Cardiac hypertrophy limits infarct expansion after myocardial infarction in mice

• Type of Material: Article
• Authors: Siiri E. Iismaa, Victor Chang Cardiac Research Institute; Ming Li, Victor Chang Cardiac Research Institute; Scott Kesteven, Victor Chang Cardiac Research Institute; Jianxin Wu, Victor Chang Cardiac Research Institute; Andrea Y. Chan, Victor Chang Cardiac Research Institute; Sara R. Holman, Victor Chang Cardiac Research Institute; John W Calvert, Emory University; Ahtesham ul Haq, Victor Chang Cardiac Research Institute; Amy M. Nicks, Victor Chang Cardiac Research Institute; Nawazish Ali Naqvi, Emory University; Ahsan Husain, Emory University; Michael P. Feneley, Victor Chang Cardiac Research Institute; Robert M. Graham, Victor Chang Cardiac Research Institute
• Language: English
• Date: 2018-04-17
• Publisher: Nature Publishing Group: Open Access Journals - Option C
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-018-24525-6
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 8
• Start Page: 6114
• End Page: 6114
• Grant/Funding Information: This work was supported by National Health and Medical Research Council of Australia grants [grant numbers 1012190 to RMG, SEI, ML; 573732 to RMG, MPF; 1074386 to RMG], Heart Foundation of Australia grant [grant number G10S 5148 to RMG, SEI, ML], RT Hall Estate grant [RMG, SEI, ML], Stem Cells Australia–the Australian Research Council Special Research Initiative in Stem Cell Science [grant number SR110001002 to RMG], National Institute of Health grants [grant numbers HL079040 to AH; HL127726 to AH, NN], American Heart Association Grant [grant number 13SDG16460006 to NN], a Leducq Transatlantic Network of Excellence in Cardiovascular Research grant [RMG, AH] and a National Nature Science Foundation of China grant [grant number 81670336 to ML].
• Keywords: CARDIOMYOPATHY; IN-VIVO; QUANTIFICATION; FAILURE; RECRUITABLE STROKE WORK; MUTATIONS; Science & Technology - Other Topics; Science & Technology; Multidisciplinary Sciences; NEONATAL MOUSE HEART
• Research Categories: Health Sciences, Medicine and Surgery; Biophysics, Medical

Abstract

We have previously demonstrated that adult transgenic C57BL/6J mice with CM-restricted overexpression of the dominant negative W v mutant protein (dn-c-kit-Tg) respond to pressure overload with robust cardiomyocyte (CM) cell cycle entry. Here, we tested if outcomes after myocardial infarction (MI) due to coronary artery ligation are improved in this transgenic model. Compared to non-transgenic littermates (NTLs), adult male dn-c-kit-Tg mice displayed CM hypertrophy and concentric left ventricular (LV) hypertrophy in the absence of an increase in workload. Stroke volume and cardiac output were preserved and LV wall stress was markedly lower than that in NTLs, leading to a more energy-efficient heart. In response to MI, infarct size in adult (16-week old) dn-c-kit-Tg hearts was similar to that of NTL after 24 h but was half that in NTL hearts 12 weeks post-MI. Cumulative CM cell cycle entry was only modestly increased in dn-c-kit-Tg hearts. However, dn-c-kit-Tg mice were more resistant to infarct expansion, adverse LV remodelling and contractile dysfunction, and suffered no early death from LV rupture, relative to NTL mice. Thus, pre-existing cardiac hypertrophy lowers wall stress in dn-c-kit-Tg hearts, limits infarct expansion and prevents death from myocardial rupture.