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 PAD globally, ~40 million in Europe. Prevalence increases with age and comorbidities ^[1].
• Geographic distribution: Higher incidence in high-income countries due to longevity; rising prevalence in low- and middle-income countries due to diabetes and smoking.
• 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 ^[2].
• Systemic risk: Patients with PAD have a 2–4× increased risk of myocardial infarction, stroke, and cardiovascular death ^[3].

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 PAD risk 2–4 fold. Smoking cessation improves survival and limb salvage ^[4].
• Diabetes mellitus: accelerates medial calcification, distal disease, and restenosis risk. Major risk factor for CLTI.
• Hypertension: contributes to endothelial dysfunction, shear stress, plaque rupture.
• Dyslipidemia: elevated LDL and reduced HDL promote plaque formation.
• Chronic kidney disease (CKD): accelerates atherosclerosis, higher risk of calcification.

Others

Additional risk factors include elevated homocysteine levels, 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 CLTI. The WIfI (Wound, Ischemia, foot Infection) classification grades limb threat and estimates amputation risk and revascularization benefit. The GLASS (Global Limb Anatomic Staging System) 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 ^[5],[6].

Non-invasive testing

Non-invasive hemodynamic tests (ABI, TBI, TcPO₂, SPP) are essential for PAD diagnosis, severity stratification, and wound-healing prediction.

For measurement techniques, see 3Ch. 3. For CLTI thresholds and WIfI integration, see 10Ch. 10.

Imaging

• DUS: first-line; PSV ratio >2.0 = >50% stenosis. Used for surveillance after revascularization.
• CTA: mainstay for preoperative planning; 3D reconstructions of iliac, femoropopliteal, tibial arteries.
• MRA: alternative when CTA contraindicated.
• 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 ^[7].

Risk factor modification & medical therapy

• Risk factor modification: Includes aggressive management of hypertension, diabetes, and dyslipidemia to target levels, alongside smoking cessation.
• Medical therapy: Antiplatelet therapy and high-intensity statins are recommended. 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 ^[8],[9].

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 [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 ^[6],[10].

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 ^[11].

Open surgery

Selection criteria:

In 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 ^[10]. The BASIL trial suggested a late survival and amputation-free survival benefit for bypass among patients surviving beyond two years ^[12].

Post-bypass antithrombotic therapy can be tailored by conduit: DAPT may benefit prosthetic grafts (CASPAR) ^[13], whereas vitamin K antagonists showed mixed results by conduit in the Dutch BOA study ^[14].

Hybrid procedures

• Example: iliac stenting + femoral endarterectomy.
• Increasingly used in multilevel disease.

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 ABI/TBI and clinical assessment ^[15].

Tables

Table 2.1. Fontaine and Rutherford Classification of PAD

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

Integrated risk stratification (WIfI, GLASS, PLAN) to guide revascularization

Contemporary CLTI management relies on integrated risk stratification systems that combine anatomic and clinical factors to guide revascularization strategy and conduit selection.

For complete 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 PAD requires individualized risk–benefit assessment based on clinical scenario (stable PAD, post-revascularization, after bypass) and bleeding risk profile.

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 PAD should receive high-intensity statin therapy unless contraindicated. The HPS and 4S trials demonstrated significant cardiovascular risk reduction with statin therapy ^[16],[17]. For very high-risk patients who do not achieve target LDL-C levels with statins alone, add ezetimibe or a PCSK9 inhibitor. The FOURIER and ODYSSEY OUTCOMES trials support this escalation strategy, with PAD subgroup analyses demonstrating both cardiovascular and limb benefits from PCSK9 inhibition ^[18],[19].

Device selection: DCB/DES evidence and paclitaxel safety context

Paclitaxel-based drug-coated balloons (DCBs) and drug-eluting stents (DES) improve patency in femoropopliteal disease compared to uncoated devices. 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 CLTI, bypass-first versus endovascular-first strategy selection depends on vein availability, anatomic complexity (GLASS staging), and patient fitness.

For BEST-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 CLTI. Toe pressure <30 mmHg or transcutaneous oxygen tension (TcPO₂) <25–30 mmHg indicates critical ischemia with low likelihood of wound healing without revascularization. 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 ^[6].