Characteristics of troponins as myocardial damage biomarkers in cynomolgus monkeys.
Recently, troponin T (TnT) and troponin I (TnI) have been reported as suitable biomarkers of myocardial injury for pre-clinical toxicity studies. The purpose of the present study was to investigate the characteristics of troponins as myocardial damage biomarkers in cynomolgus monkeys. Initially, tissue distribution of biomarkers was investigated in nine organs (including the heart, liver, and kidneys) collected from naive cynomolgus monkeys. The results showed that TnT and TnI were distributed specifically in the heart, and were not detected in other tissues. Secondly, changes in blood biomarker levels and histopathological changes in cardiac tissue were investigated following myocardial injury induced by concomitant administration of isoproterenol (ISO) and vasopressin (VASO). Compared with pre-dosing, TnT and TnI were markedly increased in the ISO + VASO groups, in which severe histopathological changes including necrosis and vacuolation of muscle fibers were observed. In order to investigate the relationship of biomarker levels with the severity of myocardial injury, Spearman's correlation coefficient was calculated between C(max) and AUC and necrosis and vacuolation scores in the heart. A high correlation between necrosis and vacuolation in the heart and TnT and TnI levels was noted. These results suggest that TnT and TnI possess high sensitivity and specificity for myocardial injury in cynomolgus monkeys, and are useful biomarkers for detection of drug-induced myocardial injury in cynomolgus monkeys.
Minomo
Hirofumi
H
Shin Nippon Biomedical Laboratories, Ltd., Drug Safety Research Laboratories, Kagoshima, Japan. minomo-hirofumi@snbl.co.jp
Torikai
Yusuke
Y
Furukawa
Tomohiro
T
Uchino
Hiroshi
H
Kadokura
Hidetomi
H
Nakama
Kazuhiro
K
Maeda
Hiroshi
H
Kamenosono
Takeshi
T
Sukamoto
Takayuki
T
Fukuzaki
Koichiro
K
Nagata
Ryoichi
R
D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D009202:Cardiomyopathies / Q000139:chemically induced / Q000175:diagnosis* / Q000473:pathology; D007545:Isoproterenol; D008252:Macaca fascicularis; D008297:Male; D009206:Myocardium / Q000473:pathology; D009336:Necrosis; D012720:Severity of Illness Index; D014018:Tissue Distribution; D019210:Troponin I / Q000032:analysis* / Q000097:blood; D020107:Troponin T / Q000032:analysis* / Q000097:blood; D014617:Vacuoles; D014662:Vasoconstrictor Agents
D015415:Biomarkers; D019210:Troponin I; D020107:Troponin T; D014662:Vasoconstrictor Agents; D007545:Isoproterenol