Связь липопротеида(а) и фенотипов апобелка(а) со стенозирующим атеросклерозом периферических артерий
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Материалы и методы. В исследование включены 998 пациентов (707 мужчин и 291 женщина, средний возраст 60±12 лет). Пациентов разделили на 4 группы в зависимости от наличия или отсутствия ПАС и ИБС: группа I (n=188, ПАС+ИБС+), группа II (n=78, ПАС+ИБС‒), группа III (n=407, ПАС−ИБС+), группа IV (n=325, ПАС‒ИБС‒).
Результаты. Концентрация Лп(а) в группах I, II и III была выше, чем у пациентов контрольной группы (медиана [25%; 75%]): 34 [15; 80], 30 [10; 49] и 22 [8; 60] мг/дл против 15 [6; 35] мг/дл соответственно, p<0,01 во всех случаях. В группе I уровень Лп(а) был выше, чем во всех остальных группах (p<0,05). Повышенный уровень Лп(а) ≥ 30 мг/дл в группах I, II, III выявлялся чаще, чем в контрольной группе: 54, 50, 43% соответственно против 30%, p<0,01 во всех случаях. Повышенный уровень Лп(а) в группе c ПАС и ИБС встречался чаще, чем в группе с ИБС без ПАС (p=0,02). Лп(а) ≥30 мг/дл ассоциировался с наличием ПАС с отношением шансов (ОШ) 1,9; 95% доверительный интервал (ДИ) 1,4–2,5; p<0,01. Низкомолекулярный фенотип апо(а) в группах I, II, III выявлялся чаще, чем в контрольной группе: 46, 56, 52% соответственно против 28%, p<0,01. Низкомолекулярный фенотип апо(а) у пациентов без ИБС ассоциируется с наличием ПАС с ОШ 3,3; 95% ДИ 1,6–6,8; p<0,01, а у пациентов с ИБС связь отсутствовала. По результатам логистического регрессионного анализа уровень Лп(а) и низкомолекулярный фенотип апо(а) являлись независимыми предиктороми ПАС при их включении в модель по отдельности.
Заключение. Повышенный уровень Лп(а) и низкомолекулярный фенотип апо(а) являются независимыми факторами риска ПАС.
У пациентов с ПАС и ИБС уровень Лп(а) выше, чем при изолированном поражении каждого сосудистого бассейна. Более высокие уровни Лп(а) связаны с наличием более тяжелого атеросклероза с вовлечением нескольких сосудистых бассейнов.
Ключевые слова: липопротеид(а), фенотипы апобелка(а), атеросклероз, периферический атеросклероз, атеросклероз артерий нижних конечностей.
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Aim. Lipoprotein(a) [Lp(a)] is an independent risk factor of coronary heart disease (CHD) and myocardial infarction. Data about the role of Lp(a) in the development of peripheral artery disease (PAD) is controversial and uncertain. The aim of the study was to evaluate the association between Lp(a), apolipoprotein(a) [apo(a)] phenotypes and PAD.
Materials and methods. The study included 998 patients (707 male and 291 female, average age 60±12). The patients were divided into
4 groups depending on the presence or absence PAD and CHD: group I (n=188, PAD+CHD+), group II (n=78, PAD+CHD−), group III (n=407, PAD−CHD+), group IV (n=325, PAD−CHD−).
Results. The level of Lp(a) was significantly higher in groups I, II, III in comparison with patients of control group (group IV): 34 [15; 80], 30 [10; 49], 22 [8; 60] mg/dl vs. 15 [6; 35] mg/dl respectively, p<0.01 in all cases. Lp(a) level was higher in the group I than in the other groups (p<0.05). The prevalence of elevated Lp(a) level (≥ 30 mg/dl) was significantly higher in groups I, II, III than in control group: 54%, 50%, 43% respectively vs. 30%, p<0.01 in all cases. The prevalence of Lp(a) ≥ 30 mg/dl was more frequent in the group with PAD and CHD than in the group with CHD and without PAD (p=0.02). The odds ratio (OR) of PAD in the presence of elevated Lp(a) level was 1.9 (95%CI, 1.4–2.5, p<0.01). Low molecular weight (LMW) apo(a) phenotype was met more frequently in groups I, II, III compared to group IV: 46%, 56%, 52% respectively vs. 28%, p<0.01. LMW apo(a) in the patients without CHD was associated with PAD (OR 3.3; 95% CI, 1.6–6.8, p<0.01), and there was no association with the patients with CHD. In logistic regression analysis adjusted for age, sex, hypertension, obesity, smoking, diabetes, LDL-C, Lp(a) and LMW apo(a) phenotype were independent predictors of PAD when included separately.
Conclusions. Elevated level of Lp(a) and LMW apo(a) phenotype are independent risk factors of PAD. The level of Lp(a) in the patients with PAD and CHD was higher than in the case of isolated lesion of each vascular pool. Higher level of Lp(a) is associated with more severe atherosclerosis involving more than one vascular pools.
Keywords: lipoprotein(a), apolipoprotein(a) phenotypes, atherosclerosis, peripheral artery disease, atherosclerosis of lower limbs arteries.
2. Selvin E, Erlinger TP. Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999–2000. Circulation. 2004;110(6): 738-43. https://doi.org/10.1016/j.accreview.2004.10.025
3. Ostchega Y, Paulose-Ram R, Dillon CF, Gu Q, Hughes JP. Prevalence of peripheral arterial disease and risk factors in persons aged 60 and older: data from the National Health and Nutrition Examination Survey 1999–2004. J Am Geriatr Soc. 2007;55(4):583-9. https://doi.org/10.1111/j.
1532-5415.2007.01123.x
4. Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, Norman PE, Sampson UK, Williams LJ, Mensah GA, Criqui MH. 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. https://doi.org/10. 1016/s0140-6736(13)61249-0
5. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Després JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jiménez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER 3rd,
Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB; American Heart Association Statistics Committee; Stroke Statistics Subcommittee. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation. 2016;133(4):e38-360. https://doi.org/10.1161/cir. 0000000000000350
6. Lamina C, Meisinger C, Heid IM, Löwel H, Rantner B, Koenig W, Kronenberg F for the KORA Study Group. Association of ankle-brachial index and plaques in the carotid and femoral arteries with cardiovascular events and total mortality in a population-based study with 13-years of follow-up. Eur Heart J. 2006;27(21):2580-7. https://doi.org/ 10.1093/ eurheartj/ehl228
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10. Kronenberg F, Utermann G. Lipoprotein(a) – resurrected by genetics.
J Intern Med. 2013;273(1):6-30. https://doi.org/10.1111/j.1365-2796. 2012.02592.x
11. Langsted A, Kamstrup PR, Nordestgaard BG. Lipoprotein(a): fasting and nonfasting levels, inflammation, and cardiovascular risk. Atherosclerosis. 2014;234(1):95-101. https://doi.org/10.1016/j.atherosclerosis.2014.01.049
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13. Kraft HG, Lingenhel A, Köchl S, Hoppichler F, Kronenberg F, Abe A, Mühlberger V, Schönitzer D, Utermann G. Apolipoprotein(a) kringle IV repeat number predicts risk for coronary heart disease. Arterioscler Thromb Vasc Biol. 1996;16(6):713-9. https://doi.org/10.1161/01.atv. 16.6.713
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22. Dieplinger B, Lingenhel A, Baumgartner N, Poelz W, Dieplinger H, Haltmayer M, Kronenberg F, Mueller T. Increased serum lipoprotein(a) concentrations and low molecular weight phenotypes of apolipoprotein(a) are associated with symptomatic peripheral arterial disease. Clin Chem. 2007;53(7):1298-305. https://doi.org/10.1373/ clinchem.2007.088013
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1. Shammas NW. Epidemiology, classification, and modifiable risk factors of peripheral arterial disease. Vasc Health Risk Manag. 2007;3(2):229-34. https://doi.org/10.2147/vhrm.2007.3.2.229
2. Selvin E, Erlinger TP. Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999–2000. Circulation. 2004;110(6): 738-43. https://doi.org/10.1016/j.accreview.2004.10.025
3. Ostchega Y, Paulose-Ram R, Dillon CF, Gu Q, Hughes JP. Prevalence of peripheral arterial disease and risk factors in persons aged 60 and older: data from the National Health and Nutrition Examination Survey 1999–2004. J Am Geriatr Soc. 2007;55(4):583-9. https://doi.org/10.1111/j.
1532-5415.2007.01123.x
4. Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, Norman PE, Sampson UK, Williams LJ, Mensah GA, Criqui MH. 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. https://doi.org/10. 1016/s0140-6736(13)61249-0
5. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Després JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jiménez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER 3rd,
Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB; American Heart Association Statistics Committee; Stroke Statistics Subcommittee. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation. 2016;133(4):e38-360. https://doi.org/10.1161/cir. 0000000000000350
6. Lamina C, Meisinger C, Heid IM, Löwel H, Rantner B, Koenig W, Kronenberg F for the KORA Study Group. Association of ankle-brachial index and plaques in the carotid and femoral arteries with cardiovascular events and total mortality in a population-based study with 13-years of follow-up. Eur Heart J. 2006;27(21):2580-7. https://doi.org/ 10.1093/ eurheartj/ehl228
7. Guo X, Li J, Pang W, Zhao M, Luo Y, Sun Y, Hu D. Sensitivity and specificity of ankle-brachial index for detecting angiographic stenosis of peripheral arteries. Circ J. 2008;72(4):605-10. https://doi.org/ 10.1253/circj.72.605
8. Kollerits B, Heinrich J, Pichler M, Rantner B, Klein-Weigel P, Wölke G, Brasche S, Strube G, Kronenberg F. Intermittent claudication in the Erfurt Male Cohort (ERFORT) Study: its determinants and the impact on mortality. A population-based prospective cohort study with 30 years of follow-up. Atherosclerosis. 2008;198(1):214-22. https://doi.org/10.1016/j. atherosclerosis.2007.09.012
9. Diehm C, Allenberg JR, Pittrow D, Mahn M, Tepohl G, Haberl RL, Darius H, Burghaus I, Trampisch HJ. Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease. Circulation. 2009;120(21):2053-61. https://doi.org/10.1016/ j.jvs. 2010.05.078
10. Kronenberg F, Utermann G. Lipoprotein(a) – resurrected by genetics.
J Intern Med. 2013;273(1):6-30. https://doi.org/10.1111/j.1365-2796. 2012.02592.x
11. Langsted A, Kamstrup PR, Nordestgaard BG. Lipoprotein(a): fasting and nonfasting levels, inflammation, and cardiovascular risk. Atherosclerosis. 2014;234(1):95-101. https://doi.org/10.1016/j.atherosclerosis.2014.01.049
12. Kronenberg F. Lipoprotein(a) in various conditions: to keep a sense of proportions. Atherosclerosis. 2014;234(1):249-51. https://doi.org/ 10.1016/j.atherosclerosis.2014.01.054
13. Kraft HG, Lingenhel A, Köchl S, Hoppichler F, Kronenberg F, Abe A, Mühlberger V, Schönitzer D, Utermann G. Apolipoprotein(a) kringle IV repeat number predicts risk for coronary heart disease. Arterioscler Thromb Vasc Biol. 1996;16(6):713-9. https://doi.org/10.1161/01.atv. 16.6.713
14. Dahlen GH. Incidence of Lp(a) among populations. In: Scanu AM, editor. Lipoprotein(a). New York: Academic Press; 1990:151-173.
15. [Afanasieva OI, Adamova IYu, Benevolenskaya GF, Pokrovsky SN. An immunoenzyme method for determining lipoprotein(a). Bull Exp Biol Med. 1995;120(10):398-401 (In Russ.)]. https://doi.org/10. 1007/bf02444976
16. [Afanasieva OI, Ezhov MV, Afanasieva MI, Safarova MS, Berestetskaya JV, Pokrovsky SN. Correlations 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 (In Russ.)]. http://dx.doi.org/10.20996/1819-6446-2010-6-4-474-480
17. Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman DE, Fleisher LA, Fowkes FG, Hamburg NM, Kinlay S, Lookstein R, Misra S, Mureebe L, Olin JW, Patel RA, Regensteiner JG, Schanzer A, Shishehbor MH, Stewart KJ, Treat-Jacobson D, Walsh ME. 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. 2017;135(12):e726-e79. http://doi.org/10.1161/CIR.0000000000000471
18. Bonaca MP, Nault P, Giugliano RP, Keech AC, Pineda AL, Kanevsky E, Kuder J, Murphy SA, Jukema JW, Lewis BS, Tokgozoglu L, Somaratne R, Sever PS, Pedersen TR, Sabatine MS. 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. 2017 Nov 13. https://doi.org/10.1161/circulationaha.117.032235
19. Erqou S, Kaptoge S, Perry PL, Di AE, Thompson A, White IR, Marcovina SM, Collins R, Thompson SG, Danesh J. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302(4):412-23. https://doi.org/10.1001/ jama.2009.1063
20. Erqou S, Thompson A, Di AE, Saleheen D, Kaptoge S, Marcovina S, Danesh J. Apolipoprotein(a) isoforms and the risk of vascular disease: systematic review of 40 studies involving 58,000 participants. J Am Coll Cardiol. 2010;55(19):2160-7. https://doi.org/10.1016/j.jacc. 2009.10.080
21. [Ezhov MV, Afanas'eva OI, Benevolenskaia GF, Savchenko AP, Balakhonova TV, Liakishev AA, Pokrovskiĭ SN. Association of lipoprotein(a) and apolipoprotein(a) phenotypes with coronary and carotid atherosclerosis in CHD men. Ter Arkh. 2000;72(1):28-32 (In Russ.)].
22. Dieplinger B, Lingenhel A, Baumgartner N, Poelz W, Dieplinger H, Haltmayer M, Kronenberg F, Mueller T. Increased serum lipoprotein(a) concentrations and low molecular weight phenotypes of apolipoprotein(a) are associated with symptomatic peripheral arterial disease. Clin Chem. 2007;53(7):1298-305. https://doi.org/10.1373/ clinchem.2007.088013
23. [Britareva VV, Afanasieva OI, Dobrovolsky AB, Ezhov MV, Titaeva EV, Karpov IuA, Pokrovsky SN. Lipoprotein(a) and apo(a) isoforms in patients with intermittent claudication. Ter Arkh. 2002;74(12):49-52 (In Russ.)].
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1 ФГБУ «Национальный медицинский исследовательский центр кардиологии» Минздрава России, Москва, Россия;
2 Центр кардиологии Таллиннского технологического университета, Таллинн, Эстония
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N.A. TMOYAN 1, M.V. EZHOV 1, O.I. AFANASIEVA 2, E.A. KLESAREVA 2, O.A. RAZOVA 2, V.V. KUKHARCHUK 1, S.N. POKROVSKY 2
1 A.L. Myasnikov Institute of Clinical Cardiology FSBI "National Medical Research Center of Cardiology" of MoH of Russia, Moscow, Russia;
2 Institute of Experimental Cardiology FSBI "National Medical Research Center of Cardiology" of MoH of Russia, Moscow, Russia