Cardiac diastolic dysfunction in aging arises from increased ventricular stiffness caused by inflammation and interstitial fibrosis. The diastolic dysfunction contributes to heart failure with preserved ejection fraction (HFpEF), which in the aging population is more common in women. This report examines its progression over 12 weeks in aging C57BL/6J mice and correlates its development with changes in macrophage polarization and collagen deposition.

Aged C57BL/6J mice were injected with dendritic cell–specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) ligand 1 (DCSL1, an anti-inflammatory agent) or saline for 12 weeks. Echo and Doppler measurements were performed before and after 4 and 12 weeks of treatment. DCSL1 prevented the worsening of diastolic dysfunction over time in females but not in males. Cardiac single cell suspensions analyzed by flow cytometry revealed changes in the inflammatory infiltrate: (1) in males, there was an increased total number of leukocytes with an increased pro-inflammatory profile compared with females and they did not respond to DCSL1; (2) by contrast, DCSL1 treatment resulted in a shift in macrophage polarization to an anti-inflammatory phenotype in females. Notably, DCSL1 preferentially targeted tumor necrosis factor-α (TNFα⁺) pro-inflammatory macrophages. The reduction in pro-inflammatory macrophage polarization was accompanied by a decrease in collagen content in the heart.

Age-associated diastolic dysfunction in mice is more severe in females and is associated with unique changes in macrophage polarization in cardiac tissue. Treatment with DCSL1 mitigates the changes in inflammation, cardiac function, and fibrosis. The characteristics of diastolic dysfunction in aging female mice mimic similar changes in aging women.

衰老过程中的心脏舒张功能障碍是由炎症和间质纤维化引起的心室僵硬度增加引起的。舒张功能障碍会导致射血分数保留的心力衰竭（HFpEF），这在老龄化人群中在女性中更为常见。本报告检查了衰老 C57BL/6J 小鼠 12 周内的进展情况，并将其进展与巨噬细胞极化和胶原沉积的变化联系起来。

老年 C57BL/6J 小鼠注射树突状细胞特异性细胞间粘附分子 3 抓取非整联蛋白 (DC-SIGN) 配体 1（DCSL1，一种抗炎剂）或盐水，持续 12 周。在治疗 4 周和 12 周之前和之后进行回波和多普勒测量。随着时间的推移，DCSL1 可以阻止女性舒张功能障碍的恶化，但不能阻止男性的舒张功能障碍。通过流式细胞术分析心脏单细胞悬浮液，揭示了炎症浸润的变化：（1）与女性相比，男性的白细胞总数增加，促炎特征增强，并且对 DCSL1 没有反应； (2) 相比之下，DCSL1 治疗导致女性巨噬细胞极化转变为抗炎表型。值得注意的是，DCSL1 优先靶向肿瘤坏死因子-α (TNFα ⁺ ) 促炎巨噬细胞。促炎巨噬细胞极化的减少伴随着心脏中胶原蛋白含量的减少。

小鼠中与年龄相关的舒张功能障碍在雌性小鼠中更为严重，并且与心脏组织中巨噬细胞极化的独特变化有关。 DCSL1 治疗可减轻炎症、心脏功能和纤维化的变化。老年雌性小鼠舒张功能障碍的特征与老年女性的类似变化相似。