Peripheral Vascular Disease

Etiology

Peripheral vascular disease is primarily driven by progressive atherosclerotic disease resulting in the reduction of major organ blood flow and end-organ ischemia. The process of atherosclerosis is complex, with the involvement of numerous cells, proteins, and pathways. Important non-modifiable and modifiable risk factors have been identified in the advancement of atherosclerosis.

Risk factors include:[4][6][7][8]

• Tobacco use
• Diabetes mellitus
• Hypertension
• HIV
• High cholesterol
• Age more than 50 years
• Elevated homocysteine levels
• BMI greater than 30
• Family history of cardiovascular disease

Of the above risk factors, smoking is associated with the highest risk of PAD development with an odds ratio of 2.7 (95% CI 2.4–3.1). History of cardiovascular disease and diabetes are also significant risk factors with odds ratios of 2.6 (95% CI 2.2-3) and 1.9 (1.7-2.1), respectively.[9]

Epidemiology

Peripheral vascular disease affects nearly 200 million people worldwide, including approximately 40 to 45 million Americans.[10] The disease is uncommon in younger populations; however, incidence increases sharply, with over 20% of people over 80 years old having PAD.[11] Data on gender differences is conflicting. In the Framingham study, intermittent claudication (IC) was more prevalent in men compared to women (1.9% to 0.8%; ratio 2.38).[12] This finding was consistent with the Rotterdam study that found men were 1.83 times more likely to have IC, with a prevalence of 2.2% in men and 1.2% in women.[13] However, a gender shift in prevalence occurs when the diagnosis of PAD is based on the ankle-brachial pressure index (ABI). For example, the Rotterdam study found the prevalence of ABI-based diagnosis of PAD to be 20.5% in women and 16.9% in adults, with a ratio of 0.82. Other studies, such as the Cardiovascular Health Study (CHS) and a population-based study, found no significant difference in ABI-based diagnosis of PAD between men and women. Proposed explanations for differences between ABI versus IC-defined PAD gender differences are that women are more likely to have atypical and late presentations and have intrinsically lower ABI values.[14]

Racial and socioeconomic disparities also exist. In regards to race, the CHS found African Americans to have an odds ratio of 2.12 for PAD compared to Non-Hispanic whites when adjusting for known risk factors.[15] The compilation of three studies addressing the impact of race on the risk of PAD found odds ratios of 2.3 to 3.1 for African Americans compared to Non-Hispanic whites when adjusting for confounders.[16] A socioeconomic survey study found patients with lower poverty-income ratios (PIR) to have a nearly 2 fold increase in the risk of PAD compared to higher PIR. Furthermore, the study found a lower educational level to be significantly associated with PAD (OR 2.8, 95% CI 1.96–4.0, p<0.0001).[17]

Pathophysiology

Peripheral vascular disease is primarily driven by the progression of atherosclerotic disease leading to macro and microvascular dysfunction. PAD typically affects the lower extremity vascular beds, but larger arteries, such as the abdominal aorta and iliac arteries, are frequently involved. More severe disease can involve multilevel and/or diffuse disease. The pathophysiology of atherosclerosis is a complex inflammatory response with the involvement of various vascular cells, thrombotic factors, and cholesterol and inflammatory molecules.

Atherosclerosis begins with lipoprotein accumulation within the intimal layer of large arteries. The lipoprotein presence within the endothelium leads to lipid oxidation and cytokine response with the infiltration of lymphocytes and macrophages.[18] Macrophages consume these oxidized lipids and form foam cells leading to the development of "fatty streaks."[19] Although not clinically significant, these fatty streaks can eventually develop into more advanced plaques consisting of necrotic lipid cores and smooth muscle cells (SMC). SMC and endothelial cells secrete cytokines and growth factors, leading to migration of SMC to the luminal side of the plaque and extracellular matrix synthesis and eventual formation of a fibrous plaque. Fibrous plaque stability is principally dependent on its composition, with more vulnerable plaques consisting of a thinner fibrous cap and more numerous inflammatory cells.

Atherosclerotic plaque builds up slowly over decades within the wall of the vessel. Plaque accumulation results in vascular stenosis and frequent vascular dilation to maximize end-organ perfusion. Once the vessel dilation capacity is maximized, the plaque continues to accumulate, which further compromises the lumen occasionally, leading to critical narrowing of the artery. As narrowing progresses and obstructs the artery, collateral circulatory beds frequently develop to preserve distal perfusion and tissue viability. These collateral circulatory pathways are unable to match the blood supply provided by a healthy vessel completely. IC results when blood flow distal to the occlusion is sufficiently compromised, resulting in fixed oxygen delivery that is unable to match oxygen demand.[20] The most severe form of PAD is critical limb ischemia, which is defined as limb pain at rest or impending limb loss.[21]

Acute ischemia may ensue if in-situ vascular thrombosis occurs or a cardioembolic source suddenly occludes the narrowed vessel.[22] Arterial thrombosis secondary to progressive atherosclerotic disease, and thrombosis represents 40% of acute limb ischemia (ALI) cases.[23] Atherosclerotic fibrous plaque rupture leads to exposure of subendothelial collagen and inflammatory cells, causing platelet adhesion and aggregation with rapid in-situ thrombosis of the vessel. Patients with in-situ vascular thrombosis tend to have improved outcomes compared to embolic causes due to the presence of extensive collateral circulation. Embolic ALI causes represent 30% of ALI cases, with the femoral artery being the most common site.[23] ALI is a vascular emergency with an immediate physician consultation required for the preservation of limb viability.

History and Physical

Diagnosis of peripheral vascular disease can be difficult due to the increasing prevalence of similarly presenting comorbid conditions and large numbers of patients having an asymptomatic or atypical presentation.[24] The clinical presentation of PAD is often dependent on the severity of arterial insufficiency and the presence of comorbid conditions, which may alter or mask the symptoms of underlying vascular disease.

Atypical presentation of PAD occurs when patients have existing comorbidities such as lumbosacral disease, spinal stenosis, or advanced diabetes mellitus - all of which may alter the perception of pain. Atypical pain is characterized by pain unrelated to physical activity, pain that occurs both at rest and exertion, and pain lasting longer than 10 minutes after exercise cessation.[25] Pseudo claudication refers to neuropathic pain observed in patients with spinal stenosis and can be differentiated from PAD with a thorough history and physical examination. Patients with pseudo claudication tend to have pain characterized by weakness and paresthesias that is irrespective of the degree of physical activity and usually is relieved by sitting down or changing body positioning rather than rest.[20]

Patients with hemodynamically significant PAD based on ABI testing are more likely to have asymptomatic rather than symptomatic disease. This illustrates the importance of maintaining a high clinical suspicion of underlying PAD for effective secondary prevention. Over 50% of patients with PAD are asymptomatic.[26] The prevalence of asymptomatic PAD may partly be explained by older individuals misinterpreting their symptoms as normal aging processes. Additionally, patients with mild to moderate PAD may be unable to exercise to a capacity where significant oxygen demand is required. Thus a mismatch between supply and demand does not occur, and patients remain asymptomatic. 

Intermittent claudication is the most classic symptom of PAD, characterized by an exercise-induced cramping sensation with associated fatigue, weakness, and or pressure. It is not uncommon for patients to deny pain, and therefore asking about discomfort while ambulating is a more useful screening question. Symptoms are exacerbated by leg elevation and relieved by placing the limb in a dependent position. Paresthesias, lower extremity weakness, stiffness, and cool extremities may also be present. Anatomically the level of obstruction is usually seen one level above the area of discomfort; for example, patients with aortoiliac disease will have buttock and thigh symptoms. 70% to 80% of patients have stable intermittent claudication over 10 years; however, a portion of patients may progress through debilitating ischemic rest pain, critical limb ischemia, and eventual amputation.[27] Critical limb ischemia is manifested by pain at rest, nonhealing wounds or ulcers, and gangrene in one or both legs. 

The physical exam begins with a general inspection with attention to fingernail tar indicative of cigarette smoking, scars from previous vascular surgeries, and the presence of amputations. A focused cardiovascular examination begins with a pulse examination to determine rate, rhythm, and strength. Chest auscultation should be performed to evaluate for pulmonary diseases such as chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis, and heart sounds or murmurs. Neurological examination is essential to evaluate for pseudo claudication. Examination of the limbs should involve assessment for pulselessness, pallor, muscular atrophy, cool or cyanotic skin, or pain with palpation.[28] Lower extremity ulcers may be arterial, venous, neuropathic, or a combination of two or more. Ulcers secondary to arterial insufficiency are tender and typically have ragged borders with a dry base and pale or necrotic centers.

Evaluation

The diagnosis of peripheral vascular disease can be sufficiently made based on patient risk factors, clinical presentation, and physical exam findings. Occasionally patients can present with atypical symptoms, and objective data can establish the diagnosis. Assessment begins with accounting for known PAD risk factors, including smoking, diabetes, hypertension, hypercholesterolemia, and obesity. Intermittent claudication must be distinguished from neurological, musculoskeletal, or vascular disorders, which may present similarly to PAD. Physical exam findings of the lower extremities may demonstrate shiny skin with coolness to palpation, reduced or absent pulses, abnormal capillary refill time, pallor with leg elevation, dependent rubor, and auscultation of bruits in major vessels, including the femoral and popliteal arteries.[29] Advanced disease may manifest as nonhealing ulcers or gangrene.

Measurement of the ankle-brachial index (ABI) is a cost-effective noninvasive objective measure for PAD diagnosis. The ABI is obtained by measuring the systolic ankle pressure ratio to the systolic brachial pressure. The test is performed by placing a blood pressure cuff above the level of the ankle and placing a Doppler ultrasonography probe on the dorsalis pedis or posterior tibialis and then inflating the cuff until the signal from the probe ceases. The cuff is then slowly deflated, and the return of the Doppler probe signal marks the systolic ankle pressure. The process is then repeated for the opposite leg. The ankle pressure of each leg is then divided by the highest systolic pressure of either brachial artery. A normal ABI ratio ranges from 0.9 to 1.2, and values less than 0.9 are diagnostic of PAD. Noncompressible vessels, as seen in people with diabetes and those with advanced kidney disease and may have falsely elevated ratios.[30] Individuals with abnormally high ABI ratios have higher all-cause mortality compared to normal ABI ratios. Further diagnostic evaluation for these patients often warrants a toe-brachial index (TBI), which is the comparison of the toe systolic pressure to the higher systolic brachial pressure.[20] These particular patients illustrate the vital importance of clinical history and physical examination in the initial evaluation of patients with suspected PAD.

Duplex ultrasonography is a safe and cost-effective method of determining PAD location, stenosis severity, and length of stenosis or occlusion. 2-dimensional imaging, along with color Doppler, provides an accurate assessment of lesion stenosis, hemodynamic severity, and plaque characteristics. Doppler ultrasonography can be used in routine follow-up post-procedure for surveillance of patency. This diagnostic modality can assist in decision-making when further intervention is contemplated.[31] 

Magnetic resonance angiography (MRA) or computed tomography angiography (CTA) both provide excellent high-quality vascular imaging. The advantages of MRA include the ability to identify small runoff vessels that sometimes may not be seen with digital subtraction angiography (DSA). Compared with DSA, MRA has 90% sensitivity and 97% specificity in identifying hemodynamically significant lesions.[31] CTA has similar diagnostic accuracy to MRA, with both imaging techniques useful for determining candidacy for bypass surgery versus angioplasty.

Treatment / Management

Patients diagnosed with peripheral vascular disease require a reasoned approach to account for age, risk factors, disease severity, and functional status. Management is divided into two broad categories aimed at decreasing cardiovascular events and improving symptoms. Persons with PAD are at increased risk of coronary artery disease mortality (relative risk = 6.6), cardiovascular mortality (relative risk = 5.9), and all-cause mortality (relative risk = 3.1).[32] Therefore PAD management begins with lifestyle modification to prevent disease progression with the addition of medical and interventional therapy required for improved symptomatic control and cardiovascular event risk reduction.

Cardiovascular Risk Factor Modification

Aggressive risk factors modification is essential to lowering cardiovascular risk. Smoking cessation reduces the risk of PAD progression, cardiovascular events, including myocardial infarction and stroke, and critical limb ischemia.[33] Patient education, along with the use of behavioral therapy, nicotine replacement therapy, or pharmacological therapy, can be used to reduce smoking and improve cardiovascular outcomes. Statin therapy has been effectively shown to reduce cardiovascular events and all-cause mortality and reduce the need for revascularization and should be routinely used in patients with PAD. Hypertension management with blood pressure reduction to less than 140/90 in nondiabetic and 130/80 in diabetic patients has been shown to improve outcomes.[34] Diabetes is a risk factor for symptomatic and asymptomatic PAD by 1.5 to 4 fold, respectively, and a hemoglobin A1c target of less than 7% should be achieved with less stringent goals for individuals with extensive comorbidities.[35](B3)

Exercise Therapy

Randomized trials have shown supervised exercise therapy programs to have significant improvement in claudication symptoms. A meta-analysis of 27 studies found exercise significantly improved pain-free walking distance by 269 feet and total walking distance by nearly 400 feet.[36] Exercise programs typically consist of 30- to 45-minute length sessions conducted 4 to 5 times a week over the course of 12 weeks. A meta-analysis of five trials found no improvement in mortality with exercise therapy programs.[36](A1)

Pharmacotherapy

Pharmacological therapy for intermittent claudication (IC) management can be offered to patients who have not benefited from exercise therapy and risk factor modification.[37] Two medications approved for IC treatment include cilostazol and naftidrofuryl. Cilostazol inhibits phosphodiesterase type 3 and has demonstrated antiplatelet effect, vasodilatory properties, and inhibition of smooth muscle cell proliferation.[38] A meta-analysis of over 2000 patients found individuals on cilostazol had significantly longer pain-free and total walking distances.[38] Naftidrofuryl is a 5-hydroxytryptamine-2-receptor antagonist that inhibits glucose uptake and increases adenosine triphosphate levels. It has fewer side effects than cilostazol and should be considered where available.[39](A1)

Daily aspirin is recommended for overall cardiovascular care. No consensus has been reached on the most effective dose.

Revascularization

Patients who have debilitating symptoms unresponsive to risk factor modification and exercise and pharmacological therapy may be candidates for endovascular, surgical, or combined endovascular and surgical intervention. Indications for intervention include individuals with incapacitating claudication interfering with daily activity and limb salvage in patients with critical limb ischemia manifested by ischemic pain at rest, ulceration, and gangrene. The decision on surgical versus percutaneous intervention is dependent on many factors, including the patient's functional status and surgical risk, skills of the operator, anatomic location and extent of disease, presence of multifocal vascular lesions, and patient preference.[40] An interprofessional team approach involving an internist, interventionalist, and vascular surgeon should be undertaken for personalized patient care to improve outcomes and patient satisfaction.

Differential Diagnosis

A provider has to take into account various differential diagnoses when a patient presents with the above-mentioned signs and symptoms. Following are some of the most important ones:

Neurological

• Nerve root compression
• Spinal stenosis 
• Peripheral neuropathy
• Nerve entrapment

Musculoskeletal

• Medial tibial stress syndrome
• Osteoarthritis 
• Muscle strain
• Baker cyst

Vascular

• Chronic venous insufficiency
• Thrombophlebitis
• Deep venous thrombosis
• Raynaud phenomenon
• Thromboangiitis obliterans

Prognosis

The overall prognosis of patients with peripheral vascular disease must take into account patient risk factors, cardiovascular health, and disease severity. In terms of limb health at 5 years, nearly 80% of patients will have stable claudication symptoms. Only 1% to 2% of patients will progress to critical limb ischemia in 5 years. 20 to 30% of patients with PAD will die within 5 years, with 75% of those deaths attributed to cardiovascular causes.[32]

Complications

Peripheral vascular disease can affect several systems in the body leading to a number of complications as listed below:

• Acute coronary syndrome
• Stroke
• Nonhealing ulcer
• Gangrene
• Amputation
• Deep vein thrombosis
• Erectile dysfunction