Time Course Characterization of Serum Cardiac Troponins, Heart Fatty Acid–binding Protein, and Morphologic Findings With Isoproterenol-induced Myocardial Injury in the Rat

Abstract

We investigated the kinetics of circulating biomarker elevation, specifically correlated with morphology in acute myocardial injury. Male Hanover Wistar rats underwent biomarker and morphologic cardiac evaluation at 0.5 to seventy-two hours after a single subcutaneous isoproterenol administration (100 or 4000 microg/kg). Dose-dependent elevations of serum cardiac troponins I and T (cTnI, cTnT), and heart fatty acid-binding protein (H-FABP) occurred from 0.5 hour, peaked at two to three hours, and declined to baseline by twelve hours (H-FABP) or forty-eight to seventy-two hours (Serum cTns). They were more sensitive in detecting cardiomyocyte damage than other serum biomarkers. The Access 2 platform, an automated chemiluminescence analyzer (Beckman Coulter), showed the greatest cTnI fold-changes and low range sensitivity. Myocardial injury was detected morphologically from 0.5 hour, correlating well with loss of cTnI immunoreactivity and serum biomarker elevation at early time points. Ultrastructurally, there was no evidence of cardiomyocyte death at 0.5 hour. After three hours, a clear temporal disconnect occurred: lesion scores increased with declining cTnI, cTnT, and H-FABP values. Serum cTns are sensitive and specific markers for detecting acute/active cardiomyocyte injury in this rat model. Heart fatty acid-binding protein is a good early marker but is less sensitive and nonspecific. Release of these biomarkers begins early in myocardial injury, prior to necrosis. Assessment of cTn merits increased consideration for routine screening of acute/ongoing cardiomyocyte injury in rat toxicity studies.

Revision of the Troponin T Release Mechanism from Damaged Human Myocardium

“…Animal studies in which diffuse AMIs of variable size were induced by different doses of isoproterenol showed a similar time to the first increases in cTnT and cTnI but faster cTnT and cTnI clearance following a small AMI. On histological examination at different times following a small AMI, damaged heart muscle cells, although fewer in number, show a more rapid loss of cTnI staining compared with damaged muscle cells in animals with a larger AMI (22 ). Although this could be a result of fast degradation of myofibrils when the damaged area is small and subjected to large plasma flow, our data indicate that washout of cTnT and therefore also cTnI can occur without extensive myofibrillar degradation, because cTnT extraction can be almost complete after 90 min.…”

“…First, serum cTnT and cTnI concentrations return to baseline levels faster, often within 24 h, after diffuse infarctions that occur in the presence of unrestricted blood flow such as after an isoproterenol injection (22)(23)(24). After isoproterenol-induced AMI in rats, necrotic myocytes are diffusely distributed in the heart and exposed to an unrestricted plasma flow, resulting in fast extraction and clearance of cTnT and cTnI, compared with a classical thrombotic AMI when the damage is focal and there is only a limited plasma flow.…”

Release Kinetics of Cardiac Biomarkers in Patients Undergoing Transcoronary Ablation of Septal Hypertrophy

“…Therefore, an exact temporal allocation of the release of biomarkers in the context of AMI onset is not feasible. Although animal models of myocardial infarction can provide information about the release kinetics of cardiac troponins (27)(28)(29)(30), such findings cannot be directly extrapolated to patients because of the different physiological parameters (e.g., metabolism, release) (28 ).…”

Comparison of Cardiac Troponin I and T, Including the Evaluation of an Ultrasensitive Assay, as Indicators of Doxorubicin-induced Cardiotoxicity

“…Histologically, injury can be detected within hours following exposure and is characterized first by multifocal myofiber hypereosinophilia. However, the peak histological severity (myodegeneration and necrosis) does not typically occur until 24 hr post dose (Clements et al 2010). The kinetics of cTn response in rats to acute myocardial injury have also been documented with other toxicants, including treatment with alcohol (Patel et al 2001), phosphodiesterase inhibitors (Zhang et al 2006), and organophosphates (Yavuz et al 2008).…”