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 19^th 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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14.3

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

15.3.2002

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 9^th 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 19^th 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.   &