The troponin complex consists of 3 protein subunits: troponin I, troponin T, and troponin C. These proteins are located in myofibrils of cardiac and skeletal muscle tissue, are expressed by different genes, and have a key role in regulating calcium-mediated muscle contraction through interaction of actin monomers with myosin heavy chains.^[29]

Troponin T (37 kd), which is responsible for binding the troponin complex to tropomyosin, is expressed in 3 different isoforms: slow- and fast-twitch skeletal muscle troponin T and cardiac troponin T. The cardiac subunit of troponin T is encoded by a separate gene that gives it a unique amino acid sequence. Troponin I (21 kd) prevents contraction in the absence of calcium through inhibition of adenosine triphosphatase activity of the actin-myosin interaction and is encoded by 3 different genes and expressed as various muscle tissue isoforms: slow- and fast-twitch skeletal and cardiac troponin I.^[30] Finally, troponin C (18 kd) is responsible for regulating the process of thin-filament activation during skeletal and cardiac muscle contraction.^[31] In this process calcium ions bind to troponin C, which inhibits the activity of troponin I.

As a result of the unique amino acid sequence, high intracellular concentration, and continuous release from damaged myocardium,^[32] immunoassays for detection of myofibrillar cardiac proteins are the most sensitive and specific serum markers of myocardial injury.

In AMI, 50% of patients have cardiac troponin T in circulation within 3 hours after the onset of pain. There is an increase in the cardiac troponin T serum concentration of 30- to 40-fold above the upper detection limit between 10 and 24 hours after AMI, with a plateau from the second to the fifth day. The serum levels remain increased until day 12 or more. In patients receiving thrombolytic therapy, the comparison of early and late increases in cardiac troponin T concentration after AMI may provide important information regarding infarct size and reperfusion.^[34] The cutoff value of cardiac troponin T for detection of AMI is 0.1 ng/mL. The sensitivity for diagnosis of AMI remains near 100% within 4 to 10 hours until the sixth day, with a specificity of 74%.^[31,34] In addition, the cardiac troponin T assay allows the monitoring of myocardial cell necrosis in patients with nonacute coronary syndrome conditions, such as those with perioperative cardiac damage, transplant rejection, or inflammatory cardiac diseases.^[31,34,51]

Despite the high sensitivity of the cardiac troponin T assay for detection of myocardial necrosis, a false-positive result can occur in renal failure, rhabdomyolysis, polymyositis, and muscular dystrophy.^[52-56] A new assay for cardiac-specific troponin T (thrombin enzyme-linked immunosorbent assay) was developed to avoid the false-positive results of the first-generation assays. In this enzyme-linked immunosorbent assay the cross-reacting antibody 1B10 has been replaced by a high-affinity, cardiac-specific antibody (M11.7). The detection limit of this new assay is lower than that of the first generation: 0.0123 µg/L versus 0.04 µg/L, respectively.^[57]

In a further study the same group reported preliminary results for the evidence of elevated serum cardiac troponin I in human end-stage heart failure.^[41] A much more sensitive immunoenzymometric assay for detection of cardiac troponin I assessed the sera of 11 male patients with end-stage heart failure and 11 healthy control subjects. This new assay had a cutoff value of 10 pg/mL and a detection limit of 3 pg/mL. These values were far below the cardiac troponin I assay used in the previous report. All but one patient with CHF had high circulating levels of cardiac troponin I, whereas the control subjects had serum levels of this marker below the detection limit. In addition, the authors observed a meaningful correlation of high cardiac troponin I levels with lower LVEF (r = -0.70, P = .01).

The final report provided the first evidence for ongoing myofibrillar degradation of cardiomyocytes and increased cardiac troponin I levels in patients with advanced heart failure.^[59] Cardiac troponin I was assessed in the sera of 35 patients with severe CHF (New York Heart Association functional class III and IV), 55 healthy blood donors, and 25 hospitalized control subjects without known cardiac disease. The newer, more sensitive assay (lower detection limit of 3 pg/mL) was used in this population. The study^[59] also assessed standard cardiac assays: troponin I (upper reference limit of 0.1 ng/mL), CK-MB isoenzyme, and myoglobin. The more sensitive troponin I assay showed a mean mass concentration significantly higher in patients with CHF (P < .01) than in healthy blood donors or hospitalized control subjects. With the standard assay, 1 patient had a positive result (0.206 ng/mL), 26 patients had results below the upper reference limit, and 8 patients had negative results. However, mean concentrations of troponin I were identical in patients undergoing heart failure and in the control group (0.02 ± 0.01 vs 0.01 ± 0.002 ng/mL). CK-MB mass and myoglobin levels were within the normal reference ranges for all groups; however, patients with CHF showed an absolute increase in CK-MB and myoglobin that paralleled the increase of the high-sensitivity cardiac troponin I assay. The authors concluded that the presence of cardiac troponin I in the sera of patients with advanced heart failure was a consequence of the cellular injury and degradative processes of the contractile apparatus involved in the progression of this disease. They also noted that the detection of cardiac troponin I depended on the sensitivity and specificity of the assay used.

The association between cardiac troponin I levels and the severity of heart failure was reported by La Vecchia et al.^[42] Serum samples from 26 inpatients and outpatients with nonischemic CHF and 25 normal control subjects were prospectively evaluated for the presence of cardiac troponin I. The study rationale was the experimental observation that clinical deteriorations or episodes of decompensation from acute heart failure are associated with myocardial cell damage. The assay used had a lower limit of detection of 0.3 ng/mL. All patients had cardiac troponin I reassayed during hospitalization to relate the changes in the serum levels to their clinical course. Detectable cardiac troponin I was observed in 6 (23%) patients, 5 of whom were admitted because of recent or severe episodes of CHF decompensation. The comparison of clinical characteristics between patients with detectable and undetectable cardiac troponin I levels in sera showed that the former group had recent episodes of deterioration (P < .0001), worse functional NYHA class (P = .003), a higher heart-failure score (P = .0009), and worse LV function (P < .0001). Three of six patients with detectable cardiac troponin I died. In addition, the normalization of cardiac troponin I levels in circulation during hospitalization was associated with an improvement of CHF. However, these findings must be confirmed in studies with larger sample sizes.

The prognostic value of a second-generation assay for detection of cardiac troponin T in CHF was reported by Setsuta et al.^[43] The study included 50 patients with ischemic and nonischemic CHF (NYHA functional class II-IV). The endpoint measured was a composite of readmission or death because of worsening CHF (cardiac event). The authors found that the event rate in patients with cardiac troponin T levels of 0.05 ng/mL or greater was significantly higher than in patients with cardiac troponin T levels of less than 0.05 ng/mL (1 year, 82.6% vs 27.3%, P = .0003). The discriminator value reported for identification of patients undergoing heart failure with a high risk for cardiac events (cardiac troponin T level of 0.05 ng/mL or greater) was lower than the discriminator value used for diagnosis of patients with AMI (cardiac troponin T level of 0.1 ng/mL or greater).

Ricchiuti et al^[30] studied the distributions of cardiac troponins I and T in an experimental model of left ventricular remodeled myocardium. The authors compared the changes in tissue cardiac troponin I and cardiac troponin T by quantifying the relative protein levels in normal and diseased cardiac tissue in a postinfarction porcine heart failure model. Heart samples were collected from similarly sized healthy (control group) and left ventricular remodeled Yorkshire pigs. Postinfarction remodeling was obtained from occlusion of the left circumflex coronary artery and subsequent left ventricular remodeling over a period of 2 months. A significant decrease in protein mass and concentration for cardiac troponins I and T in left ventricular remodeled hearts was observed. The authors hypothesized that the decrease in tissue cardiac troponins could be due to decreased synthesis of cardiac troponin I and cardiac troponin T through downregulation of their respective mRNA, chronic loss of cardiac troponins associated with LV dysfunction, decreased coronary flow reserves, and bioenergetic abnormalities. However, this study did not quantitate cardiac troponin T and cardiac troponin I in blood from left ventricular remodeled pigs to correlate their serum levels with the loss of these proteins observed in remodeled myocardium.

The preliminary observation of serum cardiac troponins in patients undergoing heart failure may be related to ongoing myocardial damage involved in the progression of this syndrome (Figure 1). However, the mechanisms by which troponins are released into circulation in CHF is unknown. The presence of recurrent episodes of ischemia in patients with CAD and CHF could be an important factor because CAD is the main etiology of CHF.^[26] However, other processes may be involved because cardiac troponins have been detected in patients with nonischemic heart failure. Experimental models of heart failure showed the importance of the coronary microcirculation and the impairment of subendocardial perfusion as possible mechanisms of myocyte necrosis with release of cardiac troponins and progression to heart failure. The release of cardiac troponins in CHF may result from apoptotic cell death in ventricular remodeling. Although there is no experimental evidence to support this assumption, it is possible that the large diagnostic window, high sensitivity, and high specificity of troponin assays may allow detection of cardiomyocyte apoptosis. Therefore experimental studies are necessary and feasible to allow testing this hypothesis.