What has been overturned: atherosclerosis is not just a cholesterol problem
For decades, the dominant view was that atherosclerosis was simply a matter of cholesterol building up in artery walls. That picture has been fundamentally revised. We now know that chronic inflammation is not a bystander but a central driver of the disease at every stage — from the first fatty streak to plaque rupture that causes heart attacks and strokes [8][11]. The strongest evidence comes from the CANTOS trial, which tested canakinumab, a drug that blocks the inflammatory cytokine IL-1β. In that trial, patients who received the drug had a 15% reduction in major cardiovascular events — and this benefit occurred independently of any change in their cholesterol levels [6]. That result alone overturned the idea that inflammation was merely a consequence of lipid accumulation.
The shift is also visible in how we think about risk. Traditional risk factors like high LDL cholesterol don't tell the whole story. Many patients who achieve optimal cholesterol levels still have heart attacks — this 'residual risk' is now linked to persistent inflammation. For example, elevated high-sensitivity C-reactive protein (hsCRP, a marker of inflammation) above 2 mg/dL is associated with increased cardiovascular risk even when lipids are well-controlled [5]. Across the studies here, the consistent finding is that inflammatory pathways operate in parallel with, and often independently of, cholesterol-driven mechanisms.
How chronic inflammation drives atherosclerosis: from the blood to the plaque
Chronic inflammation fuels atherosclerosis through several interconnected mechanisms. First, inflammatory signals from risk factors like high blood pressure, smoking, or diabetes activate the bone marrow to produce more pro-inflammatory white blood cells, which then enter the artery wall [8]. Once there, these cells — particularly macrophages — release cytokines like IL-6, TNF-α, and IL-1β that perpetuate a vicious cycle of inflammation, oxidative stress, and further immune cell recruitment [2][9]. In children with obstructive sleep apnea, for instance, elevated levels of IL-6 and IL-8 were associated with stiffer, less distensible carotid arteries — an early sign of vascular damage — even before any structural plaque was visible on ultrasound [4]. This shows inflammation precedes and predicts structural changes.
Second, the inflammatory process directly destabilizes plaques. In stable plaques, a fibrous cap keeps the fatty core contained. But inflammatory cytokines like TNF-α and IL-1β promote the breakdown of this cap by activating enzymes that degrade collagen, making the plaque prone to rupture [8][11]. Rupture is what causes most heart attacks and strokes. The studies here also highlight that different vascular beds — coronary arteries, carotid arteries, femoral arteries — have distinct inflammatory profiles, meaning the specific inflammatory drivers may vary depending on which arteries are affected [7]. This is a newer insight that complicates the picture but also opens the door to more targeted therapies.
Third, the resolution of inflammation — the body's natural process of shutting down an inflammatory response — fails in atherosclerosis. Normally, after an acute inflammatory insult, specialized pro-resolving mediators (like lipoxins and resolvins) are produced to clear dead cells and promote healing. In atherosclerosis, this resolution program is impaired: there is an imbalance between pro-inflammatory and pro-resolving mediators, and dead cells (apoptotic foam cells) accumulate in plaques, fueling ongoing inflammation [12]. This failure of resolution is now considered a major underlying cause of the chronicity of the disease.
What this means for treatment: anti-inflammatory drugs are now a reality
The recognition that inflammation drives atherosclerosis has already led to new treatments. The CANTOS trial proved the concept: canakinumab, an antibody that neutralizes IL-1β, reduced cardiovascular events by 15% in patients with prior heart attack and persistent inflammation (hsCRP ≥2 mg/L) [6]. Importantly, this benefit was independent of lipid lowering. However, canakinumab is expensive and increased the risk of fatal infections, so it is not widely used. A more practical option is colchicine, an old anti-inflammatory drug used for gout. The COLCOT trial (not among the papers here but referenced in [6]) showed that low-dose colchicine reduced cardiovascular events by 23% in post-heart-attack patients. Colchicine is cheap and oral, making it a more accessible option.
Beyond these specific drugs, many existing cardiovascular medications have anti-inflammatory effects that contribute to their benefit. Statins, for example, lower cholesterol but also reduce CRP levels and dampen inflammatory signaling [6]. SGLT2 inhibitors (used for diabetes and heart failure) and PCSK9 inhibitors (potent cholesterol-lowering drugs) also have pleiotropic anti-inflammatory properties [6]. The emerging paradigm is that optimal cardiovascular prevention may require targeting both lipids and inflammation simultaneously.
Several experimental approaches are under investigation. One strategy is to boost the body's own resolution pathways by administering pro-resolving mediators or by modulating the phenotype of plaque cells — for example, converting pro-inflammatory macrophages into reparative ones [10][12]. Another is to target specific inflammatory pathways that are particularly active in certain vascular beds, such as the NLRP3 inflammasome pathway, which is implicated in large artery atherosclerosis [1]. In mice, the natural compound sinomenine suppressed early atherosclerosis by reducing inflammatory cytokines like IL-6, TNF-α, and MCP-1, and by lowering oxidative stress markers [2]. While these are preclinical, they illustrate the breadth of anti-inflammatory strategies being explored.
A key caveat: anti-inflammatory therapy is not a replacement for lifestyle changes and lipid management. The evidence shows that inflammation and cholesterol are synergistic — both need to be addressed. Moreover, not all patients with atherosclerosis have the same inflammatory profile; some have high IL-6, others high TNF-α, and still others have elevated Lp(a) (a lipid particle that also has pro-inflammatory effects) [5]. Personalized approaches based on biomarkers are likely the future [6][7].
About These Sources
This answer is built on 12 peer-reviewed studies — published from 2021 to 2025, 7 from 2024 or later, 12 in Q1 journals, collectively cited 572 times — selected as the most relevant from 15 studies that passed quality screening, drawn from 65 papers retrieved from a database of over 500 million.
Sources used in this answer
EDNRA affects susceptibility to large artery atherosclerosis stroke through potential inflammatory pathway
In a case-control study of 428 stroke patients and 434 controls, a specific genetic variant in the EDNRA gene (rs5343 TT) was associated with a 3.2-fold increased risk of large artery atherosclerotic stroke, and this risk was linked to upregulation of the NLRP3 inflammatory pathway and higher levels of IL-18 and CCL-18.
Sinomenine protects against atherosclerosis in apolipoprotein E-knockout mice by inhibiting of inflammatory pathway
In a mouse model of atherosclerosis (ApoE-/- mice fed a high-fat diet), treatment with sinomenine (5-15 mg/kg) for 12 weeks significantly suppressed body weight, improved lipid profiles, reduced oxidative stress markers (e.g., MDA), and lowered inflammatory cytokines (IL-1β, TNF-α, IL-6) and adhesion molecules (VCAM-1, ICAM-1), indicating that anti-inflammatory compounds can slow early plaque development.
Lithium exposure and chronic inflammation with activated macrophages and monocytes associated with atherosclerosis in bipolar disorder
In 103 patients with bipolar I disorder, higher blood levels of lithium were associated with reduced carotid intima-media thickness (a measure of subclinical atherosclerosis), while higher levels of soluble TNF receptor 1 and soluble IL-6 receptor were associated with greater thickness, suggesting that chronic inflammation (with activated macrophages/monocytes) links bipolar disorder to atherosclerosis and that lithium may be protective.
Early Atherosclerotic Inflammatory Pathways in Children with Obstructive Sleep Apnea
In a study of 96 children (43 with obstructive sleep apnea, 53 healthy controls), OSA was associated with elevated proinflammatory cytokines (CD40-L, IL-6, IL-8) and hsCRP, and higher IL-6 and IL-8 levels were linked to stiffer, less distensible carotid arteries, indicating that inflammation precedes structural atherosclerotic changes.
Lipoprotein (a), Inflammation, and Atherosclerosis
This review summarizes evidence that high lipoprotein(a) (>125 nmol/L) and chronic inflammation (hsCRP >2 mg/dL) are independent risk factors for atherosclerotic cardiovascular disease, and that anti-inflammatory drugs like canakinumab and colchicine reduce cardiovascular risk, supporting the concept that inflammation drives atherosclerosis.
Targeting Inflammatory Pathways in Atherosclerosis: Exploring New Opportunities for Treatment
This review highlights that the CANTOS trial was the first to demonstrate cardiovascular risk reduction with anti-inflammatory therapy (canakinumab) independent of lipid levels, and discusses emerging immunomodulatory therapies (low-dose IL-2, PTPN22 modulation) and the pleiotropic anti-inflammatory effects of SGLT2 inhibitors and PCSK9 inhibitors.
Distinct inflammatory pathways shape atherosclerosis in different vascular beds
This review describes how different arterial beds (coronary, carotid, femoral) exhibit distinct atherosclerotic progression and inflammatory profiles, with smoking accelerating abdominal aortic disease, diabetes affecting lower limb arteries, and hypertension driving coronary/carotid disease, implying that inflammatory mechanisms are vascular-bed-specific.
Inflammation in atherosclerosis: Lessons and therapeutic implications
This review details how cardiovascular risk factors activate bone marrow to produce pro-inflammatory myeloid cells that enter the arterial wall, where macrophages orchestrate the inflammatory milieu at all stages of atherosclerosis, and discusses emerging anti-inflammatory therapies targeting these pathways.
Antioxidant and Anti-Inflammatory Effects of Bioactive Compounds in Atherosclerosis
This review summarizes evidence that bioactive compounds (polyphenols, flavonoids, omega-3 fatty acids, etc.) can mitigate atherosclerosis by reducing oxidative stress (ROS) and inflammation (suppressing NF-κB and inflammatory cytokines), supporting their use as complementary strategies.
Chronic inflammation and vascular cell plasticity in atherosclerosis
This review shows that chronic inflammation drives phenotypic switching of vascular smooth muscle cells, endothelial cells, and macrophages in plaques, and proposes that modulating these cell phenotypes (rather than just blocking inflammation) represents a new therapeutic paradigm.
Atherosclerosis and Inflammation: Insights from the Theory of General Pathological Processes
This review characterizes atherosclerosis as an independent form of inflammation that shares features with both low-grade and canonical inflammation, driven by endothelial dysfunction, metabolic dysregulation, and autoimmune/infectious factors, and notes that acute complications (stroke, shock) involve systemic hyperinflammation.
Inflammation Resolution: Implications for Atherosclerosis
This review demonstrates that failed resolution of inflammation — including an imbalance of pro-inflammatory vs. pro-resolving mediators, impaired clearance of dead cells, and persistent immune cell activation — is a major underlying cause of chronic inflammation in atherosclerosis.