Decoding Atherosclerotic Plaque Inflammation: Insights from Experimental Studies, Part One

Atherosclerosis, a leading cause of cardiovascular diseases, is increasingly recognized as a chronic inflammatory condition. Inflammation serves as a shared pathway that connects both traditional and emerging cardiovascular risk factors to the progression of atherosclerosis, ultimately contributing to conditions such as coronary artery disease (CAD), large artery thrombotic stroke, and cerebral aneurysms (1,2). Recent experimental studies have illuminated the complex role of inflammation in the development and progression of atherosclerotic plaques.

Inflammation in Plaque Progression

In the study “Inflammation during the life cycle of the atherosclerotic plaque” (3), it was emphasized that inflammation is present from the earliest stages of atherosclerosis, with endothelial activation leading to the recruitment of leukocytes into the arterial intima, where they interact with accumulated lipoproteins. Inflammation drives plaque progression by promoting cell death and necrotic core formation, while also regulating plaque rupture and healing, thereby affecting stability. The effects of inflammation on plaque growth and stability are not confined to the local site; systemic inflammation can also amplify these processes and worsen plaque progression.

The Inflammatory Cascade in Atherogenesis

The initiation of atherosclerosis involves endothelial cell activation, leading to the recruitment of leukocytes into the arterial intima. In their study “Where the Action Is—Leukocyte Recruitment in Atherosclerosis,” the authors demonstrated that monocyte recruitment predominates in the early stages of atherogenesis, while local proliferation of these cells characterizes established plaques (4). Once within the intima, monocytes differentiate into macrophages, ingest oxidized low-density lipoproteins (oxLDL), and transform into foam cells, a hallmark of early atherosclerotic lesions.

Macrophage Dynamics and Plaque Stability

Macrophages play a dual role in atherosclerosis, contributing to both plaque progression and stability. Their phenotypic plasticity allows them to adopt pro-inflammatory (M1) or anti-inflammatory (M2) states. Experimental studies (5,6) have shown that promoting the M2 phenotype can enhance plaque stability by reducing inflammation and promoting tissue repair. Conversely, an abundance of M1 macrophages exacerbates inflammation, leading to plaque vulnerability.

Role of Chemokines and Cytokines

Chemokines and cytokines are key regulators in attracting and activating immune cells within atherosclerotic plaques. Research by Zernecke and Weber (7) demonstrated that blocking chemokine signaling pathways can effectively reduce leukocyte infiltration into the arterial wall, thereby mitigating inflammation and plaque progression. Similarly, Charo and Taubman (8) highlighted the role of broad-spectrum chemokine inhibitors in decreasing macrophage accumulation and limiting collagen degradation, which contributes to plaque stabilization. These findings underscore the potential of targeting chemokine activity to manage the inflammatory components of atherosclerosis.

Emerging Therapeutic Targets

Targeting inflammatory pathways offers promising avenues for therapeutic intervention. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) provided clinical evidence that inhibiting interleukin-1β reduces cardiovascular event rates, underscoring the potential of anti-inflammatory therapies (9).

The LoDoCo2 (Low-Dose Colchicine 2) Trial, led by Nidorf et al. (2020), investigated the effects of low-dose colchicine on cardiovascular outcomes in patients with chronic coronary disease. The study demonstrated that colchicine significantly reduced the incidence of cardiovascular events, emphasizing its potential as an anti-inflammatory therapy in the management of atherosclerosis (10).

The COLCOT (Colchicine Cardiovascular Outcomes Trial), conducted by Tardif et al. (2019), evaluated the effects of colchicine in patients who recently experienced a myocardial infarction. The trial demonstrated that colchicine significantly reduced the risk of ischemic cardiovascular events, providing strong support for its role as an anti-inflammatory therapy in the management of cardiovascular diseases (11).

Conclusion

Inflammation plays a fundamental role in all stages of atherosclerosis, from plaque formation to rupture, with experimental and clinical studies highlighting key mechanisms such as leukocyte recruitment, macrophage polarization, and cytokine signaling. Recent trials like CANTOS, LoDoCo2, and COLCOT have demonstrated that targeting these inflammatory pathways can reduce cardiovascular events, offering promising avenues for therapeutic intervention.

References:

1. Henein MY, Vancheri S, Longo G, Vancheri F. The Role of Inflammation in Cardiovascular Disease. International Journal of Molecular Sciences. 2022; 23(21):12906. https://doi.org/10.3390/ijms232112906
2. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Glynn RJ. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. The New England Journal of Medicine. 2017; 377(12):1119–1131. https://doi.org/10.1056/NEJMoa1707914
3. Libby P. Inflammation during the life cycle of the atherosclerotic plaque. Cardiovascular Research. 2021; 117(13):2525–2536. https://doi.org/10.1093/cvr/cvab303
4. Mauersberger C, et al. Where the Action Is—Leukocyte Recruitment in Atherosclerosis. Frontiers in Cardiovascular Medicine. 2021. https://doi.org/10.3389/fcvm.2021.813984
5. Gianopoulos I, Daskalopoulou SS. Macrophage profiling in atherosclerosis: understanding the unstable plaque.Basic Research in Cardiology. 2024; 119:35–56. https://doi.org/10.1007/s00395-023-01023-z
6. An TH, He QW, Xia YP, et al. MiR-181b Antagonizes Atherosclerotic Plaque Vulnerability Through Modulating Macrophage Polarization by Directly Targeting Notch1. Molecular Neurobiology. 2017; 54:6329–6341. https://doi.org/10.1007/s12035-016-0163-1
7. Zernecke A, Weber C. Chemokines in atherosclerosis: proceedings resumed. Arteriosclerosis, Thrombosis, and Vascular Biology. 2014; 34(4):742-750. https://doi.org/10.1161/ATVBAHA.113.301655
8. Charo IF, Taubman MB. Chemokines in the Pathogenesis of Vascular Disease. Circulation Research. 2004; 95(9):858-866. https://doi.org/10.1161/01.RES.0000146672.10582.1
9. Crossman D, Rothman A. The Canakinumab Antiinflammatory Thrombosis Outcome Study trial—the starting gun has fired. Journal of Thoracic Disease. 2017; 9(12):4922-4925. https://doi.org/10.21037/jtd.2017.11.96
10. Nidorf SM, et al. Colchicine in Patients with Chronic Coronary Disease. The New England Journal of Medicine.2020; https://doi.org/10.1056/NEJMoa2021372
11. Tardif JC, et al. Colchicine in Patients with a Recent Myocardial Infarction. The New England Journal of Medicine.2019; https://doi.org/10.1056/NEJMoa1912388