13. Mars
Uffe Ravnskov
Skeptics!
As I mentioned in my previous letter I have invited Professor
emer. Morley Sutter to become a member of our group. It is a pleasure for me tell you that
he has now joned us. His letter is enclosed below.
I will highly
recommend the two papers mentioned in the letter (one of them is attached, the other one
will be sent directly to you by Morley because a page was missing in the copy that I
received). Most probably Paul Rosch and also I myself will object to Morley’s
scepticism against stress as a causal factor of CHD - a subject for future
discussions.
The idea of atherosclerosis having an infectious origin, however, is also one of my
favorite hypotheses and many supportive observations have been published since Morleys
1995 paper. This is a subject we haven´t discussed at all. Let Morleys paper be an
inspiration. Uffe
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Paul Rosch
Interesting paper (By
Morley Sutter) but would object to conclusions of non-role of stress in ulcers or
tuberculosis. As Bill Stehbens would probably point out, the tubercle bacillus is
the causa vera of tuberculosis since the disorder cannot occur if it is absent.
H. pylori may play a similar role for most peptic ulcers but the fact is that the
vast majority of patients with H. pylori do not develop clinical pathology and the same is
true for tuberculosis. Stress lowers immune system resistance to these and other
pathogens and numerous epidemiological studies show its role in the increased incidence of
tb in Irish immigrants to the U.S. in the 19th century due to the potato famine
in Ireland and Navajo Indians transplanted to reservations where sanitary conditions were
actually better. It seems quite clear that tb was precipitated by the stress of
sudden change and relative absence of family ties and social support. The role of
stress in accelerated atherosclerosis, coronary heart disease and sudden death is also
well established, particularly with respect to depression, acute and chronic anxiety
states, etc. as I have pointed out elsewhere. Paul
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Tom Clayton
Does anybody know
where I can get a synopsis of the “acid causes ulcers” mistakes that were
made years ago before it was recognized that helicobacter pylori was causing most of
them?
That is, a brief historical summary of what happened and how the incorrect assumption that
“acid” causes ulcers was responsible for creating an entire branch of medical
treatment where the wrong things were done? Thanks!! Tom
Morley Sutter
Dear
All, It is delightful to read your
comments midst all the faddish statements about cholesterol and lipids in atherosclerosis.
The attached paper which appeared in Perspectives in Biology and Medicine is the
distillation of my thoughts about diseases including those in which cholesterol is
deposited abnormally in various tissues. I would add that in writing about assigning
causation, I failed to adequately stress that any intervention must be selective and do
only one thing if the intervention (e.g. drug) is to be used as a tool to assign
causation. This is the problem with the statins: they have more than one
pharmacological action and their ability to alter lipids might or might not be involved
any modestly beneficial effects they posses (Relative risk reduction of approx 25%
regrdless of pre-existing lipid status (just like aspirin)!
At any rate I hope you find this article of interest.
Regards to all and
thank you Uffe for accepting me as a member of your group.
Morley
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Morley Sutter
Dear Doctor
Rosch, Thanks for your comments on my
editorial.
As you can tell, I think that stress as a causal factor in
disease, is
not a very useful concept. “One man’s stress is another man’s
thrill”.
The word
“stress”, or more accurately, “Generalised stress reaction” was
introduced into medical parlance by Hans Selye at the University of Montreal in relation
to his production of severe pathology in rats given large doses of cortisol and made
potasium deficient. The word stress is usually used as a misnomer for
anxiety. The
latter is a problem for all of us in terms of our ability
to function.
I suggest that
attempts to causally link the presence of “stress” and more importantly its
reduction or removal, to any disease have been singularly unsuccessful. I
realise that certain activities called stressful such as high level exercise put people at
some risk of heart attacks, perhaps due to high sympathetic nervous activity. But
such precipitating factors are not what most people think of as the “stress of daily
living”.
You mention TB or
peptic ulcer not occuring in every one who harbours the microbes. This is true and
we are usually overly simplistic in thinking about parasite-host interactions which
clearly are altered by genetic make-up, nutrition and how large the “dose” of
microbe is. The evidence that ordinary stress of daily living alters our response to
microbial invasion is minimal but it is possible.
I actually think that
microbes are the necessary but insufficient cause of most chronic diseases, but am
well aware how difficult it is to establish a clear relationship. The best evidence
must come from attempts to manipulate or eradicate the microbe but if its effect is of the
“hit and run” variety, life gets very complicated indeed. At any
rate, if
you have read this far, I am grateful. Yours sincerely,
Morley
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Paul Rosch
Dear Morley and Uffe:
I was
a Fellow at Hans Selye’s Institute of Experimental Medicine and Surgery at the
University of Montreal in 1951, shortly after his magnum opus Stress was
published,
co-authored several papers and chapters with him, including the lead chapter
Integration of Endocrinology for the AMA Textbook of Glandular Physiology and Therapy
and enjoyed a close personal and professional relationship with him until his death.
The term stress was deleted from his original 1936 article in Nature (A
Syndrome Caused By Diverse Nocuous Agents) by the editor because it was
confusing.
At the time, the general consensus was that every disease had a specific cause based on
Koch’s postulates. The tubercle bacillus caused tuberculosis, anthrax bacillus
caused anthrax, etc. What Selye proposed was quite different, namely that many
difference agencies both physical and mental could cause the same pathology.
(This was not based on injecting cortisol or compound F (which was not available at the
time) or potassium depletion.)
Unfortunately, he was not aware
that stress had been used for centuries in physics to explain elasticity, the property of
a material that allows it to resume its original size and shape after having been
compressed or stretched by an external force. As expressed in Hooke’s Law of
1658, the magnitude of an external force, or stress, produces a proportional amount
of deformation, or strain, in a malleable metal. The maximum amount of stress
a material can withstand before becoming permanently deformed is referred to as its
elastic limit. This ratio of stress to strain is a characteristic property of each
material, and is called the modulus of elasticity. Its value is high for rigid
materials like steel, and much lower for flexible metals like tin. Selye several
times complained to me that had his knowledge of English been more precise, he would have
gone down in history as the father of the “strain” concept.
This created
considerable confusion when his research had to be translated into foreign
languages.
There was no suitable word or phrase that could convey what he meant, since he was
really describing strain. In 1946, when he was asked to give an address at the
prestigious Collège de France the academicians responsible for maintaining the purity of
the French language struggled with this problem for several days, and subsequently decided
that a new word would have to be created. Apparently, the male chauvinists
prevailed, and le stress was born, quickly followed by el stress, il stress,
lo stress, der stress in other European languages, and similar neologisms in
Russian, Japanese, Chinese and Arabic. Stress is one of the very few words you will
see preserved in English in these latter languages. Selye’s concept of stress
and its relationship to illness quickly spread from the research laboratory to all
branches of medicine, and stress ultimately became a “buzz” word in vernacular
speech. However, the term was used interchangeably to describe both physical and
emotional challenges, the body’s response to such stimuli, as well as the ultimate
result of this interaction. Thus, an unreasonable and over demanding boss might give
you heartburn or stomach pain, which eventually resulted in an ulcer. For some
people, stress was the bad boss, while others used stress to describe either their
“agita” or their ulcer.
Because it was
clear that most people viewed stress as some unpleasant threat, he had to create a new
word, “stressor”, in order to distinguish between stimulus and
response.
Even Selye had difficulties when he tried to extrapolate his laboratory research to
humans. In helping to prepare the First Annual Report On Stress in 1951, I included
the comments of one critic in the BMJ, who, using verbatim citations from Selye’s own
writings, concluded that “Stress, in addition to being itself, was also the cause of
itself, and the result of itself.”
Selye struggled unsuccessfully throughout
his life to come up with a satisfactory definition of stress and in his later
years, in
attempting to explain his theories to a lay public, settled on “The rate of wear and
tear on the body”, which is actually a pretty good definition of biological
aging.
Although
stress cannot be defined scientifically (much less quantified) since it is a highly
personalized phenomenon it is not likely to be replaced by any other term or phrase that
more meaningfully reflects the myriad mind/body relationships that contribute to disease
or promote health and I have written a great deal about this. With respect to
coronary heart disease and other disorders due to accelerated atherosclerosis there are
numerous mechanisms other than increased sympathetic tone that can be involved and
verified by demonstrating that stress reduction strategies can prevent or mitigate this
effect as I pointed out in an Editorial in Stress Medicine several years ago.
The American
Institute of Stress was formed in 1978 and my involvement in this was at Selye’s
request and you can find out more about this on our web site www.stress.org Sorry to have gone on for so long
and as you wrote “At any rate, if you have read this far, I am grateful.” Paul
J. Rosch, M.D. President, The American
Institute of Stress
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Martin Sturman
Dear Tom, Acid Does
cause ulcers, otherwise proton pump inhibitors, H-2 blockers, and antacids would not
work.
And why would people with achlorhydria not get peptic ulcer? I am quite puzzled by your
suggestion that this is mistaken. I also agree with my friend Dr. Paul Rosch- that stress
and other factors must be considered in the causation of ulcer. Koch’s
Postulates for peptic ulcer have never been fulfilled by H. pylori.
Similarly, as Blaser observes, ulcer disease was rare in the days when H. pylori was highly prevalent in what
now are developed countries, and is uncommon today in many developing countries where
almost all adults are colonized!!! Why did ulcer disease arise just as H. pylori was
beginning to recede from humans? Moreover, no one knows which of its highly diverse
strains could be related to the genesis of peptic ulcer since the majority of
people Without Ulcer also harbor this organism. It is highly likely that H. pylori is in
fact a commensal organism present in human stomachs for thousands of years. Strains differ
among geographic regions, and the relation between genotypes and clinical outcomes as well
as other interesting facts about Helicobacter are covered nicely in an editorial “In
a World of black and White, Helicobacter pylori Is Gray” Blaser, mj,
Ann.Int.
Med;130:8;695-697 20 Apr. 1999 available at http://www.acponline.org The issue of
which patients to treat is still being debated in terms of susceptibility to reflux
disease, Barret esophagus, and adenocarcinomas of the lower esophagus. Much remains
unknown. I also refer you to one of the
best articles on the subject, “Not all Helicobacter pylori strains are created
equal:
should all be eliminated?”, also by Blaser in Lancet Apr.5, 1997;349: 1020-1022.
Yes,
HCl secreted by the stomach IS the proximate cause of ulcer. In my opinion the H. pylori
story if far from told-and may never be resolved. It reminds me a bit of the remark
attributed to Foucault about Derrida, “He gives (bovine feces) a bad
name.” Best wishes, Martin
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18.3
Bogdan Sikorski
Dear Morley, Paul and
others For what it is worth, may I have a go
at this interesting topic - stress and disease. There is volumes of evidence suggesting
the importance of stress in
etiology of various diseases. The problem is that stress is not cited as a key word in many of them. For
instance, the effect
of stress on the performance of the immune system has been well and extensively
documented. There are even number of animal odels of stress which are use in the research
- stomach ulcer is the one that comes to my mind at present. Then again there is an
interaction between stress and nutrition. Not many of you may realize that different
nutrition predisposes to a particular
response to a given stress stimulus. Generally speaking, many followers of JK’s diet,
including me, have reported different stress levels in response to similar stimuli
(work
stress, physical exercise, physical exhaustion, accident, et c.), compared with responses
on a previous nutrition. It appears that nutritional modification has a lot to do
with the way the body handles the stress.To my surprise JK (Jan Kwasniewski for new
members) does not consider stress to have much influence on disease, particularly stomach
ulcers. But I have a feeling that he is wrong there - big time, at least as far as I can
see based on the evidence I had a chance to see.May I suggest that anyone wanting to have
a clear picture about ulcer etiology and metabolic/pharmacological mechanisms involved
should follow the research of two real heavy weights in that area - Prof. S. Konturek and
Prof. T. Brzozowski, both from the Institute of Physiology, Jagielonian Univ.
(previously
Medical Academy) in Krakow.Their publications are easily found on the
Medline. But be
prepared for a large number of papers in the last 20 years.
Stress appears to be a very complicated topic, particularly when one takes into
consideration interaction with nutrition.For instance, it is well known that both animals
and humans can die of stress. Animals which are being chased and humans who have lost
hope. The latter have been described in the literature (factual), for instance
concentration camp inmates in German (not Polish as a certain “group” insists on
calling them) camps during WWII.Surprising as it may be, many concentration camp inmates
“cured” themselves of different diseases, but most of them ended up with
different ones (mainly infectious) when they were lucky to survive (nutrition?).
Surprisingly also, JK insists that not many, if any, had problems with stomach or duodenal
ulcers while in camps. I think his memory will be quite good since he had a chance to talk
to “few” of these survivors and probably even treat them. Bogdan
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Malcolm Kendrick
Dear All, I think that
you have to separate mental, from physical stress. For example,
the stress of surgery is mainly that of physical assualt on the body. Known, in surgey as
‘aggression.’ Aggression would also cover road traffic accidents,
knifing,
shooting etc.
In this situation, the metabolism enters a state known as Post-aggression metabolism. This
is characterised by high circulating levels of adrenaline, growth hormone, cortisol and
glucagon. This state can be replicated by giving these four hormones in physiological
doses. When you do this, you create severe insulin resistance (IR), hyperinsulinaemia and
hyperglycaeamia
(post glucose tolerance test). In general the insulin and sugar levels are three times
higher than normal in PAM .
Using this model of ‘stress-hormones lead to IR’, it can be shown that patients
in a state of depression and vital exhaustion (VE) also demonstrate raised levels of
stress hormones. (This is also true of anxiety). Depressed patients develop insulin
resistance (sometimes frank diabetes), which recovers when the depression is cured (or
just goes away). Which shows that there is a clear causal associaiton between depression
and insulin resistance (mediated by the hypothalamic pituitary adrenal axis HPA-axis and -
mainly - excess cortisol secretion).
So it is possible to see the connection
between acute, physical stress, and longer term psychologcial ‘stress’ through
the HPA-axi,s and the abnormal secretion of the stress hormones. This, I
believe, is where
the link between ‘stress’ and CHD is made via syndrome X. Regards Malcolm
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Paul
Rosch.
Dear Malcolm:
A complex and controversial
subject and while I agree with most of what you say there are other factors to
consider.
I would also like to congratulate you on the draft of your book which you kindly
asked me to review. I was fortunate to know both Paul Dudley White and George
Pickering who were superb clinicians sensitive to the role of stress and emotions in
cardiovascular disease and who recognized that “the secret in the cure of the patient
is in the care of the patient.”
With respect to the MRFIT study it should be
mentioned that this approximately $120 million multi-center study conducted over seven
years was designed to show that not only reduction of cholesterol but also the other
standard “risk factors” of hypertension and cigarette smoking would lower the
incidence of coronary morbidity and mortality. Although the risk factor lowering
goal was achieved for all, there was no reduction in fatality rates, which were actually
higher in a subset of hypertensives treated with diuretics, probably because of terminal
arrhythmias due to hypokalemia.
Bradford Hill’s “Canons” are
certainly on target but I believe that Bill Stehbens has done an even more persuasive job
of debunking the current risk factor dogma for CHD as presented at one of our Congresses
years ago, which also featured presentations by George Mann, Ray Rosenman, Stewart Wolf
and others that supported his views. Finally, I did not see any reference to
the research of Pamela Peeke and others on the role of stress and increased cortisol
in abdominal obesity, especially in perimenopausal women.
I was just interviewed by a reporter from the LA Times who is doing an
article on this subject as well as the role of insulin resistance in obesity and Type 2
diabetes and have reproduced some of the correspondence below. As indicated, it is
likely that our next Congress will be devoted to various aspects of this intriguing
subject and would welcome your participation in this. Details will be posted on our
web site www.stress.org, which also contains
highlights on past Congresses. Congratulations again on your book and hope some of
the above comments may prove helpful
subject:
stress Re: Los Angeles Times story -
Patricia King wrote:
Dr. Rosch: I looked up your newsletters. It’s #6, 2000 where you discuss
weight and stress. If you could fax a copy to me, that would be great 415/258-9782.
You’ve already answered my question about how solid the connection is between
overweight/obesity and stress and I’m sure your newsletter will help as
well. So in
my questions I’d like to focus on treatments: Are there studies that show that
destressing techniques lead to permanent weight loss? Or are there studies that show that
destressing techniques combined with a changed diet words for weight loss? Has any one
destressing approach been shown to work better than any other approach? Is, for
example, exercise, as some say, the best destressing technique? Also, there are biochemically
oriented doctors who believe that when it comes to treating overweight
people, destressing
techniques are not enough for those genetically predisposed to stress eat. They believe
you have to boost whichever neurotransmitters in the brain need boosting using drugs or
amino acids. That argument goes, as I’m sure you know, that stress makes the
neurotransmitter imbalance worse and no amount of destressing is going to work unless you
balance the neurotransmitters. Without such treatment, they argue, most people
backslide,
gaining all the weight they’ve lost and more. Many thanks in advance for your input.
Patricia KingLos Angeles Times415/455-0438
Dear Patricia:
The links between
stress and obesity are quite complex and involve psychological, metabolic and genetic
influences that mediate their effects through varied neuroendocrine and hormonal
pathways.
Stress-related insulin resistance that leads to obesity, Type II diabetes and
Syndrome X is one example. Why and when we eat certain foods or eat too much is also
often stress related, particularly in women. One recent study evaluated over 5000
individuals at birth and at age 1, 14 and 31. Based on eating habits and stress
coping characteristics, adults who said they often tried to make themselves feel better by
eating were designated as “stress-driven eaters”. Comfort foods tended to
be greasy, salty or sweet. Women who felt a lack of emotional support in their lives
had a greater tendency to eat to cope with stress. Men in this category were apt to
be single, divorced or frequently unemployed. This tendency was also seen in those
with academic degrees despite the fact that higher education is associated with lower
obesity rates. Not surprisingly, the stress-driven eaters and especially females
weighed more on average and had a higher body mass index and also drank more
alcohol.
Popular diet plans like Weight Watchers and Jenny Craig now routinely include stress
management as an integral part of their overall program because of studies showing its
proven benefits. However it is important to recognize that stress is different for
each of us. Things that are distressful for some individuals can be pleasurable for
others or seemingly have little effect either way, as can be readily illustrated by
watching passengers on a roller coaster ride. Similarly, no stress reduction
strategy works for everyone. Jogging and meditation are fine for some but prove
dull, boring and stressful when arbitrarily imposed on others. You have to find
something you enjoy and will adhere to rather than complying with some regimen that you
will most likely quit after a short period. Regular aerobic exercise has some
advantages since it helps burn up calories in addition to reducing stress for certain
individuals.
The neurotransmitter story is also complicated and while serotonin, dopamine and others
play an important role in the response to stress, it is not their levels but rather the
balance between them that is most important. In addition to
medications, there are
also nutritional supplements that reduce stress and therefore obesity and some that can be
useful in losing weight that helps lower stress levels for many, thus breaking up the
vicious cycle of stress—overeating—obesity—stress. I have also
written a great deal about all of the above in other Newsletters but will fax you the
issue requested. It is possible that our next Congress will deal with this
fascinating topic. (see www.stress.org)
If I can be of any further assistance, let me know. Paul J. Rosch, M.D
Jørgen Vesti
Nielsen
Dear all sceptics The link between depression and
mortality after heart infarction is clear
enough. (see Medline for hundreds of references) A two to fourfold mortality increase is
the rule in depressed patients. Note: 200 - to 400 percent!! (The risk reductions in
patients after heart infarctions, which are brought about by medical interventions, are in
the range of 25-30 percent). Something important is certainly happening in the depressive
state influencing risk of dying of heart disease. High cortisol output, activation of the
HPA axis, probably. Insulin resistance with all the concomitant abnormalities affecting
vessels. Try reading Malcolm’s (not yet published) book. Read it -- and love
it. Jorgen
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Morley Sutter
Dear Doctor
Vesti-Nielsen, With all due respect, the
correlation between depression and mortality in heart attacks unfortunately does not
demonstrate a causal relationship between the two phenomena. It is quite possible
that a common factor initiates both. For instance what is the role ( if any) of
Borna virus in depression and/or heart disease? Does treatment of depression reduce
the mortality due to coronary artery disease? The uncertainty of the
relationship between these events must always be part of the equation. I firmly believe
that observational studies (e.g., epidemiology can proveide clues but never conclusion
concerning causal relationships. With all good wishes, Morley
19.3.
Igor Stojiljkovics
Dear Uffe:
> I have been following the discussion on the role of different factors in
causation of CHD with great interest. Although I do not study this field in particular I
found two data quite believeble: the role of iron excess and the possibility of infectious
agent as a causative agent of CHD. I would like to remind you and possibly others that
iron is a rate-limiting factor for growth of many microorganisms in the body.
Unfortunately, not much is known about iron assimilation systems of C. pneumoniae, one
possible candidate for the infectious origin of CHD. Since this microorganism is an
intracellular pathogen, it probably obtains iron via a normal tranferrin-dependent uptake
of iron by infected endothelial cells. Hopefully, better understanding of iron
assimilation system of obligate intracellular pathogens will asist us in understanding of
seemingly unrelated diseases.
The other info that I
have found is that some micoroorganisms have sterols in their membranes (Mycoplasmae; I do
not know whether C. pneumoniae has the same composition). Could it be that statins
prevent growth and developemnt of these miroorganisms in the endothelial cells of CHD
patients and therefore limit the progression of diseases? Sincerely igor
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20. Mars
Jerome Sullivan
Intracellular
growth of C pneumoniae appears to be inhibited by iron restriction or iron
chelation. (See
attached pdf paper: Sullivan JL, Weinberg ED. Iron and the role of Chlamydia
pneumoniae in heart disease. Emerging Infectious Diseases 1999;5:724-6.
Unfortunately,
portions of the papers before and after this paper are included in the pdf.) There is also
an interesting paper in this month’s European Journal of Clinical Investigation on
inhibition by iron chelation of inflammatory response of C pneumoniae infected endothelial
cells (See abstract below). In fact a supplement to the March 2002 issue of EJCI is
devoted to various aspects of the role of iron in disease, including important
contributions on iron and heart disease. Sincerely, Jerome
Visseren FL, Verkerk MS, van Der BT et al. Iron chelation and hydroxyl radical scavenging
reduce the inflammatory response of endothelial cells after infection with Chlamydia
pneumoniae or influenza A. Eur J Clin Invest. 2002;32 Suppl 1:84-90. Abstract:
Background: Chronic low-grade inflammation is associated with increased risk of vascular
diseases. The source of inflammation is unknown but may well be chronic and/or repetitive
infections with microorganisms. Direct infection of endothelial cells (ECs) may also be a
starting point for atherogenesis by initiating endothelial procoagulant activity,
increased monocyte adherence and increased cytokine production. We hypothesized that
iron-mediated intracellular hydroxyl radical formation after infection is a key event in
triggering the production of interleukin-6 (IL-6) by ECs in vitro. METHODS: Cultured ECs
were incubated with Fe(II) and Fe(III) or infected with Chlamydia pneumoniae or influenza
A/H1N1/Taiwan/1/81 for 48 and 24 h, respectively. To determine the role of iron and
reactive oxygen species, cells were coincubated with the H2O2 scavenger
N-acetyl-l-cysteine, with the iron chelator deferoxamine (DFO) or with the intracellular
hydroxyl radical scavenger dimethylthiourea (DMTU). After the incubation periods,
supernatants were harvested for IL-6 determination. RESULTS: Incubating ECs with
Fe(II)
and Fe(III) resulted in increased IL-6 production. Similarly, infection with C. pneumoniae
and influenza A also induced an IL-6 response. Coincubating ECs with DFO or DMTU blocked
this response. Nuclear factor-kappaB activity was increased after infection and blocked by
coincubation with DFO or DMTU. CONCLUSION: Cultured ECs respond to infection and iron
incubation with increased production of IL-6. Iron, the generation of intracellular
hydroxyl radical and NF-kappaB activity are essential in cellular activation, suggesting
that reactive oxygen species generated in the Haber—Weiss reaction are essential in
invoking an immunological response to infection by ECs.
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Malcolm Kendricks
Dear all, I too believe that some factor has to damage the
endothelium to get atherosclerosis started, and an infective agent seems as probable as
any other (single) factor. My difficulty with this hypothesis is the difficulty that I
normally have with any single extrinsic factor being the cause of CHD. In this case, can
different rates of bactieral infection, in different countries, explain the pattern of CHD
throughout the world over the last fifty years?
With regard to the
iron concept, this took hold, I believe, because women tend to have less CHD
(age-matched)
than men, although their CHD rate appears to accelerate rapidly after the menopause -
and women lose more iron than men through their periods. Ergo, less iron, less
CHD. However, as some of you will know, it is possible to find countries where women have more
CHD than men e.g. Brazil. And when women develop type II diabetes all relative protection
against CHD disappears. In addition, women in Scotland (for example) have more CHD than
men in France. In short, I think the
biological plausibility of iron and/or infectious agents causing atherosclerotic plaques
is strong. It just doesn’t fit the pattern of CHD. Or if it does, I can’t see
how it does. Regards Malcolm
Morley Sutter
Dear All: May I add my 2-cents worth to the comments by
Malcolm and Jerome on this topic. First the
infecting agents should not be limited to bacteria: the term microbe seems preferable.
Viruses could well be culprits in iniiation of inflammation leading to
atherosclerosis.
Second, any disease
where the etiolgy involves a microbe, is subject to the vagaries of host-parasite
interaction. The latter clearly involves pathogen load, nutrition, immune status and
genetic makeup of both host and parasite. We don’t get a cold eachtime we are
exposed to the cold virus.
Third, the pathology
of atherosclerosis must be more accurately staged and/or defined than at present.
For instance do all “fatty streaks” lead to plaques at that site? An
analogy would be caseation which occurs with both TB and sarcoidosis but they are
distinguishable.
Fourth, the
identification of the presence of an infecting agent such as Chlamydia pneumoniae should
not depend solely on antibody identification. As with streptococcal infections
change in titre is likely much more important than an single determination. More
reliable would be detection of the organism itself.
Fifth, the waxing and
waning of atheroscleosis at different times in diffeerent places was noted by Skrabanek in
a publication in the BMJ in 1988 or 89. Apparently Chlamydia pneumoniae has
approximately a cycle of seven years in Japan. All microbially-associated epidemics
cycle as apparently does atherosclerosis.
Sixth and (finally)
any necessary but insufficient causal agent should increase incidence of disease by
at least 10-fold as does cigarette smoking and lung cancer. Cholesterol fails
miserably in this test as atherosclerosis currently is defined. Comments on and criticism
of the above points are welcome. Warmest regrds to all,
Morley
Sutter.
21.Mars
Malcolm Kendricks
Morley, I agree that microbial infections
wax and wane, as have CHD rates throughout the world. However, the cycle in CHD in the USA
and the UK would appear to be in the order of one hundred years - which doesn’t
correlate at all with chlamydia (or any other infectious agent that I have ever heard of) In addition, within the USA, the rate
of CHD in caucasians has reduced by ~50% in the last thirty years, yet the rate has gone
up in African Americans during that period. These are two populations that live side by
side. Perhaps most difficult to explain would be the fact that, in Finland, those of
Eastern Orthodox religion suffer five times the rate of CHD of Lutharians - in the same
communities. I cannot believe that religion protects against infection. Nor can I believe
that all of Eastern Europe suddenly became exposed to a unique infective agent in the last
ten or fifteen years. The rate of CHD in Russia increased by 70% during the 1990s.
(Absolute rate) Life expectancy dropped by almost five years in a four year period. From,
if memory serves, 63 to 58. Equally, Asian
Indians in the USA have three times the rate of surrounding Caucasians. In what way can
they be uniquely infected? (By the way, the rate of CHD in emigrant Asian indians in the
USA and the UK is approximately twenty times as high as the rate of CHD in rural Asian
Indians). Equally, whilst the rate of
infection with Chlamydia may have waxed and waned in Japan over a seven year
cycle, there
is no corresponding cycle of CHD. Death rates from CHD in Japan have dropped steadily for
the last thirty years. Again, if you
expose the ‘infective agent causes CHD’ hypothesis to some closer
epidemiological scrutiny, I can’t see any causal correlation appearing. By the way, I fully agree that a more
accurate definition of atherosclerosis is needed. The AHA have produced a scientific
statement on early and late stage atherosclerosis (about 150 pages between
them). You can
find it on their website. Frankly the only thing it did for me was to cure any tendency to
insomnia. As to the key quesiton, do fatty streaks develop into the full atherosclerotic
plaque - deathly silence. No-one has actually sat and watched a fatty streak over a five
year period. Realistically (in a human) how could you?
Regards Malcolm
Bogdan
Sikorski
Dear Malcolm,
Morley and others Looking for infectious
trigger (as a main cause) of atherosclerosis seems to
me a futile exercise. It is logical I hope that diseased organism would be more
predisposed to infection or colonization by normally non-pathogenic or kept-in-check
organisms. For years people have been trying to pin-point a causative organism on MS and
have failed. The problem is that most MS patients come down with all sorts of
infections,
because as you know their immune system is off the track big time.Secondly,
atherosclerosis as you know is not a general disease - it is focal (“localized in
regions of sharp curvatures and branching”) in nature and in many cases found
exclusively in very specific regions of particular arteries. As some of you might have
seen during visits to prosectorium, in some individuals artery blockages are found in the
femoral arteries but not
in the carotids. Some arteries never develop atherosclerosis, and in coronaries apparently
atherosclerosis disappears as they enter the muscle! If it were infection-based you would
need a pretty good explanation for those strange preferences. I have found two
excellent chapters (21 & 22) on the mechanism of atherosclerosis in the “Handbook
of Bioengineering” (1987) R Skalak & Shu
Chien eds. Mc Graw-Hill Book Company. Amazing that such an information is not available in
many modern physiology and pathophysiology textbooks. I guess engineers do not buy crap
that has invaded (been pushed in by drug lobby?) “respectable” medical textbooks
these days. Whatever happen to Best & Taylor, vintage 9th edition. Some of
you claim that atherosclerosis is initiated within endothelial cells by specific
defects.
Yet atherosclerotic changes begin in the intima!, starting with a smooth muscle
proliferation and then build up of fat and cholesterol (which nota bene has to be made in
situ (Stout!!!) under the promoting influence of insulin. Hong Li describes the process of
HMGCR upregulation in the endothelium. I bet the same happens in the smooth muscle cells
in response to ischemia (unoxia) or a similar assault, as is the case in kidney
(Zager). Why? I do not know, but nutrition must have an influence, as obviously has the mechanical
stress. It is only logical that well nourished body (blood vessels) can tolerate
mechanical stress better than malnourished one. As to infective agents being responsible
for diseases (?) - I would like to point your attention to an excellent and “very
controversial” article in the last Nexus by Greg Fredericks. Super-microscopes and
the mysteries of morphogenesis. You may also try the website nu-lookbiologics@bigpond.com.
Does the name Bechamp or Rife ring the bell? Is it possible that what we were told in
microbiology classes is not exactly correct? Regards to you all Bogdan
Robert
Sieber
Dear sceptics Under
http://link.springer.de/link/service/journals/10096/contents/01/00647/paper/s10096-001-0647-3.pdf
you can find the following publication of H. M. Freidank, A. Lux, P. Dern, U. Meyer-Konig,
T. Els Chlamydia pneumoniae DNA in
Peripheral Venous Blood Samples from Patients with Carotid Artery Stenosis Eur J Clin Microbiol Infect Dis (2002)
21: 60-62 Regards Robert
Paul
Rosch
The late Meyer Texon
showed that atherosclerotic deposits tended to occur on the inner surface of arteries
where blood flow was the fastest (bifurcation of the aorta very sharp curves in
arteries)
since negative pressure was greatest based on the physics of closed hydraulic systems and
Bernoulli’s theorem. However, this was one of only many factors that influenced the
severity of such lesions.
Morley
Sutter
Dear Malcolm, Thank you for your incisive and erudite comments. Your points are well taken. I would
never underestimate microbes and personally think that they have driven much of human
history. Is there any explanation for the reduction in the prevalence of
atherosclerosis in North America? It seems negatively correlated with the
number of MacDonald Hamburger outlets. Particularly if atherosclerosis is triggered
by more than one microbe, the cycle length of the prevalence of atherosclerosis would
be quite unpredictable. The differing
prevalence of atherosclerosis in South Asians and Blacks living in the USA could be due to
genetic susceptibility to the effects of one or more microbes. We know that past
history (i.e., selection) as well as the genome, probably alter resistance to
syphillis,
TB and small pox. Why not to other microbes?
In regard to Finland, I have no explanation and do not know the
genetic make-up or secular characteristics of the religious groups. Do you have an
explanation? In respect of
Japan, I have read that the incidence of atherosclerosis has decreased despite
industrialisation (stress?) and introduction of a Western diet (and
MacDonalds).
Can you propose an explanation?
It might be possible to observe fatty streaks using
MRI, but I don’t know. The point is that all sorts of observational techniques
could and should be applied to further defining the precise pathology of
atherosclerosis. I would adhere to the
philosophical position enunciated in my Perspectives article. We need intervnetional
studies based on the best epidemiological evidence. The fat-in-the-diet intervention
has failed. Let’s try something else: microbes deserve consideration for
interventional studies. Someone
has said that most scientific discussions are like two individuals playing golf whereas it
is tennis that should be played. Thank you for playing tennis. I hope that I
have returned the ball. Regards,
Morley
Malcolm Kendrick
Morley, My
first point would be, can you make your point size a bit bigger, I need a magnifying
glass. I do have an
alternative explanation. Uffe is tearing it apart as we communicate, but it took me one
hundred and seventy eight pages to explain - and a few people now think that I may be
close to the true causes of CHD. My
serve, try this for size: The
stress of social dislocation is a primary cause of CHD (there are other things as
well,
but you don’t want a one hundred a seventy eight page e-mail, I suspect). Thus, Japanese who move from
Japan to the USA (and don’t change their diet) suffer a rate of CHD of about four
times that of native Japanese. Those Japanese who maintain a traditional Japanese
lifestyle in the USA retain native Japanese rates of CHD
Asian Indians - who emigrate, suffer very high rates of CHD
wherever they go, and whatever they eat. And Indians living in cities in India
suffer much higher rates of CHD than rural Indians (with no change in diet) The USA had an explosion
of immigrants in the early part of the twentieth century, this was followed by an
explosion in the rate of CHD in the middle part of the twentieth century. And is now
followed by a fall, as the first and second generation immigrants are being replaced by
third and fourth generation immigrants - who are better integrated into American society,
and have better develop social structures in place.
The breakdown of communism in Eastern Europe has been
followed by huge change, destruction of old ways of life etc. and the rate of CHD has
exploded. Finns with
Eastern Orthodox religion are ‘immigrants’ Lutharians are well-established
Finns. Lutharians suffer one fifth the rate of CHD.
The social dislocation in Japan
following the second world war is now gone, and Japanes society is more
settled. In
short, when you
tear apart the social support network, you create levels of chronic stress that lead to
HPA-axis abnormalities, syndrome X, insulin resistance, abdominal obesity and a very high
rate of CHD. Thirty
fifteen, your shot. Regards Malcolm
Jerome
Sullivan
Dear Malcolm, I am not an
expert in Brazilian cardiovascular epidemiology, but it does appear that women overall may
have more CHD than men in Brazil. However, is this CHD at all ages, or is there a male
disadvantage among young subjects?
Clearly the vast preponderance of CHD occurs in older men and women. But, the pattern that
inspired the iron hypothesis concerns the sex difference while the women are
menstruating.
Do you have definitive data on this question for Brazilian populations? I note one paper
reporting a series of MIs in Brazilian patients under 40 in which 90% of the subjects were
male (1), suggesting a markedly lower rate in younger women. A higher rate for older women
is not necessarily inconsistent with the iron hypothesis (2;3). With replenished iron
stores, the older women’s risk may be more accurately determined by other risk
factors.
For international comparisons, the role of iron in heart disease may be significantly
modified by cultural practices, dietary practices, distribution of all relevant genetic
polymorphisms and/or epidemiology of infectious diseases. These may affect the patterns of
iron acquisition as a function of age in men and in women, and may also modify the impact
of a given iron storage level on disease expression.
The hypothesis that iron depletion protects against ischemic heart disease does not imply
that the protection cannot be overwhelmed by sufficiently high levels of some other risk
factor or combination of risk factors. This could be the basis for explaining anomalies in
various population groups worldwide. However, my working hypothesis is that iron depletion
greatly diminishes the impact of other risk factors. The sex difference in disease
expression in familial hypercholesterolemia may be an extreme example of protection by
iron depletion against an otherwise extreme disease promoting stimulus (quote from
reference 4): “The remarkably low incidence of clinically apparent heart disease in
young women with familial hypercholesterolemia is further evidence that uncouples disease
rates from cholesterol and lipoprotein concentrations [5,6,7]. Young women with familial
hypercholesterolemia have plasma cholesterol concentrations equal to, or perhaps greater
than [7], those in young men with the disorder. From childhood, affected men and women
usually have plasma cholesterol levels of greater than 600 mg/dL, i.e., roughly three
times the upper limit of normal as defined by the National Cholesterol Education Program.
However, the young women have no more clinically evident heart disease than their
unaffected female relatives, while the young men have a large excess of cardiovascular
events. This phenomenon is a key anomaly for the cholesterol
hypothesis. Cholesterol
levels in these young women are at levels thought to be toxic. Nonetheless, the women are
protected from heart disease. Women with the disease are clearly susceptible to the
development of heart disease since their event rate increases rapidly after about age 45.
“The anomaly may be explainable within the context of the iron theory as
follows: The
young women are protected from the development of heart disease as long as they continue
to lose excess iron through regular menstrual blood loss. The regular loss of excess iron
in the young women with the disease boosts endogenous antioxidant defenses by suppressing
damaging iron-catalyzed reactions. Iron depletion may have an antioxidant effect as strong
as that of BHT in the cholesterol-fed rabbits discussed above [8].
“Animal experiments suggest that iron depletion has a potent antioxidant effect in
vivo [9,10,11,12,13]. There is also direct experimental evidence in humans suggesting that
decreasing the level of stored iron increases the plasma concentration of HDL and the
resistance of LDL to oxidation [14]. These effects of iron depletion in humans strongly
support iron loss as a mechanism for the protection of young women with familial
hypercholesterolemia. Even monumental levels of cholesterol may not be inherently
hazardous so long as stored iron is absent.”
Sincerely,
Jerome
Reference List
1. Tanajura
LF, Piegas LS, Timerman A et al. [Acute myocardial infarction in patients under 40 years
of age]. Arq Bras Cardiol. 1990;55:237-240.
2. Sullivan
JL. Iron and the sex difference in heart disease risk. Lancet. 1981;1:1293-1294.
3. Sullivan
JL. The sex difference in ischemic
heart disease. Perspect
Biol Med. 1983;26:657-671.
4. Sullivan JL. Iron versus
cholesterol—perspectives on the iron and heart disease debate. J Clin Epidemiol. 1996;49:1345-1352.
5. Sullivan
JL. The iron paradigm of ischemic heart disease. Am Heart J. 1989;117:1177-1188.
6. Stone
NJ, Levy RI, Fredrickson DS et al. Coronary
artery disease in 116 kindred with familial type II hyperlipoproteinemia. Circulation.
1974;49:476-488.
7. Hill
JS, Hayden MR, Frohlich J et al. Genetic and environmental factors affecting the incidence
of coronary artery disease in heterozygous familial hypercholesterolemia. Arterioscler
Thromb. 1991;11:290-297.
8. Bjorkhem
I, Henriksson-Freyschuss A, Breuer O et al. The antioxidant butylated hydroxytoluene
protects against atherosclerosis. Arterioscler Thromb. 1991;11:15-22.
9. Sullivan
JL, Till GO, Ward PA. Iron depletion decreases lung injury after systemic complement
activation. Fed.Proc. 45, 452. 1986.
10. Sullivan
JL, Till GO, Ward PA et al. Nutritional iron restriction diminishes acute
complement-dependent lung injury. Nutrition Research. 1989;9:625-634.
11. Andrews
FJ, Morris CJ, Lewis EJ et al. Effect of nutritional iron deficiency on acute and chronic
inflammation. Ann
Rheum Dis. 1987;46:859-865.
12. Chandler
DB, Barton JC, Briggs DD, III et al. Effect
of iron deficiency on bleomycin-induced lung fibrosis in the hamster. Am Rev Respir Dis.
1988;137:85-89.
13. Patt A,
Horesh IR, Berger EM et al. Iron depletion or chelation reduces
ischemia/reperfusion-induced edema in gerbil brains. J Pediatr Surg. 1990;25:224-227.
14. Salonen
JT, Korpela H, Nyyssonen K et al. Lowering of body iron stores by blood letting and
oxidation resistance of serum lipoproteins: a randomized cross-over trial in male smokers.
J Intern Med.
1995;237:161-168.
Morley Sutter
Dear Malcolm, I
hope the font is a better size now.
There are many attractive features to your “Rent in the
Social Fabric” hypothesis of the etiology of atherosclerosis. It is
however,
difficult to disprove or to test. Has any one shown that intervention to repair the
social fabric has reduced the prevalence or otherwise altered the course of atherosclerosi
and more importantly shown this in a blinded randomised situation with appropriate
comparison groups (controls)? Exercise
does not improve survival post myocardial infarction (Dorn et al. Circulation 1999 100:
1764-1769) so perhaps you would agree that the usefulness of exercise is questionable
in spite of the numerous papers correlating exercise with lessened incidence of
atherosclerosis in epidemiologiacl terms. This emphasises the need for
interventional studies before drawing conclusions.
It seems that the epidemiology of
psychological stress as a trigger for atheroscleosis is also questionable (Moore et al.,
International Journal of Epidemiology 1999 28: 652-658). What “rent “ in
the social fabric do you then consider necessary to trigger atherosclerosis? Another interesting and developing
microbe story is that of Human Papilloma Virus (HPV) and cervical
cancer. It is indeed complex: not all who are infected with HPV get
cervical cancer (some get condylomata accuminata or other squamous
dysplasias) and only a
few of the some 16 strains of HPV are associated with cervical cancer. I
mention this only to point out the the microbe-host interaction is complex
indeed. But it should be studied. Did my
serve hit the baseline or do we need the ruling of an umpire? Regards, Morley
22.
Mars
Barry Groves
Hello all
I too have difficulty with this hypothesis. When we look at CHD rates
a century ago, the disease was almost unknown. It didn’t ‘take off’ until
the 1920s. If iron were a causal factor, why didn’t the relatively larger amount
of red meat (which contains a greater amount of haem iron) eaten then and
before, have an
apparent effect? I’m sure that plotting the intakes of iron over the past century
will find very little correlation with the rise and decline in the disease in
any country. Barry
Malcolm Kendrick
Dear all, It would be interesting to know what
we all actually agree on. Rather than what we all disagree on. I will make a start.
None of us believe
that CHD is caused by eating too much saturated fat
None of of believe
that CHD is casued by a high cholesterol/LDL level (within reason)
We all agree that CHD
was rare, anywhere in the world, before the middle of the twentieth century
We all agree that the
rate of CHD in the USA (Caucasians) went up from about 1920 to about 1960, and since then
has dropped.
We all agree that
smoking is an important factor in causing, or accelerating, the development of CHD
We all agree that
insulin resistance/syndrome X/type II diabetes is an important causal factor in CHD (That
probably needs a bit of clafication) Any
other offers Malcolm
Jørgen Vesti Nielsen
Malcolm and sceptics Smoking is bad for you, don’t get me
wrong,
but can it really be shown to be an important factor in the development of
CHD?
The MONICA study’s description of the correlations between risk factors and
ischemic heart disease is the best picture we’ll ever get of the real state of
the world. Looking at 37 centres in 26 countries at the same time should give
the same effect as stepping a couple of steps backwards in front of
floor-to-ceiling painting in a museum in order to see the whole canvas instead
of the myopic examination of a five times five cm square in the lower right
corner. There is in the MONICA
study no correlation whatsoever between degree of
smoking and risk of ischemic hear disease in women. Correlation coefficient = - 0,01.
Explanatory power = zero percent. No correlation means no causation. (1) Smoking per se does not contribute to the
incidence of ischemic heart disease in women. If it is related in men it has to be another
factor - the missing link - that at the same time increases the risk in these men and
makes them smoke. Personality types? Hormones? The Japanese and the Chinese are heavy
smokers, they have extremely low rates of ischemic heart disease. How was it now—the
MRFIT study. Didn’t 35 percent of the men quit smoking? With no reduction in risk to
show for it. (Not because of negative effects of the blood pressure treatment such as it
was postulated by the study directors; an analysis of the study’s own figures showed
no relationship(2)) And besides, smoking pattern in USA did not fit the pattern of CHD
as seen in a impressive analysis by Reuel Stallone in 1980(3)
Reference.
1 Kuulasmaa K, Tubstall-Pedoe H, Dobson A, et al. Estimation of contribution
of changes in classic risk factors to trends in coronary-event rates across
the WHO MONICA Project populations. Lancet
2000;355:675-87.
2 Reuel Stallones, ‘Mortality and the Multiple-risk Factor Intervention
Trial’, American Journal of
Epidemiology, 1983, vol. 117, pp. 647-9.
3 Stallone RA, the Rise and Fall of Heart Disease Scientific
American 1980; 243(5):43-49
Jorgen
Jerome
Sullivan
Dear Barry, My understanding the last time I looked at this
specific question was that meat consumption did not achieve its current high level in the
developed countries until some time after 1900. Before that meat was not as freely
available to most of the population. Iron is
of course derived from the environment, however the level of storage iron in the body is
determined by a number of factors other than the amount of dietary iron. One major factor
internationally and historically is the state of public sanitation. Iron-wasting GI and GU
parasites (hook worm, schistosomiasis, etc) remain very common among impoverished people
today. (See quote below.)
Sincerely, Jerome
From: Sullivan JL. Iron versus cholesterol—perspectives on the iron and heart disease
debate. J Clin Epidemiol. 1996;49:1345-1352. [Emphasis added]
“. . . low iron stores might explain some of the very low heart disease rates among
poor people in third world countries. Iron deficiency is widespread among impoverished
populations with high fiber diets that retard iron absorption and large gastrointestinal
parasite loads causing chronic blood loss. It is among these groups that the world’s
lowest rates of myocardial infarction are seen today. Stored iron as a risk factor might
also explain the emergence of an epidemic of heart disease in affluent countries over the
last century. Industrialized countries were at one time similar to poor countries today
with respect to several factors that influence iron retention. Over the last
century, good
public sanitation, iron-fortified foods, commercial promotion of non-prescription iron
supplements, and high levels of meat consumption coupled with low fiber diets have become
common in industrialized countries. The epidemic in cardiovascular disease in developed
countries has arisen during the transition from difficult to easy acquisition of stored
iron.”
Leslie Klevay
Our latest paper
“Low dietary magnesium increases supravertricular ectopy” seems to have appeared
in the Am. J. Clin.Nutr. (75:550,2002). The RDA for Mg seems OK.
I also showed how “Iron overload can induce mild
copper deficiency “ (J Trace Elements Med. Biol. 14:237,2001). Manifestations
included low cardiac copper and increased plasma cholesterol. The latest chapter in the
copper deficiency theory of IHD now is available in PDF. Please open the
attachment. Finally, I agree, more or less, with Malcom’s 22March. Sincerely, Leslie
Malcolm Kendrick
Dear
Jerome, Yes, well, what about the Massai who, according to George Mann, stuff themselves
with meat and blood (thus iron) and have almost no detectable CHD at all (in their
traditional setting). Equally, what of Finland, where the rate of CHD has fallen by ~70%
in the last twenty years. Has their consumption of iron decreased during this time period?
Malcolm
P.S. Why do women with type II diabetes lose their protection against CHD - if it is all
to do with iron?
Morley Sutter
Dear Malcolm, If the
chalk flew up, I won that point. I agree that
everything cannot be measured. The trouble is that in that
circumstance, social context, conditioning and belief or faith are what govern our actions and lead to
acceptance or rejection of best explanations (cf. taste in music and religion).
Would you agree that prospective interventional studies with appropriately
randomised comparison groups and double blind assessment of outcome are the
“gold standard” for seeking best explanations? (If you don’t, it
maight be that you are playing Real Tennis while I am playing Lawn Tennis). Any
simply epidemiological or observational study without intervention and appropriate
comparison groups, cannot determine etiology or possible causality in my world.
While there are a lot of epidemiological observations showing that people who
exercise live longer than those who do not, self selection is a problem so all these
studies are suspect.
In respect of your
query whether all atherosclerotic lesions contain microbes, I don’t
know. There
are several technical problems: one is the need to accurately define the pathology
of a particular lesion. I think that I earlier mentioned caseation as not being
unique to TB, nor is all haemoptysis. The latter can be caused by
malignancy, S. pneumoniae or M. tuberculosis. The pathology of any
potential disease must be painstakingly defined before dismissing a microbe as a causal
factor. Failure to find a microbe might mean that a different disease was present.
Identification of microbes also is difficult and antibodies are inadequate for this
purpose. The Mantoux or Tuberculin test for TB can demonstrate
that exposure has occurred, but in overwhelming TB, the Mantoux test can be negative.
I therefore am uncertain as to the cause(s) of what is termed
atherosclerosis. I am
also a pragmatist and former physician who suffers from the idea that most diseases should
be treatable or preventable. It is too difficult to prevent “social
disruption” ecxcept by increasing income. I believe that income is
negatively correlated with death due to atherosclerosis, so increasing income might
help,
but not greatly. Tennis anyone? (Preferably Lawn, I don’t have the necessary
court for Real Tennis). Regards, Morley
23.
Mars
Jerome
Sullivan
Dear Malcolm, The
Masai - What are the actual iron status measurements on Masai in their traditional
setting? I don’t have reported numbers and there may be none available, however it is
by no means clear that they were iron overloaded, and indeed may have been iron
deficient.
In that part of the world, hookworm and schistosomiasis are endemic and, in rural areas,
are associated with iron deficiency anemia in a significant percentage of adults (1-4).
Again, iron storage levels are not a simple function of the amount and quality of dietary
iron. Even large intakes of iron can be associated with iron deficiency
anemia, if there
is chronic blood loss, eg from GI or GU parasites.
Another factor in both the uptake of iron from diet and the impact of iron on disease
expression is vitamin C status. Vitamin C can enhance iron absorption (5). Low vitamin C
levels also appear to decrease the impact of high iron levels (6). Again, the knowledge
base on this question is spotty, but it is likely that traditional Masai had low ascorbate
levels (7).
A comprehensive answer to your question on iron and heart disease in traditional Masai
would also need to consider life expectancy among these people. Did traditional Masai live
long enough to experience the chronic diseases of the industrialized world?
The Finns - The iron hypothesis does not offer an obvious explanation for decreases in
coronary disease rates over the past couple of decades. This failure does not mean that
the core hypothesis, that iron depletion protects against ischemic heart
disease, is
invalid.
My working hypothesis is that iron depletion decreases the effect of other risk factors.
An extreme example, noted in an earlier message, may be the remarkably low rate in women
heterozygous for familial hypercholesterolemia so long as they continue to menstruate (8).
Their cholesterol levels are equal to men with the disorder or possibly slightly higher
from birth, however disease onset is markedly delayed in comparison to men.
In iron replete subjects such as Finnish men and postmenopausal women, other risk factors
would have a greater impact on disease rates and may be responsible for trends in disease
rates over time.
Diabetic women - If some other factor is capable of eliminating a protective effect of
iron depletion, this does not invalidate the core hypothesis. Judging from the example of
women with familial hypercholesterolemia, iron depletion may not be overwhelmed by even
heroic levels of cholesterol. Perhaps diabetes can overcome a protective
effect. A
comprehensive answer to the role of iron in diabetic women would require actual
measurements of iron status and coronary disease rates as a function of age in diabetic
women.
The interactions of iron and diabetes in heart disease are not yet adequately
defined.
Skeptics might be interested in an important recent paper showing protective effects of
iron chelation in the hearts of diabetic patients (9). A general account of
iron, diabetes
and heart disease is beyond the scope of this reply (some interesting recent papers
include the following: 10-13).
Sincerely, Jerome
1. Hall
A, Latham MC, Crompton DW et al. Intestinal parasitic infections of men in four regions of
rural Kenya. Trans R Soc Trop Med Hyg.
1982;76:728-733.
2. Greenham
R. Anaemia and Schistosoma haematobium infection in the North-Eastern Province of Kenya. Trans R Soc Trop Med Hyg. 1978;72:72-75.
3. Latham
MC, Stephenson LS, Hall A et al. A comparative study of the nutritional status, parasitic
infections and health of male roadworkers in four areas of Kenya. Trans R Soc Trop Med Hyg. 1982;76:734-740.
4. Latham
MC, Stephenson LS, Hall A et al. Parasitic infections, anaemia and nutritional status: a
study of their interrelationships and the effect of prophylaxis and treatment on workers
in Kwale District, Kenya. Trans R Soc Trop Med
Hyg. 1983;77:41-48.
5. Olivares M, Pizarro F,
Pineda O et al. Milk inhibits and ascorbic acid favors ferrous
bis-glycine chelate bioavailability in humans. J Nutr. 1997;127:1407-1411.
6. Nienhuis
AW. Vitamin C and iron. N Engl J Med.
1981;304:170-171.
7. Davies
JD, Newson J. Low ascorbate status in the Masai of Kenya. Am J Clin Nutr. 1974;27:310-314.
8. Sullivan
JL. Iron versus cholesterol—perspectives on the iron and heart disease
debate. J Clin Epidemiol. 1996;49:1345-1352.
9. Nitenberg
A, Ledoux S, Valensi P et al. Coronary microvascular adaptation to myocardial metabolic
demand can be restored by inhibition of iron-catalyzed formation of oxygen free radicals
in type 2 diabetic patients. Diabetes. 2002;51:813-818.
10. Hua NW,
Stoohs RA, Facchini FS. Low iron status and enhanced insulin sensitivity in lacto-ovo
vegetarians. Br J Nutr.
2001;86:515-519.
11. Facchini
FS. Effect of phlebotomy on plasma glucose and insulin concentrations [letter]. Diabetes
Care. 1998;21:2190.
12. Sasaki K,
Hashida K, Michigami Y et al. Restored vulnerability of cultured endothelial cells to high
glucose by iron replenishment. Biochem Biophys Res Commun. 2001;289:664-669.
13. Tuomainen
TP, Nyyssonen K, Salonen R et al. Body iron stores are
associated with serum insulin and blood glucose concentrations. Population study in 1,013
eastern Finnish men. Diabetes Care. 1997;20:426-428.
Barry Groves
Dear all
While I agree with most of Malcolm’s “We all
agree”, I’m not so sure about smoking. I am aware that CO from smoking
increases carboxyhaemoglobin in blood and reduces its ability to transport oxygen, but I
have yet to find anything other than assumption about a causal link to CHD (or, for that
matter, lung cancer). The hypothesis that smoking could be a risk
factor for CHD originated in 1978 from: The Pooling Project Research Group:
relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG
abnormalities to incidence of major coronary event. Final report of the Pooling Project. J
Chron Dis 1978; 31: 201-305. But
again, we had been smoking for centuries before this without overt harm.
Also, in plotting
trends in various ‘risk factors’ thoughout the USA, Stallones found to
correlation between trends in smoking habit and incidence of CHD. Stallones
R A. The Rise and Fall of Ischemic Heart Disease. Scientific American. 1980: 243
(5); 43. Here are a couple of quotes
you might like:
“Tobacco,
divine, rare, superexcellent tobacco, which goes far beyond all their
panaceas, potable gold, and philosopher’s stones, a sovereign remedy to all
diseases.” Robert Burton (1577-1640) “It is now proved beyond doubt that
smoking is one of the leading causes of statistics.” Fletcher Knebel, Readers’
Digest, Dec 1961.Barry
Dear Jerome Certainly there were great strides made in
improving sanitation in Britain in the 19th century and, probably throughout
the rest of the industrialised world. But iron and steel industry have been spewing wastes
into the environment ever since the industrial revolution—with no sign of
CHD.
Dietary changes were
much more gradual and dissimilar in different countries. Yet the dramatic rise suddenly
happened everywhere at roughly the same time—during the 1920s. It was 1920 in the
USA, 1928 in Britain. At that time we in Britain ate ‘black pudding’,
a type of sausage made of blood. And in parts of the nation we still do.
It’s a favourite for breakfast.
CHD is a disease of
affluent nations, but it is more prevalent in poorer elements in those nations. These are
not people who live on red meat, as the poor generally cannot afford it. Iron
deficiency anaemia among the poor has a higher incidence than among the rich. Also
the poor may more prone to parasites as sanitation in poorer areas is not so good. If the
hypothesis that iron sufficiency is a risk factor for CHD is right, surely we would expect
less CHD among the poor, but that is not the case. Or are other factors in
poorer society masking a possible protective effect of iron deficiency?
Then
again, in view of
Leslie Klevay’s ‘Advances in Cardiovascular-Copper Research’, is the
problem iron sufficiency or could it be copper deficiency. The way we farm today, I
suspect that depleted copper in soils where food is produced is a more
likely candidate for suspicion. Sincerely Barry
24. Mars
Fred and Alice
Ottoboni
Dear
Skeptics: There
were questions several days ago about the mechanism of heart disease causation by smoking.
What follows is based on Kilmer McCully’s book, The Heart Revolution,
HarperCollins Publishers, 1999. Carbon
monoxide in inhaled smoke enters the bloodstream via the lungs. It combines with
pyridoxamine, a form of vitamin B6, and inactivates it. The resulting deficiency of
B6 allows the blood homocysteine level to rise. High homocysteine levels damage
the cells and tissues of the arteries. This leads to arteriosclerosis or hardening
of the arteries (McCully, pages 9, 133-34).
Cholesterol and fat are then deposited in these damaged arteries and
this leads to atherosclerosis. Arteriosclerois must occur before atherosclerosis can
occur (McCully, page 14).
The fact that high levels of
homocysteine in the blood are the underlying cause of heart disease explains the
“French Paradox”. Homocysteine levels are higher in northern Europe than
in southern Europe, thus heart disease rates are higher in northern Europe even though the
French eat more fat and more cholesterol than in the north (McCully, page 15). The cholesterol theory does not explain the
French Paradox because the cholesterol theory is not fact.
Vitamin C also plays a role. Homcysteine is removed from
the body by biochemical conversion into a inorganic sulfate. This conversion
largely depends upon vitamin C. Without enough vitamin C in the diet, homocysteine
builds up in the blood. When this happens, blood vessels disintegrate, blood
platelets don’t work right, and the small blood vessels in the gums and skin start to
hemorrhage (McCully, pages 161-62).
It has been known for many years in the field
of occupational hygiene that chronic exposure to carbon monoxide caused heart
disease. This problem was controlled by reducing carbon monoxide exposure levels.
Thus human exposure studies prove the relationship between heart disease and carbon
monoxide. (We do not have a reference available here, but know this from many years of
work in the field) McCully
has not only provided the biochemical explanation for carbon monoxide/heart disease, but
also, in our opinion, the best answer available today for one of the true
underlying causes of heart disease, namely homocysteine buildup caused by
deficiencies of vitamins B6, B12, and folic acid (and vitamin C). These vitamins are
required for the biochemical degradation of homocysteine.
Fred and Alice
Ottoboni
Uffe Ravnskov
Skeptics! May I suggest participants in
this interesting discussion to distinguish between atherosclerosis and CHD, two different
conditions with different causes. Further, atherosclerosis by itself is most certainly
many different things. Let me explain.
It seems questionable to use the term “disease” for the loss of elasticity and
the increasing stiffness of the arterial walls, that occur with age. This must be a normal
and most useful process, because if our arteries at age thirty were just as soft and
elastic as in the newborn the heart would not be able to perform properly. The much larger
amount of circulating blood in the adult and the larger distance to the periphery demands
relatively stiff arteries for the blood to be
distributed at the necessary speed and efficiency. William Stehbens and Meyer Texon have presented much evidence that it
is the hemodynamic forces that are causing this stiffness in some way or
another.
Saul et al has argued convincingly that it is the transmural or net
pressure, e.g.
the difference between the pressure inside and outside the artery, that is crucial for the
development of atherosclerosis (Med Hypotheses 1991;36:228-237; and 1999;52:349-. Somebody
with access to Med Hypotheses, please send the files). A few of the examples they
have used to illustrate their point are that atherosclerosis is prevalent in coronary
arteries because they are surrounded by the negative pressure of the thoracic
cavity, and
that atherosclerosis is absent in the intramural coronary arteries and in arteries located
in bony channels because their surroundings prevent them from being dilated during systole
– they need not be stiff. The localized changes, seen around branchings, may be
fortifications at places where the mechanical stress is particular strong, as ssuggested
by Stehbens and Texon. Thus, assume
that atherosclerosis may be a normal and
harmless phenomenon, as long as it is not
too advanced. If so, the question is not what causes atherosclerosis, but what makes
atherosclerotic plaques dangerous? What makes them grow into the lumen? What makes them
soften? What makes them unstable? Could it be recurrent microbial invasions?
Antigen-antibody formation? Toxic chemicals? Oxidants? Imbalance of normal constituents
such as homocystein? And which are the conditions, environmental or
hereditary, that
smooth such worsening? Here is room for many
risk factors and none of them need to be obligatory.
In the presence of advanced atherosclerosis the risk of
myocardial damage (CHD) is obviously increased and risk factors for atherosclerosis
therefore may be risk factors for CHD also. But CHD may occur without atherosclerosis.
About 20 % of those who die from an acute myocardial infarction have no coronary
atherosclerosis at all which means that something else may obstruct the coronary vessels
to cause CHD. This “something else” may be an exaggerated contraction of the
coronary arteries or arterioles. For instance, cocaine effectively makes coronary arteries
contract and CHD is a common cause of premature death in drug addicts. There are most
probably other drugs and other exogenous factors with a similar effect, but the most
common cause may be adrenal hyperactivity. Again, these mechanisms opens for further risk
factors, but risk factors for CHD, not necessarily for atherosclerosis. From the above
follows that it is highly unlikely that we ever will find a single cause of
CHD.
There
is more
to disagree about. I am most sceptical to the so-called CHD epidemic. One of the greatest
mistakes in cardiovascular epidemiology has been to rely on vital statistics. In my book I
have given several examples of the many types of bias involved in the activity of writing
death certificates. When it comes to CHD mortality, remember that this disease was unknown
by most doctors in the start of the 19. century. Slowly, knowledge improved, but it was
the introduction of ECG in clinical practice
during the thirties and forties that gave
doctors the possibility to use that diagnosis during life with reasonable
accuracy.
Further progress in diagnostic skill was achieved when analysis of the transaminases
became routine in the fifties. These diagnostic improvements occurred during the rise of
the so-called CHD epidemic. Recall also that a post mortem is performed in a small
minority of the deaths only, in particular outside university hospitals and to tell
anything about the cause of death without a post-mortem, is highly inaccurate – see
my book .The “epidemic” of CHD is therefore most likely due to a steadily
increasing habit of using that diagnosis on the piece of paper called death
“certificate”. At least, it is impossible to exclude that
possibility. Several
authors have pointed to this phenomenon (Read for instance Stehbens WE. Lancet 1987;I:606;
Stehbens WE. Med. Hypothesis 1995;45:449-54). Secular changes of CHD mortality are simply
useless as argument for or against any hypothesis about the causation of CHD, let alone
the causation of atherosclerosis.
I do not agree either that the CHD rate has decreased during the last 20 or 30
years. CHD mortality has declined, yes, but the prevalence has increased, most probably
due to better treatment – more people survive an acute coronary (see for instance the
figures from Framingham presented by Sytkowski et al. N Engl J Med 1990;322:1635-41).
I also oppose the common confusion of risk factors with cause. Smoking is not
necessarily causing CHD or atherosclerosis just because the risk ratio of smokers is
larger than one. Smokers are different from non-smokers in many ways – just ask the
question: why do you smoke? – and a number of additional, potential causes
appear.
I agree that it
is difficult to prove a protective effect of physical
activity because physical activity demands good health. However, I have analysed a large
number of observational and experimental studies of sequential changes of cholesterol and
sequential changes of coronary atherosclerosis. In at least 22 studies dose-response was
analysed between these two factors and the only study that reported dose-response
used regular, controlled and graded physical activity as intervention. In that study degree
of exercise was inversely correlated with degree of atherosclerosis growth (Hambrecht
et al. J Am Coll Cardiol 1993;22:468-77.). It is also the only trial that has reported
regress of atherosclerosis in a substantial number of patients. In conclusion, to play tennis demands
agreement about the rules. Uffe
25. Mars
Malcolm Kendricks
Uffe, What fun. (and Morley, I am playing lawn tennis -
I hope). I did think it would be interesting
to see what everyone agreed on. So far, I think, I am left with one fact. CHD has nothing
to do with saturated fat consumption. Various poeple disagreed with smoking as a
cause, a
few do not agree that death rates from CHD did go up, in the twentieth
century. Others
think that it hasn’t gone down in the USA over the last thirty years. Keep
going, and
we will end up in the same place as Rene Descartes (I think, therefore I am). Or, my
favoured alteration, ‘I’m pink, therefore I’m spam.’ I shall try again.
Does everyone agree with the following fact?
The rate of CHD varies widely between different populations. Malcolm
Lesley, Thanks. I think that I now have three facts that everyone is willing to agree with:
1: The rate of CHD has nothing to do with the consumption of saturated
fat
2: The rate of CHD varies considerably from population to population
3: The thing that kills you with CHD is a lack of blood supply to the
heart muscle
I think that one of the biggest problems that I can see looming in an attempt to build
more of a consensus is in the definition of atherosclerosis. Like Uffe, I find it very
difficult to get a handle on what people mean by this term. On the basis that the final
pathological mechanism in CHD is rupture of
an atherosclerotic plaque, leading to clot formation within the coronary
artery, then
infarction of the heart muscle, it is presumably unstable plaques that are the problem,
not generalised atherosclerosis. Therefore, could I throw open a several part question -
to which I do not have an answer. Is generalised atherosclerosis a normal part of the
ageing process? If so, what exactly is the disease, in CHD, that kills people
prematurely.
Is it the development of unstable plaques - or is it something else. Or are there several
parallel process going on within the artery any, or all of which, can lead to
occlusion? Personally, I do not like the idea that there are several diseases processes all going on
at the same time. Medical history would also suggest that single/coherent disease
processes usually emerge from initial confusion, once people more clearly understand what
is going on. But within our group we have those in favour of the glycaemic index, those
who favour iron overload, those who favour stress, those who favour copper deficiency etc.
I would suggest that they cannot all cause occlusive plaque development. So, perhaps we
could agree on a discussion which starts with the disease process that causes plaque development. Build from the bottom-up so to
speak. I only suggest this because, at present, this discussion group – whilst fascinating - is beginning to resemble the Tower
of Babel. Malcolm
Morley
Sutter
Dear All: I
certainly agree that the diagnosis, pathological criteria and terminology of
atheroscelrosis is loose and often inadequate. Does “Monckeberg’s medial
sclerosis”, which was supposedly mainly due to smoking, still exist? Coronary
artery disease of course has several causes, including syphillis. Therefore it is
imperative to be as accurate and precise in our terminology as emphasised by Uffe.
To follow up on smoking, if one stops smoking your chances of getting lung cancer are
reduced almost to non-smoking levels after 5 years. According to JS Yudkin
(BMJ 1993,
306:1313-8) if one stops smoking, after 10 years deaths due to “CHD” would be
reduced by 2.7 per 1000 persons from the baseline (smoking) value of 14.4 per1000.
This is not a very large effect. Regards to all. Morley
Alena Langsjoen
Dear Malcolm, Uffe, et al., Malcolm’s latest email made me think of a Lewis
Thomas quote that I found on a book cover of Edward R. Gruberg & Stephen A.
Raymond’s book (copyright 1981 and out of print now), titled: “Beyond Cholesterol. Vitamin B6,
Arteriosclerosis, and Your Heart”. Since
last Summer I have had a used book search for this book on Amazon.com to be shipped
directly to Uffe as a present from us...I thought it would be a good addition to
Uffe’s library but so far a copy was not found by Amazon. As Uffe, these
authors did an excellent critical review of the history of the cholesterol
hypothesis. Anyway, here is the statement from the jacket of the book’s cover
that Malcolm’s note made me think of today: “....Even
people who seem healthy and carefully monitor their diet, exercise and enviroment are
dying from arteriosclerotic disease. But is there a single cause, an underlying
mechanism behind the risk factors that relates to all of them? As Lewis Thomas has
written: “Every disease that we do know about and for which we have really
settled the issue, so that we can either turn it off, or prevent it once and for all -
every such disease turns out to be a disease in which there is one central
mechanism”. On the basis of years of research into every aspect of the
disease,
Dr. Gruberg and Dr. Raymond have assembled for the first time the evidence behind a
different theory—one involving a single compound in the bloodstream called
homocysteine, and its relationship to vitamin B6 and our intake of protein—which
could very well be a breakthrough in medical science....” Of course, in the book, the authors do give credit
to the pioneer of the homocysteine theory, our fellow member, Kilmer McCully.
It’s been probably 10 years since I read the whole book, but they primarily
concentrate on B6. We all know that folic acid, B12 and biotin and perhaps some
methyl donors are also important in keeping homocysteine metabolized
properly. By
the way, Edward R. Gruberg and Stephen A. Raymond are both neurophysiologists
(PhD’s). They were professors at MIT when the book was written and it appears
that they wrote this book outside of their fields. After they wrote this
book, they
went on to other things. Last I checked, Dr. Gruberg and was investigating
“the neural mechanisms underlying selective attention
to visual stimuli” in the frog at Temple University in Philadelphia. I
am not sure where Dr. Raymond is (he may still be at MIT) and judging from his abstracts,
his work involves sensory nerve fibres etc. So,
back to Lewis Thomas’ quote. The big question is, is there just one central
underlying mechanism for the cause CHD (and strokes)? Can CHD be ‘cured’ only if
there is just one central mechanism for the cause? All
my best, --Alena
26. Mars
Malcolm Kendrick
Barry,
Thanks. I am
finding this a slightly weird format in which to gain any form of consensus. I assume that
most people are listening (or reading most e-mails). But people respond at different
times, to different questions. First, next question, does anyone think that my attempt to
gain some sort of a consensus has any merit or am I, to use a good old British expression,
pissing in the wind. If people think
that attempting to build a consensus has any value, does anyone have any idea how to do it
better than I am currently managing? Which is not that well. I just thought that the idea of writing a
‘sceptic’ book was probably a good idea, but I didn’t think it would be
much use if Chaper One was: Why it is all to do with homocysteine. Chapter
two: Why it has
nothing to do with homocysteine. Chapter three: Why CHD is caused by trans-fatty
acids.
Chapter four: Why CHD is not caused by trans-fatty acids etc. etc. So I thought that, if we could at
least find a few agreed starting points, it may be possible to build up from
there. Also,
of course, there is nothing wrong with a book that presents a series of competing
hypotheses to the cholesterol hypotheses. But I thought that such a book would have to
start from some agreed ‘facts’ e.g. the rate of CHD went up in most
industrialised countries during the twentieth century. But there are those, in this group,
who disagree with this fact. Or, the rate of CHD has gone down in many countries
e.g.
Finland, in the last thirty years (often dramtically). Again, there are those who disagree
with this ‘fact.’ Or that smoking (whilst not a primary cause) does accelerate
the development of occlusive atherosclerotic plaques. Once again, many people don’t
agree with this. Where can you go from
here.
Where can anyone go? If there is not one single fact that people can agree with, then we
are completely stuck. Uffe, any suggestions? Malcolm
Uffe Ravnskov
Hi Malcolm I don´t see
disagreements as an obstacle. Long enough the world has been given the impression that
there is unanimous agreement about this and that, in particular when it comes to
atherosclerosis and CHD. Medical science is complicated - we are not studying chemical
reactions in a test tube, but biological mechanisms in homo sapiens, a species which has
occupied most of the habitats on this globe, developed the most fantastic variations of
cultural life and who has survived by eating almost everything in almost all thinkable
proportions. Of course there are major disagreements around such an achievement, but it
would be wonderful, (naive thought I agree), if the world could learn that we have yet
a long distance to walk to find the truths about health and disease. But we know a little,
in particular about what is unimportant, and more may be revealed in this way of writing.
A book with a
presentation of various hypotheses, one for each chapter, followed, in the same chapter,
by critical comments by the devil´s advocate (he has several colleagues in our
group), ending up with the proponent´s answer, could be exciting reading. The question
is, are there any potential customers for such a book outside our group? Uffe
Jerome Sullivan
Dear Malcolm, But
where is the bottom to build up from? There is more to ischemic heart disease than plaque
development. Michael Oliver noted some years ago that (1), as a target for preventive
efforts, ischemic myocardium “is a Cinderella to the ugly sisters of coronary
atheroma and the ‘classic’ risk factors,” since it is “the source of
pain, arrhythmias, failure, and death.” A given coronary plaque can be harmless or
life threatening depending on the vulnerability of myocardium to ischemia. The discussion
is incomplete if it focuses exclusively on plaque development. A “Tower of Babel” accurately
captures Thomas Kuhn’s picture of how scientists respond to crisis. His chapter
“Response to Crisis” (2) is worth reading by every scientist who sees the
failure of the cholesterol paradigm as a scientific crisis, in this case also a pressing
public health crisis. A couple of pertinent
quotes from Kuhn (2): “The early attacks
upon the resistant problem will have followed the paradigm rules quite
closely. But with
continuing resistance, more and more of the attacks upon it will have involved some minor
or not so minor articulations of the paradigm, no two of them quite alike, each partially
successful, but none sufficiently so to be accepted as a paradigm by the group. Through
this proliferation of divergent articulations (more and more frequently they will come to
be described as ad hoc adjustments), the rules of normal science become increasingly
blurred. Though there is still a paradigm, few practitioners prove to be entirely agreed
about what it is. Even formerly standard solutions of solved problems are called into
question.”
“Let us then
assume that crises are a necessary precondition for the emergence of novel theories and
ask next how scientists respond to their existence. Part of the answer, as obvious as it
is important, can be discovered by noting first what scientists never do when confronted
by even severe and prolonged anomalies. Though they may begin to lose faith and then to
consider alternatives, they do not renounce the paradigm that has led them into
crisis.
. . . once it has achieved the status of a paradigm, a scientific theory is
declared invalid only if an alternative candidate is available to take its
place.” Sincerely, Jerome
1. Oliver
MF. Prevention of coronary heart disease—propaganda, promises, problems, and
prospects. Circulation. 1986;73:1-9.
2. Kuhn
TS. The Structure of Scientific Revolutions. Second ed. The University of Chicago Press,
Chicago, 1970.
Morley Sutter
Dear Malcolm: Golf
anyone? I understand your frustration but am leary of concensus in science. It is
one of the reasons the cholesterol hypothesis is so widely accepted. How many NIH or
AHF panels have widely publicised their concensus views on this topic? My credo: If I can
believe the statistics the epidemiologists present, the rates of atherosclerosis differ
among countries and groups. Atherosclerosis
has decreased in several countries.
Smoking increases
the severity of atherosclerosis.
By the way, the
incidence of TB has markedly increased in Russia.
Warm regards, Morley
Malcolm Kendrick
Jerome, I like Kuhn’s stuff, although I am a bit of a
Popper man myself. But, to be prosiac for a moment. Ischaemia is caused by a lack of
oxygen to the heart muscle. Infarction is caused by an absolute lack of oxygen leading to
cell death. There is one basic
cause. The
myocardium is working too hard for the coronary arteries to deliver enough oxygen. In
general, this is because the coronary arteries are narrowed. Chronically, or
acutely, or
acute on chronic. I don’t understand the concept of the myocardium being vulnerable
to ischaemia. The myocardium can only be vulnerable to ischaemia if the blood
supply, and
therefore the oxygen supply, is compromised in some way (unless you have some lung problem
e.g. COPD). Or perhaps I am missing something. Malcolm
Jerome Sullivan
Malcolm Kendrick wrote: “So,
perhaps we could agree on a discussion which starts with the disease process that causes
plaque development. Build from the bottom-up so to speak. “I only suggest this
because, at present, this discussion group - whilst fascinating - is beginning to resemble
the Tower of Babel.”
Dear Malcolm, But where is the bottom to build up from? There
is more to ischemic heart disease than plaque development. Michael Oliver noted some years
ago that (1), as a target for preventive efforts, ischemic myocardium “is a
Cinderella to the ugly sisters of coronary atheroma and the ‘classic’ risk
factors,” since it is “the source of pain, arrhythmias, failure, and
death.” A given coronary plaque can be harmless or life threatening depending on the
vulnerability of myocardium to ischemia. The discussion is incomplete if it focuses
exclusively on plaque development. A
“Tower of Babel” accurately captures Thomas Kuhn’s picture of how
scientists respond to crisis. His chapter “Response to Crisis” (2) is worth
reading by every scientist who sees the failure of the cholesterol paradigm as a
scientific crisis, in this case also a pressing public health crisis. A couple of
pertinent quotes from Kuhn (2): “The early attacks upon the resistant problem will
have followed the paradigm rules quite closely. But with continuing
resistance, more and
more of the attacks upon it will have involved some minor or not so minor articulations of
the paradigm, no two of them quite alike, each partially successful, but none sufficiently
so to be accepted as a paradigm by the group. Through this proliferation of divergent
articulations (more and more frequently they will come to be described as ad hoc
adjustments), the rules of normal science become increasingly blurred. Though there is
still a paradigm, few practitioners prove to be entirely agreed about what it is. Even
formerly standard solutions of solved problems are called into question.” “Let
us then assume that crises are a necessary precondition for the emergence of novel
theories and ask next how scientists respond to their existence. Part of the
answer, as
obvious as it is important, can be discovered by noting first what scientists never do
when confronted by even severe and prolonged anomalies. Though they may begin to lose
faith and then to consider alternatives, they do not renounce the paradigm that has led
them into crisis. . . . once it has achieved the status of a paradigm, a scientific
theory is declared invalid only if an alternative candidate is available to take its
place.” Sincerely, Jerome
1. Oliver
MF. Prevention of coronary heart disease—propaganda, promises, problems, and
prospects. Circulation. 1986;73:1-9.
2. Kuhn
TS. The Structure of Scientific Revolutions. Second ed. The University of Chicago Press,
Chicago, 1970.
Barry
Groves
Hi Malcolm, Uffe and all Hopkins
P N, Williams R R. A survey of 246 suggested coronary risk factors. Atherosclerosis.
1981; 40: 1-52, lists 246 ‘risk factors’ for CHD. Since then many more have been
added and the number now is well over three hundred.
Some
are obviously frivolous, but many have been suggested as serious contenders in the battle
to wreck hearts. We obviously cannot write a book that considers them all, or even all the
more likely ones. I think epidmiology must come to our rescue here.
CHD
is a twentieth century phenomenon. Whatever caused the dramatic rise that began in the
1920s, it cannot have been 246 or more different things: That many could not have all
started at the same time. And if they all really did play a part, we have no hope of
understanding the aetiology of the disease. Was
it better detection that found a ‘new disease’ that had been there for
centuries? I don’t believe so. Physicians were very good at dissecting corpses to
find causes for disease. Had there been the degree of blocked coronary
arteries in the 18th century that we saw in the 20th, I am sure
that it would have been recorded. I
believe that probably no more than two or three factors came together at the time. So, what happened that
could possibly have precipitated that increase in CHD in the 1920s? If atherosclerosis
plays a causal part, it must be something in the late 19th or early 20th
centuries as atheroma doesn’t build up overnight. And, if you have read my
paper, “Why is CHD Declining?”, you will know that I believe something in or
about 1926 started the present decline in CHD mortality we see today in Britain. So what few factors came
into our lives (environment) in the late 19th century and went out of it in the
middle of the 1920s, or were modified at that time? And if homocysteine, or
bacteria, or
inflammation, or iron sufficiency, etc, are causally related to CHD now, what stopped
them affecting us a century ago?
Isn’t this philosophy fun! As to potential
readers,
Uffe, there is the rub. Publishers are in business to make money: they don’t
care what the book is about, so long as it sells. To make money I think this
book will have to be written to appeal to the public at large (I don’t
think that there would be a big takeup in the medical professions as it will not be
politically correct.). And I am not sure how it could be written, to make it appeal to
such a readership—in a publisher’s eyes.
Barry
Tom Clayton
Does anybody know where I can get a list of the 246
“risk factors.”? It just goes to show you how screwed up the medical
establishment is when it is concluded that there are 246 risk factors that, it is
assumed,
if modified, will decrease the “risk” of heart disease. Logically, this is
absurd, as the parameters of what constitutes a risk factor obviously do not exist or they are so faulty as to permit this to happen.
This is more and more like a bureaucracy as each little fiefdom tries to get
more money so that they can do more “research.” If the problem is
solved,
the research money dries up. So that is a big no-no. The intelligent mind
simplifies, not complicates, and to suggest cause and effect for most of these factors is simply
wrong. There are some very basic features that are overlooked, as people continue looking for the
forest without seeing the trees. How about the fact that processed foods did not
exist before the first of the 20
century?
That farmland deprived of its mineral nutrients was rare? That the average
age of death of males was 47 in 1900 and that many of
those deaths were related to infectious disease or trauma? What about the fact that
infectious diseases were often
localized,
because travel was not nearly as widespread as it is today? How do we
really know that CHD disease did not exist where most doctors had no idea what to look
for, and many people died prematurely of other causes? We act like
record-keeping systems were as good as they are today, but the fact is that they were not. Tom Clayton,
27.Mars
Uffe
Ravnskov
Hi Barry CHD was certainly known by a few. But vital
statistics is based on all death certificates of a country and post mortems are performed on a few
only. If no post mortem is performed on 80-90 per cent of the deaths, how could doctors
put the correct diagnosis on the death certificate without any hard evidence for CHD
before death? A true number of individuals dying from CHD every year demands that all
practising doctors in that country know the disease and are able to diagnose it. Without
an ECG apparatus and without access to a laboratory with diagnostic tests to verify the
diagnosis I would guess that the majority of CHD cases were classified as something
else. Uffe
Martin Sturman
Dear All, especially
Barry, Uffe, and Malcolm, I find it
daunting to step into this chaotic discussion and attempt to give only my “two cents
worth”-sans bibliography, no less. I will just add a few comments related to the
correspondence over the past few days about coronary disease. First CHD is Not a new
“disease” -it is, in fact, not a single entity in the first place, but a
spectrum of degenerative/metabolic/genetic/ emotional, and anatomic factors
(remember Paul
Rosch’s comment on Poiseulles’s Law?) that combine in various ways to produce
what we insist on giving a name -a kind of rampant reductionism, not uncommon to medicine
Atherosclerosis and its various forms have been identified in preserved
bodies, including
Egyptian mummies, and going back before, perhaps to the dawn of civilization. The
relation of angina to disease of the coronary arteries was not recognized as a
clinical entity until Hering, I think in the late 19th century, but
historically autopsy studies before the early 1900’s do not offer us any insight into
the prevalence of the condition, prior to modern times. Moreover, the clearcut
progression of various vasculopathies with age-atherosclerosis, medial
necrosis, arterial
calcification-occurring in various vascular territories, cardiac, cerebral,
renal, aorta,
lower extremities,etc. related to age-and sex (plus diabetes, lipid disorders, etc.),
makes it is almost impossible to draw broad conclusions about the occurrence of this
syndrome prior to modern times. This is particularly true since the average life
expectancy in the late 19th Century, was about 40-45 years -or less. As to the 264 Risk factors, they are
Associations, some incontestable (smoking, heredity, hypertension, stress,
diabetes, sex, age), and some factitious, some undiscovered. Even, if strong
statistical data exists or can be extracted from the newest work on CoQ10, nitric
oxide,
antioxidants, infection-all of which may play a role-a cause or result of vascular
disease?, no association is evidence of causality. Unlike diseases of known
etiology, such as the infections diseases, the causation of CHD will never fulfill
Koch’s postulates, simply because coronary disease or vascular sclerosis or
atherosclerosis is not a single entity but an assemblage of them.
Our problem, gentlemen and ladies, is simply one of data drowning. As Finagel’s
law states:
The data we have are not the data we want
The data we want are not the data we need
The data we need are not
available.
I do not agree to any unitary hypothesis of Grand Unified Field Theory of the etiology of
atherosclerosis or CHD, let alone Aging, nor do I think there will ever be
one. If
the physicists want to explain reality with a set of equations and reduce the universe to
one quark or elementary particle, I say, “good show” -but they can never tell me
what strawberry jam tastes like. I do think abnormalities in lipid metabolism play a role
(pace!, members), but other factors, known and unknown, and many
undiscoverable, are important. This doesn’t mean we should not pursue our discussions and
speculations, but let us not get carried away with unprovable assertions. As a great
British physician once said, “They explain the inexplicable by invoking the
unknowable.”
For
the meantime, I will refrain from smoking, and statin ingestion, and keep to my normal
diet: fat, salt , and sugar. This is not meant to be dismissive of attempts to find
factors associated with atherogenesis and vascular disease. I am only
saying, that
in certain realms of medicine, we have to confess that the strict laws of causality do not
hold. But then again, getting back to physics, true causality is an idiot’s
chimera. Any comments? Martin Sturman
Kilmer McCully
In reply to Barry
Groves, the factor introduced in the late 19th century that could explain the
20th century occurrence of coronary heart disease is food processing,
especially extraction of sugar, steel roller press milling of grains into refined flours,
extraction of oils, canning, and the use of chemical additives such as bleach,
bromination, etc. The effect of consuming these refined foods is to decrease the
dietary consumption of the chemically sensitive B vitamins, folic acid and B6, which are
largely destroyed by these methods of food processing. The decreased dietary intake
of these two B vitamins probably led to an increase in blood homocysteine, causing
arterial plaques by a direct effect of homocysteine on the cells and tissues of artery
walls. The reason that mortality from coronary heart disease has declined since
peaking in the early 1960s is the introduction of synthetic folic acid and pyridoxine to
the food supply. These B vitamins are now consumed mainly in the form of voluntary
fortification of cereals and vitamin supplements. Since 1997, folic acid has been
mandated by the flours. The consequence is the nearly doubling of plasma folic acid
concentrations and the significant decline in plasma homocysteine concentrations, as
reported in Framingham Heart Study participants. At a nation-wide conference at the
National Institutes of Health in 1979, the traditional risk factors, such as dietary
cholesterol and fats, smoking, exercise, hypertension, etc were not found to have changed
sufficiently to explain the decline in coronary heart disease mortality in the US since
the 1960s. As I explained in my book The Heart Revolution, the introduction of food
processing with the Industrial Revolution in the 19th century and the use of
chemical additives and other processes in the 20th century is the only
satisfactory explanation for the dramatic changes in incidence of vascular disease in the
20th century. Kilmer S. McCully
Dale Atrens
Dear Barry
–Forgive me for being orthogonal, but I’m really following up an earlier posting
of yours. You mentioned skepticism over the health effects of smoking. I am
not terribly familiar with this area but I am deeply suspicious of ANY argument that rests
heavily on epidemiological research. There is a substantial literature showing that
people who take up smoking are unhealthier to begin with and these initial differences
badly confound subsequent health differences. Clearly,
controlled experiments can’t be done with humans so this basically leaves animal
research. I have asked repeatedly anti-smoking zealots to show me evidence from
infra-human species indicating that smoking causes cancer (or any illness at all). I
am aware of a few studies showing no effects at all, but in spite of my oft-repeated
request for experimental evidence, I have yet to see any. At the moment, I see the
smoking-health as eminently plausible, but plausibility is a long way from
proof. Perhaps you could clarify this for
me. All the best
dale
Barry Groves
Hello Dale There is more to tobacco than meets the eye. The late Dr Richard Passey of the Chester Beatty Research
Institute, London, spent 20
years investigating smoking and cancer. He was intrigued by the different cancer rates
between cigarette smokers and cigar smokers. So he looked into the different tobaccos and
the smoke they produced. He noted that cigar tobacco is air-cured, while most British
cigarette tobacco was flue-cured. In cigarettes in other countries—the USA,
France—these two types are mixed, which gives the different tastes in those
countries. The significance of
the different cures is that flue-cured tobaccos use sugar or molasses in their
cure, while
air-cured tobaccos do not. Passey showed that high-sugar tobacco made a much more acid
smoke, while air-cured tobacco smoke was weakly acid or alkaline.
Passey’s thesis was supported by Dr GB Gori, associate director of the
USA’s NCI and chairman of the Tobacco Working Group. He said that acid tobacco would
be inhaled more than the air-cured tobacco. Passey pointed out in Medical World News 14 January 1972 and 16 March 1973, that:
1. England and Wales had the world’s highest rates
of lung cancer for men. British cigarettes had the highest sugar content at 17%.
2. American men smoked more cigarettes per
capita than the British but had a lung cancer incidence only half the British rate.
Their tobacco was blended and had an average 10% sugar.
3. French men smoked 2/3 as many cigarettes but had
only 1/3 the lung cancer. Their tobacco was air dried and had 2% sugar.
4. In Russia, China, Formosa and other countries where
only air-dried tobacco was used for cigarettes, similar to the native American
Indians’ tobacco, Passey found no correlation at all between smoking
and lung cancer.
This was confirmed,
says Passey, by Japanese doctor friends who were amused at the official US doctrine. He
says they were confident that within a decade, the NCI would have to admit that the
tremendous excess sugar and artificial chemicalisation of food, particularly
chemicalisation of animal protein, were involved in causing lung cancer.
Malhotra and Pathania
also found no difference in CHD incidence between Sikhs who smoked and Hindus who did not.
(Reference isn’t to hand, but I remember it was in the Lancet, in 1958.) Barry
Malcolm Kendrick
Martin, For your
interest, the reference for the 246 risk factors is, as follows: Hopkins PN, Williams RR.
AA survey of 246 suggested coronary risk factors. Atherosclerosis 1981 Aug-Sep;40(1)1-52)
1: Positive family
history of early CHD 2:Age 3: Male sex etc. 246: Drug allergies
Just a few other ‘facts’ to throw
into your letter: 1: John Hunter described angina in 1793,
and is thought to have died of an MI
2: Virchow and Rokitansky were
both examining atherosclerotic plaques in 1850
3: I have read the paper on
atherosclerotic plaques in mummified Egyptian bodies. They had them 4: Osler was
describing CHD patients at the turn of the nineteenth century 5: William
Harvey (who first described the circulatory system 1628) described symptoms of angina -
possibly.
I do take issue with your comment that the
average life expectancy was 40 - 45. This is true, but the average tells you litte about
how long people actually lived. For that you need the mode. An awful lot of children died
in earlir days, as did a lot of women of childbearing age. In
reality, the
increase in life expectancy, once you managed to reach the age of 16, has
increased, in
the UK, by 18 months since 1900. In short, get past childhood, and not much has changed in
terms of life expectancy. So what’s my
point. Not quite sure. However, I think we can safely say that CHD has been present for
thousands of years - it is not new. However, we seem to have no idea what the actual rate
was, say, one hundred years ago. It is definitely true that, in the UK, ‘dropsy’
was quite common (don’t ask me what quite common means. Jane Austin described it).
Dropsy was the term used to describe, loosely, heart failure. And by far the commonest
cause of heart failure is a previous MI. So it is possible that CHD was fairly common in
the UK prior to the twentieth century. So, if
we are looking for causes, they must have been present prior to processed
foods. So, if it
is all due to a lack of vitamin B6 this doesn’t fit. Nor can a lack of Vitamin B6 be
made to fit with CHD rates in teh UK. During world war 2 the Goverment made bread that was
full of vitamins, including viatmin B6 to offset the effects of rationing. During the next
ten years the rate of CHD in the UK quadrupled.
I suppose, also, finally, everything does have a
cause. At
present, I believe, the rate of CHD in rural China is less that one thirtieth the rate of
CHD in Lithuania, age matched. It has to be possible to say that there is a cause in there
somewhere that can be found. Malcolm
Jerome Sullivan
Malcolm Kendrick
wrote: “I don’t understand the concept of the myocardium
being vulnerable to ischaemia.”
Dear Malcolm,
Much of research and practice in cardiology is predicated upon the
possibility that vulnerability of myocardium to ischemia can be modified. Specifically with regard to the role of
iron, the
following papers may be a start in helping to understand the concept of myocardium being
vulnerable to ischemia (1-6). Sincerely, Jerome
1. Sullivan
JL. The iron paradigm of ischemic heart disease. Am Heart J. 1989;117:1177-1188.
2. Horwitz
LD, Rosenthal EA. Iron-mediated cardiovascular injury. Vasc Med. 1999;4:93-99.
3. de
Valk B, Marx JJ. Iron, atherosclerosis, and ischemic heart
disease. Arch Intern Med. 1999;159:1542-1548.
4. Sullivan
JL, Zacharski LR. Hereditary haemochromatosis and the hypothesis
that iron depletion protects against ischemic heart disease. Eur J Clin Invest.
2001;31:375-377.
5. Nitenberg
A, Ledoux S, Valensi P et al. Coronary microvascular adaptation to myocardial metabolic
demand can be restored by inhibition of iron-catalyzed formation of oxygen free radicals
in type 2 diabetic patients. Diabetes. 2002;51:813-818.
6. Sasaki
K, Hashida K, Michigami Y et al. Restored vulnerability of cultured endothelial cells to
high glucose by iron replenishment. Biochem Biophys Res Commun. 2001;289:664-669.
Martin Sturman
Malcolm, Many thanks for your interesting letter, the
reference, and your general agreement with my thesis that coronary disease has been with
us at least for thousands of years. I agree with your assessment of life expectancy in the
19th century when the high infant and maternal mortality rate caused a
misperception of the modal rate, which, as you say, has not changed all that much since
the early 1900’s. It is true that Virchow and Rokitansky were examining
atherosclerotic plaques in the 1850’s, but I have no idea of the incidence of these
lesions at that time, nor of the recorded results, prevalence of these lesions at autopsy
until well into the 20th Century. I have to assume that heart
failure, dropsy, was secondary to coronary disease, as well as rheumatic valvular disease
which was probably even more common until the advent of penicillin. As an aside, you may be
interested to know that Sir John Hunter (1728-1793) , the great British
surgeon, once remarked, “I am at the mercy of anyone who chooses to annoy
me.” Indeed,
he dropped dead in the heat of an argument in the Board room of St. George’s
Hospital. I would
like to think “everything has a cause” -or more likely multiple
causes, but in
the case of CHD, I remain a non-reductionist. Undoubtedly geography, diet, and multiple
other factors cause wider disparities in the distribution of coronary
disease, but there
are multiple associated confounding biases that make interpretation of causality
exceedingly difficult. Thanks again for your thoughtful letter
Joel Kaufmann
Dear Uffe: My opinion remains that there
are a only few hundred potential customers for the proposed book for medical
professionals. True, there are at least 2 million who should read such a
book, but... Some of
the recent e-mails indicate that Medical Hypotheses is a good format for
chapter-equivalents “from” the “book”, and these could include
devil’s advocates. (Of course, I assume that Medical Hypotheses is not
reactionary.) --Joel
27. Mars
Uffe Ravnskov
Hi Jörgen If you never have heard
about CHD you will call chest and arm pains for anything else: musculoskeletal disease,
dyspepsia, gallstone etc. When knowledge about CHD and its many diverse symptoms was
disseminated, more and more doctors changed their diagnostic habit and more and more
patients got the diagnosis CHD. And when ECG and later on transaminase analyses became
available, even the many less characteristic cases were included in that diagnostic group.
By this reason it is simply impossible to say whether CHD has increased or not - the
question is unavailable for falsification. Uffe
28. Mars
Jørgen Vesti Nielsen
Thanks Uffe That is what I
mean.
We’ll never be able to know! There are historical arguments of the archaeological
type for and against an ‘epidemic’. (when you interpret your finds from a dig
you try to imagine what sort of people used them)
For example—for: To give an exact diagnosis (including autopsy) and prognosis
was the central purpose for doctors in those days, since they were unable to actually do
very much. I would not think it likely that they should have overlooked such an obvious
set of symptoms, all pointing to involvement of the heart, in so many mid-adult
people,
including their friends and colleagues, if the rates had been high. I am sure more and
more doctors changed their diagnostic habits, but the reason I object to this theory
as the sole and only explanation is that it gives a poor fit. For instance was the upward
trend for the general term ‘diseases of the heart’ that began in 1920 in USA
markedly greater for males right from the beginning.
Against: The deaths
certificates are highly inaccurate and potentially misleading except, as Stebhens points
out in Lancet, March 14, 1987, when used to indicate a very general trend. Is a very
general trend, perhaps, what we are talking about?
And, further.... Oops, I seem to be getting an attack of acute
stubbornness. Anyway, as you say, the question is not available for
falsification. Happy Easter Jorgen
Malcolm Kendrick
Jorgen Happy Easter.
Whilst we cannot travel back into the past to establish whether or not CHD
was very rare, or common, one hundred years ago, or two thousand years ago.We
can, perhaps, efffectively travel back in time by looking at populations, today, who live a
lifesytle that is less industrialised - or roughly equivalent to the way the people used
to live in Europe hundreds of years ago e.g. Massa villagers in Kenya, Rural Chinese or
Indian populations. I think I can
state, with
relative confidence, that rural, non-industrialsed populations all have a very low rate of
CHD. This is independent of any dietary factor. However, when you take, for
example, the
rural Indian population and move them into cities, the rate of CHD increases
dramatically.
When you take an Indian population and move them to a highly industrialised society
e.g.
the USA, the rate of CHD jumps again, perhpas a fifteen to twentyfold absolute increase in
CHD deaths. Again independent of any dietary factor. This would fit with the general
observation that CHD is primarily a disease of modern, industrialised civilisations, and
would support the hypothesis that CHD did, in fact, increase pretty dramatically during
most of the twentieth century. There are still populations, I believe, with no cases of
death from CHD. Tuvalu, I think, is one such place. In short, although
unproveable, I
think that it is extremely likely that death from CHD (before say, the age of 75) was
uncommon in Europe and the USA one hundred years ago. It is now, still, the leading cause
of death. I would also say that James MacKenzie’s finding of a high rate of CHD in
Northern England one hundred years ago would not, in any way contradict this general
hypothesis. The North of England, at that time, was highly industrialised, and further
advanced (if that is the right word for it) than anywhere else in the world. Malcolm
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