Background: The Consensus Statement from the European Atherosclerosis Society (EAS) Consensus Panel 2017 concludes on the basis of 3 different types of clinical studies that low-density lipoprotein (LDL) causes atherosclerotic cardiovascular disease (ASCVD). In Mendelian randomization studies, rare genetic mutations affecting LDL receptor function were found to cause higher or lower LDL-C levels, which are associated with correspondingly altered ASCVD risk. In prospective cohort studies and randomized controlled trials (RCTs) of statins, a remarkably consistent log-linear association was demonstrated between the absolute magnitude of LDL-C exposure and ASCVD risk. The EAS Statement proposes that any mechanism of lowering plasma LDL concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C. However, as we explain, we do not find this conclusion acceptable. Summary: Our review points out that different interpretations are possible for the results of Mendelian randomization studies. As for prospective cohort studies, many inconsistent reports on the association of LDL-C and ASCVD were disregarded when drafting the Statement, reports with and without genetic factors related to LDL receptor function should be analyzed separately, and the term ASCVD in the Statement is used inappropriately because myocardial infarction and cerebral infarction differ in their association with LDL-C. As for RCTs, clinical reports on statins published before and after the implementation of new regulations affecting clinical trials (2004/2005) should not both be included in meta-analyses because the evaluated efficacy of statins changed markedly, and the irreversible adverse effects of statins need to be evaluated more rigorously now that their mechanisms have been elucidated. Key Messages: Apart from the EAS hypothesis that LDL causes ASCVD, recent pharmacological/biochemical studies, as summarized in this review and elsewhere, have revealed that atherosclerosis is caused by statins taken to lower LDL-C, as well as by warfarin and some types of vegetable fats and oils, in the absence of significantly elevated LDL-C levels. Thus, the promotion of statin treatment by the Statement is rather risky and we do not feel that the conclusions are justified for the prevention of ASCVD.

Keywords:
Consensus Statement from the European Atherosclerosis Society Consensus Panel 2017, Critical interpretation, Low-density lipoprotein, Atherosclerotic cardiovascular disease, Mendelian randomization study, Statin, Warfarin , Vegetable oil, Randomized controlled trial, Prospective cohort study
1.
Multiple risk factor intervention trial. Risk factor changes and mortality results. Multiple Risk Factor Intervention Trial Research Group. JAMA 1982; 248: 1465–1477.
2.
Strandberg TE, Salomaa VV, Naukkarinen VA, Vanhanen HT, Sarna SJ, Miettinen TA: Long-term mortality after 5-year multifactorial primary prevention of cardiovascular diseases in middle-aged men. JAMA 1991; 266: 1225–1229.
3.
Ramsden CE, Zamora D, Leelarthaepin B, Majchrzak-Hong SF, Faurot KR, Suchindran CM, Ringel A, Davis JM, Hibbeln JR: Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis. BMJ 2013; 346:e8707.
4.
Ramsden CE, Zamora D, Majchrzak-Hong S, Faurot KR, Broste SK, Frantz RP, Davis JM, Ringel A, Suchindran CM, Hibbeln JR: Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968–1973). BMJ 2016; 353:i1246.
5.
Lands WEM, Fish, Omega-3 and Human Health, ed 2. Urbana, AOCS Publishing, 2005.
6.
Okuyama H, Ichikawa Y, Sun YJ, Hamazaki T, Lands WEM: Prevention of Coronary Heart Disease-from the Cholesterol Hypothesis to ω6 to ω3 balance. Karger, Basel, 2007.
7.
Calder PC: Old study sheds new light on the fatty acids and cardiovascular health debate. BMJ 2013; 346:f493.
8.
Kang JX: A transgenic mouse model for gene-nutrient interactions. J Nutrigenet Nutrigenomics 2008; 1: 172–177.
9.
Kang JX, Gleason ED: Omega-3 fatty acids and hippocampal neurogenesis in depression. CNS Neurol Disord Drug Targets 2013; 12: 460–465.
10.
Okuyama H, Langsjoen PH, Langsjoen AM, Ohara N: Industrial control of guidelines for lipid nutrition; in Rosch PJ (ed): Fat and Cholesterol Don’t Cause Heart Attacks and Statins Are Not the Solution. Cwmbran, Columbus Publishing, 2016.
11.
de Lorgeril M: Cholesterol Mensonges et Propagande, Thierry Souccar Editions, France, 2008.
12.
Rabaeus M, Nguyen PV, de Lorgeril M: Recent flaws in evidence-based medicine: statin effects in primary prevention and consequences of suspending the treatment. J Controversies Biomed Res 2017; 3: 1–10.
13.
Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, Hegele RA, Krauss RM, Raal FJ, Schunkert H, Watts GF, Borén J, Fazio S, Horton JD, Masana L, Nicholls SJ, Nordestgaard BG, van de Sluis B, Taskinen MR, Tokgözoglu L, Landmesser U, Laufs U, Wiklund O, Stock JK, Chapman MJ, Catapano AL: Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017; 38: 2459–2472.
14.
Okuyama H, Langsjoen PH, Ohara N, Hashimoto Y, Hamazaki T, Yoshida S, Kobayashi T, Langsjoen AM: Medicines and vegetable oils as hidden causes of cardiovascular disease and diabetes. Pharmacology 2016; 98: 134–170.
15.
Südhof TC, Goldstein JL, Brown MS, Russell DW: The LDL receptor gene: a mosaic of exons shared with different proteins. Science 1985; 228: 815–822.
16.
Surgrue DD, Trayner I, Thompson GR, Vere VJ, Dimeson J, Stirling Y, Meade TW: Coronary artery disease and haemostatic variables in heterozygous familial hypercholesterolaemia. Br Heart J 1985; 53: 265–268.
17.
Hamazaki T, Okuyama H, Ogushi Y, Hama R: Towards a paradigm shift in cholesterol treatment. A re-examination of the cholesterol issue in Japan. Ann Nutr Metab 2015; 66(suppl 4):1–116.
18.
Nioi P, Sigurdsson A, Thorleifsson G, Helgason H, Agustsdottir AB, Norddahl GL, Helgadottir A, Magnusdottir A, Jonasdottir A, Gretarsdottir S, Jonsdottir I, Steinthorsdottir V, Rafnar T, Swinkels DW, Galesloot TE, Grarup N, Jørgensen T, Vestergaard H, Hansen T, Lauritzen T, Linneberg A, Friedrich N, Krarup NT, Fenger M, Abildgaard U, Hansen PR, Galløe AM, Braund PS, Nelson CP, Hall AS, Williams MJ, van Rij AM, Jones GT, Patel RS, Levey AI, Hayek S, Shah SH, Reilly M, Eyjolfsson GI, Sigurdardottir O, Olafsson I, Kiemeney LA, Quyyumi AA, Rader DJ, Kraus WE, Samani NJ, Pedersen O, Thorgeirsson G, Masson G, Holm H, Gudbjartsson D, Sulem P, Thorsteinsdottir U, Stefansson K: Variant ASGR1 associated with a reduced risk of coronary artery disease. N Engl J Med 2016; 374: 2131–2141.
19.
Okamura T: Dyslipidemia and cardiovascular disease: a series of epidemiologic studies in Japanese populations. J Epidemiol 2010; 20: 259–265.
20.
Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK, Hindy G, Hólm H, Ding EL, Johnson T, Schunkert H, Samani NJ, Clarke R, Hopewell JC, Thompson JF, Li M, Thorleifsson G, Newton-Cheh C, Musunuru K, Pirruccello JP, Saleheen D, Chen L, Stewart A, Schillert A, Thorsteinsdottir U, Thorgeirsson G, Anand S, Engert JC, Morgan T, Spertus J, Stoll M, Berger K, Martinelli N, Girelli D, McKeown PP, Patterson CC, Epstein SE, Devaney J, Burnett MS, Mooser V, Ripatti S, Surakka I, Nieminen MS, Sinisalo J, Lokki ML, Perola M, Havulinna A, de Faire U, Gigante B, Ingelsson E, Zeller T, Wild P, de Bakker PI, Klungel OH, Maitland-van der Zee AH, Peters BJ, de Boer A, Grobbee DE, Kamphuisen PW, Deneer VH, Elbers CC, Onland-Moret NC, Hofker MH, Wijmenga C, Verschuren WM, Boer JM, van der Schouw YT, Rasheed A, Frossard P, Demissie S, Willer C, Do R, Ordovas JM, Abecasis GR, Boehnke M, Mohlke KL, Daly MJ, Guiducci C, Burtt NP, Surti A, Gonzalez E, Purcell S, Gabriel S, Marrugat J, Peden J, Erdmann J, Diemert P, Willenborg C, König IR, Fischer M, Hengstenberg C, Ziegler A, Buysschaert I, Lambrechts D, Van de Werf F, Fox KA, El Mokhtari NE, Rubin D, Schrezenmeir J, Schreiber S, Schäfer A, Danesh J, Blankenberg S, Roberts R, McPherson R, Watkins H, Hall AS, Overvad K, Rimm E, Boerwinkle E, Tybjaerg-Hansen A, Cupples LA, Reilly MP, Melander O, Mannucci PM, Ardissino D, Siscovick D, Elosua R, Stefansson K, O'Donnell CJ, Salomaa V, Rader DJ, Peltonen L, Schwartz SM, Altshuler D, Kathiresan S: Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012; 380: 572–580.
21.
Harada-Shiba M, Tajima S, Yokoyama S, Miyake Y, Kojima S, Tsushima M, Kawakami M, Yamamoto A: Siblings with normal LDL receptor activity and severe hypercholesterolemia. Arterioscler Thromb 1992; 12: 1071–1078.
22.
Lotta LA, Sharp SJ, Burgess S, Perry JRB, Stewart ID, Willems SM, Luan J, Ardanaz E, Arriola L, Balkau B, Boeing H, Deloukas P, Forouhi NG, Franks PW, Grioni S, Kaaks R, Key TJ, Navarro C, Nilsson PM, Overvad K, Palli D, Panico S, Quirós JR, Riboli E, Rolandsson O, Sacerdote C, Salamanca EC, Slimani N, Spijkerman AM, Tjonneland A, Tumino R, van der A DL, van der Schouw YT, McCarthy MI, BarrosoI, O’Rahilly S, Savage DB, Naveed Sattar N, Langenberg C, Scott RA, Wareham NJ: Association between LDL-cholesterol lowering genetic variants and risk of type 2 diabetes. JAMA 2016; 316: 1383–1391.
23.
Culver AL, Ockene IS, Balasubramanian R, Olendzki BC, Sepavich DM, Wactawski-Wende J, Manson JE, Qiao Y, Liu S, Merriam PA, Rahilly-Tierny C, Thomas F, Berger JS, Ockene JK, Curb JD, Ma Y: Statin use and risk of diabetes mellitus in postmenopausal women in the Women’s Health Initiative. Arch Intern Med 2012; 172: 144–152.
24.
Cederberg H, Stančáková A, Yaluri N, Modi S, Kuusisto J, Laakso M: Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort. Diabetologia 2015; 58: 1109–1117.
25.
Ooba N, Setoguchi S, Sato T, Kubota K: Lipid-lowering drugs and risk of new-onset diabetes: a cohort study using Japanese healthcare data linked to clinical data for health screening. BMJ Open 2017; 7:e015935.
26.
Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, Lopez-Sendon J, Mosca L, Tardif JC, Waters DD, Shear CL, Revkin JH, Buhr KA, Fisher MR, Tall AR, Brewer B; ILLUMINATE Investigators: Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007; 357: 2109–2122.
27.
Rossebø AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K, Gerdts E, Gohlke-Bärwolf C, Holme I, Kesäniemi YA, Malbecq W, Nienaber CA, Ray S, Skjaerpe T, Wachtell K, Willenheimer R; SEAS Investigators: Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008; 359: 1343–1356.
28.
Zanoni P, Khetarpal SA, Larach DB, Hancock-Cerutti WF, Millar JS, Cuchel M, DerOhannessian S, Kontush A, Surendran P, Saleheen D, Trompet S, Jukema JW, De Craen A, Deloukas P, Sattar N, Ford I, Packard C, Majumder Aa, Alam DS, Di Angelantonio E, Abecasis G, Chowdhury R, Erdmann J, Nordestgaard BG, Nielsen SF, Tybjærg-Hansen A, Schmidt RF, Kuulasmaa K, Liu DJ, Perola M, Blankenberg S, Salomaa V, Männistö S, Amouyel P, Arveiler D, Ferrieres J, Müller-Nurasyid M, Ferrario M, Kee F, Willer CJ, Samani N, Schunkert H, Butterworth AS, Howson JM, Peloso GM, Stitziel NO, Danesh J, Kathiresan S, Rader DJ; CHD Exome+ Consortium; CARDIoGRAM exome consortium; global lipids genetics consortium: rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science 2016; 351: 1166–1171.
29.
Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC: Myocardial fatty acid metabolism in health and disease. Physiol Rev 2010; 90: 207–258.
30.
Hartenbach W: Die Cholesterin-Luge, das Marchen vom bosen Cholesterin, F.A. Herbig Verlagsbuchhandlung Gmbh, Munchen, 26th edition, 2008.
31.
Awan Z, Baass A, Genest J: Proprotein convertase subtilisin/kexin type 9 (PCSK9): lessons learned from patients with hypercholesterolemia. Clin Chem 2014; 60: 1380–1389.
32.
Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR; FOURIER Steering Committee and Investigators: Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017; 376: 1713–1722.
33.
Raal FJ, Honarpour N, Blom DJ, et al; (TESLA Investigators): Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 2015; 385: 341–350.
34.
Raal FJ, Stein EA, Dufour R, et al; (RUTHERFORD-2 Investigators): PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 2015; 385: 331–340.
35.
Blom DJ, Hala T, Bolognese M et al; (DESCARTES Investigators): A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med 2014; 370: 1809–1819.
36.
Sabatine MS, Giugliano RP, Wiviott SD, et al; (OSLER Investigators): Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372: 1500–1509.
37.
Robinson JG, Farnier M, Krempf M et al; (ODYSSEY LONG TERM Investigators): Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372: 1489–1499.
38.
MedCheckTIP editorial team: New cholesterol lowering injection: PCSK9 inhibitors. MedCheckTIP 2017; 17: 8–9.
39.
Holven KB, Damås JK, Yndestad A, Waehre T, Ueland T, Halvorsen B, Heggelund L, Sandberg WJ, Semb AG, Frøland SS, Ose L, Nenseter MS, Aukrust P: Chemokines in children with heterozygous familiar hypercholesterolemia: selective upregulation of RANTES. Arterioscler Thromb Vasc Biol 2006; 26: 200–205.
40.
Narverud I, Ueland T, Nenseter MS, Retterstøl K, Telle-Hansen VH, Halvorsen B, Ose L, Aukrust P, Holven KB: Children with familial hypercholesterolemia are characterized by an inflammatory imbalance between the tumor necrosis factor α system and interleukin-10. Atherosclerosis 2011; 214: 163–168.
41.
van der Net JB, Versmissen J, Oosterveer DM, Defesche JC, Yazdanpanah M, Aouizerat BE, Steyerberg EW, Malloy MJ, Pullinger CR, Kane JP, Kastelein JJ, Sijbrands EJ: Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and coronary heart disease risk in familial hypercholesterolemia. Atherosclerosis 2009; 203: 472–478.
42.
Hashimoto Y, Okuyama H: Statins cause lifestyle-related diseases-biochemical mechanism. Endocrinol Diabetes Res 2017; 3: 2.
43.
Prospective Studies Collaboration; Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J, Qizilbash N, Peto R, Collins R: Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 2007; 370: 1829–1839.
44.
Kannel WB, Neaton JD, Wentworth D, Thomas HE, Stamler J, Hulley SB, Kjelsberg MO: Overall and coronary heart disease mortality rates in relation to major risk factors in 325,348 men screened for the MRFIT. Multiple risk factor intervention trial. Am Heart J 1986; 112: 825–836.
45.
Anderson KM, Castelli WP, Levy D: Cholesterol and mortality. 30 years of follow-up from the Framingham study. JAMA 1987; 257: 2176–2180.
46.
Ulmer H, Kelleher C, Diem G, Concin H: Why eve is not adam: prospective follow-up in 149650 women and men of cholesterol and other risk factors related to cardiovascular and all-cause mortality. J Womens Health (Larchmt) 2004; 13: 41–53.
47.
Mabuchi H, Miyamoto S, Ueda K, Oota M, Takegoshi T, Wakasugi T, Takeda R: Causes of death in patients with familial hypercholesterolemia. Atherosclerosis 1986; 61: 1–6.
48.
Hamazaki T, Okuyama H, Ogushi Y, Hama R: Cholesterol issues in Japan – why are the goals of cholesterol levels set so low? Ann Nutr Metab 2013; 62: 32–36.
49.
Tsuji H: Low serum cholesterol level and increased ischemic stroke mortality. Arch Intern Med 2011; 171: 1121–1123.
50.
Okamura T, Tanaka H, Miyamatsu N, Hayakawa T, Kadowaki T, Kita Y, Nakamura Y, Okayama A, Ueshima H; NIPPON DATA80 Research Group: The relationship between serum total cholesterol and all-cause or cause-specific mortality in a 17.3-year study of a Japanese cohort. Atherosclerosis 2007; 190: 216–223.
51.
Sugiyama D, Okamura T, Watanabe M, Higashiyama A, Okuda N, Nakamura Y, Hozawa A, Kita Y, Kadota A, Murakami Y, Miyamatsu N, Ohkubo T, Hayakawa T, Miyamoto Y, Miura K, Okayama A, Ueshima H; NIPPON DATA 80/90 Research Group: Risk of hypercholesterolemia for cardiovascular disease and the population attributable fraction in a 24-year Japanese cohort study. J Atheroscler Thromb 2015; 22: 95–107.
52.
Song YM, Sung J, Kim JS: Which cholesterol level is related to the lowest mortality in a population with low meancholesterol level: 6.4-year follow-up study of 482,472 Korean men. Am J Epidemiol 2000; 151: 739–747.
53.
Cui R, Iso H, Toyoshima H, Date C, Yamamoto A, Kikuchi S, Kondo T, Watanabe Y, Koizumi A, Inaba Y, Tamakoshi A; JACC Study Group: Serum total cholesterol levels and risk of mortality from stroke and coronary heart disease in Japanese: the JACC study. Atherosclerosis 2007; 194: 415–420.
54.
Noda H, Iso H, Irie F, Sairenchi T, Ohtaka E, Doi M, Izumi Y, Ohta H: Low-density lipoprotein cholesterol concentrations and death due to intraparenchymal hemorrhage: the Ibaraki Prefectural Health Study. Circulation 2009; 119: 2136–2145.
55.
Nago N, Ishikawa S, Goto T, Kayaba K: Low cholesterol is associated with mortality from stroke, heart disease, and cancer: the Jichi Medical School Cohort Study. J Epidemiol 2011; 21: 67–74.
56.
Jee SH, Jang Y, Oh DJ, Oh BH, Lee SH, Park SW, Seung KB, Mok Y, Jung KJ, Kimm H, Yun YD, Baek SJ, Lee DC, Choi SH, Kim MJ, Sung J, Cho B, Kim ES, Yu BY, Lee TY, Kim JS, Lee YJ, Oh JK, Kim SH, Park JK, Koh SB, Park SB, Lee SY, Yoo CI, Kim MC, Kim HK, Park JS, Kim HC, Lee GJ, Woodward M: A coronary heart disease prediction model: the Korean Heart Study. BMJ Open 2014; 4:e005025.
57.
Ogushi Y: Never Take Medicines for High Cholesterol and Neutral Fat Levels. Tokyo, Shodensha, 2008, pp 35–37.
58.
Cui R, Iso H, Yamagishi K, Saito I, Kokubo Y, Inoue M, Tsugane S; JPHC Study Group: High serum total cholesterol levels is a risk factor of ischemic stroke for general Japanese population: the JPHC study. Atherosclerosis 2012; 221: 565–569.
59.
Hamer M, Batty GD, Stamatakis E, Kivimaki M: Comparison of risk factors for fatal stroke and ischemic heart disease: a prospective follow up of the health survey for England. Atherosclerosis 2011; 219: 807–810.
60.
Petursson H, Sigurdsson JA, Bengtsson C, Nilsen TI, Getz L: Is the use of cholesterol in mortality risk algorithms in clinical guidelines valid? Ten years prospective data from the Norwegian HUNT 2 study. J Eval Clin Pract 2012; 18: 159–168.
61.
Bae JM, Yang YJ, Li ZM, Ahn YO: Low cholesterol is associated with mortality from cardiovascular diseases: a dynamic cohort study in Korean adults. J Korean Med Sci 2012; 27: 58–63.
62.
Okamura T, Kokubo Y, Watanabe M, Higashiyama A, Miyamoto Y, Yoshimasa Y, Okayama A: Low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol and the incidence of cardiovascular disease in an urban Japanese cohort study: the Suita study. Atherosclerosis 2009; 203: 587–592.
63.
Muldoon MF, Manuck SB, Matthews KA: Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials. BMJ 1990; 301: 309–314.
64.
Ravnskov U, Diamond D, Karatay MC, Miller DW, Okuyama H: No scientific support for linking dietary saturated fat to CHD. Br J Nutr 2012; 107: 455–457.
65.
Sauvaget C, Nagano J, Hayashi M, Yamada M: Animal protein, animal fat, and cholesterol intakes and risk of cerebral infarction mortality in the adult health study. Stroke 2004; 35: 1531–1537.
66.
Yamagishi K, Iso H, Yatsuya H, Tanabe N, Date C, Kikuchi S, Yamamoto A, Inaba Y, Tamakoshi A; JACC Study Group: Dietary intake of saturated fatty acids and mortality from cardiovascular disease in Japanese: the Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC) Study. Am J Clin Nutr 2010; 92: 759–765.
67.
Hamano M, Mashiko S, Onda T, Tomita I, Tomita T: Effect of cholesterol-diet on the incidence of stroke and life-span in malignant stroke prone spontaneously hypertensive rats. Jpn Heart J 1995; 36: 511.
68.
Gillman MW, Cupples LA, Millen BE, Ellison RC, Wolf PA: Inverse association of dietary fat with development of ischemic stroke in men. JAMA 1997; 278: 2145–2150.
69.
Okuyama H, Kobayashi T, Watanabe S: Dietary fatty acids – the N-6/N-3 balance and chronic elderly diseases. Excess linoleic acid and relative N-3 deficiency syndrome seen in Japan. Prog Lipid Res 1996; 35: 409–457.
70.
Schwingshackl L, Hoffmann G: No significant risk reduction could be observed for reduced/modified fat diets on all-cause mortality, CV mortality, combined CV events, or MI. “The present systematic review provides no evidence for the beneficial effects of reduced/modified fat diets in the secondary prevention of coronary heart disease.” Recommending higher intakes of PUFA in replacement of SFA was not associated with risk reduction. BMJ Open 2014; 4:e004487.
71.
Teicholz N, Thorn E: Saturated Fats and CVD: AHA Convicts, We Say Acquit. The heart.org Medscape, July 12, 2017.
72.
Ogushi Y, Haruki Y, Shibata T, Kobayashi S; JSSRS group: Hyperlipidemic effects on clinical indices of stroke in Japanese patients. Jpn J Stroke 2010; 32: 242–253.
73.
Markaki I, Nilsson U, Kostulas K, Sjöstrand C: High cholesterol levels are associated with improved long-term survival after acute ischemic stroke. J Stroke Cerebrovasc Dis 2014; 23:e47–e53.
74.
Orth M, Bellosta S: Cholesterol: its regulation and role in central nervous system disorders. Cholesterol 2012; 2012: 292598.
75.
Hanaka S, Abe T, Itakura H, Matsumoto A: Gene expression related to cholesterol metabolism in mouse brain during development. Brain Dev 2000; 22: 321–326.
76.
Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, Holtzman DM, Miller CA, Strickland DK, Ghiso J, Zlokovic BV: Clearance of Alzheimer’s amyloid-b1–40 peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 2000; 106: 1489–1499.
77.
Dehouck B, Fenart L, Dehouck MP, Pierce A, Torpier G, Cecchelli R: A new function for the LDL receptor: transcytosis of LDL across the blood-brain barrier. J Cell Biol 1997; 138: 877–889.
78.
Wang H, Eckel RH: What are lipoproteins doing in the brain? Trends Endocrinol Metab 2014; 25: 8–14.
79.
Ravnskov U, Diamond DM, Hama R, Hamazaki T, Hammarskjöld B, Hynes N, Kendrick M, Langsjoen PH, Malhotra A, Mascitelli L, McCully KS, Ogushi Y, Okuyama H, Rosch PJ, Schersten T, Sultan S, Sundberg R: Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open 2016; 6:e010401.
80.
Okuyama H, Hamazaki T, Ogushi Y. New cholesterol guidelines for longevity. World Rev Nutr Diet 2011; 102: 124–136.
81.
Okuyama H, Langsjoen PH, Hamazaki T, Ogushi Y, Hama R, Kobayashi T, Uchino H: Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms. Expert Rev Clin Pharmacol 2015; 8: 189–199.
82.
Wendling P: Veracity of Clinical-Trial Publications Comes Under Fire. The Heart.org Medscape Cardiology. May 09, 2017: June 08, 2017.
83.
Matsuzaki M, Kita T, Mabuchi H, Matsuzawa Y, Nakaya N, Oikawa S, Saito Y, Sasaki J, Shimamoto K, Itakura H; J-LIT Study Group: Japan lipid intervention trial. Large scale cohort study of the relationship between serum cholesterol concentration and coronary events with low-dose simvastatin therapy in Japanese patients with hypercholesterolemia. Circ J 2002; 66: 1087–1095.
84.
Horiuchi H, Kita T, Mabuchi H, Matsuzaki M, Matsuzawa Y, Nakaya N, Oikawa S, Saito Y, Sasaki J, Shimamoto K, Itakura H J-LIT Study Group: Primary cardiovascular events and serum lipid levels in elderly Japanese with hypercholesterolemia undergoing 6-year simvastatin treatment: a subanalysis of the Japan lipid intervention trial. J Am Geriatr Soc 2004; 52: 1981–1987.
85.
Mustanoja S, Strbian D, Putaala J, Meretoja A, Curtze S, Haapaniemi E, Sairanen T, Hietikko R, Sirén J, Kaste M, Tatlisumak T: Association of prestroke statin use and lipid levels with outcome of intracerebral hemorrhage. Stroke 2013; 44: 2330–2332.
86.
Larsen S, Stride N, Hey-Mogensen M, Hansen CN, Bang LE, Bundgaard H, Nielsen LB, Helge JW, Dela F: Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance. J Am Coll Cardiol 2013; 61: 44–53.
87.
Nakazato R, Gransar H, Berman DS, Cheng VY, Lin FY, Achenbach S, Al-Mallah M, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cury RC, Chinnaiyan K,Chow BJ, Delago A, Hadamitzky M, Hausleiter J, Kaufmann P, Maffei E, Raff G, Shaw LJ, Villines TC, Dunning A, Feuchtner G, Kim YJ, Leipsic J, Min JK: Statins use and coronary artery plaque composition: results from the international multicenter CONFIRM registry. Atherosclerosis 2012; 225: 148–153.
88.
Hashimoto Y, Mori M, Kobayashi S, Hanya A, Watanabe S, Ohara N, Noguchi T, Kawai T, Okuyama H: Canola and hydrogenated soybean oils accelerate ectopic bone formation induced by implantation of bone morphogenetic protein in mice. Toxicology Reports 2014; 1: 955–962.
89.
Binnington B, Nguyen L, Kamani M, Hossain D, Marks DL, Budani M, Lingwood CA: Inhibition of Rab prenylation by statins induces cellular glycosphingolipid remodeling. Glycobiology 2016;26:166–180.
90.
Leconte I, Auzan C, Debant A, Rossi B, Clauser E: N-linked oligosaccharide chains of the insulin receptor beta subunit are essential for transmembrane signaling. J Biol Chem 1992; 267: 17415–17423.
91.
Ming JE, Roessler E, Muenke M: Human developmental disorders and the Sonic hedgehog pathway. Mol Med Today 1998; 4: 343–349.
92.
Mitchell N, Petralia RS, Currier DG, Wang YX, Kim A, Mattson MP, et al: Sonic hedgehog regulates presynaptic terminal size, ultrastructure and function in hippocampal neurons. J Cell Sci 2012; 125: 4207–4213.
93.
Carson DD, Lennarz WJ: Inhibition of polyisoprenoid and glycoprotein biosynthesis causes abnormal embryonic development. Proc Natl Acad Sci U S A 1979; 76: 5709–5713.
94.
Forbes K, Shah VK, Siddals K, Gibson JM, Aplin JD, Westwood M: Statins inhibit insulin-like growth factor action in first trimester placenta by altering insulin-like growth factor 1 receptor glycosylation. Mol Hum Reprod 2015; 21: 105–114.
95.
Oury F, Sumara G, Sumara O, Ferron M, Chang H, Smith CE, Hermo L, Suarez S, Roth BL, Ducy P, Karsenty G: Endocrine regulation of male fertility by the skeleton. Cell 2011; 144: 796–809.
96.
Oury F, Khrimian L, Denny CA, Gardin A, Chamouni A, Goeden N, Huang YY, Lee H, Srinivas P, Gao XB, Suyama S, Langer T, Mann JJ, Horvath TL, Bonnin A, Karsenty G: Maternal and offspring pools of osteocalcin influence brain development and functions. Cell 2013; 155: 228–241.
97.
Jones TH, Arver S, Behre HM, Buvat J, Meuleman E, Moncada I, Morales AM, Volterrani M, Yellowlees A, Howell JD, Channer KS; TIMES2 Investigators: Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 2011; 34: 828–837.
98.
Khaw KT, Dowsett M, Folkerd E, Bingham S, Wareham N, Luben R, Welch A, Day N: Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation 2007; 116: 2694–2701.
99.
Okuyama H, Ohara N, Tatematsu K, Fuma S, Nonogaki T, Yamada K, Ichikawa Y, Miyazawa D, Yasui Y, Honma S: Testosterone-lowering activity of canola and hydrogenated soybean oil in the stroke-prone spontaneously hypertensive rat. J Toxicol Sci 2010; 35: 743–747.
100.
Tatematsu K, Fuma SY, Satoh J, Ichikawa Y, Fujii Y, Okuyama H: Dietary canola and soybean oil fed to SHRSP rat dams differently affect the growth and survival of their male pups. J Nutr 2004; 134: 1347–1352.
101.
Newman TB, Hulley SB: Carcinogenicity of lipid-lowering drugs. JAMA 1996; 275: 55–60.
102.
Skogastierna C, Johansson M, Parini P, Eriksson M, Eriksson LC, Ekström L, Björkhem-Bergman L: Statins inhibit expression of thioredoxin reductase 1 in rat and human liver and reduce tumour development. Biochem Biophys Res Commun 2012; 417: 1046–1051.
103.
Ravnskov U: Comment on ‘Statin use and all-cancer survival: prospective results from the Women’s Health Initiative’. Brit J Cancer 2017; 116:e9.
104.
Gravelin D: My Statin Story. 2016. https://spacedoc.com/articles/my-statin-story.
105.
Gaist D, Jeppesen U, Andersen M, García Rodríguez LA, Hallas J, Sindrup SH: Statins and risk of polyneuropathy: a case-control study. Neurology 2002; 58: 1333–1337.
106.
Mikus CR, Boyle LJ, Borengasser SJ, Oberlin DJ, Naples SP, Fletcher J, Meers GM, Ruebel M, Laughlin MH, Dellsperger KC, Fadel PJ, Thyfault JP: Simvastatin impairs exercise training adaptations. J Am Coll Cardiol 2013; 62: 709–714.
107.
Fusaro M, Tripepi G, Noale M, Plebani M, Zaninotto M, Piccoli A, Naso A, Miozzo D, Giannini S, Avolio M, Foschi A, Rizzo MA, Gallieni M; Vertebral Fractures and Vascular Calcifications Study Group: Prevalence of vertebral fractures, vascular calcifications, and mortality in warfarin treated hemodialysis patients. Curr Vasc Pharmacol 2015; 13: 248–258.
108.
Okuyama H, Yamada K, Miyazawa D, Yasui Y, Ohara N: Dietary lipids impacts on healthy ageing. Lipids 2007; 42: 821–825.
109.
Ohara N, Naito Y, Nagata T, Tatematsu K, Fuma SY, Tachibana S, Okuyama H: Exploration for unknown substances in rapeseed oil that shorten survival time of stroke-prone spontaneously hypertensive rats. Effects of super critical gas extraction fractions. Food Chem Toxicol 2006; 44: 952–963.
110.
Ohara N, Kasama K, Naito Y, Nagata T, Saito Y, Kuwagata M, Okuyama H: Different effects of 26-week dietary intake of rapeseed oil and soybean oil on plasma lipid levels, glucose-6-phosphate dehydrogenase activity and cyclooxygenase-2 expression in spontaneously hypertensive rats. Food Chem Toxicol 2008; 46: 2573–2579.
111.
Ratnayake WM, L’Abbé MR, Mueller R, Hayward S, Plouffe L, Hollywood R, Trick K: Vegetable oils high in phytosterols make erythrocytes less deformable and shorten the life span of stroke-prone spontaneously hypertensive rats. J Nutr 2000; 130: 1166–1178.
112.
Booth SL, Lichtenstein AH, O’Brien-Morse M, McKeown NM, Wood RJ, Saltzman E, Gundberg CM: Effects of a hydrogenated form of vitamin K on bone formation and resorption. Am J Clin Nutr 2001; 74: 783–790.
113.
Troy LM, Jacques PF, Hannan MT, Kiel DP, Lichtenstein AH, Kennedy ET, Booth SL: Dihydrophylloquinone intake is associated with low bone mineral density in men and women. Am J Clin Nutr 2007; 86: 504–508.
114.
Schmid A, Schmid H: [Rapeseed poisoning of wild herbivores]. Tierarztl Prax 1992; 20: 321–325.
115.
Geleijnse JM, Vermeer C, Grobbee DE, Schurgers LJ, Knapen MH, van der Meer IM, Hofman A, Witteman JC: Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr 2004; 134: 3100–3105.
116.
Choi HJ, Yu J, Choi H, An JH, Kim SW, Park KS, Jang HC, Kim SY, Shin CS: Vitamin K2 supplementation improves insulin sensitivity via osteocalcin metabolism: a placebo-controlled trial. Diabetes Care 2011; 34:e147.
117.
Nimptsch K, Rohrmann S, Kaaks R, Linseisen J: Dietary vitamin K intake in relation to cancer incidence and mortality: results from the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg). Am J Clin Nutr 2010; 91: 1348–1358.
118.
Iwamoto J, Takeda T, Ichimura S: Effect of combined administration of vitamin D3 and vitamin K2 on bone mineral density of the lumbar spine in postmenopausal women with osteoporosis. J Orthop Sci 2000; 5: 546–551.
119.
Brandt EJ, Myerson R, Perraillon MC, Polonsky TS: Hospital admissions for myocardial infarction and stroke before and after the trans-fatty acid restrictions in New York. JAMA Cardiol 2017; 2: 627–634.
120.
Wang Q, Afshin SA, Yakoob MY, Singh GM, Rehm CD, Khatibzadeh S, Peilin Shi M, Mozaffarian D: Impact of nonoptimal intakes of saturated, polyunsaturated, and trans fat on global burdens of coronary heart disease. Am Heart Assoc 2016; 5:e002891.
121.
Gebauer SK, Destaillats F, Dionisi F, Krauss RM, Baer DJ: Vaccenic acid and trans fatty acid isomers from partially hydrogenated oil both adversely affect LDL cholesterol: a double-blind, randomized controlled trial. Am J Clin Nutr 2015; 102: 1339–1346.
122.
de Souza RJ, Mente A, Maroleanu A, Cozma AI, Ha V, Kishibe T, Uleryk E, Budylowski P, Schünemann H, Beyene J, Anand SS: Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: systematic review and meta-analysis of observational studies. BMJ 2015; 351:h3978.
123.
Dong L, Zou H, Yuan C, Hong YH, Kuklev DV, Smith WL: Different fatty acids compete with arachidonic acid for binding to the allosteric or catalytic subunits of cyclooxygenases to regulate prostanoid synthesis. J Biol Chem 2016; 291: 4069–4078.
124.
Bibus D, Lands B: Balancing proportions of competing omega-3 and omega-6 highly unsaturated fatty acids (HUFA) in tissue lipids. Prostaglandins Leukot Essent Fatty Acids 2015; 99: 19–23
125.
Harcombe Z, Baker JS, Cooper SM, Davies B, Sculthorpe N, DiNicolantonio JJ, Grace F: Evidence from randomised controlled trials did not support the introduction of dietary fat guidelines in 1977 and 1983: a systematic review and meta-analysis. Open Heart 2015; 2:e000196.
126.
Arita M, Clish CB, Serhan CN: The contributions of aspirin and microbial oxygenase to the biosynthesis of anti-inflammatory resolvins: novel oxygenase products from omega-3 polyunsaturated fatty acids. Biochem Biophys Res Commun 2005; 338: 149–157.
127.
Katakura M, Hashimoto M, Inoue T, Al Mamun A, Tanabe Y, Iwamoto R, Arita M, Tsuchikura S, Shido O: Omega-3 fatty acids protect renal functions by increasing docosahexaenoic acid-derived metabolite levels in SHR.Cg-Lepr(cp)/NDmcr rats, a metabolic syndrome model. Molecules 2014; 19: 3247–3263.
128.
Serhan CN, Hong S, Gronert K, Colgan SP, Devchand PR, Mirick G, Moussignac RL: Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J Exp Med 2002; 196: 1025–1037.
129.
Asatryan A, Bazan NG: Molecular mechanisms of signaling via the docosanoid neuroprotectin D1 for cellular homeostasis and neuroprotection. J Biol Chem 2017; 292: 12390–12397.
130.
Sekikawa A, Curb JD, Ueshima H, El-Saed A, Kadowaki T, Abbott RD, Evans RW, Rodriguez BL, Okamura T, Sutton-Tyrrell K, Nakamura Y, Masaki K, Edmundowicz D, Kashiwagi A, Willcox BJ, Takamiya T, Mitsunami K, Seto TB, Murata K, White RL, Kuller LH; ERA JUMP (Electron-Beam Tomography, Risk Factor Assessment Among Japanese and U.S. Men in the Post-World War II Birth Cohort) Study Group: Marine-derived n-3 fatty acids and atherosclerosis in Japanese, Japanese-American, and white men: a cross-sectional study. J Am Coll Cardiol 2008; 52: 417–424.
131.
Brault M, Ray J, Gomez YH, Mantzoros CS, Daskalopoulou SS: Statin treatment and new-onset diabetes: a review of proposed mechanisms. Metabolism 2014; 63: 735–745.
132.
American Heart Association/American Stroke Association: Cardiovascular Disease: A Costly Burden for America Projections through, 2035. http://www.heart.org/idc/groups/heart-public/@wcm/@adv/documents/downloadable/ucm_491543.pdf.
133.
Rosch PJ (ed): Fat and Cholesterol Don’t Cause Heart Attacks and Statins Are Not the Solution. Cwmbran, Columbus Publishing, 2016.
© 2018 S. Karger AG, Basel
2018
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.