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Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality studyCommentary: Role of other genes and environment should not be overlooked in monogenic disease

BMJ 2001; 322 doi: https://doi.org/10.1136/bmj.322.7293.1019 (Published 28 April 2001) Cite this as: BMJ 2001;322:1019

Evidence that a high cholesterol does not cause atherosclerosis

The findings by Sijbrands et al1 that unselected individuals from a
pedigree with familial hypercholesterolemia had a normal life span and a
standard mortality close to one is further evidence that the LDL-
hypothesis, the foundation of the cholesterol campaign, is wrong. Patients
with familial hypercholesterolaemia usually have a total serum cholesterol
around ten or even higher. Extrapolating from the data of the MR.FIT
screenees2 a cholesterol value of that level is associated with a risk of
coronary death that is at least ten times higher than in individuals with
a low to normal cholesterol. The low standard mortality seen in the Dutch
pedigree of individuals with familial hypercholesterolaemia is therefore
best explained by a protective effect of a high cholesterol in this
condition, for instance against infections, as suggested by the authors.

This explanation is in accord with the idea that atherosclerosis has an
infectious origin, but also with the fact that in many studies a high
cholesterol in old people was associated with a low risk of coronary and
total mortality.

Why then is a high cholesterol a risk factor for coronary heart disease in
individuals without familial hypercholesterolaemia? And why does coronary
heart disease occur at a very young age in some individuals affected with
this disease? In the first group the high cholesterol may be secondary to
other, more important factors, such as lack of exercise, mental stress,
smoking, and overweight, all of which are known to be associated with an
elevated cholesterol.3 In the second, the deposition of cholesterol in the
artery walls may, by genetic or environmental reasons,1 be more pronounced
in some pedigrees.

That a high cholesterol is a secondary phenomenon and not the very cause
of atherosclerosis is in accord with other observations. For instance,
there is no correlation between the serum cholesterol concentration and
the degree of atherosclerosis seen at autopsy;3 there is no association
between spontaneous or induced variations in the serum cholesterol
concentration and atherosclerosis growth at angiography;3 a lowering of
cholesterol by diet or non-statin drugs does not affect coronary or total
mortality;3 and the protective effect of the statins is independent on the
degree of cholesterol lowering, indicating that the statins exert their
effect by other ways than by a lowering of the cholesterol concentration.3
It is time for a paradigm shift in atherosclerosis research.

Uffe Ravnskov

1. Sijbrands EJG, Westendorp J, Defesche JC, de Meier PHEM, Smelt
AHM, Kastelein JP. Mortality over two centuries in large pedigree with
familial hyper cholesterolaemia: family tree mortality study. BMJ
2001;322:1019-1023 ( 28 April ).

2. Stamler J, Wentworth D, Neaton JD. Is relationship between serum
cholesterol and risk of premature death from coronary heart disease
continuous and graded? JAMA 1986;256:2823-8.

3. Ravnskov U. The Cholesterol Myths. New Trends Publishing, Washington
D.C. 2000.

Competing interests: No competing interests

30 April 2001
Uffe Ravnskov
Magle Stora Kyrkogata 9, S-22350, Lund
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