by Duane Graveline, MD, MPH

According to Dorland’s Illustrated Medical Dictionary (1), inflammation is defined as “A protective response elicited by injury or destruction of tissues that serves to destroy, dilute, or sequester both the injurious agent and injured tissue.”

Under the influence of this inflammatory response, normal homeostatic mechanisms are replaced by new defensive or adaptive reactions. Inflammation then, is a natural physiological response helping the body to defend itself against injuries of all types.

The original inflammatory response can be subtle and localized or extreme and widespread. If inflammation becomes prolonged, as it often is in conditions such as renal insufficiency, there is often endothelial damage and atherosclerosis.

Dialysis patients have proven to be a fertile source of investigation into the many subtle factors involved in cardiovascular disease development. Renal insufficiency now is considered an independent risk factor for cardiovascular diseases.

It is believed that inflammation may have an important role in the increased prevalence of cardiovascular disease and mortality associated with renal insufficiency.  In recent years, more attention has been focused on inflammatory processes as the possible cause of accelerated atherosclerosis.  

In the general population, it recently was shown that such indicators of inflammation as an increased serum C-reactive protein (CRP) level, are much stronger predictors of cardiovascular events than low-density lipoprotein (LDL) hypercholesterolemia (2).

As to my choice of words in referring to cholesterol causation, it was prompted by my realization of just how difficult it must be for physicians to radically change their treatment philosophy after so many years of constant brainwashing about the evils of cholesterol elevation.

The knowledge of just how important cholesterol is to cell structure and function is now beginning to be appreciated. One most certainly cannot live without it and your natural cholesterol level is without a doubt the ideal value for proper functioning of your body's cells.

In January 2003, the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (Crestor) [JUPITER] investigators began to enroll 17,802 men and women with no evidence of cardiovascular disease and ‘normal’ cholesterol levels—low-density lipoprotein (LDL) cholesterols all under 130—in an intentionally controversial trial, testing whether subjects with enhanced inflammatory responses (high CRP level) might benefit from statin therapy.

At study entry, none of these trial participants were considered candidates for statin therapy. Using existing criteria, all were considered to be low risk for cardiovascular disease. Also at study entry, all trial participants had levels of the inflammatory bio-marker high sensitivity C-reactive protein (hsCRP) equal to or greater than 2 mg/L, putting them at substantial risk for future cardiovascular disease, according to the developers of this more refined test.

Ridker then divided these final selectees into two groups. The test group received a mid-range dose of the commonly used statin, Crestor. The control group took a placebo. After 19 months the ethics committee ordered the test be stopped because of excessive numbers of heart attacks and strokes appearing in the control (placebo) group. Because this study was considered potentially controversial from the very beginning, special pains were taken that the methodology be clear cut and unassailable.

The results of this study clearly indicated that cholesterol levels no longer should be considered a reliable risk marker for cardiovascular diseases and that statin drugs provided some benefits for cardiovascular disease by an anti-inflammatory and immunomodulatory process having no relationship to cholesterol reduction. 

It was Ora Shovman who announced to the world in 2001 the anti-inflammatory and immunomodulatory properties of statins (3). Several years prior to the publication of his paper Shovman had been aware of these statin actions unrelated to cholesterol reduction.

Since he considered that atherosclerosis was a form of inflammation in which the immune system played an important role, he went on to discuss how these functionally interwoven factors helped best to explain the pleiotropic effects of statins (multiple effects independent of cholesterol reduction). Shovman further anticipated that what was learned about the effect of statins on atherosclerosis might be applicable to other inflammatory diseases in which autoimmune reactions played a role.

According to Shovman, “Two major critical pathways of statin influence on atherogenesis could be identified: anti-atherosclerotic and anti-thrombotic.” He described maintenance of endothelial function, tissue anti-oxidant capacity, inhibition of smooth muscle cell proliferation and inhibition of inflammation as key elements of  anti-atherogenic properties of statins, whereas following plaque disruption, statins may inhibit thrombosis through inhibitory effects on platelets, coagulation and fibrinolysis.

In documenting his concept of atherosclerosis as a form of inflammation, he called attention to the already existing literature on the relationship between infection and atherosclerosis noting that both Chlamydia pneumonia and herpes viruses had been found in atherosclerotic lesions and the predictive value of their respective antibodies against them was well known.

In a direct quote supporting the anti-inflammatory action of statins, Shovman states, “The evolution of an atherosclerotic process involves an interaction between four major cell types: endothelial cells, smooth muscle cells, macrophages and lymphocytes. Statins may interfere with key mechanisms necessary for involvement of the different cellular elements in the inflammatory response in all the steps of atherogenesis.”

Shovman then went on to document the vast amount of literature available in 2001 on this important subject and by doing so, greatly enhanced our knowledge of the mechanism of action of statin drugs.

Most definitely statins are far more than cholesterol reduction agents. These unexpected pleiotropic properties of statins are turning out to be of much greater importance than their originally designed purpose.

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

References
1) Newman Dorland W, Anderson D: Dorland’s Illustrated Medical Dictionary, Philadelphia, PA, Saunders, 2000
2) Ridker PM, Rifai N, Rose L, Buring JE, Cook NR: Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 347:1557-1565, 2002
3) Shovman O and others. Anti-inflammatory and immunomodulatory properties of statins. Immuno. Research 25(3); 272-85, 2002

Updated August 2016