Lipid hypothesis

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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]

Contents

As of 2023, there is international clinical acceptance of the lipid hypothesis. [3] [4] [5] [6]

History

In 1856, the German pathologist Rudolf Virchow first described lipid accumulation in arterial walls. [7] 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. [8] In 1913, a study by Anichkov showed that rabbits fed on cholesterol developed lesions in their arteries similar to atherosclerosis, suggesting a role for cholesterol in atherogenesis. [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 CVD 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. 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. [13] 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. [13]

Seven Countries Study

Keys presented his diet-lipid-heart disease hypothesis at a 1955 expert meeting of the World Health Organization in Geneva. [14] 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. [15] 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 causality. [16] 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. [17] This historic recommendation was reported on the cover of Time Magazine in that same year. [18]

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%. [19]

Keys' book Eat Well and Stay Well  [20] 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. [21] 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. [22] 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. [3]

The National Lipid Association have stated that by 2012, a wealth of evidence including numerous clinical trials examined by the Cholesterol Treatment Trialists' Collaboration has confirmed the lipid hypothesis. [31] 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." [3] 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. [3]

A review from the Journal of the American College of Cardiology in 2018 concluded:

The causal effect of LDL and other apo B–containing lipoproteins on the risk of cardiovascular disease is determined by both the magnitude and the cumulative duration of exposure to these lipoproteins. The goal of maintaining optimal lipid levels throughout life is to keep the concentration of circulating LDL and other apo B–containing lipoproteins low to minimize the number of particles that become retained in the arterial wall and thereby minimize the rate of progression of atherosclerotic plaques. [32]

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)". [33]

The European Society of Cardiology have noted:

For almost a century, evidence has been overwhelming that lipids and diet are related and have a negative impact on CVD. It is also clear that lipids, and especially LDL, play a crucial role in atherosclerosis. However, groups of “non-believers” decelerated developments and clinical progress, sometimes for decades. [34]

In 2023, the World Heart Federation published a report which stated that high levels of low-density lipoprotein (LDL) cholesterol are a major risk factor for cardiovascular diseases and that elevated LDL cholesterol contributed to 3.8 million deaths in 2021. [6]

See also

Related Research Articles

<span class="mw-page-title-main">Coronary artery disease</span> Reduction of blood flow to the heart

Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the cardiac muscle due to build-up of atherosclerotic plaque in the arteries of the heart. It is the most common of the cardiovascular diseases. Types include stable angina, unstable angina, and myocardial infarction.

<span class="mw-page-title-main">Cholesterol</span> Sterol biosynthesized by all animal cells

Cholesterol is the principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.

High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are typically composed of 80–100 proteins per particle. HDL particles enlarge while circulating in the blood, aggregating more fat molecules and transporting up to hundreds of fat molecules per particle.

<span class="mw-page-title-main">Low-density lipoprotein</span> One of the five major groups of lipoprotein

Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). LDL delivers fat molecules to cells. LDL is involved in atherosclerosis, a process in which it is oxidized within the walls of arteries.

<span class="mw-page-title-main">Atherosclerosis</span> Form of arteriosclerosis

Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. These lesions may lead to narrowing of the arterial walls due to buildup of atheromatous plaques. At onset there are usually no symptoms, but if they develop, symptoms generally begin around middle age. In severe cases, it can result in coronary artery disease, stroke, peripheral artery disease, or kidney disorders, depending on which body part(s) the affected arteries are located in the body.

<span class="mw-page-title-main">Ancel Keys</span> American physiologist (1904–2004)

Ancel Benjamin Keys was an American physiologist who studied the influence of diet on health. In particular, he hypothesized that replacing dietary saturated fat with polyunsaturated fat reduced cardiovascular heart disease. Modern dietary recommendations by health organizations, systematic reviews, and national health agencies corroborate this.

<span class="mw-page-title-main">Statin</span> Class of drugs used to lower cholesterol levels

Statins are a class of medications that reduce illness and mortality in people who are at high risk of cardiovascular disease. They are the most commonly prescribed cholesterol-lowering drugs.

<span class="mw-page-title-main">Cardiovascular disease</span> Class of diseases that involve the heart or blood vessels

Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases, heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, arrhythmia, congenital heart disease, valvular heart disease, carditis, aortic aneurysms, peripheral artery disease, thromboembolic disease, and venous thrombosis.

<span class="mw-page-title-main">Hypercholesterolemia</span> High levels of cholesterol in the blood

Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia, hyperlipoproteinemia, and dyslipidemia.

Dyslipidemia is a metabolic disorder characterized by abnormally high or low amounts of any or all lipids or lipoproteins in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular diseases (ASCVD), which include coronary artery disease, cerebrovascular disease, and peripheral artery disease. Although dyslipidemia is a risk factor for ASCVD, abnormal levels don't mean that lipid lowering agents need to be started. Other factors, such as comorbid conditions and lifestyle in addition to dyslipidemia, is considered in a cardiovascular risk assessment. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood. This is often due to diet and lifestyle. Prolonged elevation of insulin resistance can also lead to dyslipidemia. Likewise, increased levels of O-GlcNAc transferase (OGT) may cause dyslipidemia.

Hyperlipidemia is abnormally high levels of any or all lipids or lipoproteins in the blood. The term hyperlipidemia refers to the laboratory finding itself and is also used as an umbrella term covering any of various acquired or genetic disorders that result in that finding. Hyperlipidemia represents a subset of dyslipidemia and a superset of hypercholesterolemia. Hyperlipidemia is usually chronic and requires ongoing medication to control blood lipid levels.

<span class="mw-page-title-main">Phytosterol</span> Class of steroids derived from plants

Phytosterols are phytosteroids, similar to cholesterol, that serve as structural components of biological membranes of plants. They encompass plant sterols and stanols. More than 250 sterols and related compounds have been identified. Free phytosterols extracted from oils are insoluble in water, relatively insoluble in oil, and soluble in alcohols.

<span class="mw-page-title-main">Familial hypercholesterolemia</span> Genetic disorder characterized by high cholesterol levels

Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein cholesterol, in the blood and early cardiovascular diseases. The most common mutations diminish the number of functional LDL receptors in the liver or produce abnormal LDL receptors that never go to the cell surface to function properly. Since the underlying body biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH. Nevertheless, treatment is usually effective.

<span class="mw-page-title-main">Lipoprotein(a)</span> Low-density lipoprotein containing apolipoprotein(a)

Lipoprotein(a) is a low-density lipoprotein variant containing a protein called apolipoprotein(a). Genetic and epidemiological studies have identified lipoprotein(a) as a risk factor for atherosclerosis and related diseases, such as coronary heart disease and stroke.

<span class="mw-page-title-main">PCSK9</span> Mammalian protein found in humans

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (orthologs) are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme. The PCSK9 gene also contains one of 27 loci associated with increased risk of coronary artery disease.

The chronic endothelial injury hypothesis is one of two major mechanisms postulated to explain the underlying cause of atherosclerosis and coronary heart disease (CHD), the other being the lipid hypothesis. Although an ongoing debate involving connection between dietary lipids and CHD sometimes portrays the two hypotheses as being opposed, they are in no way mutually exclusive. Moreover, since the discovery of the role of LDL cholesterol (LDL-C) in the pathogenesis of atherosclerosis, the two hypotheses have become tightly linked by a number of molecular and cellular processes.

<span class="mw-page-title-main">Seven Countries Study</span>

The Seven Countries Study is an epidemiological longitudinal study directed by Ancel Keys at what is today the University of Minnesota Laboratory of Physiological Hygiene & Exercise Science (LPHES). Begun in 1956 with a yearly grant of US$200,000 from the U.S. Public Health Service, the study was first published in 1978 and then followed up on its subjects every five years thereafter.

<span class="mw-page-title-main">Evacetrapib</span> Chemical compound

Evacetrapib was a drug under development by Eli Lilly & Company that inhibits cholesterylester transfer protein. CETP collects triglycerides from very low-density lipoproteins (VLDL) or low-density lipoproteins (LDL) and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), and vice versa, but primarily increasing high-density lipoprotein and lowering low-density lipoprotein. It is thought that modifying lipoprotein levels modifies the risk of cardiovascular disease. The first CETP inhibitor, torcetrapib, was unsuccessful because it increased levels of the hormone aldosterone and increased blood pressure, which led to excess cardiac events when it was studied. Evacetrapib does not have the same effect. When studied in a small clinical trial in people with elevated LDL and low HDL, significant improvements were noted in their lipid profile.

Therapeutic Lifestyle Changes, also known as the TLC Diet, is a dietary pattern recommended by the National Cholesterol Education Program, part of the National Institutes of Health, to control hypercholesterolemia. This pattern focuses on saturated fats and cholesterol, dietary options to enhance LDL cholesterol lowering, weight control, and physical activity.

Remnant cholesterol, also known as remnant lipoprotein, is a very atherogenic lipoprotein composed primarily of very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL). Stated another way, remnant cholesterol is all plasma cholesterol that is not LDL cholesterol or HDL cholesterol, which are triglyceride-poor lipoproteins. However, remnant cholesterol is primarily chylomicron and VLDL, and each remnant particle contains about 40 times more cholesterol than LDL.

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 3 4 Ference BA, Ginsberg HN, Graham I, et al. (August 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.
  4. ↑ Linton MF, Yancey PG, Davies SS, et al. (3 January 2019). "The Role of Lipids and Lipoproteins in Atherosclerosis". Endotext. PMID   26844337.
  5. ↑ Duarte Lau F, Giugliano RP (July 2022). "Lipoprotein(a) and its Significance in Cardiovascular Disease: A Review". JAMA Cardiology. 7 (7): 760–769. doi:10.1001/jamacardio.2022.0987. PMID   35583875.
  6. 1 2 "World Heart Report 2023: Confronting the World's Number One Killer" (PDF). World Heart Federation. 2023. Retrieved 22 January 2024.
  7. ↑ Virchow, Rudolf (1856). "Gesammelte Abhandlungen zur wissenschaftlichen Medizin". Vierteljahrschrift für die praktische Heilkunde. Germany: Staatsdruckerei Frankfurt. Phlogose und Thrombose im Gefäßsystem.
  8. ↑ 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.
  9. ↑ Steinberg, Daniel (2013). "In celebration of the 100th anniversary of the lipid hypothesis of atherosclerosis". Journal of Lipid Research. 54 (11): 2946–2949. doi: 10.1194/jlr.R043414 . PMC   3793599 . PMID   23975896.
  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. 1 2 Keys, Ancel; Taylor, Henry Longstreet; Blackburn, Henry; et al. (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.
  14. ↑ 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
  15. ↑ Keys, Ancel (1980). Seven Countries: A Multivariate Analysis of Death and Coronary Heart Disease . Harvard University Press. ISBN   978-0-674-80237-7.
  16. ↑ Yerushalmy J, Hilleboe HE (1957). "Fat in the diet and mortality from heart disease. A methodologic note". NY State J Med. 57: 2343–54.
  17. ↑ "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.
  18. ↑ "TIME Magazine Cover: Ancel Keys". TIME.com. 13 January 1961. Retrieved 23 July 2017.
  19. ↑ 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.
  20. ↑ Keys, Ancel (1959). Eat Well and Stay Well. United States: Doubleday. ISBN   978-0-385-06575-7.
  21. ↑ "Ancel Keys Obituary". The American Physiological Society. Archived from the original on 27 September 2007. Retrieved 15 April 2007.
  22. ↑ 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.
  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. S2CID   7075128.
  31. ↑ "The Lipid Hypothesis". lipid.org. Retrieved 22 January 2024.
  32. ↑ Ference BA, Graham I, Tokgozoglu L, Catapano AL (2018). "Impact of Lipids on Cardiovascular Health: JACC Health Promotion Series". Journal of the American College of Cardiology. 72 (10): 1141–1156. doi:10.1016/j.jacc.2018.06.046. PMID   30165986. S2CID   52136486.
  33. ↑ Pearson GJ, Thanassoulis G, Anderson TJ, et al. (August 2021). "2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults". The Canadian Journal of Cardiology. 37 (8): 1129–1150. doi:10.1016/j.cjca.2021.03.016. PMID   33781847.
  34. ↑ Kuijpers PM (13 January 2021). "History in medicine: the story of cholesterol, lipids and cardiology". e-Journal of Cardiology Practice. 18 (9).
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