LDL-C : The Other “Good” Cholesterol?

DR. Neville Wilson

ABSTRACT:

A fundamental precept of modern medicine is that LDL-cholesterol is harmful to health and should be “managed” with a view to maximum reduction. This view reflects the policy statements of the National
Cholesterol Education Programme (NCEP) and its target proposals. (1)

This theory has been further modified to incorporate the widely held perception of “good cholesterol” and “bad cholesterol” with reference to HDL-C and LDL-C. The assumption that LDL-C is causative in atherosclerosis derives from unfounded conclusions regarding premature mortality in some cases of familial hypercholesterolaemia (FH). (2)

Concerted efforts to reduce LDL-C, the “bad cholesterol” have not produced the anticipated benefits of health, leading to the recognition, over the past two decades, that LDL is not a reliable risk factor for Coronary Heart Disease (CHD). Hence the current preoccupation with developing CETP inhibitors for purposes of increasing HDL-C activity.

(The dichotomy between “good” and “bad” cholesterol is false, since it has no scientific basis, and serves to obstruct, rather than aid, a correct understanding of the nature and purpose of circulating cholesterol in human physiology).
Notions of LDL and HDL being “bad” or “good” cholesterol is meaningless, since neither is a cholesterol. They are both lipoproteins and serve as circulating cholesterol carriers, and while each can be modified and become dysfunctional under certain physiological conditions, in their unaltered state they both serve “good” and necessary physiological purposes. Manipulating their circulating levels with pharmacological agents therefore remains a questionable objective.

HOW “BAD” IS LDL-C ?

The early assertions by Scott Grundy, an influential promoter of the cholesterol hypothesis, that “LDL is a major cause of CHD and that lowering serum LDL levels reduces CHD risk”, is not supported by evidence.
Numerous clinical trials, seeking to verify these pronouncements, have failed to do so.

A recent survey among European cardiologists revealed that public statements about LDL-C lowering were not being translated into their clinical practice, raising questions about their convictions. (3)

The purported benefits of LDL-C reduction, as promoted by the American Heart Association (AHA) and the National Heart, Lung and Blood Institute ( NHLBI ), are contradicted by the Framingham report, which in fact clearly states, “for each 1% mg/dl drop of cholesterol there was an 11% increase in coronary mortality”(4)

Recommendations in 2004 by the National Cholesterol Education Programme ( NCEP) to reduce LDL-C levels to below 1.81mmol/L in high risk patients have been shown by several investigators to have no supporting evidence from clinical trials. (5) (6)
The same investigators discovered that reducing LDL-C levels below 3.36mmol/L in some groups has been shown to INCREASE the cardiovascular risk, again suggestive of a protective rather than a harmful role for LDL-C.

In several clinical trials an association between high cholesterol and mortality is present, but evidence of a causal relationship is strikingly absent. Such an association can be understood by the presence of other factors, such as smoking, obesity, hypertension or stress, which are often co-existent in trial subjects. Assessments of risk reduction in LDL-C lowering trials, while observational, are not experimental, since they do not take account of these potential confounders.

Attempts by Ancel Keys to demonstrate such a causal relationship in his 7 COUNTRIES STUDY were unconvincing, and the facts reveal that communities with the same cholesterol levels had different rates of cardiac mortality. (7 )

The MONICA study, involving 27 countries, likewise failed to link mortality rates to blood cholesterol levels, and demonstrated that the highest mortality, which was 5 x greater than the lowest mortality, occurred at the SAME levels of blood cholesterol. (8)

An extensive review of all studies examining the benefits of LDL-C lowering concludes, “current clinical evidence DOES NOT demonstrate that titrating lipid therapy to achieve proposed low LDL-C levels is beneficial or safe…” (9) Neither the overall mortality benefits, nor the safety, of aggressive LDL-C lowering has been demonstrated in the major lipid trials.

Interestingly, the INTERHEART STUDY, exploring the major risk factors associated with myocardial infarction (MI) in 52 countries, make no mention of LDL, and ranks the 9 major risk factors as, smoking, (apo)B/APO A ratio, hypertension, diabetes, abdominal obesity, psychological factors, low anti-oxidant levels, alcohol and lack of physical activity. (10)
Of note, is the fact that these risk factors strongly suggest the presence of oxidative stress, operating within the vascular wall at various stages of CHD.

FAMILIAL HYPERCHOLESTEROLAEMIA.

One of the supporting arguments for the cholesterol hypothesis is the assumption that Familial Hypercholesterolaemia (FH) “causes severe atherosclerosis and early death” (11) and that raised cholesterol levels are therefore predictive of CAD in non-FH patients.

Such a conclusion is unwarranted since the basic premise is false. FH does not lead to early death in all cases, and many persons with this genetic predisposition have a normal lifespan.

Several studies of family groups with FH show that neither the incidence nor the prevalence of cardiovascular disease is related to LDL-C levels. (12) (13).

Sijbrands et al examined the mortality over 2 centuries in large pedigree with FH and observed a large variability in mortality over this period. (14). Their conclusions were suggestive of environmental factors rather than lipid levels, giving rise to a variability in mortality risk.

Since inborn errors of coagulation (fibrinogen and factor 8) are common in these persons it is more likely that the extremely high cholesterol levels represent a protective role of the lipid fractions. (15).

Hypercoagulability, rather than hyperlipidaemia, has been suggested by Sugrue et al to play a role in the pathogenesis of CAD in patients with FH. Dr. Sijbrands and his colleagues support this view citing evidence of protection against severe bacterial infections in genetically modified mice with high cholesterol.

Many persons, with FH and high levels of cholesterol, live into their seventies and eighties.

The failure of the ENHANCE TRIAL to produce evidence of clinical benefit, despite massive LDL-C reductions ( 58% with Ezitemibe/ Simvastatin and 42% with Simvastatin) supports the view that LDL-C levels are a poor indicator of cardiovascular mortality risk. It cannot thus be called “bad”.

LDL-C FUNCTIONS:

It is not surprising that LDL-C is a poor predictor of CHD, since it’s primary function is one of benefit, through it’s delivery of cholesterol from the liver to the peripheral cells where much needed cholesterol is utilized for cellular membrane stability, as well as a variety of other health-giving cellular functions. LDL-C is one of several lipoproteins which vary in size and density, serving the life-sustaining purpose of cholesterol transport and homoeostasis.

LDL receptors are strategically placed on cellular membranes to receive this life giving and life preserving molecule. The discovery of LDL receptors in 1973 by Nobel Prize winners Brown and Goldstein reinforces the notion of purposeful cellular incorporation of a physiologically vital factor for maintaining cellular stability.
Such a molecule can only be called “bad” by the wildest stretch of imagination.

Unutilized or excess cholesterol is returned to the liver for recycling and reuse by the HDL- C lipoprotein.
To label these vital cholesterol carriers as “bad” or “good” is as senseless as attaching similar labels to an ambulance that transports a patient from home to hospital and home again, suggesting that one route it is “good” and on the reverse route it is “bad”!

BENEFITS OF LDL-C:

Laboratory, epidemiological and clinical evidence supports a protective role for LDL-C against infection and atherosclerosis. (16)

Gram negative bacterial endotoxins bind rapidly to LDL-C, suggesting an immunoprotective function of certain lipoproteins.
Rauch et al support this view in their endotoxin-lipoprotein hypothesis. (17)

The inverse correlation between serum cholesterol and infection related mortality, demonstrated in a meta-analysis of 19 cohort studies, (18 ) was also found in a 15 year follow-up study of more than 120,000 individuals (19).

Not only does cholesterol provide for the structure and stability of cellular membranes, but it’s unique role in vitamin D synthesis, bile acid formation, nerve impulse conduction and synthesis of life-sustaining hormones like estrogen, progesterone, testosterone, dihydroepiandrostenone, and cortisol renders it everything but harmful.

OXIDATIVE STRESS:

Oxidative stress plays a significant role in atherogenesis.
Current research supports the concept of endothelial damage by pro-oxidant factors with a “response to vascular injury” triggering an inflammatory process within the arterial wall, and subsequent plaque formation, which may remain stable, or become unstable under certain physiological conditions.

Factors that have been shown to create unfavourable subendothelial conditions leading to oxidative stress, are cigarette smoking, poor glycaemic control, infection, homocysteine, iron, excessive refined carbohydrate intake, excessive dietary omega 6 and inadequate omega 3 intake, dietary transfats, stress and nitric oxide depletion.

MODIFIED LIPOPROTEINS.

Circulating lipoproteins serve as water soluble carriers for cholesterol and can be modified, giving rise to an altered state which no longer serves it’s primary function.
Since HDL-C can be modified, under unfavourable physiological conditions, to behave in a pro-oxidant and pro-inflammatory state, rather than as an anti-inflammatory agent, it may under these circumstances cease to play a “good” role. LDL-C, likewise, can be modified, under unfavourable conditions, and become dysfunctional, through oxidation and trapping within the arterial wall. (20)

OXIDIZED LDL (OX-LDL).

Oxidative waste within the cells of the arterial wall may trap specific phospholipids in native LDL-C and cause them to be oxidized, through the destruction of their naturally occuring and biological enzymes. These protective enzymes, platelet activating factor acetyl hydrolase and HDL paraoxonase, are neutralized by the unfavourable microenvironment within the arterial wall, giving rise to the formation of biologically active oxidized lipids that initiate changes in the arterial wall. (21)

The regulation and expression of these enzymes are determined genetically, and are likewise modified by environmental factors and an atherogenic diet. (This diet has nothing to do with cholesterol or saturated fat intake, and may be linked to an imbalance between dietary omega 6 and omega 3).

ANTIOXIDANTS:

An anti-oxidant rich diet, by contrast, as provided by a Mediterranean type diet, has been shown to reduce OX-LDL without any changes in plasma LDL-C levels. (22). These findings support earlier observations from the Lyon Diet Heart Study that LDL-C levels were not altered in the reduction of MI risk in response to a Mediterranean diet, as did the ATTICA STUDY, in 2004, showing reductions in OX-LDL, but not LDL-C in response to a Mediterranean diet.(23)
The complex consequences of oxidized LDL-C have been researched and reported by many investigators (Berlinin, Navab, Ross, Reaven ) in the early 1990’s, showing patterns of monocyte transformation, macrophage formation, and trapping of mildly oxidized LDL and its conversion to highly oxidized OX-LDL.

Several studies are suggestive of the potent pro-atherosclerotic stimulus provided by OX-LDL as compared with native, unmodified LDL-C (24)

HDL-C has long been known to possess capabilities of preventing LDL oxidation through the action of paraoxinase, which inhibits the production of lipoperoxides. Low paroxinase levels, as found in diabetic patients, thus permits the oxidation of LDL-C, which promotes the atherogenic process seen in these patients.

(The protective effect of HDL may not be dependent on the absolute level of HDL-C in the blood, but may rather be dependent on the abundance of HDL particles that contain protective enzymes relative to the concentration of mildly oxidized and active LDL in the arterial wall, a ratio that is environmentally and genetically driven.)

The gene expression of endothelial nitric oxide synthase (eNOS), which facilitates vasodilation, is decreased by OX-LDL, (25) while, in addition, platelet eNOS activity is diminished in the presence of OX-LDL creating thereby a pro-thrombotic state.( 26).

GENETICS:

Genetics and environmental influences can thus be shown to play a significant role in the alteration of both HDL and LDL. In their natural state, however, they serve vital functions which can hardly be labelled as “bad”.
What is “bad” is the unfavourable microenvironment within the arterial wall that initiates alterations of HDL and LDL. Manipulating the levels of HDL and LDL pharmacologically serves little purpose if no attention is given to the factors that create a pro-oxidant state in the arterial wall.
The benefits of lifestyle changes and anti-oxidant status in the prevention of CAD has been demonstrated in trials, such as the GISSI-Prevenzione, the Lyon Heart study and the ATTICA study.

The clinical relevance, therefore of strict adherence to lipid guidelines, or a “low cholesterol diet”, is highly questionable if no consideration is given to life style modification and avoidance of factors that precipitate OX-LDL in the first place.

PLAQUE:

The prevailing notion that high levels of “bad” cholesterol stick to arterial walls “plugging” the vessels is simplistic and scientifically untenable. Yet this notion commonly finds expression in pronouncements by health professionals and in health articles appearing in the lay press. These unscientific and inaccurate statements serve only to misinform and confuse the public, instilling unfounded and unnecessary fears about cholesterol consumption or “cholesterol levels”.

Plaque formation is the end result of the complex cascade of inflammatory events that occur within the vascular wall. It is not a consequence of circulating lipid levels, and reductions in lipid levels do not produce corresponding plaque reductions. Furthermore, plaque stenosis does not cause the majority of acute MIs, and many AMIs occur in the absence of significant stenosis. It is the predisposition of plaque to rupture that presents the risk of an event.

The complex composition of plaque and it’s transition to a vulnerable state preceding rupture, is dependent upon several factors such as smooth muscle proliferation, calcium, connective tissue, leucocytes and oxidized LDL content.
OX-LDL increases the formation of metalloproteinases, thus setting the stage for rupture of soft plaque.(27)

Plaque also contains a disproportionately high concentration of pro-inflammatory omega 6 (linoleic acid),(28) a major component of many “heart-healthy” polyunsaturated vegetable oils, which purportedly promote cardiac health by “lowering cholesterol”. Such claims are false.

Mounting evidence suggests that these vegetable oils are not heart-healthy since they generate an unhealthy balance of omega 6 / omega 3 fatty acids, and increase reactive oxygen species (ROS) in the subendothelial space. These proportionately high levels of omega 6 predispose to plaque rupture. (29)

Lp-PLA2

The enzyme lipoprotein – associated phospholipase, Lp-PLA2, recently discovered within unstable plaque, reflects levels of LDL-oxidation suggestive of plaque instability and imminent rupture, and may in future serve as a predictive measurement of CAD risk. The anti-oxidant properties of omega-3 fatty acids have been shown to reduce such plaque (30), confirming earlier studies showing the plaque stabilizing effect of n-3 PUFA (omega 3) intake. (31).
The PLAC test identifies OX-LDL induced atheroma, and may in future dispel all notions of LDL-C as being “bad”.

Dr. Neville Wilson.
The Leinster Clinic.
25 October, 2008.

REFERENCES:

1. Circulation. 2004; 110:227-39
2. Irish Medical Times Article, Aug 29,2008, p 22.
3. Irish Medical Times Article, Aug 29, 2008, p 53.
4. JAMA 1987, April 24; 257; 2176-80
5. Annals of Int Med 2006, 140:650-8
6. Annals of Int Med 2006, 140:644-9
7. Circulation 41,Supp 1, 1-211, 1970.
8. Canadian MAJ. 103, 927-931, 1070
9. Annals of Int Med Oct 3, 2006.vol 145, issue 7; p 520-530
10. Lancet 2004; 364:937-95
11. Irish Medical Times Article Aug 29, 2008 p22.
12. J Int Med 2004; 256,482-90
13. J Int Med 2003;253;161-8
14. BMJ 2001; 322: 1019-1023
15. B Heart J. 1985; 53:265-8
16. QJMed 2003; 96: 927-934
17. Lancet 2000.356:930-3
18. Circulation 1992; 86:1046-60
19. Epid Infection 1995; 121:335-47
20. J.Lipid Res 1983: 24:1070-1076
21. Arterio, Thrombosis and Vascular Biol 1996; 16:831-842
22. J Nut135; 410-415
23. Nutr Metab Cardiov Disease 2006, Mar;16(2):91-9
24. Am J Physiol. 1998; 275 H568-576
25. Biochem Biophys Res Comm 2001, 289; 857-861
26. Circ 1996; 93: 1740-1746
27. Atherothromb Vasc Biol 2003; 23:816-821
28. Arterio Thromb Vasc Biol 1992; 12; 911-919
29. Arterio Thromb Vasc Biol 1997; 17 1337-1345
30. Atherosclerosis 2008 Jan, 196(1); 420-4
31. Lancet 2003; 361:477-485

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