Comprehensive ECG reference intervals in C57BL/6N substrains provide a generalizable guide for cardiac electrophysiology studies in mice
Manuela A. Oestereicher, Janine M. Wotton, Shinya Ayabe, Ghina Bou About, Tsz Kwan Cheng, Jae‐Hoon Choi, Dave Clary, Emily M. Dew, L. Elfertak, Alain Guimond, Hamed Haseli Mashhadi, Jason D. Heaney, Lois Kelsey, Piia Keskivali-Bond, Federico López, Susan Marschall, Michael McFarland, Hamid Méziane, Violeta Muñoz‐Fuentes, Ki‐Hoan Nam, Zuzana Nichtová, Dale Pimm, Lynette Bower, Jan Procházka, Jan Rozman, Luís Santos, Michelle Stewart, Nobuhiko Tanaka, Christopher Ward, Amelia Willett, Robert Wilson, Robert E. Braun, Mary E. Dickinson, Ann M. Flenniken, Yann Hérault, K. C. Kent Lloyd, Ann‐Marie Mallon, Colin McKerlie, Stephen A. Murray, Lauryl M. J. Nutter, Radislav Sedláček, Je Kyung Seong, Tania Sorg, Masaru Tamura, Sara Wells, Elida Schneltzer, Helmut Fuchs, Valérie Gailus‐Durner, Martin Hrabě de Angelis, Jacqueline K. White, Nadine Spielmann
Abstract
Reference ranges provide a powerful tool for diagnostic decision-making in clinical medicine and are enormously valuable for understanding normality in pre-clinical scientific research that uses in vivo models. As yet, there are no published reference ranges for electrocardiography (ECG) in the laboratory mouse. The first mouse-specific reference ranges for the assessment of electrical conduction are reported herein generated from an ECG dataset of unprecedented scale. International Mouse Phenotyping Consortium data from over 26,000 conscious or anesthetized C57BL/6N wildtype control mice were stratified by sex and age to develop robust ECG reference ranges. Interesting findings include that heart rate and key elements from the ECG waveform (RR-, PR-, ST-, QT-interval, QT corrected, and QRS complex) demonstrate minimal sexual dimorphism. As expected, anesthesia induces a decrease in heart rate and was shown for both inhalation (isoflurane) and injectable (tribromoethanol) anesthesia. In the absence of pharmacological, environmental, or genetic challenges, we did not observe major age-related ECG changes in C57BL/6N-inbred mice as the differences in the reference ranges of 12-week-old compared to 62-week-old mice were negligible. The generalizability of the C57BL/6N substrain reference ranges was demonstrated by comparison with ECG data from a wide range of non-IMPC studies. The close overlap in data from a wide range of mouse strains suggests that the C57BL/6N-based reference ranges can be used as a robust and comprehensive indicator of normality. We report a unique ECG reference resource of fundamental importance for any experimental study of cardiac function in mice.