Part 1/Chapter 2/13-min read

Atherosclerosis and Risk Factors

Pathogenesis of atherosclerosis, plaque progression, and medical management of occlusive disease

Edited by Tal M. Hörer MD, PhD · David T. McGreevy MD, PhD·Reviewed ·21 sections · 32 references

Background

Atherosclerotic occlusive disease is a systemic, progressive condition characterized by plaque formation within the arterial wall. It is the leading cause of vascular morbidity and mortality worldwide, affecting coronary, carotid, and peripheral arteries.

  • Global burden: >200 million people affected by peripheral arterial disease (PAD) globally, ~40 million in Europe. Prevalence increases with age and comorbidities .
  • Geographic distribution and health disparities: Higher incidence in high-income countries due to longevity; rising prevalence in low- and middle-income countries due to diabetes and smoking. Within developed nations, significant racial and ethnic disparities persist in PAD outcomes, with minority populations experiencing higher rates of advanced disease and limb loss .
  • Natural history: Many remain asymptomatic; 20–30% develop claudication, ~5–10% progress to chronic limb-threatening ischemia (CLTI), associated with high amputation and mortality rates . In patients with diabetes mellitus (DM), PAD often presents with more distal, multi-segmental involvement and a higher risk of rapid progression to limb-threatening stages .
  • Systemic risk: Patients with PAD have a 2–4× increased risk of myocardial infarction, stroke, and cardiovascular death . Emerging evidence highlights the role of lipoprotein(a) [Lp(a)] as an independent, genetically determined risk factor for atherosclerotic progression, though its clinical implementation in risk stratification remains a significant gap .

Associated vascular beds: Atherosclerosis rarely affects a single territory. Screening and surveillance should extend to: *Carotid arteries:** see 7Ch. 7 for management of extracranial carotid stenosis *Renal and mesenteric arteries:** see 11Ch. 11 for evaluation and treatment

Non-modifiable

  • Age: prevalence doubles every decade after 60 years.
  • Sex: historically more common in men; recent data show increasing rates in women.
  • Genetics: familial clustering; loci associated with lipid metabolism and inflammation.

Modifiable

  • Smoking: most important risk factor; increases peripheral artery disease (PAD) risk 2–4 fold. Smoking cessation improves survival and limb salvage .
  • Diabetes mellitus (DM): accelerates medial calcification, distal disease, and restenosis risk. It is a major risk factor for chronic limb-threatening ischemia (CLTI), requiring comprehensive risk factor modification and multidisciplinary care .
  • Hypertension: contributes to endothelial dysfunction, shear stress, and plaque rupture.
  • Dyslipidemia: elevated low-density lipoprotein (LDL) and reduced high-density lipoprotein (HDL) promote plaque formation.
  • Chronic kidney disease (CKD): accelerates atherosclerosis and is associated with a higher risk of vascular calcification.

Others

Additional risk factors include elevated homocysteine levels, which serve as both a predictor and prognostic marker for atherosclerotic cardiovascular disease . Other contributors include lipoprotein(a) and chronic inflammation markers such as C-reactive protein. Each contributes to endothelial injury and accelerated atherosclerosis.

Pathophysiology

Atherosclerosis is a chronic inflammatory disease of the arterial wall.

  1. Endothelial dysfunction
  2. * Triggered by smoking, hypertension, hyperlipidemia.
  3. * Loss of nitric oxide → vasoconstriction, platelet adhesion, leukocyte infiltration.
  4. Lipid accumulation and foam cell formation
  5. * LDL enters intima, oxidizes.
  6. * Macrophages engulf oxidized LDL → foam cells → fatty streak.
  7. Chronic inflammation
  8. * T-cells, cytokines (TNF-α, IL-6).
  9. * Matrix metalloproteinases (MMPs) degrade extracellular matrix.
  10. Plaque progression
  11. * Smooth muscle cell migration, collagen deposition → fibrous cap.
  12. * Progressive luminal narrowing → flow-limiting stenosis.
  13. Complications
  14. * Plaque rupture → acute thrombosis → acute limb ischemia.
  15. * Calcification → reduced vessel compliance, complicating interventions.

Clinical Presentation

Risk stratification and staging systems guide clinical decision-making in chronic limb-threatening ischemia (CLTI). The Wound, Ischemia, and foot Infection (WIfI) classification grades limb threat and estimates amputation risk and revascularization benefit, a strategy emphasized by the American College of Cardiology/American Heart Association (ACC/AHA) for the management of patients with diabetes to optimize limb salvage . The Global Limb Anatomic Staging System (GLASS) stages anatomic complexity of femoropopliteal and infrapopliteal disease. The PLAN framework (Patient risk, Limb severity [WIfI], ANatomic complexity [GLASS]) integrates these systems to guide revascularization strategy selection, conduit choice, and perfusion targets . Systematic clinical staging is also critical for value-based medicine to ensure the appropriate allocation of imaging resources and minimize diagnostic misallocation .

Non-invasive testing

Non-invasive hemodynamic tests—including ankle-brachial index (ABI), toe-brachial index (TBI), transcutaneous oximetry (TcPO₂), and skin perfusion pressure (SPP)—are essential for peripheral arterial disease (PAD) diagnosis, severity stratification, and wound-healing prediction. These tests represent the high-value, first-line diagnostic approach, helping to avoid the misallocation of more expensive advanced imaging resources . In patients with diabetes, where medial arterial calcification (MAC) may lead to falsely elevated or non-compressible ABI values, TBI and other physiological assessments are particularly critical for accurate assessment .

For measurement techniques, see 3Ch. 3. For chronic limb-threatening ischemia (CLTI) thresholds and Wound, Ischemia, and foot Infection (WIfI) integration, see 10Ch. 10.

Imaging

  • DUS: first-line; PSV ratio >2.0 = >50% stenosis. Used for surveillance after revascularization.
  • computed tomography angiography (CTA): mainstay for preoperative planning; 3D reconstructions of iliac, femoropopliteal, tibial arteries.
  • magnetic resonance angiography (MRA): alternative when CTA contraindicated.
  • digital subtraction angiography (DSA): gold standard for intra-procedural imaging; now primarily therapeutic.

Advanced imaging

  • IVUS: vessel sizing, stent optimization, plaque morphology.
  • OCT: research, limited in peripheral arteries.
  • AI-based imaging: machine learning models for automated stenosis detection, perfusion analysis, outcome prediction .

Risk factor modification & medical therapy

  • Risk factor modification: Includes aggressive management of hypertension (HTN), diabetes mellitus (DM), and dyslipidemia to target levels, alongside smoking cessation. These factors remain the primary drivers of cardiovascular disease (CVD) burden globally .
  • Medical therapy: Antiplatelet therapy and high-intensity statins are recommended for patients with peripheral artery disease (PAD). Cilostazol improves walking distance but is not available in all regions; pentoxifylline has limited evidence.

Note on renal artery stenosis: Routine revascularization for atherosclerotic renal artery stenosis is NOT recommended based on CORAL and ASTRAL trial data showing no benefit over optimal medical therapy for most patients. Intervention is reserved for high-risk phenotypes (flash pulmonary edema, rapidly declining renal function with bilateral stenosis, truly refractory hypertension). See 11Ch. 11 for detailed criteria .

Endovascular therapy (first-line in most cases)

Strategy selection:

Endovascular therapy is first-line for most patients with anatomically suitable disease. Strategy selection should be individualized using the PLAN framework (Patient risk, Limb severity [Wound, Ischemia, and foot Infection (WIfI)], ANatomic complexity [GLASS]). Endovascular therapy is preferred for GLASS stage I–II femoropopliteal lesions and in high surgical risk patients. Bypass-first strategy is favored when adequate great saphenous vein is available and anatomic complexity is high (e.g., GLASS III) or after failed endovascular therapy .

When using drug-coated devices, discuss the historical paclitaxel safety signal with patients and document shared decision-making. A 2018 meta-analysis reported an association with increased late mortality after paclitaxel-coated balloon/stent use in femoropopliteal interventions, prompting subsequent regulatory reviews .

Open surgery

Selection criteria:

In chronic limb-threatening ischemia (CLTI), bypass-first should be considered when adequate great saphenous vein (GSV) is available and anatomic complexity is high or after failed endovascular therapy. The BEST-CLI trial showed lower rates of major adverse limb events (MALE) and death with bypass versus endovascular therapy in patients with usable vein; when no adequate vein was available, outcomes were similar between strategies . Recent meta-analytical data reinforces the role of bypass surgery in providing durable limb salvage compared to endovascular therapy in CLTI patients . The BASIL trial suggested a late survival and amputation-free survival benefit for bypass among patients surviving beyond two years . Furthermore, patient-specific risk factors such as frailty are increasingly recognized as critical determinants of postoperative success, with higher frailty scores correlating with increased morbidity and mortality after open revascularization .

Post-bypass antithrombotic therapy can be tailored by conduit: dual antiplatelet therapy (DAPT) may benefit prosthetic grafts (CASPAR) , whereas vitamin K antagonists showed mixed results by conduit in the Dutch BOA study .

Hybrid procedures

  • Hybrid procedures combine open surgical and endovascular techniques, typically performed in a single setting to treat multilevel disease .
  • Example: common femoral artery (CFA) endarterectomy combined with proximal iliac stenting or distal infrainguinal endovascular intervention .
  • These approaches are increasingly utilized to reduce surgical morbidity compared to completely open reconstruction while achieving durable patency in complex, multilevel peripheral artery disease (PAD) .

Follow-up

Surveillance protocols should be tailored to procedure type and conduit. Consider duplex ultrasound (DUS) at 1, 6, and 12 months then annually after infrainguinal endovascular therapy or vein bypass, with shorter intervals for high-risk reconstructions (e.g., below-knee targets, prosthetic conduits). Combine imaging with ankle-brachial index (ABI)/toe-brachial index (TBI) and clinical assessment .

Tables

While the ankle-brachial index (ABI) remains the diagnostic standard, significant heterogeneity exists across international guidelines regarding screening recommendations for asymptomatic patients .

Table 2.1ClassificationFontaine and Rutherford Classification of peripheral artery disease (PAD)
I
**Rutherford Category**
0
**Clinical Presentation**
Asymptomatic
IIa/IIb
**Rutherford Category**
1–3
**Clinical Presentation**
Claudication (mild–severe)
III
**Rutherford Category**
4
**Clinical Presentation**
Rest pain
IV
**Rutherford Category**
5–6
**Clinical Presentation**
Ulcer/gangrene

Note: Modern management also incorporates the Wound, Ischemia, and foot Infection (WIfI) classification for chronic limb-threatening ischemia (CLTI) .

Table 2.2GuidelinesEvidence-Based Medical Therapy in PAD
Smoking cessation
**Major Trials**
Armstrong 2014?,
**Key Findings**
↓ Mortality, ↓ limb loss
Exercise therapy
**Major Trials**
Cochrane 2017?
**Key Findings**
↑ Walking distance 50–200%
Antiplatelets
**Major Trials**
CAPRIE?
**Key Findings**
↓ cardiovascular (CV) events, clopidogrel > aspirin
High-intensity Statins
**Major Trials**
, ,
**Key Findings**
↓ CV events, improved patency post-revascularization
Rivaroxaban + aspirin
**Major Trials**
COMPASS?,
**Key Findings**
↓ major adverse cardiovascular events (MACE), ↓ major adverse limb events (MALE)
SGLT2 inhibitors / GLP-1 RAs
**Major Trials**
**Key Findings**
↓ MACE in patients with diabetes mellitus (DM)
PCSK9 inhibitors
**Major Trials**
**Key Findings**
↓ MACE and MALE in high-risk patients
Cilostazol
**Major Trials**
Thompson 2002?
**Key Findings**
↑ Claudication distance, no effect on CV outcomes
Table 2.3Endovascular vs Surgical Revascularization
Comparison A

POBA

Trade-offs
  • Not durable
Comparison B

DCB

Trade-offs
  • Cost
Comparison C

DES

Trade-offs
  • Limited length
Comparison D

Covered stent

Trade-offs
  • Stent fracture
Comparison E

Bypass (vein)

Trade-offs
  • Major surgery
Comparison F

Prosthetic bypass

Trade-offs
  • Inferior distal

References

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  5. Conte MS, et al. Global Vascular Guidelines on CLTI. J Vasc Surg. 2019. PubMed
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Integrated risk stratification (WIfI, GLASS, PLAN) to guide revascularization

Contemporary chronic limb-threatening ischemia (CLTI) management relies on integrated risk stratification systems that combine anatomic and clinical factors to guide revascularization strategy and conduit selection.

For complete Wound, Ischemia, and foot Infection (WIfI), GLASS, and PLAN classification definitions and clinical applications, see 10Ch. 10.

Antithrombotic therapy optimization across scenarios (symptomatic PAD, post-LER, post-bypass)

Antithrombotic therapy in peripheral arterial disease (PAD) requires individualized risk–benefit assessment based on clinical scenario (stable PAD, post-revascularization, after bypass) and bleeding risk profile.

In patients with concomitant diabetes mellitus, the risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) is significantly elevated . For these high-risk individuals, dual pathway inhibition (DPI) consisting of low-dose rivaroxaban (2.5 mg twice daily) plus aspirin is recommended to reduce ischemic risk, particularly following lower extremity revascularization (LER).

For detailed trial evidence (COMPASS, VOYAGER-PAD, EUCLID, CASPAR, BOA) and dosing recommendations, see 10Ch. 10.

Intensive lipid lowering and non-statin therapy in PAD (targets and limb outcomes)

All patients with peripheral arterial disease (PAD) should receive high-intensity statin therapy unless contraindicated. The Heart Protection Study (HPS) and Scandinavian Simvastatin Survival Study (4S) trials demonstrated significant cardiovascular risk reduction with statin therapy . For very high-risk patients, particularly those with concomitant diabetes mellitus, who do not achieve target low-density lipoprotein cholesterol (LDL-C) levels with statins alone, the addition of ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor is recommended . The FOURIER and ODYSSEY OUTCOMES trials support this escalation strategy, with PAD subgroup analyses demonstrating both cardiovascular and limb benefits from PCSK9 inhibition .

Device selection: DCB/DES evidence and paclitaxel safety context

Paclitaxel-based drug-coated balloons (DCB) and drug-eluting stents (DES) improve patency in femoropopliteal disease compared to uncoated devices. Recent network meta-analysis data reinforces the efficacy of these endovascular treatments across various lesion locations and severities . Regulatory review following an initial safety signal (Katsanos 2018) has been ongoing; subsequent large real-world analyses have not confirmed excess mortality.

For detailed device evidence, current regulatory guidance, and shared decision-making requirements, see 10Ch. 10.

Bypass selection criteria and conduit choice informed by contemporary RCTs

In patients with chronic limb-threatening ischemia (CLTI), the selection between a bypass-first and an endovascular-first strategy depends on the availability of an adequate autologous vein conduit, anatomic complexity as defined by the Global Anatomic Staging System (GLASS), and patient surgical fitness. For patients with diabetes, management strategies must account for the high prevalence of infrapopliteal disease and increased wound complications . Accurate preoperative imaging is essential to ensure appropriate staging and conduit assessment, as misallocation of imaging resources can lead to suboptimal revascularization choices .

For BEST-critical limb ischemia (CLI) and BASIL trial evidence, conduit selection criteria, and revascularization algorithm, see 10Ch. 10.

Objective perfusion targets for wound healing (toe pressure, TcPO2, SPP) and their use

Objective perfusion measurements are essential for assessing tissue viability and guiding revascularization in chronic limb-threatening ischemia (CLTI). Toe pressure (TP) <30 mmHg or transcutaneous oxygen tension (TcPO₂) <25–30 mmHg indicates critical ischemia with low likelihood of wound healing without revascularization . In patients with diabetes, TP and TcPO₂ are more reliable diagnostic tools than the ankle-brachial index (ABI), which may be falsely elevated due to medial arterial calcification (MAC) . Skin perfusion pressure (SPP) <30–40 mmHg similarly predicts poor healing. These thresholds should be used to establish hemodynamic targets for revascularization and to reassess nonhealing wounds after intervention.

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