Generic placeholder image

Cardiovascular & Hematological Disorders-Drug Targets

Editor-in-Chief

ISSN (Print): 1871-529X
ISSN (Online): 2212-4063

Research Article

Effects of Simvastatin on the Metabolism of Fatty Acids in Combined Secondary Prevention of Coronary Heart Disease: Dosage and Gender Differences between the Effects

Author(s): Mikhail Y. Kotlovskiy*, Elena V. Udut, Gaisa T. Kairov, Vladimir P. Fisenko and Vladimir V. Udut

Volume 20, Issue 2, 2020

Page: [93 - 107] Pages: 15

DOI: 10.2174/1871529X20666200109144353

Price: $65

Abstract

Background: Statins are currently used for secondary prevention of Coronary Heart Disease (CHD), as the lipid-lowering therapy with them is proven safe and effective.

Objective: The purpose of this research is to investigate the dose-dependent effect of statins used for secondary prevention of coronary heart disease, as well as mechanisms of quantitative and qualitative changes in lipoproteins, fatty acids and cholesterol in the blood and tissues of people of both sexes.

Methods: In a clinical trial (n=125, of which 89 patients belong to group 1 and 36 to group 2) and an experiment on laboratory animals (n = 100), simvastatin reduced the total level of fatty acids in blood plasma, when given in the amount that was within the therapeutic dose range.

Results: This effect was achieved through a drug-induced improvement in the capacity of hepatic cells to absorb Low-density (LDL) and Very-low-density (VLDL) lipoproteins.

Conclusion: Considering the formation of saturated fatty acids, statin performed better in males. With Omega-3 polyunsaturated fatty acids involved, changes in lipoproteins, cholesterol and fatty acids (liver and myocardium) were similar to those caused by small doses of a statin drug. Effects of the combination of bisoprolol and acetylsalicylic acid were completely different from those caused by the use of statin.

Keywords: Simvastatin, fatty acids, coronary heart disease, LDL, myocardial infarction, stroke.

Graphical Abstract

[1]
Afilalo, J.; Majdan, A.A.; Eisenberg, M.J. Intensive statin therapy in acute coronary syndromes and stable coronary heart disease: a comparative meta-analysis of randomised controlled trials. Heart, 2007, 93(8), 914-921.
[http://dx.doi.org/10.1136/hrt.2006.112508] [PMID: 17277349]
[2]
Briel, M.; Schwartz, G.G.; Thompson, P.L.; de Lemos, J.A.; Blazing, M.A.; van Es, G.A.; Kayikçioglu, M.; Arntz, H.R.; den Hartog, F.R.; Veeger, N.J.; Colivicchi, F.; Dupuis, J.; Okazaki, S.; Wright, R.S.; Bucher, H.C.; Nordmann, A.J. Effects of early treatment with statins on short-term clinical outcomes in acute coronary syndromes: a meta-analysis of randomized controlled trials. JAMA, 2006, 295(17), 2046-2056.
[http://dx.doi.org/10.1001/jama.295.17.2046] [PMID: 16670413]
[3]
Stolk, R.P.; Rosmalen, J.G.M.; Postma, D.S.; de Boer, R.A.; Navis, G.; Slaets, J.P.; Ormel, J.; Wolffenbuttel, B.H. Universal risk factors for multifactorial diseases: LifeLines: a three-generation population-based study. Eur. J. Epidemiol., 2008, 23(1), 67-74.
[http://dx.doi.org/10.1007/s10654-007-9204-4] [PMID: 18075776]
[4]
Aronov, D.M. Statins as the main drug to reduce mortality from coronary heart disease. Russ. Med. J., 2012, 4, 1-7.
[5]
Task Force Members. Montalescot, G.; Sechtem, U.; Achenbach, S.; Andreotti, F.; Arden, C.; Di Mario, C. ESC guidelines on the management of stable coronary artery disease: The Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur. Heart J., 2013, 34(38), 2949-3003.
[PMID: 23996286]
[6]
Tikkanen, M.J.; Fayyad, R.; Faergeman, O.; Olsson, A.G.; Wun, C.C.; Laskey, R.; Kastelein, J.J.; Holme, I.; Pedersen, T.R. IDEALInvestigators.Effect of intensive lipid lowering with atorvastatin on cardiovascular outcomes in coronary heart disease patients with mild-to-moderate baseline elevations in alanine aminotransferase levels. Int. J. Cardiol., 2013, 168(4), 3846-3852.
[http://dx.doi.org/10.1016/j.ijcard.2013.06.024] [PMID: 24001698]
[7]
Belenkov, Yu.N.; Sergienko, I.V.; Lyakishev, A.A. Statins in modern cardiological practice. Russian Cardiology Research and Production Complex; A.L. Myasnikov Clinical Cardiology Institute, 2010, p. 230.
[8]
Zhou, G.; Ge, S.; Liu, D.; Xu, G.; Zhang, R.; Yin, Q.; Zhu, W.; Chen, J.; Liu, X. Atorvastatin reduces plaque vulnerability in an atherosclerotic rabbit model by altering the 5-lipoxygenase pathway. Cardiology, 2010, 115(3), 221-228.
[http://dx.doi.org/10.1159/000296017] [PMID: 20234134]
[9]
Dongiovanni, P.; Petta, S.; Mannisto, V.; Mancina, R.M.; Pipitone, R.; Karja, V.; Maggioni, M.; Kakela, P.; Wiklund, O.; Mozzi, E.; Grimaudo, S.; Kaminska, D.; Rametta, R.; Craxi, A.; Fargion, S.; Nobili, V.; Romeo, S.; Pihlajamaki, J.; Valenti, L. Statin use and non-alcoholic steatohepatitis in at risk individuals. J. Hepatol., 2015, 63(3), 705-712.
[http://dx.doi.org/10.1016/j.jhep.2015.05.006] [PMID: 25980762]
[10]
Titov, V.N. Atherosclerosis as a pathology of polyenoic fatty acids, Biological underpinnings of pathogenesis, diagnosis, prevention and treatment; Altus Publishing House: Moscow, 2002, p. 730.
[11]
Scholtens, S.; Smidt, N.; Swertz, M.A.; Bakker, S.J.; Dotinga, A.; Vonk, J.M.; van Dijk, F.; van Zon, S.K.; Wijmenga, C.; Wolffenbuttel, B.H.; Stolk, R.P. Cohort Profile: LifeLines, a three-generation cohort study and biobank. Int. J. Epidemiol., 2015, 44(4), 1172-1180.
[http://dx.doi.org/10.1093/ije/dyu229] [PMID: 25502107]
[12]
Poldermans, D.; Boersma, E.; Bax, J.J.; Thomson, I.R.; van de Ven, L.L.; Blankensteijn, J.D.; Baars, H.F.; Yo, T.I.; Trocino, G.; Vigna, C.; Roelandt, J.R.; van Urk, H. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group.The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. N. Engl. J. Med., 1999, 341(24), 1789-1794.
[http://dx.doi.org/10.1056/NEJM199912093412402] [PMID: 10588963]
[13]
Shilov, A.M.; Svyatov, I.S.; Sanodze, I.D. Antiaggregants: Current state of issue. Russ. Med. J., 2003, 11(9), 552-556.
[14]
Marchioli, R.; Barzi, F.; Bomba, E.; Chieffo, C.; Di Gregorio, D.; Di Mascio, R.; Franzosi, M.G.; Geraci, E.; Levantesi, G.; Maggioni, A.P.; Mantini, L.; Marfisi, R.M.; Mastrogiuseppe, G.; Mininni, N.; Nicolosi, G.L.; Santini, M.; Schweiger, C.; Tavazzi, L.; Tognoni, G.; Tucci, C.; Valagussa, F. GISSI-Prevenzione Investigators.Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Circulation, 2002, 105(16), 1897-1903.
[http://dx.doi.org/10.1161/01.CIR.0000014682.14181.F2] [PMID: 11997274]
[15]
Davidson, M.H.; Stein, E.A.; Bays, H.E.; Maki, K.C.; Doyle, R.T.; Shalwitz, R.A.; Ballantyne, C.M.; Ginsberg, H.N. COMBination of prescription Omega-3 with Simvastatin (COMBOS) Investigators.Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: An 8-week, randomized, double-blind, placebo-controlled study. Clin. Ther., 2007, 29(7), 1354-1367.
[http://dx.doi.org/10.1016/j.clinthera.2007.07.018] [PMID: 17825687]
[16]
Maki, K.C.; Dicklin, M.R.; Davidson, M.H.; Doyle, R.T.; Ballantyne, C.M. COMBination of prescription Omega-3 with Simvastatin (COMBOS) Investigators.Baseline lipoprotein lipids and low-density lipoprotein cholesterol response to prescription omega-3 acid ethyl ester added to Simvastatin therapy. Am. J. Cardiol., 2010, 105(10), 1409-1412.
[http://dx.doi.org/10.1016/j.amjcard.2009.12.063] [PMID: 20451686]
[17]
Strukova, E.G.O. Oral microbiome quantitation using GC-MS spectrometry analysis of microbial markers:, PhD Thesis in Chemistry. 2010.184
[18]
Reaven, P.D.; Grasse, B.J.; Tribble, D.L. Effects of linoleate-enriched and oleate-enriched diets in combination with alpha-tocopherol on the susceptibility of LDL and LDL subfractions to oxidative modification in humans. Arterioscler. Thromb., 1994, 14(4), 557-566.
[http://dx.doi.org/10.1161/01.ATV.14.4.557] [PMID: 8148354]
[19]
Shevchenko, O.; Shevchenko, A. Statins. Inhibitors of HMG-CoA reductase; Reafarm Publishing House: Moscow, 2003, p. 112.
[20]
Utzschneider, K.M.; Kahn, S.E. Review: The role of insulin resistance in nonalcoholic fatty liver disease. J. Clin. Endocrinol. Metab., 2006, 91(12), 4753-4761.
[http://dx.doi.org/10.1210/jc.2006-0587] [PMID: 16968800]
[21]
Nielsen, L.B.; Bartels, E.D.; Bollano, E. Overexpression of apolipoprotein B in the heart impedes cardiac triglyceride accumulation and development of cardiac dysfunction in diabetic mice. J. Biol. Chem., 2002, 277(30), 27014-27020.
[http://dx.doi.org/10.1074/jbc.M203458200] [PMID: 12015323]
[22]
Watt, M.J.; Spriet, L.L. Triacylglycerol lipases and metabolic control: implications for health and disease. Am. J. Physiol. Endocrinol. Metab., 2010, 299(2), E162-E168.
[http://dx.doi.org/10.1152/ajpendo.00698.2009] [PMID: 20071561]
[23]
Castera, L.; Vilgrain, V.; Angulo, P. Noninvasive evaluation of NAFLD. Nat. Rev. Gastroenterol. Hepatol., 2013, 10(11), 666-675.
[http://dx.doi.org/10.1038/nrgastro.2013.175] [PMID: 24061203]
[24]
Pchelintsev, M.V. Evidence-based clinical and pharmacological effects of eicosapentanoic and decoshexaenoic (omega-3) acids in the treatment of coronaty heart disease and the prevention of sudden cardiac death. Cardiol. J., 2010, 50(3), 74-82.
[PMID: 20459410]
[25]
Titov, V.N.; Lisitsin, D.M. Fatty acids. Physical chemistry, biology and medicine; Triada Publishing House: Tver, 2006, p. 672.
[26]
Gillingham, L.G.; Gustafson, J.A.; Han, S.Y.; Jassal, D.S.; Jones, P.J. High-oleic rapeseed (canola) and flaxseed oils modulate serum lipids and inflammatory biomarkers in hypercholesterolaemic subjects. Br. J. Nutr., 2011, 105(3), 417-427.
[http://dx.doi.org/10.1017/S0007114510003697] [PMID: 20875216]
[27]
Athyros, V.G.; Giouleme, O.; Ganotakis, E.S.; Elisaf, M.; Tziomalos, K.; Vassiliadis, T.; Liberopoulos, E.N.; Theocharidou, E.; Karagiannis, A.; Mikhailidis, D.P. Safety and impact on cardiovascular events of long-term multifactorial treatment in patients with metabolic syndrome and abnormal liver function tests: a post hoc analysis of the randomised ATTEMPT study. Arch. Med. Sci., 2011, 7(5), 796-805.
[http://dx.doi.org/10.5114/aoms.2011.25554] [PMID: 22291824]
[28]
Delarue, J.; Magnan, C. Free fatty acids and insulin resistance. Curr. Opin. Clin. Nutr. Metab. Care, 2007, 10(2), 142-148.
[http://dx.doi.org/10.1097/MCO.0b013e328042ba90] [PMID: 17285001]
[29]
Nascimbeni, F.; Aron-Wisnewsky, J.; Pais, R.; Tordjman, J.; Poitou, C.; Charlotte, F.; Bedossa, P.; Poynard, T.; Clément, K.; Ratziu, V. LIDO study Group.Statins, antidiabetic medications and liver histology in patients with diabetes with non-alcoholic fatty liver disease. BMJ Open Gastroenterol., 2016, 3(1)e000075
[http://dx.doi.org/10.1136/bmjgast-2015-000075] [PMID: 27110380]
[30]
Kris-Etherton, P.M.; Griel, A.E.; Psota, T.L.; Gebauer, S.K.; Zhang, J.; Etherton, T.D. Dietary stearic acid and risk of cardiovascular disease: intake, sources, digestion, and absorption. Lipids, 2005, 40(12), 1193-1200.
[http://dx.doi.org/10.1007/s11745-005-1485-y] [PMID: 16477802]
[31]
Simon, J.A.; Fong, J.; Bernert, J.T., Jr Serum fatty acids and blood pressure. Hypertension, 1996, 27(2), 303-307.
[http://dx.doi.org/10.1161/01.HYP.27.2.303] [PMID: 8567056]
[32]
Eslami, L.; Merat, S.; Malekzadeh, R.; Nasseri-Moghaddam, S.; Aramin, H. Statins for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Cochrane Database Syst. Rev., 2013, (12)CD008623
[http://dx.doi.org/10.1002/14651858.CD008623.pub2] [PMID: 24374462]
[33]
Ghebremeskel, K.; Bitsanis, D.; Koukkou, E.; Lowy, C.; Poston, L.; Crawford, M.A. Liver triacylglycerols and free fatty acids in streptozotocin-induced diabetic rats have atypical n-6 and n-3 pattern. Comp. Biochem. Physiol. C Toxicol. Pharmacol., 2002, 132(3), 349-354.
[http://dx.doi.org/10.1016/S1532-0456(02)00074-1] [PMID: 12161168]
[34]
Peter, A.; Weigert, C.; Staiger, H.; Machicao, F.; Schick, F.; Machann, J.; Stefan, N.; Thamer, C.; Häring, H.U.; Schleicher, E. Individual stearoyl-coa desaturase 1 expression modulates endoplasmic reticulum stress and inflammation in human myotubes and is associated with skeletal muscle lipid storage and insulin sensitivity in vivo. Diabetes, 2009, 58(8), 1757-1765.
[http://dx.doi.org/10.2337/db09-0188] [PMID: 19478146]
[35]
Hodson, L.; Frayn, K.N. Hepatic fatty acid partitioning. Curr. Opin. Lipidol., 2011, 22(3), 216-224.
[http://dx.doi.org/10.1097/MOL.0b013e3283462e16] [PMID: 21494141]
[36]
Trebicka, J.; Hennenberg, M.; Odenthal, M.; Shir, K.; Klein, S.; Granzow, M.; Vogt, A.; Dienes, H.P.; Lammert, F.; Reichen, J.; Heller, J.; Sauerbruch, T. Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells. J. Hepatol., 2010, 53(4), 702-712.
[http://dx.doi.org/10.1016/j.jhep.2010.04.025] [PMID: 20633948]
[37]
Listenberger, L.L.; Ory, D.S.; Schaffer, J.E. Palmitate-induced apoptosis can occur through a ceramide-independent pathway. J. Biol. Chem., 2001, 276(18), 14890-14895.
[http://dx.doi.org/10.1074/jbc.M010286200] [PMID: 11278654]
[38]
Schierwagen, R.; Maybüchen, L.; Hittatiya, K.; Klein, S.; Uschner, F.E.; Braga, T.T.; Franklin, B.S.; Nickenig, G.; Strassburg, C.P.; Plat, J.; Sauerbruch, T.; Latz, E.; Lütjohann, D.; Zimmer, S.; Trebicka, J. Statins improve NASH via inhibition of RhoA and Ras. Am. J. Physiol. Gastrointest. Liver Physiol., 2016, 311(4), G724-G733.
[http://dx.doi.org/10.1152/ajpgi.00063.2016] [PMID: 27634010]
[39]
Lisitsin, D.M.; Pozdnyak, T.; Razumovsky, M.D. Cardiac tamponade and blunt abdominal injuries in children Kinet. Catal., 1975, 17, 1049-1055.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy