Statins, Inflammation and Heart Disease

How strange it is that a class of drugs developed solely for the purpose of interfering with the biosynthesis of cholesterol has now been shown to reduce cardiovascular risk by a novel and unsuspected anti-inflammatory role completely unrelated to cholesterol manipulation.

For nearly four decades I was a staunch advocate of the anti-cholesterol crusade. I talked the merits of margarine at schools and libraries. I lectured at men's clubs about the evils of eggs. Despite my diet of whole milk, rich butter and daily eggs as a farm boy, I raised my family on skim milk, almost complete absence of eggs and the use of healthy margarine instead of infarction-causing butter. So great was my brainwashing during my 23 years of duty as a family doctor that I counseled thousands of my often-bewildered patients about the heretofore unknown evils of eggs, milk and butter.

Often times I could see skepticism in their eyes but I was the doctor, parroting what the pharmaceutical industry, AMA and AHA told me. How could I be wrong? I wrote thousands of prescriptions for whatever cholesterol buster was in vogue at the time. I regarded the first statin as a boon to mankind. I now am humbled at my colossal ignorance, never suspecting that all this time I had been led astray by my naivety, my unfailing allegiance and faith in "those in charge". It never occurred to me to challenge.

Now we find that cholesterol seemingly has little to nothing to do with cardiovascular disease. It is the most important biochemical in our bodies. Our brains and cells are absolutely dependent upon abundant supplies of cholesterol. Inflammation it now appears is the true cause of cardiovascular disease, according to many researchers.

Longitudinal studies have shown that statins seem to work their magic not because of cholesterol manipulation but by an inherent and previously unsuspected, anti-inflammatory action. Inflammation and oxidation are the latest buzz-words. Inflammation is associated with a tendency for "free radical" formation. Anti-oxidants are necessary to neutralize these free radicals by giving them an electron or two.

Inflammation suppression it appears is now the goal. Atherosclerosis is an inflammatory process from the very beginning of its birth as a bit of endothelial change. My head is whirling! Somehow I liked cholesterol better, something I could raise or lower. But we seem to be stuck with inflammation and immuno-defense and the bewildering involvement of statins.

My introduction to all this was by Ora Shovman of the Department of Medicine at Tel-Aviv. His review article was titled "Anti-inflammatory and immunomodulatory properties of statins". This read was a remarkable journey for me into a land of monocyte adhesion, macrophage response, platelet activation, smooth muscle migration, pro-inflammatory cytokines, tumor necrosis factors and many more bewildering terms.

This was alien territory for a family doctor. But it did supply me with an understanding of the how and why of the statins' remarkable, pleomorphic effects. It reinforced a concept slowly growing in my mind that the immunosuppressive effects of statins are both novel and real. The statins do suppress budding atherosclerotic plaques and as such are very helpful for the thousands of high-risk people out there but the impact of these statins on the mevalonate pathway is disastrous. That is the root cause of their terrible side effect legacy.

Designing a drug twenty years ago that inhibited the ubiquitous mevalonate pathway of cholesterol synthesis was a mistake. We thought we needed a cholesterol inhibitor but what we really needed was a drug designed to inhibit inflammation. Instead we got a product destined for major metabolic disaster. Of course we did not know the true cause of atherosclerosis then.

The inflammatory cascade is first initiated by a transcriptase (DNA-speak for "recipe") known as nuclear factor kappa B (NF-kB). It is this substance that starts the process of platelet activation, monocyte adhesion, macrophage attraction and smooth muscle migration, key elements in an inflammatory reaction, anywhere in the body.

Not only do statins inhibit NF-kB, they inhibit the inflammatory process of each element of the inflammatory reaction. It is here that we hear the words interleukin, cytokines and tumor factors. It is here we hear about oxidation and the anti-free radical role of vitamins E and C, superoxide dismutase and glutathione and the importance of CoQ10, key element of the anti-oxidation barrier to inflammation. Wait a minute, you say. "Isn't CoQ10 one of the branches of the mevalonate tree - the one collaterally damaged by statins - the one responsible for so many of the really bad side effects - the one that cuts our Q10 by some fifty percent?"

Talk about a two-edge sword! Statins both inhibit and promote inflammation. Surely our pharmaceutical industry can do better than this when then finally decide to develop a proper anti-inflammatory drug - one that does not sabotage our mevalonate pathway? Using our present statins to fight inflammation is like putting an upper and a downer in the same pill.

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

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