Search for ways to optimize management tactics for patients with peripheral artery atherosclerosis: focus on the use of statins and the identification of specific biomarkers

Authors: M.A. Keren, N.A. Sheykina

Company: Bakoulev National Medical Research Center for Cardiovascular Surgery, Moscow, 121552, Russian Federation

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Type:  Reviews


For citation: Keren M.A., Sheykina N.A. Search for ways to optimize management tactics for patients with peripher- al artery atherosclerosis: focus on the use of statins and the identification of specific biomarkers. Creative Cardiology. 2020; 14 (2): 158–66 (in Russ.). DOI: 10.24022/1997-3187-2020-14-2-158-166

Received / Accepted:  01.06.2020 / 10.06.2020

Keywords: peripheral arterial atherosclerosis statins biomarkers of atherosclerosis

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According to numerous studies, atherosclerosis is a cause of high mortality and cardiovascular morbidity in a population. Particular attention is required for patients with multifocal atherosclerosis – atherosclerosis of two or more vascular regions. In part, the reasons for the high morbidity among these patients are an insufficient assessment of systemic atherosclerosis as a marker of systemic inflammation, the late detection of systemic vascular lesions, not optimal therapy, and low patient adherence to treatment. Patients with severe peripheral arterial atherosclerosis have a negative prognosis, and therefore need more intensive drug therapy. In this situation, statin therapy comes to the fore. However, we should recognize that in the medical community there is a significant underestimation of the importance of prescribing precisely the highly intense statins of the latest generation and achieving target levels of specific markers of atherosclerosis. Recently, special attention has been paid to the biomarkers of atherosclerosis. Elevated levels of specific markers (LDL, LP (a), CRP, IL-1, 2 and 6, selectins, hemostatic factors, metalloproteinases, adhesion molecules, tumor necrosis factor alpha) are the risk factors for peripheral arterial atherosclerosis. However, despite advances in the diagnosis of peripheral atherosclerosis, the significance of some of these markers in the onset and progression of atherosclerosis remains underestimated. A detailed understanding of the pathophysiological processes, the search and study of new markers of atherosclerosis can decrease in the incidence rate, and, ultimately, an improved prognosis among these patients.


  1. Fowkes F.G., Rudan D., Rudan I., Aboyans V., Denenberg J.O., McDermott M.M. 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. 2013; 382 (9901): 1329–40. DOI: 10.1016/s01406736(13)61249-0
  2. Criqui M.H., Aboyans V. Epidemiology of peripheral artery disease. Circ. Res. 2015; 116 (9): 1509–26. DOI: 10.1161/circresaha.116.303849
  3. KumbhaniD.J.,StegP.G.,CannonC.P.,EagleK.A., Smith S.C., Jr. et al. Statin therapy and long-term adverse limb outcomes in patients with peripheral artery disease: insights from the REACH registry. Eur. Heart J. 2014; 35 (41): 2864–72. DOI: 10.1093/eurheartj/ehu080
  4. Mach F., Baigent C., Catapano A.L., Koskinas K.C., Casula M., Badimon L. et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur. Heart J. 2020; 41 (3): 111–88. DOI: 10.1093/eurheartj/ehz455
  5. Sundbøll J., Larsen A.P., Veres K., Adelborg K., Sørensen H.T. Cardiovascular event rates and trajectories of LDL-cholesterol levels and lipid-lowering therapy in patients with atherosclerotic cardiovascular disease: A population-based cohort study. Thromb. Res. 2019; 183: 124–30. DOI: 10.1016/j.thromres.2019.09.034
  6. Kislyak O.A., Sergienko O.V., Davidenko M.N. Vasoprotective effect of statins and modern view of the role of statins in primary and secondary prevention of cardiovascular diseases. Medical Care. 2019; 4: 49–56 DOI: 10.24411/2071-5315-2019-12156 (in Russ.)
  7. Foley T.R., Singh G.D., Kokkinidis D.G., Choy H.K., Pham T., Amsterdam E.A. et al. High-intensity statin therapy is associated with improved survival in patients with peripheral artery disease. J. Am. Heart Assoc. 2017; 6 (7). DOI: 10.1161/ jaha.117.005699
  8. Catapano A.L., Graham I., De Backer G., Wiklund O., Chapman M.J., Drexel H. et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur. Heart J. 2016; 37 (39): 2999–3058. DOI: 10.1093/eurheartj/ehw272
  9. KumbhaniD.J., StegP.G., CannonC.P., EagleK.A., Smith S.C., Jr. et al. Statin therapy and long-term adverse limb outcomes in patients with peripheral artery disease: insights from the REACH registry. Eur. Heart J. 2014; 35 (41): 2864–72. DOI: 10.1093/eurheartj/ehu080
  10. 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. 2007; 45 (4): 645–54. DOI: 10.1016/j.jvs.2006.12.054
  11. Arya S., Khakharia A., Binney Z.O., DeMartino R.R., Brewster L.P., Goodney P.P. et al. Association of statin dose with amputation and survival in patients with peripheral artery disease. Circulation. 2018; 137 (14): 1435–46. DOI: 10.1161/circulationaha.117.032361
  12. Aung P.P., Maxwell H.G., Jepson R.G., Price J.F., Leng G.C. Lipid-lowering for peripheral arterial disease of the lower limb. Cochrane Database Syst. Rev. 2007; 4: CD000123. DOI: 10.1002/14651858.cd000123.pub2
  13. Collins R., Armitage J., Parish S., Sleigh P., Peto R. MRC/BHF Heart Protection Study of cholesterollowering with simvastatin in 5963 people with diabetes: a randomised placebocontrolled trial. Lancet. 2003; 361 (9374): 2005–16. DOI: 10.1016/s0140-6736(03)13636-7
  14. Walter D.H., Schächinger V., Elsner M., Mach S., Auch-Schwelk W., Zeiher A.M. Effect of statin therapy on restenosis after coronary stent implantation. Am. J. Cardiol. 2000; 85 (8): 962–8. DOI: 10.1016/s0002-9149(99)00910-8
  15. Amarenco P., Labreuche J. Lipid management in the prevention of stroke: review and updated metaanalysis of statins for stroke prevention. Lancet. Neurol. 2009; 8 (5): 453–63. DOI: 10.1016/s14744422(09)70058-4
  16. Nordestgaard B.G., Langsted A. Lipoprotein(a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology. J. Lipid. Res. 2016; 57 (11): 1953–75. DOI: 10.1194/jlr.r071233
  17. Ezhov M.V., Safarova M.S., Afanasieva O.I., Kukharchuk V.V., Pokrovsky S.N. Lipoprotein (a) level and apolipoprotein (a) phenotype as predictors of long-term cardiovascular outcomes after coronary artery bypass grafting. Atherosclerosis. 2014; 235 (2): 477–82 (in Russ.)
  18. Van Buuren F., Sommer J.A., Kottmann T., Horstkotte D., Mellwig K.P. Extracardiac manifestation of elevated lipoprotein(a) levels – cumulative incidence of peripheral arterial disease and stenosis of the carotid artery. Clin. Res. Cardiol. Suppl. 2015; 10: 39–45.
  19. Shah P.K., Lecis D. Inflammation in atherosclerotic cardiovascular disease. F1000Research. 2019; 8 (F1000 Faculty Rev): 1402. DOI: 10.12688/ f1000research.18901.1
  20. Tmoyan N.A., Ezhov M.V., Afanasieva O.I., Klesareva E.A., Razova O.A., Kukharchuk V.V. et al. The association of lipoprotein(a) and apolipoprotein(a) phenotypes with peripheral artery disease. Therapeutic Archive. 2018; 90 (9): 31–6 (in Russ.)
  21. Afanasieva O.I., Ezhov M.V., Afanasieva M.I., Safarova M.S., Berestetskaya Yu.V., Pokrovsky S.N. Сorrelations of low molecular weight phenotype of apoprotein(a) and serum level of lipoprotein(a) with multifocal atherosclerosis in patients with coronary heart disease. Rational Pharmacotherapy in Cardiology. 2010; 6 (4): 474–80. DOI: 10.20996/1819-6446-2010-6-4-474-480 (in Russ.)
  22. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C., Blackwell L., Emberson J., Holland L.E., Reith C., Bhala N. et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010; 376 (9753): 1670–81. DOI: 10.1016/s01406736(10)61350-5
  23. Boekholdt S.M., Hovingh G.K., Mora S., Arsenault B.J., Amarenco P., Pedersen T.R. et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J. Am. Coll. Cardiol. 2014; 64 (5): 485–94.
  24. Yamamoto H., Kawamura M., Kochi I., Imai M., Murata Y., Suzuki T. et al. Serum anti-apo b antibody level as residual CVD marker in dm patients under statin treatment. J. Atheroscler. Thromb. 2019; 26 (10): 931–43. DOI: 10.5551/jat.46797
  25. Cao J., Nomura S.O., Steffen B.T., Guan W., Remaley A.T., Karger A.B. et al. Apolipoprotein B discordance with low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol in relation to coronary artery calcification in the Multi-Ethnic Study of Atherosclerosis (MESA). J. Clin. Lipidol. 2020; 14 (1): 109–21.e5. DOI: 10.1016/j.jacl.2019.11.005
  26. McDermott M.M., Lloyd-Jones D.M. The role of biomarkers and genetics in peripheral arterial disease. J. Am. Coll. Cardiol. 2009; 54 (14): 1228–37. DOI: 10.1016/j.jacc.2009.04.081
  27. Rifai N. High-sensitivity C-reactive protein: a useful marker for cardiovascular disease risk prediction and the metabolic syndrome. Clin. Chem. 2005; 51 (3): 504–5. DOI: 10.1373/clinchem. 2004.044990
  28. Murabito J.M., Keyes M.J., Guo C.Y., Keaney J.F., Jr., Vasan R.S., D'Agostino R.B., Sr. et al. Cross-sectional relations of multiple inflammatory biomarkers to peripheral arterial disease: The Framingham Offspring Study. Atherosclerosis. 2009; 203 (2): 509–14. DOI: 10.1016/j.atherosclerosis. 2008.06.031
  29. Ridker P.M., Cannon C.P., Morrow D., Rifai N., Rose L.M., McCabe C.H. et al. C-reactive protein levels and outcomes after statin therapy. N. Engl. J. Med. 2005; 352 (1): 20–8. DOI: 10.1056/ nejmoa042378
  30. McDermott M.M., Guralnik J.M., Corsi A., Albay M., Macchi C., Bandinelli S. et al. Patterns of inflammation associated with peripheral arterial disease: the InCHIANTI study. Am. Heart J. 2005; 150 (2): 276–81. DOI: 10.1016/j.ahj.2004.09.032
  31. Sinkevich N.S., Maslennikov M.A., Bulkina O.S., Karpov Yu.A. Peripheral atherosclerosis diagnostics by the circulating biomarkers determination. Atherosclerosis and Dyslipidemias. 2015; 2: 22–9.
  32. Tzoulaki I., Murray G., Lee A.J., Rumley A., Lowe G.D., Fowkes F.G. Inflammatory, haemostatic, and rheological markers for incident peripheral arterial disease: Edinburgh Artery Study. Eur. Heart J. 2007; 28 (3): 354–62. DOI: 10.1093/eurheartj/ehl441
  33. Potaczek D.P., Undas A., Nowakowski T., Szczeklik A. Association between inflammatory markers and the interleukin-6 -174 G/C polymorphism is abolished in peripheral arterial occlusive disease. Int. Angiol. 2007; 26 (4): 318–23.
  34. Tzoulaki I., Murray G.D., Lee A.J., Rumley A., Lowe G.D., Fowkes F.G. C-reactive protein, interleukin-6, and soluble adhesion molecules as predictors of progressive peripheral atherosclerosis in the general population. Edinburgh Artery Study. Circulation. 2005; 112 (7): 976–83. DOI: 10.1161/ circulationaha.104.513085
  35. Ragino Yu.I., Stryukova E.V., Murashov I.S., Polonskaya Ya.V., Volkov A.M., Kashtanova E.V. et al. Association of endothelial dysfunction factors with the presence of unstable atherosclerotic plaques in the coronary arteries. Russian Journal of Cardiology. 2019; 24 (5): 26–9 (in Russ.)
  36. Merten M., Thiagarajan P. P-selectin in arterial thrombosis. Z. Kardiol. 2004; 93 (11): 855–63. DOI: 10.1007/s00392-004-0146-5
  37. Boulbou M.S., Koukoulis G.N., Vasiou K.G., Petinaki E.A., Gourgoulianis K.I., Fezoulidis I.B. Increased soluble E-selectin levels in type 2 diabetic patients with peripheral arterial disease. Int. Angiol. 2004; 23 (1): 18–24.
  38. Signorelli S.S., Malaponte G., Libra M., Di Pino L., Celotta G., Bevelacqua V. et al. Plasma levels and zymographic activities of matrix metalloproteinases 2 and 9 in type II diabetics with peripheral arterial disease. Vasc. Med. 2005; 10 (1): 1–6. DOI: 10.1191/1358863x05vm582oa
  39. Mustonen P., Lepäntalo M., Lassila R. Physical exertion induces thrombin formation and fibrin degradation in patients with peripheral atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 1998; 18 (2): 244–9. DOI: 10.1161/01.atv.18.2.244
  40. Joosten M.M., Pai J.K., Bertoia M.L., Gansevoort R.T., Bakker S.J., Cooke J.P. et al. β2-microglobulin, cystatin C, and creatinine and risk of symptomatic peripheral artery disease. J. Am. Heart Assoc. 2014; 3 (4). DOI: 10.1161/ jaha.114.000803

About Authors

Milena A. Keren, Dr. Med. Sc., Researcher,
Nina A. Sheykina, Cardiologist

Chief Editor

Leo A. Bockeria, MD, PhD, DSc, Professor, Academician of Russian Academy of Sciences, Director of Bakoulev National Medical Research Center for Cardiovascular Surgery