Timecourse of Troponin Isoforms

Within the cardiomyocyte, troponins are primarily localized to the sarcomere, which forms the myofibrillar apparatus, with only a small fraction in the cytosol, estimated at 3.5% and 7.0% of total TnI and TnT by mass, respectively [19]. During a myocardial infarction, TnI is released as a single peak, while TnT is usually released in a biphasic manner, with the second peak occurring approximately 80 h after the onset of chest pain, regardless of reperfusion [20]. One hypothesis for this biphasic behavior is that cytosolic TnT is released immediately into the circulation following damage to myocytes, whereas myofibrillar TnT takes longer to be released [20]. However, alternative explanations such as differences in the half-life of immune-reactive TnT fragments cannot be ruled out [20]. A recent study which used advanced biochemical techniques including gel filtration revealed that following myocardial infarction (MI), much of detectable TnT is part of a ternary complex of TnI, TnT, and TnC, which progressively gets degraded to lower molecular weight species, and that a complex of TnI and TnC also exists alongside free TnT fragments [21]. However, other studies have found contrasting results with no clear consensus [22–24]. Further complicating the matter is that troponins are subject to pro-teolytic degradation after release, with matrix metalloproteinase-2 (MMP-2), calpain-1 and calpain-2 cleaving TnI, and MMP-2 and calpain-1 cleaving TnT [24,25]. Notably, knowledge of which fragments are found in the serum is useful for rationally designing antibodies against the most stable Tn epitopes, but it is possible that different Tn com-plexes are found in different disease states. A fascinating prospect suggested by pre-liminary data, which has yet to be realized, is the discovery of disease-specific Tn complex isoforms, which could enable the differentiation of the etiology of Tn elevation and lead to more specific diagnoses [26–28].

There are many mechanisms for Tn release into the serum after cardiomyocyte in-jury. The most common mechanism is myocyte necrosis, when myocytes undergo necrosis due to ischemic injury—for example, Ca2+ leaks into the cytoplasm, which causes massive contraction of all sarcomeres and subsequent consumption of all ATP, resulting in the total destruction of cell contents [29]. However, apoptosis can also be responsible for Tn release: in a porcine model of brief (10 min) coronary occlusion, which is not long enough to cause necrosis or infarction, significant amounts of TnI were released into the serum from apoptotic cells [30]. Even transient increases in left ventricular end-diastolic pressure using a model of reversible left ventricular dysfunction can cause stretch-induced myocardial stunning, apoptosis, and Tn release [31]. Finally, it is even possible to have Tn release from living cells by mechanisms including ischemia-induced membrane blebbing, a stretch-induced integrin response, cell turnover, and inflammation [32,33].