Unmasking of oestrogen-dependent changes in left ventricular structure and function in aged female rats: a potential model for pre-heart failure with preserved ejection fraction
Unmasking of oestrogen-dependent changes in left ventricular structure and function in aged female rats: a potential model for pre-heart failure with preserved ejection fraction
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DOI：
10.1113/jp277479
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发表时间：
2019-04-01
影响因子：
5.5
通讯作者：
Villarreal, Francisco
中科院分区：
文献类型：
--
作者：
Bustamante, Moises;Garate-Carrillo, Alejandra;Villarreal, Francisco
射血分数保留型心力衰竭 (HFpEF) 在老年女性中更为常见；危险因素包括年龄、高血压和体重过重。早期重塑（HFpEF 前）的雌性动物模型尚未研究过这些因素的融合对心脏结构和功能的影响。在这项研究中，我们证明衰老会导致轻度心室重塑、弥漫性纤维化和舒张功能丧失。雌激素的丧失会导致心输出量显着下降（同时保留正常射血分数），从而进一步加剧这种变化，而弥漫性纤维化在心内膜中更为突出，并伴有乳头状纤维化。体重过重并没有明显加剧这些结果。该动物模型概括了老年女性 HFpEF 患者的许多特征，因此可用于检查候选治疗药物的效果。三分之二的射血分数保留的心力衰竭 (HFpEF) 患者是老年女性，危险因素包括高血压和超重/肥胖。驱动早期疾病发展（心力衰竭发生之前）的病理生理因素仍然不清楚，并且缺乏雌性动物模型。该研究评估了衰老、雌激素消耗和体重过重对改变心脏结构/功能的交叉作用。将雌性、18个月大的Fischer F344大鼠分为老年组、老年+卵巢切除术(OVX)和老年+卵巢切除+饮用水中的10%果糖(OVF)(n = 8-16/组)以诱导体重增加。通过超声心动图监测左心室（LV）结构/功能。 22 个月大时，将动物麻醉并评估基于导管的血流动力学，然后进行腔室形态测量和胶原密度的组织学测量。所有老年动物均出现高血压。 OVF动物体重增加。超声心动图仅检测到随年龄增长而出现的轻度心室重塑，而心室内压力-容量环分析显示，每搏输出量（OVX 为 13%，OVF 为 15%）、每搏做功（OVX 为 13% 和 52%）和心输出量（OVX 为 29% 和 27%）与年龄相比显着降低（P < 0.05），舒张时间增加（10% OVX），射血分数保留。组织学显示随着年龄的增长，乳头状和间质纤维化，其中OVX和OVF组的心内膜纤维化程度更高。随着年龄的增长，卵巢切除术会导致舒张功能和整体左心室功能丧失，同时保留射血分数。该模型概括了 HFpEF 患者存在的许多心血管特征，可能有助于了解衰老和雌激素消耗在早期（HFpEF 前）疾病发展中所起的作用。
Key pointsHeart failure with preserved ejection fraction (HFpEF) is seen more frequently in older women; risk factors include age, hypertension and excess weight. No female animal models of early stage remodelling (pre-HFpEF) have examined the effects that the convergence of such factors have on cardiac structure and function. In this study, we demonstrate that ageing can lead to the development of mild chamber remodelling, diffuse fibrosis and loss of diastolic function. The loss of oestrogens further aggravates such changes by leading to a notable drop in cardiac output (while preserving normal ejection fraction) in the presence of diffuse fibrosis that is more predominant in endocardium and is accompanied by papillary fibrosis. Excess weight did not markedly aggravate such findings. This animal model recapitulates many of the features recognized in older, female HFpEF patients and thus, may serve to examine the effects of candidate therapeutic agents. Two-thirds of patients with heart failure with preserved ejection fraction (HFpEF) are older women, and risk factors include hypertension and excess weight/obesity. Pathophysiological factors that drive early disease development (before heart failure ensues) remain obscure and female animal models are lacking. The study evaluated the intersecting roles of ageing, oestrogen depletion and excess weight on altering cardiac structure/function. Female, 18-month-old, Fischer F344 rats were divided into an aged group, aged + ovariectomy (OVX) and aged + ovariectomy + 10% fructose (OVF) in drinking water (n = 8-16/group) to induce weight gain. Left ventricular (LV) structure/function was monitored by echocardiography. At 22 months of age, animals were anaesthetized and catheter-based haemodynamics evaluated, followed by histological measures of chamber morphometry and collagen density. All aged animals developed hypertension. OVF animals increased body weight. Echocardiography only detected mild chamber remodelling with ageing while intraventricular pressure-volume loop analysis showed significant (P < 0.05) decreases vs. ageing in stroke volume (13% OVX and 15% for OVF), stroke work (34% and 52%) and cardiac output (29% and 27%), and increases in relaxation time (10% OVX) with preserved ejection fraction. Histology indicated papillary and interstitial fibrosis with ageing, which was higher in the endocardium of OVX and OVF groups. With ageing, ovariectomy leads to the loss of diastolic and global LV function while preserving ejection fraction. This model recapitulates many cardiovascular features present in HFpEF patients and may help understand the roles that ageing and oestrogen depletion play in early (pre-HFpEF) disease development.