Isoproterenol-Induced Cardiac Diastolic Dysfunction in Mice: A Systems Genetics Analysis

Jessica Wang,Aldons J Lusis,Yibin Wang,Adriana Huertas-Vazquez

doi:10.3389/fcvm.2019.00100

Jessica Wang, Aldons J Lusis + Show 2 more

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https://doi.org/10.3389/fcvm.2019.00100

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Abstract

We examined an isoproterenol heart failure model across a panel of diverse inbred strains of mice, the Hybrid Mouse Diversity Panel (HMDP), using left atrial (LA) and lung weights as well as echocardiogram parameters as surrogates for cardiac diastolic function. We identified gene transcripts that significantly correlated with diastolic function. In addition, we mapped echocardiographic parameters associated with diastolic function. We identified a locus near Tns3-Hus1 to be associated with baseline E/A ratio in mice (p = 1.65E-06), the syntenic region of which was recently associated with E/A ratio in a genome-wide association study (GWAS) meta-analysis of the EchoGen consortium in humans. We also identified a locus near Cdkn2a-Cdkn2b, which is a region syntenic to the human 9p21 locus, to be associated with week 3 A/E ratio (p = 2.15E-06). Our study is the first study to map diastolic dysfunction in mice, in which a locus was found to be shared with a recent human GWAS on diastolic function. Moreover, our cardiac transcriptome correlation and eQTL analysis generated hypotheses for future basic investigations. These results showed that, although technical and physiological challenges limit diastolic function assessment in mice and humans, future investigations examining the genetic architecture of diastolic function among a diverse mouse population, such as the HMDP, in controlled experimental settings, offer distinct advantages in understanding the genetic determinants of diastolic function.

Highlights

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome that is characterized by diastolic dysfunction, involving impaired relaxation and compliance of the left ventricle (LV), leading to increased LV filling pressures, heart failure symptoms and an elevated risk of mortality [1,2,3,4]
Diastolic function was assessed by echocardiographic measures, such as E and A velocities, and left atrial and lung weights, which reflect cumulative impact of isoproterenol on LV filling pressures over time, leading to atrial volume increase, pulmonary congestion, and edema [17]
We examined isoproterenol-treated transcripts that were most significantly correlated with diastolic function traits such as left atrial weight, lung weight, E and A velocities (Table 1)

Summary

Introduction

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome that is characterized by diastolic dysfunction, involving impaired relaxation and compliance of the left ventricle (LV), leading to increased LV filling pressures, heart failure symptoms and an elevated risk of mortality [1,2,3,4]. Diastolic function can be assessed by directly measuring LV filling pressures via invasive hemodynamic monitoring [12], it can be assessed by a number of echocardiographic findings non-invasively. These parameters, E and A velocities, tissue E’ velocity, and their derivatives E/A ratio and E/E’ ratio, have been used to study diastolic function in mice [13]. In this study we analyzed diastolic function parameters from the heart failure HMDP to identify candidate genomic loci and gene transcripts that may more accurately reflect the pathophysiology of diastolic dysfunction. We hypothesize the use of a diverse mouse population, such as the HMDP, to help us better understand diastolic dysfunction

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