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Epidemiology
- Most studies use ABI to diagnose PAD
- Abnormal: ≥40 y/o (6%), ≥65 y/o (15-20%)
- Blacks have higher prevalence of PAD than non-Hispanic whites
- Claudication – prevalence increases with age, men > women

Risk factors for PAD

- Smoking, T2DM, HTN, and hypercholesterolemia account for about 75% of the risk of developing
PAD
- Other risk factors: inflammation (measured by CRP), CKD, diet, and sedentary lifestyle
- DM and metabolic syndrome associate strongly with incident PAD
- Distal disease affecting tibial and peroneal arteries occurs more frequently
- Diabetic patients more likely to have CLI or undergo amputation (microvascular disease)
- Elevations in total and LDL increase risk

Skeletal Muscle Structure and Metabolic Function

- Type 1 oxidative slow-twitch fibers are preserved
- Type 2 glycolytic fast-twitch fibers are lost
- Correlates with decreased muscle strength and reduced exercise capacity

CLINICAL FEATURES
Symptoms
- Cardinal symptoms of PAD: limb pain with exercise (intermittent claudication) or at rest
- Can include pain, ache, sense of fatigue, or other discomfort that occurs with exercise and
Pathophysiology of Peripheral Artery Disease resolves with rest
- Intermittent claudication results from O2 supply-demand mismatch - Location is related to the site of the most proximal stenosis
- Blood flow and O2 consumption are normal at rest but obstructive lesions limit blood flow and O2 - Gastrocnemius muscle consumes more oxygen during walking (most frequent symptoms
delivery during exercise reported)
- In CLI, multiple occlusive lesions cannot meet nutritional needs even at rest - Symptoms should resolve several minutes after cessation of effort
- Factors regulating blood supply - Episodic calf or thigh pain that occurs during rest (nocturnal cramps) are not symptoms of PAD
- Flow through an artery is directly related to perfusion pressure and inversely related to - Questionnaires: Rose Questionnaire, Edinburgh Questionnaire, San Diego Claudication
vascular resistance Questionnaire, Walking Impairment Questionnaire
- Poiseuille equation - Neurogenic pseudoclaudication
- Pressure gradient across the stenosis - Lumbosacral radiculopathy resulting from degenerative joint disease, spinal stenosis, and
- Radius of the residual lumen herniated discs
- Blood viscosity - Cause pain in the buttock, hip, thigh, calk, or foot when walking
- Length of the vessel affected by the stenosis - Exertional compartment syndrome
- A BP gradient exists at rest if the stenosis reduces the diameter of the lumen by > 50% - Most often occurs in athletes with large calf muscles
- As flow through a stenosis increases, distal perfusion pressure drops - Increased tissue pressure during exercise limits microvascular flow
- Local metabolites: adenosine, nitric oxide, potassium, hydrogen ions (peripheral resistance dilate) - Symptoms improve after cessation of exercise
- Glycogen storage disease type V (McArdle syndrome)
- Deficient skeletal muscle phosphorylase
- Chronic venous insufficiency
- Can also present as leg discomfort with exertion (venous claudication)
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- Ulcers of venous insufficiency localizes near the medial malleolus, have irregular border,
and a pink base with granulation tissue
- Cause milder pain
- CLI
- Pain or paresthesias at rest
- Worsens with leg elevation and improves with leg dependency
- Skin is very sensitive
- Patients tend to sit on the edge of the bed and dangle their legs
- Neuropathic ulcers occur at sites of pressure or trauma (usually on the sole)
- Usually deep, frequently infected, and not generally painful due to loss of sensation

Physical Findings
- Bruits are a sign of accelerated blood flow velocity and flow disturbance at sites of stenosis
- Pallor can be elicited on the soles by performing a maneuver in which the feet are elevated above
the heart and the calf muscles are exercised by repeated dorsiflexion and plantar flexion
- Chronic aortoiliac disease may lead to leg muscle atrophy TESTING FOR PERIPHERAL ARTERY DISEASE
- Additional sings of chronic low-grade ischemia: hair loss, dystrophic, thickened and brittle
toenails, smooth and shiny skin, and atrophy of the subcutaneous fat of the digital pads Segmental Pressure Measurement
- Ulcers of PAD typically have a pale base with irregular borders and usually involve the tips of the - Lower extremities: upper and lower portions of the thigh, calf, above the ankle, over the metatarsal
toes or heel and at sites of pressure area of the foot
- May vary in size and may be as small as 3-5 mm - Upper extremities: biceps, forearm below the elbow, at the wrist
- Most convenient to place the Doppler probe on the foot over the posterior tibial artery (courses
Categorization inferior and posterior to the medial malleolus) or over the dorsalis pedis artery
- Depends on the severity of the symptoms and abnormalities detected on physical examination - Approximately 90% of the CSA of the aorta must be narrowed before a pressure gradient
- Chronic limb threatening ischemia or CTLI – advanced PAD with rest pain, gangrene, or ulceration develops
of greater than 2 weeks - In smaller vessels, a 70-90% decrease in CSA will cause a pressure gradient sufficient to
decrease SBP
- A BP gradient in excess of 20 mmHg between successive cuffs is generally used as evidence of
arterial stenosis in the lower extremities
- A gradient of 10 mmHg in the upper extremities
- SBP in the toes and fingers is 60% of SBP at the ankle and wrist

Ankle-Brachial Index
- How to get ABI: Take the higher pressure of the 2 arteries at the ankle, divided by the higher of
the two brachial arterial systolic pressure
- Values:
- Normal – 1.00-1.40
- Borderline – 0.91-0.99
- Abnormal – ≤0.90
- ABI >1.40 indicates a non-compressible artery
- Not informative for confirming or excluding PAD
- Toe-brachial index (TBI) may be used with ≥0.70 being normal
- An ankle SBP <55 mmHg predicts poor ulcer healing

Treadmill Exercise Testing

- Claudication onset time – time when symptoms of claudication first develop
- Peak walking time – occurs when the patient can no longer continue walking because of severe
leg discomfort
- Fixed workload test – constant grade of 12% and speed of 1.5-2.0 mph
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- Progressive or graded protocol – constant speed of 2 mph while grade gradually increases by 2% − dye
every 2-3 minutes − Sensitivity of 67-100%, specificity of 72-100% for PAD Dx
- Ankle and brachial SBP measured during rest, within 1 minute after exercise, and repeatedly − Indications: diagnosis, monitoring in revascularization, assessment for potential
until baseline values are reestablished amputation, visualization of perfusion
- BP increase should be the same with a constant ABI of 1.0 or greater being maintained 2. Transcutaneous oxygen pressure measurement (TcpO2)
- Diagnostic for PAD = 25% or greater decrease in ABI after exercise in a patient whose walking − In patients with CLI to assess the likelihood of healing after amputation
capacity is limited by claudication − Normal: >55 mmHg
− <30 mmHg = low probability of wound healing
Pulse Volume Recording 3. Venous occlusion plethysmography (VOP)
- Normal pulse volume contour − Quantify limb blood flow and hemodynamic compromise in PAD
- Resembles a BP waveform
- Sharp systolic upstroke rising rapidly to a peak, a dicrotic notch, a concave downslope that PROGNOSIS
drops off gradually toward the baseline
− Heightened risk of severe ischemic limb complications, loss of function
- Abnormal pulse volume contour (stenosis)
− Worsening symptoms develop in approximately 25% of patients with claudication
- Loss of the dicrotic notch, a slower rate of rise, a more rounded peak, a slower descent
− over 3 years, approximately 20% will require
− an intervention to improve lower extremity perfusion
Doppler Ultrasonography
− Smoking and DM - independently predict disease progression
− Doppler probe positioned at approximately a 60º angle over the common femoral, superficial
− DM - 12X higher likelihood of amputation
femoral, popliteal, dorsalis pedis, and posterior tibial arteries
− 3 components of normal Doppler waveform:
TREATMENT
1. rapid forward-flow component during systole
Goals of treatment:
2. transient flow reversal during early diastole
− Improve quality of life and function
3. slow anterograde component during late diastole
− Reduce the risk of ischemic limb and CV complications
Duplex Ultrasound Imaging
Class I recommendation:
− Direct, noninvasive assessment of anatomic characteristics of peripheral arteries and the
1. Antiplatelet therapy with aspirin alone (range, 75–325 mg/day) or clopidogrel alone (75 mg/day)
functional significance of arterial stenoses
is recommended to reduce MI, stroke, and vascular death in patients with symptomatic PAD.
− ≥2X increase in PSV = ≥50% stenosis
2. Treatment with statin is indicated for all patients with PAD.
− 3X increase = ≥75%
3. Antihypertensive therapy should be administered to patients with hypertension and PAD.
− No signal = occluded artery
4. Advise to quit smoking cigarettes or use other forms of tobacco.
5. Pharmacotherapy for smoking cessation: varenicline, bupropion, and/or nicotine replacement
Magnetic Resonance Angiography
therapy
− Non-invasive visualization of aorta and peripheral artery
6. Management of diabetes mellitus in the patient with PAD should be coordinated
− Comparison of MRA with intra-arterial DSA: 95% sensitivity and 96% specificity for detecting 7. Cilostazol is an effective therapy to improve symptoms and increase walking distance in
segmental stenotic and occlusive lesions patients with claudication.
− Greatest usefulness in the evaluation of symptomatic patients to assist in decision making 8. Patients with PAD should have an annual influenza vaccination.
before endovascular and surgical intervention or in patients at risk for renal, allergic, or other
complications during conventional angiography RISK FACTOR MODIFICATION
− Diet: Lower risk of incident PAD on Mediterranean diet
CT Angiography
− Smoking cessation: Nonsmokers have lower rates of MI and mortality; PAD patients who
− Permits imaging of peripheral arteries with excellent spatial resolution discontinue smoking have approximately twice the 5-year survival rate
− Optimized visualization of arterial stenoses − Treatment of diabetes: Aggressive treatment of diabetes decreases the risk for
microangiopathic events
Contrast-Enhanced Angiography
− EMPA-REG – Empagliflozin reduced all-cause mortality by 32% in patients with type 2
− Can aid in evaluation of the arterial anatomy before a revascularization procedure
− DM at increased risk of CV events, including PAD
− Liraglutide and Semaglutide – improved macrovascular outcomes
Other measurement tools:
− LEADER trial – reduction in amputations with Liraglutide in patients with diabetes and
1. Near-infrared fluorescence imaging (NIR)
vascular disease
− Uses near-infrared laser light to produce fluorescence of an intravenously injected
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− BP control: − 48% increase in the risk of amputation and death after surgery if smoked >1 pack/day
− International Verapamil-SR/Trandolapril: PAD associated with higher ischemic risk
− ALLHAT trial: SBP <120 mmHg and ≥160 mmHg was associated with higher hazard of PAD Supervised and Home-Based Exercise Training
events − Exercise training – most effective noninvasive intervention for improving limb-related symptoms
− Several clinical trials support the use of ACEi and ARBs patients with atherosclerosis − Increases the expression of angiogenic factors
− Beta blockers can worsen extremity symptoms in PAD; no significant impairment of walking − Greatest benefit when:
capacity 1. Sessions are at least 30 minutes in duration
2. Take place at least 3X a week for 6 months
Lipid-Lowering Therapy 3. When walking is the mode of exercise
− LDL-lowering agents improve PAD outcomes even in patients with no known coronary or − CLEVER trial (iliac artery stenosis): supervised exercise training > endovascular intervention
cerebrovascular disease improved mean walking time
− Heart Protection Study (Simvastatin): Simvastatin reduced the risk of a first acute peripheral − ERASE trial: combination of endovascular revascularization and exercise in patients with
vascular event femoropopliteal disease was superior to exercise alone
− TREADMILL trial (Atorvastatin): Atorvastatin 80 mg increased pain-free walking distance by >
60% Pharmacotherapy to Improve Claudication
− FOURIER trial (Evolocumab): Approximately 50% reduction MALE with Evolocumab overall with − Pentoxifylline – decrease blood viscosity and to improve erythrocyte flexibility
consistent effects in patients with PAD − Cilostazol – inhibits PDE3 → decreased degradation of cAMP → increased cAMP in platelets,
− ODYSSEY trial (Alirocumab): consistent reduction in MALE blood vessels
− Lipoprotein(a) associates with PAD risk and adverse outcomes and is lowered by PCSK9 − Cilostazol improves absolute claudication distance by 40% to 50%
inhibition − Vasodilators – failed to demonstrate efficacy

Antithrombotic Therapy for Reduction of Major Adverse Cardiovascular and Limb Events
− 23% reduction in vascular death, myocardial infarction, or stroke with antiplatelet monotherapy
− 60% increase in major extracranial bleeding
− Trials:
o CAPRIE trial (Clopidogrel vs. Aspirin): Clopidogrel associated with a greater 23.8% relative
risk reduction
o EUCLID trial (Ticagrelor vs. Clopidogrel): No difference in outcome
o CHARISMA trial (Aspirin + Clopidogrel vs. Aspirin): Neutral
o PEGASUS-TIMI 54 trial: Ticagrelor + Aspirin resulted in a 5.2% absolute risk reduction;
significant reduction in adjudicated MALE including a reduction in ALI by 35%
o THEMIS trial: Ticagrelor superior to placebo for MACE reduction
o CASPAR trial: DAPT vs. Aspirin did not reduce primary composite endpoint of morbidities in
patients undergoing below-knee bypass surgery for PAD; moderate or severe bleeding
increased
o WAVE trial (antiplatelet + VKA vs. antiplatelet): Did not reduce the primary composite
endpoint; >3X increase in life-threatening bleeding
o COMPASS trial (Rivaroxaban + Aspirin vs. Rivaroxaban): 24% reduction in MACE; 70%
increase in major bleeding
o VOYAGER PAD (Rivaroxaban + Aspirin vs. Aspirin): Combination of Aspirin and
Rivaroxaban superior; increase in bleeding
o TRA2°P-TIMI 50 (Vorapaxar + Aspirin/Clopidogrel): Vorapaxar reduced the risk of MI,
stroke, and CV death; increase in moderate or severe bleeding

TREATMENT OF SYMPTOMS AND PREVENTION OF LIMB VASCULAR EVENTS

Smoking cessation
− Reduces risk for developing symptomatic PAD
− Lessens risk of progression to CLI and amputation
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− Autogenous saphenous vein bypass graft can be considered if a target vessel for the distal
anastomosis is available
− Hyperbaric oxygen therapy may improve healing and reduce amputations
− Bosentan – can be considered for severe refractory cases

Fibromuscular Dysplasia
− Affects medium and large arteries (eg: renal, carotid, vertebral arteries)
− Rarely causes intermittent claudication or CLI
− Aneurysm or dissection present in >40% of patients
− Most frequent S/Sx: hypertension, headache, pulsatile tinnitus, dizziness; SCAD (uncommon)
− Diagnostics:
− Imaging (CT, MRI, duplex)
− DSA – for patients with a high clinical suspicion and nondiagnostic noninvasive imaging
− vs. Atherosclerosis: younger, lack of atherosclerosis risk factors
− vs. Vasculitis: absence of clinical signs, symptoms, or testing suggesting inflammation
− Histology: fibroplasia most often affecting the media, but can involve the intima or adventitia
− 2 subtypes (angiographic):
VASCULITIS 1. Multifocal FMD - more common; classic “string of beads”; associated with intimal fibroplasia,
medial hyperplasia, and to perimedial fibroplasia
Thromboangiitis Obliterans 2. Focal FMD - tubular stenosis; associated with medial hyperplasia and periarterial
− Affects the medium and small vessels of the arms hyperplasia
− Upper ex: radial, ulnar, palmar, digital arteries − Symptomatic FMD patients can undergo angioplasty
− Lower ex: tibial, peroneal, plantar, digital arteries
− Affects younger persons who smoke
− Pathologic findings: occlusive, highly cellular thrombus that incorporates PMNs, leukocytes,
microabscesses, and occasionally multinucleated giant cells
− Increased/elevated: prothrombin gene mutation, plasma homocysteine concentration, levels of
anticardiolipin antibodies
− Clinical features:
− Asian, symptoms before 45 y/o, men > women
− Pain at rest and digital ulcerations; frequently, more than one extremity affected
− Raynaud phenomenon in 45%
− Superficial thrombophlebitis in 40%
− 5-year risk for amputation: 25%
− Radial, ulnar, DP and PTP may be absent
− 2/3 abnormal Allen test
− Diagnosis:
− No specific tests except for biopsy
− Arteriography of an affected limb: segmental occlusion of small and medium arteries, Popliteal Artery Entrapment Syndrome
absence of atherosclerosis, and corkscrew collateral vessels circumventing the occlusion − Uncommon
− Also seen in scleroderma, SLE, mixed connective tissue disease, and APAS − Occurs when medial head of the gastrocnemius muscle compresses the popliteal artery
− Onset <45 y/o, hx of tobacco use, PE demonstrating distal limb ischemia − Bilateral in 1/3
− Treatment: − Suspected when a young, typically athletic, usually male person is evaluated for claudication
− Cessation of tobacco use − Potential consequences: popliteal artery thrombosis, embolism, aneurysm formation
− Intravenous iloprost – may be more effective than Aspirin for rest pain and ischemic ulcers − Peripheral pulse examination: Normal unless provocative maneuvers
− Vascular reconstructive surgery not usual option (segmental nature) − Confirmation of diagnosis: duplex ultrasonography, CTA, MRA, or conventional angiography
− Tx: Release of the popliteal artery, surgical bypass (occlusion)
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ACUTE LIMB ISCHEMIA − Optimal long-term antithrombotic strategy uncertain

− When an arterial occlusion suddenly reduces blood flow to the arm or leg − Long-term anticoagulation usually indicated for patients with an embolic source (eg. AF)
− PE: absence of pulses distal to the occlusion, cool skin, pallor, delayed capillary return and − For patients with symptomatic PAD who develop ALI from thrombotic complications in the
venous filling, diminished or absent sensory perception, and muscle weakness or paralysis. limbs, intensive antithrombotic therapy may be more effective than aspirin alone
− 6 Ps: pain, paresthesias, pallor, pulselessness, poikilothermia, and paralysis

Prognosis
Among patients with atherosclerosis presenting with ALI, 18% required amputation, 15% died

Pathogenesis
− Causes: Embolism, thrombosis in situ, dissection, and trauma
− Thrombotic occlusion of an infrainguinal bypass graft - one of the most common causes

Diagnostics
− History and physical examination usually establish the diagnosis
− If flow is detectable by Doppler ultrasonography, pressure in the affected limb and
− corresponding ABI can be measured
− Doppler – assess blood flow
− Duplex ultrasonography – determine the site of occlusion, evaluate graft patency
− MRA, CTA, and conventional arteriography – demonstrate site of occlusion and provide an
anatomic guide for revascularization

Treatment
− Bed positioned such that the feet are lower than chest level → increase limb perfusion pressure
by hydrostatic effects
− Administer Heparin
− 80-100 units/kg IV bolus + 18 units/kg/hr continuous infusion
− Target aPTT 2-2.5x control
− Revascularization is indicated when the viability of the limb is threatened or when symptoms of
ischemia persist
− Options:
1. Endovascular revascularization
2. Intra-arterial thrombolytic therapy: plus thrombectomy – initial treatment option for
category I or II ALI (no contraindication)
− Catheter-based thrombolytic therapy should be continued for 24-48 hours for optimal
benefit, limit bleeding risk
3. Surgical revascularization: eg. thromboembolectomy, bypass occluded – option for
restoration of blood flow to an ischemic limb
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ATHEROEMBOLISM "atherogenic embolism" "cholesterol embolism"

− Occlusion of arteries resulting from detachment and embolization of atheromatous debris
− Originate most frequently from “shaggy,” protruding atheroma of the aorta
− Typically occlude small downstream arteries and arterioles
− Most affected: men >60 y/o with atherosclerosis

Pathogenesis
− Identification of large, protruding atheromas by transesophageal UTZ predicts future embolic
events
− Catheter manipulation – 1-2%

Clinical Features
− In extremities: painful cyanotic toes (“blue toe syndrome")
− Livedo reticularis in 50%
− Local areas of erythematous or violaceous discoloration on lateral aspects of the feet, soles,
calves
− Digital and foot ulcerations, nodules, purpura, and petechiae
− Pedal pulses present → emboli tend to lodge in the more distal digital arteries and arterioles
− Renal involvement – increased BP, azotemia

Diagnostics
− Elevated ESR, eosinophilia, and eosinophiluria
− Anemia, thrombocytopenia, hypocomplementemia, and azotemia
− Imaging (TEE, MRA, CTA) – may identify sites of severe atherosclerosis indicating source
− Definitive test: skin or muscle biopsy
− Elongated needle-shaped clefts in small arteries caused by cholesterol crystals; often
accompanied by inflammatory infiltrates (lymphocytes, giant cells and eosinophils), intimal
thickening, and perivascular fibrosis

Treatment
− No definitive treatment
− Risk factor modification: statins, smoking cessation
− Effect of antiplatelet therapy in preventing recurrence is unknown; antiplatelets are generally
indicated in patients with atherosclerosis
− Warfarin is controversial
− Surgical removal of the source should be considered in patients with atheroembolism, particularly
in those with recurrence