Peripheral arterial disease (PAD) is a chronic vascular disease where blood flow in the limb arteries is obstructed [1,2]. The chance of PAD increases as age advances and affects a considerable proportion of the elderly population (> 20% in > 80-year old individuals) [3]. The overall prevalence of PAD among the general population has been found to be 12 - 14%, affecting up to 20% of those over 70 [4]. Worldwide, PAD was estimated as 202 million and 236.62 million in 2010 and 2015 respectively [5].

Major subtypes of PAD are Atherosclerotic Obliterans (ASO), Buerger’s disease (Thromboangiitis Obliterans, TAO) and PAD due to connective tissue diseases. TAO is strongly associated with cigarette smoking. Underlying risk factors leading to ASO are older age, hypertension, cigarette smoking, hyperlipidemia and/or diabetes mellitus. According to the current recommendations, to prevent vascular damage and improve functional status, patients with PAD should receive an intensive program of guideline-based medical therapy including structured exercise and lifestyle modifications. Symptomatic PAD patients are needed to take antiplatelet therapy with either aspirin alone (range, 75 - 325 mg/day) or clopidogrel alone (75 mg/day) [6]. All patients with PAD should be treated with a statin medication [6]. Patients with PAD who smoke cigarettes or use any other forms of tobacco should be counseled at every visit to quit. For patients with symptoms of claudication, Cilostazol is an effective initial therapy to improve symptoms and increase walking distance [6]. Unfortunately, even with all conservative measures, many of those patients progress towards severe rest pain and/or limb ulceration. When severe rest pain and/or ulcerations of ischemic limbs are developed, this is defined as the state of chronic critical limb ischaemia (CLI). Chronic CLI is associated with a high risk of major amputation, cardiovascular events and death. Around 25% of the patients require amputation within a year after the onset of chronic CLI [7].

References

1. Joan Henderson., et al. “Peripheral arterial disease”. Australian Family Physician6 (2013): 363.
2. Duff Steve., et al. "The burden of critical limb ischemia: a review of recent literature”. Vascular Health and Risk Management 15 (2019): 187.
3. Shu Jun and Gaetano Santulli. "Update on peripheral artery disease: epidemiology and evidence-based facts”. Atherosclerosis 275 (2018): 379-381.
4. Shammas Nicolas W. "Epidemiology, classification, and modifiable risk factors of peripheral arterial disease”. Vascular Health and Risk Management 2 (2007): 229.
5. Song Peige., et al. "Global, regional, and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis”. The Lancet Global Health8 (2019): e1020-e1030.
6. Gerhard-Herman., et al. "2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines”. Circulation 12 (2017): e726-e779.
7. Norgren Lars., et al. "Inter-society consensus for the management of peripheral arterial disease (TASC II)”. Journal of Vascular Surgery1 (2007): S5-S67.
8. Tateishi-Yuyama Eriko., et al. "Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial”. The Lancet9331 (2002): 427-435.
9. Kondo Kazuhisa., et al. "Long-term clinical outcomes survey of bone marrow-derived cell therapy in critical limb ischemia in Japan”. Circulation Journal4 (2018): 1168-1178.
10. Yusoff Farina Mohamad., et al. "Review of the long-term effects of autologous bone-marrow mononuclear cell implantation on clinical outcomes in patients with critical limb ischemia”. Scientific Reports1 (2019): 1-7.
11. Idei Naomi., et al. "Autologous bone-marrow mononuclear cell implantation reduces long-term major amputation risk in patients with critical limb ischemia: a comparison of atherosclerotic peripheral arterial disease and Buerger disease”. Circulation: Cardiovascular Interventions1 (2011): 15-25.
12. Higashi Yukihito., et al. "Autologous bone-marrow mononuclear cell implantation improves endothelium-dependent vasodilation in patients with limb ischemia”. Circulation10 (2004): 1215-1218.
13. Amariglio Ninette., et al. "Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient”. PLOS Medicine 2 (2009): e1000029.
14. Chowdhury M., et al. “Umbilical cord blood stem cells as a source of non-hematopoietic cells: role in regenerative medicine”. Regenerative Research2 (2013): 1-7.
15. Yang Shin-Seok., et al. "A phase I study of human cord blood-derived mesenchymal stem cell therapy in patients with peripheral arterial occlusive disease”. International Journal of Stem Cells1 (2013): 37.
16. Kondo Kazuhisa., et al. "Therapeutic Angiogenesis for Critical Limb Ischemia by Implantation of Autologous Adipose-Derived Regenerative Cells: A Clinical Pilot Study”. Circulation 1 (2016): A18595-A18595.
17. Gupta Pawan K., et al. "A double blind randomized placebo controlled phase I/II study assessing the safety and efficacy of allogeneic bone marrow derived mesenchymal stem cell in critical limb ischemia”. Journal of Translational Medicine1 (2013): 143.
18. Belch Jill., et al. "Effect of fibroblast growth factor NV1FGF on amputation and death: a randomised placebo-controlled trial of gene therapy in critical limb ischaemia”. The Lancet9781 (2011): 1929-1937.
19. Powell Richard J., et al. "Safety and efficacy of patient specific intramuscular injection of HGF plasmid gene therapy on limb perfusion and wound healing in patients with ischemic lower extremity ulceration: results of the HGF-0205 trial”. Journal of Vascular Surgery6 (2010): 1525-1530.
20. RJ Powell., et al. “Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischaemia”. Circulation1 (2008): 58-65.
21. Kontopodis Nikolaos., et al. "Effectiveness of platelet-rich plasma to enhance healing of diabetic foot ulcers in patients with concomitant peripheral arterial disease and critical limb ischemia”. The International Journal of Lower Extremity Wounds1 (2016): 45-51.
22. Kulikovsky Moshe. "Hyperbaric oxygen therapy for non-healing wounds”. Israel Medical Association Journal 11 (2009): 480-485.
23. Murad Mohammad Hassan., et al. "Using GRADE for evaluating the quality of evidence in hyperbaric oxygen therapy clarifies evidence limitations”. Journal of Clinical Epidemiology1 (2014): 65-72.
24. Kranke Peter., et al. "Hyperbaric oxygen therapy for chronic wounds”. Cochrane Database of Systematic Reviews 6 (2015).
25. Mikami Shinsuke., et al. "Low-Intensity Pulsed Ultrasound Improves Endothelial Function in Leg Circulation in Patients with Peripheral Arterial Disease”. Circulation (2012): A14003.