Lipid hypothesis

The lipid hypothesis (also known as the cholesterol hypothesis) is a medical theory postulating a link between blood cholesterol levels and occurrence of heart 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'. Or, more concisely, 'decreasing blood cholesterol... significantly reduces coronary heart disease'. The lipid hypothesis (also known as the cholesterol hypothesis) is a medical theory postulating a link between blood cholesterol levels and occurrence of heart 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'. Or, more concisely, 'decreasing blood cholesterol... significantly reduces coronary heart disease'. An accumulation of evidence has led to the acceptance of the lipid hypothesis by most of the medical community. The German pathologist Rudolf Virchow described lipid (medical term for fat-soluble molecules) accumulation in arterial walls. In 1913, a study by Nikolai Anitschkow showed that rabbits fed on cholesterol developed lesions in their arteries similar to atherosclerosis, suggesting a role for cholesterol in atherogenesis. 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.' 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. 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 men were followed through 1981 and the first major report appeared in 1963. 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. Meanwhile, in the mid-1950s, with improved methods and design, Keys recruited collaborating researchers in seven countries to mount the first cross-cultural comparison of heart attack risk in populations of men engaged in traditional occupations in cultures contrasting in diet, especially in the proportion of fat calories of different composition, the Seven Countries Study still under observation today. Even before the study had begun, there had been criticism of its methods. 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. 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 USA, with 75% and highest in one of the Japanese cohorts, with 100%. Keys' book Eat Well and Stay Well popularized the supplementary idea that reducing the amount of saturated fat in the diet would reduce cholesterol levels and the risks of serious diseases due to atheroma. 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; By the end of the 1980s, there were widespread academic statements that the lipid hypothesis was proven beyond reasonable doubt, or, as one article stated, 'universally recognized as a law.' 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.' 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, falsely claiming instead that heart disease is not caused by cholesterol, and demonizing the cholesterol-lowering drugs statins. A 1992 paper by Uffe Ravnskov looking a frequency of cholesterol-lowering trial citations, said that trials that were supportive of the lipid hypothesis were cited almost six times as often as those that were not, and although there was a similar number of trials unsupportive of the hypothesis, none of them were cited after 1970; some of the supportive reviews also exclude and ignore certain trials which were less favorable to the hypothesis.