Fisher Edward, Tufanli Ozlem, Scolaro Bianca, Civieri Giovanni, Schlamp Florencia, Delbare Sofie, Weinstock Ada, Cathomas Flurin, Pena Stephanie, Berrío Angélica Torres, Parise Eric, Chan Kenny, Parise Lyonna, Osborne Michael, Fayad Zahi, Nestler Eric, Swirski Filip, Tawakol Ahmed, Russo Scott
NYU Grossman School of Medicine.
Massachusetts General Hospital.
Res Sq. 2025 Jun 9:rs.3.rs-6727599. doi: 10.21203/rs.3.rs-6727599/v1.
Atherosclerotic cardiovascular diseases (ASCVD) remain the leading cause of death globally. Animal and human studies link psychological stress-related disorders to ASCVD. Despite this accumulating evidence linking stress to increased cardiovascular disease (CVD) risk, it remains unclear whether stress impairs the benefits of standard risk-reduction therapies, of which lipid-lowering remains the most common, or whether this increased risk is driven by systemic inflammatory states. We tested the hypothesis that psychological stress limits the benefits of lipid lowering on resolving inflammation in atherosclerotic plaques by combining two established mouse models, namely one in which levels of atherogenic LDL cholesterol (LDL-C) can be lowered after plaques develop, and the other a model of chronic social defeat stress (CSDS). Here we show that mice susceptible to CSDS ("SUS") had attenuated benefits of LDL-C lowering compared to control (CON) or resilient (RES) mice. Moreover, in SUS mice (vs. CON or RES) there was heightened inflammation in the plaque macrophages, with evidence that this was a result of re-programming in the bone marrow (BM) of the precursors of macrophages, namely monocytes. Remarkably, these observations aligned with human imaging studies, in which LDL-C lowering therapy was not as effective in reducing either systemic or arterial inflammation in subjects with higher (vs. lower) neural imaging measures of psychological stress. In summary, the integration of the mouse model and human data provides important mechanistic and clinical insights into the crucial role of chronic stress in ASCVD, highlighting that this common risk factor impairs the anti-atherosclerotic benefits of lipid-lowering medications and may represent an important determinant of residual ASCVD risk.
动脉粥样硬化性心血管疾病（ASCVD）仍然是全球主要的死亡原因。动物和人体研究将心理应激相关障碍与ASCVD联系起来。尽管有越来越多的证据表明应激与心血管疾病（CVD）风险增加有关，但目前尚不清楚应激是否会削弱标准风险降低疗法（其中降脂疗法仍然是最常见的）的益处，或者这种增加的风险是否由全身炎症状态驱动。我们通过结合两种已建立的小鼠模型来检验这一假设，即心理应激会限制降脂对解决动脉粥样硬化斑块炎症的益处，一种模型是在斑块形成后可以降低致动脉粥样硬化的低密度脂蛋白胆固醇（LDL-C）水平，另一种是慢性社会挫败应激（CSDS）模型。在这里，我们表明，与对照（CON）或有恢复力（RES）的小鼠相比，易受CSDS影响的小鼠（“SUS”）在降低LDL-C方面的益处减弱。此外，在SUS小鼠（与CON或RES小鼠相比）中，斑块巨噬细胞中的炎症加剧，有证据表明这是巨噬细胞前体即单核细胞在骨髓（BM）中重新编程的结果。值得注意的是，这些观察结果与人体影像学研究一致，在人体影像学研究中，降脂治疗在降低心理应激神经影像学测量值较高（与较低相比）的受试者的全身或动脉炎症方面效果不佳。总之，小鼠模型和人体数据的整合为慢性应激在ASCVD中的关键作用提供了重要的机制和临床见解，强调了这一常见风险因素会损害降脂药物的抗动脉粥样硬化益处，并且可能是ASCVD残余风险的重要决定因素。
