LDL Cholesterol:
Bad Cholesterol, or Bad Science?

By now  you will all have a bit of an idea how the odds are quite stacked in favour of the so-called Lipid theory, that is the belief that low-density lipoprotein (LDL) cholesterol causes atherosclerosis and subsequent heart disease, a fundamental precept of modern medicine. Therapies will be aimed at reducing serum LDL cholesterol and are currently considered to be an essential element of any attempt to prevent coronary heart disease (CHD).   But as we have seen, numerous lines of evidence raise questions about the LDL hypothesis.  LDL cholesterol is a vitally important substance and does not in any way clog arteries in itself. Statin drugs, although lowering LDL may be doing so at a tremendous and probably via mechanisms totally unrelated to LDL cholesterol reduction.
As it turns out statin drugs works as an anti inflammatory. Well guess what? So does Aspirin, which is a lot cheaper.
However there appears to be evidence that oxidized LDL may be involved in causing damage, but this form of LDL shows no correlation with serum levels of native LDL. So in order to address this, one might want to have a closer look at antioxidants.

Millions of people worldwide have been convinced by extensive promotional campaigns that if you want to avoid CHD you reduce cholesterol levels by using lipid-lowering drugs and diets low in saturated fats. This campaign has produced billions in profits for drug companies and the manufacturers of low-fat food products.
It is amazing what you can do with grains and potatoes, that you cannot with animal products...
Processing, processing, processing. We have been taught to largely subsist on highly processed food. Which often make us sick, for which we need a drug...
The worlds current top-selling pharmaceutical, for example, is Pfizers cholesterol-lowering drug Lipitor (atorvastatin), which in a single year will give the company over a dozen billion dollars in sales..
The war on cholesterol has also proven to be extremely lucrative for the food industry. However it has delivered no benefit to public health. CHD is still the leading cause of death in Western countries.
While the number of deaths from CHD has indeed decreased since the late 1960s, total incidence of CHD has not declined. We have become more adept at managing this epidemic.   If cholesterol reduction were effective in preventing CHD, then it would surely lower both fatal and nonfatal CHD.

This has not happened. Modern medicine has helped us extending the lives of those who have already had heart attacks, but it has failed to help people avoid it in the first place.
In addition, the relentless drive to steer people to low-fat, high carbohydrate diets has been accompanied by a marked increase in  obesity and diabetes. .
Cholesterol, contrary to its popular image as a potent enemy of health and longevity, is actually a crucial substance that performs innumerable vital functions in the body. Cholesterol is needed for the synthesis of bile acids, which are essential for the absorption of fats, and of many hormones such as testosterone, estrogen,  progesterone, and cortisol. Together with sun exposure, cholesterol is required to produce vitamin D.
Cholesterol is an essential element of cell membranes, where it provides structural support and may even serve as a protective antioxidant. It is essential for conducting nervous impulses..
Because cholesterol is water-insoluble, it must be transported inside lipoproteins. Various types of lipoproteins exist, but the two most abundant are low-density lipoprotein (LDL) and high-density lipoprotein (HDL). The main function of LDL is to transport cholesterol from the liver to tissues that incorporate it into cell membranes. HDL carries old cholesterol that has been discarded by cells back to the liver for recycling or excretion.

Recognizing that cholesterol serves a number of important functions, Proponents of the cholesterol hypothesis have modified their theory to incorporate the good cholesterol, bad cholesterol paradigm, in which LDL cholesterol forms fatty deposits in arterial walls, which become plaques that grow, rupture, and  stimulate the formation of artery-blocking blood clots (!!). HDL cholesterol, on the other hand, is the heart-friendly lipoprotein that counters the action of LDL by removing cholesterol from the arteries and transporting it back to the liver for safe disposal. This theory (!) is overly simplistic and not supported by the evidence. If LDL cholesterol causes atherosclerosis, logic dictates that there should be a strong correlation between blood levels of LDL  cholesterol and atherosclerosis. Proponents of the LDL hypothesis have repeatedly maintained that this is true. However, a review of the available evidence suggests otherwise. Despite popular perception, atherosclerotic plaques are not simply big wads of fat and cholesterol drywalling the walls of arteries like mud inside a pipe. The growth of atherosclerotic plaques takes place primarily inside the artery wall, between the inner and outer layers and often at stress points. The plaques are complex entities with numerous components, including smooth muscle cells, calcium, connective tissue, white blood cells, cholesterol, and fatty acids. Proliferation of plaques may occur, not because of simple elevations in blood cholesterol, but because of unfavorable physiological conditions that damage or weaken the structure of the arterial wall. These factors include nutrient deficiencies, poor glycemic control, cigarette smoking, homocysteine, psychological stress, nitric oxide depletion, high iron levels, microbial infection, dietary trans fatty acids, excessive refined carbohydrate intake, and excessive omega-6 fatty acid intake and/or deficient omega-3 fat intake.  In fact a whole slew of factors most likely caused by a wrong lifestyle and wrong nutritional habits.
And we haven't even mentioned the lectins yet. (see Link)
All of these factors have been shown to exert an atherogenic effect unrelated to serum cholesterol elevation. I repeat that : atherogenic effect unrelated to serum cholesterol levels.
Damage to the arterial wall triggers an inflammatory state in which the body recognizes injury and sets about to repair it.
This response-to-injury scenario is well accepted by the vast majority of cardiovascular researchers, although many of them continue to promote the hypothesis that LDL cholesterol is involved in triggering or aggravating the inflammatory state that eventually leads to heart disease or stroke. There is little evidence to support such a contention. In fact, cholesterol, like other components, may be present in atherosclerotic plaque as part of the repair mechanism. 
During the 1980s, some researchers began to recognize that LDL itself was not a reliable independent risk factor for CHD; half of those who suffer CHD have LDL levels within normal limits. Among the 28,000-plus participants of theWomens Health Study, for example, 46% of first cardiovascular events occurred in women with LDL cholesterol levels less than 130 mg/dLthe desirable target for primary prevention set by the National Cholesterol Education Program (NCEP). (by the way a ludicrously level) Research in both animals and humans has shown that oxidized LDL is a better predictor of atherosclerosis and cardiovascular disease than regular LDL cholesterol. Whether or not oxidizedLDL is a direct contributor to the atherogenic process cannot be determined with any certainty based upon the available evidence.
The stronger association between oxidized LDL and cardiovascular disease suggests that a person's antioxidant status is a far more important determinant than LDL levels of the risk of developing advanced plaques.
In animal studies, administration of antioxidant drugs like probucol impairs LDL oxidation and arterial plaque formation, even when there is no change in blood cholesterol levels. In fact, administration of the antioxidant butylated hydroxytoluene (BHT) significantly reduces the degree of atherosclerosis in the aorta of rabbits, even though it raises LDL cholesterol levels. A similar phenomenon is observed in humans. Among elderly Belgians, higher levels of oxidized LDL were accompanied by a significantly increased risk of heart attack, regardless of total LDL levels.

In Japanese patients undergoing surgery to remove plaque from their carotid arteries, blood levels of oxidized LDL were significantly higher than those measured in healthy controls. Advanced carotid plaques removed from these patients showed far higher levels of oxidized LDL than neighboring sections of artery  that were disease-free. Elevated oxidized LDL was also associated with an increased susceptibility of plaque rupture. However, there was no association between oxidized LDLconcentrations and total LDLlevels. Von Shacky and coworkers, in a 2-year double-blind trial in patients with CHD, found that daily fish-oil supplementation increased the incidence of atherosclerotic regression, and decreased the loss in minimal luminal diameter, as assessed by  quantitative coronary angiography. Fish-oil recipients also experienced fewer cardiovascular events. LDL cholesterol levels tended to be greater in the fish-oil group. The lack of importance of total LDL levels was further underscored by two recent trials that examined the impact of LDLlowering therapy on calcified coronary plaque progression. In the first of these studies, patients given aggressive LDL cholesterollowering treatment (statins plus niaicin) were compared with those receiving less aggressive treatment (statins alone). Despite greater LDL reductions in the former group, there were no differences in calcified plaque progression as detected by electron beam tomography. The authors concluded:  with respect to LDL cholesterol lowering, lower is better is not supported by changes in calcified plaque progression. In the Scottish Aortic Stenosis and Lipid Lowering Trial, patients with calcific aortic stenosis were randomly assigned to receive either 80 mg of atorvastatin daily or placebo. After 25 months, serum LDL concentrations remained at an average 130 mg/dL in the placebo group but fell significantly to 63 mg mg/dL in the atorvastatin group.lllll Despite the fact that LDL levels were reduced by more than half in the atorvastatin subjects, there was no difference in aortic-jet velocity or progression in aortic-valve calcification between the treatment or placebo groups.lllll
It is well-established that plaque rupture is a major trigger of acute coronary events. Analysis of the lipid portion of atherosclerotic plaques shows they contain a disproportionately high concentration of the omega-6 fatty acid linoleic acid, and that plaque content of linoleic acid correlates with dietary intake.
Higher plaque concentrations of linoleic acid are also associated with an increased likelihood of plaque rupture. The major sources of linoleic acid in Western diets are heart-healthy polyunsaturated vegetable oils that have been heavily promoted because of their clinically demonstrated ability to lower total and LDL cholesterol levels.
In 1997 Swedish researchers published a comparison of CHD risk factors among men from Vilnius in Lithuania and Linkoping in Sweden. These two groups were selected because the former had a four-fold higher death rate from CHD than the latter. Very little difference in traditional risk factors existed between the two groups, except that the men from CHD-prone Vilnius had lower total andLDLcholesterol levels.
According to common wisdom, the lower total and LDL cholesterol of the Lithuanian men should have placed them at reduced risk of heart disease. When the researchers probed further, they discovered that the men from Vilnius had significantly higher concentrations of oxidized LDL. They also displayed significantly poorer blood levels of important diet-derived antioxidants such as beta carotene, lycopene, and gamma tocopherol (a form of vitamin E). Blood levels of these particular nutrients are largely determined by dietary intake, especially from the consumption of antioxidant-rich fruits, nuts, and vegetables. So while the Lithuanian men had lower LDL levels, they were more
prone to the formation of oxidized LDL owing to what appeared to be a poorer intake of antioxidant-rich foods.
This may well have explained their greater susceptibility to cardiovascular disease; in tightly controlled clinical trials, discussed below, individuals randomized to increase their intake of fruits and vegetables have experienced significant reductions in cardiovascular and all-cause mortality.

No tightly controlled clinical trial has ever conclusively demonstrated that LDL cholesterol reductions can prevent cardiovascular disease or increase longevity.

In the large GISSI-Prevenzione trial in Italy, the mortality benefits of omega-3-rich fish oil appeared early on in the study as did an increase in LDL cholesterol levels. Mean LDL levels in the subjects given fish oil rose from 136 mg/dL at baseline to 150 mg/dL after 6 months, before gradually returning to initial levels at 42 months. A similar pattern was observed in the control group. This extended period of elevated LDL levels did not prevent the fish-oil patients from experiencing significantly more favorable cardiovascular and mortality outcomes.

In the Lyon Diet Heart Study, an experimental group advised to increase consumption of root vegetables, green vegetables, fish, fruit, and omega-3 fatty acids also experienced greatly improved cardiovascular and survival outcomes. The study was originally intended to follow the patients for 4 years, but death rates diverged so dramatically early on that researchers decided it would be unethical to continue, and called an end to the trial. After an average follow-up of 27 months, the all-cause death rate of the control group was more than twice that of the experimental group. One little-publicized finding from this well-known trial was that the total and LDL cholesterol levels of the treatment and control groups were virtually identical throughout the study. Those in the treatment group, however, did show significantly higher blood levels of omega-3 fatty acids and antioxidants. According to medical opinion leaders, recent trials with statin drugs have proven that LDL reduction is beneficial. Allegedly, these trials have also shown that the greater the LDL reductions, the better.

First, it must be emphasized that statin drugs have only been shown to exert consistent mortality-lowering benefits in a select group of patients; namely, middle-aged males with existing CHD.
Statins may also lower mortality in diabetic patients. Trials with men free of heart disease have not shown any consistent and significant mortality-lowering benefit from the use of statin drugs. In women of any age, statins have not been shown to exert any reduction in cardiovascular or all-cause mortality whatsoever when used for primary prevention, and no reduction in all-cause mortality when used for secondary prevention.
The only study to date focusing on elderly subjects, the PROSPER trial, did find a reduction in cardiovascular deaths, but this was negated by a similar increase in cancer mortality. Rarely mentioned are two studies showing that lovastatin was associated with increased all-cause mortality in healthy hypercholesterolemic males and females. In those trials showing decreased mortality with statins, the reduction in death rates are no greater than, and often inferior to, that seen with other less toxic interventions, such as omega-3 fatty acid supplementation, fruit-and-vegetable-rich diets, and exercise.
Secondly, the claim that LDL reduction is responsible for any statin-induced reduction in cardiovascular events or mortality rates is unsupported. Statin drugs exert their lipid-lowering effect by blocking 3-hydroxy- 3-methylglutaryl (HMG) coenzyme A reductase, an enzyme in the liver that is involved in the early stages of cholesterol synthesis. Statins inhibit the synthesis not only of cholesterol, but of many important intermediate metabolites, including, but not limited to, mevalonate pyrophosphate, isopentanyl pyrophosphate, geranyl-geranyl pyrophosphate, and farnesyl pyrophosphate. Inhibition of these compounds means that statins exert a plethora of effects unrelated to cholesterol lowering. , animal and human studies show that these pleiotropic actions possess beneficial cardiovascular effects that occur independently of cholesterol reduction. Some of these cholesterol-independent effects include: Statins reverse or impede the progression of atherosclerosis in rabbits, without any accompanying change in serum cholesterol. In elderly diabetic patients, cerivastatin increased dilation of the brachial artery (improved blood flow) after only three days, before any change in cholesterol levels had occurred. In healthy young males with normal cholesterol levels, improved endothelial function was observed within 24 hours of treatment with atorvastatin; again, this improvement preceded any drop in serum cholesterol levels.
In human volunteers with slightly elevated cholesterol, researchers found that 4 weeks of simvastatin therapy significantly enhanced forearm blood flow. The improvement increased with continued administration of simvastatin despite no further reduction in serum cholesterol, and there was no relation between the decrease in cholesterol and improvement in endothelial function. Statins have been shown to reduce platelet production of thromboxane, an eicosanoid that encourages blood clotting. This effect was not seen with older drugs that lowered total or LDL cholesterol such as cholestyramine, cholestipol, and fibrates. Puccetti et al. observed that simvastatin, atorvastatin, and fluvastatin reduced platelet reactivity before significant reductions in LDL cholesterol occurred.
In research with mice, statins  markedly reduce measures of both inflammation and atherosclerosis, despite little change in serum cholesterol levels.  In humans, statin therapy produces significant reductions in C-reactive protein, a marker of inflammatory activity that has repeatedly been associated with increased cardiovascular risk. This statin-induced reduction in CRP levels is not correlated with any decrease in LDL cholesterol levels. Statins also reduce the effects of adhesion molecules and chemo attractants, which play a key role in the inflammatory process and plaque formation by promoting migration of leukocytes and their adherence to the arterial wall plaque. Weitz-Schmidt and coworkers have shown that statins exert anti-adhesion properties . In an important experiment, this group produced a specially modified form of lovastatin with no inhibitory effect on HMG-CoA reductase. This designer statin still possessed potent anti-adhesive, antichemoattractant effects, despite complete disablement of its cholesterol-lowering actions.
In animal studies, statins reduce various measures of oxidative stress, even when cholesterol levels remain unchanged. In humans, a mere nine days of atorvastatin administration (20 mg/day) significantly decreased platelet levels of oxidized LDL. These changes were observed before any noteworthy drop in LDL cholesterol was evident. In patients randomly assigned to receive 10 mg of pravastatin or 20 mg of fluvastatin for 12 weeks, significant reductions in oxidized LDL occurred in both groups. The reduction was significantly higher in the fluvastatin group than in the pravastatin group (47.5% vs 25.2%, respectively).
But again reductions in total and LDL cholesterol, however, did not differ between the two groups.
This phenomenon, which is independent of lipid-lowering, was first confirmed when researchers observed that addition of mevalonate, geraniol, farnesol and geranylgeraniol, but not LDL, prevented the antiproliferative effect of statins. Animal research also shows a disconnect between the lipid-lowering and anti-proliferative effects of statins. When collars were placed around one of the carotid arteries in rabbits, treatment with lovastatin, simvastatin, and fluvastatin significantly reduced intimal lesion formation, despite no change in the animals' cholesterol levels. Plaque rupture is believed to be the instigating factor in a significant portion of acute coronary events. In patients with symptomatic carotid atherosclerosis, 40 mg/d of pravastatin reduced the lipid and oxidized LDL content but increased the collagen content of plaques as compared to control subjects. These changes are like those seen in stable plaques that are less prone to rupture. 
Compared to controls, adult male monkeys fed an atherogenic diet and given pravastatin or simvastatin showed significantly reduced inflammatory activity in plaques, while markedly increasing their collagen content. This effect was independent of cholesterol reduction; blood lipid levels in the animals were kept stable by manipulating dietary cholesterol intake. (Unlike in humans, dietary cholesterol levels can significantly influence serum cholesterol concentrations in monkeys.)
Takemoto and coworkers demonstrated the ability of statins to prevent cardiac hypertrophy in mice. This benefit occurred despite no change in serum  cholesterol levels. Research by these and other researchers suggests the antihypertrophic effect of statins may derive from their antioxidant properties.
The numerous actions of statins unrelated to lipid lowering are no doubt a major reason why almost all of the major controlled, randomized trials with these drugs have shown no association between the degree of total or LDL cholesterol lowering and the CHD survival rate. In most of these studies, the risk of a fatal heart attack was similarly reduced whether total or LDLcholesterol levels were lowered by a small or large amount.
There are two exceptions to this phenomenon: the PROSPER trial, which recorded the highest survival rates in both the treatment and control groups among those with the highest LDL levels, and the Japanese Lipid Intervention Trial (J-LIT). In the latter, a 6-year study of more than 47,000 patients treated with simvastatin, those with a total cholesterol level of 200-219 mg/dL had a lower rate of coronary events than those whose levels were above or below this range. The lowest all-cause mortality rate was seen in the patients whose total and LDL cholesterol levels were between 200-259 mg/dLand 120-159 mg/dL, respectively.
When confronted with nonsupportive evidence, the anticholesterol mainstream typically engages a two-pronged strategy. First, it simply ignores contradictory evidence. Second, it simultaneously seeks out supportive evidence, no matter how flimsy, and then embarks on an aggressive propaganda campaign to educate as many people as possible about it. The end result is that the public receives a distorted picture of the existing evidence.
A classic example of this process occurred in April 2004, when the results of the Pravastatin or Atorvastatin Evaluation and Infection Therapy trial (PROVE-IT) were published. The PROVEIT researchers randomized patients who had recently been hospitalized for an acute coronary event to either 40 milligrams of pravastatin (Pravachol) or 80 milligrams of atorvastatin daily. Not surprisingly, median LDL cholesterol levels were lowered to a greater extent on high-dose atorvastatin. After an average follow-up of 2 years, the high-dose atorvastatin group enjoyed a 30%reduction in CHD mortality and a 28%decrease in all-cause mortality.
In the media barrage about the trial, medical opinion leaders asserted that PROVE-IT finally proved that the lower the LDL level, the better. Actually, PROVE-IT proved no such thing. Neither did TNT (Treating NewTargets), the vigorously promoted study published in March 2005, which also allegedly proved the value of aggressive LDL lowering. In this study, 10,001 CHD patients with LDL cholesterol levels of less than 130 mg/dL were randomly assigned to either 10 or 80 milligrams of atorvastatin daily. In those receiving low-dose atorvastatin mean LDL cholesterol levels were reduced to 101 mg/dL, compared to 77 mg/dLin those taking the high dose.
After a median follow-up of 4.9 years, 2.5% of the low-dose group had died from coronary causes, compared to 2% in the high-dose group, a 20% reduction in relative risk (RR). Again, leading proponents of the lipid hypothesis dominated the subsequent extensive media coverage, enthusiastically hailing these results as triumphant confirmation of the PROVE-IT findings. According to these prestigious commentators, the lower is better era of LDL reduction had officially arrived. The fact that all-cause mortality did not differ between the two groups, owing to an increase in noncardiovascular deaths among the high-dose subjects, evidently escaped notice.

That statins exert a whole host of biochemical effects beyond mere lipid lowering is beyond question. It is entirely possible, therefore, that the statins pleiotropic effects and not LDL lowering produced the favorable cardiovascular outcomes seen in PROVE-IT or TNT. To claim otherwise, especially when little attempt was made to measure the impact of these lipid-independent effects, is somewhat illogical. C-reactive protein (CRP) has gained much attention since a large study published in 2002 suggested that it was a significantly better predictor of future cardiovascular events than LDL cholesterol. While it is not yet clear whether CRP itself is directly
atherogenic, it is well-known that CRP serves as a marker for inflammation.
In January 2005, the published two studies examining the interplay between statin use, CRPlevels, and subsequent coronary event rates. The first of these, using data from the PROVE-IT study, found: Patients who have low CRP levels after statin therapy have better clinical outcomes than those with higher CRP levels, regardless of the resultant level of LDLcholesterol.
In the second study, researchers used intravascular ultrasonography to examine the association of LDL and CRP with the continued development of atherosclerosis in 502 CHD patients. They found: Atherosclerosis regressed in patients with the greatest reduction in CRP levels, but not in those with the greatest reduction in LDL cholesterol levels. These two studies were not the only ones to reinforce the importance of inflammation, and to show a disconnect between statins anti-inflammatory effects, their lipid-lowering actions, and clinical outcomes. Among postinfarction patients in the CARE (Cholesterol and Recurrent Events) trial, subjects with the highest
levels of CRPand serum amyloidA (another inflammatory marker) had a higher risk of subsequent coronary events and benefited more from pravastatin therapy than those without elevated levels of these inflammatory markers. The relative risk of a recurrent coronary event was reduced by 54% and 25% in the two groups, respectively, compared with placebo. At baseline, both groups had nearly identical plasma lipid and lipoprotein profiles. Although baselinemedian CRPlevels for active treatment and placebo were similar, the median level after 5 years was 21.6% lower in the pravastatin group than in the placebo group.
The change in CRP levels associated with pravastatin treatment was not correlated with the reduction in LDL cholesterol levels. In the Effects of Atorvastatin vs Simvastatin on Atherosclerosis Progression (ASAP) study, baseline CRP values were similar among patients given either simvastatin (40 mg/d) or atorvastatin (80 mg/d), but declined over the next 2 years to a greater extent in the latter group. A significant correlation was found between the decrease of CRP and reduction in intima media thickness (IMT) of carotid artery segments. No correlation was observed between change inCRPand change in lipids.

The concept that LDL is bad cholesterol is a simplistic and scientifically untenable hypothesis. The inordinate focus on cholesterol, a perfectly natural substance that performs many crucial functions in the body, has taken and continues to take valuable resources and attention away from factors more closely related to heart disease. Independent-thinking practitioners must look at the readily available evidence for themselves, instead of relying on the continual stream of anticholesterol propaganda emanating from health authorities. By doing so, they will quickly realize that the LDL hypothesis is aggressively promoted for reasons other than public health.


REFERENCES

Pfizer. 2004 Financial Report. Available at: www.pfizer.com/pfizer/annual
report/2004/financial/financial2004.pdf. Accessed Jun 19, 2005.
Rosamond WD, Chambless LE, Folsom AR, et al. Trends in incidence of
myocardial infarction and in mortality due to coronary heart disease, 1987
to 1994 1998;339:861-867.
Centers for Disease Control Hospitalization rates for
ischemic heart diseaseUS, 1970-1986. 1989;38;275-276,281-284.
Lampe FC, Morris RW,Walker M, et al. Trends in rates of different forms of
diagnosed coronary heart disease, 1978 to 2000: prospective,
population-based study of British men. 2005;330:1046.
Sytkowski PA, Kannel WB, DAgostino RB. Changes in risk factors and the
decline in mortality from cardiovascular disease. The Framingham Study.
1990;322:1635-1641.
Gross LS, Li L, Ford ES, et al. Increased consumption of refined
carbohydrates and the epidemic of type 2 diabetes in the US: an ecologic
assessment. 2004;79(5):774-779.
Olshansky SJ, Passaro DJ, Hershow RC, et al. A potential decline in life expectancy
in theUSin the 21st century. 2005;352:1138-1145.
Hume R, Boyd GS. Cholesterol metabolism and steroid-hormone
production. 1978;6:893-898.
Bouillon R, Okamura WH, Norman AW. Structure-function relationships in
the vitaminDendocrine system. 1995;16:200-257.
Alberts B, Bray D, Lewis J, et al. 3 ed. New
York, N.Y.: Garland Publishing; 1994.
Girao H, Mota C, Pereira P. Cholesterol may act as an antioxidant in lens
membranes. 1999;18:448-454.
Barres BA, Smith SJ. Cholesterolmaking or breaking the synapse.
2001;294:1296-1297.
Ross R. Atherosclerosisan inflammatory disease.
1999;340:115-126.
Klevay LM. Ischemic heart disease as deficiency disease.
2004;50:877-884.
Ceriello A, Motz E. Is oxidative stress the pathogenic mechanism
underlying insulin resistance, diabetes, and cardiovascular disease? The
common soil hypothesis revisited.
2004;24:816-823.
Ambrose JA, Barua RS. Pathophysiology of cigarette smoking and
cardiovascular disease: an update. 2004;43:1731-1737.
Aguilar B, Rojas JC, Collados MT. Metabolism of homocysteine and its
relationship with cardiovascular disease.
2004;18:75-87.
Rozanski A, Blumenthal JA, Kaplan J. Impact of psychological factors on
the pathogenesis of cardiovascular disease and implications for therapy.
1999;99:2192-2217.
Ignarro LJ, Napoli C. Novel features of nitric oxide, endothelial nitric oxide
synthase, and atherosclerosis. 2005;5:17-23.
Shah SV, Alam MG. Role of iron in atherosclerosis.
2003;41(3 Suppl 1):S80-S83.
Muhlestein JB, Anderson JL. Chronic infection and coronary artery
disease. 2003;21:333-362.
Belland RJ, Ouellette SP, Gieffers J, et al. Chlamydia pneumoniae and
atherosclerosis. 2004;6:117-127.
Kummerow FA, Zhou Q, Mahfouz MM. Effect of trans fatty acids on
calcium influx into human arterial endothelial cells.
1999;70:832-838.
Ceriello A, Bortolotti N, Crescentini A, et al. Antioxidant defences are
reduced during the oral glucose tolerance test in normal and non-insulindependent
diabetic subjects. 1998;28:329-333.
Turpeinen AM, Basu S, Mutanen M. A high linoleic acid diet increases
oxidative stress in vivo and affects nitric oxide metabolism in humans.
1998;59:229-233.
Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and
low-density lipoprotein cholesterol levels in the prediction of first
cardiovascular events. 2002;347:1557-1565.
Sasahara M, RainesEW, Chait A, et al. Inhibition of hypercholesterolemiainduced
atherosclerosis in the nonhuman primate by probucol, I: is extent
of atherosclerosis related to resistance of LDL to oxidation?
1994;94:155-164.
Tangirala RK, Casanada F, Miller E, et al. Effect of the antioxidant N,N-
diphenyl 1,4-phenylenediamine (DPPD) on atherosclerosis in apo Edeficient
mice 1995;15:1625-1630.
Carew TE, Schwenke DC, Steinberg D. Antiatherogenic effect of probucol
unrelated to its hypocholesterolemic effect: evidence that antioxidants in
vivo can selectively inhibit low density lipoprotein degradation in
macrophage-rich fatty streaks and slow the progression of
atherosclerosis in the Watanabe-heritable hyperlipidemic rabbit.
1987;84:7725-7729.
Daugherty A, Zweifel BS, Schonfeld G. Probucol attenuates the
development of aortic atherosclerosis in cholesterol-fed rabbits.
1989;98:612-618.
Bjorkhem I, Henriksson-Freyschuss A, Breuer O, et al. The antioxidant
butylated hydroxytoluene protects against atherosclerosis.
1991;11:15-22.
Holvoet P, Kritchevsky SB, Tracy RP, et al. The metabolic syndrome,
circulating oxidized LDL, and risk of myocardial infarction in wellfunctioning
elderly people in the Health, Aging, and Body Composition
Cohort. 2004;53:1068-1073.
Holvoet P, Harris TB, Tracy RP, et al. Association of high coronary heart
disease risk status with circulating oxidized LDL in the well-functioning
elderly: Findings from the Health, Aging, and Body Composition Study.
2003;23:1444-1448.
Nishi K, Itabe H, Uno M, et al. Oxidized LDL in carotid plaques and plasma
associates with plaque instability.
2002;22:1649-1654.
Von Schacky C, Angerer P, Kothny W, et al. The effect of dietary omega-3
fatty acids on coronary atherosclerosis: A randomized, double-blind,
placebo-controlled trial. 1999;130:554-562.
Hecht HS, Harman SM. Relation of aggressiveness of lipid-lowering
treatment to changes in calcified plaque burden by electron beam
tomography. 2003;92:334-336.
Cowell SJ, Newby DE, Prescott RJ, et al. A randomized trial of intensive
lipid-lowering therapy in calcific aortic stenosis.
2005;352:2389-2397.
Shah PK. Plaque disruption and coronary thrombosis: new insight into
pathogenesis and prevention. 1997;20(11 Suppl 2):II-38-44.
Carpenter KL, Taylor SE, Ballantine JA, et al. Lipids and oxidised lipids in
human atheroma and normal aorta.
1993;1167:121-130.
Felton CV, Crook D, Davies MJ, et al. Dietary polyunsaturated fatty acids
and composition of human aortic plaques. 1994;344:1195-1196.
Felton CV, Crook D, Davies MJ, et al. Relation of plaque lipid composition
and morphology to the stability of human aortic plaques.
1997;17:1337-1345.
Mensink RF, Katan MB. Effect of dietary fatty acids on serum lipids and
lipoproteins: A meta-analysis of 27 trials.
1992;12:911-919.
Kristenson M, Zieden B, Kucinskiene Z, et al. Antioxidant state and mortality
from coronary heart disease in Lithuanian and Swedish men: concomitant
cross sectional study of men aged 50. 1997;314:629-633.
Kristenson M, Kucinskiene Z, Schafer-Elinder L, et al. Lower serum levels
of beta-carotene in Lithuanian men are accompanied by higher urinary
excretion of the oxidative DNA adduct, 8-hydroxydeoxyguanosine. The
LiVicordia study. 2003;19(1):11-15.
Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death
by n-3 polyunsaturated fatty acids after myocardial infarction: time-course
analysis of the results of the Gruppo Italiano per lo Studio della
Sopravvivenza nellInfarto Miocardico (GISSI)-Prevenzione.
2002;105:1897-1903.
De Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic
acid-rich diet in secondary prevention of coronary heart disease.
1994;343:1454-1459.
Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of
cardiovascular disease with atorvastatin in type 2 diabetes in the
Collaborative Atorvastatin Diabetes Study (CARDS): multi-center
randomized placebo-controlled trial. 2004;364:685-696.
Bradford RH, Shear CL, Chremos AN, et al. Expanded Clinical Evaluation
of Lovastatin (EXCEL) study results. I. Efficacy in modifying plasma
lipoproteins and adverse event profile in 8245 patients with moderate
hypercholesterolemia. 1991;151:43-49.
Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease
with pravastatin in men with hypercholesterolemia. West of Scotland
Coronary Prevention Study Group. 1995;333:1301-1308.
Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute
coronary events with lovastatin in men and women with average
cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary
Atherosclerosis Prevention Study. 1998;279:1615-1622.
The ALLHAT Officers and Coordinators for the ALLHAT Collaborative
Research Group. Major outcomes in moderately hypercholesterolemic,
hypertensive patients randomized to pravastatin vs usual care: the
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack
Trial (ALLHAT-LLT). 2002;288:2998-3007.
Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke
events with atorvastatin in hypertensive patients who have average or
lower-than-average cholesterol concentrations, in the Anglo-
Scandinavian Cardiac Outcomes TrialLipid Lowering Arm (ASCOTLLA):
a multi-center randomized controlled trial. 2003;361:1149-
1158.
Walsh JE, Pignone M. Drug treatment of hyperlipidemia in women.
2004;291:2243-2252.
Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals
at risk of vascular disease (PROSPER): a randomized controlled trial.
2002;360:1623-1630.
Watts GF, et al. Effects on coronary artery disease of lipid-lowering diet, or
diet plus cholestyramine, in the St Thomas atherosclerosis regression
study (STARS). 1992;339:563-569.
Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre
intakes on death and myocardial reinfarction: diet and reinfarction trial
(DART). 1989;2:757761.
Bonetti PO, Lerman LO, Napoli C, et al. Statin effects beyond lipid
loweringare they clinically relevant? 2003;24:225-248.
Davignon J. Beneficial cardiovascular pleiotropic effects of statins.
2004;109(23, Suppl):III-39-III-43.
Kano H, Hayashi T, Sumi D, et al. A HMG-CoA reductase inhibitor
improved regression of atherosclerosis in the rabbit aorta without
affecting serum lipid levels: possible relevance of up-regulation of
endothelial NO synthase mRNA.
1999;259:414-419.
Soma MR, Donetti E, Parolini C, et al. HMG CoA reductase inhibitors: in
vivo effects on carotid intimal thickening in normocholesterolemic rabbits.
1993;13:571-578.
Tsunekawa T, Hayashi T, Kano H, et al. Cerivastatin, a
hydroxymethylglutaryl coenzyme a reductase inhibitor, improves
endothelial function in elderly diabetic patients within three days.
2001;104:376.
Laufs U, Wassmann S, Hilgers S, et al. Rapid effects on vascular function
after initiation and withdrawal of atorvastatin in healthy,
noncholesterolemic men. 2001;88:1306-1307.
ODriscoll G, Green D, Taylor RR. Simvastatin, an HMG-coenzyme a
reductase inhibitor, improves endothelial function within one month.
1997;95:1126-1131.
Schror K. Platelet reactivity and arachidonic acid metabolism in type II
hyperlipoproteinaemia and its modification by cholesterol-lowering
agents. 1990;3:67-73.
Puccetti L, Pasqui AL, Pastorelli M, et al. Time-dependent effect of statins
on platelet function in hypercholesterolaemia.
2002;32:901-908.
Puccetti L, Sawamura T, Pasqui AL, et al. Atorvastatin reduces plateletoxidized-
LDL receptor expression in hypercholesterolaemic patients.
2005;35:47-51.
Sparrow CP, Burton CA, Hernandez M, et al. Simvastatin has antiinflammatory
and antiatherosclerotic activities independent of plasma
cholesterol lowering. 2001;21:115-121.
Ridker PM, Rifai N, Pfeffer MA, et al. Long-term effects of pravastatin on
plasma concentration of C-reactive protein. 1999;100:230-
235.
Albert MA, Danielson E, Rifai N, et al. Effect of statin therapy on C-reactive
protein levels: the Pravastatin Inflammation/CRP Evaluation (PRINCE):
randomized trial and cohort study. 2001;286:64-70.
Jialal I, Stein D, Balis D, et al. Effect of hydroxymethyl glutaryl coenzyme A
reductase inhibitor therapy on high sensitive C-reactive protein levels.
2001;103:1933-1935.
Plenge JK, Hernandez TL, Weil KM, et al. Simvastatin lowers C-reactive
protein within 14 days: an effect independent of low-density lipoprotein
cholesterol reduction. 2002;106:1447-1452.
Blake GJ, Ridker PM. Novel clinical markers of vascular wall inflammation.
2001;89:763771.
Weitz-Schmidt G, Welzenbach K, Brinkmann V, et al. Statins selectively
inhibit leukocyte function antigen-1 by binding to a novel regulatory
integrin site 2001;7:687-692.
Wilson SH, Simari RD, Best PJM, et al. Simvastatin preserves coronary
endothelial function in hypercholesterolemia in the absence of lipid
lowering. 2001;21:546-554.
Rikitake Y, Kawashima S, Takeshita S, et al. Anti-oxidative properties of
fluvastatin, an HMG-CoA reductase inhibitor, contribute to prevention of
atherosclerosis in cholesterol-fed rabbits. 2001;154:87-96.
Inami S, Okamatsu K, Takano M, et al. Effects of statins on circulating
oxidized low-density lipoprotein in patients with hypercholesterolemia.
2004;45:969-975.
Yasunari K, Maedi K, Minami M, Yosikawa J. HMG-CoA reductase
inhibitors prevent migration of human coronary smooth muscle cells
through suppression of increase in oxidative stress.
2001;21:937-942.
Hidaka Y, Eda T, Yonemoto M, Kamei T. Inhibition of cultured vascular
smooth muscle cell migration by simvastatin (MK-733).
1992;95:87-94.
Raiteri M, Arnaboldi L, McGeady P, et al. Pharmacological control of the
mevalonate pathway: effect on arterial smooth muscle cell proliferation.
1997;281:1144-1153.
Axel DI, Riessen R, Runge H, et al. Effects of cerivastatin on human arterial
smooth muscle cell proliferation and migration in transfilter cocultures.
2000;35:619-629.
Corsini A, Mazzotti M, Raiteri M, et al. Relationship between mevalonate
pathway and arterial myocyte proliferation: in vitro studies with inhibitors
of HMG-CoA reductase. 1993;101:117-125.
Crisby M, Nordin-Fredriksson G, Shah PK, et al. Pravastatin treatment
increases collagen content and decreases lipid content, inflammation,
metalloproteinases, and cell death in human carotid plaques:
implications for plaque stabilization. 2001;103:926933.
Bea F, Blessing E, Bennett B, et al. Simvastatin promotes atherosclerotic
plaque stability in apoe-deficient mice independently of lipid lowering.
2002;22:1832-1837.
Sukhova GK, Williams JK, Libby P. Statins reduce inflammation in
atheroma of nonhuman primates independent of effects on serum
cholesterol. 2002;22:452-1458.
Eggen DA, Strong JP, Newman WP, et al. Regression of experimental
atherosclerotic lesions in rhesus monkeys consuming a high saturated fat
diet. 1987;7:125-134.
Takemoto M, Node K, Nakagami H, et al. Statins as antioxidant therapy for
preventing cardiac myocyte hypertrophy. 2001;108:1429-1437.
Nadruz W, Lagosta VJ, Moreno H, et al. Simvastatin prevents loadinduced
protein tyrosine nitration in overloaded hearts.
2004;43:1060-1066.
Sacks FM, PfefferMA, Moye LA, et al. The effect of pravastatin on coronary
events after myocardial infarction in patients with average cholesterol
levels. 1996;335:1001-1009.
Sacks FM, Moye 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.
1998;97:1446-1452.
The Long-Term Intervention with Pravastatin In Ischaemic Disease (LIPID)
Study Group. Prevention of cardiovascular events and death with
pravastatin in patients with coronary heart disease and a broad range of
initial cholesterol levels. 1998;339:1349-1357.
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection
Study of cholesterol lowering with simvastatin in 20,536 high risk
individuals: a randomized, placebo-controlled trial. 2002;360:7-22.
Ravnskov U. Implications of 4S evidence on baseline lipid levels.
1995;346:181.
Matsuzaki M, Kita T, Mabuchi H, et al. Large scale cohort study of the
relationship between serum cholesterol concentration and coronary
events with low-dose simvastatin therapy in Japanese patients with
hypercholesterolemia. 2002;66:1087-1095.
Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate
lipid lowering with statins after acute coronary syndromes.
2004;350:1495-1504.
LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with
atorvastatin in patients with stable coronary disease.
2005;352:1425-1435.
Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and
outcomes after statin therapy. 2005;352:20-28.
Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL
cholesterol,C-reactive protein, and coronary artery disease.
2005;352:29-38.
Ridker PM, Rifai N, Pfeffer MA, et al. for the Cholesterol and Recurrent
Events (CARE) Investigators. Inflammation, pravastatin, and the risk of
coronary events after myocardial infarction in patients with average
cholesterol levels. 1998;98:839-844.
Van Wissen S, Trip MD, Smilde TJ, et al. Differential hs-CRP reduction in
patients with familial hypercholesterolemia treated with aggressive or
conventional statin therapy. 2002;165:361-366.

Plaque Rupture
SerumLDLvsAntioxidant and FattyAcid Status
84 Journal of American Physicians and Surgeons Volume 10 Number 3 Fall 2005
LDLTheory onTrial
Statins and Mortality
Effects of Statins
In vitro
Impairment or reversal of atherosclerotic plaque formation:
Improvements in arterial function:
Longer-term improvements in arterial function:
Anti-clotting effects:
Journal of American Physicians and Surgeons Volume 10 Number 3 Fall 2005 85
Anti-inflammatory effects:
Antioxidant effects:
Inhibition of the migration and proliferation of smooth
muscle cells seen during plaque formation:
Prevention of atherosclerotic plaque rupture:
in vitro
Prevention of cardiac hypertrophy:
Selective Citation and Contradictory Evidence
86 Journal of American Physicians and Surgeons Volume 10 Number 3 Fall 2005
Explaining Favorable CardiovascularOutcomes
New England Journal of Medicine
Links

Why Not use Statin Drugs

No Evidence that Saturated  Fat causes Heart Disease

Not all Calories are the Same

The Saturated Fat Debate

It Takes an Open Mind and Courage

The Lectin Story, not for the faint of heart
Omega 6 to watch out for
Linoleic acid not to be confused with linolenic
You will need extra Co-enzyme Q10