Like many age-related conditions, atherosclerosis is accelerated by the chronic inflammation of aging. An atherosclerotic plaque is an inflammatory environment, in which macrophage cells are overwhelmed by excess cholesterol and toxic derivatives of cholesterol. Macrophages attempt to remove cholesterol from the plaque, returning it to the bloodstream attached to HDL particles, and otherwise repair the damage. Inflammatory signaling both attracts macrophages to the plaque and hinders macrophage repair efforts, overall making it more likely that the macrophages will die and add their mass to the growing plaque. Further, it distorts the behavior of cells close to the plaque, which can also act to accelerate plaque growth, such as via the transformation of smooth muscle cells into more macrophages.
Thus there are good reasons to try anti-inflammatory strategies in the context of atherosclerosis, and a range of studies exist in which varieties of anti-inflammatory therapy were assessed for their ability to affect atherosclerotic plaque. In general, results were little more effective than drugs that statins that lower cholesterol bound to LDL particles in the bloodstream, which is to say that treatments only modestly slow plaque growth and modestly reduce the risk of a plaque rupture leading to heart attack or stroke. This is interesting, and perhaps suggests that researchers have not yet found the right inflammatory signals or regulatory mechanisms to target. The research community remains interested in further exploration of novel anti-inflammatory strategies, in search of better outcomes.
Atherosclerosis remains the leading cause of global mortality, most commonly manifesting as ischemic heart disease, stroke, and peripheral arterial disease. Although age-adjusted cardiovascular mortality has declined in many developed nations, the global burden of atherosclerotic disease continues to rise due to population aging and growth. This narrative review examines the evolving understanding of atherosclerosis, which has shifted from a predominantly lipid-centric model to a chronic inflammatory disease.
Atherosclerosis is initiated by the retention and modification of apolipoprotein B-containing lipoproteins within the arterial wall and propagated by innate and adaptive immune responses. Central to this process is activation of the NLRP3 inflammasome and downstream IL-1β-IL-6 signaling and pyroptotic cell death, which amplify vascular inflammation and promote plaque progression and instability. Clinical evidence demonstrates that targeting inflammation, independent of lipid lowering, reduces cardiovascular events, as exemplified by agents such as canakinumab and colchicine. Consequently, the therapeutic landscape is rapidly evolving, with ongoing efforts to refine cytokine-targeted approaches (e.g., IL-6 inhibition), develop selective NLRP3 inhibitors, and advance innovative modalities including cell-based interventions. These strategies aim to provide more durable, precise, and potentially disease-modifying or even curative approaches. However, challenges related to safety, the high cost of biologic agents, and optimal patient selection have limited widespread implementation.
A major barrier remains the lack of sensitive and specific biomarkers to identify patients with active vascular inflammation, complicating trial design and therapeutic targeting. In addition to circulating markers such as high-sensitivity C-reactive protein (hsCRP) and IL-6, emerging insights highlight the liver as a central hub linking inflammation and thrombosis through complement and coagulation pathways, offering potential avenues for developing novel biomarkers. Despite promising advances, clinical translation faces persistent challenges, including increased infection risk, inadequate biomarkers for patient selection, cost constraints, and regulatory and payer requirements for hard clinical endpoints.
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