How can a patient with low cholesterol develop carotid atherosclerotic plaque?

Carotid Plaque Formation Despite Low Cholesterol

Patients with low cholesterol can still develop carotid atherosclerotic plaque because the relationship between LDL cholesterol and atherosclerosis is log-linear across all cholesterol ranges, meaning cardiovascular risk persists even at low LDL levels, and multiple non-lipid risk factors—including hypertension, smoking, diabetes, inflammation, and age—independently drive plaque formation. 1

Understanding the Cholesterol-Plaque Relationship

The association between LDL cholesterol and atherosclerotic disease follows a log-linear pattern rather than a threshold effect. This means:

• Risk reduction continues even at very low LDL levels, but absolute risk is never eliminated entirely 1
• When persons with low LDL have the same absolute risk as those with high LDL (due to other risk factors), they derive similar absolute benefit from further LDL lowering 1
• Recent trials found no threshold LDL level below which atherosclerotic risk completely disappears 1

Multiple Non-Lipid Mechanisms Drive Plaque Formation

Traditional Cardiovascular Risk Factors

Carotid atherosclerosis is driven by numerous factors beyond cholesterol 1:

• Hypertension (odds ratio 1.70) 1
• Diabetes mellitus (odds ratio 1.75) 1
• Current smoking (odds ratio 1.58) 1
• Age (odds ratio 1.79 per 10 years) 1
• Each additional risk factor exponentially increases atherosclerotic burden, even when LDL is controlled 2

Inflammatory and Structural Mechanisms

Atherosclerosis is fundamentally a chronic inflammatory disease, not purely a lipid storage disorder 2, 3:

• Activated macrophages and T-lymphocytes drive plaque progression through metalloproteinase secretion and extracellular matrix degradation 2
• Intraplaque hemorrhage from neovascularization can cause plaque expansion independent of circulating lipid levels 1, 2
• Oxidative stress and endothelial dysfunction promote LDL oxidation and foam cell formation even at low circulating LDL concentrations 3

Carotid-Specific Pathophysiology

The carotid arteries have distinct vulnerability patterns 1:

• Nodular calcifications and calcific nodule phenotypes occur more frequently in carotid than coronary arteries, particularly in males 1
• Carotid plaques express a higher proportion of fibro-fatty components compared to coronary lesions 1
• Hemodynamic stress at carotid bifurcations creates focal areas of endothelial injury regardless of systemic cholesterol levels 1

Clinical Evidence Supporting Multi-Factorial Causation

Epidemiological Data

• The Framingham Heart Study showed that carotid stenosis risk increases approximately 1.1-fold for every 10 mg/dL increase in total cholesterol, but substantial risk remains even at low cholesterol levels 1
• In the ARIC study, relationships between lipid values and incident ischemic stroke were weak, suggesting other factors predominate 1
• The Women's Health Study found strong associations between cholesterol and stroke, but the lowest quintile still experienced events 1

Plaque Composition Studies

Even patients achieving very low LDL levels retain atherosclerotic plaques 4:

• In patients with LDL <50 mg/dL on high-dose statins, 48.2% still had lipid plaques on optical coherence tomography 4
• These plaques showed more stable features (thicker fibrous caps, smaller lipid arcs) but were not eliminated 4
• Cholesterol content in plaques correlates with vulnerability markers, but plaque presence persists across all LDL ranges 5

Important Clinical Caveats

The "Low Cholesterol Paradox"

• At older ages (70-89 years) and in those with systolic blood pressure >145 mmHg, total cholesterol shows an inverse relationship with hemorrhagic stroke mortality 1
• This does not negate the causal role of LDL in ischemic events but highlights the complexity of stroke mechanisms 1

LDL Subclass Considerations

• Patients with "normal" total LDL may have elevated small dense LDL (sd-LDL) particles, which are more atherogenic 6
• LDL-3 and LDL-4 subclasses independently associate with unstable plaque features even when total LDL appears acceptable 6

Residual Risk Despite Optimal Lipid Control

The 2025 ESC consensus emphasizes that 816 million people worldwide have carotid plaque, with traditional risk factors as primary drivers 1. Even with aggressive lipid lowering:

• Statin therapy in SPARCL reduced stroke risk by only 16% overall, leaving substantial residual risk 1
• Among patients with carotid stenosis treated with atorvastatin 80 mg, stroke risk reduction was 33%, meaning two-thirds of baseline risk persisted 1

Management Implications

For patients with carotid plaque despite low cholesterol, focus on comprehensive risk factor modification 7:

• Target LDL <55 mg/dL with intensive statin therapy, adding ezetimibe or PCSK9 inhibitors as needed 7
• Aggressively manage hypertension, with particular attention to systolic blood pressure control 1
• Ensure smoking cessation and diabetes optimization (HbA1c targets) 1, 7
• Consider antiplatelet therapy (ticagrelor superior to aspirin in symptomatic patients, HR 0.68) 7
• Evaluate for revascularization if high-grade stenosis with increased-risk morphology or embolic signals 7

The key takeaway: cholesterol is necessary but not sufficient for atherosclerosis—its presence accelerates disease, but its absence does not prevent it when other pathogenic mechanisms remain active 1, 2.