Stress drives myelopoiesis to impair atherosclerosis resolution

Area of Science:

• Cardiovascular Science
• Immunology
• Neuroscience

Background:

• Atherosclerotic cardiovascular diseases (ASCVD) are a leading global cause of death.
• Psychological stress is linked to increased ASCVD risk, but its impact on lipid-lowering therapy benefits is unclear.
• Inflammation within atherosclerotic plaques plays a critical role in ASCVD progression.

Purpose of the Study:

• To investigate if psychological stress diminishes the anti-inflammatory benefits of lipid-lowering therapy in atherosclerosis.
• To explore the mechanisms by which stress might affect plaque inflammation and treatment response.
• To correlate findings from mouse models with human data on stress, lipid levels, and inflammation.

Main Methods:

• Combined a mouse model for lowering LDL cholesterol (LDL-C) with a chronic social defeat stress (CSDS) model.
• Compared LDL-C lowering benefits in stress-susceptible (SUS), stress-resilient (RES), and control (CON) mice.
• Analyzed plaque inflammation, macrophage characteristics, and monocyte precursor programming in bone marrow (BM).
• Correlated mouse findings with human imaging data on psychological stress and response to LDL-C lowering therapy.

Main Results:

• Stress-susceptible mice showed significantly reduced benefits from LDL-C lowering compared to control or resilient mice.
• SUS mice exhibited heightened plaque inflammation, linked to altered monocyte precursor programming in the bone marrow.
• Human studies mirrored these findings, showing less effective reduction in systemic and arterial inflammation with LDL-C lowering in individuals with higher psychological stress.

Conclusions:

• Psychological stress impairs the anti-atherosclerotic effects of lipid-lowering medications.
• Stress-induced inflammation, originating from bone marrow monocyte reprogramming, contributes to reduced treatment efficacy.
• Chronic stress is a significant factor in residual ASCVD risk, impacting therapeutic outcomes.