Elsevier

Progress in Cardiovascular Diseases

Volume 65, March–April 2021, Pages 2-8
Progress in Cardiovascular Diseases

Asymptomatic peripheral artery disease: Silent but deadly

https://doi.org/10.1016/j.pcad.2021.02.009Get rights and content

Abstract

Peripheral Artery Disease (PAD) is a manifestation of atherosclerosis characterized by diminished perfusion of the limb and a state of dysmetabolism. The asymptomatic PAD phenotype is a relatively recent classification. It is unknown how many people currently live with asymptomatic PAD because there are no universal screening recommendations for patients at risk for PAD. Patients with asymptomatic PAD suffer from a similar risk profile of morbidity and mortality as their counterparts with claudication. Despite this increased risk, there is a dearth of clinical investigations into therapies that specifically benefit the asymptomatic PAD population. At present, current pharmacotherapies that have been studied in PAD patient populations do not stratify by symptom status. We believe that further investigation of the impact of existing therapies in this unique population presents an opportunity to reduce morbidity and mortality due to PAD. This can only be achieved in combination with wide-spread adoption of screening for asymptomatic PAD.

Introduction

Peripheral artery disease (PAD) is a manifestation of atherosclerosis in the lower extremities. In 2000, it was estimated that 8 million people in the United States were living with PAD among the over 200 million people afflicted with the condition globally.1,2 This number has likely increased in the United States as the aged population has increased. PAD can be characterized as a state of diminished limb perfusion and dysmetabolism. The PAD phenotype can manifest across a broad spectrum that ranges from: asymptomatic, functionally impaired, intermittent claudication, to critical limb ischemia (CLI).3 It is conservatively estimated that 6 million patients in the United States have asymptomatic or atypically symptomatic PAD while the remainder experience intermittent claudication and limb ischemia at rest. Approaching intermittent claudication from a historic perspective provides the context for asymptomatic and atypically symptomatic peripheral artery disease as a more recently identified phenomenon.

Section snippets

Evolution of the definitions of symptomatic and asymptomatic PAD

In 1854, French Neurologist Jean-Martin Charcot characterized dysbasia intermittens angiosclerotica or what we have come to understand as intermittent claudication of the lower extremities. His description of the constellation of symptoms defining intermittent claudication holds to this day: ‘persons past middle life are seized after walking a short distance, occupying perhaps five to ten minutes of time with a helpless, cramp-like feeling in the legs so severe as to render further progress

Asymptomatic PAD and progression to symptomatic PAD

Despite the definition of PAD (ABI) requiring decreased perfusion of the distal extremity due to arterial occlusive disease, the presence or absence of symptoms is not a reliable indicator of outcomes. Mohler et al. designed a prospective cohort study of asymptomatic PAD patients over follow up period of one year to evaluate the time course and pathophysiology of converting from asymptomatic to symptomatic PAD. The study included patients with abnormal ABI's both with and without complaints of

Asymptomatic PAD, morbidity, and mortality

Beyond progression of limb disease and functional decline, patients with asymptomatic PAD are at heightened risk for cardiovascular morbidity and mortality. Criqui et al. studied prospectively cohorts of age matched control subjects without PAD, patients with asymptomatic large-vessel PAD and patients with symptomatic disease over a ten- year period. Only 3 in 5 patients with asymptomatic large vessel PAD were alive after a ten year period, while their symptomatic counterparts fared worse.13

Extremity specific characteristics of asymptomatic PAD

Asymptomatic PAD is associated with more adverse lower extremity characteristics than intermittent claudication. McDermott et al. studied a group of 429 men and women with PAD noting that individuals with PAD who are always asymptomatic, despite completing a 6-min walk test, have significantly smaller calf muscle area, higher calf muscle percent fat, lower calf muscle density, poorer lower extremity peripheral nerve function, and poorer lower extremity functional performance compared with PAD

Pathophysiologic differences between claudicants and non-claudicants with PAD

The understanding of the role of inflammation as a core principle of atherogenesis continues to evolve. Traditionally, flow-limiting stenosis to the lower limb and inability to meet oxygen demand has been thought to be the primary driver of claudication in PAD. Several studies suggest the role of oxidative stress, inflammation and endothelial dysfunction evoked by exercise in limb ischemia as an alternative explanation. Increased levels of exercise induced-inflammatory mediators have been

Pharmacotherapeutic differences in PAD by symptom status

PAD is underdiagnosed and undertreated.11 PAD has an established increased risk profile for developing incident CVD events. Examples of classes of medications previously investigated to prevent incident CVD events in PAD patients include: Proprotein Convertase Subtilisin/Kexin type 9 (PSCK-9: Evolocumab) inhibitors,33 Protease-activated receptor-1 antagonists (Vorapaxar)34 and Factor Xa inhibitors35,36 but their study was not focused on asymptomatic PAD. The mainstays of pharmacotherapy for

Exercise programs

Supervised exercise therapy improves walking ability, overall functional status, and health-related quality of life in patients with claudication.52 Exercise therapy also appears to help those with asymptomatic PAD. Patients with asymptomatic PAD were enrolled in a 12 week in home self-monitored physical activity program while the control group was six bimonthly online videos involving health recommendations related to PAD but were otherwise asked to continue normal activities and routines.

Cost-effectiveness in screening

The ABI is a low cost, non-invasive study with far-reaching access to both urban and rural healthcare providers.62 Attempts have been made to demonstrate the cost effectiveness of initiating targeted screening and pharmacotherapeutic interventions to prevent subsequent CVD in this patient population.63,64 Currently, access to the ABI for diagnostic testing is variable with unsupported criteria to limit its use.65 Further, population screening, despite evidence of reductions in mortality and

Summary

Symptomatic PAD, what we have come to know as intermittent claudication, was initially described in the mid 19th century. In contrast, asymptomatic PAD is a modern construction and less understood phenomenon. The disease is best characterized as decreased perfusion at the level of the ankle, as measured by ABI, and absence of claudication symptoms reported with validated claudication questionnaires. Asymptomatic PAD associates directly with systemic manifestations, limb and CVD morbidity, and

Declaration of Competing Interest

Dr. Behroozian has no financial disclosures to make. Dr. Beckman reports consulting income from Amgen, Bayer, and Janssen. Ownership in Janacare and EMX.

Acknowledgements

American Heart Association Strategically Focused Research Network Grant in Vascular Disease 18SFRN33960373. 18SFRN3396037318SFRN33960373.

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