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

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.

Human Atrial Fibroblast Adaptation to Heterogeneities in Substrate Stiffness

“…During the inflammatory phase following myocardial infarction, tissue stiffness in the infarct area is decreased due to collagen degradation and death of cardiomyocytes. This is followed by massive collagen deposition over weeks leading to an increase in tissue stiffness to more than 55 kPa, depending on species, form of fibrosis, and duration of tissue remodeling (Holmes et al, 2005;Berry et al, 2006;Gluck et al, 2017;Farré et al, 2018). In contrast, the elastic modulus of in vitro mouse fibroblast spheroids was determined to be in the range of 0.5-3.5 kPa (Jorgenson et al, 2017).…”

Piezo1 Channels Contribute to the Regulation of Human Atrial Fibroblast Mechanical Properties and Matrix Stiffness Sensing

“…Of note, HAF grown on CyPhyGels were stiffer than HAF on plastic, which may be explained by a biphasic relationship between matrix stiffness and cell stiffness, or by differences in surface chemistry (nature and density of ligands for cell attachment) between CyPhyGels and tissue culture plastic. Both states of the matrix used in this study are at the lower end of myocardial tissue (ranging from ~5 to more than 50 kilopascals depending on age and disease state [ 3 , 4 , 5 , 6 , 7 ]), and more work will be required to assess whether Piezo1 knock-down can also impair fibroblast adaptation to stiffnesses that are in the mid or high range of myocardial tissue properties. In addition, it needs to be considered that in vivo cells face a 3D environment, in which mechano-sensing and -adaptation will differ from our 2D model.…”

“…For example, the early inflammatory phase following myocardial infarction is characterized by a softening of the myocardium down to stiffnesses of a few kilopascals [ 3 ], due to collagen degradation and cardiomyocyte death. In contrast, values exceeding 50 kilopascals have been observed in fully mature ventricular scars several months or years after injury [ 4 , 5 , 6 , 7 ]. The current state of knowledge about the sensing of passive mechanics from cell to tissue levels in the heart has been reviewed recently in detail [ 8 ].…”

Mineralocorticoid receptor blockade with finerenone improves heart function and exercise capacity in ovariectomized mice

“…12 Moreover, regarding myocardial stiffness, Farré et al proposed that a reduction measured in LV strips after 6 months of ovariectomy in mice aged 9 months was due to cardiomyocytes rather than extracellular matrix, because the difference between OVX and controls disappeared in decellularized strips. 29 These publications argue in favour of the importance of the intracellular component in ovariectomy-induced diastolic dysfunction that we showed to be ameliorated in OVX mice treated with finerenone.…”