Benefits of Statins - part 2 of 2


dr_duane_graveline_m.d._134By Dr. Duane Graveline, M.D., M.P.H.

The endothelium is the thin layer of cells that line the interior surface of blood vessels, forming an interface between circulating blood and the rest of the blood vessel wall. These endothelial cells line the entire circulatory system. They are a variant form of our skin, a modification of our simple squamous epithelium.

Think of a tiny spot of damage, a divot in an otherwise featureless plain. It is in these endothelial cells that arachnidonic acid along with its precursors and derivatives are located, now suddenly directly exposed to the blood stream and all its contents. This is where platelets come in to action. This is their entire purpose in life - to seek out defects (divots, if you will).

Thromboxane-A synthase, an enzyme found in platelets, on sensing the presence of arachnidonic acid immediately begins the conversion of it into thromboxane, a powerful thrombotic agent also causing constriction of the blood vessel (stopping any further blood leakage) as well as facilitating platelet aggregation - "calling in the troops" to bring in additional thrombotic resources.

Without further tweaking of the thrombosis / anti-thrombosis system a thrombotic crisis could occur - complete shutdown of circulation to the area with gangrene a possible consequence. This is where a substance known as prostacyclin comes into action.

Predictably, prostacyclin is produced in damaged endothelial cells by the action of a specific enzyme. The role of prostacyclin is primarily to inhibit formation of the platelet aggregation (plug) critical to hemostasis. On one hand the platelet mechanism is trying desperately to cut down on blood flow through platelet aggregation while the endothelial based prostacyclin mechanism is trying just as desperately to make certain that excess hemostasis is avoided.

Similarly the vasoconstriction of the platelet mechanism is offset by prostacyclin's vasodilation. Take heart from the fact that despite the past fifty years of research this subject remains an extraordinarily complex mechanism to everyone.

Despite there being much to learn about the various mechanisms involved, aspirin has continued to be widely endorsed by the medical community. Rarely do we find a drug so economical, effective and relatively safe.

Aspirin use irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on subsequent platelet aggregation. This anticoagulant property makes aspirin useful for reducing the incidence of heart attacks. Numerous studies have shown that low dose aspirin taken daily is able to inhibit a large proportion of thromboxane with prostacyclin synthesis being little affected.

It was Hilgendorff et. al.(4) who drew my attention to the effect of statins on inhibiting inflammation via blocking nuclear factor kappa B (NF-κB) activation. In his paper "Statins differ in their ability to block NF-κB activation in human blood monocytes", his team demonstrated early on that the effect of statins went far beyond that of cholesterol reduction.

In the Justus Liebig University, Giessen, Germany the results of their studies revealed that statins differ markedly in their effectiveness in preventing activation of NF-κB, a transcription factor involved in the activation of the early genes involved in inflammation.

Using six statins: (atorvastatin (Lipitor), cerivastatin (Baycol), fluvastatin (Lescol), lovastatin (Mevacor), pravastatin (Pravachol) and simvastatin (Zocor), his team tested for their ability to influence the induction of NF-κB in human monocytes during inflammation. All statins inhibited NF-κB binding activity in monocytes in a dose-dependent manner.

The inhibitory effect was due to reduced phosphorylation and was primarily dependent on the absence of mevalonate, the expected effect of reductase inhibitors (statins). While the effect appeared with all statins, there were marked differences in the degree of inhibition between the statins.

Of particular interest to me was their graph comparing degree of inflammation suppression with the range of statin dosages used. Even at the minimal statin dose of each statin there was already very substantial suppression of inflammation, in the range of 70 percent. Further dosage increases resulted in only minimal gains in inflammation suppression.

The point here is that only minimal statin doses were necessary to produce most of the effect on inflammation suppression. I have for several years now believed that there should be studies to see whether statin sensitive people could tolerate very low dose statins ( 2 to 3mg of the newer, stronger statins ). Then for the statin intolerant, a low dose of statin rather than stopping the drug entirely, in the hope of gaining anti-inflammatory benefit without the dose dependent risk of severe side effects might become an option. This has the potential to offer real benefits if inflammation associated with excess free radical oxidation is indeed the true cause of cardiovascular disease.

In an era where Big Pharma, the food industry and the medical community still could see no wrong with the broad scale use of statin drugs to lower our cholesterol "villain", Shovman was introducing the concept in 2002 that atherosclerosis was a form of inflammation and was pointing out the possible role of autoimmune mechanisms in the development and progression of atherosclerotic plaque. His assumptions were based upon histological evidence of the close relationship between the atherosclerosis plaque and such chronic inflammatory disease as rheumatoid arthritis and cirrhosis.

Additional support for the idea of atherosclerosis as an inflammatory reaction is the association of infection with atherosclerosis. Shovman documented the basis for inflammation as the underling process in atherosclerosis and supported the use of statins for their anti-inflammatory effect years before the JUPITER study.

Supporting Hilgendorff's results, Bonnet J and others (5) compared the effects of 10-mg versus 80-mg Lipitor on (hs)CRP levels reporting that the lower dose gave 70 percent of the value of the higher dose. In other words one eighth the dose gave nearly as much (hs)CRP lowering. This type of study has been repeated many times with other statins giving similar results - the smaller dose giving nearly as much effect as the higher dose on reduction of inflammatory markers. The research evidence has allowed me to strengthen my belief that small doses might be able to trigger a satisfying anti-inflammatory effect without the risk of side effects known to result from mevalonate blockade.

Statins drugs have two primary effects on the human body. The first of these is the effect for which these drugs were designed 20 years ago - reductase inhibition of the mevalonate metabolic pathway thereby achieving inhibition of cholesterol synthesis.

The second primary effect of statin drugs is serendipity's gift to us - meaning that it was just stumbled on to - nuclear factor kappa B inhibition, the powerful anti-inflammatory action responsible for benefit in cardiovascular risk reduction.

Atherosclerosis, I believe, is an inflammatory process. Statins work because of their anti-inflammatory action. Statins, in my opinion, should be dosed on the basis of anti-inflammatory response, not cholesterol reduction.

Benefits of Statins - part 1 of 2 

Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor

References:
4) Hilgendorff. Internat J Clin Pharm and Therapeut, 41(9), 2003
5) Bonnet J and others. Clin Ther, 30(12):2298-313, Dec.2008

January 2012


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