According to the WHO-MONICA project in men aged 55 to 64 years, 10-year population changes in serum cholesterol level alone explained 35% of the variance of change in fatal and nonfatal coronary events. (1) When comparing people within in the same country (more like a controlled study), less LDL is associated with less heart disease. Dr. Kendrick only told us about ONE exception. A subset of men with the lowest educational achievement who drink too much alcohol in Russia. They must be the only ones or he would have told us about the rest of them.
On the other hand, the data in Dr. Kendrick's graph comparing average serum cholesterol and heart disease death rates in 21 countries plus the Australian aborigines amounts to an uncontrolled observational study. The same is true of his graph of saturated fat consumption. Such studies can be useful for generating hypotheses but they can't prove cause and effect of lack of it. There are too many confounding variables (e.g. affluence, quality of healthcare, malnutrition, sanitation, stress levels, smoking rates and alcoholism etc. etc.)
MORE EVIDENCE THAT ELEVATED LDL IS A MAJOR RISK FACTOR FOR CORONARY ARTERY DISEASE
1. People with two copies of the mutation for familial hypercholesterolemia (FH), have LDL levels 6 to 10 fold above normal and can have a heart attack as early as 18 months of age. People with one copy of the mutation have LDL levels 2 to 4 times above normal and develop clinical symptoms between the ages of 30 and 60. (1) In the era before the statins, FH patients aged 20 to 39 years old were 100 times more likely die of heart disease and 10 times more likely to die from all causes than someone in the general population. (2) In a later study, FH patients treated with statins lived just as long as people without FH. (3)
2. Atherosclerotic plaque contains a lot of cholesterol.
3. People with very low LDL tend to be protected from CHD. The normal LDL cholesterol range is 50 to 70 mg/dl for modern hunter-gatherers, healthy human newborns, free-living primates, and other wild mammals (all of whom do not develop atherosclerosis). (4) And during the 80s, rural Chinese had an average serum cholesterol level of 127 mg/dl. And the men in rural China had a rate of CHD that was only 1/17th that of American men. This was in spite of the fact that close to 80% of them smoked. (5) According to the third report of the National Cholesterol Education Program (NCEP), "Only in populations that maintain very low levels of serum cholesterol, e.g., total cholesterol <150 mg/dL (or LDL cholesterol <100 mg/dL) throughout life do we find a near-absence of clinical CHD." (6)
4. People with an intermediate level of LDL have intermediate levels of heart disease. Virtually 100% of observational studies comparing people within the same country show a strong association between serum cholesterol and heart disease. (7,8,9)
5. The fact that HDL is protective and carries LDL away from the arteries is further proof of the harmfulness of elevated LDL. The INTERHEART study looked at 52 different countries and found that the ratio of apo-B (mostly LDL) to apo-A1 (HDL) could account for 50% of the risk of CHD mortality. (10) Dr. Kendrick says INTERHEART supports his stress theory but as I show in the next section stress can't be the most important cause.
6. Atherosclerosis can be induced in many different animal species including non-human primates by raising serum cholesterol high enough and maintaining it long enough. And atherosclerosis can then be reversed by lowering serum cholesterol low enough and maintaining it long enough. (11) This can't be explained away by stress or some infectious agent. Although adding inflammatory factors can speed up the process, oxidized LDL, foam cells and cholesterol crystals inside the artery wall provide their own inflammation. See point eight.
7. In a meta-analysis of 35 randomized trials using diet and/or medication for every 10 percentage points of cholesterol lowering, CHD mortality was reduced by 13% and total mortality by 10% (12). Dr. Kendrick makes a big deal about LDL not being important for elderly people, but a meta-analysis of 9 randomized trials shows that when statins are used for secondary prevention in elderly patients they can reduce all-cause mortality by 22% and heart disease mortality by 30%. (13)
8. Last but not least elevated LDL is essential to the mechanism of atherosclerosis. Apo B lipoproteins (mostly LDL) diffuse into the artery wall. They become oxidized and cause inflammation which attracts macrophages. Macrophages devour oxidized LDL and become foam cells which form plaque and produce more inflammatory chemicals. They grow and eventually rupture depositing cholesterol crystals in the plaque. The crystals penetrate the artery wall causing even more inflammation. Elevated LDL also impairs endothelial function, reduces nitric oxide production and promotes platelet aggregation which promotes clotting. There are other factors besides elevated LDL that contribute to heart disease like smoking, hypertension, diabetes, abdominal obesity, stress, inflammation, homocysteine, sedentary lifestyle and excess sucrose but according to the INTERHEART study the ratio of apo-B (mostly LDL) to apo-A1 (HDL) can account for 50% of the risk. (14,15,16,10)
9. People who know the most about the subject agree. Scientists studying atherosclerosis know more about the subject than anyone else and the vast majority think that cholesterol is connected to heart disease. This is according a scientist who supports the cholesterol hypothesis as well as Dr. Kendrick himself. (17,18)
EVIDENCE THAT STRESS IS NOT THE MAIN FACTOR IN CORONARY ARTERY DISEASE
1. Atherosclerosis can be induced in many different animal species including non-human primates by raising serum cholesterol high enough and maintaining it long enough. And atherosclerosis can then be reversed by lowering serum cholesterol low enough and maintaining it long enough. There is no evidence that increased stress followed by decreased stress is involved. (11)
2. Statins reduce heart attacks but there is no evidence that they lower cortisol levels. (19)
3. Fruit and vegetables reduce heart attacks but Dr. Kendrick admits he can see no connection to the HPA-axis. They can however reduce hypertension and oxidized LDL. (20)
4. Dr. Esselstyn's study got better results than Dr. Ornish's study even though Dr. Ornish used stress reduction therapy and Dr. Esselstyn didn't. However Dr. Esselstyn's patients had lower LDL levels. (21,22)
There is no doubt that stress is one of the risk factors for CAD. And there is no doubt that injury to the endothelium and blood clots are part of the mechanism. But unless you are an alcoholic elevated LDL is probably more important.
EVIDENCE THAT EATING GRAIN FED MEAT AND DAIRY RAISES SERUM CHOLESTEROL
Dr. Kendrick says the body can't turn saturated fat into cholesterol. That's correct but that's not the problem. Dietary saturated fat causes LDL receptors in the liver to down regulate causing LDL to build up in the blood. (23)
Dr. Stephen Phinney conducted a normal caloric intake metabolic ward trial with nine healthy lean men, "The human metabolic response to chronic ketosis without caloric restriction: physical and biochemical adaptation." These men consumed nothing but meat, fish, eggs, cheese and cream (no hydrogenated vegetable oil) for 35 days. Their carbohydrate intake was less than 20 grams a day. Their blood cholesterol went up from 159 to 208 on average in 35 days. That is a 31% increase. The average adult in this country has a cholesterol level of 199. A 31% increase would give 261. The high risk category is anything over 240. (24)
A meta-analysis of 395 metabolic ward experiments concluded that in typical British diets replacing 60% of saturated fats by other fats and avoiding 60% of dietary cholesterol would reduce blood total cholesterol by about 0.8 mmol/l (that is, by 10-15%), with four fifths of this reduction being in low density lipoprotein cholesterol. (25)
THE LIMITS OF OBSERVATIONAL STUDIES
Heart disease has several risk factors. Therefore in uncontrolled observational studies we can see a lot of inconsistent results. But associations or lack of associations in an uncontrolled observational study can only suggest, not prove cause and effect or lack of it. The results depend on:
1) CONFOUNDING VARIABLES. These include smoking, hypertension, diabetes, abdominal obesity, stress, sucrose consumption etc. For example, in an uncontrolled study lower saturated fat can be associated with either less heart disease or more heart disease depending on whether people replaced the saturated fat with canola oil or stick margarine with trans fat.
2) THE RANGE OF THE VARIABLE. Studies where the difference between the lowest level of saturated fat and highest level is very great have better resolution than studies with a smaller difference. When the difference is large, the effect of confounding variables is less pronounced. For example, in studies of very high saturated fat diets, even if they are not controlled, the harmful effects of saturated fat override the confounding variables and give consistent positive associations between saturated fat and heart disease.
3) PAST VERSUS PRESENT. Before statins or the link between saturated fat and heart disease was discovered, people with chest pain or survivors of heart attacks did not reduce saturated fat or take medication to lower cholesterol. Now LDL is routinely measured every time someone gets a complete physical, and dietary changes or prescription medication is recommended to high risk individuals long before they have a heart attack. Atherosclerosis is slowed and the heart attack is delayed for several years and occurs with lower saturated fat consumption and a lower LDL level. The lifetime average cholesterol level is much more relevant than the level when admitted to the hospital.
Dr. Kendrick relies heavily on observational studies to ridicule the conclusions of experimental studies when it's the experimental studies that carry the most weight.
EXPERIMENTAL EVIDENCE OF WHAT SAVES LIVES IN PEOPLE WITH HEART DISEASE
In the 1950s, Dr. Morrison put 50 heart attack survivors on a 15% fat diet and another 50 survivors were told to eat as usual. Total cholesterol fell from 312 mg/dl to 220 mg/dl in the experimental group. That's a reduction of 29%. And over a period of 8 years, 38 patients eating as usual died while only 22 in the experimental group died. (26)
In the 80s, Dr. Esselstyn used a 10% fat, high fiber diet plus low dose statins to reverse heart disease in 17 men and one woman. The average for total cholesterol and LDL was maintained at 145 mg/dl and 82 mg/dl respectively. We know it worked because of before and after coronary angiograms and cardiac PET scans. People given less than a year to live are alive and healthier over 23 years later. During that time no patient died of coronary artery disease, but one died of an arrhythmia. (27)
Dr. Ornish also reversed heart disease using a similar diet plus exercise and meditation but no statins. Since then Dr. Ornish has enrolled at least 3800 patients in demonstration projects (to demonstrate savings on surgery) which resulted in over 40 insurance companies including Medicare covering a program in diet and lifestyle for heart disease patients. According to Dr. Ornish, "In brief, we found that almost 80 percent of patients who were eligible for bypass surgery or angioplasty were able to safely avoid it for at least three years." (28)
In the Lyon Diet-Heart Study of heart attack survivors there was a 76% reduction in major cardiovascular events in the group eating a Mediterranean diet where they replaced saturated fat with canola based margarine. (29)
A meta-analysis shows that when statins are used for secondary prevention in elderly patients they can reduce all-cause mortality by 22% and heart disease mortality by 30%. (20)
OBSERVATIONAL EVIDENCE OF DIET AND LONGEVITY
1. Vegetarian Adventist men and women live an average of 87 and 89 years, respectively and have a typical cholesterol level in the 180s. They abstain from alcohol and tobacco, exercise regularly and eat nuts, eggs and dairy products.
2. In the 50's and 60's Crete had the best longevity in the world. They ate 40% fat mostly from olive oil, but only 8% saturated fat. The total red meat, poultry and fish consumed per-person, per-week in Crete was only about 371 grams (13 ounces). Ancel Keys followed this version of the Mediterranean diet and lived to be 100 years old. (29)
3. Japan has the best life expectancy of any country. The average man lives 79.4 years and the average women 86.1 years. They eat more carbs (about 59% versus 49%) and less fat (about 28% versus 38%) than the U.S. They eat more seafood than they do meat.
4. Iceland has the best longevity in Europe. The average man lives 80.1 years and the average women 83.5 years. They eat less carbs and more fat than the U.S. They eat more seafood than they do meat and their meat is grass fed. (In France they also eat grass fed meat.)
REFERENCES
1. Brown MS, Goldstein JL. Human mutations affecting the low density lipoprotein pathway. Am J Clin Nutr. 1977 Jun;30(6):975-8.
2. Risk of fatal coronary heart disease in familial hypercholesterolemia. British Medical Journal, 1991;303:893-896.
3. Neil HA, Hawkins MM, Durrington PN, Betteridge DJ, Capps NE, Humphries SE; Simon Broome Familial Hyperlipidaemia Register Group and Scientific Steering Committee. Non-coronary heart disease mortality and risk of fatal cancer in patients with treated heterozygous familial hypercholesterolaemia: a prospective registry study. Atherosclerosis. 2005 Apr;179(2):293-7.
4. O'Keefe JH Jr, Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol. 2004 Jun 2;43(11):2142-6.
5. Campbell TC, Campbell TM. The China Study. 2005, BenBella Books. Pages 78-79.
6. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. Circulation 2002;106;3143.
7. Wilson PW, Garrison RJ, Castelli WP, Feinleib M, McNamara PM, Kannel WB. Prevalence of coronary heart disease in the Framingham Offspring Study: role of lipoprotein cholesterols. Am J Cardiol. 1980 Oct;46(4):649-54.
8. Menotti A, Keys A, Kromhout D, Blackburn H, Aravanis C, Bloemberg B, Buzina R, Dontas A, Fidanza F. Giampaoli S, et al. Inter-cohort differences in coronary heart disease mortality in the 25-year follow-up of the seven countries study. Eur J Epidemiol. 1993 Sep;9(5):527-36.
9. Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 1986 Nov 28;256(20):2823-8.
10. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L; INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004 Sep 11-17;364(9438):937-52.
11. Malinow MR. Atherosclerosis. Regression in nonhuman primates. Circ Res. 1980 Mar;46(3):311-20.
12. A. Lawrence Gould, PhD; Jacques E. Rossouw, MD; Nancy C. Santanello, MD, MSc; Joseph F. Heyse, PhD; Curt D. Furberg, MD Cholesterol Reduction Yields Clinical Benefit. Circulation. 1995;91:2274-2282.
13. Afilalo J, Duque G, Steele R, Jukema JW, de Craen AJ, Eisenberg MJ. Statins for secondary prevention in elderly patients: a hierarchical bayesian meta-analysis. J Am Coll Cardiol. 2008 Jan 1;51(1):37-45.
14. Badimon L, Storey RF, Vilahur G. Update on lipids, inflammation and atherothrombosis. Thromb Haemost. 2011 Apr 11;(Suppl. 1).
15. Abela GS. Cholesterol crystals piercing the arterial plaque and intima trigger local and systemic inflammation. J Clin Lipidol. 2010 May-Jun;4(3):156-64.
16. Miller M, Beach V, Sorkin JD, Mangano C, Dobmeier C, Novacic D, Rhyne J, Vogel RA. Comparative effects of three popular diets on lipids, endothelial function, and C-reactive protein during weight maintenance. J Am Diet Assoc. 2009 Apr;109(4):713-7
17. Steinberg, Daniel. The Cholesterol Wars. 2007, Academic Press. Page 211.
18. Kendrick, Malcolm. The Great Cholesterol Con. 2007, John Blake Publishing. Page 79.
19. Wani TA, Samad A, Tandon M, Saini GS, Sharma PL, Pillai KK. The effects of rosuvastatin on the serum cortisol, serum lipid, and serum mevalonic acid levels in the healthy Indian male population. AAPS PharmSciTech. 2010 Mar;11(1):425-32. Epub 2010 Mar 19.
20. Crujeiras AB, Parra D, Abete I, MartÃnez JA. A hypocaloric diet enriched in legumes specifically mitigates lipid peroxidation in obese subjects. Free Radic Res. 2007 Apr;41(4):498-506.
21. [[ASIN:1583333002 Prevent and Reverse Heart Disease: The Revolutionary, Scientifically Proven, Nutrition-Based Cure]]
22. [[ASIN:0804110387 Dr. Dean Ornish's Program for Reversing Heart Disease: The Only System Scientifically Proven to Reverse Heart Disease Without Drugs or Surgery]]
23. John M. Dietschy. Dietary Fatty Acids and the Regulation of Plasma Low Density Lipoprotein Cholesterol Concentrations. J. Nutr. February 1, 1998 vol. 128 no. 2 444S-448S.
24. Phinney SD, Bistrian BR, Wolfe RR, Blackburn GL. The human metabolic response to chronic ketosis without caloric restriction: physical and biochemical adaptation. Metabolism. 1983 Aug;32(8):757-68.
25. Clarke R, Frost C, Collins R, Appleby P, Peto R. Dietary lipids and blood cholesterol: quantitative meta-analysis of metabolic ward studies. BMJ. 1997 Jan 11;314(7074):112-7.
26. [[ASIN:B00129IJJ2 The Low-Fat Way to Health and Longer Life]]
27. [[ASIN:1583333002 Prevent and Reverse Heart Disease: The Revolutionary, Scientifically Proven, Nutrition-Based Cure]]
28. [[ASIN:0804110387 Dr. Dean Ornish's Program for Reversing Heart Disease: The Only System Scientifically Proven to Reverse Heart Disease Without Drugs or Surgery]]
29. De Lorgeril M, Salen P, Martin JL, Mamelle N, Monjaud I, Touboul P, Delaye J. Effect of a mediterranean type of diet on the rate of cardiovascular complications in patients with coronary artery disease. Insights into the cardioprotective effect of certain nutriments. J Am Coll Cardiol. 1996 Nov 1;28(5):1103-8. (Lyon Diet-Heart Study)
30. Various biographies of Ancel Keys are available on the Internet.
