Why do journals publish two articles that draw opposite
conclusions concerning the same issue?
Simply put the industry article is published because no major journal
can significantly offend their major sources for articles and income. All
major journal in order to maintain
credibility with readers must publish quality articles of critics that meet
scientific standards, thus the critics still have a voice. However there are
limits for criticism,. Some articles are thus turned down to please
pharma, and in a couple of cases the corporate politics behind the decision not
to publish are exposed—see Bad Pharma
for one example.. The editors and reviewers are aware of the
low standards of industry written articles—95% of what they publish. The
standard held for the critics is thus
higher. This article exposing the
cholesterol myth meets the highest standards.
I have checked a number of Prof. Ravnskov’s citations. That Oxford (University)
Journ al made the full article available for free is an indication of its
merit. Other article require a
subscription or a payment of $38.
http://qjmed.oxfordjournals.org/content/95/6/397.full
Is
atherosclerosis caused by high cholesterol?
Prof. Uffe Ravhskov
DOI: http://dx.doi.org/10.1093/qjmed/95.6.397 397-403 First
published online: 1 June 2002
Introduction According to the low‐density‐lipoprotein
(LDL) receptor hypothesis, development of atherosclerosis is caused by a high
concentration of LDL‐cholesterol in the blood, and lowering LDL‐cholesterol
reverses, or at least retards, atherosclerosis, thus preventing cardiovascular
disease.1
As a scientific hypothesis, it is open to falsification: if the concentration
of LDL‐cholesterol or total cholesterol and the degree of
atherosclerosis do not correlate, or if there is no exposure‐response,
e.g. if there is no association between the cholesterol changes (ΔLDL‐cholesterol
or Δtotal cholesterol) and atherosclerosis progression.
The successful statin trials, with their substantial reduction
of LDL‐cholesterol
seemed to confirm the LDL receptor hypothesis, but their outcome was
independent of the initial cholesterol concentration and the degree of its
lowering. For instance, the p values for the relationships between the
outcome, and the percentage or the absolute change in LDL cholesterol, as
calculated in one of the trial reports,2
were 0.76 and 0.97, respectively. The lack of exposure‐response,
together with the benefit of the treatment in disorders and age groups where
LDL‐cholesterol
concentration has little if any predictive value, suggests that statins must
have more important effects on cardiovascular disease than a lowering of cholesterol.3
Indeed, there is evidence that the statins have anti‐thrombotic
and anti‐inflammatory effects, and also a beneficial influence
on endothelial dysfunction, LDL oxidation, re‐vascularization and smooth muscle
cell proliferation.
Even if these effects were operating in the trials, the substantial
lowering
of LDL‐cholesterol should at least have contributed to the
improvement if the LDL receptor hypothesis were correct. The lack of exposure‐response
also questions whether atherosclerosis is truly caused by high LDL‐cholesterol.
However, the outcome in the clinical trials was cardiovascular
disease, not
atherosclerotic progression. To answer the question, we need to compare the
cholesterol concentration and the degree of atherosclerosis, and in particular,
to study the influence of ΔLDL‐cholesterol on atherosclerotic
progression, rather than clinical outcome.
According to the low‐density‐lipoprotein
(LDL) receptor hypothesis, development of atherosclerosis is caused by a high
concentration of LDL‐cholesterol in the blood, and lowering LDL‐cholesterol
reverses, or at least retards, atherosclerosis, thus preventing cardiovascular
disease.1
As a scientific hypothesis, it is open to falsification: if the concentration
of LDL‐cholesterol or total cholesterol and the degree of
atherosclerosis do not correlate, or if there is no exposure‐response,
e.g. if there is no association between the cholesterol changes (ΔLDL‐cholesterol
or Δtotal cholesterol) and atherosclerosis progression.
The successful statin trials, with their substantial reduction
of LDL‐cholesterol
seemed to confirm the LDL receptor hypothesis, but their outcome was
independent of the initial cholesterol concentration and the degree of its
lowering. For instance, the p values for the relationships between the
outcome, and the percentage or the absolute change in LDL cholesterol, as
calculated in one of the trial reports,2
were 0.76 and 0.97, respectively. The lack of exposure‐response,
together with the benefit of the treatment in disorders and age groups where
LDL‐cholesterol
concentration has little if any predictive value, suggests that statins must
have more important effects on cardiovascular disease than a lowering of cholesterol.3
Indeed, there is evidence that the statins have anti‐thrombotic
and anti‐inflammatory effects, and also a beneficial influence
on endothelial dysfunction, LDL oxidation, re‐vascularization and smooth muscle
cell proliferation.
Even if these effects were operating in the trials, the substantial
lowering
of LDL‐cholesterol should at least have contributed to the
improvement if the LDL receptor hypothesis were correct. The lack of exposure‐response
also questions whether atherosclerosis is truly caused by high LDL‐cholesterol.
However, the outcome in the clinical trials was cardiovascular
disease, not
atherosclerotic progression. To answer the question, we need to compare the
cholesterol concentration and the degree of atherosclerosis, and in particular,
to study the influence of ΔLDL‐cholesterol on atherosclerotic
progression, rather than clinical outcome.
Cholesterol does
not predict degree of atherosclerosis at autopsy: In
1936, Landé and Sperry noted that the degree of aortic atherosclerosis at
autopsy of healthy individuals who had died violently, was independent on their
blood cholesterol concentration analysed immediately after death.4
Their finding was confirmed by Mathur et
al.5
and similar results were obtained by others.6–,8
The objection that an analysis of cholesterol after death may not reflect its
concentration during life was met by Mathur et
al.5
who found that the cholesterol concentration was almost constant up to 16 h
after death. Paterson et
al.6
bypassed the problem by comparing the degree of atherosclerosis at death with
the individuals’ cholesterol measured previously on several occasions. In all
these studies, plots of blood cholesterol concentrations vs. the lipid content
of the aorta or the coronary arteries were widely scattered.
More recent autopsy studies
have found weak or inconsistent correlations between LDL‐cholesterol or total
cholesterol and
various measures of atherosclerosis.9
For instance, the most severe degree of atherosclerosis was found mainly in
individuals with extremely high cholesterol, whereas small differences were
seen in the rest.10
A correlation was found in White men, but not in Black men,11
in men but not in women,12
in individuals below, but not above age 80 years,13
and in the coronary arteries, but not in the thoracic or abdominal aorta.14
The weak and unpredictable
correlations probably reflect bias, because most of the studies were performed
on selected individuals. In such large projects, the main object of which was
to study risk factors for cardiovascular disease, individuals with such
diseases, or with high cholesterol, were preferred for post‐mortem examination,10–,15
which means that the proportion of individuals with familial hypercholesterolaemia
must have been much larger than in the general population. As such patients
have very high cholesterol and are more prone to vascular changes, their
inclusion automatically creates a correlation between degree of atherosclerosis
and LDL or total cholesterol. Accordingly, it is obvious from a figure in a
preliminary report that the correlation disappears if individuals with total
cholesterol >350 mg/ml (9 mmol/l) are excluded.16
It is questionable if the vascular changes seen in familial
hypercholesterolaemia are synonymous with atherosclerosis.17,,18
Therefore, to prove that the concentration of LDL‐cholesterol has importance
in the
general population, it is necessary to exclude individuals with familial
hypercholesterolaemia.
Cholesterol
does not correlate with degree of coronary atherosclerosis on angiography: A correlation
between the pathological findings seen
on coronary angiography and cholesterol has been found in many studies.19
However, the correlation coefficients in these studies were never >0.36 and
often much smaller; in some studies no correlation was found.20–,23
When present, the correlation found may have been due to bias by the process
mentioned above, because coronary angiography is mainly performed on patients
with symptomatic coronary disease, and more often on middle‐aged and younger patients. The correlation disappeared in one study after
exclusion of patients treated with lipid‐lowering drugs.24
Cholesterol does
not correlate with degree of coronary calcification: In contrast to conventional
angiography, electron beam angiography detects coronary plaques independent of
their location in the vessel wall, but only calcified plaques. Degree of
coronary calcification seems a good surrogate for degree of coronary
atherosclerosis, because it correlates strongly with total plaque volume and
obstructive coronary disease, and is a powerful predictor of clinical outcome.
Nonetheless, degree of coronary calcification did not correlate with any lipid
fraction in the blood.25
Cholesterol
does not correlate with degree of peripheral atherosclerosis:
Many studies have found an
association between LDL‐ or total cholesterol and peripheral
atherosclerosis, depicted by
angiography or ultrasonography, but only in dichotomous analyses, and again,
differences have been found mainly between individuals with very high
cholesterol concentrations and the rest. In ultrasonographic studies, where
degree of carotic atherosclerosis was graded as a continuous variable, no
correlation was found with individual LDL‐cholesterol concentrations.26,,27
In similar studies using aortic28
and femoral29
angiography, no correlation was found either. Mean femoral intima‐media thickness was evaluated by ultrasonography in patients with
familial hypercholesterolaemia and in control individuals with normal
cholesterol. Using all observations, a correlation was found (r=0.41),
but from a
visual judgement of the scatterplot, within each group no clear correlation was
present.30
No
exposure-response: The
lack of an association in these
studies may be explained by an influence of other important risk factors. A
more reliable parameter is exposure‐response.
If the amount of circulating cholesterol has any importance, sequential changes
of its concentrations should be followed by parallel changes of atherosclerosis
growth.
In a few observational
studies with coronary angiography, the correlation of these two parameters,
graded as continuous variables, was analysed. In three studies, no correlation
was found;32–,34
in two others, progression of atherosclerosis was associated with a decrease in
cholesterol, not an increase.35,,36
Experimentally, many trials
have analysed the effect of cholesterol lowering on the angiographic changes.
Most of them have looked at the association with on‐trial LDL‐cholesterol
or final LDL‐cholesterol only, but in sixteen
trials,36–,51
exposure‐response
was also analysed (Table 1). Two of them found exposure‐response. In one of them ΔLDL‐cholesterol and Δtotal cholesterol
were larger in the non‐progression
group, but only in a unifactorial analysis.43
In another trial, treadmill exercise was used as intervention only. After one
year, degree of exercise and ΔLDL‐cholesterol,
but not Δtotal cholesterol, were inversely associated with the rate of
progression.40
In the rest of the trials exposure‐response
was absent (Table 1).
Several explanations were
offered: most commonly that other lipids or lipid combinations explained the
findings. However, Δhigh‐density
lipoprotein (HDL) cholesterol was analysed in twelve studies,36–38,40–44,46,47,50,,51
Δtriglycerides in ten,36–38,40–42,44,47,50,,51
Δapo‐lipoprotein
B in six,37,42,47,48,50,,51
Δapo‐lipoprotein
A1 in three,37,,47
Δvery‐low‐density‐lipoprotein cholesterol in three,36,50,,51
and Δsmall, dense LDL‐cholesterol
in one study,50
but none of them were associated with atherosclerosis growth. In an early trial
using visual evaluation of the angiographic findings36
Δintermediate‐density
lipoprotein cholesterol was associated with atherosclerotic progression, but in
two others using computer‐assisted
analysis,50,,51
no association was found. In three trials, the ratio Δtotal cholesterol/HDL
cholesterol was inversely associated with atherosclerotic progression,41,43,,47
but in one it was seen only in the placebo group,41
and in another the analysis was not corrected for other risk factors.43
Table
1
Changes (Δ) in low‐density lipoprotein
cholesterol
and of total cholesterol in relation to atherosclerotic progression, graded as
a continuous variable, in 18 cholesterol‐lowering, angiographic trials
Trial
|
Type of intervention
|
Measurement of angiographic progress or regress
|
Baseline LDL‐C and (tC) (mmol/l)
|
Trial length (years, months)
|
Patients
| | |
Increase in atherosclerosis associated with
| | | | | | |
n
|
Males (%)
|
Mean age (years)
|
ΔtC
|
ΔLDL‐C
| | | |
Krauss et
al. 198736
|
Cholestyramine
|
MLD c, v
|
6.08 (7.08)
|
5,0
|
143
|
80
|
–
|
No*
|
No*
| | | |
Blankenhorn et
al. 199037
|
Colestipol, niacin
|
MLD c, v
|
4.36 (6.26)
|
2,0
|
162
|
100
|
54
|
No*
|
No*
| | | |
Olsson et
al. 199038
|
Nicotinic acid
|
Global estimate f, v
|
6.44 (9.68)
|
1,6
|
20
|
100
|
50
|
No
|
No
| | | | |
+fenofibrate
| | | | | | | | | | | |
Tatami et
al. 199239
|
LDL‐apheresis
|
%Stenosis c, q
|
8.89 (11.1)
|
>1,0
|
37
|
59
|
–
|
No*
|
No*
| | | | |
+probucol
| | | | | | | | | | | | |
and/or pravastatin
| | | | | | | | | | | |
Hambrecht et
al. 199340
|
Physical exercise
|
MLD; %stenosis c, q
|
4.21 (6.0)
|
1,0
|
88
|
100
|
53
|
No*
|
Yes*
| | | |
Hodis et
al. 199441
|
Lovastatin
|
%Stenosis c, q
|
4.00 (5.90)
|
2,0
|
220
|
91
|
58
|
No*
|
No*
| | | |
Sacks et
al. 199442
|
Various lipid‐lowering
|
MLD; %stenosis c, q
|
3.56 (5.5)
|
2,9
|
79
|
89
|
58
|
No*
|
No*
| | | | |
drugs
| | | | | | | | | | | |
Quinn et
al. 199443
|
Multiple risk factor
|
MLD c, q
|
4.02 (5.88)
|
2,0
|
257
|
86
|
57
|
Yes
|
Yes
| | | | |
reduction
| | | | | | | | | | | |
Schuff‐Werner et al.
199444
|
LDL‐apheresis
|
%Stenosis c, q
|
7.54 (9.36)
|
2,0
|
33
|
70
|
47
|
No
|
No
| | | |
Kitabatake et
al. 199445
|
LDL‐apheresis+various
|
%Stenosis, c, q
|
6.62 (8.46)
|
1,0
|
13
|
77
|
48
|
–
|
No
| | | | |
lipid‐lowering drugs
| | | | | | | | | | | |
Regnström et
al. 199646
|
Probucol
|
Global estimate f, q
|
6.52 (8.83)
|
3,0
|
303
|
57
|
54
|
No
|
No
| | | |
Niebauer et
al. 199647
|
Low‐fat diet+physical
|
%Stenosis c, q
|
4.22 (6.06)
|
1,0
|
92
|
100
|
54
|
No*
|
No*
| | | | |
exercise
| | | | | | | | | | | |
Kroon et
al. 199648
|
LDL‐apheresis+simvastatin
|
MLD; %stenosis c, q
|
7.82 (9.79)
|
2,0
|
40
|
100
|
52
|
No
|
No
| | | | |
vs. simvastatin
| | | | | | | | | | | |
Tamura et
al. 199749
|
Pravastatin
|
%Stenosis c, q
|
3.11 (4.73)
|
2,0
|
80
|
81
|
64
|
No
|
No
| | | |
Ruotolo et
al. 199850
|
Bezafibrate
|
MLD; %stenosis c, q
|
4.64
|
5,0
|
81
|
100
|
41
|
–
|
No*
| | | |
Sutherland et
al. 199851
|
Simvastatin
|
% stenosis c, q
|
4.33 (6.91)
|
2,0
|
38
|
53
|
57
|
No
|
No
| | | |
*Adjusted for other risk factors; MLD, minimum
lumen diameter; LDL‐C,
LDL‐cholesterol; tC,
total
cholesterol; c, coronary angiography; f, femoral angiography; v, visual
judgement; q, quantitative, computerized image analysis.
Objections:
Doubt has been raised
against the use of coronary angiography as a measure of atherosclerotic changes.52 The most serious objection, that angiography
underestimates the amount of subendothelial deposits, and cannot depict the
intramural ones, is not relevant in studies of exposure‐response, because
associations are
sought to the changes, not to the degree of atherosclerosis. Large inter‐ and intra‐observer variabilities are found in
studies using visual judgement of the angiographic changes, but thirteen of the
sixteen mentioned trials used quantitative, computerized image analysis (Table
1). Other objections include imprecise measurements of lumen diameter and
misinterpretation of its initial compensatory enlargement as atherosclerotic
regression. In particular, percent stenosis has been questioned as a reliable
measure of progress or regress because of uncontrolled physiological influences
on the lumen of the reference vessels.52–,54 However, if measured with care, the minimum
lumen diameter, used in half of the studies as a measure of atherosclerosis
(Table 1), has a low coefficient of variation for repeated measurements55 and is a strong predictor of the coronary
flow reserve,56 the reactive hyperaemic response,53 the transstenotic pressure gradient57 and thallium scintigraphic changes after
exercise,57 all of which reflect degree of
atherosclerotic narrowing of the coronary vessels. Angiographic deterioration
strongly predicted cardiovascular events in the studies that included a
clinical follow‐up.36,37,,39
Why
does a high cholesterol predict cardiovascular disease?
If LDL‐cholesterol
and ΔLDL‐cholesterol do not correlate with
degree of atherosclerosis or with atherosclerosis growth, why does a high
cholesterol predict cardiovascular disease? The answer may be that
cardiovascular disease is not synonymous with atherosclerosis. A high LDL or
total cholesterol may be secondary to uncontrolled factors that promote
cardiovascular disease in other ways and cause hypercholesterolaemia at the
same time, for instance lack of physical activity,58
mental stress,59
smoking, and obesity.60
It is generally assumed that their effect on cardiovascular disease is mediated
through the high cholesterol, but this may be a secondary phenomenon. Physical
activity may benefit the cardiovascular system by improving endothelial
function,61
or by stimulating the formation of collateral vessels;62
mental stress may have a harmful influence on adrenal hormone secretion,
smoking increases the oxidant burden; in these all situations the high
cholesterol may be an epiphenomenal indicator that something is wrong. This
argument also explains why some studies found atherosclerotic growth to be
associated with initial or on‐study
LDL‐cholesterol,
but not with ΔLDL or total cholesterol. If the amount of LDL‐cholesterol in the
blood were the
determining factor, atherosclerotic growth should have been associated with
ΔLDL‐cholesterol
as well and to a higher degree.
Conclusion
‘The more LDL there is in
the blood, the more rapidly atherosclerosis develops.’ This 1984 statement by
the Nobel Award winners Michael Brown and Joseph Goldstein1
has dominated research on atherosclerosis since then. As shown here, this
hypothesis appears to be falsified by the fact that degree of atherosclerosis,
and atherosclerotic growth, were independent on the concentration or the change
of LDL‐cholesterol
in almost all studies. The role of LDL‐cholesterol
for atherosclerosis growth has been exaggerated, a finding with consequences
for the prevention of cardiovascular disease. For instance, as the statins
exert their beneficial influence on the cardiovascular system by several
mechanisms, it may be wiser to search for the lowest effective dose instead of
the dose with maximal effect on LDL‐cholesterol.
Neither should an elevated LDL‐cholesterol
be the primary target in cardiovascular prevention, as recently claimed by the
American National Cholesterol Education Program, and researchers should direct
more attention to other hypotheses.
I may have overlooked
studies that have found an association between changes of LDL‐cholesterol or other lipid fractions,
and atherosclerotic progression. However, although the presence of exposure‐response is not sufficient
proof in
itself of causality, it is difficult to explain its absence.
Footnotes
↵Address
correspondence to Dr U. Ravnskov, Magle Stora Kyrkogata 9, S‐22350
Lund, Sweden. e‐mail:
uffe.ravnskovswipnet.se
- Š
Association of Physicians
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Copyright Š 2014
Association of Physicians of Great Britain and Ireland
The book below by Prof
Ravnskov is the best that I have read on the topic. Unlike most book on this
issue, this one
meets professional standards. The theory
of cholesterol causing cardiovascular disease has been repeatedly exposed, over
a dozen books on Amazon deal with this and the failure of statins to prevent
coronary artery disease and deaths, made all the worse by their serious side
effects. That such has been swept under
the rug for 20 years is proof of the control that pharma exerts upon the
production of information and thus beliefs.
At http://healthfully.org/rl/id8.html is an article he authored on the same subject.
Notes on Ravnskov’s
Cholesterol Myth book
Ignore the Awkward! How the Cholesterol Myths are Kept Alive,
2010 Uffe Ravnskov, M.D. from
U of Copenhagen 1961 (born 1934, clinician and researcher in Sweden, PhD. U. of
Lund, published more than 100 papers and letter critical of cholesterol
campaign, most of them in major medical journals. He is the creator and
spokesman for THINCS (The
International Nework of Cholesterol Skeptics (WWW.thincs.org). Uffe has
done important work in neurology,
his specialty. Note, number after a sentence indicates which page the material
is on. Each major assertion is supported
by footnotes, mostly to journal articles.
Chapter
1: The
Animal Argument. Examples of bad
studies such as, the use of rabbits
(vegetarians) to show that dietary cholesterol causes atherosclerosis.
Chapter 2:
The diet
Argument. High cholesterol in the
elderly not associated with death, 19.
Saturated fats not associated with deaths.
Saturated fats don’t raise cholesterol level,
21. Flaws in Ancel Keys work (misses
industry funding, and his reversal of position on saturated fats; flaw in death
certificates, etc. 21-23. Dairy
products
saturated fats okay, 24. Dietary
guidelines, Swedish, WHO,
Chapter 3:
The Nobel
Prize Argument. Familial
hypercholesterolemia (FH), homozygous extremely rate. They have damaged LDL-receptors causes higher
blood level of cholesterol. Most
people
with FH don‘t die early, though they have a higher rate of dying from heart
disease and a lower rate for cancer and other diseases, 30. Before 1900 those with FH lived longer than
the average Dutchman. Lipoproteins
bind
to and neutralize bacteria and viruses and their toxic products, 31.
People with low cholesterol have an increased
risk of dying from diseases of the stomach, the guts, and lungs, 31.
“If high cholesterol were the cause of
atherosclerosis in these people, all of their arteries should be in danger, not
only those going to the heart… Even those with the rare homozygous variant, the
cerebral arteries are not more atherosclerotic than the normal people… although
their cholesterol may be almost three times higher, 31.”
“They may have abnormally high levels of
fibrinogen, factor VIII, or prothrombin, molecules that are necessary actors in
the coagulation process, 32. Since
the
introduction of the cholesterol reducing statins, young people with FH dies
less often from heart disease. This
is
correct, but it cannot be the result of a reduction in cholesterol.
Study after study has shown that the small
effect achieved with these drugs is independent of the degree of cholesterol
reduction…. The explanation is probably that the statins have other, more
useful qualities than reducing cholesterol.
For example, statins have anti-clogging effect on the blood, which
evidently is useful for people who are born with too much fibrinogen, factor
VIII or prothrombin in their blood, 32
Chapter 4:
The Risk
factor Argument. “Women with
low
cholesterol run the same risk as women with high cholesterol…. Canadian
researchers studied almost 5000 healthy middle-aged men for twenty years and
came up with the same result…. In addition, study after study has shown that
cholesterol is unimportant for those who have already had a heart attack.”
36. “At least fifteen
studies have
shown that high cholesterol is not a risk factor for diabetic patients either… In
a large study of old people living in the Bonx in New York, low cholesterol,
not high, was a risk factor”, 37.
*** Chapter 5: An
Argument to Forget. Autopsy of
Japanese and Americans failed to find an association of blood levels and AS of
the aorta, 41-2. Similar problem
with
angiography, bypass surgery, 42-3.
Electron beam tomography 43-4.
*** Chapter 6: The
Trial Argument. Lists
the trials with
weak to no benefits, points out that it isn’t the cholesterol lower effect that
causes this weak improvement as to deaths from MI, but other effects of
statins. However, the overall mortality
remained about the same, more died of cancer, heart failure, etc.
“What has been forgotten is that low
cholesterol is a frequent finding in people with various types of mental
disturbances… In addition
people with
high cholesterol develop Parkinson’s disease and dementia less often than
people with low cholesterol.” 56. “If
Alzheimer’s disease is seen less often in statin-treated people, is it because
they have lived most of their life with high cholesterol, or is it because they
received statin treatment? Nobody
knows.” 57. “Fatty
streaks are found in
the vessels of all children, even in populations where atherosclerosis is rare
… Several studies have shown that about half of the children with high
cholesterol at age two have a normal cholesterol when they reach puberty”, 57.
*** Chapter 7: How to
keep a False idea Alive. LRC trial
over
the first four years had 612 journal citations, while the unfavorable Miettinen
trial (morality increased) over the same period had15 citations.
What he misses is ghost writing and rewritten
of the same article by pharma’s staff—see Ben Goldacre.
Chapter 8:
How to
Exaggerate Insignificant Results.
Subgroup analysis—limited chapter on just 2 studies
Chapter 9:
How to
Explain Away Awkward Results. “Even
independent researchers may find it difficult to challenge an idea that is
accepted by everyone,” 75. The
collection of side effects. “other
researchers have described patients who suffered with progressive dementia, who
recovered after they had stopped their treatment.” 82 Cognitive impairment associated with
atorvastatin and simvastatin, DS King et al Pharmacotherapy 2003:23:871-80; http://onlinelibrary.wiley.com/doi/10.1592/phco.23.15.1663.31953/abstract http://www.neurology.org/content/58/9/1333.short Statins and
Risk of [idiopathic]
Polyneuropathy, 2002:
“For patients treated
with statins for 2 or more years the odds ratio of definite idiopathic
polyneuropathy was 26.4.” “In the CARE trial thirteen women
had developed
breast cancer in the treatment group, but only one in the control group. Some of them were new cases; others were
recurrences of previously treated breast cancer. Since then, all patients who have undergone
cancer treatment have been excluded from the trials.” 86.
[probably the great risk in part was caused
by the reduction in the cancer preventative estradiol]. He falls for the BS of the PROSPER study
author that for all the Pravachol trials the net increase in cancer was zero;
BS because the other studies did not make public the cancer stats, and most
were to short to have a significant increase.
Lots of deception space in the company reply on cancer. Uffe does point out that in the previous
studies the patients were 25 years younger.
Thus another reason heart failure for excluding the elderly from
studies. Goes into the hassle on
filling
reports on side effects. “Dr.
Kendrick
estimated that filing an adverse drug report, then dealing with the follow up
paperwork, takes about two to three hours of work. Then nothing at all happens. “ 89
Chapter
10: How to Lie convincingly. On the Framingham study: …according to the original report mortality
increased 11%.... Without presenting
anything other than complicated ratios and statistical calculations, and
without referring to their previous report, they stated: The most important overall finding is the
emergence of the total cholesterol concentration as a risk factor for CHD in
the elderly. “ 98.
Chapter
11: How to Ignore Alternative
Explanations. Rather sketchy chapter
which blames stress in two examples on increase in MI, one on monkey with heart
attack, the others on Japanese who adopted a western diet, but not those who
live a traditional lifestyle.
Chapter
12: How to Ignore the Critics. Gives examples of how is submission was
criticized for irrelevant issues, and how his letters to the editor were not
published. Of interest was Uffe’s
2002
systematic review of angiographic trials that found “no relationship between
the degree of cholesterol lowering and the angiographic changes, meaning that
the plaques or the diameter of the arteries increased or decreased haphazardly
whether cholesterol was reduced a lot or not at all.” 114.
This paper was rejected by the first six
journals, with only two sending it to referees.
Finally it was accepted in Oxford Journal at http://qjmed.oxfordjournals.org/content/95/6/397.full. He
highlights the problem that the referees believe the cholesterol myth and
saturated fat myth, and are unlikely to evaluate the evidence.
Other paper went unpublished, and at
conferences on those supporting the cholesterol theory are invited.
Chapter
13: When Arguments Stop Working. The media used him to present an attack on
his book, and in a Finish broadcast after being criticized the book was burned. In a Danish show a leading Danish cholesterol
expert said of Uffe “ an eccentric and irresponsible headbanger who had been
kicked out of the universities in Copenhagen and Lund, a misfit whom no Danish
hospital would ream of employing..” 120
Chapter 14:
Industrial Tricks. “Consider for
example, that in 2002 the combined profits for the ten drug companies on the
global business magazine Fortune’s 500 list were greater than the profits for
all the over 490 business put together.” 125.
Ghost writing, guideline authors, paying doctors to recruit trial
patients $10,000 each and a bonus of $30,000 for the 6th one. False advertising, hiding side effect for
Vioxx, and fake journals
Part III ON INFECTION as
cuase
Assuming LDL is disease protective, then why are women
protected by estradiol and not middle age men??? Answer,
as men’s levels fall by the 4th
decade their protection from AS diminishes but for a woman a similar hormonal
decline doesn’t occur until about the age of 55. Estrogen appears to affect endothelial cells
better than testosterone.
Chapter 15: The Real
Cause? For Example, remnants
from more
than fifty different bacterial species [http://www.sciencedirect.com/science/article/pii/0014480084900509]
and a number of viruses as well [http://circ.ahajournals.org/content/113/7/929.short]
have been identified in atherosclerotic tissue, and antibodies against several
of these micro-organisms are present in abnormally high amounts in the blood of
patients with cardiovascular disease and people who die from it later in life.
“ 134. [Many other with the JL Melnick article]. “…Erling Flak. He
examined the hearts of patients who had
died because of an acute myocardial infarction and noted the the occluding
thrombus usually was situated close to a ruptured bubble.” 134.[E, Flak, BR
Heart J. 1983;50; 127-34. COPIED
chapter
7/31. “The first part of our
hypothesis
is not our own. It was proposed
more
than a hundred years ago and it says. To express it very simply, that
atherosclerosis is the result of an infection in the artery wall.
The second part explains why and how
LDL-cholesterol and the microorganisms end up here and what happens before a
thrombus is created inside the artery.
Most researchers agree that
atherosclerosis starts as an inflammation in the arterial wall [and that] heart
disease and stroke are associated in some way with infectious species and a
number of viruses as well have been identified in atherosclerotic tissue, and
antibodies against several of these microorgranism are present in abnormally
high amounts in the blood of patients…. The
following statement by two American pathologists, Oskar Klotz and M. F. Manning
is typical for the general view at that time [1911]: There
is every indication that the production of tissue in the intima (the innermost
layer of the arterial wall) is the result of a direct irritation of that tissue
by the presence of infection or toxins.” 134
“According to the present
view…. That LDL-cholesterol enters the intima when it is activated …. The
activated endothelium is also said to attract a type of whole blood cells named
monocytes and invite them to enter the interior of the arterial wall. When the LDL-cholesterol passed through the
endothelia cells [of the artery walls] they are said to be attacked by cells in
the intima resulting in a change of their structure: LDL becomes oxidized. It
is this process which is considered as the
cause of inflammation. After having
been
oxidized the monocytes, now converted to macrophages, take up the oxidized
LDL-cholesterol” 134-6.
The Contradictions (of the current theoretical
mechanism):
Why do people with low cholesterol become jaust
as
atherosclerotic as people with high cholesterol?
Why do people with high cholesterol live
longest? [Farringham study]
Why is high cholesterol not a risk factor for
women?
Why is the degree of endothelial dysfunction
the same in
people with high cholesterol as in people with low? (136-7)
The Vulnerable
plaque: Uffe
then goes on to describe the appearance under a microscope of the vulnerable
immature plaque which clearly shows signs of inflammation, including elevated
temperature. “Another interesting
finding is the numerous lipid droplets that are found in the inflamed arterial
wall outside the vulnerable plaques.
They are rarely seen directly beneath the endothelium like the foam
cells, as should be expected if LDL cholesterol entered by the way of the
endothelium. This observation is
crucial
for the understanding of our hypothesis” 137.
For bacteria in vulnerable plaque http://www.scielo.br/scielo.php?pid=S1807-59322006000500016&script=sci_arttext
The lipoprotein immune system: Sixty
years ago researchers discovered that the lipoproteins participate in our
immune system by binding and inactivating bacteria, viruses and their toxic
products. The lipoprotein immune system may be particularly important in early
childhood, because in contrast to the antibody producing system, which needs
repeated stimulation to function properly, the lipoproteins work immediately
and with great efficiency. There are
many ways to demonstrate it…. In the laboratory it has been shown that human
LDL is able to inactivate more than 90% of the most toxic bacterial products….
[when] reduced blood cholesterol in rats and gave them an injection of
bacterial toxin, most of them died quickly but if they injected a purified
human LDL beforehand, they survived. When we are attacked by microbes, the
white blood cells send a message to the liver by excreting their hormones, the
cytokines. The liver responds by
increasing the production of lipoprotein including the ‘bad’ LDL; yet another
indication that LDL is a useful molecule.”
Uffe states that medical textbooks are silent about this role of
LDL.
The new hypothesis: When the lipoproteins bind the toxic
intruders to their surface, all of them, toxins, microorganisms and
lipoproteins, aggregate, meaning that they lump together into microscopic
clumps that circulate in the blood. Also if too much homocysteine is present in
the blood, it reacts with LDL molecules and makes them lump together.
In our view these particles play a crucial
role in the creation of the vulnerable plaque… we think the vulnerable plaque
is a pustule, a small boil. Its
interior
looks like the interior of a boil, it temperature is higher than the
surrounding tissue, just as is the case with a boil, and it may burst and empty
its content like a boil. The idea
is not
new. As far as we know it was first
suggested by Sir William Osler… a leading physician of his time. In one of his
papers he described the vulnerable plaque as atherosclerotic Pustule [1908]
The
Mechanism: Large vessels
such as arteries and veins are nourished through capillaries, the so-called
vasa vasorum, which surround these vessels like an intricate meshwork.
. What
we suggest is that LDL clumps may become so numerous and of a size that they
are able to obstruct the vasa vasorum.
Consequently small parts of the arterial walls become malnourished, get
too little oxygen, and may even die—small infarct of the artery wall…. Becomes inflamed….
Hypoxia has been shown by intricate chemical analysis of atherosclerotic
arteries. Hypoxia is most pronounced
in
the deeper parts of the inflamed arterial walls where the macrophages are
dominant. If the immune system is OK, the surrounding white blood cells and the
antibodies attack the microogranisms.
Fibroblasts and new capillaries grow into the inflamed tissue and
eventually it will be transformed into a scar, the fibrous plaque. If not, a pustule is created, its thin
membrane may burst, the content of the plaque flows out into the blood, a clot
is created at the margins and if it becomes too large the blood flow becomes
obstructed and the tissue that is nourished by the artery dies [unstable, young
plaque]. [See for ex. http://journals.lww.com/co-lipidology/Abstract/2009/10000/The_role_of_hypoxia_in_atherosclerosis.9.aspx)
Everything
fits: myocardial
infarction and stoke increases during influenza epidemics, and people with
infected teeth, or with bacteria in the blood… one-third of all patients… had
an infectious disease immediately before onset… most common are respiratory
dieases,… other types tuberculosis, HIV, tooth and urinary tract
infections. If a vulnerable plaqe
may
appear in normal arteries, and if mcroogansims cause stroke and myocardial
infarction, then vascular disease may occur in all ages. Finnish researcher Erkki Pesonen and his team
noted that the coronary arteries were narrowed in children with infectious
diseases, both in those who died and those who survived…. Why don’t the
LDL-compleses obstruct the vasa vasorum of the veins? The pressure in the veins is very low…. The LDL
clumps have no problem passing by. In
the arteries the pressure is high. Each
stroke of the heart stops the blood flow completely in these vasa vasorum:
the blood is only able to pass by during the
short time when the heart is relaxed. [Contradicts
claim that LDL is oxidized inside the artery.]
No, LDL is oxidized after having been taken up by the macrophages
together with its toxic passengers as part of a normal physiological
process. When white blood
ells take up
foreing, dangerous material they neutralize it by oxidation and at the same
time LDL is oxidized as well. Probably
HDL reconstructs LDL, because laboratory experiments have shown that HDL is
able to convert oxidized LDL back to normal.
A
final comment: Recommends vitamin
D, especially in the winter, and vitamin C which is concentrated inside white
blood cells “80 times higher than in the blood.”
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