Effects of repeated restraint and blood sampling with needle injection on blood cardiac troponins in rats, dogs, and cynomolgus monkeys

Abstract

While cardiac troponins (cTnT and cTnI) have been used as blood biomarkers of myocardial injury such as myocardial infarction in both humans and animals, their high diagnostic sensitivity inevitably leads to decreased diagnostic specificity. For example, it is difficult to judge whether a slight increase of cardiac troponins in toxicological studies is a treatment-related response or not. Drawing an accurate conclusion requires reliable background data and definitive criteria based on that data. However, no organized efforts in setting such criteria has been reported. Here, we measured blood cTnI and cTnT concentrations in Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys from repeated blood samplings using needle cylinders under restraint up until 24 h after a single oral dose of 0.5 w/v% methyl cellulose solution as a vehicle. We revealed the extent of individual differences in baseline levels and operational effects. Our results can be useful in making criteria for judgment of treatment-related changes in cardiac troponins.

Scientific and Regulatory Policy Committee Points to Consider: Integration of Clinical Pathology Data With Anatomic Pathology Data in Nonclinical Toxicology Studies

“…Cardiac troponins are a sensitive indicator of cardiac injury in preclinical species, but they are subject to considerable procedure-related, interspecies, and inter/intra animal variability in preclinical species. [54][55][56][57][58][59] Furthermore, due to the kinetics of cTn release with an early peak and subsequent plateau and their relatively short circulating half-life, 6,7 histopathologic changes can be temporally distant from peak concentrations or detectable changes in cTn concentrations. Given the relative insensitivity of histopathology changes, the inherent variability in cTn concentrations from preclinical species, and the fact that these changes may not be concurrent, several factors should be considered when integrating cTn concentrations with histopathology changes.…”

Lack of Toxicity in Nonhuman Primates Receiving Clinically Relevant Doses of an AAV9.U7snRNA Vector Designed to Induce DMD Exon 2 Skipping

“…Only animal 2003, treated at the low dose (3 • 10 13 vg/kg), showed a minimal cTnI increase (2.4 • ) between 8 and 19 weeks postinjection, the level of which returned to baseline in week 23; such variability in cTnI levels in NHPs has been previously described. [16][17][18] The cardiac biomarker CK-MB showed no significant difference among animals at either 3 or 6 months (as did neither of the other isoforms, CK-MM and CK-BB). Urinalysis parameters remained normal throughout the study.…”

Scientific and Regulatory Policy Committee Points to Consider: Integration of Clinical Pathology Data With Anatomic Pathology Data in Nonclinical Toxicology Studies

“…Cardiac troponins are a sensitive indicator of cardiac injury in preclinical species, but they are subject to considerable procedure-related, inter-species, and inter/intra-animal variability in preclinical species. [54][55][56][57][58][59] Furthermore, due to the kinetics of cTn release with an early peak and subsequent plateau and their relatively short circulating half-life, 6,7 histopathologic changes can be temporally distant from peak concentrations or detectable changes in cTn concentrations. Given the relative insensitivity of histopathology changes, the inherent variability in cTn concentrations from preclinical species, and the fact that these changes may not be concurrent, several factors should be considered when integrating cTn concentrations with histopathology changes.…”

“…In routine toxicity studies, the standard practice of evaluating a limited number of heart sections limits overall sensitivity, as only a fraction of the heart is examined histologically. Cardiac troponins are a sensitive indicator of cardiac injury in preclinical species, but they are subject to considerable procedure‐related, inter‐species, and inter/intra‐animal variability in preclinical species 54–59 . Furthermore, due to the kinetics of cTn release with an early peak and subsequent plateau and their relatively short circulating half‐life, 6,7 histopathologic changes can be temporally distant from peak concentrations or detectable changes in cTn concentrations.…”