OBSERVATIONAL EVIDENCE
1. Michael Brown and Joseph Goldstein discovered that the number of functional LDL receptors on the surface of cells, especially liver cells determines the level of LDL in the blood. If the receptors are defective or too few in number, LDL builds up in the blood instead of being taken into the cells. Familial hypercholesterolemia (FH) is caused by the mutation of a single gene that does one thing; make LDL receptors. People with two copies of the mutation for 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. In 1856 a German pathologist named Rudolf Virchow proposed that lipid accumulation in the artery wall caused atherosclerosis. In 1914 Nikolai Anitschkow also observed cholesterol crystals in advanced plaque in the aorta of cholesterol fed rabbits.
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 an 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)
EXPERIMENTAL EVIDENCE
6. Atherosclerosis can be induced in a great variety of animal species including vegetarian and carnivore species (e.g. insects, birds, cats, dogs, non-human primates etc.) by raising serum cholesterol high enough and maintaining it long enough. Atherosclerosis can also be reversed by lowering TC enough and maintaining it long enough. The lipid deposits and foam cells disappeared but some fibrous tissue remained. Some species, such as the dog and rat, do not get elevated TC from a diet high in saturated fat and cholesterol. But when a way was found to elevate their TC they also developed atherosclerosis. This is so consistent no matter which species is tested that it appears to be a scientific law that elevated LDL can cause atherosclerosis. (11) This can't be explained away by stress, inflammation or some infectious agent. In clinical trials, Dr. Esselstyn's group did better than Dr. Ornish's group even though Dr. Ornish used stress reduction and Dr. Esselstyn didn't. However Dr. Esselstyn's patients had lower LDL. And 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). And 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. Lowering LDL can halt and even reverse heart disease in humans. In the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, coronary atherosclerosis was virtually stopped in its tracks when LDL was maintained at 79 mg/dL. (14) And Dr. Esselstyn was able to reverse atherosclerosis by maintaining LDL at 81 mg/dL using a 10% fat, high fiber diet and a low dose statin. (15)
How does LDL cause atherosclerosis?
9. Last but not least elevated LDL is essential to the mechanism of atherosclerosis. Apo B lipoproteins (mostly LDL) diffuse into the artery wall that has been damaged by hypertension, smoking, or high blood pressure. 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. (16,17,18,10)
----
10. 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 a leading cholesterol skeptic. (19,20)
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. [[ASIN:B0041D843M The China Study: The Most Comprehensive Study of Nutrition Ever Conducted And the Startling Implications for Diet, We]] 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. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, Crowe T, Howard G, Cooper CJ, Brodie B, Grines CL, DeMaria AN; REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004 Mar 3;291(9):1071-80.
15. [[ASIN:1583333002 Prevent and Reverse Heart Disease: The Revolutionary, Scientifically Proven, Nutrition-Based Cure]]
16. Badimon L, Storey RF, Vilahur G. Update on lipids, inflammation and atherothrombosis. Thromb Haemost. 2011 Apr 11;(Suppl. 1).
17. 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.
18. 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
19. Steinberg, Daniel. The Cholesterol Wars. 2007, Academic Press. Page 211.
20. Kendrick, Malcolm. The Great Cholesterol Con. 2007, John Blake Publishing. Page 79.
