Variable outcomes of human heart attack recapitulated in genetically diverse mice

• Published in: npj Regenerative medicine 2019-03, Vol.4 (1), p.5, Article 5
• Main Authors: Salimova, Ekaterina, Nowak, Kristen J., Estrada, Ana C., Furtado, Milena B., McNamara, Elyshia, Nguyen, Quang, Balmer, Lois, Preuss, Christoph, Holmes, Jeffrey W., Ramialison, Mirana, Morahan, Grant, Rosenthal, Nadia A.
• Format: Article
• Language: English
• Subjects: 631/208/727/2000; 692/308/575; Biomaterials; Biomedical and Life Sciences; Biomedicine; Cell Biology; Heart attacks; Immunology; Laboratory animals; Regenerative Medicine/Tissue Engineering; Stem Cells
• ISSN: 2057-3995; 2057-3995
• DOI: 10.1038/s41536-019-0067-6

Clinical variation in patient responses to myocardial infarction (MI) has been difficult to model in laboratory animals. To assess the genetic basis of variation in outcomes after heart attack, we characterized responses to acute MI in the Collaborative Cross (CC), a multi-parental panel of genetically diverse mouse strains. Striking differences in post-MI functional, morphological, and myocardial scar features were detected across 32 CC founder and recombinant inbred strains. Transcriptomic analyses revealed a plausible link between increased intrinsic cardiac oxidative phosphorylation levels and MI-induced heart failure. The emergence of significant quantitative trait loci for several post-MI traits indicates that utilizing CC strains is a valid approach for gene network discovery in cardiovascular disease, enabling more accurate clinical risk assessment and prediction. Cardiology: Genetically diverse mice show human-like responses to heart attack Mice from a genetically diverse panel of inbred strains show a variety of biological outcomes after a heart attack (myocardial infarction), just as humans do. This ‘Collaborative Cross’ mouse resource—which is already widely used in other disciplines of biomedical research—thus provides a tractable system for investigating the genetic factors contributing to acute and chronic presentations of heart disease. Ekaterina Salimova from Monash University in Clayton, Australia, and colleagues experimentally induced myocardial infarctions in the 32 founder or recombinant strains from the Collaborative Cross. They documented large differences in survival, cardiac dilation and scar size among different strains. Gene expression profiling and quantitative trait locus mapping revealed a large number of candidate genes and molecular pathways linked to adverse outcomes. These could offer promising drug targets for treating the damage wrought by heart attacks.