Atherosclerosis and Risk Factors

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 (Fowkes 2013).
• 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 (Repella 2025).
• 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 (Criqui 2015)📄. 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 (Das 2025).
• Systemic risk: Patients with PAD have a 2–4× increased risk of myocardial infarction, stroke, and cardiovascular death (Hiatt 2015)📄. 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 (Yang 2026).

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 (Willigendael 2004)📄.
• 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 (Das 2025).
• 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 (Habib 2023). 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 (ACC) for the management of patients with diabetes to optimize limb salvage (Mills 2014)^,(Das 2025). 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 (Conte 2019)📄. Systematic clinical staging is also critical for value-based medicine to ensure the appropriate allocation of imaging resources and minimize diagnostic misallocation (Raskin 2025).

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 (Raskin 2025). 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 (Das 2025).

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 [16].

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 (Tsao 2023).
• 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 (Cooper 2014)📄^,(Wheatley 2009)📄.

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 (Conte 2019)📄^,(Farber 2022).

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 (Katsanos 2018)📄.

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 (Farber 2022). Recent meta-analytical data reinforces the role of bypass surgery in providing durable limb salvage compared to endovascular therapy in CLTI patients (Ramesh 2025). The BASIL trial suggested a late survival and amputation-free survival benefit for bypass among patients surviving beyond two years (BASIL 2005). 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 (Gonzalez 2024).

Post-bypass antithrombotic therapy can be tailored by conduit: dual antiplatelet therapy (DAPT) may benefit prosthetic grafts (CASPAR) (Belch 2010)📄, whereas vitamin K antagonists showed mixed results by conduit in the Dutch BOA study (Dutch Bypass 2000).

Hybrid procedures

• Hybrid procedures combine open surgical and endovascular techniques, typically performed in a single setting to treat multilevel disease (Gornik 2024).
• Example: common femoral artery (CFA) endarterectomy combined with proximal iliac stenting or distal infrainguinal endovascular intervention (Gornik 2024).
• 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) (Gornik 2024).

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 (Naylor 2018)📄.

Tables

While the ankle-brachial index (ABI) remains the diagnostic standard, significant heterogeneity exists across international guidelines regarding screening recommendations for asymptomatic patients (Uyagu 2022).

Table 2.1. Fontaine and Rutherford Classification of peripheral artery disease (PAD)

Note: Modern management also incorporates the Wound, Ischemia, and foot Infection (WIfI) classification for chronic limb-threatening ischemia (CLTI) (Gornik 2024).

Table 2.2. Evidence-Based Medical Therapy in PAD

Table 2.3. Endovascular vs Surgical Revascularization

References

1. Fowkes FGR, et al. Global prevalence of PAD. Lancet. 2013. PubMed
2. Criqui MH, Aboyans V. Epidemiology of PAD. Circ Res. 2015. PubMed
3. Hiatt WR, et al. PAD as systemic disease. NEJM. 2015. PubMed
4. Willigendael EM, et al. Smoking and PAD. J Vasc Surg. 2004. PubMed
5. Conte MS, et al. Global Vascular Guidelines on CLTI. J Vasc Surg. 2019. PubMed
6. van Engelen A, et al. AI in PAD imaging. Eur Heart J. 2020. PubMed
7. Aboyans V, et al. ESVS/SVS Guidelines on PAD. Eur J Vasc Endovasc Surg. 2018. PubMed
8. CAPRIE Steering Committee. Clopidogrel vs aspirin. Lancet. 1996. PubMed
9. Eikelboom JW, et al. COMPASS trial. NEJM. 2017. PubMed
10. Gornik HL, et al. 2024 ACC/AHA/SVS Guideline for PAD. J Am Coll Cardiol. 2024. PMID: 38752899
11. Uyagu OD, et al. Quality assessment of PAD screening guidelines. BMJ Open. 2022. PMID: 36104133

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 (Das 2025). 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) (Das 2025).

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 (Heart Protection 2002)^,[@4s1994?]. 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 (Das 2025). The FOURIER and ODYSSEY OUTCOMES trials support this escalation strategy, with PAD subgroup analyses demonstrating both cardiovascular and limb benefits from PCSK9 inhibition (Sabatine 2017)📄^,(Schwartz 2018)📄.

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 (Zhou 2025). 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 (Das 2025). Accurate preoperative imaging is essential to ensure appropriate staging and conduit assessment, as misallocation of imaging resources can lead to suboptimal revascularization choices (Raskin 2025).

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 (Conte 2019)📄. In patients with diabetes, the 2025 ACC scientific statement emphasizes that 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) (Das 2025). 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 [@conte2019; @acc2025-h].