Time course characterization of serum cardiac troponins, heart fatty acid-binding protein, and morphologic findings with isoproterenol-induced myocardial injury in the rat.
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.
Clements
Peter
P
GlaxoSmithKline, Safety Assessment Pathology, Hertfordshire, UK. peter.j.clements@gsk.com
Brady
Sally
S
York
Malcolm
M
Berridge
Brian
B
Mikaelian
Igor
I
Nicklaus
Rosemary
R
Gandhi
Mitul
M
Roman
Ian
I
Stamp
Clare
C
Davies
Dai
D
McGill
Paul
P
Williams
Thomas
T
Pettit
Syril
S
Walker
Dana
D
Turton
John
J
D000818:Animals; D015415:Biomarkers / Q000097:blood*; D002316:Cardiotonic Agents / Q000633:toxicity; D050556:Fatty Acid-Binding Proteins / Q000097:blood*; D006321:Heart / Q000187:drug effects; D006335:Heart Injuries / Q000097:blood* / Q000473:pathology*; D007118:Immunoassay; D007545:Isoproterenol / Q000633:toxicity; D049449:Luminescence; D008297:Male; D046529:Microscopy, Electron, Transmission; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D013995:Time; D014336:Troponin / Q000097:blood*
D015415:Biomarkers; D002316:Cardiotonic Agents; D050556:Fatty Acid-Binding Proteins; D014336:Troponin; D007545:Isoproterenol