Understanding Atherosclerosis: A Patient’s Guide to Noninvasive Imaging of Plaque Composition and Disease Activity

Table of Contents

• Key Points
• Background: Why This Research Matters
• How This Review Was Conducted
• How Atherosclerosis Causes Heart Attacks and Strokes
• Stable vs. Unstable Atherosclerotic Plaque
• Current Imaging Strategies and Their Limits
• Imaging the Carotid Arteries
• Imaging the Coronary Arteries
• Clinical Implications
• Limitations of These Imaging Approaches
• Recommendations for Patients
• Frequently Asked Questions
• Source Information

Key Points

• Plaque rupture causes 60-70% of acute heart attacks and about 90% of ischemic strokes.
• Most heart attacks occur at sites with less than severe narrowing, so imaging plaque biology is important.
• Calcium score zero is reassuring: in a meta-analysis, only 0.47% of such patients had a cardiovascular event.
• In the SCOT-HEART trial, CT angiography-guided care reduced fatal or nonfatal heart attack at five years.
• Statins lowered arterial wall inflammation on FDG PET in a meta-analysis of 7 studies with 287 participants.

Background: Why This Research Matters

Cardiovascular disease remains one of the leading causes of death and disability worldwide, placing a major burden on health care systems. Atherosclerosis is the main disease process behind ischemic heart disease and cerebrovascular disease (conditions caused by reduced blood flow to the heart or brain). It is a systemic, multifocal process that often begins early in life and has a long silent phase before symptoms appear.

Symptoms vary depending on what the plaque looks like. For example, obstructive coronary artery disease can cause myocardial ischemia (reduced blood flow to heart muscle) and angina (chest pain), usually associated with stable plaque. But unstable atherosclerotic plaque is prone to abrupt rupture or erosion. This can be clinically silent, yet may result in thrombotic vessel occlusion (a blood clot blocking the artery), leading to acute stroke or myocardial infarction (heart attack).

Modern imaging techniques now make it possible, for the first time, to directly and noninvasively image plaque in the carotid and coronary arteries. This allows assessment of plaque composition and disease activity, rather than only looking at how blocked an artery is. The review discusses how these novel approaches might differentiate stable from unstable patterns of atherosclerosis and complement existing imaging techniques, ultimately improving care.

How This Review Was Conducted

This article is a state-of-the-art review, not a new clinical trial. The authors—from the British Heart Foundation Centre for Cardiovascular Science at the University of Edinburgh and the Translational and Molecular Imaging Institute at the Icahn School of Medicine at Mount Sinai, New York—collected and interpreted existing research on noninvasive imaging of atherosclerotic plaque.

They focused on both carotid and coronary applications and examined several imaging modalities: ultrasound, computed tomography (CT), magnetic resonance (MR), and positron emission tomography (PET). The review discusses how these techniques assess plaque composition (such as lipid core, fibrous cap, calcification, and hemorrhage) and disease activity (such as inflammation and macrophage infiltration). The authors also summarized data from key clinical studies and meta-analyses to support their conclusions.

How Atherosclerosis Causes Heart Attacks and Strokes

Atherosclerosis is an inflammatory process that affects the inner layer of arteries (the intima). It involves extensive lipid (fat) deposition, foam cell formation, and migration of vascular smooth muscle cells. The resulting plaque can behave in two ways:

• Stable disease: The plaque causes progressive luminal narrowing, ischemia, and symptoms such as stable angina.
• Unstable disease: The plaque ruptures abruptly, causing thrombus (clot) formation, vessel occlusion, and myocardial or cerebral infarction.

Plaque rupture is the main way atherosclerosis causes clinical events. It accounts for 60% to 70% of acute heart attacks and approximately 90% of ischemic strokes.

Importantly, although stable angina and cardiac ischemia symptoms are associated with severe coronary artery narrowing, most heart attacks actually occur at sites of non-obstructive plaque—areas that had less than severe narrowing on prior angiography. This is why the traditional approach of simply looking for blockages is not enough.

Stable vs. Unstable Atherosclerotic Plaque

Unstable plaques that are at high risk of rupture are sometimes called “vulnerable plaques.” They have distinct pathological features:

• Stable lesions: Thick fibrous cap, macrocalcification (large calcium deposits), and extensive fibrous tissue.
• Vulnerable plaques: Large necrotic (dead) core, very thin fibrous cap (under 65 micrometers), inflammation (mainly macrophage infiltration), positive remodeling (the artery expands outward rather than narrowing), neoangiogenesis (new blood vessel growth), intraplaque hemorrhage (bleeding within the plaque), and microcalcification (tiny calcium spots).

Interestingly, culprit lesions (the plaques that cause events) are often associated with a large area of plaque but frequently have a luminal stenosis of less than 75% because of positive remodeling. These adverse features often coexist in a structure called the thin-cap fibroatheroma. Each of these features represents a potential imaging target.

Early attempts to identify vulnerable plaques used invasive imaging, such as intravascular ultrasound (IVUS), optical coherence tomography, and near-infrared spectroscopy. These provide excellent detail but cannot easily be used to survey the entire coronary or carotid tree in low-risk patients.

A landmark invasive study, PROSPECT, enrolled 697 patients with acute coronary syndromes and performed three-vessel virtual histology IVUS (VH-IVUS). The researchers identified 596 high-risk plaques (VH-IVUS-defined thin-cap fibroatheromas). However, after 3 years of follow-up, only 21 heart attacks occurred. This means most vulnerable plaques either heal or rupture subclinically without causing hard clinical events. The authors argue that imaging entire vascular beds noninvasively may be more useful: although individual plaques are unlikely to cause an event, patients who develop unstable patterns of disease have a higher overall risk.

Current Imaging Strategies and Their Limits

For many decades, the clinical approach to atherosclerosis has centered on detecting obstructive luminal stenoses (blockages). In the carotid arteries, the degree of narrowing—measured by ultrasound, CT angiography, or MR angiography—is used to decide whether a patient needs surgical revascularization (such as carotid endarterectomy).

But a severe stenosis provides only modest prediction of future events, especially in people without symptoms. In the coronary arteries, CT angiography can directly assess stenosis severity, often aided by CT-derived fractional flow reserve. Myocardial stress perfusion imaging and stress echocardiography detect the consequences of blockages on heart muscle.

Yet the COURAGE and BARI-2D trials showed that percutaneous coronary intervention (PCI, or angioplasty/stenting) failed to reduce the risk of heart attack despite effectively relieving ischemia. This suggests the relationship between obstructive narrowing, ischemia, and adverse outcomes is not simple and may not be causal. Therefore, interest has shifted toward imaging plaque burden and plaque type.

Plaque burden imaging is based on the idea that the more plaque a patient has, the more likely one will rupture. In carotid arteries, ultrasound-derived plaque burden assessments improve risk prediction beyond traditional cardiovascular risk scores. In coronary arteries, CT calcium scoring quantifies macroscopic calcified deposits and acts as a surrogate for total coronary atherosclerotic burden.

One large observational study of 25,253 patients in the United States, with a mean follow-up of 6.8 years, showed that survival varied significantly according to the extent of coronary artery calcification (CAC) (p < 0.0001). Survival rates were:

• 99.4% for CAC score of 0
• 94.7% for CAC score of 400 to 699
• 87.8% for CAC score of 1,000 or higher

Multiple studies have examined very low event rates in patients with a CAC of zero. A meta-analysis by Sarwar and colleagues analyzed 13 studies with 71,595 asymptomatic patients. They found that 0.47% of patients without CAC had a cardiovascular event during follow-up, compared with 4.14% among those with CAC.

However, CAC scoring provides a surrogate of plaque burden at a relatively low radiation dose (about 1 mSv), but it specifically quantifies calcified plaques, which themselves are relatively unlikely to cause events. This has led to the idea that imaging should also consider plaque type—both anatomic composition and molecular disease activity.

Imaging the Carotid Arteries

Cerebrovascular disease is one of the main causes of death and the most important cause of disability globally. Many risk factors are similar to coronary artery disease. Because the carotid arteries are large, close to the surface, and relatively still, they are easier to image than the coronary arteries. Most novel plaque imaging techniques are therefore first tested in the carotids, and researchers can validate imaging findings against tissue removed during carotid endarterectomy surgery.

Plaque Composition Imaging

Ultrasound is widely used to measure carotid stenosis, but its ability to assess plaque composition is limited. It can distinguish between echolucent heterogeneous plaques (suggesting unstable disease) and echogenic plaques (suggesting calcified, stable lesions), but this distinction is not yet used clinically.

CT angiography provides high-resolution anatomic images and can be useful when ultrasound is difficult, but it requires radiation and iodinated contrast. MR angiography is generally preferred because it is more sensitive and specific.

Magnetic resonance (MR) imaging is particularly well suited to plaque characterization because of its soft-tissue contrast. Fast, high-resolution black-blood MR techniques suppress blood signal and give detailed views of the vessel wall and plaque composition. Multispectral MR can categorize plaque into different tissue types, quantify lipid content, and identify a ruptured fibrous cap. Gadolinium contrast improves the ability to discriminate the lipid core from the overlying fibrous cap. T1-weighted techniques are especially good at identifying intraplaque hemorrhage and luminal thrombosis because methemoglobin, a breakdown product of hemoglobin, amplifies the T1 signal in areas of recent thrombus or hemorrhage.

MR can also target plaque inflammation using ultrasmall superparamagnetic particles of iron oxide (USPIO). These particles are injected intravenously and taken up by macrophages. The T2* effect produces signal loss (hypointensity) in areas with active macrophage infiltration. Increased USPIO uptake has been shown in culprit carotid plaques after stroke and in asymptomatic carotid stenoses compared with nonculprit or healthy vessels. Larger trials are still needed to establish USPIO’s clinical role.

MR-identified adverse plaque features are associated with future events. In one study by Takaya and colleagues of asymptomatic patients with 50% to 70% carotid stenosis, arteries with thinned or ruptured fibrous caps, intraplaque hemorrhage, and a large lipid core were associated with subsequent cerebrovascular events. This was confirmed in a systematic review of 9 studies. Importantly, adverse carotid plaque features are also associated with clinical events arising from the coronary arteries, highlighting that atherosclerosis is a systemic disease.

Disease Activity Imaging

Hybrid PET imaging combines a PET scanner with CT or MR to overlay molecular activity on anatomic images. A radioactive tracer is injected intravenously, accumulates where the disease process is active, and emits positrons that are detected and localized.

The most common tracer is 18F-fluorodeoxyglucose (18F-FDG), which labels cells with high glucose metabolism, including activated inflammatory cells. Increased 18F-FDG uptake in carotid plaque closely corresponds to macrophage infiltration, making it a surrogate for vascular inflammation. Studies have shown increased 18F-FDG activity in culprit carotid plaques after a cerebrovascular event compared with the opposite carotid artery. Other work using 18F-fluoromisonidazole showed symptomatic carotid plaques are more hypoxic (low oxygen) than asymptomatic lesions, and hypoxia contributes to increased FDG uptake.

18F-FDG uptake in the carotids correlates with predicted cardiovascular risk, although it sometimes fails to discriminate between culprit and nonculprit lesions. In a retrospective study of 309 patients who underwent FDG PET-CT (mostly for suspected cancer), uptake in the ascending aorta was a predictor of future coronary heart disease events independent of Framingham risk scores.

18F-FDG has also been used to monitor treatment. A meta-analysis of 7 studies with 287 participants found that statin treatment was associated with a significant reduction in arterial wall inflammation, measured by tissue-to-background ratio (TBR) on FDG PET-CT.

However, FDG is a glucose analogue and is not entirely specific for inflammation. More inflammation-specific tracers are under investigation:

• DOTATATE targets somatostatin receptor subtype-2, abundant on proinflammatory M1 macrophages. Pedersen and colleagues demonstrated increased uptake of 64Cu-DOTATATE in carotid plaque, with uptake correlating with macrophage burden on histology. Tarkin and colleagues found increased 68Ga-DOTATATE uptake in culprit carotid plaques, and this tracer appeared to outperform 18F-FDG.
• 18-kDa translocator protein (TSPO) tracers, such as 11C-PK11195, target a protein found in the outer mitochondrial membrane of macrophages. 11C-PK11195 shows increased uptake in culprit carotid plaques after stroke, independent of stenosis, and correlates with inflammatory cell burden on histology. It can distinguish recently symptomatic from asymptomatic plaque and improves risk stratification. However, it has high nonspecific binding and a short half-life (about 20 minutes), requiring an on-site cyclotron. Second-generation TSPO tracers have been disappointing because binding varies with the rs6971 genetic polymorphism. Third-generation tracers are under evaluation.

Imaging the Coronary Arteries

Coronary CT angiography (CTA) is now well established for noninvasive assessment of suspected coronary artery disease. Two large randomized controlled trials support its use:

SCOT-HEART: The use of CTA increased diagnostic certainty, changed clinical management, and reduced fatal or nonfatal heart attack at 5 years compared with standard care. The difference was 2.3% versus 3.9% (hazard ratio [HR]: 0.59; 95% confidence interval [CI]: 0.41 to 0.84).

PROMISE: This trial recruited a lower-risk population and had a shorter follow-up of 25 months. There was no difference in the composite primary outcome (death, heart attack, hospitalization for unstable angina, or major procedural complication). However, at 12 months, the risk of death or nonfatal heart attack was lower in the CTA group compared with the stress-imaging group, with a hazard ratio of 0.66.

Coronary CTA can also assess adverse plaque features similar to those seen in the carotids, including positive remodeling, low-attenuation plaque, napkin-ring sign, and spotty calcification. However, the review focuses on how PET tracers can add molecular information to CT or MR anatomy. While coronary imaging is more technically challenging than carotid imaging because of the small size and constant motion of the coronary arteries, advances in hybrid PET/CT and PET/MR systems are enabling assessment of plaque biology in the coronary bed.

Clinical Implications

The authors emphasize that these noninvasive techniques hold the potential to improve risk stratification beyond simple measures of stenosis or calcium score. The key implications are:

• Patients with unstable plaque features—even without severe narrowing—may be at higher risk of future events, and imaging could identify these patients earlier.
• Imaging disease activity (such as inflammation) can monitor response to preventive therapies. The FDG PET meta-analysis showing statins reduce arterial wall inflammation is a powerful example.
• Because atherosclerosis is systemic, detecting unstable plaque in the carotid arteries can also signal higher risk of coronary events, and vice versa.
• Combining anatomic imaging (CT or MR) with molecular imaging (PET) provides a more complete picture: plaque composition, plaque burden, and disease activity all in one assessment.

However, the authors note that there are few randomized data, beyond the SCOT-HEART trial, demonstrating that imaging-guided management improves outcomes. This explains why current guidelines make relatively weak recommendations for many of these emerging approaches.

Limitations of These Imaging Approaches

The review is careful to acknowledge important limitations:

• Few randomized outcome trials. Most evidence comes from observational studies or small mechanistic trials. SCOT-HEART is the main randomized trial showing improved outcomes with a modern imaging approach.
• Most vulnerable plaques never cause events. As PROSPECT showed, only a small number of high-risk plaques lead to heart attacks during follow-up. Imaging more plaques may therefore lead to overtreatment if interpreted at the individual plaque level.
• Tracer limitations. 18F-FDG is not specific for inflammation, TSPO tracers are limited by genetic polymorphism and short half-lives, and many tracers are not yet approved for routine human use.
• Technical challenges. Coronary imaging is difficult because of cardiac and respiratory motion, small vessel size, and the need for high spatial resolution. Radiation exposure remains a concern, although CAC scoring is low dose (around 1 mSv).
• USPIO and MR techniques still require larger clinical trials before they become standard clinical tools.
• Histological validation is easier in the carotids (where surgery provides tissue), but such validation is rarely possible in the coronaries.

Recommendations for Patients

If you or a loved one are concerned about heart attack or stroke risk, this review offers several practical takeaways:

1. Talk with your doctor about your risk factors. High blood pressure, high cholesterol, smoking, diabetes, and family history all contribute to atherosclerosis. Imaging may add information beyond traditional risk scores.
2. Understand that a normal stress test or non-calcified plaque does not mean zero risk. A calcium score of zero is reassuring but not a guarantee—0.47% of people with no CAC still had a cardiovascular event in the Sarwar meta-analysis.
3. Ask about advanced imaging if you have had a stroke or transient ischemic attack (TIA). MR and PET imaging of the carotid arteries can sometimes identify unstable plaque features and guide treatment.
4. If you have coronary artery disease, discuss CT angiography with your cardiologist. SCOT-HEART showed that CTA-guided management reduced heart attacks compared with standard care.
5. Do not skip statin therapy just because you feel fine. Statins not only lower cholesterol but also reduce arterial wall inflammation, as shown by FDG PET imaging studies.
6. Know that symptoms matter. Chest pain, shortness of breath, sudden weakness, or difficulty speaking warrant prompt medical attention, even if previous imaging showed only mild narrowing.
7. Stay informed. These imaging techniques are evolving rapidly. What is experimental today may become standard care tomorrow.

Frequently Asked Questions

What is atherosclerosis and how does it cause heart attacks and strokes?

Atherosclerosis is an inflammatory process inside artery walls, with fat deposits and plaque buildup. Stable plaque narrows arteries gradually, causing symptoms like angina. Unstable plaque can rupture abruptly, forming a clot that blocks blood flow, leading to heart attack or stroke. Plaque rupture causes most heart attacks and about 90% of ischemic strokes.

Why might my doctor recommend a CT scan of my coronary arteries?

Coronary CT angiography gives detailed images of artery blockages and plaque. In the SCOT-HEART trial, using CTA changed management and reduced fatal or nonfatal heart attacks at five years compared with standard care. Your doctor may use it to assess both narrowing and plaque features, helping guide treatment decisions.

What is a coronary calcium score and what does a score of zero mean?

A calcium score measures calcified plaque in coronary arteries. In one meta-analysis of 71,595 asymptomatic patients, 0.47% of those with a calcium score of zero had a cardiovascular event during follow-up, compared with 4.14% in those with calcium. Zero is reassuring but not a guarantee of zero risk.

Can imaging tell whether my plaque is unstable and likely to rupture?

Advanced CT, MR, and PET scans can identify features of vulnerable plaque, such as a thin fibrous cap, inflammation, or intraplaque hemorrhage. However, the PROSPECT study found that most vulnerable plaques do not cause events during follow-up. Imaging may help assess overall risk, but individual plaque behavior remains unpredictable.

What is FDG PET imaging and how is it used for cardiovascular risk?

FDG PET uses a radioactive tracer that labels cells with high glucose metabolism, including activated inflammatory cells in artery plaque. Increased FDG uptake indicates vascular inflammation. A meta-analysis of 7 studies with 287 participants found that statin treatment was associated with a significant reduction in arterial wall inflammation on FDG PET.

Are these advanced plaque imaging tests widely available in routine care?

Most of these techniques are still emerging. Coronary CT angiography is well established, but many PET and MR approaches are not yet standard. The review notes that few randomized outcome trials exist beyond SCOT-HEART, so guidelines make relatively weak recommendations for many of these methods. Availability varies by center.

If I have had a stroke or TIA, what advanced imaging might help evaluate my carotid arteries?

MR imaging can characterize carotid plaque composition and detect features like a ruptured fibrous cap or intraplaque hemorrhage, which are associated with future cerebrovascular events. PET tracers such as FDG can measure inflammation. These techniques may help identify unstable plaque and guide treatment, though larger trials are still needed.

Source Information

This patient-friendly article is based on the following peer-reviewed publication:

Original title: Noninvasive Imaging to Assess Atherosclerotic Plaque Composition and Disease Activity: Coronary and Carotid Applications

Authors: Marwa Daghem, MBChB; Rong Bing, MBBS; Zahi A. Fayad, BSEE, MSE, PhD; Marc R. Dweck, BSc, MBChB, PhD

Journal: JACC: Cardiovascular Imaging, Volume 13, No. 4, April 2020, pages 1055–1068

Publisher: Elsevier on behalf of the American College of Cardiology Foundation

DOI: 10.1016/j.jcmg.2019.03.033

Access: This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

This patient-friendly article is based on peer-reviewed research and is intended for educational purposes. It does not replace individualized medical advice from a qualified health care provider.