in cardiomyocyte membrane permeability, formation and release of membranous blebs, and the release of smaller cTn fragments following proteolytic degradation ( Figure A). 6 However, in the absence of robust evidence to support the relevance of these alternative mechanisms, caspase-mediated apoptosis in isolated vulnerable myocytes seems the most likely explanation for cTn elevations in response to transient myocardial ischemia. Download figure Download PowerPoint Figure. Mechanisms of the release and detection of cardiac troponin complex following transient myocardial ischemia. A, In acute myocardial infarction, hypoxic injury of the cardiomyocyte results in necrosis with cell lysis releasing all intracellular contents into the surrounding tissue. Alternative mechanisms could explain cardiac troponin release in the absence of infarction, including programmed cell death through caspase-mediated apoptosis, formation and release of membranous blebs in the absence of cell death, changes in cardiomyocyte membrane permeability, and the release of smaller fragments following proteolytic degradati -Abstract Truncated-