Passive Stiffness of Left Ventricular Myocardial Tissue Is Reduced by Ovariectomy in a Post-menopause Mouse Model

Núria Farré,Bryan Falcones,Ramon Farré,Daniel Navajas,Ignasi Jorba,Marta Torres,Julio Martí-Almor,Isaac Almendros

doi:10.3389/fphys.2018.01545

Abstract

Background: Heart failure (HF) – a very prevalent disease with high morbidity and mortality – usually presents with diastolic dysfunction. Although post-menopause women are at increased risk of HF and diastolic dysfunction, poor attention has been paid to clinically and experimentally investigate this group of patients. Specifically, whether myocardial stiffness is affected by menopause is unknown.Aim: To investigate whether loss of female sexual hormones modifies the Young’s modulus (E) of left ventricular (LV) myocardial tissue in a mouse model of menopause induced by ovariectomy (OVX).Methods: After 6 months of bilateral OVX, eight mice were sacrificed, fresh LV myocardial strips were prepared (∼8 × 1 × 1 mm), and their passive stress–stretch relationship was measured. E was computed by exponential fitting of the stress–stretch relationship. Subsequently, to assess the relative role of cellular and extracellular matrix components in determining OVX-induced changes in E, the tissues strips were decellularized and subjected to the same stretching protocol to measure E. A control group of eight sham-OVX mice was simultaneously studied.Results: E (kPa; m ± SE) in OVX mice was ∼twofold lower than in controls (11.7 ± 1.8 and 22.1 ± 4.4, respectively; p < 0.05). No significant difference between groups was found in E of the decellularized tissue (31.4 ± 12.05 and 40.9 ± 11.5, respectively; p = 0.58).Conclusion: Loss of female sexual hormones in an OVX model induces a reduction in the passive stiffness of myocardial tissue, suggesting that active relaxation should play a counterbalancing role in diastolic dysfunction in post-menopausal women with HF.

Highlights

Heart failure (HF) is a global health problem associated with high mortality and healthcare system expenditure (Farré et al, 2016, 2017)
After 6 months of OVX/SHAM surgery, mice were euthanized by exsanguination under intraperitoneal urethane anesthesia (1 g/kg). Their hearts and uteri were immediately excised and weighed, and hearts were subjected to left ventricular (LV) myocardial sample preparation for further imaging and mechanical measurements both carried out by investigators who were unaware of the sample group (OVX vs. SHAM)
Representative stress–stretch curves in native and decellularized LV myocardium tissue samples for OVX and SHAM mice are shown in Figure 2A

Summary

Introduction

Heart failure (HF) is a global health problem associated with high mortality and healthcare system expenditure (Farré et al, 2016, 2017). Sex differences in prevalence and outcomes of diastolic dysfunction and HF have been reported (O’Meara et al, 2007; Meyer et al, 2013; Gori et al, 2014) and might be partially explained by withdrawal of estrogens at the time of menopause (Merz and Cheng, 2016) given that functional estrogen receptors reside in the myocardium (Mahmoodzadeh et al, 2006). Myocardium remodeling can result from pathways involving sex hormones and the natriuretic peptide system, which modulates diastolic dysfunction and HF (Hong et al, 1992; Maffei et al, 2001; Lam et al, 2011; Goncalves et al, 2017; Subramanya et al, 2018; Ying et al, 2018). Heart failure (HF) – a very prevalent disease with high morbidity and mortality – usually presents with diastolic dysfunction.

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