The Cholesterol Myths by Uffe Ravnskov, M.D., Ph.D.

9. The benefits of high cholesterol

 

     People with high cholesterol live the longest. 
     This statement seems so incredible that it takes a long time to clear one´s brainwashed mind to fully understand its importance. Yet the fact that people with high cholesterol live the longest emerges clearly from many scientific papers.1 But let us take a look at heart mortality, the risk of dying from a heart attack if cholesterol is high.
     
Consider for instance the finding of Dr. Harlan Krumholz of the Department of Cardiovascular Medicine at Yale University, who reported that old people with low cholesterol died twice as often from a heart attack as did old people with a high cholesterol.2 Supporters of the cholesterol campaign consistently ignore his observation, or consider it as a rare exception, the result of chance among a huge number of studies finding the opposite.
     
But it is not an exception; there are now a large number of findings that contradict the lipid hypothesis. To be more specific, most studies of old people have shown that high cholesterol is not a risk fact for coronary heart disease. This was the result of my search in the Medline database for studies addressing that question.3 Eleven studies of old people came up with that result, and a further seven studies found that high cholesterol did not predict all-cause mortality either, and more such studies have been published since then.
    
I have mentioned it before, but it is worth repeating, that more than 90 percent of those who die from a heart attack or a stroke have passed the age of 65. You may also recall that high cholesterol is not a risk factor for women nor for a number of other population groups. Thus, high cholesterol is only a risk factor for less than five percent of those who die from a heart attack.
     
But there is more comfort for those who have high cholesterol. At least fifteen studies found that total mortality was inversely associated with either total or LDL-cholesterol, or both. This means that it is actually much better to have high than to have low cholesterol if you want to live to be very old.
     Many studies have found that low cholesterol in certain respects is worse than high cholesterol. For instance, in nineteen large studies of more than 68,000 deaths, reviewed by David R. Jacobs and his co-workers from the Division of Epidemiology at the University of Minnesota, low cholesterol predicted an increased risk of dying from gastrointestinal and respiratory diseases.4
     
Most gastrointestinal and respiratory diseases have an infectious origin. Therefore, a relevant question is whether it is the infection that lowers cholesterol or the low cholesterol that predisposes to infection? You have probably already guessed what the directors of the cholesterol campaign have said, but is it true?
    
To answer that question Jacobs and his group, led this time by Dr. Carlos Iribarren, followed more than 100,000 healthy individuals in the San Francisco area for fifteen years. At the end of the study those who had low cholesterol at the start of the study had been admitted more often to hospital, either because of an infectious disease of the respiratory system5 or because of another type of infection.6 This finding cannot be explained away with the argument that the infection had caused cholesterol to go down, because how could low cholesterol, recorded when these people had no evidence of infection, be caused by a disease they had not yet encountered? Isn´t it much more likely that low cholesterol in some way made them more vulnerable to infection, or that high cholesterol protected those who did not become infected? Much evidence exists to support that interpretation. 
     Young, unmarried men with a previous sexually transmitted disease or liver disease run a much greater risk of becoming infected with HIV virus than other people. The Minnesota researchers followed such individuals for seven or eight years. After having excluded those who became HIV-positive during the first four years, they ended up with a group of 2446 men. At the end of the study, 140 of these people tested positive for HIV; those who had low cholesterol at the beginning of the study were twice as likely to test postitive for HIV compared with those with the highest cholesterol.7 
     
Similar results came from a study of the MRFIT screenees. Sixteen years later four times more among those with the lowest cholesterol had died from AIDS compared with those who had the highest.8 

      Heart disease may lead to a weakening of the heart muscle. A weak heart means that less blood and therefore less oxygen is delivered to the arteries. To compensate for the decreased power, the heart beat goes up, but in severe heart failure this is not sufficient. Such patients become short of breath because too little oxygen is delivered to the tissues, the pressure in their veins increases because the heart cannot deliver the blood away from the heart with sufficient power, and they become edematous, meaning that fluid accumulates in the legs and in serious cases also in the lungs and other parts of the body. This condition is called congestive or chronic heart failure.
     
There are many indications that bacteria or other microorganisms play an important role in chronic heart failure. For instance, patients with severe chronic heart failure have high levels of endotoxin and various types of cytokines in their blood. Endotoxin, also named lipopolysaccharide, is the most toxic substance produced by Gram-negative bacteria. Cytokines are hormones secreted by white blood cells in their battle against pathogenic microorganisms; high levels of cytokines in the blood indicate that inflammatory processes are going on somewhere in the body.
     
The role of infections in chronic heart failure has been studied by Dr. Mathias Rauchhaus and his team at the Medical Department, Martin-Luther-University in Halle, Germany. They found that the strongest predictor of death for patients with chronic heart failure was the concentration of cytokines in the blood, in particular in patients with heart failure due to coronary heart disease. To explain their finding they suggested that bacteria from the gut may more easily penetrate into the tissues when the pressure in the abdominal veins is increased because of heart failure. In accordance with this theory, they found more endotoxin in the blood of patients with congestive heart failure and edema than in patients with non-congestive heart failure without edema, and endotoxin concentrations decreased significantly when the heart’s function was improved by medical treatment.9
     
A simple way to test the functional state of the immune system is to inject antigens from microorganisms under the skin. If the immune system is normal, an induration (hard spot) will appear about 48 hours later at the place of the injection. If the induration is very small, with a diameter of less than a few millimeters, this indicates the presence of "anergy," a reduction in or failure of response to recognize antigens. In accordance, anergy has been found associated with an increased risk of infection and mortality in healthy elderly individuals, in surgical patients and in heart transplant patients.10
     
Dr. Donna Vredevoe and her group from the School of Nursery and the School of Medicine, University of California at Los Angeles tested more than 200 patients with severe heart failure with five different antigens and followed them for twelve months. The cause of heart failure was coronary heart disease in half of them and other types of heart disease in the rest. Almost half of the patients were anergic, and those who were anergic and had coronary heart disease had a much higher mortality than the rest.11 
     
Now to the salient point: to their surprise the researchers found that mortality was higher, not only in the patients with anergy, but also in the patients with the lowest lipid values in the blood.11 
     
The latter finding was confirmed by Dr. Rauchhaus, this time in co-operation with researchers at several German and British university hospitals. They found that the risk of dying for patients with chronic heart failure was strongly and inversely associated with total cholesterol, LDL-cholesterol and also triglycerides; those with high lipid values lived much longer than those with low values.12
     
Other researchers have made similar observations. The largest study has been performed at the UCLA Department of Medicine and Cardiomyopathy Center in Los Angeles. It  included more than a thousand patients with severe heart failure. After five years 62 percent of the patients with cholesterol below 129 had died, but only half as many of the patients with cholesterol above 223.13
     
When proponents of the cholesterol hypothesis are confronted with findings showing a bad outcome associated with low cholesterol--and there are many such observations--they usually argue that severely ill patients are often malnourished, and malnourishment is therefore said to cause low cholesterol. However, the mortality of the patients in this study was independent of their degree of nourishment; low cholesterol predicted early mortality whether the patients were malnourished or not. 
      Children born with very high cholesterol, so-called familial hypercholesterolemia, are protected against infection. But if inborn high cholesterol protects against infections, inborn low cholesterol should have the opposite effect. Indeed, this seems to be true.
      Children with the Smith-Lemli-Opitz syndrome have very low cholesterol because the enzyme that is necessary for the last step in the body’s synthesis of cholesterol does not function properly. Most children with this syndrome are either stillborn or they die early because of serious malformations of the brain. Those who survive are imbecile, they have extremely low cholesterol, and they suffer from frequent and severe infections. However, if their diet is supplemented with pure cholesterol or extra eggs, their cholesterol goes up and their bouts of infection become less serious and less frequent.14 
      Laboratory studies are crucial for learning more about the mechanisms by which the lipids exert their protective function. One of the first to study this phenomenon was Dr Sucharit Bhakdi from the Institute of Medical Microbiology, University of Giessen, Germany along with his team of researchers from various institutions in Germany and Denmark.15
     
Staphylococcus aureus α-toxin is the most toxic substance produced by strains of the disease-promoting bacteria called staphylococci. It is able to destroy a wide variety of human cells, including red blood cells. For instance, if minute amounts of the toxin are added to a test tube with red blood cells dissolved in a saline solution, the blood is hemolyzed, that is the membranes of the red blood cells burst and hemoglobin from the interior of the red blood cells leaks out into the solvent. Dr. Bhakdi and his team mixed purified α-toxin with human serum (the fluid in which the blood cells reside) and saw that 90 percent of its hemolyzing effect disappeared. By various complicated methods they identified the protective substance as LDL, the carrier of the so-called bad cholesterol. In accordance, no hemolysis occurred when they mixed α-toxin with purified human LDL, whereas HDL or other plasma constituents were ineffective in this respect. 
     
Dr. Willy Flegel and his co-workers at the University of Ulm, and the Institute of Immunology and Genetics at the German Cancer Research Center in Heidelberg, Germany studied endotoxin in another way.16 As mentioned, one of the effects of endotoxin is that white blood cells are stimulated to produce cytokines. The German researchers found that the cytokine-stimulating effect of endotoxin on the white blood cells disappeared almost completely if the endotoxin was mixed with human serum for 24 hours before they added the white blood cells to the test tubes. In a subsequent study17 they found that purified LDL from patients with familial hypercholesterolemia had the same inhibitory effect as the serum. 
      The immune systems in various mammals including human beings have many similarities. Therefore, it is interesting to see what experiments with rats and mice can tell us. Professor Kenneth Feingold at the Department of Medicine, University of California, San Francisco, and his group have published several interesting results from such research. In one of them they lowered LDL-cholesterol in rats. After that, injection of endotoxin was followed by a much higher mortality in the low-cholesterol rats compared with normal rats. The high mortality was not due to the cholesterol-lowering drugs because, if the drug-treated animals were injected with lipoprotein just before the injection of endotoxin, their mortality was reduced to normal.18
     
Dr. Mihai Netea and his team from the University Hospital in Nijmegen, The Netherlands, injected purified endotoxin into normal mice, and into mice with familial hypercholesterolemia that had LDL-cholesterol four times higher than normal. Whereas all normal mice died, they had to inject eight times as much endotoxin to kill the mice with familial hypercholesterolemia. In another experiment they injected live bacteria and found that twice as many mice with familial hypercholesterolemia survived compared with normal mice.19
 
      Several researchers have found that children with allergic symptoms, including asthma, have lower cholesterol than healthy children. As allergic diseases have been more common and as their frequency is still increasing in the Western world it is tempting to suggest that the cause is the increasing consumption of the polyunsaturated vegetable oils. But there is room for another explanation.
    
At the Department of Dermatology, Skin and Allergy Hospital in Helsinki, Finland Dr.Maria Pesonen and her coworkers followed 200 children from their birth to their 20 year anniversary.20 They found that the children with allergic disorders had lower total and LDL cholesterol than the others. The difference was significant already at age 2 months at a time where all 200 children were breastfed. Thus, the difference could not be explained by different dietary habits. The researchers had no explanation to their findings, but as the lipoproteins are able to bind microbial products, it seems not too farfetched to assume that they can bind other molecules as well, for instance allergens, those that starts the allergic reactions.   
     There is no contradictory observation that can´t be explained away by the believers. One of the most striking aberrations appeared in two recent studies from the US. 
    
The first one came from the medical department at the University of California in LA.21 A total of 137,000 patients from 541 hospitals in the US had been admitted because of an acute heart attack. In all of them, their cholesterol was analysed within the first 24 hours of hospital admission. To their surprise, the authors found that their cholesterol was lower than normal when compared with the average. To be precise, their mean total cholesterol was 174 (4.46 mmol/l) and the ‘bad’ LDL cholesterol was also much lower than normal.
    
It is not possible to explain away the result by using the argument that it was a result of chance, considering that this is the largest study of the cholesterol levels of heart patients, which has ever been published.The researchers were of course surprised. One explanation could be the well-known fact that cholesterol goes down in patients with an acute myocardial infarction, but they rejected it, because this happens first after two-three days and the reduction is only fifteen percent at most.22
    
Did the authors, three of whom were supported by up to eight drug companies, realize that they had stumbled upon something important? That high cholesterol may not be the cause of heart disease? 
     Of course not. What they concluded was that cholesterol must be reduced even further. 
    
A few months later a research group from Henry Ford Heart and Vascular Institute in Detroit came up with a similar result.23 Again, LDLcholesterol measured within the first 24 hours of admission was lower than normal, not higher. To be precise, in half of the 500 patients LDLcholesterol was lower than 105 (2.69 mmol/l). 
    
They thought that something had gone wrong and were convinced that those whose LDL was below 105 had a much better chance to survive than those whose LDL was higher, because this is what all of us have been told by the American Heart Association and the drug companies repeatedly.
    
Three years later it appeared that among those with low LDL twenty-six patients had died, but only twelve among those with high LDL. The authors considered their finding very salient. They warned their readers against feeling a false sense of security in patients with low LDL. Although more of those with low LDL were on statin treatment, they wrote , ”these patients may in fact need more aggressive risk modification.” 

      References

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    Rudman D al. Antecedents of death in the men of a Veterans Administration nursing home.
    J Am Geriatr Soc. 1987 Jun;35(6):496-502.  

    Forette B et al.. Cholesterol as risk factor for mortality in elderly women. Lancet. 1989 Apr 22;1(8643):868-70.

    Staessen J, et al.
    Is a high serum cholesterol level associated with longer survival in elderly hypertensives? J Hypertens. 1990 Aug;8(8):755-61.

    Harris Tet al. The low cholesterol-mortality association in a national cohort. J Clin Epidemiol. 1992 Jun;45(6):595-601.a

    Casiglia E et al.
    Predictors of mortality in very old subjects aged 80 years or over.
    Eur J Epidemiol. 1993 Nov;9(6):577-86. 

    Krumholz HM et al.
    Lack of association between cholesterol and coronary heart disease mortality and morbidity and all-cause mortality in persons older than 70 years. JAMA. 1994 Nov 2;272(17):1335-40.  

    Weverling-Rijnsburger AW et al.
    High-density vs low-density lipoprotein cholesterol as the risk factor for coronary artery disease and stroke in old age. Arch Intern Med. 2003;163(13):1549-54.

    Jonsson A, Sigvaldason H, Sigfusson N. Total cholesterol and mortality after age 80 years. Lancet. 1997 Dec 13;350(9093):1778-9  

    Räihä I, Marniemi J, Puukka P, Toikka T, Ehnholm C, Sourander L.
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    Behar S et al.
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    Bathum L et al, Depont Christensen R, Engers Pedersen L, Lyngsie Pedersen P, Larsen J, Nexøe J. Association of lipoprotein levels with mortality in subjects aged 50 + without previous diabetes or cardiovascular disease: A population-based register study. Scand J Prim Health Care. 2013;31:172-80    
  2. Krumholz HM and others. JAMA. 272, 1335-40, 1994.  
  3. Ravnskov U. QJM 96, 927-934, 2003.  
  4. Jacobs D and others. Circulation  86, 1046–60, 1992
  5. Iribarren C and others. Int J Epidemiol 26, 1191–202, 1997
  6. Iribarren C and others. Epidemiol Infect 121, 335–47, 1998. 
  7. Claxton AJ and others. J Acquir Immune Defic Syndr Hum Retrovirol 17, 51–7, 1998. 
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  10. Niebauer J and others. Lancet 353, 1838-1842, 1999. 
  11. Vredevoe DL and others. Am J Cardiol 82, 323-8, 1998. 
  12. Rauchhaus M and others. J Am Coll Cardiol 42, 1933-40, 2003.  
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  19. Netea MG and others. J Clin Invest 97, 1366–72, 1996. 
  20. Pesonen M and others. Clin Exp Allergy 2007 Epub ahead of print
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  24. Al-Mallah MH. Cardiol J 2009;16:227-33

Some of my scientific papers about this and similar issues:

The questionable role of saturated and polyunsaturated fatty acids in cardiovascular disease. J Clin Epidemiol 1998;51:443-460.   Read also a dissent to the paper: Golomb BA. Dietary fats and heart disease-dogma challenged? and my answer; same journal and same issue. This paper won the Skrabanek award 1999
A hypothesis out-of-date: The diet-heart idea. Published in Journal of Clinical Epidemiology (2002 Nov;55:1057-63. Same issue: Dissent by W.S.Weintraub, and Reply by U. Ravnskov An evaluation of our discussion is available 
Is atherosclerosis caused by high cholesterol?
published in Quarterly Journal of Medicine (2002; 95:397–403)
High cholesterol may protect against infections and atherosclerosis published in Quarterly Journal of Medicine (2003;96:927-34). 
Should medical science ignore the past? BMJ 2008;337:a1681

My popular-scientific books, where you can read much more:

A shortened, simplified
 and updated version of 
my first book 
The Cholesterol Myths
Here you can read about 
how scientists and editors 
of scientific journals have 
deceived a whole world,
unintentionally or on purpose.
Also available as a 
Kindle version

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© Uffe Ravnskov