Stress drives myelopoiesis to impair atherosclerosis resolution

TL;DR

Chronic psychological stress reduces the effectiveness of lipid-lowering treatments in reducing atherosclerosis by increasing inflammation in blood vessels.

Contribution

This study reveals that stress impairs the benefits of lipid-lowering therapy through stress-driven myelopoiesis and inflammation in atherosclerotic plaques.

Findings

Mice susceptible to chronic stress showed reduced benefits from LDL-C lowering compared to control or resilient mice.

Stress-induced inflammation in plaque macrophages was linked to re-programmed monocyte precursors in the bone marrow.

Human imaging confirmed that stress reduces the effectiveness of LDL-C lowering in reducing arterial inflammation.

Abstract

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.

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