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Cholesterol Myth

This is a summary article that is from Oxford Journal that reviews the evidence that counters the assumption that high cholesterol causes coronary heart disease.  Because of the consistent clear evidence that CVD is not caused by cholesterol a chorus of critic have come called it the cholesterol myth.  The main cause is infectious agents (see /id8 and /id9) with high sugar & refined carbohydrate diet and its health consequences accelerating the process.  
At the bottom of the page is a summary of Prof. Uffe Ravnskov book on the cholesterol myth.

 


 

The links below contain numerous journal articles which show that LDL isn’t the problem but that of pathogen within the artery walls.  They are the cause of the formation of plaque within the artery walls that accumulates to become atherosclerosis with its associated comorbidities—the most significant being heart attacks, stroke, and kidney disease.  LDL in its immune function is actively transported through receptors on the endothelial cells into the artery walls where it binds the toxins released by the pathogens (a good thing).  Journal articles on LDL’s immune functions http://healthfully.org/rl/id8.html, http://healthfully.org/rja/id1.html, and http://healthfully.org/rja/id1.html and review article on infections causing pathogenesis resulting in atherosclerosis  by Uffre Ravnskov and Kilmer McCully at http://healthfully.org/rl/id8.html.   Also published are articles on the Cholesterol Myth and Cholesterol Myth, Source History.and list of best on YouTube   

For plain language recommendations http://healthfully.org/rns/index.html

 









Why do journals publish two articles that draw opposite conclusions concerning the same issue?  Simply put the industry article is published because no major journal can significantly offend their major sources for articles and income.   All major journal in order to maintain credibility with readers must publish quality articles of critics that meet scientific standards, thus the critics still have a voice.  However there are limits for criticism,.  Some articles are thus turned down to please pharma, and in a couple of cases the corporate politics behind the decision not to publish are exposed—see Bad Pharma for one example..  The editors and reviewers are aware of the low standards of industry written articles—95% of what they publish.  The standard held for the critics is thus higher.  This article exposing the cholesterol myth meets the highest standards.  I have checked a number of Prof. Ravnskov’s citations. That Oxford (University) Journ al made the full article available for free is an indication of its merit.   Other article require a subscription or a payment of $38. 


http://qjmed.oxfordjournals.org/content/95/6/397.full


Is atherosclerosis caused by high cholesterol?

Prof. Uffe Ravhskov

DOI: http://dx.doi.org/10.1093/qjmed/95.6.397 397-403 First published online: 1 June 2002


Introduction  According to the lowdensitylipoprotein (LDL) receptor hypothesis, development of atherosclerosis is caused by a high concentration of LDLcholesterol in the blood, and lowering LDLcholesterol reverses, or at least retards, atherosclerosis, thus preventing cardiovascular disease.1 As a scientific hypothesis, it is open to falsification: if the concentration of LDLcholesterol or total cholesterol and the degree of atherosclerosis do not correlate, or if there is no exposureresponse, e.g. if there is no association between the cholesterol changes (ΔLDLcholesterol or Δtotal cholesterol) and atherosclerosis progression.


The successful statin trials, with their substantial reduction of LDLcholesterol seemed to confirm the LDL receptor hypothesis, but their outcome was independent of the initial cholesterol concentration and the degree of its lowering. For instance, the p values for the relationships between the outcome, and the percentage or the absolute change in LDL cholesterol, as calculated in one of the trial reports,2 were 0.76 and 0.97, respectively. The lack of exposureresponse, together with the benefit of the treatment in disorders and age groups where LDLcholesterol concentration has little if any predictive value, suggests that statins must have more important effects on cardiovascular disease than a lowering of cholesterol.3 Indeed, there is evidence that the statins have antithrombotic and antiinflammatory effects, and also a beneficial influence on endothelial dysfunction, LDL oxidation, revascularization and smooth muscle cell proliferation.


Even if these effects were operating in the trials, the substantial lowering of LDLcholesterol should at least have contributed to the improvement if the LDL receptor hypothesis were correct. The lack of exposureresponse also questions whether atherosclerosis is truly caused by high LDLcholesterol.


However, the outcome in the clinical trials was cardiovascular disease, not atherosclerotic progression. To answer the question, we need to compare the cholesterol concentration and the degree of atherosclerosis, and in particular, to study the influence of ΔLDLcholesterol on atherosclerotic progression, rather than clinical outcome.


According to the lowdensitylipoprotein (LDL) receptor hypothesis, development of atherosclerosis is caused by a high concentration of LDLcholesterol in the blood, and lowering LDLcholesterol reverses, or at least retards, atherosclerosis, thus preventing cardiovascular disease.1 As a scientific hypothesis, it is open to falsification: if the concentration of LDLcholesterol or total cholesterol and the degree of atherosclerosis do not correlate, or if there is no exposureresponse, e.g. if there is no association between the cholesterol changes (ΔLDLcholesterol or Δtotal cholesterol) and atherosclerosis progression.


The successful statin trials, with their substantial reduction of LDLcholesterol seemed to confirm the LDL receptor hypothesis, but their outcome was independent of the initial cholesterol concentration and the degree of its lowering. For instance, the p values for the relationships between the outcome, and the percentage or the absolute change in LDL cholesterol, as calculated in one of the trial reports,2 were 0.76 and 0.97, respectively. The lack of exposureresponse, together with the benefit of the treatment in disorders and age groups where LDLcholesterol concentration has little if any predictive value, suggests that statins must have more important effects on cardiovascular disease than a lowering of cholesterol.3 Indeed, there is evidence that the statins have antithrombotic and antiinflammatory effects, and also a beneficial influence on endothelial dysfunction, LDL oxidation, revascularization and smooth muscle cell proliferation.


Even if these effects were operating in the trials, the substantial lowering of LDLcholesterol should at least have contributed to the improvement if the LDL receptor hypothesis were correct. The lack of exposureresponse also questions whether atherosclerosis is truly caused by high LDLcholesterol.


However, the outcome in the clinical trials was cardiovascular disease, not atherosclerotic progression. To answer the question, we need to compare the cholesterol concentration and the degree of atherosclerosis, and in particular, to study the influence of ΔLDLcholesterol on atherosclerotic progression, rather than clinical outcome.


Cholesterol does not predict degree of atherosclerosis at autopsy:  In 1936, Landé and Sperry noted that the degree of aortic atherosclerosis at autopsy of healthy individuals who had died violently, was independent on their blood cholesterol concentration analysed immediately after death.4 Their finding was confirmed by Mathur et al.5 and similar results were obtained by others.6–,8 The objection that an analysis of cholesterol after death may not reflect its concentration during life was met by Mathur et al.5 who found that the cholesterol concentration was almost constant up to 16 h after death. Paterson et al.6 bypassed the problem by comparing the degree of atherosclerosis at death with the individuals’ cholesterol measured previously on several occasions. In all these studies, plots of blood cholesterol concentrations vs. the lipid content of the aorta or the coronary arteries were widely scattered.


More recent autopsy studies have found weak or inconsistent correlations between LDLcholesterol or total cholesterol and various measures of atherosclerosis.9 For instance, the most severe degree of atherosclerosis was found mainly in individuals with extremely high cholesterol, whereas small differences were seen in the rest.10 A correlation was found in White men, but not in Black men,11 in men but not in women,12 in individuals below, but not above age 80 years,13 and in the coronary arteries, but not in the thoracic or abdominal aorta.14


The weak and unpredictable correlations probably reflect bias, because most of the studies were performed on selected individuals. In such large projects, the main object of which was to study risk factors for cardiovascular disease, individuals with such diseases, or with high cholesterol, were preferred for postmortem examination,10–,15 which means that the proportion of individuals with familial hypercholesterolaemia must have been much larger than in the general population. As such patients have very high cholesterol and are more prone to vascular changes, their inclusion automatically creates a correlation between degree of atherosclerosis and LDL or total cholesterol. Accordingly, it is obvious from a figure in a preliminary report that the correlation disappears if individuals with total cholesterol >350 mg/ml (9 mmol/l) are excluded.16 It is questionable if the vascular changes seen in familial hypercholesterolaemia are synonymous with atherosclerosis.17,,18 Therefore, to prove that the concentration of LDLcholesterol has importance in the general population, it is necessary to exclude individuals with familial hypercholesterolaemia.


Cholesterol does not correlate with degree of coronary atherosclerosis on angiography:   A correlation between the pathological findings seen on coronary angiography and cholesterol has been found in many studies.19 However, the correlation coefficients in these studies were never >0.36 and often much smaller; in some studies no correlation was found.20–,23 When present, the correlation found may have been due to bias by the process mentioned above, because coronary angiography is mainly performed on patients with symptomatic coronary disease, and more often on middleaged and younger patients. The correlation disappeared in one study after exclusion of patients treated with lipidlowering drugs.24


Cholesterol does not correlate with degree of coronary calcification:  In contrast to conventional angiography, electron beam angiography detects coronary plaques independent of their location in the vessel wall, but only calcified plaques. Degree of coronary calcification seems a good surrogate for degree of coronary atherosclerosis, because it correlates strongly with total plaque volume and obstructive coronary disease, and is a powerful predictor of clinical outcome. Nonetheless, degree of coronary calcification did not correlate with any lipid fraction in the blood.25


Cholesterol does not correlate with degree of peripheral atherosclerosis:  Many studies have found an association between LDL or total cholesterol and peripheral atherosclerosis, depicted by angiography or ultrasonography, but only in dichotomous analyses, and again, differences have been found mainly between individuals with very high cholesterol concentrations and the rest. In ultrasonographic studies, where degree of carotic atherosclerosis was graded as a continuous variable, no correlation was found with individual LDLcholesterol concentrations.26,,27 In similar studies using aortic28 and femoral29 angiography, no correlation was found either. Mean femoral intimamedia thickness was evaluated by ultrasonography in patients with familial hypercholesterolaemia and in control individuals with normal cholesterol. Using all observations, a correlation was found (r=0.41), but from a visual judgement of the scatterplot, within each group no clear correlation was present.30


No exposure-response:  The lack of an association in these studies may be explained by an influence of other important risk factors. A more reliable parameter is exposureresponse. If the amount of circulating cholesterol has any importance, sequential changes of its concentrations should be followed by parallel changes of atherosclerosis growth.


In a few observational studies with coronary angiography, the correlation of these two parameters, graded as continuous variables, was analysed. In three studies, no correlation was found;32–,34 in two others, progression of atherosclerosis was associated with a decrease in cholesterol, not an increase.35,,36


Experimentally, many trials have analysed the effect of cholesterol lowering on the angiographic changes. Most of them have looked at the association with ontrial LDLcholesterol or final LDLcholesterol only, but in sixteen trials,36–,51 exposureresponse was also analysed (Table 1). Two of them found exposureresponse. In one of them ΔLDLcholesterol and Δtotal cholesterol were larger in the nonprogression group, but only in a unifactorial analysis.43 In another trial, treadmill exercise was used as intervention only. After one year, degree of exercise and ΔLDLcholesterol, but not Δtotal cholesterol, were inversely associated with the rate of progression.40 In the rest of the trials exposureresponse was absent (Table 1).


Several explanations were offered: most commonly that other lipids or lipid combinations explained the findings. However, Δhighdensity lipoprotein (HDL) cholesterol was analysed in twelve studies,36–38,40–44,46,47,50,,51 Δtriglycerides in ten,36–38,40–42,44,47,50,,51 Δapolipoprotein B in six,37,42,47,48,50,,51 Δapolipoprotein A1 in three,37,,47 Δverylowdensitylipoprotein cholesterol in three,36,50,,51 and Δsmall, dense LDLcholesterol in one study,50 but none of them were associated with atherosclerosis growth. In an early trial using visual evaluation of the angiographic findings36 Δintermediatedensity lipoprotein cholesterol was associated with atherosclerotic progression, but in two others using computerassisted analysis,50,,51 no association was found. In three trials, the ratio Δtotal cholesterol/HDL cholesterol was inversely associated with atherosclerotic progression,41,43,,47 but in one it was seen only in the placebo group,41 and in another the analysis was not corrected for other risk factors.43


Table 1 


Changes (Δ) in lowdensity lipoprotein cholesterol and of total cholesterol in relation to atherosclerotic progression, graded as a continuous variable, in 18 cholesterollowering, angiographic trials


Trial

Type of intervention

Measurement of angiographic progress or regress

Baseline LDLC and (tC) (mmol/l)

Trial length (years, months)

Patients

Increase in atherosclerosis associated with

n

Males (%)

Mean age (years)

ΔtC

ΔLDLC

Krauss et al. 198736

Cholestyramine

MLD c, v

6.08 (7.08)

5,0

143

 80

No*

No*

Blankenhorn et al. 199037

Colestipol, niacin

MLD c, v

4.36 (6.26)

2,0

162

100

54

No*

No*

Olsson et al. 199038

Nicotinic acid

Global estimate f, v

6.44 (9.68)

1,6

 20

100

50

No

No

   +fenofibrate

Tatami et al. 199239

LDLapheresis

%Stenosis c, q

8.89 (11.1)

>1,0

 37

 59

No*

No*

   +probucol

   and/or pravastatin

Hambrecht et al. 199340

Physical exercise

MLD; %stenosis c, q

4.21 (6.0)

1,0

 88

100

53

No*

Yes*

Hodis et al. 199441

Lovastatin

%Stenosis c, q

4.00 (5.90)

2,0

220

 91

58

No*

No*

Sacks et al. 199442

Various lipidlowering

MLD; %stenosis c, q

3.56 (5.5)

2,9

 79

 89

58

No*

No*

   drugs

Quinn et al. 199443

Multiple risk factor

MLD c, q

4.02 (5.88)

2,0

257

 86

57

Yes

Yes

   reduction

SchuffWerner et al. 199444

LDLapheresis

%Stenosis c, q

7.54 (9.36)

2,0

 33

 70

47

No

No

Kitabatake et al. 199445

LDLapheresis+various

%Stenosis, c, q

6.62 (8.46)

1,0

 13

 77

48

No

   lipidlowering drugs

Regnström et al. 199646

Probucol

Global estimate f, q

6.52 (8.83)

3,0

303

 57

54

No

No

Niebauer et al. 199647

Lowfat diet+physical

%Stenosis c, q

4.22 (6.06)

1,0

 92

100

54

No*

No*

   exercise

Kroon et al. 199648

LDLapheresis+simvastatin

MLD; %stenosis c, q

7.82 (9.79)

2,0

 40

100

52

No

No

   vs. simvastatin

Tamura et al. 199749

Pravastatin

%Stenosis c, q

3.11 (4.73)

2,0

 80

 81

64

No

No

Ruotolo et al. 199850

Bezafibrate

MLD; %stenosis c, q

4.64

5,0

 81

100

41

No*

Sutherland et al. 199851

Simvastatin

% stenosis c, q

4.33 (6.91)

2,0

 38

 53

57

No

No


  • *Adjusted for other risk factors; MLD, minimum lumen diameter; LDLC, LDLcholesterol; tC, total cholesterol; c, coronary angiography; f, femoral angiography; v, visual judgement; q, quantitative, computerized image analysis.


Objections: 


Doubt has been raised against the use of coronary angiography as a measure of atherosclerotic changes.52 The most serious objection, that angiography underestimates the amount of subendothelial deposits, and cannot depict the intramural ones, is not relevant in studies of exposureresponse, because associations are sought to the changes, not to the degree of atherosclerosis. Large inter and intraobserver variabilities are found in studies using visual judgement of the angiographic changes, but thirteen of the sixteen mentioned trials used quantitative, computerized image analysis (Table 1). Other objections include imprecise measurements of lumen diameter and misinterpretation of its initial compensatory enlargement as atherosclerotic regression. In particular, percent stenosis has been questioned as a reliable measure of progress or regress because of uncontrolled physiological influences on the lumen of the reference vessels.52–,54 However, if measured with care, the minimum lumen diameter, used in half of the studies as a measure of atherosclerosis (Table 1), has a low coefficient of variation for repeated measurements55 and is a strong predictor of the coronary flow reserve,56 the reactive hyperaemic response,53 the transstenotic pressure gradient57 and thallium scintigraphic changes after exercise,57 all of which reflect degree of atherosclerotic narrowing of the coronary vessels. Angiographic deterioration strongly predicted cardiovascular events in the studies that included a clinical followup.36,37,,39


Why does a high cholesterol predict cardiovascular disease?


If LDLcholesterol and ΔLDLcholesterol do not correlate with degree of atherosclerosis or with atherosclerosis growth, why does a high cholesterol predict cardiovascular disease? The answer may be that cardiovascular disease is not synonymous with atherosclerosis. A high LDL or total cholesterol may be secondary to uncontrolled factors that promote cardiovascular disease in other ways and cause hypercholesterolaemia at the same time, for instance lack of physical activity,58 mental stress,59 smoking, and obesity.60 It is generally assumed that their effect on cardiovascular disease is mediated through the high cholesterol, but this may be a secondary phenomenon. Physical activity may benefit the cardiovascular system by improving endothelial function,61 or by stimulating the formation of collateral vessels;62 mental stress may have a harmful influence on adrenal hormone secretion, smoking increases the oxidant burden; in these all situations the high cholesterol may be an epiphenomenal indicator that something is wrong. This argument also explains why some studies found atherosclerotic growth to be associated with initial or onstudy LDLcholesterol, but not with ΔLDL or total cholesterol. If the amount of LDLcholesterol in the blood were the determining factor, atherosclerotic growth should have been associated with ΔLDLcholesterol as well and to a higher degree.


Conclusion


‘The more LDL there is in the blood, the more rapidly atherosclerosis develops.’ This 1984 statement by the Nobel Award winners Michael Brown and Joseph Goldstein1 has dominated research on atherosclerosis since then. As shown here, this hypothesis appears to be falsified by the fact that degree of atherosclerosis, and atherosclerotic growth, were independent on the concentration or the change of LDLcholesterol in almost all studies. The role of LDLcholesterol for atherosclerosis growth has been exaggerated, a finding with consequences for the prevention of cardiovascular disease. For instance, as the statins exert their beneficial influence on the cardiovascular system by several mechanisms, it may be wiser to search for the lowest effective dose instead of the dose with maximal effect on LDLcholesterol. Neither should an elevated LDLcholesterol be the primary target in cardiovascular prevention, as recently claimed by the American National Cholesterol Education Program, and researchers should direct more attention to other hypotheses.


I may have overlooked studies that have found an association between changes of LDLcholesterol or other lipid fractions, and atherosclerotic progression. However, although the presence of exposureresponse is not sufficient proof in itself of causality, it is difficult to explain its absence.


Footnotes



  • © Association of Physicians


References



Brown M, Goldstein JL. How LDL receptors influence cholesterol and atherosclerosis. Sci Am1984; 251:58–66.


MedlineWeb of Science



Sacks FM, Moyé LA, Davis BR, et al. Relationship between plasma LDL concentrations during treatment with pravastatin and recurrent coronary events in the cholesterol and recurrent events trial. Circulation1998; 97:1446–52.


Abstract/FREE Full Text



Ravnskov U. Implications of 4S evidence on baseline lipid levels. Lancet1995; 346:181.


CrossRef



Landé KE, Sperry WM. Human atherosclerosis in relation to the cholesterol content of the blood serum. Arch Pathol1936; 22:301–12.


Web of Science



Mathur KS, Patney NL, Kumar V, Sharma RD. Serum cholesterol and atherosclerosis in man. Circulation1961; 23:847–52.


Abstract/FREE Full Text



Paterson JC, Dyer L, Armstrong EC. Serum cholesterol levels in human atherosclerosis. Can Med Ass J1960; 82:6–11.


  1. Marek Z, Jaegermann K, Ciba T. Atherosclerosis and levels of serum cholesterol in postmortem investigations. Am Heart J1962; 63:768–74.


CrossRefMedlineWeb of Science



Cabin HS, Roberts WC. Relation of serum total cholesterol and triglyceride levels to the amount and extent of coronary artery narrowing by atherosclerotic plaque in coronary heart disease. Am J Med1982; 73:227–34.


CrossRefMedlineWeb of Science



Sharrett AR. Serum cholesterol levels and atherosclerosis. Coron Artery Dis1993; 4:867–70.


MedlineWeb of Science



Solberg LA, Strong JP, Holme I, et al. Stenoses in the coronary arteries. Relation to atherosclerotic lesions, coronary heart disease, and risk factors. The Oslo Study. Lab Invest1985; 53:648–55.


MedlineWeb of Science



Oalmann MC, Malcom GT, Toca VT, Guzman MA, Strong JP. Community pathology of atherosclerosis and coronary heart disease: post mortem serum cholesterol and extent of coronary atherosclerosis. Am J Epidemiol1981; 113:396–403.


Abstract/FREE Full Text



Feinleib M, Kannel WB, Tedeschi CG, Landau TK, Garrison RJ. The relation of antemortem characteristics to cardiovascular findings at necropsy. The Framingham Study. Atherosclerosis1979; 34:145–57.


CrossRefMedlineWeb of Science



Sadoshima S, Kurozumi T, Tanaka K, et al. Cerebral and aortic atherosclerosis in Hisayama, Japan. Atherosclerosis1980; 36:117–26.


CrossRefMedlineWeb of Science



Reed DM, Strong JP, Resch J, Hayashi T. Serum lipids and lipoproteins as predictors of atherosclerosis. An autopsy study. Arteriosclerosis1989; 9:560–4.


Abstract/FREE Full Text



Sorlie PD, Garcia‐Palmieri MR, Costas R, Oalmann MC, Havlik R. The relation of antemortem factors to atherosclerosis at autopsy. The Puerto Rico Heart Health Program. Am J Pathol1981; 103:345–52.


MedlineWeb of Science



Solberg LA, Hjermann I, Helgeland A, Holme I, Leren PA, Strong JP. Association between risk factors and atherosclerotic lesions based on autopsy findings in the Oslo study: a preliminary report. In: Schettler G, Goto Y, Hata Y, Klose G, eds. Atherosclerosis IV. Proc 4. Int. Symp. Berlin, Springer Verlag, 1977:98–100.



Stehbens WE, Martin M. The vascular pathology of familial hypercholesterolemia. Pathology1991; 23:54–61.


MedlineWeb of Science



Stehbens WE. Coronary heart disease, hypercholesterolemia, and atherosclerosis I: false premises. Exp Mol Pathol2001; 70:103–19


CrossRefMedlineWeb of Science



Pearson TA. Coronary arteriography in the study of epidemiology of coronary artery disease. Epidemiol Rev1984; 6:140–66.


FREE Full Text



Nitter‐Hauge S, Enge I. Relation between blood lipid levels and angiographically evaluated obstructions in coronary arteries. Br Heart J1973; 35:791–5.


FREE Full Text


  1. Barboriak JJ, Rimm AA, Anderson AJ, Tristani FE, Walker JA, Flemma RJ. Coronary artery occlusion and blood lipids. Am Heart J1974; 87:716–21


CrossRefMedlineWeb of Science


  1. Fuster V, Frye RL, Connolly DC, Danielson MA, Elveback LR, Kurland LT. Arteriographic patterns early in the onset of the coronary syndromes. Br Heart J1975; 37:1250–5.


Abstract/FREE Full Text



Krishnaswami S, Jose VJ, Joseph G. Lack of correlation between coronary risk factors and CAD severity. Int J Cardiol1994; 47:37–43.


CrossRefMedlineWeb of Science



Cramér K, Paulin S, Werkö L. Coronary angiographic findings in correlation with age, body weight, blood pressure, serum lipids, and smoking habits. Circulation1966; 33:888–900.


Abstract/FREE Full Text



Hecht HS, Superko HR. Electron beam tomography and National Cholesterol Education Program guidelines in asymptomatic women. J Am Coll Cardiol2001; 37:1506–11.


CrossRefMedlineWeb of Science



Crouse JR, Toole JF, McKinney WM, et al. Risk factors for extracranial carotid artery atherosclerosis. Stroke1987; 18:990–6.


Abstract/FREE Full Text



Nishino M, Sueyoshi K, Yasuno M, Yamada Y, Abe H, Hori M, Kamada T. Risk factors for carotid atherosclerosis and silent cerebral infarction in patients with coronary heart disease. Angiology1993; 44:432–40.



Palomäki H, Kaste M, Raininko R, Salonen O, Juvela S, Sarna S. Risk factors for cervical atherosclerosis in patients with transient ischemic attack or minor ischemic stroke. Stroke1993; 24:970–5.


Abstract/FREE Full Text



Erikson U, Ericsson M, Persson R. On the relation between peripheral atherosclerosis and serum lipoproteins. Upsala J Med Sci1979; 84:95–104.


MedlineWeb of Science



Wendelhag I, Wiklund O, Wikstrand J. Atherosclerotic changes in the femoral and carotid arteries in familial hypercholesterolemia. Ultrasonographic assessment of intima‐media thickness and plaque occurrence. Arteriosclerosis1993; 13:1404–11.


Abstract/FREE Full Text


  1. Kramer JR, Kitazume H, Proudfit WL, Matsuda Y, Williams GW, Sones FM. Progression and regression of coronary atherosclerosis: relation to risk factors. Am Heart J1983; 105:134–44.


CrossRefMedlineWeb of Science



Bruschke AVG, Kramer JR Jr, Bal ET, Haque IU, Detrano RC, Goormastic M. The dynamics of progression of coronary atherosclerosis studied in 168 medically treated patients who underwent coronary arteriography three times. Am Heart J1989; 117:296–305.


CrossRefMedlineWeb of Science


  1. Bissett JK, Wyeth RP, Matts JP, Johnson JW. Plasma lipid concentrations and subsequent coronary occlusion after a first myocardial infarction. The POSCH group. Am J Med Sci1993; 305:139–44.


MedlineWeb of Science



Bemis CE, Gorlin R, Kemp HG, Herman MV. Progression of coronary artery disease: a clinical arteriographic study. Circulation1973; 47:455–64.


Abstract/FREE Full Text



Shub C, Vlietstra RE, Smith HC, Fulton RE, Elveback LR. The unpredictable progression of symptomatic coronary artery disease: a serial clinical‐angiographic analysis. Mayo Clin Proc1981; 56:155–60.


MedlineWeb of Science



Krauss RM, Lindgren FT, Williams PT, et al. Intermediate‐density lipoproteins and progression of coronary artery disease in hypercholesterolaemic men. Lancet1987; 2:62–6.


CrossRefMedlineWeb of Science



Blankenhorn DH, Alaupovic P, Wickham E, Chin HP, Azen SP. Prediction of angiographic change in native human coronary arteries and aortocoronary bypass grafts: lipid and nonlipid factors. Circulation1990; 81:470–6.


Abstract/FREE Full Text



Olsson AG, Ruhn G, Erikson U. The effect of serum lipid regulation on the development of femoral atherosclerosis in hyperlipidaemia: a non‐randomized controlled study. J Int Med1990; 227:381–90.


MedlineWeb of Science



Tatami R, Inoue N, Itoh H, et al. Regression of coronary atherosclerosis by combined LDL‐apheresis and lipid‐lowering drug therapy in patients with familial hypercholesterolemia: a multicenter study. Atherosclerosis1992; 95:1–13.


CrossRefMedlineWeb of Science



Hambrecht R, Niebauer J, Marburger C, et al. Various intensities of leisure time physical activity in patients with coronary artery disease: effects on cardiorespiratory fitness and progression of coronary atherosclerotic lesions. J Am Coll Cardiol1993; 22:468–77.


CrossRefMedline



Hodis HN, Mack WJ, Azen SP, et al. Triglyceride‐ and cholesterol‐rich lipoproteins have a differential effect on mild/moderate and severe lesion progression as assessed by quantitative coronary angiography in a controlled trial of lovastatin. Circulation1994; 90:42–9.


Abstract/FREE Full Text



Sacks FM, Pasternak RC, Gibson CM, Rosner B, Stone PH, for the Harvard Atherosclerosis Reversibility Project (HARP) Group. Effect on coronary atherosclerosis of decrease in plasma cholesterol concentrations in normocholesterolaemic patients. Lancet1994; 344:1182–6.


CrossRefMedlineWeb of Science



Quinn TG, Alderman EL, McMillan A, Haskell W. Development of new coronary atherosclerotic lesions during a 4‐year multifactor risk reduction program: The Stanford Coronary Risk Reduction Project (SCRIP). J Am Coll Cardiol1994; 24:900–8.


MedlineWeb of Science



Schuff‐Werner P, Gohlke H, Bartmann U, et al. and the HELP‐STUDY GROUP. The HELP‐LDL‐apheresis multicentre study, an angiographically assessed trial on the role of LDL‐apheresis in the secondary prevention of coronary heart disease. II: Final evaluation of the effect of regular treatment on LDL‐ cholesterol plasma concentrations and the course of coronary heart disease. Eur J Clin Invest1994; 24:724–32.


MedlineWeb of Science



Kitabatake A, Sato H, Hori M, et al. Coronary atherosclerosis reduced in patients with familial hypercholesterolemia after intensive cholesterol lowering with low‐density lipoprotein‐apheresis: 1‐year follow‐up study. Clin Ther1994; 16:416–28.


MedlineWeb of Science



Regnström J, Walldius G, Nilsson S, et al. The effect of probucol on low density lipoprotein oxidation and femoral atherosclerosis. Atherosclerosis1996; 125:217–29.


MedlineWeb of Science



Niebauer J, Hambrecht R, Velich T, et al. Predictive value of lipid profile for salutary coronary angiographic changes in patients on a low‐fat diet and physical exercise program. Am J Cardiol1996; 78:163–7.


MedlineWeb of Science



Kroon AA, Aengevaeren WRM, van der Werf T, et al. LDL‐apheresis atherosclerosis regression study (LAARS). Effect of aggressive versus conventional lipid lowering treatment on coronary atherosclerosis. Circulation1996; 93:1826–35.


Abstract/FREE Full Text



Tamura A, Mikuriya Y, Nasu M, and the coronary artery regression study (CARS) group. Effect of Pravastatin (10 mg/day) on progression of coronary atherosclerosis in patients with serum total cholesterol levels from 160 to 220 mg/dl and angiographically documented coronary disease. Am J Cardiol1997; 79:893–6.


CrossRefMedlineWeb of Science



Ruotolo G, Ericsson CG, Tettamanti C, et al. Treatment effects on serum lipoprotein lipids, apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the bezafibrate coronary atherosclerosis intervention trial (BECAIT). J Am Coll Cardiol1998; 32:1648–56.


CrossRefMedlineWeb of Science



Sutherland WHF, Restieaux NJ, Nye ER, et al. IDL composition and angiographically determined progression of atherosclerotic lesions during simvastatin therapy. Arteriosclerosis1998; 18:577–83.


Abstract/FREE Full Text



Hong MK, Mintz GS, Popma JJ, et al. Limitations of angiography for analyzing coronary atherosclerosis progression or regression. Ann Intern Med1994; 121:348–54.


MedlineWeb of Science



Harrison DG, White CW, Hiratzka LF, et al. The value of lesion cross‐sectional area determined by quantitative coronary angiography in assessing the physiologic significance of proximal left anterior descending coronary arterial stenoses. Circulation1984; 69:1111–19.


Abstract/FREE Full Text



White CW, Wright CB, Doty DB, et al. Does visual interpretation of the coronary arteriogram predict the physiologic importance of a coronary stenosis? N Engl J Med1984; 310:819–24.


CrossRefMedlineWeb of Science



Ellis S, Sanders W, Goulet C, et al. Optimal detection of the progression of coronary artery disease: comparison of methods suitable for risk factor intervention trials. Circulation1986; 74:1235–42.


Abstract/FREE Full Text



Zijlstra F, van Ommeren J, Reiber JH, Serruys PW. Does the quantitative assessment of coronary artery dimensions predict the physiologic significance of a coronary stenosis? Circulation1987; 75:1154–61.


Abstract/FREE Full Text



Wijns W, Serruys PW, Reiber JHC, et al. Quantitative angiography of the left anterior descending coronary artery: correlations with pressure gradient and results of exercise thallium scintigraphy. Circulation1985; 71:273–9.


Abstract/FREE Full Text



Stefanick ML, Mackey S, Sheehan M, Ellsworth N, Haskell WL, Wood PD. Effects of diet and exercise in men and postmenopausal women with low levels of HDL cholesterol and high levels of LDL‐cholesterol. N Engl J Med1998; 339:12–20.


CrossRefMedlineWeb of Science



Muldoon MF, Herbert TB, Patterson SM, Kameneva M, Raible R, Manuck SB. Effects of acute psychological stress on serum lipid levels, hemoconcentration, and blood viscosity. Arch Intern Med1995; 155:615–20.


CrossRefMedlineWeb of Science



Ravnskov U. The Cholesterol Myths. Washington DC, New Trends Publishing, 2000.



Hambrecht R, Wolf A, Gielen S, et al. Effect of exercise on coronary endothelial function in patients with coronary artery disease. N Engl J Med2000; 342:454–60.


CrossRefMedlineWeb of Science



Belardinelli R, Georgiou D, Ginzton L, Cianci G, Purcaro A. Effects of moderate exercise training on thallium uptake and contractile response to low‐dose dobutamine of dysfunctional myocardium in patients with ischemic cardiomyopathy. Circulation1998; 97:553–61.


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The book below by Prof Ravnskov is the best that I have read on the topic.  Unlike most book on this issue, this one meets professional standards.  The theory of cholesterol causing cardiovascular disease has been repeatedly exposed, over a dozen books on Amazon deal with this and the failure of statins to prevent coronary artery disease and deaths, made all the worse by their serious side effects.  That such has been swept under the rug for 20 years is proof of the control that pharma exerts upon the production of information and thus beliefs. 


At http://healthfully.org/rl/id8.html is an article he authored on the same subject. 


Notes on Ravnskov’s Cholesterol Myth book


Ignore the Awkward!  How the Cholesterol Myths are Kept Alive, 2010 Uffe Ravnskov, M.D. from U of Copenhagen 1961 (born 1934, clinician and researcher in Sweden, PhD. U. of Lund, published more than 100 papers and letter critical of cholesterol campaign, most of them in major medical journals. He is the creator and spokesman for THINCS (The International Nework of Cholesterol Skeptics (WWW.thincs.org).  Uffe has done important work in neurology, his specialty. Note, number after a sentence indicates which page the material is on.  Each major assertion is supported by footnotes, mostly to journal articles.


Chapter 1:  The Animal Argument.  Examples of bad studies such as, the use of rabbits (vegetarians) to show that dietary cholesterol causes atherosclerosis.


Chapter 2:  The diet Argument.  High cholesterol in the elderly not associated with death, 19.  Saturated fats not associated with deaths.  Saturated fats don’t raise cholesterol level, 21.  Flaws in Ancel Keys work (misses industry funding, and his reversal of position on saturated fats; flaw in death certificates, etc. 21-23.  Dairy products saturated fats okay, 24.  Dietary guidelines, Swedish, WHO,


Chapter 3:  The Nobel Prize Argument.  Familial hypercholesterolemia (FH), homozygous extremely rate.  They have damaged LDL-receptors causes higher blood level of cholesterol.  Most people with FH don‘t die early, though they have a higher rate of dying from heart disease and a lower rate for cancer and other diseases, 30.  Before 1900 those with FH lived longer than the average Dutchman.  Lipoproteins bind to and neutralize bacteria and viruses and their toxic products, 31.  People with low cholesterol have an increased risk of dying from diseases of the stomach, the guts, and lungs, 31.   “If high cholesterol were the cause of atherosclerosis in these people, all of their arteries should be in danger, not only those going to the heart… Even those with the rare homozygous variant, the cerebral arteries are not more atherosclerotic than the normal people… although their cholesterol may be almost three times higher, 31.”  “They may have abnormally high levels of fibrinogen, factor VIII, or prothrombin, molecules that are necessary actors in the coagulation process, 32.  Since the introduction of the cholesterol reducing statins, young people with FH dies less often from heart disease.  This is correct, but it cannot be the result of a reduction in cholesterol.  Study after study has shown that the small effect achieved with these drugs is independent of the degree of cholesterol reduction…. The explanation is probably that the statins have other, more useful qualities than reducing cholesterol.  For example, statins have anti-clogging effect on the blood, which evidently is useful for people who are born with too much fibrinogen, factor VIII or prothrombin in their blood, 32


Chapter 4:  The Risk factor Argument.  “Women with low cholesterol run the same risk as women with high cholesterol…. Canadian researchers studied almost 5000 healthy middle-aged men for twenty years and came up with the same result…. In addition, study after study has shown that cholesterol is unimportant for those who have already had a heart attack.” 36.   “At least fifteen studies have shown that high cholesterol is not a risk factor for diabetic patients either… In a large study of old people living in the Bonx in New York, low cholesterol, not high, was a risk factor”, 37. 


*** Chapter 5: An  Argument to Forget.  Autopsy of Japanese and Americans failed to find an association of blood levels and AS of the aorta, 41-2.  Similar problem with angiography, bypass surgery, 42-3.  Electron beam tomography 43-4. 


*** Chapter 6:  The Trial Argument.    Lists the trials with weak to no benefits, points out that it isn’t the cholesterol lower effect that causes this weak improvement as to deaths from MI, but other effects of statins.  However, the overall mortality remained about the same, more died of cancer, heart failure, etc.  “What has been forgotten is that low cholesterol is a frequent finding in people with various types of mental disturbances…  In addition people with high cholesterol develop Parkinson’s disease and dementia less often than people with low cholesterol.” 56.  “If Alzheimer’s disease is seen less often in statin-treated people, is it because they have lived most of their life with high cholesterol, or is it because they received statin treatment?  Nobody knows.” 57.   “Fatty streaks are found in the vessels of all children, even in populations where atherosclerosis is rare … Several studies have shown that about half of the children with high cholesterol at age two have a normal cholesterol when they reach puberty”, 57.


*** Chapter 7:  How to keep a False idea Alive.  LRC trial over the first four years had 612 journal citations, while the unfavorable Miettinen trial (morality increased) over the same period had15 citations.  What he misses is ghost writing and rewritten of the same article by pharma’s staff—see Ben Goldacre. 


Chapter 8:  How to Exaggerate Insignificant Results.  Subgroup analysis—limited chapter on just 2 studies


Chapter 9:  How to Explain Away Awkward Results.  “Even independent researchers may find it difficult to challenge an idea that is accepted by everyone,” 75.      The collection of side effects.  “other researchers have described patients who suffered with progressive dementia, who recovered after they had stopped their treatment.”  82 Cognitive impairment associated with atorvastatin and simvastatin, DS King et al Pharmacotherapy 2003:23:871-80; http://onlinelibrary.wiley.com/doi/10.1592/phco.23.15.1663.31953/abstract      http://www.neurology.org/content/58/9/1333.short   Statins and Risk of [idiopathic] Polyneuropathy, 2002:  For patients treated with statins for 2 or more years the odds ratio of definite idiopathic polyneuropathy was 26.4.”   “In the CARE trial thirteen women had developed breast cancer in the treatment group, but only one in the control group.  Some of them were new cases; others were recurrences of previously treated breast cancer.  Since then, all patients who have undergone cancer treatment have been excluded from the trials.” 86.  [probably the great risk in part was caused by the reduction in the cancer preventative estradiol].  He falls for the BS of the PROSPER study author that for all the Pravachol trials the net increase in cancer was zero; BS because the other studies did not make public the cancer stats, and most were to short to have a significant increase.  Lots of deception space in the company reply on cancer.   Uffe does point out that in the previous studies the patients were 25 years younger.  Thus another reason heart failure for excluding the elderly from studies.  Goes into the hassle on filling reports on side effects.  “Dr. Kendrick estimated that filing an adverse drug report, then dealing with the follow up paperwork, takes about two to three hours of work.  Then nothing at all happens. “ 89


 


Chapter 10:  How to Lie convincingly.  On the Framingham study:   …according to the original report mortality increased 11%....  Without presenting anything other than complicated ratios and statistical calculations, and without referring to their previous report, they stated:  The most important overall finding is the emergence of the total cholesterol concentration as a risk factor for CHD in the elderly. “ 98. 


Chapter 11:  How to Ignore Alternative Explanations.  Rather sketchy chapter which blames stress in two examples on increase in MI, one on monkey with heart attack, the others on Japanese who adopted a western diet, but not those who live a traditional lifestyle.  


Chapter 12:  How to Ignore the Critics.  Gives examples of how is submission was criticized for irrelevant issues, and how his letters to the editor were not published.  Of interest was Uffe’s 2002 systematic review of angiographic trials that found “no relationship between the degree of cholesterol lowering and the angiographic changes, meaning that the plaques or the diameter of the arteries increased or decreased haphazardly whether cholesterol was reduced a lot or not at all.” 114.    This paper was rejected by the first six journals, with only two sending it to referees.  Finally it was accepted in Oxford Journal at http://qjmed.oxfordjournals.org/content/95/6/397.full.  He highlights the problem that the referees believe the cholesterol myth and saturated fat myth, and are unlikely to evaluate the evidence.  Other paper went unpublished, and at conferences on those supporting the cholesterol theory are invited. 


Chapter 13:  When Arguments Stop Working.  The media used him to present an attack on his book, and in a Finish broadcast after being criticized the book was burned.  In a Danish show a leading Danish cholesterol expert said of Uffe “ an eccentric and irresponsible headbanger who had been kicked out of the universities in Copenhagen and Lund, a misfit whom no Danish hospital would ream of employing..” 120


Chapter 14:  Industrial Tricks.  “Consider for example, that in 2002 the combined profits for the ten drug companies on the global business magazine Fortune’s 500 list were greater than the profits for all the over 490 business put together.” 125.  Ghost writing, guideline authors, paying doctors to recruit trial patients $10,000 each and a bonus of $30,000 for the 6th one.  False advertising, hiding side effect for Vioxx, and fake journals


Part III  ON INFECTION as cuase


Assuming LDL is disease protective, then why are women protected by estradiol and not middle age men???  Answer, as men’s levels fall by the 4th decade their protection from AS diminishes but for a woman a similar hormonal decline doesn’t occur until about the age of 55.  Estrogen appears to affect endothelial cells better than testosterone. 


Chapter 15:  The Real Cause?   For Example, remnants from more than fifty different bacterial species [http://www.sciencedirect.com/science/article/pii/0014480084900509] and a number of viruses as well [http://circ.ahajournals.org/content/113/7/929.short] have been identified in atherosclerotic tissue, and antibodies against several of these micro-organisms are present in abnormally high amounts in the blood of patients with cardiovascular disease and people who die from it later in life. “ 134. [Many other with the JL Melnick article].  “…Erling Flak.  He examined the hearts of patients who had died because of an acute myocardial infarction and noted the the occluding thrombus usually was situated close to a ruptured bubble.” 134.[E, Flak, BR Heart J. 1983;50; 127-34.  COPIED chapter 7/31.  “The first part of our hypothesis is not our own.  It was proposed more than a hundred years ago and it says. To express it very simply, that atherosclerosis is the result of an infection in the artery wall.  The second part explains why and how LDL-cholesterol and the microorganisms end up here and what happens before a thrombus is created inside the artery. 


Most researchers agree that atherosclerosis starts as an inflammation in the arterial wall [and that] heart disease and stroke are associated in some way with infectious species and a number of viruses as well have been identified in atherosclerotic tissue, and antibodies against several of these microorgranism are present in abnormally high amounts in the blood of patients….  The following statement by two American pathologists, Oskar Klotz and M. F. Manning is typical for the general view at that time [1911]:  There is every indication that the production of tissue in the intima (the innermost layer of the arterial wall) is the result of a direct irritation of that tissue by the presence of infection or toxins.” 134 


“According to the present view…. That LDL-cholesterol enters the intima when it is activated …. The activated endothelium is also said to attract a type of whole blood cells named monocytes and invite them to enter the interior of the arterial wall.  When the LDL-cholesterol passed through the endothelia cells [of the artery walls] they are said to be attacked by cells in the intima resulting in a change of their structure:  LDL becomes oxidized.  It is this process which is considered as the cause of inflammation.  After having been oxidized the monocytes, now converted to macrophages, take up the oxidized LDL-cholesterol” 134-6.


The Contradictions (of the current theoretical mechanism):


Why do people with low cholesterol become jaust as atherosclerotic as people with high cholesterol?


Why do people with high cholesterol live longest?  [Farringham study]


Why is high cholesterol not a risk factor for women?


Why is the degree of endothelial dysfunction the same in people with high cholesterol as in people with low? (136-7)


The Vulnerable plaque:  Uffe then goes on to describe the appearance under a microscope of the vulnerable immature plaque which clearly shows signs of inflammation, including elevated temperature.  “Another interesting finding is the numerous lipid droplets that are found in the inflamed arterial wall outside the vulnerable plaques.  They are rarely seen directly beneath the endothelium like the foam cells, as should be expected if LDL cholesterol entered by the way of the endothelium.  This observation is crucial for the understanding of our hypothesis” 137.   For bacteria in vulnerable plaque http://www.scielo.br/scielo.php?pid=S1807-59322006000500016&script=sci_arttext


The lipoprotein immune system:  Sixty years ago researchers discovered that the lipoproteins participate in our immune system by binding and inactivating bacteria, viruses and their toxic products. The lipoprotein immune system may be particularly important in early childhood, because in contrast to the antibody producing system, which needs repeated stimulation to function properly, the lipoproteins work immediately and with great efficiency.  There are many ways to demonstrate it…. In the laboratory it has been shown that human LDL is able to inactivate more than 90% of the most toxic bacterial products…. [when] reduced blood cholesterol in rats and gave them an injection of bacterial toxin, most of them died quickly but if they injected a purified human LDL beforehand, they survived. When we are attacked by microbes, the white blood cells send a message to the liver by excreting their hormones, the cytokines.  The liver responds by increasing the production of lipoprotein including the ‘bad’ LDL; yet another indication that LDL is a useful molecule.”  Uffe states that medical textbooks are silent about this role of LDL. 


The new hypothesis:  When the lipoproteins bind the toxic intruders to their surface, all of them, toxins, microorganisms and lipoproteins, aggregate, meaning that they lump together into microscopic clumps that circulate in the blood. Also if too much homocysteine is present in the blood, it reacts with LDL molecules and makes them lump together.  In our view these particles play a crucial role in the creation of the vulnerable plaque… we think the vulnerable plaque is a pustule, a small boil.  Its interior looks like the interior of a boil, it temperature is higher than the surrounding tissue, just as is the case with a boil, and it may burst and empty its content like a boil.  The idea is not new.  As far as we know it was first suggested by Sir William Osler… a leading physician of his time. In one of his papers he described the vulnerable plaque as atherosclerotic Pustule [1908]


The Mechanism:  Large vessels such as arteries and veins are nourished through capillaries, the so-called vasa vasorum, which surround these vessels like an intricate meshwork.  .  What we suggest is that LDL clumps may become so numerous and of a size that they are able to obstruct the vasa vasorum.  Consequently small parts of the arterial walls become malnourished, get too little oxygen, and may even die—small infarct of the artery wall…. Becomes inflamed…. Hypoxia has been shown by intricate chemical analysis of atherosclerotic arteries.  Hypoxia is most pronounced in the deeper parts of the inflamed arterial walls where the macrophages are dominant. If the immune system is OK, the surrounding white blood cells and the antibodies attack the microogranisms.  Fibroblasts and new capillaries grow into the inflamed tissue and eventually it will be transformed into a scar, the fibrous plaque.  If not, a pustule is created, its thin membrane may burst, the content of the plaque flows out into the blood, a clot is created at the margins and if it becomes too large the blood flow becomes obstructed and the tissue that is nourished by the artery dies [unstable, young plaque].   [See for ex. http://journals.lww.com/co-lipidology/Abstract/2009/10000/The_role_of_hypoxia_in_atherosclerosis.9.aspx)    


Everything fits:  myocardial infarction and stoke increases during influenza epidemics, and people with infected teeth, or with bacteria in the blood… one-third of all patients… had an infectious disease immediately before onset… most common are respiratory dieases,… other types tuberculosis, HIV, tooth and urinary tract infections.  If a vulnerable plaqe may appear in normal arteries, and if mcroogansims cause stroke and myocardial infarction, then vascular disease may occur in all ages.  Finnish researcher Erkki Pesonen and his team noted that the coronary arteries were narrowed in children with infectious diseases, both in those who died and those who survived…. Why don’t the LDL-compleses obstruct the vasa vasorum of the veins?  The pressure in the veins is very low…. The LDL clumps have no problem passing by.  In the arteries the pressure is high.  Each stroke of the heart stops the blood flow completely in these vasa vasorum:  the blood is only able to pass by during the short time when the heart is relaxed.  [Contradicts claim that LDL is oxidized inside the artery.]  No, LDL is oxidized after having been taken up by the macrophages together with its toxic passengers as part of a normal physiological process.   When white blood ells take up foreing, dangerous material they neutralize it by oxidation and at the same time LDL is oxidized as well.  Probably HDL reconstructs LDL, because laboratory experiments have shown that HDL is able to convert oxidized LDL back to normal. 


A final comment:  Recommends vitamin D, especially in the winter, and vitamin C which is concentrated inside white blood cells “80 times higher than in the blood.”   


 


 


 


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