Lipid hypothesis

The lipid hypothesis (also known as the cholesterol hypothesis) is a medical theory postulating a link between blood cholesterol levels and the occurrence of cardiovascular disease. A summary from 1976 described it as: "measures used to lower the plasma lipids in patients with hyperlipidemia will lead to reductions in new events of coronary heart disease".[1] It states, more concisely, that "decreasing blood cholesterol [...] significantly reduces coronary heart disease".[2]

An accumulation of evidence has led to the acceptance of the lipid hypothesis by most of the medical community.[3][4][5]

History

In 1856, the German pathologist Rudolf Virchow first described lipid accumulation in arterial walls,[6] however the initial connection between arteriosclerosis and dietary cholesterol would not be established until the research of Russian pathologist Nikolay Anichkov, prior to World War I.[7] In 1913, a study by Nikolay Anichkov showed that rabbits fed on cholesterol developed lesions in their arteries similar to atherosclerosis, suggesting a role for cholesterol in atherogenesis.[8][9]

Dutch physician Cornelis de Langen noted the correlation between nutritional cholesterol intake and incidence of gallstones in Javanese people in 1916.[10][11] de Langen showed that the traditional Javanese diet, poor in cholesterol and other lipids, was associated with a low level of blood cholesterol and low incidence of cardiovascular disease (CVD), while the prevalence of CVD in Europeans living in Java on a Western diet was higher.[10] Since de Langen published his results only in Dutch, his work remained unknown to most of the international scientific community until the 1940s and 1950s.[10] By 1951, it was accepted that, although the causes of atheroma were still unknown, fat deposition was a major feature of the disease process. "The so-called fatty flecks or streaks of arteries are the early lesions of atherosclerosis and... may develop into the more advanced lesions of the disease."[12]

Ancel Keys and the Seven Countries Study

Ancel Keys

With the emergence of cardiovascular disease as a major cause of death in the Western world in the middle of the 20th century, the lipid hypothesis received greater attention. In the 1940s, a University of Minnesota researcher, Ancel Keys, postulated that the apparent epidemic of heart attacks in middle-aged American men was related to their mode of life and possibly modifiable physical characteristics.[13] He first explored this idea in a group of Minnesota business and professional men that he recruited into a prospective study in 1947, the first of many cohort studies eventually mounted internationally. The first major report appeared in 1963 and the men were followed through until 1981.[14] After fifteen years follow-up, the study confirmed the results of larger studies that reported earlier on the predictive value for heart attack of several risk factors: blood pressure, blood cholesterol level, and cigarette smoking.

Seven Countries Study

Keys presented his diet-lipid-heart disease hypothesis at a 1955 expert meeting of the World Health Organization in Geneva.[15] In response to criticism at the conference, Keys recruited collaborating researchers in seven countries to mount the first cross-cultural comparison, the years-long Seven Countries Study, which is still under observation today. This was to compare the heart attack risk in populations of men engaged in traditional occupations and being from cultures with different diets, especially in the proportion of fat calories of different composition.[16] There was also criticism before the study began: Yerushalmy and Hilleboe pointed out that Keys had selected for the study the countries that would give him the results he wanted, while leaving out data from sixteen countries that would not; they also pointed out that Keys was studying a "tenuous association" rather than any possible proof of causation.[17] Keys then joined the nutrition committee of the American Heart Association (AHA), successfully promulgated his idea, and in 1961 the AHA became the first group anywhere in the world to advise cutting back on saturated fat (and dietary cholesterol) to prevent heart disease.[18] This historic recommendation was reported on the cover of Time Magazine in that same year.[19]

The Seven Countries Study was formally started in fall 1958 in Yugoslavia. In total, 12,763 males, 40–59 years of age, were enrolled in seven countries, in four regions of the world (United States, Northern Europe, Southern Europe, Japan). One cohort is in the United States, two cohorts in Finland, one in the Netherlands, three in Italy, five in Yugoslavia (two in Croatia, and three in Serbia), two in Greece, and two in Japan. The entry examinations were performed between 1958 and 1964 with an average participation rate of 90%, lowest in the US, with 75% and highest in one of the Japanese cohorts, with 100%.[20]

Keys' book Eat Well and Stay Well[21] popularized the idea that reducing the amount of saturated fat in the diet would reduce cholesterol levels and the risks of serious diseases due to atheroma.[22] Keys was followed during the rest of the 20th century by an accumulation of work that repeatedly demonstrated associations between cholesterol levels (and other modifiable risk factors including smoking and exercise) and risks of heart disease. These led to the acceptance of the lipid hypothesis as orthodoxy by much of the medical community.[3] By the end of the 1980s, there were widespread academic statements that the lipid hypothesis was proven beyond reasonable doubt,[23][24][25] or, as one article stated, "universally recognized as a law."[26][27][28][29][30]

Consensus

The medical consensus supports the lipid hypothesis as evidence from separate meta-analyses, prospective epidemiologic studies and randomized clinical trials have demonstrated that elevated levels of LDL blood cholesterol are a significant risk factor for cardiovascular disease.[4] Too much LDL (called 'bad cholesterol') can lead to fatty deposits building up in the arteries which increases the risk of cardiovascular disease. A 2017 consensus statement from the European Atherosclerosis Society concluded that "consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD."[4] The consensus statement noted:

Most publications that question the causal effect of LDL on the development of ASCVD tend to cite evidence from individual studies or a small group of highly selected studies, often without a quantitative synthesis of the presented evidence. Therefore, to avoid this type of selection bias, we have based our conclusions on the totality of evidence from separate meta-analyses of genetic studies, prospective epidemiologic studies, Mendelian randomization studies, and randomized clinical trials. This evidence base includes over 200 studies involving over 2 million participants with over 20 million person-years of follow-up and more than 150 000 cardiovascular events. Together these studies provide remarkably consistent and unequivocal evidence that LDL causes ASCVD.[4]

The 2021 Canadian Cardiovascular Society Guidelines say "We recommend that for any patient with triglycerides > 1.5 mmol/L, non-HDL-C or ApoB be used instead of LDL-C as the preferred lipid parameter for screening (Strong Recommendation, High-Quality Evidence)".[31]

Dissenting views

A small number of "cholesterol skeptics", particularly those in The International Network of Cholesterol Skeptics (THINCS), take a contrary position to the accepted scientific consensus of the lipid hypothesis, claiming instead that heart disease is not caused by elevated LDL, and demonizing the cholesterol-lowering drugs statins.[32]

In 2016, Uffe Ravnskov, director of THINCS, was the lead author of a systematic review to examine how low-density lipoprotein cholesterol is associated with mortality in older adults. They concluded that "High LDL-C is inversely associated with mortality in most people over 60 years" and since "elderly people with high LDL-C live as long or longer than those with low LDL-C, our analysis provides reason to question the validity of the cholesterol hypothesis."[33] The review has been criticized for cherry picking data and confirmation bias. Nine of the authors are members of THINCS. The National Health Service noted that "the review searched only a single literature database, excluded studies only available in non-English language, and excluded studies where the title and abstract did not appear to contain information on the link between LDL and mortality in older adults."[34] Several medical experts responded to the review claiming it had a number of "serious weaknesses" and was contradicted by robust experimental data from clinical trials. Professor Jeremy Pearson Associate Medical Director of the British Heart Foundation commented that "there is nothing in the current paper to support the authors' suggestions that the studies they reviewed cast doubt on the idea that LDL cholesterol is a major cause of heart disease or that guidelines on LDL reduction in the elderly need re-evaluating."[35][36]

Cardiologist Robert DuBroff acknowledges that there is good evidence statins improve cardiovascular risk but suggest that there is not good evidence that the benefit follows from reducing cholesterol levels. A June 2021 article in Nature quoted DuBroff saying "If this concept of lowering cholesterol is valid then why aren’t these other [non-statin] agents [that lower cholesterol] equally effective at reducing cardiovascular events?"[37]

Further lipid hypotheses

Lipid hypothesis of osteoporosis

The "lipid hypothesis of osteoporosis" postulates that lipids involved in causing heart disease also contribute to causing osteoporosis. Osteoporosis is characterized by a decrease of bone marrow cells, or osteoblasts, and an increase of fat cells, or adipocytes. The formation of osteoblasts from pre-osteoblasts is reduced by oxidized lipids and in mice fed with a high fat diet. (Needs elaborating: Exact list of diet ingredients.) Observations from this model suggest that LDL oxidation products can cause osteoporosis through changing the developmental rate of bone cells leading to a reduced number of osteoblasts and increased numbers of fat cells.[38]

Lipid hypothesis of cold tolerance

In plants and microbes, changes in the lipid composition of cell membranes have been linked to cold tolerance.[39] The enhanced resistance to cold treatment appears to be caused by an increased amount of fatty acid desaturases produced under cold stress transforming saturated into unsaturated fatty acids in the membrane. This effect can be reproduced artificially in genetically engineered plants.[40] The changes in membrane lipid composition lead to a higher membrane fluidity, thus keeping the membrane from "freezing" at low temperatures. This "lipid hypothesis of cold tolerance" is less well supported in animals. In fruit flies, cold acclimation does not coincide with a reduced amount of saturated fatty acids,[41] and recent genetic studies on a nematode indicate that the mechanisms involved in cold adaptation in animals may be different from those in plants and microbes.[42]

See also

References

  1. ↑ Ahrens EH Jr (July 1976). "The management of hyperlipidemia: whether, rather than how". Ann Intern Med. 85 (1): 87–93. doi:10.7326/0003-4819-85-1-87. PMID 779574.
  2. ↑ Steinberg D (2006). "An interpretive history of the cholesterol controversy, part IV: The 1984 coronary primary prevention trial ends it - almost". J Lipid Res. 47 (1): 1–14. doi:10.1194/jlr.R500014-JLR200. PMID 16227628.
  3. 1 2 Steinberg D (2006). "Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy, part V: the discovery of the statins and the end of the controversy". J. Lipid Res. 47 (7): 1339–51. doi:10.1194/jlr.R600009-JLR200. PMID 16585781.
  4. 1 2 3 4 Brian A. Ference, Henry N. Ginsberg, Ian Graham, Kausik K. Ray, Chris J. Packard, Eric Bruckert, Robert A. Hegele, Ronald M. Krauss, Frederick J. Raal, Heribert Schunkert, Gerald F. Watts, Jan Borén, Sergio Fazio, Jay D. Horton, Luis Masana, Stephen J. Nicholls, Børge G. Nordestgaard, Bart van de Sluis, Marja-Riitta Taskinen, Lale Tokgözoğlu, Ulf Landmesser, Ulrich Laufs, Olov Wiklund, Jane K. Stock, M. John Chapman, Alberico L. Catapano (2017). "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". European Heart Journal. 38 (32): 2459–2472. doi:10.1093/eurheartj/ehx144. PMC 5837225. PMID 28444290.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ↑ Linton MF, Yancey PG, Davies SS, Jerome WG, Linton EF, Song WL, Doran AC, Vickers KC. (2019). "The Role of Lipids and Lipoproteins in Atherosclerosis". In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K, Grossman A, Hershman JM, Hofland HJ, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Purnell J, Singer F, Stratakis CA, Trence DL, Wilson DP. Endotext. South Dartmouth.
  6. ↑ Virchow, Rudolf (1856). "Gesammelte Abhandlungen zur wissenschaftlichen Medizin". Vierteljahrschrift für die praktische Heilkunde. Germany: Staatsdruckerei Frankfurt. Phlogose und Thrombose im Gefäßsystem.
  7. ↑ Steinberg, Daniel (21 April 2004). "Thematic review series: The Pathogenesis of Atherosclerosis. An interpretive history of the cholesterol controversy: Part I". Journal of Lipid Research. 45 (9): 1583–1593. doi:10.1194/jlr.R400003-JLR200. PMID 15102877.
  8. ↑ Anitschkow NN, Chatalov S (1913). "Über experimentelle Cholesterinsteatose und ihre Bedeutung für die Entstehung einiger pathologischer Prozesse". Zentralbl Allg Pathol. 24: 1–9.
  9. ↑ Anitschkow NN (1913). "Über die Veränderungen der Kaninchenaorta bei experimenteller Cholesterinsteatose". Beitr Pathol Anat. 56: 379–404.
  10. 1 2 3 Blackburn, Henry (2012). "20th-Century "Medical Marco Polos" in the Origins of Preventive Cardiology and Cardiovascular Disease Epidemiology". The American Journal of Cardiology. 109 (5): 756–767. doi:10.1016/j.amjcard.2011.10.038. PMID 22470931.
  11. ↑ de Langen, Cornelis (1916). "Cholesterine-stofwisseling en rassenpathologie". Geneeskundig Tijdschrift voor Nederlandsch-Indie (in Dutch). 56: 1–34.
  12. ↑ Duff GL, McMillan GC (1951). "Pathology of atherosclerosis". Am J Med. 11 (1): 92–108. doi:10.1016/0002-9343(51)90011-3. PMID 14837929.
  13. ↑ Teicholz, Nina (6 May 2014). "The Questionable Link Between Saturated Fat and Heart Disease". The Wall Street Journal. Retrieved 9 May 2015.
  14. ↑ Keys, Ancel; Taylor, Henry Longstreet; Blackburn, Henry; Brozek, Josef; Anderson, Joseph T.; Simonson, Ernst (1 September 1963). "Coronary Heart Disease among Minnesota Business and Professional Men Followed Fifteen Years". Circulation. 28 (3): 381–95. doi:10.1161/01.cir.28.3.381. PMID 14059458.
  15. ↑ Famous Polemics on Diet-Heart Theory. Henry Blackburn, School of Public Health, University of Minnesota. http://www.epi.umn.edu/cvdepi/essay.asp?id=33 accessed 18 March 2014
  16. ↑ Keys, Ancel (1980). Seven Countries: A Multivariate Analysis of Death and Coronary Heart Disease. Harvard University Press. ISBN 978-0-674-80237-7.
  17. ↑ Yerushalmy J, Hilleboe HE (1957). "Fat in the diet and mortality from heart disease. A methodologic note". NY State J Med. 57: 2343–54.
  18. ↑ "Dietary Fat and Its Relation to Heart Attacks and Strokes". JAMA. 175 (5): 389–391. 4 February 1961. doi:10.1001/jama.1961.63040050001011. PMID 14447694.
  19. ↑ "TIME Magazine Cover: Ancel Keys". TIME.com. 13 January 1961. Retrieved 23 July 2017.
  20. ↑ Keys A (Ed). Seven Countries: A multivariate analysis of death and coronary heart disease. Harvard University Press. Cambridge, Massachusetts. 1980. ISBN 0-674-80237-3.
  21. ↑ Keys, Ancel (1959). Eat Well and Stay Well. United States: Doubleday. ISBN 978-0-385-06575-7.
  22. ↑ "Ancel Keys Obituary". The American Physiological Society. Archived from the original on 27 September 2007. Retrieved 15 April 2007.
  23. ↑ Steinberg D (1989). "The cholesterol controversy is over. Why did it take so long?". Circulation. 80 (4): 1070–1078. doi:10.1161/01.cir.80.4.1070. PMID 2676235.
  24. ↑ LaRosa JC (1998). "Cholesterol & atherosclerosis: a controversy resolved". Adv Nurse Pract. 6 (5): 36–37. PMID 9633288.
  25. ↑ Steinberg D (2002). "Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime". Nature Medicine. 8 (11): 1211–1217. doi:10.1038/nm1102-1211. PMID 12411947. S2CID 30459713.
  26. ↑ Thompson GR, Packard CJ, Stone NJ (2002). "Goals of statin therapy: three viewpoints". Curr Atheroscler Rep. 4 (1): 26–33. doi:10.1007/s11883-002-0059-6. PMID 11772419. S2CID 72257114.
  27. ↑ Bucher, HC; Griffith, LE; Guyatt, GH (February 1999). "Systematic review on the risk and benefit of different cholesterol-lowering interventions". Arteriosclerosis, Thrombosis, and Vascular Biology. 19 (2): 187–195. doi:10.1161/01.atv.19.2.187. PMID 9974397.
  28. ↑ Tyroler HA (1987). "Review of lipid-lowering clinical trials in relation to observational epidemiologic studies". Circulation. 76 (3): 515–522. doi:10.1161/01.cir.76.3.515. PMID 3304704.
  29. ↑ Brown WV (1990). "Review of clinical trials: proving the lipid hypothesis". Eur Heart J. 11 Suppl H: 15–20. doi:10.1093/eurheartj/11.suppl_h.15. PMID 2073909.
  30. ↑ Kroon AA, Stalenhoef AF (1997). "LDL-cholesterol lowering and atherosclerosis -- clinical benefit and possible mechanisms: an update". Neth J Med. 51 (1): 16–27. doi:10.1016/S0300-2977(97)00031-4. hdl:2066/26174. PMID 9260486.
  31. ↑ Glen J Pearson, George Thanassoulis, Todd J Anderson; et al. (2021). "2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults". Can J Cardiol. TBA (TBA): 1129–1150. doi:10.1016/j.cjca.2021.03.016. PMID 33781847.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  32. ↑ Hall H (9 October 2008). "Cholesterol Skeptics Strike Again". Science-Based Medicine. THINCS would like us to believe that cholesterol has nothing to do with heart disease; that low cholesterol is harmful and high cholesterol is beneficial; and they demonize statins, even claiming that they cause cancer.
  33. ↑ Ravnskov U; Diamond DM; Hama R (12 June 2016). "Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review". BMJ Open. 6 (6): e010401. doi:10.1136/bmjopen-2015-010401. PMC 4908872. PMID 27292972.
  34. ↑ "Study says there's no link between cholesterol and heart disease". National Health Service. Retrieved 18 December 2018.
  35. ↑ "Flawed cholesterol study makes headlines". British Heart Foundation. Retrieved 27 May 2019.
  36. ↑ "Expert reaction to systematic review reporting lack of an association between LDL cholesterol and mortality in the elderly". Science Media Centre. 13 July 2017. Retrieved 27 May 2019.
  37. ↑ Natalie Healey, Is there more to a healthy-heart diet than cholesterol? Nature Vol 594, Issue 7862, S12-S13, 9 June 2021
  38. ↑ Parhami F, Jackson SM, Tintut Y, Le V, Balucan JP, Territo M, Demer LL (1999). "Atherogenic diet and minimally oxidized low density lipoprotein inhibit osteogenic and promote adipogenic differentiation of marrow stromal cells". J. Bone Miner. Res. 14 (12): 2067–78. doi:10.1359/jbmr.1999.14.12.2067. PMID 10620066. S2CID 22923541.
  39. ↑ Finegold L (1986). "Molecular aspects of adaptation to extreme cold environments". Adv Space Res. 6 (12): 257–64. Bibcode:1986AdSpR...6l.257F. doi:10.1016/0273-1177(86)90094-3. PMID 11537829.
  40. ↑ H. Kodama; T. Hamada; G. Horiguchi; M. Nishimura; K. Iba (1994). "Genetic Enhancement of Cold Tolerance by Expression of a Gene for Chloroplast [omega]-3 Fatty Acid Desaturase in Transgenic Tobacco". Plant Physiology. 105 (2): 601–605. doi:10.1104/pp.105.2.601. PMC 159399. PMID 12232227.
  41. ↑ Ohtsu T, Kimura M, Katagiri C (1998). "How Drosophila species acquire cold tolerance--qualitative changes of phospholipids". Eur. J. Biochem. 252 (3): 608–11. doi:10.1046/j.1432-1327.1998.2520608.x. PMID 9546680.
  42. ↑ Hayward S, Murray P, Gracey A, Cossins A (2007). Beyond the lipid hypothesis: mechanisms underlying phenotypic plasticity in inducible cold tolerance. Adv. Exp. Med. Biol. Advances in Experimental Medicine and Biology. Vol. 594. pp. 132–42. doi:10.1007/978-0-387-39975-1_12. ISBN 978-0-387-39974-4. PMID 17205681.
This article is issued from Offline. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.