Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Update on the pathophysiology and medical treatment of peripheral artery disease

Abstract

Approximately 6% of adults worldwide have atherosclerosis and thrombosis of the lower limb arteries (peripheral artery disease (PAD)) and the prevalence is rising. PAD causes leg pain, impaired health-related quality of life, immobility, tissue loss and a high risk of major adverse events, including myocardial infarction, stroke, revascularization, amputation and death. In this Review, I describe the pathophysiology, presentation, outcome, preclinical research and medical management of PAD. Established treatments for PAD include antithrombotic drugs, such as aspirin and clopidogrel, and medications to treat dyslipidaemia, hypertension and diabetes mellitus. Randomized controlled trials have demonstrated that these treatments reduce the risk of major adverse events. The drug cilostazol, exercise therapy and revascularization are the current treatment options for the limb symptoms of PAD, but each has limitations. Novel therapies to promote collateral and new capillary growth and treat PAD-related myopathy are under investigation. Methods to improve the implementation of evidence-based medical management, novel drug therapies and rehabilitation programmes for PAD-related pain, functional impairment and ischaemic foot disease are important areas for future research.

Key points

  • Peripheral artery disease (PAD) is present in 6% of adults and is associated with leg pain, walking impairment and high risk of major adverse cardiovascular events, including amputation and death.

  • PAD usually presents with leg pain, ischaemic ulceration or gangrene and is usually caused by atherosclerosis and thrombosis, although all current animal models use surgically created hindlimb ischaemia.

  • Treatment options for the leg symptoms of PAD include cilostazol, exercise therapy and revascularization, with novel therapies under investigation including autologous cell therapy, organic nitrates and antioxidants.

  • Antithrombotic and LDL-cholesterol-lowering medications, smoking cessation and treatment of hypertension and diabetes mellitus reduce the risk of major adverse events, but programmes to improve uptake of these measures are needed.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Prevalence of PAD in relation to age and country income.
Fig. 2: Risk factors, pathological mechanisms and effects of PAD.
Fig. 3: Arteriogenesis induced by lower limb artery occlusion.
Fig. 4: Angiogenesis induced by lower limb artery occlusion.
Fig. 5: The two-stage hindlimb ischaemia mouse model of peripheral artery disease.
Fig. 6: Comparison of the hindlimb blood supply and function in the one-stage and two-stage HLI models of PAD.

References

  1. Nastasi, D. R. et al. The cost-effectiveness of intensive low-density lipoprotein cholesterol lowering in people with peripheral artery disease. J. Vasc. Surg. 73, 1396–1403 (2021).

    Article  PubMed  Google Scholar 

  2. Anand, S. S. et al. Major adverse limb events and mortality in patients with peripheral artery disease: the COMPASS trial. J. Am. Coll. Cardiol. 71, 2306–2315 (2018).

    Article  PubMed  Google Scholar 

  3. McDermott, M. M. et al. Leg symptom categories and rates of mobility decline in peripheral arterial disease. J. Am. Geriatr. Soc. 58, 1256–1262 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sampson, U. K. et al. Global and regional burden of death and disability from peripheral artery disease: 21 world regions, 1990 to 2010. Glob. Heart 9, 145–158 (2014).

    Article  PubMed  Google Scholar 

  5. Song, P. et al. Global, regional, and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis. Lancet Glob. Health 7, e1020–e1030 (2019).

    Article  PubMed  Google Scholar 

  6. Criqui, M. H. et al. Lower extremity peripheral artery disease: contemporary epidemiology, management gaps, and future directions: a scientific statement from the American Heart Association. Circulation 144, e171–e191 (2021).

    Article  PubMed  Google Scholar 

  7. Golledge, J. & Drovandi, A. Evidence-based recommendations for medical management of peripheral artery disease. J. Atheroscler. Thromb. 28, 573–583 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bonaca, M. P. et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk). Circulation 137, 338–350 (2018).

    Article  CAS  PubMed  Google Scholar 

  9. Anand, S. S. et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 391, 219–229 (2018).

    Article  CAS  PubMed  Google Scholar 

  10. Cooke, J. P. & Meng, S. Vascular regeneration in peripheral artery disease. Arterioscler. Thromb. Vasc. Biol. 40, 1627–1634 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gerhard-Herman, M. D. 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 135, e726–e779 (2017).

    PubMed  Google Scholar 

  12. Aboyans, V. et al. Editor’s Choice - 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS). Eur. J. Vasc. Endovasc. Surg. 55, 305–368 (2018).

    Article  PubMed  Google Scholar 

  13. Abola, M. T. B. et al. Asia-Pacific consensus statement on the management of peripheral artery disease: a report from the Asian Pacific Society of Atherosclerosis and Vascular Disease Asia-Pacific Peripheral Artery Disease Consensus Statement Project Committee. J. Atheroscler. Thromb. 27, 809–907 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schorr, E. N. & Treat-Jacobson, D. Methods of symptom evaluation and their impact on peripheral artery disease (PAD) symptom prevalence: a review. Vasc. Med. 18, 95–111 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Conte, M. S. et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur. J. Vasc. Endovasc. Surg. 58, S1–S109 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Fowkes, F. G. et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 382, 1329–1340 (2013).

    Article  PubMed  Google Scholar 

  17. Hirsch, A. T. et al. A call to action: women and peripheral artery disease: a scientific statement from the American Heart Association. Circulation 125, 1449–1472 (2012).

    Article  PubMed  Google Scholar 

  18. Srivaratharajah, K. & Abramson, B. L. Women and peripheral arterial disease: a review of sex differences in epidemiology, clinical manifestations, and outcomes. Can. J. Cardiol. 34, 356–361 (2018).

    Article  PubMed  Google Scholar 

  19. Heart Protection Study Collaborative Group. Randomized trial of the effects of cholesterol-lowering with simvastatin on peripheral vascular and other major vascular outcomes in 20,536 people with peripheral arterial disease and other high-risk conditions. J. Vasc. Surg. 45, 645–654 (2007).

    Article  Google Scholar 

  20. Marjoribanks, J., Farquhar, C., Roberts, H., Lethaby, A. & Lee, J. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst. Rev. 1, CD004143 (2017).

    PubMed  Google Scholar 

  21. Choi, J., Joseph, L. & Pilote, L. Obesity and C-reactive protein in various populations: a systematic review and meta-analysis. Obes. Rev. 14, 232–244 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Aboyans, V. et al. Intrinsic contribution of gender and ethnicity to normal ankle-brachial index values: the Multi-Ethnic Study of Atherosclerosis (MESA). J. Vasc. Surg. 45, 319–327 (2007).

    Article  PubMed  Google Scholar 

  23. Fowkes, F. G. et al. Peripheral artery disease: epidemiology and global perspectives. Nat. Rev. Cardiol. 14, 156–170 (2017).

    Article  PubMed  Google Scholar 

  24. Allison, M. A. et al. Ethnic-specific prevalence of peripheral arterial disease in the United States. Am. J. Prev. Med. 32, 328–333 (2007).

    Article  PubMed  Google Scholar 

  25. Klarin, D. et al. Genome-wide association study of peripheral artery disease in the Million Veteran Program. Nat. Med. 25, 1274–1279 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Harwood, A. E. et al. Exercise training for intermittent claudication: a narrative review and summary of guidelines for practitioners. BMJ Open Sport. Exerc. Med. 6, e000897 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Hirsch, A. T. et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 286, 1317–1324 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Zhang, Y. et al. Global disability burdens of diabetes-related lower-extremity complications in 1990 and 2016. Diabetes Care 43, 964–974 (2020).

    Article  PubMed  Google Scholar 

  29. Prompers, L. et al. High prevalence of ischaemia, infection and serious comorbidity in patients with diabetic foot disease in Europe. Baseline results from the Eurodiale study. Diabetologia 50, 18–25 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Morbach, S. et al. Long-term prognosis of diabetic foot patients and their limbs: amputation and death over the course of a decade. Diabetes Care 35, 2021–2027 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Rosi, L. M., Jones, A. S., Topliss, D. J. & Bach, L. A. Demographics and outcomes of inpatients with diabetic foot ulcers treated conservatively and surgically in a metropolitan hospital network. Diabetes Res. Clin. Pract. 175, 108821 (2021).

    Article  PubMed  Google Scholar 

  32. Misra, S. et al. Perfusion assessment in critical limb ischemia: principles for understanding and the development of evidence and evaluation of devices: a scientific statement from the American Heart Association. Circulation 140, e657–e672 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Criqui, M. H. & Aboyans, V. Epidemiology of peripheral artery disease. Circ. Res. 116, 1509–1526 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. Golledge, J. et al. High ankle brachial index predicts high risk of cardiovascular events amongst people with peripheral artery disease. PLoS ONE 15, e0242228 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. McDermott, M. M. et al. The ankle brachial index is associated with leg function and physical activity: the Walking and Leg Circulation Study. Ann. Intern. Med. 136, 873–883 (2002).

    Article  PubMed  Google Scholar 

  36. Golledge, J. et al. Relationship between disease specific quality of life measures, physical performance, and activity in people with intermittent claudication caused by peripheral artery disease. Eur. J. Vasc. Endovasc. Surg. 59, 957–964 (2020).

    Article  PubMed  Google Scholar 

  37. Nayak, P. et al. Association of six-minute walk distance with subsequent lower extremity events in peripheral artery disease. Vasc. Med. 25, 319–327 (2020).

    Article  CAS  PubMed  Google Scholar 

  38. McDermott, M. M. et al. Femoral artery plaque characteristics, lower extremity collaterals, and mobility loss in peripheral artery disease. Vasc. Med. 22, 473–481 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  39. McDermott, M. M. et al. Unsupervised exercise and mobility loss in peripheral artery disease: a randomized controlled trial. J. Am. Heart Assoc. 4, e001659 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  40. McDermott, M. M. et al. Pathophysiological changes in calf muscle predict mobility loss at 2-year follow-up in men and women with peripheral arterial disease. Circulation 120, 1048–1055 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  41. McDermott, M. M. et al. Community walking speed, sedentary or lying down time, and mortality in peripheral artery disease. Vasc. Med. 21, 120–129 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Morris, D. R. et al. Association of lower extremity performance with cardiovascular and all-cause mortality in patients with peripheral artery disease: a systematic review and meta-analysis. J. Am. Heart Assoc. 3, e001105 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  43. McDermott, M. M. et al. Association of 6-minute walk performance and physical activity with incident ischemic heart disease events and stroke in peripheral artery disease. J. Am. Heart Assoc. 4, e001846 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  44. McDermott, M. M. et al. Decline in functional performance predicts later increased mobility loss and mortality in peripheral arterial disease. J. Am. Coll. Cardiol. 57, 962–970 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Sigvant, B., Lundin, F. & Wahlberg, E. The risk of disease progression in peripheral arterial disease is higher than expected: a meta-analysis of mortality and disease progression in peripheral arterial disease. Eur. J. Vasc. Endovasc. Surg. 51, 395–403 (2016).

    Article  CAS  PubMed  Google Scholar 

  46. Faglia, E. et al. Early and five-year amputation and survival rate of diabetic patients with critical limb ischemia: data of a cohort study of 564 patients. Eur. J. Vasc. Endovasc. Surg. 32, 484–490 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Surinach, J. M. et al. Differences in cardiovascular mortality in smokers, past-smokers and non-smokers: findings from the FRENA registry. Eur. J. Intern. Med. 20, 522–526 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Rymer, J. A. et al. Association of disease progression with cardiovascular and limb outcomes in patients with peripheral artery disease: insights from the EUCLID trial. Circ. Cardiovasc. Interv. 13, e009326 (2020).

    Article  PubMed  Google Scholar 

  49. Hiatt, W. R. et al. Ticagrelor versus clopidogrel in symptomatic peripheral artery disease. N. Engl. J. Med. 376, 32–40 (2017).

    Article  CAS  PubMed  Google Scholar 

  50. McDermott, M. M. et al. Associations of borderline and low normal ankle-brachial index values with functional decline at 5-year follow-up: the WALCS (Walking and Leg Circulation Study). J. Am. Coll. Cardiol. 53, 1056–1062 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Narcisse, D. I. et al. The association of healthcare disparities and patient-specific factors on clinical outcomes in peripheral artery disease. Am. Heart J. 239, 135–146 (2021).

    Article  PubMed  Google Scholar 

  52. Makowski, L. et al. Sex related differences in therapy and outcome of patients with intermittent claudication in a real-world cohort. Atherosclerosis 325, 75–82 (2021).

    Article  CAS  PubMed  Google Scholar 

  53. Djerf, H. et al. Low risk of procedure related major amputation following revascularisation for intermittent claudication: a population based study. Eur. J. Vasc. Endovasc. Surg. 59, 817–822 (2020).

    Article  PubMed  Google Scholar 

  54. Madabhushi, V. et al. Revascularization of intermittent claudicants leads to more chronic limb-threatening ischemia and higher amputation rates. J. Vasc. Surg. 74, 771–779 (2021).

    Article  PubMed  Google Scholar 

  55. Kim, T. I. et al. Multiple reinterventions for claudication are associated with progression to chronic limb-threatening ischemia. Ann. Vasc. Surg. 72, 166–174 (2021).

    Article  PubMed  Google Scholar 

  56. Verwer, M. C., Wijnand, J. G. J., Teraa, M., Verhaar, M. C. & de Borst, G. J. Long term survival and limb salvage in patients with non-revascularisable chronic limb threatening ischaemia. Eur. J. Vasc. Endovasc. Surg. 62, 225–232 (2021).

    Article  PubMed  Google Scholar 

  57. de Donato, G. et al. Evaluation of clinical outcomes after revascularization in patients with chronic limb-threatening ischemia: results from a prospective national cohort study (RIVALUTANDO). Angiology 72, 480–489 (2021).

    Article  PubMed  CAS  Google Scholar 

  58. Wijeyaratne, M. et al. Clinical outcomes following lower extremity vein bypass for chronic limb threatening ischaemia (CLTI) at the University of Colombo, Sri Lanka. Eur. J. Vasc. Endovasc. Surg. 60, 560–566 (2020).

    Article  PubMed  Google Scholar 

  59. Kodama, A. et al. Editor’s Choice - relationship between Global Limb Anatomic Staging System (GLASS) and clinical outcomes following revascularisation for chronic limb threatening ischaemia in the bypass versus angioplasty in severe ischaemia of the leg (BASIL)-1 Trial. Eur. J. Vasc. Endovasc. Surg. 60, 687–695 (2020).

    Article  PubMed  Google Scholar 

  60. Tay, W. L. et al. Two-year clinical outcomes following lower limb endovascular revascularisation for chronic limb threatening ischaemia at a tertiary Asian vascular centre in Singapore. Singap. Med. J. https://doi.org/10.11622/smedj.2020104 (2020).

    Article  Google Scholar 

  61. Long, C. A. et al. Incidence and factors associated with major amputation in patients with peripheral artery disease: insights from the EUCLID trial. Circ. Cardiovasc. Qual. Outcomes 13, e006399 (2020).

    Article  PubMed  Google Scholar 

  62. Gutierrez, J. A. et al. Polyvascular disease and risk of major adverse cardiovascular events in peripheral artery disease: a secondary analysis of the EUCLID trial. JAMA Netw. Open. 1, e185239 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Smith, S. L., Matthews, E. O., Moxon, J. V. & Golledge, J. A systematic review and meta-analysis of risk factors for and incidence of 30-day readmission after revascularization for peripheral artery disease. J. Vasc. Surg. 70, 996–1006 (2019).

    Article  PubMed  Google Scholar 

  64. Smith, S. L. et al. Outcomes and costs of open and endovascular revascularisation for chronic limb ischaemia in an australian cohort. Heart Lung Circ. 30, 1552–1561 (2021).

    Article  PubMed  Google Scholar 

  65. Kaplovitch, E. et al. Rivaroxaban and aspirin in patients with symptomatic lower extremity peripheral artery disease: a subanalysis of the COMPASS randomized clinical trial. JAMA Cardiol. 6, 21–29 (2021).

    PubMed  Google Scholar 

  66. Hopley, C. W. et al. Chronic kidney disease and risk for cardiovascular and limb outcomes in patients with symptomatic peripheral artery disease: the EUCLID trial. Vasc. Med. 24, 422–430 (2019).

    Article  PubMed  Google Scholar 

  67. Samsky, M. D. et al. Association of heart failure with outcomes among patients with peripheral artery disease: insights from EUCLID. J. Am. Heart Assoc. 10, e018684 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Galani, J. et al. Association of chronic obstructive pulmonary disease with morbidity and mortality in patients with peripheral artery disease: insights from the EUCLID trial. Int. J. Chron. Obstruct Pulmon Dis. 16, 841–851 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Cronin, O., Morris, D. R., Walker, P. J. & Golledge, J. The association of obesity with cardiovascular events in patients with peripheral artery disease. Atherosclerosis 228, 316–323 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Fudim, M. et al. Association of hypertension and arterial blood pressure on limb and cardiovascular outcomes in symptomatic peripheral artery disease: the EUCLID trial. Circ. Cardiovasc. Qual. Outcomes 13, e006512 (2020).

    Article  PubMed  Google Scholar 

  71. Boc, V., Bozic Mijovski, M., Pohar Perme, M. & Blinc, A. Diabetes and smoking are more important for prognosis of patients with peripheral arterial disease than some genetic polymorphisms. Vasa 48, 229–235 (2019).

    Article  PubMed  Google Scholar 

  72. Rymer, J. A. et al. Association of health status scores with cardiovascular and limb outcomes in patients with symptomatic peripheral artery disease: insights from the EUCLID (Examining Use of Ticagrelor in Symptomatic Peripheral Artery Disease) trial. J. Am. Heart Assoc. 9, e016573 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Singh, T. P., Morris, D. R., Smith, S., Moxon, J. V. & Golledge, J. Systematic review and meta-analysis of the association between C-reactive protein and major cardiovascular events in patients with peripheral artery disease. Eur. J. Vasc. Endovasc. Surg. 54, 220–233 (2017).

    Article  CAS  PubMed  Google Scholar 

  74. Singh, N. et al. Preoperative hemoglobin A1c levels and increased risk of adverse limb events in diabetic patients undergoing infrainguinal lower extremity bypass surgery in the Vascular Quality Initiative. J. Vasc. Surg. 70, 1225–1234 e1221 (2019).

    Article  PubMed  Google Scholar 

  75. Kremers, B. et al. Plasma biomarkers to predict cardiovascular outcome in patients with peripheral artery disease: a systematic review and meta-analysis. Arterioscler. Thromb. Vasc. Biol. 40, 2018–2032 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Pastori, D. et al. Statins and major adverse limb events in patients with peripheral artery disease: a systematic review and meta-analysis. Thromb. Haemost. 120, 866–875 (2020).

    Article  PubMed  Google Scholar 

  77. Kim, C., Yang, Y. S., Ryu, G. W. & Choi, M. Risk factors associated with amputation-free survival for patients with peripheral arterial disease: a systematic review. Eur. J. Cardiovasc. Nurs. 20, 295–304 (2021).

    Article  PubMed  Google Scholar 

  78. Kreutzburg, T. et al. Editor’s Choice-the GermanVasc score: a pragmatic risk score predicts five year amputation free survival in patients with peripheral arterial occlusive disease. Eur. J. Vasc. Endovasc. Surg. 61, 248–256 (2021).

    Article  PubMed  Google Scholar 

  79. Narula, N., Olin, J. W. & Narula, N. Pathologic disparities between peripheral artery disease and coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 40, 1982–1989 (2020).

    Article  CAS  PubMed  Google Scholar 

  80. Pandya, Y. K., Lowenkamp, M. N. & Chapman, S. C. Functional popliteal artery entrapment syndrome: a review of diagnostic and management approaches. Vasc. Med. 24, 455–460 (2019).

    Article  PubMed  Google Scholar 

  81. Francois, C. J. Peripheral vascular imaging focusing on nonatherosclerotic disease. Radiol. Clin. North Am. 58, 831–839 (2020).

    Article  PubMed  Google Scholar 

  82. Yahagi, K. et al. Pathophysiology of native coronary, vein graft, and in-stent atherosclerosis. Nat. Rev. Cardiol. 13, 79–98 (2016).

    Article  CAS  PubMed  Google Scholar 

  83. Virmani, R., Kolodgie, F. D., Burke, A. P., Farb, A. & Schwartz, S. M. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler. Thromb. Vasc. Biol. 20, 1262–1275 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Fahed, A. C. & Jang, I. K. Plaque erosion and acute coronary syndromes: phenotype, molecular characteristics and future directions. Nat. Rev. Cardiol. 18, 724–734 (2021).

    Article  PubMed  Google Scholar 

  85. Golledge, J., Greenhalgh, R. M. & Davies, A. H. The symptomatic carotid plaque. Stroke 31, 774–781 (2000).

    Article  CAS  PubMed  Google Scholar 

  86. Narula, N. et al. Pathology of peripheral artery disease in patients with critical limb ischemia. J. Am. Coll. Cardiol. 72, 2152–2163 (2018).

    Article  CAS  PubMed  Google Scholar 

  87. Krishna, S. M., Omer, S. M. & Golledge, J. Evaluation of the clinical relevance and limitations of current pre-clinical models of peripheral artery disease. Clin. Sci. 130, 127–150 (2016).

    Article  CAS  Google Scholar 

  88. Krishna, S. M., Moxon, J. V. & Golledge, J. A review of the pathophysiology and potential biomarkers for peripheral artery disease. Int. J. Mol. Sci. 16, 11294–11322 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. McDermott, M. M. et al. Skeletal muscle pathology in peripheral artery disease: a brief review. Arterioscler. Thromb. Vasc. Biol. 40, 2577–2585 (2020).

    Article  CAS  PubMed  Google Scholar 

  90. Annex, B. H. & Cooke, J. P. New directions in therapeutic angiogenesis and arteriogenesis in peripheral arterial disease. Circ. Res. 128, 1944–1957 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Farber, A. & Eberhardt, R. T. The current state of critical limb ischemia: a systematic review. JAMA Surg. 151, 1070–1077 (2016).

    Article  PubMed  Google Scholar 

  92. Venkatesh, B. A. et al. Baseline assessment and comparison of arterial anatomy, hyperemic flow, and skeletal muscle perfusion in peripheral artery disease: the Cardiovascular Cell Therapy Research Network “Patients with Intermittent Claudication Injected with ALDH Bright Cells” (CCTRN PACE) study. Am. Heart J. 183, 24–34 (2017).

    Article  PubMed  Google Scholar 

  93. Tronc, F. et al. Role of matrix metalloproteinases in blood flow-induced arterial enlargement: interaction with NO. Arterioscler. Thromb. Vasc. Biol. 20, E120–E126 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Hutchings, G. et al. Molecular mechanisms associated with ROS-dependent angiogenesis in lower extremity artery disease. Antioxidants 10, 735 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Mercier, C., Rousseau, M. & Geraldes, P. Growth factor deregulation and emerging role of phosphatases in diabetic peripheral artery disease. Front. Cardiovasc. Med. 7, 619612 (2020).

    Article  CAS  PubMed  Google Scholar 

  96. Beltran-Camacho, L., Rojas-Torres, M. & Duran-Ruiz, M. C. Current status of angiogenic cell therapy and related strategies applied in critical limb ischemia. Int. J. Mol. Sci. 22, 2335 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Morris, D. R., Skalina, T. A., Singh, T. P., Moxon, J. V. & Golledge, J. Association of computed tomographic leg muscle characteristics with lower limb and cardiovascular events in patients with peripheral artery disease. J. Am. Heart Assoc. 7, e009943 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. McDermott, M. M. et al. Lower extremity ischemia, calf skeletal muscle characteristics, and functional impairment in peripheral arterial disease. J. Am. Geriatr. Soc. 55, 400–406 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Baum, O. et al. Capillary ultrastructure and mitochondrial volume density in skeletal muscle in relation to reduced exercise capacity of patients with intermittent claudication. Am. J. Physiol. Regul. Integr. Comp. Physiol. 310, R943–R951 (2016).

    Article  PubMed  Google Scholar 

  100. Duscha, B. D. et al. Skeletal muscle capillary density is related to anaerobic threshold and claudication in peripheral artery disease. Vasc. Med. 25, 411–418 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ho, T. K., Rajkumar, V., Black, C. M., Abraham, D. J. & Baker, D. M. Increased angiogenic response but deficient arteriolization and abnormal microvessel ultrastructure in critical leg ischaemia. Br. J. Surg. 93, 1368–1376 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. White, S. H. et al. Walking performance is positively correlated to calf muscle fiber size in peripheral artery disease subjects, but fibers show aberrant mitophagy: an observational study. J. Transl. Med. 14, 284 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Anderson, C. P., Pekas, E. J. & Park, S. Y. Microvascular dysfunction in peripheral artery disease: is heat therapy a viable treatment? Int. J. Env. Res. Public Health 18, 2384 (2021).

    Article  CAS  Google Scholar 

  104. Behroozian, A. & Beckman, J. A. Microvascular disease increases amputation in patients with peripheral artery disease. Arterioscler. Thromb. Vasc. Biol. 40, 534–540 (2020).

    Article  CAS  PubMed  Google Scholar 

  105. Grenon, S. M. et al. Walking disability in patients with peripheral artery disease is associated with arterial endothelial function. J. Vasc. Surg. 59, 1025–1034 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Treat-Jacobson, D. et al. Implementation of supervised exercise therapy for patients with symptomatic peripheral artery disease: a science advisory from the American Heart Association. Circulation 140, e700–e710 (2019).

    Article  PubMed  Google Scholar 

  107. Yang, C. et al. Retinal microvascular findings and risk of incident peripheral artery disease: an analysis from the Atherosclerosis Risk in Communities (ARIC) study. Atherosclerosis 294, 62–71 (2020).

    Article  CAS  PubMed  Google Scholar 

  108. Krishna, S. M. et al. Development of a two-stage limb ischemia model to better simulate human peripheral artery disease. Sci. Rep. 10, 3449 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Lane, R., Harwood, A., Watson, L. & Leng, G. C. Exercise for intermittent claudication. Cochrane Database Syst. Rev. 12, CD000990 (2017).

    PubMed  Google Scholar 

  110. Parikh, P. P. et al. A reliable mouse model of hind limb gangrene. Ann. Vasc. Surg. 48, 222–232 (2018).

    Article  PubMed  Google Scholar 

  111. Gomes de Almeida Schirmer, B. et al. The NO-donor MPC-1011 stimulates angiogenesis and arteriogenesis and improves hindlimb ischemia via a cGMP-dependent pathway involving VEGF and SDF-1alpha. Atherosclerosis 304, 30–38 (2020).

    Article  CAS  PubMed  Google Scholar 

  112. Yao, Z. et al. Bone marrow mesenchymal stem cell-derived endothelial cells increase capillary density and accelerate angiogenesis in mouse hindlimb ischemia model. Stem Cell Res. Ther. 11, 221 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Cui, Y. et al. N-acetylcysteine differentially regulates the populations of bone marrow and circulating endothelial progenitor cells in mice with limb ischemia. Eur. J. Pharmacol. 881, 173233 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Gotze, A. M. et al. IL10 alters peri-collateral macrophage polarization and hind-limb reperfusion in mice after femoral artery ligation. Int. J. Mol. Sci. 21, 2821 (2020).

    Article  PubMed Central  CAS  Google Scholar 

  115. Hollander, M. R. et al. Stimulation of collateral vessel growth by inhibition of galectin 2 in mice using a single-domain llama-derived antibody. J. Am. Heart Assoc. 8, e012806 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  116. O’Neill, K. M. et al. NOX4 is a major regulator of cord blood-derived endothelial colony-forming cells which promotes post-ischaemic revascularization. Cardiovasc. Res. 116, 393–405 (2020).

    PubMed  Google Scholar 

  117. Ryan, T. E. et al. PFKFB3-mediated glycolysis rescues myopathic outcomes in the ischemic limb. JCI Insight 5, e139628 (2020).

    Article  PubMed Central  Google Scholar 

  118. Orfany, A. et al. Mitochondrial transplantation ameliorates acute limb ischemia. J. Vasc. Surg. 71, 1014–1026 (2020).

    Article  PubMed  Google Scholar 

  119. Troidl, K. et al. The lipopeptide MALP-2 promotes collateral growth. Cells 9, 997 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  120. Golledge, J., Ward, N. C. & Watts, G. F. Lipid management in people with peripheral artery disease. Curr. Opin. Lipidol. 30, 470–476 (2019).

    Article  CAS  PubMed  Google Scholar 

  121. MacKeigan, D. T. et al. Updated understanding of platelets in thrombosis and hemostasis: the roles of integrin psi domains and their potential as therapeutic targets. Cardiovasc. Hematol. Disord. Drug Targets 20, 260–273 (2020).

    Article  CAS  PubMed  Google Scholar 

  122. Montarello, N. J., Nguyen, M. T., Wong, D. T. L., Nicholls, S. J. & Psaltis, P. J. Inflammation in coronary atherosclerosis and its therapeutic implications. Cardiovasc. Drugs Ther. https://doi.org/10.1007/s10557-020-07106-6 (2020).

    Article  PubMed  Google Scholar 

  123. Singh, A., Tandon, S. & Tandon, C. An update on vascular calcification and potential therapeutics. Mol. Biol. Rep. 48, 887–896 (2021).

    Article  CAS  PubMed  Google Scholar 

  124. Deppen, J. N. et al. A Swine hind limb ischemia model useful for testing peripheral artery disease therapeutics. J. Cardiovasc Transl. Res https://doi.org/10.1007/s12265-021-10134-8 (2021).

    Article  PubMed  Google Scholar 

  125. Hashimoto, A., Miyakoda, G., Hirose, Y. & Mori, T. Activation of endothelial nitric oxide synthase by cilostazol via a cAMP/protein kinase A- and phosphatidylinositol 3-kinase/Akt-dependent mechanism. Atherosclerosis 189, 350–357 (2006).

    Article  CAS  PubMed  Google Scholar 

  126. Kherallah, R. Y., Khawaja, M., Olson, M., Angiolillo, D. & Birnbaum, Y. Cilostazol: a review of basic mechanisms and clinical uses. Cardiovasc. Drugs Ther. https://doi.org/10.1007/s10557-021-07187-x (2021).

    Article  PubMed  Google Scholar 

  127. Brown, T. et al. Cilostazol for intermittent claudication. Cochrane Database Syst. Rev. 6, CD003748 (2021).

    PubMed  Google Scholar 

  128. Desai, K., Han, B., Kuziez, L., Yan, Y. & Zayed, M. A. Literature review and meta-analysis of the efficacy of cilostazol on limb salvage rates after infrainguinal endovascular and open revascularization. J. Vasc. Surg. 73, 711–721 e713 (2021).

    Article  PubMed  Google Scholar 

  129. Thanigaimani, S. et al. Network meta-analysis comparing the outcomes of treatments for intermittent claudication tested in randomized controlled trials. J. Am. Heart Assoc. 10, e019672 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Castellsague, J. et al. Characterization of new users of cilostazol in the UK, Spain, Sweden, and Germany. Pharmacoepidemiol. Drug. Saf. 26, 615–624 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Castaneda, P. R. et al. Outcomes and safety of electronic consult use in vascular surgery. J. Vasc. Surg. 71, 1726–1732 (2020).

    Article  PubMed  Google Scholar 

  132. Golledge, J. et al. Risk of major amputation in patients with intermittent claudication undergoing early revascularization. Br. J. Surg. 105, 699–708 (2018).

    Article  CAS  PubMed  Google Scholar 

  133. Polonsky, T. S. & McDermott, M. M. Lower extremity peripheral artery disease without chronic limb-threatening ischemia: a review. JAMA 325, 2188–2198 (2021).

    Article  PubMed  Google Scholar 

  134. McDermott, M. M. et al. Walking exercise therapy effects on lower extremity skeletal muscle in peripheral artery disease. Circ. Res. 128, 1851–1867 (2021).

    Article  CAS  PubMed  Google Scholar 

  135. Biswas, M. P. et al. Exercise training and revascularization in the management of symptomatic peripheral artery disease. JACC Basic Transl. Sci. 6, 174–188 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Treat-Jacobson, D. et al. Optimal exercise programs for patients with peripheral artery disease: a scientific statement from the American Heart Association. Circulation 139, e10–e33 (2019).

    Article  PubMed  Google Scholar 

  137. Parmenter, B. J., Mavros, Y., Ritti Dias, R., King, S. & Fiatarone Singh, M. Resistance training as a treatment for older persons with peripheral artery disease: a systematic review and meta-analysis. Br. J. Sports Med. 54, 452–461 (2020).

    PubMed  Google Scholar 

  138. Duscha, B. D. et al. Angiogenesis in skeletal muscle precede improvements in peak oxygen uptake in peripheral artery disease patients. Arterioscler. Thromb. Vasc. Biol. 31, 2742–2748 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Allen, J. D. et al. Plasma nitrite flux predicts exercise performance in peripheral arterial disease after 3 months of exercise training. Free Radic. Biol. Med. 49, 1138–1144 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Woessner, M. et al. Beet the best? Circ. Res. 123, 654–659 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Kenjale, A. A. et al. Dietary nitrate supplementation enhances exercise performance in peripheral arterial disease. J. Appl. Physiol. 110, 1582–1591 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Harwood, A. E., Smith, G. E., Cayton, T., Broadbent, E. & Chetter, I. C. A systematic review of the uptake and adherence rates to supervised exercise programs in patients with intermittent claudication. Ann. Vasc. Surg. 34, 280–289 (2016).

    Article  PubMed  Google Scholar 

  143. Golledge, J. et al. Meta-analysis of clinical trials examining the benefit of structured home exercise in patients with peripheral artery disease. Br. J. Surg. 106, 319–331 (2019).

    Article  CAS  PubMed  Google Scholar 

  144. Pymer, S. A. et al. An updated systematic review and meta-analysis of home-based exercise programmes for individuals with intermittent claudication. J. Vasc. Surg. 74, 2076–2085.e20 (2021).

    Article  PubMed  Google Scholar 

  145. McDermott, M. M. et al. Home-based walking exercise intervention in peripheral artery disease: a randomized clinical trial. JAMA 310, 57–65 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. McDermott, M. M. et al. Effect of a home-based exercise intervention of wearable technology and telephone coaching on walking performance in peripheral artery disease: the HONOR randomized clinical trial. JAMA 319, 1665–1676 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  147. McDermott, M. M. et al. Effect of low-intensity vs high-intensity home-based walking exercise on walk distance in patients with peripheral artery disease: the LITE randomized clinical trial. JAMA 325, 1266–1276 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Saratzis, A. et al. Supervised exercise therapy and revascularization for intermittent claudication: network meta-analysis of randomized controlled trials. JACC Cardiovasc. Interv. 12, 1125–1136 (2019).

    Article  PubMed  Google Scholar 

  149. Pandey, A. et al. Comparative efficacy of endovascular revascularization versus supervised exercise training in patients with intermittent claudication: meta-analysis of randomized controlled trials. JACC Cardiovasc. Interv. 10, 712–724 (2017).

    Article  PubMed  Google Scholar 

  150. Jansen, S. C. P. et al. Successful implementation of the exercise first approach for intermittent claudication in the Netherlands is associated with few lower limb revascularisations. Eur. J. Vasc. Endovasc. Surg. 60, 881–887 (2020).

    Article  PubMed  Google Scholar 

  151. Katsanos, K., Spiliopoulos, S., Kitrou, P., Krokidis, M. & Karnabatidis, D. Risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the leg: a systematic review and meta-analysis of randomized controlled trials. J. Am. Heart Assoc. 7, e011245 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Dan, K. et al. Paclitaxel-related balloons and stents for the treatment of peripheral artery disease: insights from the Food and Drug Administration 2019 Circulatory System Devices Panel Meeting on late mortality. Am. Heart J. 222, 112–120 (2020).

    Article  CAS  PubMed  Google Scholar 

  153. Dinh, K. et al. Mortality rates after paclitaxel-coated device use in patients with occlusive femoropopliteal disease: an updated systematic review and meta-analysis of randomized controlled trials. J. Endovasc. Ther. 28, 755–777 (2021).

    Article  PubMed  Google Scholar 

  154. Hiramoto, J. S., Teraa, M., de Borst, G. J. & Conte, M. S. Interventions for lower extremity peripheral artery disease. Nat. Rev. Cardiol. 15, 332–350 (2018).

    Article  PubMed  Google Scholar 

  155. Adam, D. J. et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet 366, 1925–1934 (2005).

    Article  CAS  PubMed  Google Scholar 

  156. International Standard Randomised Controlled Trial Number Registry. ISRCTN https://www.isrctn.com/ISRCTN27728689 (2020).

  157. International Standard Randomised Controlled Trial Number Registry. ISRCTN https://www.isrctn.com/ISRCTN14469736 (2019).

  158. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02060630 (2021).

  159. Schwartz, G. G. et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N. Engl. J. Med. 379, 2097–2107 (2018).

    Article  CAS  PubMed  Google Scholar 

  160. Jukema, J. W. et al. Alirocumab in patients with polyvascular disease and recent acute coronary syndrome: ODYSSEY OUTCOMES trial. J. Am. Coll. Cardiol. 74, 1167–1176 (2019).

    Article  CAS  PubMed  Google Scholar 

  161. Ishikawa, Y. et al. Preventive effects of eicosapentaenoic acid on coronary artery disease in patients with peripheral artery disease. Circ. J. 74, 1451–1457 (2010).

    Article  CAS  PubMed  Google Scholar 

  162. Bhatt, D. L. et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N. Engl. J. Med. 380, 11–22 (2019).

    Article  CAS  PubMed  Google Scholar 

  163. Ostergren, J. et al. Impact of ramipril in patients with evidence of clinical or subclinical peripheral arterial disease. Eur. Heart J. 25, 17–24 (2004).

    Article  CAS  PubMed  Google Scholar 

  164. SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N. Engl. J. Med. 373, 2103–2116 (2015).

    Article  CAS  Google Scholar 

  165. ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N. Engl. J. Med. 362, 1575–1585 (2010).

    Article  CAS  Google Scholar 

  166. Goldman, M. P. et al. Effect of intensive glycemic control on risk of lower extremity amputation. J. Am. Coll. Surg. 227, 596–604 (2018).

    Article  PubMed  Google Scholar 

  167. Verma, S. et al. Cardiovascular outcomes and safety of empagliflozin in patients with type 2 diabetes mellitus and peripheral artery disease: a subanalysis of EMPA-REG OUTCOME. Circulation 137, 405–407 (2018).

    Article  PubMed  Google Scholar 

  168. Neal, B., Perkovic, V. & Matthews, D. R. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N. Engl. J. Med. 377, 644–657 (2017).

    Article  CAS  PubMed  Google Scholar 

  169. Cannon, C. P. et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N. Engl. J. Med. 383, 1425–1435 (2020).

    Article  CAS  PubMed  Google Scholar 

  170. Bonaca, M. P. et al. Dapagliflozin and cardiac, kidney, and limb outcomes in patients with and without peripheral artery disease in DECLARE-TIMI 58. Circulation 142, 734–747 (2020).

    Article  PubMed  Google Scholar 

  171. Wiviott, S. D. et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 380, 347–357 (2019).

    Article  CAS  PubMed  Google Scholar 

  172. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 348, 1329–1339 (1996).

    Article  Google Scholar 

  173. Bonaca, M. P. et al. Rivaroxaban in peripheral artery disease after revascularization. N. Engl. J. Med. 382, 1994–2004 (2020).

    Article  CAS  PubMed  Google Scholar 

  174. Hennrikus, D. et al. Effectiveness of a smoking cessation program for peripheral artery disease patients: a randomized controlled trial. J. Am. Coll. Cardiol. 56, 2105–2112 (2010).

    Article  PubMed  Google Scholar 

  175. Thomas Manapurathe, D. et al. Cohort study examining the association between blood pressure and cardiovascular events in patients with peripheral artery disease. J. Am. Heart Assoc. 8, e010748 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Golledge, J., Quigley, F., Velu, R., Walker, P. J. & Moxon, J. V. Association of impaired fasting glucose, diabetes and their management with the presentation and outcome of peripheral artery disease: a cohort study. Cardiovasc. Diabetol. 13, 147 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Machline-Carrion, M. J. et al. Effect of a multifaceted quality improvement intervention on the prescription of evidence-based treatment in patients at high cardiovascular risk in Brazil: the BRIDGE cardiovascular prevention cluster randomized clinical trial. JAMA Cardiol. 4, 408–417 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Vernooij, J. W. et al. Internet based vascular risk factor management for patients with clinically manifest vascular disease: randomised controlled trial. BMJ 344, e3750 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Peterson, G. G. et al. Effect of the million hearts cardiovascular disease risk reduction model on initiating and intensifying medications: a prespecified secondary analysis of a randomized clinical trial. JAMA Cardiol. 6, 1050–1059 (2021).

    Article  PubMed  Google Scholar 

  180. Hong, F. F. et al. Roles of eNOS in atherosclerosis treatment. Inflamm. Res. 68, 429–441 (2019).

    Article  CAS  PubMed  Google Scholar 

  181. Ismaeel, A. et al. The nitric oxide system in peripheral artery disease: connection with oxidative stress and biopterins. Antioxidants 9, 590 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  182. Allen, J. D., Giordano, T. & Kevil, C. G. Nitrite and nitric oxide metabolism in peripheral artery disease. Nitric Oxide 26, 217–222 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Loffredo, L. et al. Imbalance between nitric oxide generation and oxidative stress in patients with peripheral arterial disease: effect of an antioxidant treatment. J. Vasc. Surg. 44, 525–530 (2006).

    Article  PubMed  Google Scholar 

  184. Loffredo, L. et al. Dark chocolate acutely improves walking autonomy in patients with peripheral artery disease. J. Am. Heart Assoc. 3, e001072 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. McDermott, M. M. et al. Cocoa to improve walking performance in older people with peripheral artery disease: the COCOA-PAD pilot randomized clinical trial. Circ. Res. 126, 589–599 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Park, S. Y. et al. Acute mitochondrial antioxidant intake improves endothelial function, antioxidant enzyme activity, and exercise tolerance in patients with peripheral artery disease. Am. J. Physiol. Heart Circ. Physiol. 319, H456–H467 (2020).

    Article  CAS  PubMed  Google Scholar 

  187. Zankl, A. R. et al. Telmisartan improves absolute walking distance and endothelial function in patients with peripheral artery disease. Clin. Res. Cardiol. 99, 787–794 (2010).

    Article  CAS  PubMed  Google Scholar 

  188. Montanari, G. et al. Treatment with low dose metformin in patients with peripheral vascular disease. Pharmacol. Res. 25, 63–73 (1992).

    Article  CAS  PubMed  Google Scholar 

  189. Sirtori, C. R. et al. Metformin improves peripheral vascular flow in nonhyperlipidemic patients with arterial disease. J. Cardiovasc. Pharmacol. 6, 914–923 (1984).

    Article  CAS  PubMed  Google Scholar 

  190. McDermott, M. M. et al. Effect of resveratrol on walking performance in older people with peripheral artery disease: the RESTORE randomized clinical trial. JAMA Cardiol. 2, 902–907 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  191. Gao, W., Chen, D., Liu, G. & Ran, X. Autologous stem cell therapy for peripheral arterial disease: a systematic review and meta-analysis of randomized controlled trials. Stem Cell Res. Ther. 10, 140 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  192. McDermott, M. M. et al. Effect of granulocyte-macrophage colony-stimulating factor with or without supervised exercise on walking performance in patients with peripheral artery disease: the PROPEL randomized clinical trial. JAMA 318, 2089–2098 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. McDermott, M. M. et al. Racial differences in the effect of granulocyte macrophage colony-stimulating factor on improved walking distance in peripheral artery disease: the PROPEL randomized clinical trial. J. Am. Heart Assoc. 8, e011001 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Gu, Y. et al. A randomized, double-blind, placebo-controlled phase II study of hepatocyte growth factor in the treatment of critical limb ischemia. Mol. Ther. 27, 2158–2165 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Hammad, T. A. et al. Stromal cell-derived factor-1 plasmid treatment for patients with peripheral artery disease (STOP-PAD) trial: six-month results. J. Endovasc. Ther. 27, 669–675 (2020).

    Article  PubMed  Google Scholar 

  196. Gorenoi, V., Brehm, M. U., Koch, A. & Hagen, A. Growth factors for angiogenesis in peripheral arterial disease. Cochrane Database Syst. Rev. 6, CD011741 (2017).

    PubMed  Google Scholar 

  197. Forster, R., Liew, A., Bhattacharya, V., Shaw, J. & Stansby, G. Gene therapy for peripheral arterial disease. Cochrane Database Syst. Rev. 10, CD012058 (2018).

    PubMed  Google Scholar 

  198. Viney, N. J. et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet 388, 2239–2253 (2016).

    Article  CAS  PubMed  Google Scholar 

  199. Everett, B. M. et al. Inhibition of interleukin-1beta and reduction in atherothrombotic cardiovascular events in the CANTOS trial. J. Am. Coll. Cardiol. 76, 1660–1670 (2020).

    Article  CAS  PubMed  Google Scholar 

  200. Ridker, P. M. & Rane, M. Interleukin-6 signaling and anti-interleukin-6 therapeutics in cardiovascular disease. Circ. Res. 128, 1728–1746 (2021).

    Article  CAS  PubMed  Google Scholar 

  201. Antonopoulos, A. S., Papanikolaou, E., Vogiatzi, G., Oikonomou, E. & Tousoulis, D. Anti-inflammatory agents in peripheral arterial disease. Curr. Opin. Pharmacol. 39, 1–8 (2018).

    Article  CAS  PubMed  Google Scholar 

  202. Parvar, S. L., Thiyagarajah, A., Nerlekar, N., King, P. & Nicholls, S. J. A systematic review and meta-analysis of gender differences in long-term mortality and cardiovascular events in peripheral artery disease. J. Vasc. Surg. 73, 1456–1465 (2021).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

J.G. received grants from the National Health and Medical Research Council (1180736), Heart Foundation, Tropical Australian Academic Health Centre, Townsville Hospital and Health Service Study, Education and Research Trust Fund and Queensland Government. J.G. holds a Practitioner Fellowship from the National Health and Medical Research Council (1117601) and a Senior Clinical Research Fellowship from the Queensland Government. The author thanks S. Thangaimani, J. Phie and C. Burrows (James Cook University, Australia) for help with production of the figures for initial submission and A. Golledge for help with proof reading. He thanks all the past and current researchers from the Queensland Research Centre for Peripheral Vascular Disease and collaborators for their ongoing research on peripheral artery disease, which has contributed towards the insights included in this Review. Finally, the author apologizes to scientists whose research could not be included in this Review owing to space limitations.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jonathan Golledge.

Ethics declarations

Competing interests

The author has received honoraria from Amgen and Bayer for giving lectures on PAD.

Additional information

Peer review information

Nature Reviews Cardiology thanks Brian H. Annex; Iris Baumgartner, who co-reviewed with Dario Häberli; Mary Kavurma; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Revascularization

Minimally invasive interventional (such as stenting) or open surgical (such as endarterectomy) procedures to improve distal blood supply.

Myopathy

Muscle damage with various causes, including impaired muscle blood supply owing to peripheral artery disease.

Arteriogenesis

The expansion of existing collateral arteries to improve distal blood supply.

Angiogenesis

The sprouting of new capillaries and formation of new networks of small vessels to improve distal blood supply.

Cell therapy

Administering stem or progenitor cells to encourage angiogenesis.

Gene therapy

Administering harmless viruses that have been modified to carry a gene of interest into the local tissue.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Golledge, J. Update on the pathophysiology and medical treatment of peripheral artery disease. Nat Rev Cardiol 19, 456–474 (2022). https://doi.org/10.1038/s41569-021-00663-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41569-021-00663-9

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing