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Most researchers to-day consider that a high intake of saturated fat and elevated LDL cholesterol are the most important causes of atherosclerosis and coronary heart disease. The lipid hypothesis has dominated cardiovascular research and prevention for almost half a century although the number of contradictory studies may exceed those that are supportive. The harmful influence of a campaign that ignores much of the science extends to medical research, health care, food production and human life. There is an urgent need to draw attention to the most striking contradictions, many of which may be unknown to most doctors and researchers.
The fallacies of the lipid hypothesis
Most researchers to day consider that a high intake of saturated fat and elevated LDL cholesterol are the most important
causes of atherosclerosis and coronary heart disease. The lipid hypothesis has dominated cardiovascular research and
prevention for almost half a century although the number of contradictory studies may exceed those that are supportive.
The harmful influence of a campaign that ignores much of the science extends to medical research, health care, food
production and human life. There is an urgent need to draw attention to the most striking contradictions, many of which
may be unknown to most doctors and researchers.
Key words: Cholesterol, saturated fat, cardiovascular disease
The lipid hypothesis consists of two main postulates.
The first says that a high intake of saturated fat raises
blood cholesterol an d the second that high choles-
terol leads to atherosclerosis and cardiovascular
disease. The philosopher Karl Popper is usually
cited as codifying the principle of falsifiability that
scientific theories must meet. The lipid hypothesis
conforms to this requirement: if saturated fat pro-
motes cardiovascular disease by raising choles terol, a
high intake should be followed by high total and/or
low-density-lipoprotein (LDL) cholesterol and
should be associated with an increased risk of
achieving cardiovascular disease; a decreased intak e
should reduce that risk. If high total or LDL
cholesterol causes atherosclerosis, people with high
cholesterol should be more atherosclerotic and run a
greater risk of achieving cardiovascular disease than
people with low cholesterol, and a lowering of total
and/or LDL cholesterol should lead to regress, or at
least to a slower progress of atherosclerosis and to a
lower risk of cardiovascular disease. If these out-
comes are not found, that is, if saturated fat does not
reliably increase cholesterol, if cholesterol does not
reliably predict atherosclerosis and cardiovascular
disease, the theory must be accepted as false. In the
following I shall demonstrate that the postulates have
been falsified effectively in many studies.
Saturated fat
According to all official guidelines a diet rich in
carbohydrates and poor in fat, in particular saturated
fat, is said to be the best non-pharmaceutical way to
prevent cardiovascular disease. The main argument
against saturated fat is that a high intake raises blood
cholesterol. A strong contradiction of this statement
is that the lowest cholesterol concentrations ever
seen have been measured in African tribes whose
diet consists almost entirely of animal food (1). Even
if this is considered an exception ! in such a complex
system, the standards of falsifiability are not absolute
! the cholesterol-raising effect cannot be considered
highly predictable, because in at least ten recent
controlled low-carbohydrate trials, where intakes of
saturated fat were 3!7 times higher than the recom-
mended upper limit, total or LDL cholesterol
remained unchanged. As the concentration of small
dense LDL particles is a stronger risk factor for
cardiovascular disease than LDL cholesterol itself it
is also a contradiction to the theory that LDL size is
inversely associated with intake of saturated fat (2).
Even if a high intake of saturated fat raised
cholesterol to any extent in more balanced diets,
this is surrogate outcome. The crucial question is
whether a high intake leads to cardi ovascular disease,
but few studies suppor t that notion. At least
Correspondence: Uffe Ravnskov, Magle Stora Kyrkogata 9, S 22350 Lund, Sweden. Tel and Fax: "46 46145022. E-mail:
Scandinavian Cardiovascular Journal. 2008; 42: 236!239
(Received 8 February 2008; accepted 12 Febr uary 2008)
ISSN 1401-7431 print/ISSN 1651-2006 online # 2008 Informa UK Ltd.
DOI: 10.1080/14017430801983082
30 cohort and case-control studies including more
than 300 000 individuals have found that coronary
patients have not eaten more saturated fat before
their first heart attack than others (1). More at odds
is that in at least seven cohort studies stroke patients
had eaten significantly less. There is no support from
autopsy studies either: low-consumers are just as
atherosclerotic as high-c onsumers (1), and a meta-
analysis of the controlled, randomised dietary clin-
ical trials found no effect of reducing saturated fat,
either on coronary morbidity, coronary mortality, or
total mortality (1).
High cholesterol
Contrary to the widely held belief among doctors
and researchers, there is little evidence that high
cholesterol leads to cardiovascular diseas e. Autopsy
studies of individuals who have died from non-
medical causes have confirmed Lande´ and Sperry?s
observation from 1936 of an absence of an associa-
tion between total or LDL cholesterol and degree of
atherosclerosis, measured before death or immedi-
ately after (Figure 1) (2). A few autopsy studie s of
patients with cardiovascular disease have found a
weak association, probably because such studies
always include proportionally more patients with
familial hypercholesterolaemia. As the latter on
average always are more atherosclerotic than others,
and as their cholesterol is higher, their inclusion
automatically creates an association between choles-
terol and atherosclerosis, although, as explained
below, their higher degree of atherosclerosis may
not be due to their high cholesterol (Figure 2) (3).
Some studies of young and middle-aged men have
found high cholesterol to be a risk factor for
coronary disease, whereas others have not (4). On
the other hand, high cholesterol has not been found
to be a risk factor in patients with diabetes (4),
patients with established heart disease (3), patients
with terminal renal failure, (5) or in women (3), and,
most surprising, rarely in old people (6), although at
least in Sweden more than 90% of all coronary
deaths occur in people above age 65. Also contra-
dictory is that neither the concentration of LDL nor
total cholesterol predict the degree of prog ress of
angiographic changes (7), and neither are associated
with peripheral atherosclerosis or intermittent clau-
dication (8). In cohorts of people with familial
hypercholesterolaemia, LDL or total cholesterol do
not predict future coronary heart disease or per iph-
eral atheroscl erosis; those with moderately elevated
cholesterol run the same risk as those whose
cholesterol is 2!3 times higher than the mean value
in normal people (9!12). Indeed, in one study those
with the highest cholesterol had the lowest risk of
heart dis ease (12). Even Brown and Goldstein were
aware of the lack of an association between choles-
terol and cardiovascular disease among these people.
Thus, in a 1983 paper they wrote: ‘Among FH
patients (both heterozygous and homozygous), there
is considerable variation in the rate of progression of
atherosclerosis, despite uniformly elevated LDL
levels.’(13). The explanation may be that other
hereditary abnormalities are seen in some of these
people, for ins tance a predisposition to abnormalities
of the coagulation system, which is a strong risk
factor for coronary heart disease in familial hyperch-
olesterolaemia (14).
Cholesterol lowering does not prevent
cardiovascular disease
Meta-analyses of the cholesterol lowering trials
before the introduction of the statins found no effect
0 50 100 150 200 250 300 350 400
Cholesterol; mg/dl
Lipid content in aorta.
Figure 1. Association between degree of atherosclerosis and total
cholesterol concentration in the blood in 40 men and women
between 50 69 years, who had died violently without preceding
disease. The figure is constructed using data from Lande´ and
Sperry (see ref. 7).
150 200 250 300 350 400
Cholesterol; mg/dl
% surface involved
Figure 2. Association between degree of atherosclerosis and total
cholesterol at autopsy. It is obvious that the weak association
disappears after exclusion of individuals with cholesterol above
350 mg/dl. (9 mmol/l). Redrawn from Solberg et al. (see ref. 7).
The lipid hypothesis 237
of cholesterol lowering on heart mortality; indeed,
total mortality increased (15). Statin treatment is
able to lower heart mortality, but the effect is trivial,
it is only presen t in high-risk, young and middle-age
male patients, and the small effect achieved is
probably due to the statins? pleiotropic effects, not
to cholesterol lowering, because there is no associa-
tion between initial cholesterol, or degree of choles-
terol lowering, and the clinical or angiographic
outcome (3,6).
Unfortunately, the statins have many side effects,
such as muscular problems, liver damage, renal
failure, depression, amnesia and nerve damage, as
well as impotence, abortion and severe birth def ects
(16!19). Ac cording to the reports from the statin
trials, all of which have been sponsored by the drug
companies, side effects are mild and rare, but
underreporting is prevalent. Muscular symptoms
for instance are said to occur in less than one
percent, but researchers independent on the drug
companies have found the frequency to be 64% (20)
and 75% (21). This side effect may not only be
painful, it also hampers exercising, the most im-
portant, the cheapest and the least harmful measure
in the prevention of heart disease.
High cholesterol may be beneficial
By 1992, a meta-analysis of 19 cohort studies
including more than 600 000 men and women
from many countries had found that cholesterol
was inversely associated with mortality from respira-
tory and digestive diseases (22), most of which were
of an infectious origin. The observation was in line
with a large number of epidemiological, laboratory
and experimental studies showing that high choles-
terol protects against infections (6). The main effect
seems to be exerted by the LDL molecule. For
instance, mice with FH challenged with bacterial
endotoxin by injection with Gram-negative bacteria,
had an 8-fold increased LD50, and a significantly
delayed and overall lower mortality than control
mice. Also, pharmacologically induced hypocholes-
terolaemia led to a markedly increased endotoxin
mortality that was returned to normal after injection
of exoge nous lipoproteins; and the haemolytic effects
of Staphylococcus aureus a-toxin was prevented by
adding purified LDL to the test tube (6). In
agreement with this idea, individua ls with famili ar
hypercholesterolaemia had a longer life expectancy
than others before year 1900, where the main cause
of mortality was infectious diseases (23). A recent,
large follow-up study found that their average life-
span was normal because the increased coronary
mortality was balanced by a decreased mortality
from other diseases (24). Older people with high
cholesterol live longer than older people with low
cholesterol, and this author has tabulated the many
clinical studies that have confirmed the benefits of
high choles terol in various types of infectious dis-
eases (6).
The cholesterol hypothesis has failed to stand up to
the standard of falsifiability. In a med ical theory, it
takes more than one counter-example, but this
review has pointed to the numerous studies that
contradict basic predictions. Although I have fol-
lowed the literature in this field meticulou sly for
almost 18 years I may have overlooked supportive
studies. However, a few supportive studies cannot
outweigh the large number of contradictory ones.
But the cholesterol campaign continues, inappropri-
ate studies are funded and controversial studies are
either ignored or cited as if they were supportive
(15,26). There is, however, increasing awareness
that the diet-heart hypothesis is sustained by a
number of soci al, political and financial factors,
most of which have little to do with science or any
established success in public health.
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14. Jansen AC, van Aalst Cohen ES, Tanck MW, Cheng S,
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we lower cholesterol as much as possible? BMJ. 2006;332:
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H, Lumb PJ, et al. Erectile dysfunction and statin treatment
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The lipid hypothesis 239
... Ancel Keys (Keys 1946) The pursuit of power and profit via the demonization of dietary factors such as alcohol and sugar dates to at least the seventeenth century (Levenstein 2012;Levinovitz 2015;Archer 2018a). Thus, as the public's fear of fat and cholesterol waned and the lipid-heart disease hypothesis began to lose empirical support (Ravnskov 2008;Ravnskov et al. 2014;Teicholz 2014Teicholz , 2015de Souza et al. 2015;Harcombe et al. 2015;Ramsden et al. 2016;Hamley 2017;Harcombe 2017;Malhotra, Redberg, and Meier 2017), it was only a matter of time before media attention, political grandstanding, and research funding were once again directed at dietary sugars (e.g., see Lustig, Schmidt, and Brindis 2012;Ax 2013;Boseley 2013;Chung et al. 2016;Tybor et al. 2018). The net result of this shift in attention and resources was an apparent 'consensus' that sugar consumption is harmful (e.g., see Lustig, Schmidt, and Brindis 2012;DGA 2015;DGAC 2015;WHO 2015;Vos et al. 2016;Fidler Mis et al. 2017;Muth et al. 2019). ...
Sugar, tobacco, and alcohol have been demonized since the seventeenth century. Yet unlike tobacco and alcohol, there is indisputable scientific evidence that dietary sugars were essential for human evolution and are essential for human health and development. Therefore, the purpose of this analytic review and commentary is to demonstrate that anti-sugar rhetoric is divorced from established scientific facts and has led to politically expedient but ill-informed policies reminiscent of those enacted about alcohol a century ago in the United States. Herein, we present a large body of interdisciplinary research to illuminate several misconceptions, falsehoods, and facts about dietary sugars. We argue that anti-sugar policies and recommendations are not merely unscientific but are regressive and unjust because they harm the most vulnerable members of our society while providing no personal or public health benefits.
... The last decades of demonization of dietary fats was kick-started by a study of Ancel Keys that led to formulation of dietary lipid hypothesis [57]. Despite an abundance of anecdotal evidence and scientific research on the therapeutic advantages of KD, there is still flourishing myths about it as being unsustainable and unsafe. ...
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The majority of modern research into health and longevity is carried out to create medical drugs targeted toward spe- cific factors and symptoms characteristic of the particular diseases and conditions. However, the last 50 years have shown a paradoxical development in the national health systems. According to the American Hospital Association data [1], the total national health expenditure in the United States increased approximately 7.5 times from 1970 to the pres- ent, and the expenditure on prescription drugs increased 10-fold [2]. Health expenditure as a percentage of GDP almost tripled, from 7% to 18% [3]. However, at the same time, the extent of lifestyle diseases has increased many-fold in a single lifetime. The obesity rate has doubled since the 1970s for adults and tripled for children [4]. The rate of diabetes has increased over 10 times [5]. The extent of cancer dou- bled, and according the prognosis by the WHO, cancer cases are expected to surge by 70% worldwide in the next 20 years in an imminent “human disaster.” This means that at least half of us will suffer cancer during our lifetimes [6]. Chronic lifestyle disease expenditures account for 86% of total national health expenditures [7]. The same trends exist worldwide as in the United States. Thus the paradox: the more money we spend on a problem—the bigger the problem becomes. To break this para- doxical development and to handle the increasing load on public health we need a paradigm change. Could hormesis be a part of the solution and this paradigm change? This chapter aims to introduce and discuss the use of nonpharmacolo- gical approaches, synergetic effects of their combined use, and the associated hormetic effects.
... The strong dependence of atherogenesis on blood coagulation has been known for many years [9]. Still, in many recent works the role of haemostasis imbalance in atherosclerosis development is omitted [10,11] despite several reports about the insufficiency of a theory that postulates the exceptional role of cholesterol in atherosclerotic plaque formation [12][13][14]. ...
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Obesity is an important factor in pathogenesis of disorders caused by chronic inflammation. Diet-induced obesity leads to dyslipidemia and insulin resistance (IR) that in turn provoke the development of type 2 diabetes and cardiovascular diseases. Thus, the aim of this work was to investigate the possible pro-atherogenic effects in the blood coagulation system and aortic wall of rats with obesity-induced IR. The experimental model was induced by a 6-month high-fat diet (HFD) in white rats. Blood samples were collected from 7 control and 14 obese IR rats. Prothrombin time (PT) and partial activated thromboplastin time (APTT) were performed by standard methods using Coagulometer Solar СТ 2410. Fibrinogen concentration in the blood plasma was determined by the modified spectrophotometric method. Levels of protein C (PC), prothrombin and factor X were measured using specific chromogenic substrates and activa­ting enzymes from snake venoms. Platelet aggregation was measured and their count determined using Aggregometer Solar AP2110. The aorta samples were stained by hematoxylin and eosin according to Ehrlich. Aortic wall thickness was measured using morphometric program Image J. Statistical analysis was performed using Mann-Whitney U Test. The haemostasis system was characterized by estimation of the levels of individual coagulation factors, anticoagulant system involvement and platelet reactivity. PT and APTT demonstrated that blood coagulation time strongly tended to decrease in obese IR rats in comparison to the control group. It was also detec­ted that 30% of studied obese IR rats had decreased factor X level, 40% had decreased level of prothrombin whereas fibrinogen concentration was slightly increased up to 3 mg/ml in 37% of obese IR rats. A prominent decrease of anticoagulant PC in blood plasma of obese rats was detected. Obese IR rats also had increased platelet count and higher rate of platelet aggregation in comparison to control animals. Histological analysis identified the disruption of aorta endothelium and tendency for the thickening of the aorta wall in the group with obesity-induced IR compared to the group of control rats. Changes of individual coagulation factors were assumed as the evidence of imbalance in the blood coagulation system. Increase of fibrinogen level, drop in PC concentration and pathological platelet reactivity were taken to corroborate the development of low-grade inflammation in obese IR rats. Instant generation of small amounts of thrombin in their blood plasma is expected. Since the aorta morphology assay detected the trend of its wall to thicken and the emergence of disruptions, we assumed there were initial stages of atherosclerosis and the danger of developing atherothrombosis. We detected an increase of blood coagulability and changes in aorta morphology in rats with obesity-induced IR which we assume indicate early development of atherosclerosis.
... Something explains this inter-individual variation, but it is not the diet". 62 Interestingly, this information is from an unpublished manuscript from the Framingham study group discovered by Mann in a basement in Washington DC. Another quotation is: "In Framingham, for example, we found that the people who ate the most cholesterol ate the most saturated fat, ate the most calories, weighed the least, and were the most physically active". ...
Our human ancestors thrived on a diet high in fat and protein of animal or fish origin for at least 2.5 million years. Foods with a high-energy content and nutritional density were required for the development of the large, energy-expensive human brain. A reduction in human height and deterioration in our health followed the introduction of agriculture 2 000-12 000 years ago. In 1977, the United States Department of Agriculture (USDA) introduced novel dietary guidelines based on an untested hypothesis of Keys that dietary fat, especially of animal origin, increases the blood cholesterol concentration, “clogging” the coronary arteries and causing heart attacks, i.e. the diet-heart hypothesis.
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Dyslipidemia is a well-established risk factor for coronary artery disease. However, the effect on cerebral artery disease, and more specifically the rupture risk of intracranial aneurysms, is unclear and has not yet been reviewed. We therefore performed a systematic review to investigate associations between different types of dyslipidemia and incidence of aneurysmal subarachnoid hemorrhage (aSAH). We used the MEDLINE, Embase, and Web of Science databases to identify clinical trials that compared the rupture risk among SAH patients with or without dyslipidemia. The risk of bias in each included study was evaluated using the Critical Appraisal Skills Program (CASP). Of 149 unique citations from the initial literature search, five clinical trials with a case-control design met our eligibility criteria. These studies compared aSAH patients to patients with unruptured aneurysms and found an overall inverse relationship between hypercholesterolemia and rupture risk of intracranial aneurysms. The quality assessment classified all included studies as high risk of bias. The evidence indicates that hypercholesterolemia is associated with a reduced rupture risk of intracranial aneurysms. However, it is not clear whether this relation is due to the dyslipidemic condition itself or the use of antihyperlipidemic medication.
Atherosclerosis and its late sequels are still the number one cause of death in Western societies. Platelets are a driving force not only during the genesis of atherosclerosis, but especially in its late stages, as evidenced by complications such as arterial thrombosis, myocardial infarction, and ischaemic stroke. Platelets are small, anucleate blood elements of critical importance in cardiovascular disease, a major cause of morbidity and mortality. Numerous risk scores exist to identify healthy individuals at increased risk of developing atherosclerosis and cardiovascular disease. However, markers of cardiovascular risk not routinely assessed (i.e. platelet activity, mean platelet volume and P-selectin) may also contribute to be useful in calculating cardiovascular risk. The present review and meta-analysis summarizes the evidence for measuring platelet function indices to identify patients at risk of developing cardiovascular events.
Animal fats are described in terms of their origin and method of processing, with specific reference to European Union legislation as the authors are based in Europe. Safety is a fundamental concern for the maximum utilization of animal fats in human food, animal feed and technical applications; these aspects are considered extensively. The applications and use of animal fats are considered in light of the continuing debate on the health effects of animal fats in the human diet. Finally, the sustainability credentials of animal fats are described in relation to other fats that may be used in similar applications.
The evidence for the lipid hypothesis is weak. After 20 years of follow-up, the Nurses Health Study, a prospective cohort study, was no longer able to demonstrate an association between intakes of saturated fat and risk of developing coronary heart disease. Randomised controlled trials with statins have shown that lowering LDL-cholesterol levels by 23% can reduce the risk of developing cardiovascular disease but reducing saturated fat can only reduce cholesterol levels by 10%. This issue can only be resolved by carrying out randomised controlled dietary trials with CVD endpoints. Although there are scientific difficulties standing in the way of such trials, it is the opinion of this author that these can be overcome. Whether there is the political will to fund them is another matter although some of the money currently spent on prospective cohort studies would be far better spent on randomised controlled trials.
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Objective: To estimate all cause mortality from untreated familial hypercholesterolaemia free from selection for coronary artery disease.Design: Family tree mortality study.Setting: Large pedigree in Netherlands traced back to a single pair of ancestors in the 19th century.Subjects: All members of pedigree aged over 20 years with 0.5 probability of carrying a mutation for familial hypercholesterolaemia.Main outcome measure: All cause mortality.Results: A total of 70 deaths took place among 250 people analysed for 6950 person years. Mortality was not increased in carriers of the mutation during the 19th and early 20th century; it rose after 1915, reached its maximum between 1935 and 1964 (standardised mortality ratio 1.78, 95% confidence interval 1.13 to 2.76; P=0.003), and fell thereafter. Mortality differed significantly between two branches of the pedigree (relative risk 3.26, 95% confidence interval 1.74 to 6.11; P=0.001).Conclusions: Risk of death varies significantly among patients with familial hypercholesterolaemia. This large variability over time and between branches of the pedigree points to a strong interaction with environmental factors. Future research is required to identify patients with familial hypercholesterolaemia who are at extreme risk and need early and vigorous preventive measures.What is already known on this topicWhat is already known on this topic Familial hypercholesterolaemia is associated with excess mortality in families of patients who present with cardiovascular diseasePopulation data are lacking
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Objective To estimate all cause mortality from untreated familial hypercholesterolaemia free from selection for coronary artery disease. Design Family tree mortality study. Setting Large pedigree in Netherlands traced back to a single pair of ancestors in the 19th century. Subjects All members of pedigree aged over 20 years with 0.5 probability of carrying a mutation for familial hypercholesterolaemia. Main outcome measure All cause mortality. Results A total of 70 deaths took place among 250 people analysed for 6950 person years. Mortality was not increased in carriers of the mutation during the 19th and early 20th century; it rose after 1915, reached its maximum between 1935 and 1964 (standardised mortality ratio 1.78, 95% confidence interval 1.13 to 2.76; P = 0.003), and fell thereafter. Mortality differed significantly between two branches of the pedigree (relative risk 3.26, 95% confidence interval 1.74 to 6.11; P = 0.001). Conclusions Risk of death varies significantly among patients with familial hypercholesterolaemia. This large variability over time and between branches of the pedigree points to a strong interaction with environmental factors. Future research is required to identify patients with familial hypercholesterolaemia who are at extreme risk and need early and vigorous preventive measures.
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To see if the claim that lowering cholesterol values prevents coronary heart disease is true or if it is based on citation of supportive trials only. Comparison of frequency of citation with outcome of all controlled cholesterol lowering trials using coronary heart disease or death, or both, as end point. 22 controlled cholesterol lowering trials. Trials considered by their directors as supportive of the contention were cited almost six times more often than others, according to Science Citation Index. Apart from trials discontinued because of alleged side effects of treatment, unsupportive trials were not cited after 1970, although their number almost equalled the number considered supportive. In three supportive reviews the outcome of the selected trials was more favourable than the outcome of the excluded and ignored trials. In the 22 controlled cholesterol lowering trials studied total and coronary heart disease mortality was not changed significantly either overall or in any subgroup. A statistically significant 0.32% reduction in non-fatal coronary heart disease seemed to be due to bias as event frequencies were unrelated to trial length and to mean net reduction in cholesterol value; individual changes in cholesterol values were unsystematically or not related to outcome; and after correction for a small but significant increase in non-medical deaths in the intervention groups total mortality remained unchanged (odds ratio 1.02). Lowering serum cholesterol concentrations does not reduce mortality and is unlikely to prevent coronary heart disease. Claims of the opposite are based on preferential citation of supportive trials.
Objective. To estimate the mortality caused by familial hypercholesterolaemia (FH) without selection based on cardiovascular disease. Design. Genealogical investigation with identification of carriers of the V408M-mutation and determination of the standardised mortality ratio (SMR). Method. The mortality in a large pedigree with FH going back to the 18th century was compared with the mortality in the Dutch population. In the pedigree, the mortality due to all causes was studied in all subjects older than 20 years with a 50% chance of having the abnormality. Results. Among 250 persons accounting for a total of 6950 person-years, there were 70 deaths. There was no excess mortality due to the abnormality in the 19th and early 20th centuries; after 1915, the mortality began to rise, reaching a maximum in 1935-1964 (SMR; 1.78; 95%-CI: 1.13-2.76; p = 0.003), after which it again decreased. Moreover, there was a significant difference in mortality between two large branches of the pedigree (relative risk: 3.26; 95%-CI: 1.74-6.11; p = 0.001). Conclusion. The mortality among the subjects with FH varied significantly. Such an extensive variation over the centuries and between the branches of a pedigree suggests a strong interaction with environmental factors. Additional research is required to be able to identify FH-patients with a sharply increased risk of mortality so that optimal preventive measures may be offered.
Background and Aim: The prevalence and significance of lipoprotein abnormalities in intermittent claudication (IC) were investigated. From an epidemiological screening of 15,253 middle-aged men in Linköping County, Sweden, 339 males were randomly selected within three strata: 115 subjects with IC, 115 healthy controls matched for sex, age and smoking habits, and 109 sex- and age-matched never-smokers. Methods and Results: All subjects underwent a treadmill exercise test to confirm or exclude hemodynamically significant peripheral atherosclerosis. The significance of the individual plasma lipoproteins was tested by multivariate logistic-regression analysis. Major risk factors for IC-smoke history, hypertension, diabetes-were included and adjustment made for factors that affect the lipoprotein concentrations. The most frequent lipoprotein abnormalities found in IC were abnormally high levels of low density lipoprotein (LDL) triglycerides (TG) and abnormally low concentrations of high density lipoprotein (HDL) cholesterol (Chol). Almost half of all claudicants had either one or both lipoprotein abnormalities. The lipid composition of LDL and HDL was changed with a significant increase of TG relative to Chol. The highest increase in risk of IC (by change of 1 standard deviation in lipoprotein concentration) was associated with elevation of LDL-Chol, 2.22 (1.44-3.43) [odds-ratio, 95% confidence interval] and lowering of HDL2-Chol 1.94 (1.19-3.19), while the lowest significant risk was associated with elevation of plasma TG 1.61 (1.01-3.09) and IDL-TG 1.55 (1.04-2.31). Multivariate logistic regression analysis in contrast to univariate disclosed that very low density lipoproteins (VLDL) were not significantly associated to IC. Neither were intermediate density lipoproteins (IDL) Chol or HDL'S major protein (HDL-apoAI), multivariately associated to IC. Apolipoprotein E phenotypes and ε-allele frequencies did not differ significantly between claudicants and healthy controls. Conclusions: The study shows that several lipoprotein abnormalities are present in claudicants. Multivariate analysis demonstrates that the risk of IC is mainly associated to the LDL and HDL particles, while VLDL, IDL-Chol, HDL-TG and HDL-apoAI lipoproteins are not associated to IC. The results of the study suggests that more attention should be paid to plasma lipoprotein concentrations in IC and that efforts should be made in lowering even slightly elevated LDL levels and increasing HDL-Chol.
A National Heart, Lung, and Blood Institute (NHLBI) Conference was held October 9-10, 1990, to review and discuss existing data on U-shaped relations found between mortality rates and blood total cholesterol levels (TC) in some but not other studies. Presentations were given from 19 cohort studies from the United States, Europe, Israel, and Japan. A representative of each study presented its findings and also submitted tables of proportional hazards regression coefficients for entry TC levels in regard to death, and these were incorporated into a formal statistical overview adjusted for age, diastolic blood pressure, cigarette smoking, body mass index, and alcohol intake, as available. The U-shape for total mortality in men and the flat relation in women resulted largely from a positive relation of TC with coronary heart disease death and an inverse relation with deaths caused by some cancers (e.g., lung but not colon), respiratory disease, digestive disease, trauma, and residual deaths. Risk for combined noncardiovascular, noncancer causes of death decreased steadily across the range of TC. The conference considered possible explanations for the statistical associations found between low TC levels or active TC lowering and certain causes of death. One is that TC is lowered by some disease conditions themselves, such as wasting in chronic pulmonary disease or reduced production and secretion of cholesterol-bearing lipoproteins with liver disease. In this sort of situation, the TC:mortality association found in observational studies may be due to preexisting disease. This was addressed by excluding early deaths from the analysis, which did not change the results. The conference considered as well the biological function of cholesterol, which, if seriously deranged, might hypothetically cause a wide variety of diseases and dysfunction. The conference also considered the biological functions that might provide plausible mechanisms for the associations found. Definitive interpretation of the associations observed was not possible, although most participants considered it likely that many of the statistical associations of low or lowered TC level are explainable by confounding in one form or another. The conference focused on the apparent existence and nature of these associations and on the need to understand their source rather than on any pertinence of the findings for public health policy. Further research is recommended to explain the observed associations of low TC levels (and TC lowering) with certain noncardiovascular diseases. This includes studies of the time course of TC change in disease, the relation of TC to morbidity, further studies of possible epidemiological confounding, monitoring of population trends in TC and mortality, further studies of the relations in women, auditing of noncardiovascular events in trials, studies of cell membrane, genetic and molecular links to cholesterol metabolism, TC level and disease, studies of disease manifestations in specific lipid disorders, and further study of the proposed causal mechanisms linking low TC and hemorrhagic stroke.
The aim of this prospective study was to explore the association of different prognostic factors including parameters of cholesterol metabolism with coronary morbidity and mortality in a study group of 96 patients who were heterozygous for familial hypercholesterolemia. During a 15-year follow-up period, 27% of the patients (44% of the men and 10% of the women, p less than 0.01) died from coronary disease, and an additional 4% died of noncoronary causes. Of the baseline characteristics, male gender, previous myocardial infarction, and smoking were the classical risk factors significantly associated with poor cardiac prognosis. In addition, a low bile acid synthesis predicted enhanced coronary mortality both in univariate and multivariate analysis, and in men bile acid synthesis was significantly correlated with cardiac mortality. Further analysis indicated that also in subjects without baseline myocardial infarction, low bile acid, cholesterol synthesis, or both predicted increased risk of coronary events. In multivariate analysis, male gender, previous myocardial infarction, and low bile acid synthesis at baseline explained 5%, 15%, and 5% (25%), respectively, of the variability of survival. Age, serum total cholesterol, and triglyceride values were unrelated to survival.
Criticism of the diet-heart idea is often met with the argument that consensus committees have settled the issue unanimously. To see how these committees have explained discordant results, quotations from papers with such findings were sought in three recent authoritative reviews. Only two of twelve groups of controversial papers were quoted correctly, and only in one of the reviews. About half of the papers were ignored. The rest were quoted irrelevantly; or insignificant findings in favour of the hypothesis were inflated; or unsupportive results were quoted as if they were supportive. Only one of six randomized cholesterol-lowering trials with a negative outcome were cited and only in one of the reviews. In contrast, each review cited two, four, and six non-randomized trials with a positive outcome, respectively. It appears as if fundamental parts of the diet-heart idea are based on biased quotation.
Although epidemiologic investigations are trying to clarify the role of plasma lipid concentrations (primarily cholesterol and its subfractions) as risk factors for both ischemic and hemorrhagic stroke, little information is available regarding the effect of sustained hypercholesterolemia on cerebral perfusion. Regional cerebral blood flow (CBF) was measured by the 133Xe inhalation method in 25 heterozygous patients (four untreated) affected with familial hypercholesterolemia. In 15 patients regional CBF was repeated 20 minutes after intravenous administration of acetazolamide (10 mg/kg body wt) to evaluate cerebrovascular reactivity. Correlations among cerebral perfusion data, present or pretreatment plasma lipid concentrations, and certain other clinical features were assessed by ANOVA. Both basal regional CBF and cerebrovascular reactivity were normal in the vast majority of patients compared with age- and sex-matched normal control subjects. CBF was significantly dependent on pretreatment low-density lipoprotein cholesterol (LDL-C) concentration (P = .005) and the presence of symptomatic ischemic heart disease (P = .015). CBF was only slightly dependent on age (P = .05) and was not dependent on either lipoprotein(a) or present LDL-C concentration. CBF did not differ between treated and untreated patients, and the perfusional increase induced by acetazolamide was not related to any other variable. Cerebral perfusion and cerebrovascular reactivity were maintained within the normal range despite long-lasting, severe hypercholesterolemia, even if a somewhat lower CBF was found in those patients with the highest LDL-C pretreatment levels. These results are in accord with the epidemiologic data that implicate hypercholesterolemia as a minor risk factor, if a risk factor at all, for intracranial atherosclerosis and ischemic stroke.