High cholesterol may protect against infections and atherosclerosis

[Guest guest]

http://qjmed.oupjournals.org/cgi/content/full/96/12/927?ijkey=172mwKXqzgmtE & keyt\

ype=refCommentaryHigh cholesterol may protect against infections and

atherosclerosis U. Ravnskov

Independent researcher

 

Introduction

Many researchers have suggested that the blood lipids play a key role in the

immune defence system.1–21 There is also a growing understanding that an

inflammatory response of the arterial intima to injury is a crucial step in the

genesis of atherosclerosis. and that infections may be one type of such

injury.22 These two concepts are difficult to harmonize with the

low-density-lipoprotein (LDL) receptor hypothesis, according to which high LDL

cholesterol is the most important cause of atherosclerosis. However, the many

observations that conflict with the LDL receptor hypothesis, may be explained by

the idea that high serum cholesterol and/or high LDL is protective against

infection and atherosclerosis.

 

Laboratory evidence

Lipopolysaccharide, or endotoxin, the main pathogenic factor of Gram-negative

bacteria, binds rapidly to lipoproteins,6 mainly LDL,7 and lipoprotein-bound

endotoxin is unable to activate the secretion of various cytokines by monocytes

in vitro.6,7,10 Also, Staphylococcus aureus -toxin, a toxin produced by most

pathogenic Staphylococcus strains and causing damage to a wide variety of cells,

is bound and almost totally inactivated by human serum and purified LDL, as

estimated by haemolytic titration.3

Mice with hypercholesterolaemia due to LDL-receptor deficiency, challenged with

bacterial endotoxin, had an 8-fold increased LD50, and a significantly lower and

delayed mortality after injection with Gram-negative bacteria, compared with

control mice.15 Also, rats made hypolipidaemic with

4-aminopyrolo-(3,4-D)pyrimide or estradiol had a greater increase in cytokine

levels and markedly increased endotoxin-induced mortality compared to normal

rats, and administration of exogenous lipoprotein reduced their mortality

substantially.12

In apparent contradiction, is a study of mice infected with Trypanosoma cruzi.

These mice developed vasculitis and also atherosclerosis, but the latter was

seen only if they were fed a Western-type high-fat diet in addition. However,

total serum cholesterol (t-C) did not differ between infected mice fed a

conventional diet and infected mice fed the high-fat diet, and t-C was lower in

the latter group than in non-infected mice on the high-fat diet who did not

develop atherosclerosis, indicating that the development of atherosclerosis was

not due to high t-C but to something else associated with the diet.23

High t-C may have other beneficial effects on the immune system, because

hypocholesterolaemic men had significantly fewer circulating lymphocytes, total

T cells, helper T-cells and CD8+ cells than hypercholesterolaemic men.17 Also,

adhesiveness to plastic surface, phagocytic activity and spontaneous motility of

mononuclear cells from hypercholesterolaemic individuals were significantly

higher compared to controls.8

In acute infections, cholesterol synthesis, measured as degree of 3H-mevalonic

acid incorporation into free cholesterol, increases, but the disappearance rate

of cholesterol from plasma is also increased,2 probably explaining why t-C may

either go up or down in an unpredictable way during the course of various

infectious diseases.1

 

Epidemiological and clinical evidence

Many epidemiological and clinical observations are in accord with the laboratory

studies. A meta-analysis of 19 cohort studies including 68 406 deaths, found an

inverse correlation between t-C and mortality from respiratory and

gastrointestinal diseases, most of which are of an infectious origin. It is

unlikely that the low cholesterol was due to these diseases because the

associations remained after the exclusion of deaths occurring during the first 5

years.24 Also, in a 15 year follow-up study of more than 120 000 individuals,

Iribarren et al. found a strong inverse association between t-C (as determined

initially) and the risk of being admitted to hospital due to an infectious

disease.20 Statistically significant, inverse associations were found for

urinary tract infections, all genitourinary infections and miscellaneous viral

infections for women, and for urinary tract infections, musculo-skeletal

infections and skin and subcutaneous infections in men. Inverse, but

non-significant associations were found for most other infectious diseases. In

a similar study of more than 100 000 individuals followed for 15 years, a

strong, inverse association was found between t-C and the risk of being admitted

to hospital because of pneumonia or influenza, but not for chronic, obstructive

pulmonary disease or asthma.18

In a study of 2446 unmarried men with a previous history of sexually transmitted

disease or liver disease followed for 14 years, a multivariate-adjusted analysis

showed a risk ratio for HIV infection of 1.66 (95%CI 1.07–2.56) in the lowest

cholesterol quartile compared with the risk in the second quartile.19 That the

low t-C was secondary to HIV is unlikely, because those who became HIV positive

during the first four years were excluded from the calculations. In accordance,

an inverse association between t-C and the risk of death in AIDS was found in a

follow-up of the MRFIT screenees.16

In patients with oedematous chronic heart failure, low t-C predicts impaired

perioperative and long-term survival. As such patients show substantial immune

activation and have raised plasma concentrations of bacterial

lipopolysaccharide, Rachhaus et al. have suggested that high t-C has a

protective effect in such patients.21 This may also explain why low t-C predicts

mortality in patients with postoperative abdominal infections.14

Patients with chemotherapy-induced neutropenia run a high risk of dying from

bacterial infectious disease. In 17 patients who developed neutropenia and fever

after chemotherapy, t-C went down by almost 30%. During the infection, t-C was

significantly higher in eleven survivors than in six non-survivors and returned

to normal. Serum levels of inflammatory cytokines on day 8 after onset were

significantly lower, and t-C before onset was also higher among the survivors,

although not significantly so.25

In China, where mean t-C is much lower than in the Western world, chronic

hepatitis B virus infection is ubiquitous and usually starts in early childhood.

Adult chronic carriers of hepatitis B surface antigen, but not individuals with

eradicated hepatitis B, have significantly lower t-C than non-carriers,

suggesting a cause-effect relationship.26 However, the opposite interpretation,

that low t-C prevents eradication, may be true as well. In support of this

conjecture, the percentage of carriers in 81 districts was proportional to the

mean t-C in these districts, suggesting that in populations with low t-C, more

children infected with hepatitis B die, resulting in a lower number of chronic

carriers.26 If hepatitis B was the cause of low t-C, the association should have

been inverse.

Evidence for anti-infectious effects of high t-C is also available from inborn

errors of cholesterol metabolism. Very low t-C is seen in Smith-Lemli-Opitz

syndrome, due to imperfect function of 7-dehydrocholesterol 7-reductase,

necessary for the last step in cholesterol synthesis. Many children with this

syndrome are stillborn or die early due to multiple malformations, and those who

survive have frequent and severe infections. It could be argued that the cause

was the high blood and tissue levels of 7-dehydrocholesterol, but low t-C may

also play a role, because the infections became less serious and less frequent

after supplementation with dietary cholesterol.27

Individuals with familial hypercholesterolaemia (FH) have very high LDL-C and

t-C due to LDL-receptor deficiency. One of the main arguments for the

LDL-receptor hypothesis is that members of such families run a great risk of

dying from coronary heart disease at an early age. The size of that risk is not

established with any certainty, however, as our clinical knowledge about this

condition is mainly based on studies of patients selected because of existing

heart disease or because of a family history of heart disease. To determine the

risk of heart disease in individuals with FH demands follow-up studies,

preferably of unselected individuals with FH, but such studies are rare. In one

cohort study, only 6/214 individuals between age 20–39, and 8/237 between age

40–59, died from CHD during a four-year follow-up. Most striking was that during

the same period, only 1/75 above age 60 died, equivalent to a standard mortality

ratio of 0.44. As the participants in this study were selected

because of a family history of heart disease, the authors concluded that the

mortality might be even lower in unselected individuals.28

This assumption seems to be true. In a Dutch population, three carriers of a

mutation for FH were identified through screening. A meticulous genealogical

search of their pedigrees backward in time identified 250 individuals with a

Mendelian probability of 0.5 of carrying the gene. Before year 1900, their

standardized mortality ratio was lower than normal, and rose to a peak of less

than twice normal in the 1930s to 1960s. The authors concluded that

environmental factors may participate in the causation of coronary heart disease

in FH, and that hypercholesterolaemia may have conferred a survival advantage

when infectious disease was prevalent.29

 

Immunoprotective effects of high cholesterol explain observations

contradicting the LDL-receptor hypothesis

According to the prevailing paradigm, high LDL cholesterol is said to promote

atherosclerosis growth, which explains why it is a risk factor for

cardiovascular disease. There is much contradictory evidence, however.30–33 It

is true that high t-C is a risk factor for coronary heart disease, but mainly in

young and middle-aged men. If high t-C or LDL-C were the most important cause of

cardiovascular disease, it should be a risk factor in both sexes, in all

populations, and in all age groups. But in many populations, including women,24

Canadian and Russian men,34,35 Maoris,36 patients with diabetes,37,38 and

patients with the nephrotic syndrome;39 the association between t-C and

mortality is absent24,34,36–39 or inverse;35 or increasing t-C is associated

with low coronary and total mortality.40 Most strikingly, in most cohort studies

of old people, high LDL-C or t-C does not predict coronary heart disease28,40–50

(Table 1) or all-cause mortality28,40,42,44,48,51–58 (Table 2); in several

of these studies the association between t-C and mortality was inverse,48,53,58

or high t-C was associated with longevity.51,54 These associations have mostly

been considered as a minor aberration from the LDL-receptor hypothesis, although

by far the highest mortality and the greatest part of all cardiovascular disease

are seen in old people.

 

Table 1 Studies of elderly people where high cholesterol did not predict

coronary morbidity or mortality.

 

 

 

Table 2 Studies of elderly people where high cholesterol did not predict

all-cause mortality or where mortality was inversely associated with cholesterol

 

 

The fact that statin treatment lowers both total and cardiovascular mortality in

high-risk individuals is taken as evidence that cholesterol lowering is

effective. However, statins are just as effective whether cholesterol is lowered

by a small amount (as in the unsuccessful non-statin trials) or by more than

40%. In addition, statin treatment is effective whether the initial LDL-C is

high or low.59,60 If high LDL-C were causal, the greatest effect should have

been seen in patients with the highest LDL-C, and in patients whose LDL-C was

lowered the most, but this is not the case. Lack of dose-response cannot be

attributed to the knowledge that the statins have other effects on plaque

stabilization, as this would not have masked the effect of cholesterol-lowering,

considering the pronounced lowering that was achieved. On the other hand, if

high cholesterol has a protective function, as suggested, its lowering would

counterbalance the beneficial effects of the statins and thus work

against a dose-response relationship, which would be more in accord with the

results seen. For example, the reduction of coronary mortality with simvastatin

was almost three times greater in the 4S trial61 than in the HPS trial,62

despite the fact that LDL-C and t-C decreased to a much lower level in the

latter.

The lack of exposure-response in the observational and experimental angiographic

studies31 may be similarly explained. Minor increases of the mean lumen diameter

were typically seen in the trials where statin treatment was used to lower

cholesterol, but much too early to be explained by a reduction of

atherosclerosis, and in the 21 trials and observational studies where

exposure-response was calculated, no association was found except in one, the

only trial where cholesterol was lowered by exercise. In addition, an inverse

association between change of t-C and atherosclerosis growth was found in two of

the five observational angiographic studies.31 It is also relevant, that in the

only cholesterol-lowering clinical trial that included a post-mortem,

complicated atherosclerosis was most pronounced in the treatment group.63

The effects of high cholesterol on the immune system may explain the inverse

association with total mortality, because a possible increase of mortality from

cardiovascular diseases may be counterbalanced by a lower mortality from

infectious diseases. But it is difficult to explain the lack of an association

between cholesterol and coronary mortality in old people, the inverse

association between change of cholesterol and atherosclerosis growth, and the

lack of exposure-response in the trials, unless high cholesterol has a

protective role against atherosclerosis that may override its alleged promoting

effect.

 

Contradictions to the hypothesis

The fact that high cholesterol predicts coronary heart disease in young and

middle-aged men would seem to argue against any protective role for high

cholesterol. However, high cholesterol may reflect the presence of factors

promoting coronary heart disease, which may outweigh the beneficial effects. As

most men of that age are in the midst of their professional career, high

cholesterol may reflect mental stress, a well-known cause of high cholesterol,

and also a significant risk factor for CHD. Thus, high cholesterol may be a risk

marker for adrenal hyperfunction, not the true cause.

It may also be argued that even if coronary mortality in FH is lower than

considered generally, it is much higher among young individuals with FH than in

the general population. For instance, the finding of 6/214 deaths in the

youngest age group mentioned above28 is equivalent to a standard mortality ratio

of about 100, i.e. 100 times higher than in the general population, because it

is extremely rare to die from CHD before age 40. However, it has been pointed

out by many researchers that the vascular changes in homozygous FH should be

characterized as a lipid storage disease, having few similarities with true

atherosclerosis. Early vascular lesions are atypical, and the usual

complications of atherosclerosis such as intimal tears, ulceration, thrombosis,

tortuosity and aortic aneurysms are rare.64 Besides, autopsy and angiographic

studies have shown a trivial or, most often, no association between plasma

cholesterol and degree of atherosclerosis, even in FH individuals.31 It is

therefore questionable that early CHD in FH patients is caused by their high

cholesterol alone.

Pathological findings similar to those seen in FH are produced in experimental

models of hypercholesterolaemic animals, but again, the pathological changes are

not identical with human atherosclerosis, and no experiment has hitherto

succeeded in producing a heart attack in an animal by hypercholesterolemia

alone.65 Besides, these experimental changes cannot be produced by pure

cholesterol, but very easily by its oxidation products, and it appears that most

studies of experimental atherosclerosis have had little control over the purity

of the dietary cholesterol.66 This issue may be complex, however. The arteries

of animals may react differently to dietary changes from those of humans, and

LDL may have various affinities to various types of infections. Thus,

LDL-receptor-deficient mice were more susceptible to acute dissiminated Candida

albicans infection than were normal mice.67 Also, in animal models of

dietary-induced atherosclerosis, the pathological changes in the arteries were

amplified by infection with Chlamydia pneumonia68 and bovine herpesvirus-4.69

The many observations mentioned above suggest that the beneficial effects of

high cholesterol on the immune system predominate in human beings, but there is

an obvious need for more research on the role of lipids in infectious and

atherosclerotic diseases.

 

Conclusions

According to the modified ‘response to injury’ hypothesis of atherogenesis,22

there are at least two pathways leading to the inflammatory and proliferative

lesions of the arterial intima. The first involves monocyte and platelet

interaction induced by hypercholesterolaemia. The second pathway involves direct

stimulation of the endothelium by a number of factors, including smoking, the

metabolic consequences of diabetes, hyperhomocysteinemia, iron overload, copper

deficiency, oxidized cholesterol, and micro-organisms. There is much evidence to

support roles for these factors, but the degree to which each of them

participates remains uncertain. However, the lack of exposure-response in the

trials between changes in LDL-cholesterol and clinical and angiographic outcome,

the inverse association between change of cholesterol and angiographic changes

seen in the observational studies, the significant increase in complicated

atherosclerotic lesions in the treatment group after cholesterol

lowering by diet, and most of all, the fact that high cholesterol predicts

longevity rather than mortality in old people, suggests that the role, if any,

of high cholesterol must be trivial. The most likely explanation for these

findings is that rather than promoting atherosclerosis, high cholesterol may be

protective, possibly through its beneficial influence on the immune system.

 

Acknowledgments

I am indebted to Kilmer McCully and Malcolm Kendrick for valuable comments. A

shorter version of this paper was presented at the Weston A. Price Foundation

4th Annual Conference in Washington, DC, May 3, 2003. I have no competing

financial interests in this subject.

 

Footnotes

 

Address correspondence to Dr U. Ravnskov, Magle Stora Kyrkogata 9, S-22350,

Sweden. e-mail: ravnskov

 

References

1. Gallin JI, Kaye D, O’Leary WM. Serum lipids in infection. N Engl J Med 1969;

281:1081–6.[Medline]

2. Fiser RH, Denniston JC, Rindsig RB, Beisel WR. Effects of acute infection on

cholesterolgenesis in the Rhesus monkey. Proc Soc Exp Biol Med 1971; 138:605–9.

3. Bhakdi S, Tranum-Jensen J, Utermann G, Füssle R. Binding and partial

inactivation of Staphylococcus aureus a-toxin by human plasma low density

lipoprotein. J Biol Chem 1983; 258:5899–904.[Free Full Text]

4. van Lenten BJ, Fogelman AM, Haberland ME, Edwards PA. The role of

lipoproteins and receptor-mediated endocytosis in the transport of bacterial

lipopolysaccharide. Proc Nat Acad Sci USA 1986; 83:2704–8.[Medline]

5. Flegel WA, Wolpl A, Mannel DN, Northoff H. Infect Immun 1989;

57:2237–45.[Medline]

6. Cavaillon JM, Fitting C, Haeffner-Cavaillon N, Kirsch SJ, Warren HS. Cytokine

response by monocytes and macrophages to free and lipoprotein-bound

lipopolysaccharide. Infect Immun 1990; 58:2375–82.[Medline]

7. Weinstock C, Ullrich H, Hohe R, Berg A, Baumstark MW, Frey I, Northoff H,

Flegel WA. Low density lipoproteins inhibit endotoxin activation of monocytes.

Arterioscler Thromb Vasc Biol 1992; 12:341–7.

8. Losche W, Krause S, Pohl A, Pohl C, Liebrenz A, Schauer I, Ruhling K, Till U.

Functional behavior of mononuclear blood cells from patients with

hypercholesterolemia. Thromb Res 1992; 65:337–42.[Medline]

9. Feingold KR, Grunfeld C. Role of cytokines in inducing hyperlipidemia.

Diabetes 1992; 41(suppl. 32):97–101.[Medline]

10. Flegel WA, Baumstark MW, Weinstock C, Berg A, Northoff H. Prevention of

endotoxin-induced monokine release by human low- and high-density lipoproteins

and by apolipoprotein A-I. Infect Immun 1993; 61:5140–6.[Abstract]

11. Hardardottir I, Grunfeld C, Feingold KR. Effects of endotoxin on lipid

metabolism. Biochem Soc Trans 1995; 23:1013–18.[Medline]

12. Feingold KR, Funk JL, Moser AH, Shigenaga JK, Rapp JH, Grunfeld C. Role for

circulating lipoproteins in protection from endotoxin toxicity. Infect Immun

1995; 63:2041–6.[Abstract]

13. Grunfeld C, Feingold KR. Regulation of lipid metabolism by cytokines during

host defense. Nutrition 1996; 12(Suppl.):S24–6.[CrossRef][Medline]

14. Pacelli F, Doglietto GB, Alfieri S, Piccioni E, Sgadari A, Gui D, Crucitti

F. Prognosis in intra-abdominal infections. Multivariate analysis on 604

patients. Arch Surg 1996; 131:641–5.[Abstract]

15. Netera MG, Demacker PNM, Kullberg BJ, Boerman OC, Verschueren I, Stalenhoef

AFH, van der Meer JWM. Low-density lipoprotein receptor-deficient mice are

protected against lethal endotoxemia and severe Gram-negative infections. J Clin

Invest 1996; 97:1366–72.[Abstract/Free Full Text]

16. Neaton JD, Wentworth DN. Low serum cholesterol and risk of death from AIDS.

AIDS 1997; 11:929–30.[Medline]

17. Muldoon MF, Marsland A, Flory JD, Rabin BS, Whiteside TL, Manuck SB. Immune

system differences in men with hypo- or hypercholesterolemia. Clin Immunol

Immunopathol 1997; 84:145–9.[CrossRef][Medline]

18. Iribarren C, Jacobs DR Jr, Sidney S, Claxton AJ, Gross MD, Sadler M,

Blackburn H. Serum total cholesterol and risk of hospitalization, and death from

respiratory disease. Int J Epidemiol 1997; 26:1191–202.[Abstract]

19. Claxton AJ, Jacobs DR Jr, Iribarren C, Welles SL, Sidney S, Feingold KR.

Association between serum total cholesterol and HIV infection in a high-risk

cohort of young men. J Acquir Immune Defic Syndr Hum Retrovirol 1998;

17:51–7.[Medline]

20. Iribarren C, Jacobs DR Jr, Sidney S, Claxton AJ, Feingold KR. Cohort study

of serum total cholesterol and in-hospital incidence of infectious diseases.

Epidemiol Infect 1998; 121:335–47.[CrossRef][Medline]

21. Rauchhaus M, Coats AJ, Anker SD. The endotoxin-lipoprotein hypothesis.

Lancet 2000; 356:930–3.[CrossRef][Medline]

22. Ross, R. The pathogenesis of atherosclerosis—an update. N Engl J Med 1986;

314:488–500.[Medline]

23. Sunnemark D, Harris RA, Frostegard J, Orn A. Induction of early

atherosclerosis in CBA/J mice by combination of Trypanosoma cruzi infection and

a high cholesterol diet. Atherosclerosis 2000; 153:273–82.[CrossRef][Medline]

24. Jacobs D, Blackburn H, Higgins M, Reed D, Iso H, McMillan G, Neaton J,

Nelson J, Potter J, Rifkind B. Report of the conference on low blood

cholesterol: Mortality associations. Circulation 1992; 86:1046–60.[Abstract]

25. Fraunberger P, Hahn J, Holler E, Walli AK, Seidel D. Serum cholesterol

levels in neutropenic patients with fever. Clin Chem Lab Med 2002;

40:304–7.[Medline]

26. Chen Z, Keech A, Collins R, Slavin B, Chen J, Campbell TC, Peto R. Prolonged

infection with hepatitis B virus and association between low blood cholesterol

concentration and liver cancer. Br Med J 1993; 306:890–4.[Medline]

27. Elias ER, Irons MB, Hurley AD, Tint GS, Salen G. Clinical effects of

cholesterol supplementation in six patients with the Smith-Lemli-Opitz syndrome

(SLOS). Am J Med Genet 1997;

68:305–10.3.0.CO;2-X & link_type=DOI " >[CrossRef][Medline]

28. Scientific steering committee on behalf of the Simon Broome Register group.

Risk of fatal coronary heart disease in familial hypercholesterolaemia. Br Med J

1991; 303:893–6.[Medline]

29. Sijbrands EJG, Westendorp RGJ, Defesche JD, de Meier PHEM, Smelt AHM,

Kastelein JJP. Mortality over two centuries in large pedigree with familial

hypercholesterolaemia: family tree mortality study. Br Med J 2001;

322:1019–23.[Abstract/Free Full Text]

30. Ravnskov U. The questionable role of saturated and polyunsaturated fatty

acids in cardiovascular disease. J Clin Epidemiol 1998;

51:443–60.[CrossRef][Medline]

31. Ravnskov U. Is atherosclerosis caused by high cholesterol. Q J Med 2002;

95:397–403.

32. Ravnskov U. A hypothesis out-of-date: The diet-heart idea. J Clin Epidemiol

2002; 55:1057–63.[CrossRef][Medline]

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

2000.

34. Dagenais GR, Ahmed Z, Robitaille NM, Gingras S, Lupien PJ, Christen A, Meyer

F, Rochon J. Total and coronary heart disease mortality in relation to major

risk factors—Quebec cardiovascular study. Can J Cardiol 1990; 6:59–65.[Medline]

35. Shestov DB, Deev AD, Klimov AN, Davis CE, Tyroler HA. Increased risk of

coronary heart disease death in men with low total and low-density lipoprotein

cholesterol in the Russian Lipid Research Clinics Prevalence Follow-up Study.

Circulation 1993; 88:846–53.[Abstract]

36. Beaglehole R, Foulkes MA, Prior IA, Eyles EF. Cholesterol and mortality in

New Zealand Maoris. Br Med J 1980; 280:285–7.[Medline]

37. Jarrett RJ. Risk factors for coronary heart disease in diabetes mellitus.

Diabetes 1992; 41(Suppl. 2):1–3.[Abstract]

38. Orchard TJ. The impact of gender and general risk factors on the occurrence

of atherosclerotic vascular disease in non-insulin-dependent diabetes mellitus.

Ann Med 1996; 28:323–33.[Medline]

39. Ravnskov U. Hypercholesterolemia does not cause coronary heart

disease—evidence from the nephrotic syndrome. Nephron 1994; 66:356–9.[Medline]

40. Anderson KM, Castelli WP, Levy D. Cholesterol and mortality. 30 years of

follow-up from the Framingham study. JAMA 1987; 257:2176–80.[Abstract]

41. Forette F, de la Fuente X, Golmard JL, Henry JF, Hervy MP. The prognostic

significance of isolated systolic hypertension in the elderly. Results of a ten

year longitudinal survey. Clin Exp Hypertens A. 1982; 4:1177–91.[Medline]

42. Siegel D, Kuller L, Lazarus NB, Black D, Feigal D, Hughes G, Schoenberger

JA, Hulley SB. Predictors of cardiovascular events and mortality in the Systolic

Hypertension in the Elderly Program pilot project. Am J Epidemiol 1987;

126:385–9.[Abstract]

43. Nissinen A, Pekkanen J, Porath A, Punsar S, Karvonen MJ. Risk factors for

cardiovascular disease among 55 to 74 year-old Finnish men: a 10-year follow-up.

Ann Med 1989; 21:239–40.[Medline]

44. Krumholz HM, Seeman TE, Merrill SS, Mendes de Leon CF, Vaccarino V,

Silverman DI, Tsukahara R, Ostfeld AM, Berkman LF. Lack of association between

cholesterol and coronary heart disease mortality and morbidity and all-cause

mortality in persons older than 70 years. JAMA 1994; 272:1335–40.[Abstract]

45. Weijenberg MP, Feskens EJ, Bowles CH, Kromhout D. Serum total cholesterol

and systolic blood pressure as risk factors for mortality from ischemic heart

disease among elderly men and women. J Clin Epidemiol 1994; 47:197–205.[Medline]

46. Simons LA, McCallum J, Friedlander Y, Simons J. Diabetes, mortality and

coronary heart disease in the prospective Dubbo study of Australian elderly.

Aust NZ J Med 1996; 26:66–74.[Medline]

47. Weijenberg MP, Feskens EJ, Kromhout D. Total and high density lipoprotein

cholesterol as risk factors for coronary heart disease in elderly men during 5

years of follow-up. The Zutphen Elderly Study. Am J Epidemiol 1996;

143:151–8.[Abstract]

48. Räihä I, Marniemi J, Puukka P, Toikka T, Ehnholm C, Sourander L. Effect of

serum lipids, lipoproteins, and apolipoproteins on vascular and nonvascular

mortality in the elderly. Arterioscler Thromb Vasc Biol 1997;

17:1224–32.[Abstract/Free Full Text]

49. Simons LA, Simons J, Friedlander Y, McCallum J. Cholesterol and other lipids

predict coronary heart disease and ischaemic stroke in the elderly, but only in

those below 70 years. Atherosclerosis 2001; 159:201–8.[CrossRef][Medline]

50. Abbott RD, Curb JD, Rodriguez BL, Masaki KH, Yano K, Schatz IJ, Ross GW,

Petrovitch H. Age-related changes in risk factor effects on the incidence of

coronary heart disease. Ann Epidemiol 2002; 12:173–81.[CrossRef][Medline]

51. Forette B, Tortrat D, Wolmark Y. Cholesterol as risk factor for mortality in

elderly women. Lancet 1989; 1:868–70.[Medline]

52. Zimetbaum P, Frishman WH, Ooi WL, Derman MP, Aronson M, Gidez LI, Eder HA.

Plasma lipids and lipoproteins and the incidence of cardiovascular disease in

the very elderly. The Bronx aging study. Arterioscl Thromb 1992;

12:416–23.[Abstract]

53. Weverling-Rijnsburger AW, Blauw GJ, Lagaay AM, Knook DL, Meinders AE,

Westendorp RG. Total cholesterol and risk of mortality in the oldest old. Lancet

1997; 350:1119–23.[CrossRef][Medline]

54. Jonsson A, Sigvaldason H, Sigfusson N. Total cholesterol and mortality after

age 80 years. Lancet 1997; 350:1778–9.

55. Fried LP, Kronmal RA, Newman AB, Bild DE, Mittelmark MB, Polak JF, Robbins

JA, Gardin JM. Risk factors for 5-year mortality in older adults: the

Cardiovascular Health Study. JAMA 1998; 279:585–92.[Abstract/Free Full Text]

56. Chyou PH, Eaker ED. Serum cholesterol concentrations and all-cause mortality

in older people. Age Ageing 2000; 29:69–74.[Abstract]

57. Menotti A, Mulder I, Nissinen A, Feskens E, Giampaoli S, Tervahauta M,

Kromhout D. Cardiovascular risk factors and 10-year all-cause mortality in

elderly European male populations; the FINE study. Eur Heart J 2001;

22:573–9.[CrossRef][Medline]

58. Schatz IJ, Masaki K, Yano K, Chen R, Rodriguez BL, Curb JD. Cholesterol and

all-cause mortality in elderly people from the Honolulu Heart Program: a cohort

study. Lancet 2001; 358:351–5.[CrossRef][Medline]

59. Sacks FM, Moye LA, Davis BR, Cole TG, Rouleau JL, Nash DT, Pfeffer MA,

Braunwald E. Relationship between plasma LDL concentrations during treatment

with pravastatin and recurrent coronary events in the cholesterol and recurrent

events trial. Circulation 1998; 97:1446–52.[Abstract/Free Full Text]

60. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A,

Chaitman BR, Leslie S, Stern T; Myocardial Ischemia Reduction with Aggressive

Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on

early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a

randomized controlled trial. JAMA 2001; 285:1711–18.[Abstract/Free Full Text]

61. Scandinavian Simvastatin Survival Study Group. Randomised trial of

cholesterol lowering in 4444 patients with coronary heart disease: the

Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383–9.[Medline]

62. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study

of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a

randomised placebo-controlled trial. Lancet 2002; 360:7–22.[CrossRef][Medline]

63. Dayton S, Pearce ML, Hashimoto S, Dixon WJ, Tomayasu U. A controlled

clinical trial of a diet high in unsaturated fat in preventing complications of

atherosclerosis. Circulation 1969; 40:1–63.[Medline]

64. Stehbens WE, Martin M. The vascular pathology of familial

hypercholesterolaemia. Pathology 1991; 23:54–61.[Medline]

65. Stehbens WE. An appraisal of cholesterol feeding in experimental

atherogenesis. Prog Cardiovasc Dis 1986; 29:107–28.[Medline]

66. Peng SK, Taylor CB. Cholesterol autoxidation, health and arteriosclerosis. A

review on situations in developed countries. World Rev Nutr Diet 1984;

44:117–54.[Medline]

67. Netea MG, Demacker PN, de Bont N, Boerman OC, Stalenhoef AF, van der Meer

JW, Kullberg BJ. Hyperlipoproteinemia enhances susceptibility to acute

disseminated Candida albicans infection in

low-density-lipoprotein-receptor-deficient mice. Infect Immun 1997;

65:2663–7.[Abstract]

68. Hu H, Pierce GN, Zhong G. The atherogenic effects of chlamydia are dependent

on serum cholesterol and specific to Chlamydia pneumoniae. J Clin Invest 1999;

103:747–53.[Abstract/Free Full Text]

69. Lin TM, Jiang MJ, Eng HL, Shi GY, Lai LC, Huang BJ, Huang KY, Wu HL.

Experimental infection with bovine herpesvirus-4 enhances atherosclerotic

process in rabbits. Lab Invest 2000; 80:3–11.[Abstract/Free Full Text]

 

 

 

 

 

 

NEW WEB MESSAGE BOARDS - JOIN HERE.

Alternative Medicine Message Boards.Info

http://alternative-medicine-message-boards.info

 

 

 

Free Pop-Up Blocker - Get it now