Relationship between atherosclerosis risks and lipoprotein-dependent phospholipase a2 activity in type 2 diabetic patients

Abstract

Aim: Atherosclerosis is the most common macro-complication of diabetes and the most common cause of coronary artery disease. We aimed to investigate the relationship between the risk of atherosclerosis and lipoprotein-dependent phospholipase A2 activity in patients with type 2 diabetes.

Methods: The study was enrolled on 48 subjects: Group I: control group consisting of 20 healthy participants. Group II: 28 patients of type 2 diabetes mellitus before statin (rosuvastatin 10 mg/day) therapy. Group III: 28 patients of type 2 diabetes mellitus after statin (rosuvastatin 10 mg/day) therapy. Lp-PLA2 activity was measured with immuno- turbidimetric method (plac test kit), HDL-C (High-Density Lipoprotein Cholesterol), LDL-C (Low-Density Lipoprotein Cholesterol), triglyceride, cholesterol and fasting blood glucose (FBG), levels were measured by spectrophotometric method using autoanalyzer (Architect C16000). LDL-C levels were measured by an assay for the direct quantification of LDL-C. Carotid intima-media thickness (IMT) was measured by B-mode ultrasonography method. 

Results: Serum Lp-PLA2 activity, serum LDL-C, triglyceride, cholesterol levels and IMT values of Group II (before 10 mg/gün rosuvastatin therapy ) and Group III (after rosuvastatin therapy) patients were statistically significant higher than Group I (control group) (p<0.01) Serum Lp-PLA2 activity, serum LDL-C, triglyceride, cholesterol levels and IMT values of Group II patients were statistically significant higher than Group III patients (p<0.01) and HDL-C levels only were lower than Group III (after 10 mg/gün rosuvastatin therapy) but It was not statistically significant (p=0.198).

Conclusion: According to our results, Increased Lp-PLA2 activity is associated with risk of atherosclerosis in diabetic patients and plays an important role in the progression of atherosclerosis.

Keywords

• Lp-PLA2,Atherosclerosis,Diabetes,Statin therapy,Intima-media thickness

Tip 2 diyabetli hastalarda ateroskleroz riski ile lipoprotein-bağımlı fosfolipaz a2 aktivitesi arasındaki ilişki

Abstract

Amaç: Ateroskleroz diyabetik en sık makro komplikasyonudur ve koroner arter hastalığının en temel nedenidir. Çalışmamızda tip 2 diyabetli hastalarda ateroskleroz riski ile lipoprotein bağımlı fosfolipaz A2 (Lp-PLA2) aktivitesi arasındaki ilişkiyi araştırmayı amaçladık.

Yöntemler: Çalışmaya 48 kişi dahil edildi. Grup I: sağlıklı katılıcılardan oluşan kontrol grubu, Grup II: Statin (Rosuvastatin 10 mg/gün) tedavisi öncesi tip 2 diyabetli 28 hasta. Grup III: Statin (Rosuvastatin 10 mg/gün) tedavisi sonrası 28 tip 2 diyabetli hasta. Hiperlipidemisi olan diyabetik hastaların ve sağlıklı gönüllülerin serum örneklerinden, Serum Lp-PLA2 aktivitesi immünotürbidimetrik yöntem (plac test kit) ile ve Serum HDL-C (Yüksek Dansiteli Lipoprotein Kolesterol), LDL-C (Düşük Dansiteli Lipoprotein Kolesterol), trigliserid, kolesterol ve açlık glikoz seviyeleri otoanalizör kullanılarak (Architect C16000) spektrofotometrik yöntemle ölçüldü. LDL-C ölçümü direct LDL kiti ile gerçekleştirildi. Karotis intima-media kalınlığı (IMK) B-mode ultrasonografi metodu ile ölçüldü.

Bulgular: Grup II (rosuvastatin (10 mg/gün) tedavisi öncesi) and Grup III (rosuvastatin (10 mg/gün) tedavisi sonrası) hastalarının serum Lp-PLA2 aktivitesi, serum LDL-C, trigliserid, kolesterol düzeyleri ve IMK değerleri Grup I’e (kontrol grubu) göre istatistiksel olarak anlamlı düzeyde yüksek bulundu (p<0,01) . Grup II’nin serum Lp-PLA2 aktivitesi, serum LDL-C, trigliserid, kolesterol düzeyleri ve IMK değerleri Grup III’e göre istatistiksel olarak anlamlı düzeyde yüksek bulunurken (p<0,001), serum HDL-C düzeylerinde istatistiksel olarak anlamlı bir fark elde edilemedi (p=0,198).

Sonuç: Sonuçlarımıza göre, artan serum Lp-PLA2 aktivitesi diyabetik hastalarda ateroskleroz riski ile ilişkilidir ve ateroskleroz gelişiminde önemli role sahiptir.

Keywords

• Ateroskleroz,Diyabet,Statin tedavisi,Lp-PLA2,İntima-media kalınlığı

References

1. 1. Distel E, Barrett TJ, Chung K, Girgis NM, Parathath S, Essau CC, et al. MiR33 inhibition overcomes deleterious effects of diabetes mellitus on atherosclerosis plaque regression in mice. Circ Res. 2014;115(9):759-69.
2. 2. Majid A, Prevention and management of coronary artery disease in patients with diabetes mellitus. Acta Med Indones. 2009;41(1):41-4.
3. 3. Sodergren A, Karp K, Bengtsson C, Möller B, Rantapaa-Dahlqvist S, Wallberg-Jonsson S. Is Lipoprotein-Associated Phospholipase A2 a Link between Inflammation and Subclinical Atherosclerosis in Rheumatoid Arthritis? Biomed Res Int. 2015;2015:673018.
4. 4. Kasikara C, Doran AC, Cai B, Tabas I. The role of non-resolving inflammation in atherosclerosis. J Clin Invest. 2018;128(7):2713-23.
5. 5. Li J, Wang H, Tian J, Chen B, Du F. Change in lipoprotein-associated phospholipase A2 and its association with cardiovascular outcomes in patients with acute coronary syndrome. Medicine (Baltimore). 2018;97(28):115-7.
6. 6. Winkler K, Hoffmann MM, Krane V, Drechsler C, Wanner C. Lipoprotein-associated phospholipase A2 and outcome in patients with type 2 diabetes on haemodialysis. European Journal of Clinical Investigation. 2012; 42(7):693-701.
7. 7. Esenwa CC, Elkind MS. Inflammatory risk factors, biomarkers and associated therapy in ischaemic stroke. Nature Reviews Neurology. 2016;12(10):594-604.
8. 8. Macphee CH, Moores KE, Boyd HF, Dhanak D, Ife RJ, Leach CA. et al. Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, generates two bioactive products during the oxidation of low-density lipoprotein: use of a novel inhibitor. Biochemical Journal. 1999;338(2):479-87.

9. 9. Maeda T, Takeuchi K, Xiaoling P, P Zankov D, Takashima N, Fujiyoshi A, et al. Lipoprotein-associated phospholipase A2 regulates macrophage apoptosis via the Akt and caspase-7 pathways. Journal of Atherosclerosis and Thrombosis. 2014;21(8):839-53.
10. 10. Zalewski A, Macphee C. Role of lipoprotein-associated phospholipase A2 in atherosclerosis biology, epidemiology, and possible therapeutic target. Arteriosclerosis. Thrombosis and Vascular Biology. 2005;25(5):923-31.
11. 11. Tsimikas S, Tsironis LD, Tselepis AD. New insights into the role of lipoprotein (a)-associated lipoprotein-associated phospholipase A2 in atherosclerosis and cardiovascular disease. Arteriosclerosis, thrombosis and vascular biology. 2007;27(10):2094-9.
12. 12. Sudhir K. Lipoprotein-associated phospholipase A2 a novel inflammatory biomarker and independent risk predictor for cardiovascular disease. The Journal of Clinical Endocrinology & Metabolism. 2005;90(5):3100-5.
13. 13. Chambless LE, Folsom AR, Clegg LX, Sharrett AR, Shahar E, Nieto FJ, et al. Carotid wall thickness is predictive of incident clinical stroke: the Atherosclerosis Risk in Communities (ARIC) study. American Journal Of Epidemiology. 2000;151(5):478-87.
14. 14. Polak JF, O'Leary DH. Carotid intima-media thickness as surrogate for and predictor of cardiovascular disease. Global Heart Journal. 2016;11(3):295-312.
15. 15. Mohler ER, Ballantyne CM, Davidson MH, Hanefeld M, Ruilope LM, Johnson JL, et al. The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study. Journal of the American College of Cardiology. 2008;51(17):1632-41.
16. 16. Herrmann J, Mannheim D, Wohlert C, Versari D, Meyer FB, McConnell JP, et al. Expression of lipoprotein-associated phospholipase A2 in carotid artery plaques predicts long-term cardiac outcome. European heart journal. 2009;30(23):2930-8.
17. 17. Nezu T, Hosomi N, Aoki S, Matsumoto M, et al. Carotid intima-media thickness for atherosclerosis. Journal of Atherosclerosis and Thrombosis. 2016;23(1):18-31.
18. 18. Lorenz MW, Price JF, Robertson C, Bots ML, Polak JF, Poppert H, et al. Carotid intima-media thickness progression and risk of vascular events in people with diabetes: results from the PROG-IMT collaboration. Diabetes Care. 2015;38(10):1921-9.
19. 19. Silva IT, Mello APQ, Damasceno NRT. Antioxidant and inflammatory aspects of lipoprotein-associated phospholipase A(2 )(Lp-PLA(2 )): a review. Lipids in Health and Disease. 2011;10:170
20. 20. Saougos VG, Tambaki AP, Kalogirou M, Kostapanos M, Gazi IF, Wolfert RL, et al. Differential effect of hypolipidemic drugs on lipoprotein-associated phospholipase A2. Arterioscler Thromb Vasc Biol. 2007;27(10):2236-43.
21. 21. Okamura K, Miura S, Zhang B, Uehara Y, Matsuo K, Kumagai K, et al. Ratio of LDL-to HDL-associated platelet-activating factor acetylhydrolase may be a marker of inflammation in patients with paroxysmal atrial fibrillation. Circulation Journal. 2007;71(2):214-9.
22. 22. Allison MA, Denenberg JO, Nelson JJ, Natarajan L, Criqui MH. The association between lipoprotein-associated phospholipase A 2 and cardiovascular disease and total mortality in vascular medicine patients. Journal of vascular surgery. 2007;46(3):500-6.
23. 23. Sabatine MS, Morrow DA, O'Donoghue M, Jablonksi KA, Rice MM, Solomon S, et al. Prognostic utility of lipoprotein-associated phospholipase A2 for cardiovascular outcomes in patients with stable coronary artery disease. Arteriosclerosis, thrombosis and vascular biology. 2007;27(11):2463-9.
24. 24. Persson M, Nilsson JA, Nelson JJ, Hedblad D, Berglund G. The epidemiology of Lp-PLA 2: distribution and correlation with cardiovascular risk factors in a population-based cohort. Atherosclerosis. 2007;190(2):388-96.
25. 25. Yang EH, McConnell JP, Lennon RJ, Barsness GW, Pumper G, Hartman SJ, et al. Lipoprotein-associated phospholipase A2 is an independent marker for coronary endothelial dysfunction in humans. Arteriosclerosis, Thrombosis and Vascular Biology. 2006;26(1):106-11.
26. 26. Sertic J, Skorić B, Lovrić J, Bozina T, Reiner Z. Does Lp-PLA2 determination help predict atherosclerosis and cardiocerebrovascular disease? Acta medica Croatica. 2010;64(4):237-45.
27. 27. Koenig W, Twardella D, Brenner H, Rothenbacher D. Lipoprotein-associated phospholipase A2 predicts future cardiovascular events in patients with coronary heart disease independently of traditional risk factors, markers of inflammation, renal function, and hemodynamic stress. Arteriosclerosis, Thrombosis and Vascular Biology. 2006;26(7):1586-93.
28. 28. Silva IT, Mello APQ, Damasceno NRT. Antioxidant and inflammatory aspects of lipoprotein-associated phospholipase A 2 (Lp-PLA 2): a review. Lipids in health and disease. 2011;10(1):170.
29. 29. Jenny NS, Solomon C, Cushman M, Tracy RP, Nelson JJ, Psaty BM, et al. Lipoprotein-associated phospholipase A 2 (Lp-PLA 2) and risk of cardiovascular disease in older adults: results from the Cardiovascular Health Study. Atherosclerosis. 2010;209(2):528-32.
30. 30. Liu J, Wang W, Qi Y, Yong Q, Zhou G, Wang M, et al. Association between the Lipoprotein-Associated Phospholipase A2 Activity and the Progression of Subclinical Atherosclerosis. Journal of Atherosclerosis and Thrombosis. 2014;21(6):532-42.
31. 31. Blake GJ, Dada N, Fox JC, Manson JE, Ridker PM. A prospective evaluation of lipoprotein-associated phospholipase A(2) levels and the risk of future cardiovascular events in women. J Am Coll Cardiol. 2001;38(5):1302-6.
32. 32. Schaefer EJ, McNamara JR, Asztalos BF, Tayler T, Daly JA, Gleason JL, et al. Effects of atorvastatin versus other statins on fasting and postprandial C-reactive protein and lipoprotein-associated phospholipase A 2 in patients with coronary heart disease versus control subjects. The American Journal Of Cardiology. 2005;95(9):1025-32.
33. 33. O’Donoghue M, Morrow DA, Sabatine MS, Murphy SA, McCabe CH, Cannon CP, et al. Lipoprotein-associated phospholipase A2 and its association with cardiovascular outcomes in patients with acute coronary syndromes in the PROVE IT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction) trial. Circulation. 2006;113(14):1745-52.
34. 34. Saougos VG, Tambaki AP, Kalogirou M, Kostapanos M, Gazi IF, Wolfert RL, et al. Differential effect of hypolipidemic drugs on lipoprotein-associated phospholipase A2. Arteriosclerosis, thrombosis, and vascular biology. 2007;27(10):2236-43.
35. 35. Muhlestein JB, May HT, Jensen JR, Horne BD, Lanman RB, Lavasani F, et al. The reduction of inflammatory biomarkers by statin, fibrate, and combination therapy among diabetic patients with mixed dyslipidemia: the DIACOR (Diabetes and Combined Lipid Therapy Regimen) study. Journal of the American College of Cardiology. 2006;48(2):396-401.
36. 36. White HD, Simes J, Stewart RA, Blankenberg S, Barnes EH, Marschner IC, et al. Changes in lipoprotein-Associated phospholipase A2 activity predict coronary events and partly account for the treatment effect of pravastatin: results from the Long-Term Intervention with Pravastatin in Ischemic Disease study. Journal of the American Heart Association. 2013;2(5).
37. 37. Le NA, Tomassini JE, Tershakovec AM, Neff DR, Wilson PW. Effect of Switching From Statin Monotherapy to Ezetimibe/Simvastatin Combination Therapy Compared With Other Intensified Lipid-Lowering Strategies on Lipoprotein Subclasses in Diabetic Patients With Symptomatic Cardiovascular Disease. J Am Heart Assoc. 2015;4(10):e001675.
38. 38. Lee SH, Kang SM, Park S, Jang Y, Chung N, Choi D. The effects of statin monotherapy and low-dose statin/ezetimibe on lipoprotein-associated phospholipase A(2). Clin Cardiol. 2011;34(2):108-12.
39. 39. Thongtang N, Ai M, Schaefer EJ. Effects of maximal atorvastatin and rosuvastatin treatment on markers of glucose homeostasis and inflammation. Am J Cardiol. 2011;107(3):387-92.
40. 40. van Staa TP, Carr DF, O'Meara H, McCann G, Pirmohamed M. Predictors and outcomes of increases in creatine phosphokinase concentrations or rhabdomyolysis risk during statin treatment. Br J Clin Pharmacol. 2014;78(3):649-59.