Statins have pleiotropic effects, ie the ability to reduce heart disease
risk and CV death via an unknown mechanism, certainly beyond the LDL
cholesterol lowering that they can achieve. Researches have known for
quite some time about these beneficial effects of HMG-CoA reductase
inhibitors (also known as “statins,” such as atorvastatin and
rosuvastatin), however the physiology behind this phenomenon remains
unclear. The answer as to why statins have these pleiotropic effects is
largely unknown, but let me throw out an interesting theory and you form
your own opinion.
Statins are antibiotics that kill the undiscovered organism responsible for the entire process of atherosclerosis.
Lets look at some facts first. Many don’t know that the first statin, mevastatin, was discovered in 1971 in the fungus
Penicillium citrinum.
As the name implies, this is the same fungus from which the first
antibiotic penicillin was found. What was the role of penicillin in this
fungus, you ask?
To kill the surrounding bacteria so they do not invade the fungi’s space, allowing the Penicillium citrinum species to grow and spread more easily ... survival of the fittest!
Then, what is the role of
mevastatin in this fungus? According
to researchers, it is the exact same: To block the cholesterol synthesis
in the invading bacteria and other fungi, acting like an antibiotic.
Think about this, as well: We know it takes decades for atherosclerotic
plaques to form, and it is an inflammatory process. We know that the
early use of statins immediately during an ACS significantly reduces
mortality according to multiple clinical trials, including
PROVE IT-TIMI 22 and the
MIRACL trial.
This benefit is thought to be from acute plaque stabilization,
decreased thrombogenicity and decreased inflammation that occurs
immediately after statin administration.
How does this make any sense if the only thing statins do is reduce LDL
cholesterol levels through inhibition of HMG-CoA reductase? How should
that short-term administration improve long-term mortality, considering
the chronic nature of atherosclerosis? Why do these beneficial effects
occur? Why is inflammation dramatically reduced so quickly? Again, maybe
statins are antibiotics!
Quite an intriguing theory, that statins are antibiotics and kill the
pathogenic cause of atherosclerosis, isn’t it? Well, of course I was not
the first person to think that perhaps the process of atherosclerosis
occurs from an infection. The organisms that have been implicated in
contributing to atherosclerosis include
Chlamydia pneumoniae (now actually called
Chlamydophila pneumoniae), cytomegalovirus (CMV) and
Helicobacter pylori. Here are a look at some studies that test this theory.
Interesting side note: Mevastatin caused liver tumors
and severe muscle problems in animal studies, and therefore was never
brought to market (although it is one of the naturally occurring statins
in red yeast rice extract, which millions take ... not good).
Chlamydia pneumoniae
Chlamydia pneumoniae has the most data to show a correlation
with atherosclerosis. This pathogen enters through the respiratory tract
and is thought to be the 3rd leading cause of upper respiratory tract
infections worldwide, with an estimated 50% of the population having
been exposed. Circulating monocytes then bring the organism into the
vascular wall and induce inflammation. Animal studies with both mice and
rabbits show that
Chlamydia pneumoniae infection, in the
setting of hypercholesterolemia, can induce atherosclerosis. Moreover,
giving azithromycin completely blocks this effect.
Translate this to humans. One study of 220 patients after an MI showed that positive
Chlamydia pneumoniae
antibody titers increase the risk of future events, and that treating
those patients subsequently with azithromycin reduces the risk down to
the level of patients with negative antibody titers.
The largest trials to evaluate antibiotic therapy directed at
Chlamydia pneumoniae
after acute MI actually failed to show any reduction in cardiac events
or mortality. These include subsets in the ACES trial, WIZARD trial, and
PROVE-IT trial, totaling close to 16,000 patients.
Perhaps the key is preventing the infection in the first place instead of trying to treat it after the MI has occurred.
Cytomegalovirus (CMV)
The evidence to link CMV and atherosclerosis is less robust. Certainly,
in heart transplant patients there is a correlation. The studies to
connect positive CMV antibody titers (serologic evidence of prior CMV
infection) to CAD patients have been conflicting. Researches have
postulated that CMV may play an important role in the initial
endothelial cell injury starting the atherosclerotic process.
Helicobacter pylori
Once again, only a casual relationship between
Helicobacter pylori infection and CAD has been shown via serologic studies.
Helicobacter pylori
has not been isolated from atherosclerotic plaque and the use of
antibiotics to eliminate this organism with the goal of reducing CV
events has not been evaluated.
Immunization for Heart Disease
How about the prospect of developing an immunization against one of these organisms? Could a cure for
Chlamydia pneumoniae actually result in, essentially, a cure for atherosclerosis?
Nobody really knows the answer to that question. Researchers are indeed
in the process of developing an immunization for heart disease!
Interestingly, it has nothing to do with
Chlamydia pneumoniae. A
protein antigen that inflammatory T cells react to is being targeted in
order to prevent the inflammatory response that they create. Let's see
how it goes!
C-Reactive Protein, Sepsis and Statins
We know that CRP (C-reactive protein) is a measurable inflammatory
marker that is significantly elevated during states of inflammation,
including atherosclerosis, ACS, inflammatory arthritis and, of course,
during infection (including sepsis). We know that statin therapy reduces
CRP significantly, independent of reductions in LDL cholesterol. So
putting these together ... infection increases CRP and statins decrease
CRP. This association, of course, does not prove the antibiotic theory,
but is a bit intriguing.
How about this factoid? Statins have been shown in more than one
analysis to decrease the incidence of sepsis (severe infection with a
systemic inflammatory response, usually bacterial) AND decrease
mortality in patients with bacteremia. Other studies examining statins
for community-acquired pneumonia and ventilator-associated pneumonia,
however, have failed to show a benefit. Fortunately, further clinical
trials are ongoing to evaluate statin therapy in patients with sepsis.
Yet another possibility that statins are acting as antibiotics in this
setting.
Pleiotropic Effects of Statins - So what’s the deal?
In my search to see if HMG-CoA reductase inhibitors, in laboratory models, have ever been studied to see if they eliminate
Chlamydophila pneumoniae, I came up empty. Also, there are no data to see if statin therapy is more effective in those seropositive for
Chlamydophila pneumoniae compared with seronegative individuals.
OK, fine, maybe it is a bit far-fetched to say that there is, perhaps,
one lone organism causing all of atherosclerosis. There are likely
multiple factors that contribute, causing the endothelial injury that
starts the process, but infection probably plays a role somewhere along
the line. However, could you imagine if there was ONE predominate
infectious etiology? A potential cure for heart disease, stroke and
peripheral vascular disease could be developed!
I see a Nobel Prize
opportunity ... discover the real reason for the pleiotropic effects of
statins!
- by Steven Lome, DO, RVT
2019 Article
Thomas Platz
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