Questions raised over the role of HDL-cholesterol in cardiovascular disease

Cholesterol in the bloodstream is transported in two main forms: ‘low-density lipoprotein-cholesterol’ (LDL-cholesterol) and ‘high-density lipoprotein-cholesterol’ (HDL-cholesterol). Conventional wisdom tells us that LDL-cholesterol is responsible for the fatty build-up on the inside of arteries known as ‘atherosclerotic plaque’, but that HDL-cholesterol clears this plaque. Because of this, HDL- and LDL-cholesterols are dubbed ‘good’ and ‘bad’ cholesterol respectively.

A paper was published recently which attempted to explore further the relationship between HDL-cholesterol and risk of cardiovascular disease. Low levels of HDL-cholesterol have been associated with enhanced risk. But just because two things are associated with each other, does not mean one is causing the other.

Low HDL-cholesterol levels often go hand-in-hand with other metabolic ‘abnormalities’ including raised triglyceride (a form of blood fat) levels, raised blood pressure, raised blood sugar levels and abdominal obesity. Could it be one or more of these associated factors or other factors entirely that account for the relationship between low HDL-cholesterol levels and heightened risk of cardiovascular disease.

To answer this question, Danish scientists isolated individuals with low HDL-cholesterol levels as a result of a genetic glitch [1]. In these individuals, HDL-cholesterol levels are low, but this is usually in isolation and not in combination with other metabolic abnormalities (such as raised triglycerides, blood pressure, blood sugar and abdominal obesity).

It turns out that in these individuals with genetically determined low HDL-cholesterol levels, risk of heart attack is no higher than in the general population. The logical conclusion here is that low HDL-cholesterol does not cause heart attacks (which means that higher levels do not protect against it either). In other words, this evidence strongly suggests the link between HDL-cholesterol levels and cardiovascular disease risk is only an association and not causal.

But if this is the case, could the same not be true for LDL-cholesterol too?

Many doctors and scientists will not hear of such a thing, of course, and will quote studies which show cholesterol-reduction with statin drugs reduces risk of cardiovascular disease as evidence of the fact LDL-cholesterol causes heart disease. However, as is well-recognised now, statins have many actions in the body which might reduce cardiovascular disease risk in a way which has nothing to do with cholesterol (including anti-inflammatory and blood-thinning properties).

Also, we have evidence that statins substantially reduce the risk of stroke, even though cholesterol is a weak or non-existent risk factor for stroke. And we have evidence that statins reduce the risk of cardiovascular disease in individuals with normal or even low levels of cholesterol. These lines of evidence suggest that statins actually work through mechanisms that are distinct from their cholesterol-reducing properties.

I know that some will tell us that cholesterol is to be found in atherosclerotic plaque and that ‘proves’ that cholesterol causes cardiovascular disease. Actually, though, it does nothing of the sort. If I graze my knee and form a scab there, chemical analysis of the scab will reveal something called fibrin (a clotting agent). Has fibrin caused my scab? Of course not.

References:

1. Haase CL, et al. LCAT, HDL Cholesterol and Ischemic Cardiovascular Disease: A Mendelian Randomization Study of HDL Cholesterol in 54,500 Individuals. The Journal of Clinical Endocrinology & Metabolism November 16, 2011

12 Responses to Questions raised over the role of HDL-cholesterol in cardiovascular disease

  1. Kevin eakins 2 December 2011 at 10:30 pm #

    This is an excellent article because it puts yet another nail (if such were needed) in the coffin of the cholesterol hypothesis. The day is coming and it is not be too far away when the whole house of cards will come tumbling down.

  2. Dan 2 December 2011 at 10:50 pm #

    This is, by far, the best most easy to understand explanation of cholesterol and statins I have ever seen. You put it so simply, yet so eloquent.

  3. Valerie H 3 December 2011 at 3:03 am #

    I’m curious if those people REALLY are genetically predispositioned to low HDL or whether it is a result of eating a modern diet.

  4. Christopher Palmer 3 December 2011 at 4:59 am #

    The observation that cholesterol is found in atherosclerotic plaques dates to about 1850. If likened to the extended ‘trial’ of cholesterol it is the first piece of evidence to be put before the ‘court’ and it is no more than ‘circumstantial’. It was another 50 years before another key witness appeared and a piece of ‘pivotal’ evidence was put before the court, and although this evidence seemed reliable at the time, it now has the look of case of mistaken identity. Another 50 years after, Keys offered his suspicions and ‘evidence’. Keys was an unreliable witness whose contribution was tantamount to ‘perjury’. The verdict is ‘unsafe’, there has been a ‘miscarriage of justice’.

    There is hole in this ‘ratio’ thing the size of the hole in the ozone layer. Folks don’t ‘see’ it because the way terminology is used obscures the issue that the lipid profile test that returns results for ‘lipoproteins’ is a ‘proxy’ method of estimating cholesterol. The ratio tells us more about the distinctions between lipoprotein types that it does about ‘cholesterol’. The cholesterol, if it is cholesterol in LDL is the same as in HDL, it has the same chemical formula, the same molecular geometry, and unless a founding philosophy of science connected with cause and effect has been ‘breached’, it has the same properties.BUT, that alone doesn’t prove cholesterol is ‘innocent’.

    There’s something in the ‘provenance’ of LDL and HDL (which are lipoproteins, and not cholesterol) that differs, and that, I feel, is big clue.

  5. Christopher Palmer 3 December 2011 at 5:05 am #

    … and unless a founding philosophy of science connected with cause and effect has been ‘breached’, it has the same properties.

    (It is early in the morning, sorry!)

  6. David Manovitch 3 December 2011 at 8:51 pm #

    Whilst the role of cholesterol may be uncertain in the genesis of atheroma, there is no be doubt that very high levels, as in the hereditary hyper- lipidaemias show a very strong association with early and severe atheromatous disease. Is this a mere chance association, or is there some other common denominator underlying both?

    Regarding Low density Lipoprotein cholesterol, is it not that this is associated with atheroma because its low density renders it more able to penetrate the already compromised intima of the arterial wall? In contrast HDL is less likely to cross this barrier. The fact that exercise increases the ratio of HDL to LDL, and is believed to be itself protective against arterial disease, suggests that LDL may be the more noxious form of cholesterol, but perhaps only once damage to the intima has already occurred. Maybe high glucose levels are a cause, or even bacterial infection as has been suggested by some research a few years ago? Back in the 60s and 70s, anyone suggesting a bacterial cause for peptic ulceration would have been ridiculed.

  7. Richard Parkes 3 December 2011 at 10:14 pm #

    I am afraid this study proves nothing. The numbers of patients with the genetic abnormality were small and the analysis was not powered to show anything. Look at the confidence intervals on the hazard ratio it’s not possible to discount even whether they had an increased or decreased CV risk. Means nothing at all. I am surprised they got it published.

  8. audrey wickham 4 December 2011 at 4:44 pm #

    HOLD ON! The penultimate paragraph says twice that Statins do in fact reduce heart attacks and strokes.

    Is this true? I have not taken the prescribed statins because I understood they would do more harm than good – if they were given to me to reduce my cholesterol and that has now been found not be the case but can be o.k. for reducing heart attacks and stokes is Dr. Briffa now saying I can take statins.

  9. Christopher Palmer 5 December 2011 at 8:43 pm #

    “Whilst the role of cholesterol may be uncertain in the genesis of atheroma, there is no be doubt that very high levels, as in the hereditary hyper- lipidaemias show a very strong association with early and severe atheromatous disease. Is this a mere chance association, or is there some other common denominator underlying both?”

    I do not know, David. If you’re referring Familial Hypercholesterolemia (FH) Dr Malcolm Kendrick (auth. ‘The Great Cholesterol Con’) indicates a systemic error creeps into the statistical analysis and folks come to the wrong conclusions on FH as a result.

    It is to be remembered the familiar lipid profile test is a proxy method where the testing of cholesterol is concerned. Experiments involving animals indicate pure cholesterol added to the diet does not promote advance of atheromas but oxy-cholesterols do. A test that is applied because folks believe quantitative regard for cholesterol is instructive is returning results for lipoproteins. Results from the lipid profile test, even epidemiological results from which the divided notion of ‘good’ and ‘bad’ cholesterol may stem, are telling us more about some aspect of lipoproteins than they are about cholesterol. We know there are qualitative differences between factions of lipoproteins, and we know factions (and fractions) may have provenance arising from different aspects of bodily function. Perhaps atheromas stem from a qualitative distinction of the lipoprotein and perhaps cholesterol, the pure kind has nothing to contribute to the explanation.

    “Regarding Low density Lipoprotein cholesterol, is it not that this is associated with atheroma because its’ low density renders it more able to penetrate the already compromised intima of the arterial wall? In contrast HDL is less likely to cross this barrier”

    I wouldn’t like to present myself as well informed, but HDL carries the most cholesterol weight for weight, and though the name carries with it a term implying magnitude it is the smallest of the lipoproteins, so on that basis I would rush to consider it the most mobile, except .. reactivity probably has more to do with receptors tuned to attract factions of lipoproteins than it does with size or density. FH is a condition attributed to a dearth of LDL receptors and arising from genetic defect.

    “LDL may be the more noxious form of cholesterol”

    The formula and geometry of a cholesterol molecule is invariable, it is difficult to comprehend how it can be innocuous in one instance and noxious in the next. The suggestion breaks the philosophy connected with cause and effect rooted in the very foundations of the scientific approach.

    Fractions of the LDL faction of the lipoproteins may have attributes, or may be a haven for something with attributes, that explain any ‘noxious’ effect. Any variable effect has been demonstrated not to associate with cholesterol.

    “Maybe high glucose levels are a cause, or even bacterial infection as has been suggested by some research a few years ago?”

    Several things have been suggested as a cause.
    1 Saturated fats and cholesterol.
    2 Stress.
    3 Homocysteine (which is a by-product of impeded protein metabolism in the face of sub-optimal supply of B vitamins)
    4 Inflammation.

    What you suggest may have a place in the inflammation hypothesis of heart disease, David.

    I do not know what causes heart disease. In a broad sense, a very broad sense, I anticipate promising causes can be linked to economics of some sort (2, 3, & 4 can).

    I am as close to believing as I think I’ll ever be that #1 has no part, but the reason(s) people are directed to think it has is(are) traceable to economics.

    Quantitative regard for HDL allied to purely quantitative regard for LDL, and some notional healthy balance between the ratio of one to the other, is diverting attention away from the likely explanation that qualitative differences exist between fractions of LDL and that epidemiological results may actually be indicating those qualitative, not quantitative differences, have a bearing upon outcome.

    Fiona, thanks for the stimulus, what do you think, incidentally?

  10. spiro A 26 March 2012 at 12:30 am #

    What is being confused here by Dr Briffa is the question – Does cholesterol cause cardiovasular disease? And Does cholesterol cause Atheroma? Atheroma causes cardiovascular disease and cholesterol is deposited in atheroma and hence plays 1 part. Your knee scab is only a problem it it was unwanted. We dont want cholesterol in the atheroma so we look to remove it. Cholesterol is part of the picture but not the only part. If we could remove the vessel damage cholesterol maty not be a problem. -

  11. Katrina Bourne 5 May 2012 at 10:23 pm #

    The tos and fros of the arguments about chloresterol shows me at least that the medical world is split over this subject. What I would like to know is how much money are the pharmacutical companies making out of statins? The production of statins is cheap, their sale expanding and the whole world seems to think that they are the cure all for all ills. Everything from heart disease, diabetes, cancer, etc. It’s getting more and more worrying that the population of the world seems to see statins as some sort of wonder drug.

    WE DON’T NEED THEM!!!!!!!!!!!!!

    What we need is a cure for cancer, a cure for diabetes and a cure for heart disease. These cures lie in our hands, not the hands of the drug companies. We need to eat healthy food, take healthy exercise and stop poisoning the planet. We don’t need to become vegetarians, (human beings are omnivores, not herbivores) but we do need to be aware of what we put in our bodies, in the air we breathe and the water we drink.

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