Age-related remodeling of the heart causes structural and functional changes in the left ventricle (LV) that are associated with a high index of morbidities and mortality worldwide. Some cardiac pathologies in the elderly population vary between genders revealing that cardiac remodeling during aging may be sex-dependent. Herein, we analyzed the effects of cardiac aging in male and female C57Bl/6 mice in four age groups, 3, 6, 12, and 18 month old (n = 6-12 animals/sex/age), to elucidate which age-related characteristics of LV remodeling are sex-specific. We focused particularly in parameters associated with age-dependent remodeling of the LV extracellular matrix (ECM) that are involved in collagen metabolism. LV function and anatomical structure were assessed both by conventional echocardiography and speckle tracking echocardiography (STE). We then measured ECM proteins that directly affect LV contractility and remodeling. All data were analyzed across ages and between sexes and were directly linked to LV functional changes. Echocardiography confirmed an age-dependent decrease in chamber volumes and LV internal diameters, indicative of concentric remodeling. As in humans, animals displayed preserved ejection fraction with age. Notably, changes to chamber dimensions and volumes were temporally distinct between sexes. Complementary to the traditional echocardiography, STE revealed that circumferential strain rate declined in 18 month old females, compared to younger animals, but not in males, suggesting STE as an earlier indicator for changes in cardiac function between sexes. Age-dependent collagen deposition and expression in the endocardium did not differ between sexes; however, other factors involved in collagen metabolism were sex-specific. Specifically, while decorin, osteopontin, Cthrc1, and Ddr1 expression were age-dependent but sex-independent, periostin, lysyl oxidase, and Mrc2 displayed age-dependent and sex-specific differences. Moreover, our data also suggest that with age males and females have distinct TGFβ signaling pathways. Overall, our results give evidence of sex-specific molecular changes during physiological cardiac remodeling that associate with age-dependent structural and functional dysfunction. These data highlight the importance of including sex-differences analysis when studying cardiac aging.

中文翻译：

---

细胞外基质代谢的年龄和性别依赖性差异与心脏功能和结构变化相关。


与年龄相关的心脏重塑会导致左心室（LV）的结构和功能变化，这与全球高发病率和死亡率相关。老年人群中的一些心脏病因性别而异，这表明衰老过程中的心脏重塑可能具有性别依赖性。在此，我们分析了 4 个年龄组（3、6、12 和 18 月龄）的雄性和雌性 C57Bl/6 小鼠心脏衰老的影响（n = 6-12 只动物/性别/年龄），以阐明哪种年龄-左心室重塑的相关特征具有性别特异性。我们特别关注与参与胶原代谢的左心室细胞外基质 (ECM) 年龄依赖性重塑相关的参数。通过传统超声心动图和斑点追踪超声心动图（STE）评估左室功能和解剖结构。然后我们测量了直接影响左心室收缩性和重塑的 ECM 蛋白。所有数据均按年龄和性别进行分析，并与左室功能变化直接相关。超声心动图证实心室容积和左心室内径随年龄的增长而减少，表明存在同心重塑。与人类一样，动物随着年龄的增长表现出保留的射血分数。值得注意的是，不同性别的房间尺寸和体积的变化在时间上是不同的。作为传统超声心动图的补充，STE 显示，与年轻动物相比，18 个月大的雌性动物的周向应变率有所下降，但雄性动物则不然，这表明 STE 可以作为两性之间心脏功能变化的早期指标。心内膜中年龄依赖性胶原沉积和表达在性别之间没有差异；然而，参与胶原蛋白代谢的其他因素具有性别特异性。 具体而言，虽然核心蛋白聚糖、骨桥蛋白、Cthrc1 和 Ddr1 的表达具有年龄依赖性但与性别无关，但骨膜蛋白、赖氨酰氧化酶和 Mrc2 表现出年龄依赖性和性别特异性差异。此外，我们的数据还表明，随着年龄的增长，男性和女性具有不同的 TGFβ 信号通路。总体而言，我们的结果提供了生理性心脏重塑过程中性别特异性分子变化的证据，这些变化与年龄依赖性结构和功能功能障碍相关。这些数据凸显了在研究心脏衰老时纳入性别差异分析的重要性。