Statins, CRP and cardiovascular inflammation

(1) the role of inflammation in the development of
cardiovascular disease, and

(2) mechanism of action through which statins in general
exert their anti-inflammatory action.

Despite many comments stating that study's confirmation of the inflammation-heart-disease connection is no less than a revolutionary breakthrough, it is all but news. As far back as 1976, the hypothesis of atherosclerosis being a response-to-injury process in which atherosclerotic plaques are formed as an attempt of healing local injuries to the thin inner lining of arterial walls (intima), was published in the New England Journal of Medicine (Ross, Glomset).

Much earlier, in 1911, Klotz and Manning published their findings in the Journal of Pathology and Bacteriology, stating basically the same, that the plaques are result of local degeneration of the intima caused by microbial infection or some other toxic presence. In short, by inflammation.

After nearly a century, we are coming back to it. Why more effort hasn't been put in that direction before? Good part of the answer is that no one before had seen a money-making opportunity in it. Why does it, all of a sudden, get all the attention? Because AstraZeneca thinks it can use it to make tons of money.

Literally hundreds of studies and research papers related to the subject of inflammation and cardiovascular disease have been published, most of them within the past decade. A number of injury agents was identified, from mechanical stress, physical (small particulate air contaminants) and chemical (heavy metals) agents, to bacterial (H. pylori, Chlamydia pneumonia, toxic periodontal bacteria in your mouth) and viral (Herpes simplex) infections, homocysteine, iron/copper overload, oxidized cholesterol, metabolic disturbances caused by diabetes, and so forth.

Obviously, it hasn't been, and it isn't in question whether or not cardiovascular inflammation poses a major risk factor for developing cardiovascular disease and suffering its consequences. Elevated CRP levels (C-Reactive Protein, marker of inflammatory process inside the body) have been shown to be

among the strongest predictors of cardiovascular complications.

What is in question is whether a blind symptom-treating approach typical of the official medicine - specifically, using a CRP-lowering pharmacological agent - is best course of action for the patient? Is it even acceptable?

Sure, it may, or may not, show positive general trend, but how reliable it is for an individual patient, or even the majority of patients? For the sake of illustration, imagine that a study agent had no effect on 85% of participants, has helped 10% and had negative effect on 5% of them. It is still likely to show better overall effect than placebo. The next step is to declare the agent generally beneficial, and push it down everyone's throat.

Is it going to help you? Well, doo noo...(when in doubt, mumble). But you still do have a statistical chance, don't you? The only sure winners are the drug maker and your doctor, who stash their pockets with your dollars.

Is there a better way? Of course. Elevated CRP can be caused by a variety of agents and conditions, including possibly undiagnosed cancer, inflammatory bowel disease, lupus, pneumonia, rheumatoid arthritis, tuberculosis, connective tissue disease, gum disease, infected tooth, and so on. Isn't it better to track your elevated inflammation marker right to the cause, and have it corrected, instead of doing nothing about it and keep taking inflammation-suppressing drug for maybe decades?

That is, isn't it better for you; the other option is, obviously, the preferred one by the drug maker.

Of course, any assessment of your cardiovascular risk would have to include a number of other risk factors: lipid peroxide level (indicating degree of oxidation of your cellular membranes by free radicals), homocysteine level, lipoprotein(a) level, coenzyme Q10, insulin, nutritional status, in particular magnesium and antioxidants, immune system efficiency, and so on.

Expensive? I would bet my horse on it being less expensive than never-ending blind treatment of individuals with "statistically beneficial" symptom-suppressing drugs.

And we still have another can of worms to open:

how is it exactly that statins exert their anti-inflammatory effect, and are there dangers to your health from their chemical interference with your vital body functions?

 According to an article co-authored by the very main author of the JUPITER study, anti-inflammatory action of statin drugs mainly results from suppressing immune system function - particularly monocytes (including machropages) and natural killer cells (some antioxidative protection may result from statins binding to the surface of cholesterol, partly preventing it from free radicals); in addition, according to the article, they reduce level of oxidized cholesterol, platelet aggregation and stimulate production of nitric oxide (Are statins anti-inflammatory?, Blake, Ridker, 2000).

The authors don't give any specifics as to how statins suppress activity of the immune system cells, other than this effect can be reversed by mevalonate, suggesting it is mediated by inhibition of HMGCoA reductase.

That's how far they'd go. Of course, they knew very well - and so did the maker at the the time of introduction of first statin drugs - that statins act by blocking mevalonate pathway, necessary for cholesterol synthesis in the liver, but also for a host of other functions. The Pharma people were not interested in publicizing, or investigating this part of the equation, since it could only spoil their money-making scheme (and who cares about the rabbits, anyway?). But we are.

By inhibiting the key mevalonate pathway enzyme, HMG-CoA reductase, statins reduce liver's cholesterol production, but also the efficiency of the entire mevalonate-pathway-dependent molecular biosynthesis within the cell. This enzyme is needed for synthesis of mevalonic acid, a

major organic compound needed for the synthesis of a
number of substances important for cellular metabolism.

These substances support vital cellular functions, from energy production, membrane maintenance, protein use and receptor function, to cell migration, re-structuring, protein linking (to other proteins, lipids and cellular carbohydrates) and cellular communication.

For instance, mevalonate-dependant N-linked glycans (form of cellular carbohydrates) are necessary for proper "folding" (structuring) of cellular proteins. Decreased N-linked glycans level result in less efficient protein structuring, with increased protein waste and decreased overall viability of cell proteins.

One particular type of cellular protein undergoing constant re-structuring as it goes from the cell-growth inhibiting to cell-growth-stimulating form are Ras proteins. They are anchored on the inside of cell membrane, acting according to the signals from hormones clinging to cellular receptors, regulating in this way the expression (on/off switch) of RAS gene, the principal gene controlling cellular growth and proliferation. Mutation or malfunction of this gene is a necessary sequence leading into cancerous growth and is, in fact, positively associated with it.

While direct link between statins and RAS gene malfunction hasn't been established (nor attempted), what has been established, from the very beginning, is that statins in animal experiments

are carcinogenic at concentrations
very close to those in their human use.

Of course, inhibiting one of the principal pathways of cellular biosynthesis can and does negatively affect cellular function in many other ways, making it more vulnerable to damages and abnormal behavior.

For instance, inhibiting dolichol (lipid-protein compound, whose sythesis requires mevalonate-pathway-produced pyrophosphates) compromises detection and repair of damages to cell's DNA. Lack of Coenzyme Q10, will expose cell's energy factory, mitochondria, to increased oxidative damage - potentially mutagenic - and so on.

Cholesterol itself is needed for the proper function of special regulatory proteins (kinases), which with insufficient cholesterol level become overactive, promoting cancerous growth.

One of the factors vital for efficient energy production and use at the cellular level, Coenzyme Q10, is is also dependant on mevalonate pathway, since its synthesis requires tyrosine and isoprene, the latter being a product of mevalonate-initiated series of sequences. Studies have found that statins can lower Coenzyme Q10 serum levels up to 40% (Ghirlanda et al., Journal of Clinical Pharmacology, 1993); cellular levels could be even more affected.

Body's endocrine system is adversely affected as well.  Among the very first sequences of biosynthesis through mevalonate pathway is lanosterol, the basic steroid hormone form. Cholesterol, as well as all other steroid hormones are synthesized from it (cholesterol itself being precursor of most steroid hormones). Obviously, by inhibiting cholesterol production, statins directly inhibit body's production of steroid hormones as well.

All of the above is only scratching the surface, but enough for anyone to conclude that inhibiting mevalonate pathway - i.e. use of statin drugs - is

not a good solution for lowering cholesterol, CRP,
or for prolonged treatment of anything, period.

No wonder that the total mortality curves for the treatment and placebo group in the JUPITER study begun to merge after less than two years.

Of course, the doctors involved, and the drug maker know all this, and more. Yet the only thing they are talking about is how effective is rosuvastatin in reducing CRP and cholesterol, and how "few adverse effects" it causes. Here, take my snake oil, and you'll live happily ever after!

A few years back, when new evidence of statins' adverse effect on brain function emerged (Pfrieger, Cellular and Molecular Life Sciences, 2003), they simply ignored it. The brain needs plenty of cholesterol for proper neural communication; inhibiting brain's cholesterol production (it has to make its own cholesterol, in the so called glial cells, since cholesterol molecules are too large to cross blood/brain barrier), has caused anything from

impaired short-term memory, confusion, disorientation,
to transient amnesia and compromised overall cognitive function.

Simply put, we need cholesterol to think.

Duane Graveline, MD MPH, former NASA astronaut, has spent a lot of time and effort to inform people of how "few and minor" statins' adverse effects actually are. As for the role of cholesterol, Swedish researcher Uffe Ravnskov, MD PhD, points out that there is compelling evidence of elevated cholesterol being actually protective, rather than harmful (which is what could be logically expected of a major functional substance of the body).

After decades-long profit-motivated cholesterol witch-hunt led by drug companies and condoned by the government and medical establishment, the truth is beginning to surface. They all failed us; the facts that will spare many from statin misery are being brought to us mainly as a result of out-of-system individual efforts. The change won't be neither quick nor easy - pharmaceutical industry is still a mighty giant, and many people are plain ignorant - but it hardly can be prevented.

By shifting to the anti-inflammatory role of statins, AstraZeneca may be trying to re-position itself ahead of the inevitable (other than to give more of a reason to physicians to prescribe $3.5 per day rosuvastatin to their patients). But there is no place for statins in this role either. There is a number of alternatives that lower CRP and internal inflammation safely and naturally.

Recent Italian study has found that dark chocolate, due to its rich flavonoids content, also efficiently lowers CRP. Take your pick: statins or chocolate, at a fraction of the price?

And the best prevention of all, undoubtedly, are healthy diet and lifestyle, along with minimizing your toxic exposure. For nearly anyone, that is all it takes to keep cardiovascular disease away.