Variable outcomes of human heart attack recapitulated in genetically diverse mice

Ekaterina Salimova,Milena B Furtado,Jeffrey W Holmes,Quang Nguyen,Kristen J Nowak,Christoph Preuss,Lois Balmer,Mirana Ramialison,Grant Morahan,Ana C Estrada,Elyshia Mcnamara,Nadia A Rosenthal

doi:10.1038/s41536-019-0067-6

Abstract

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.

Highlights

The mortality rate among patients having heart failure (HF) with reduced ejection fraction (EF) following a heart attack has gradually been reduced through the cumulative benefit of medications such as angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, β-blockers, and mineralocorticoidreceptor antagonists.[1,2] surviving patients with ischemic cardiomyopathy and HF face a broad spectrum of symptoms, emphasizing the need for new prognostic models to stratify patient subgroups and to develop new therapies
A preliminary survey of Collaborative Cross (CC) founder and recombinant inbred (RI) strains revealed marked differences in various morphological parameters, e.g., coat color and quality, body weight (BWt), behavior, neurological activity, and bleeding, in accordance with previous reports on variation in aspects such as motor performance,[13] hematological parameters,[14] susceptibility to infections,[15,16,17] immunological conditions,[18,19] reproduction,[20] toxicokinetics,[21] glycome repertoire,[22] and traits associated with skin cancer.[23]
Strains displaying severe and minimal LV systolic dysfunction (LVSD) based on the combination of ΔEF and LV dilation (LVD) traits are highlighted on Fig. 3a in red and green, respectively

Summary

Introduction

The mortality rate among patients having heart failure (HF) with reduced ejection fraction (EF) following a heart attack has gradually been reduced through the cumulative benefit of medications such as angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, β-blockers, and mineralocorticoidreceptor antagonists.[1,2] surviving patients with ischemic cardiomyopathy and HF face a broad spectrum of symptoms, emphasizing the need for new prognostic models to stratify patient subgroups and to develop new therapies. Inbred mouse models comprise useful experimental systems for functional analysis of genetic variants in the context of disease phenotyping, with validation in controlled conditions, high reproducibility, and unlimited access to tissues for the identification of genes contributing to simple Mendelian traits. Experimental strategies for complex trait analyses in the mouse have not kept pace with rapid developments in human genetic studies, and new strategies for using model organisms are needed. With over 20,000 interacting mammalian genes, each with multiple variants, genetically diverse experimental mouse systems have proven a more powerful tool to dissect cardiovascular features.[6] Such systems are essential for building predictive models of predisposing traits for outcomes with such a complex etiology as cardiovascular disease and for making precision medicine a reality

Methods

Results

Conclusion