Inflammation and Atherosclerosis: What Actually Drives Plaque and Cardiovascular Risk

This article is part of our Preventive Cardiology Guide, which looks at cardiovascular risk through biomarkers, metabolic health and direct assessment of atherosclerotic plaque.

The idea that heart disease is simply a cholesterol problem has been obsolete for some time. So has the opposite idea that cholesterol does not matter because inflammation is the real cause.

Atherosclerosis involves both.

ApoB-containing particles, including LDL, remnant lipoproteins and lipoprotein(a), can cross into the arterial wall and become retained there. Once trapped, they undergo changes that attract immune cells and generate an inflammatory response. Macrophages ingest lipid, foam cells accumulate, connective tissue changes and an atherosclerotic plaque begins to develop.

Inflammation is therefore not an alternative explanation for atherosclerosis. It is part of the biological response to the material accumulating in the artery wall.

What Actually Starts Atherosclerosis?

The current model of atherosclerosis begins with ApoB-containing lipoproteins entering and becoming retained within the inner layer of the artery.

ApoB matters because each major atherogenic particle carries one ApoB molecule. Measuring ApoB therefore gives us an approximation of the number of circulating particles capable of entering the arterial wall. LDL-C tells us how much cholesterol is being carried inside a major class of those particles. The two measurements answer related but slightly different questions.

Once ApoB-containing particles become trapped within arterial tissue, they can aggregate or undergo chemical modification. The artery no longer treats the material as harmless cargo passing through the circulation. Endothelial cells and immune cells begin responding to it.

Monocytes move into the arterial wall and differentiate into macrophages. Those macrophages take up modified lipoproteins and become lipid-filled foam cells. Repeated over years, this process contributes to the fatty streaks and more complex plaques associated with atherosclerosis.

This is why the newer cardiovascular discussion should not be framed as cholesterol versus inflammation. Without adequately addressing atherogenic particle burden, we leave one of the central drivers of plaque formation untreated.

The 2026 ACC/AHA dyslipidemia guideline gives ApoB a larger role in risk refinement, particularly when triglycerides are elevated, diabetes is present or LDL-C has already been driven relatively low and residual particle risk is still uncertain.

Where Inflammation Enters the Process

The immune response begins very early in plaque formation and continues throughout the life of the plaque.

Macrophages, T cells, neutrophils and other immune cells release cytokines and enzymes that influence the behavior of the arterial wall. Pathways involving interleukin-1 beta, interleukin-6 and the NLRP3 inflammasome have received particular attention because they connect cholesterol accumulation with innate immune activation.

The artery responds by attempting to contain the injury. Smooth-muscle cells migrate and produce collagen. A fibrous cap develops over the lipid-rich portion of the plaque. Calcification may accumulate as the lesion matures.

Some of these responses are protective. A thick fibrous cap can make a plaque more stable. Calcification can represent part of the healing and remodeling response. Inflammation becomes most clinically concerning when the balance shifts toward continued injury, tissue degradation and plaque instability.

This is another reason that saying simply "inflammation causes heart disease" does not tell us very much. The location, trigger, intensity and duration of the inflammatory response all matter.

How Does Plaque Become Dangerous?

The degree of arterial narrowing is only one part of coronary risk.

A plaque can become dangerous if its structure makes it vulnerable to disruption. Lipid-rich plaques with large necrotic cores, inflammatory activity and relatively thin fibrous caps have historically been associated with plaque rupture. Other cardiovascular events occur through plaque erosion without classic rupture.

When the surface of a plaque is disrupted, circulating blood is suddenly exposed to material it normally does not encounter. Platelets activate and a clot can form. If that thrombus obstructs coronary blood flow, the result may be an acute myocardial infarction.

This explains why someone can have coronary disease for decades without symptoms and then experience what feels like a sudden event. The event may be sudden. The underlying biology usually is not.

What Does hs-CRP Actually Tell Us?

High-sensitivity C-reactive protein, or hs-CRP, is one of the most useful clinical markers for looking at systemic inflammatory risk in cardiovascular medicine.

CRP is produced primarily by the liver in response to inflammatory signals, especially interleukin-6. The high-sensitivity assay allows us to measure lower concentrations than a conventional CRP test, which makes it more useful for cardiovascular risk assessment.

An hs-CRP of 2 mg/L or greater has commonly been used as a cardiovascular risk-enhancing threshold. The 2026 ACC/AHA dyslipidemia guideline continues to include hs-CRP among biomarkers that can help refine an individual's estimated ASCVD risk.

It is important to understand what that does not mean.

hs-CRP does not identify the source of inflammation. It cannot tell us whether the signal is coming from visceral adipose tissue, periodontal disease, arthritis, infection, smoking or another inflammatory process. It cannot show which coronary plaque is inflamed, and it does not replace imaging.

A transient infection can raise hs-CRP substantially. An unexpectedly elevated result often makes more sense when repeated after the person has returned to their usual state of health rather than interpreted in isolation.

Residual Cholesterol Risk and Residual Inflammatory Risk Are Different

This distinction has become increasingly useful in preventive cardiology.

A patient can have residual lipoprotein-related risk because ApoB-containing particle burden remains too high despite what looks like an acceptable conventional cholesterol panel.

A patient can also have residual inflammatory risk, often reflected by a persistently elevated hs-CRP despite appropriate lipid management.

The two frequently overlap, but they are not interchangeable.

This is one reason we may look at LDL-C, non-HDL cholesterol, ApoB, Lp(a), triglycerides and hs-CRP together rather than allowing one laboratory value to stand in for the entire disease process.

The 2026 dyslipidemia guideline also recommends measuring Lp(a) at least once in adulthood to identify inherited risk that may not otherwise be apparent on a standard lipid panel.

For a broader look at this approach, see our Preventive Cardiology and Coronary Plaque Assessment resource.

Insulin Resistance, Visceral Fat and Inflammation

Atherosclerosis also develops within a metabolic environment.

Visceral adipose tissue is biologically active. As visceral fat increases, adipocytes and immune cells within fat tissue can release inflammatory cytokines and free fatty acids. Insulin resistance frequently develops alongside these changes.

The result may include higher fasting insulin, post-meal glucose excursions, increased triglycerides, fatty liver, hypertension and a shift toward more atherogenic lipoprotein patterns.

Metabolic dysfunction can therefore increase cardiovascular risk through several routes at the same time. It can worsen lipoprotein metabolism, endothelial function, blood pressure and inflammatory signaling.

Someone can also have significant ApoB-related risk without obvious insulin resistance. Genetics, Lp(a), familial lipid disorders and individual response to diet can produce atherogenic particle burden in otherwise metabolically healthy people. Good insulin sensitivity is favorable, but it does not cancel a high ApoB.

That is why we measure rather than assume.

Learn more in our Metabolic Syndrome and Cardiometabolic Risk review.

Can Treating Inflammation Prevent Cardiovascular Events?

This question moved from theory into clinical medicine with several major randomized trials.

The CANTOS trial provided some of the clearest proof that inflammation itself could be therapeutically relevant. More than 10,000 patients with a previous myocardial infarction and an hs-CRP of at least 2 mg/L were randomized to canakinumab, an antibody targeting interleukin-1 beta, or placebo.

One dose of canakinumab reduced recurrent cardiovascular events without lowering lipid concentrations. That was important scientifically because it demonstrated that modifying an inflammatory pathway could change cardiovascular outcomes independently of cholesterol reduction.

It did not create a simple new prevention strategy. Canakinumab was associated with more fatal infections and did not reduce overall mortality. It is not routinely used as general anti-inflammatory therapy for coronary prevention.

Low-dose colchicine has produced another chapter in the story.

In LoDoCo2, more than 5,500 patients with chronic coronary disease were randomized to colchicine 0.5 mg daily or placebo. Cardiovascular events were significantly lower in the colchicine group. COLCOT similarly reported fewer cardiovascular events when colchicine was used after myocardial infarction.

The story became less straightforward with CLEAR SYNERGY. In that large trial, colchicine started shortly after acute myocardial infarction did not significantly reduce cardiovascular death, recurrent myocardial infarction, stroke or unplanned ischemia-driven revascularization over approximately three years.

The current interpretation is therefore more selective. U.S. chronic coronary disease guidelines allow low-dose colchicine to be considered in selected patients with chronic stable coronary disease and recurrent or residual risk. It is not an automatic medication for everyone with an elevated hs-CRP, and it is not a replacement for lipid-lowering treatment.

The trials also reinforce a broader point: inflammation is biologically important, but cardiovascular medicine rarely benefits from reducing the entire problem to one pathway.

Statins Affect More Than LDL

Statins remain foundational therapy for many patients with established or sufficiently elevated atherosclerotic cardiovascular risk.

Their principal clinical value comes from reducing LDL-C and the cholesterol carried by ApoB-containing lipoproteins. Statins also tend to lower hs-CRP and influence inflammatory signaling within atherosclerotic plaques.

Those effects should not be used to turn statins into purely anti-inflammatory drugs. Their cardiovascular benefit tracks strongly with the reduction in atherogenic lipoprotein exposure.

The practical message is simpler: lipid lowering and inflammatory risk reduction often move in the same favorable direction rather than competing with one another.

Blood Tests Estimate Risk. Imaging Can Show Plaque.

ApoB and hs-CRP tell us about the biological environment in which atherosclerosis develops. They do not tell us exactly how much plaque is already present in the coronary arteries.

This is where imaging can change the conversation.

A coronary artery calcium score detects calcified coronary plaque. It is useful for risk refinement in appropriately selected patients and is specifically incorporated into contemporary prevention guidelines.

A calcium score cannot show noncalcified plaque.

Coronary CT angiography, or CCTA, provides an anatomic view of the coronary arteries using intravenous contrast and can visualize both calcified and noncalcified plaque as well as coronary narrowing.

Cleerly® is an AI-assisted analysis applied to suitable CCTA images. It can quantify plaque burden and characterize different plaque types. It does not directly measure inflammation, and it should not be described as an inflammation test.

For patients in whom a more detailed anatomic assessment is clinically appropriate, see our Cleerly® CCTA Coronary Plaque Testing guide.

The distinction is useful: biomarkers tell us about risk and physiology. Imaging tells us whether structural disease is already visible and, depending on the study, how much plaque is present.

How We Put the Pieces Together

At HormoneSynergy®, we do not treat hs-CRP as an isolated target and we do not treat atherosclerosis as an LDL number alone.

The more useful question is what the overall cardiovascular pattern looks like.

That may include LDL-C, ApoB, Lp(a), triglycerides, hs-CRP, blood pressure, glucose regulation, fasting insulin, kidney function, smoking exposure, visceral adiposity, exercise capacity, family history and evidence of plaque on vascular or coronary imaging.

The relative importance of each factor varies from person to person. Someone with markedly elevated ApoB and low hs-CRP still has a lipoprotein problem that deserves attention. Someone with established coronary disease, well-controlled LDL-C and persistently elevated hs-CRP may have meaningful residual inflammatory risk. Someone with visceral adiposity, hypertension and insulin resistance may have several interacting drivers at once.

Once plaque has been identified, the purpose of prevention is not merely to improve laboratory numbers. It is to reduce the probability that plaque progresses or produces a cardiovascular event.

That may involve lipid-lowering therapy, blood-pressure treatment, management of diabetes or insulin resistance, smoking cessation, weight reduction when appropriate, regular exercise, improved nutrition and other individualized therapies based on the patient's actual risk.

Our broader cardiovascular approach is outlined in the Preventive Cardiology Guide.

The Bottom Line

Atherosclerosis is both a lipoprotein disease and an inflammatory disease, but those two processes do not begin independently.

ApoB-containing particles enter and become retained in the arterial wall. The immune system responds. Over time, lipid accumulation, inflammation, fibrosis, calcification and vascular remodeling determine what that plaque becomes.

hs-CRP gives us useful information about systemic inflammatory risk. ApoB helps estimate atherogenic particle burden. Lp(a) identifies an important inherited source of risk. Imaging can determine whether plaque is already present.

No single one of those measurements tells the entire story.

Preventive cardiology becomes more useful when the pieces are interpreted together.

Frequently Asked Questions

Is atherosclerosis caused by inflammation or cholesterol?

Both are involved, but they play different roles. Retention of ApoB-containing lipoprotein particles within the arterial wall is a key initiating event in common atherosclerosis. The resulting immune and inflammatory response contributes to plaque development, progression and instability.

What is ApoB?

Apolipoprotein B is the structural protein found on major atherogenic lipoprotein particles, including LDL, IDL, VLDL remnants and lipoprotein(a). Because each particle carries one ApoB molecule, ApoB provides an estimate of circulating atherogenic particle number.

What is hs-CRP?

High-sensitivity C-reactive protein is a blood marker of systemic inflammatory activity. In cardiovascular medicine, an hs-CRP of 2 mg/L or greater may be considered a risk-enhancing signal in the appropriate clinical setting.

Does a high hs-CRP mean my arteries are inflamed?

Not necessarily. hs-CRP is nonspecific and can be elevated by infection, obesity, smoking, inflammatory disease and other conditions. It cannot directly measure inflammation inside an individual coronary plaque.

Can I have heart disease with a normal hs-CRP?

Yes. Atherosclerosis can develop despite a low hs-CRP, particularly when ApoB, LDL-C, Lp(a), blood pressure, smoking or other risk factors are unfavorable. A low hs-CRP does not rule out coronary plaque.

Can I have high hs-CRP but no coronary plaque?

Yes. hs-CRP reflects systemic inflammation and is not specific to atherosclerosis. Infection, inflammatory disease, obesity and many other conditions can elevate it even when coronary plaque is absent.

Do statins reduce inflammation?

Statins primarily reduce atherogenic lipoprotein exposure by lowering LDL-C and related ApoB-containing cholesterol. They also tend to lower hs-CRP and influence inflammatory pathways within atherosclerotic disease.

Does colchicine prevent heart attacks?

Low-dose colchicine reduced cardiovascular events in several randomized trials involving patients with established coronary disease, including LoDoCo2 and COLCOT. CLEAR SYNERGY, however, found no cardiovascular benefit when colchicine was started immediately after myocardial infarction. Current guidelines therefore reserve it for selected patients rather than recommending it universally.

Can insulin resistance increase cardiovascular inflammation?

Yes. Insulin resistance and visceral adiposity are commonly associated with inflammatory signaling, altered lipid metabolism, hypertension and other pathways that can increase atherosclerotic cardiovascular risk.

Does a calcium score show inflammation?

No. A coronary calcium score measures calcified coronary plaque. It does not directly measure inflammation and does not show noncalcified plaque.

Can CCTA show more than a calcium score?

Yes. CCTA uses intravenous contrast to visualize the coronary arteries and can show both calcified and noncalcified plaque as well as coronary narrowing. It still does not directly measure plaque inflammation.

Research & References

1. American Heart Association and American College of Cardiology. 2026 Guideline on the Management of Dyslipidemia. AHA Guideline Summary
2. Kumarapperuma H, et al. Response to retention hypothesis as a source of targets for arterial wall-directed therapies to prevent atherosclerosis: A critical review. Atherosclerosis. 2024. PubMed
3. Atherosclerosis: from lipid-lowering and anti-inflammatory therapies to targeting arterial retention of ApoB-containing lipoproteins. 2025. PubMed
4. Ridker PM, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. New England Journal of Medicine. 2017. PubMed
5. Nidorf SM, et al. Colchicine in Patients with Chronic Coronary Disease. New England Journal of Medicine. 2020. PubMed
6. Jolly SS, et al. Colchicine in Acute Myocardial Infarction. New England Journal of Medicine. 2025. PubMed
7. American College of Cardiology. The Evolving Role of Colchicine in Coronary Atherosclerosis Management. 2025. American College of Cardiology
8. American College of Cardiology. Prioritizing Health: hsCRP, A Promising Risk Assessment Tool. 2025. American College of Cardiology