Cholesterol, Statins and Heart Attack

  Ischemic heart disease (IHD) is a condition whereby the heart muscle receives insufficient oxygen for continued healthy function, due to arterial blockages that prevent oxygenated cells from getting to their destination. The result is what is commonly called a heart attack.

As researchers examined those who died of IHD-related causes, what they often found were arterial cholesterol buildups that had become so large they blocked blood flow in the vessel. Cholesterol became public enemy #1 and reducing the amount in the blood became accepted as the way to avoid IHD.

Now, that is gospel. So much so that pharmaceutical research has been almost entirely devoted to developing drugs that block the body's production of cholesterol, the most common of which are a class called statins. Statins such as Lipitor®, Zocor®, Crestor®, Vytorin®, the now discredited Baycol®, and others all work in basically the same way. They're mevalonate inhibitors. Simply put, they attack the weak link in the cholesterol synthesis chain, by inhibiting the enzyme that activates cholesterol production inside the cell.

And they work. They both lower serum cholesterol and are proven to be effective in preventing heart attacks. Thus, statins have become the most prescribed (and profitable) drugs in the country, with tens of millions of Americans regularly taking them. Case closed.

Or is it? As the anti-cholesterol era progressed, a few open-minded researchers began to question whether cholesterol buildup on arterial walls might be a symptom, rather than a root cause. To put it another way, is excess cholesterol a bad thing per se, or is the actual bad thing some underlying condition that causes the cholesterol to stick?

Before answering that question, a brief side trip into physiology is necessary. Many people have the mistaken impression that cholesterol is some evil, alien substance that we'd do much better without. Not so. It is present in every cell of our bodies. Its functions are numerous, and still not fully understood. Suffice it to say that without it, we wouldn't be alive.

Cholesterol is produced naturally by the body, as well as being absorbed from food. Generally lumped under the term are triglycerides, low-density lipoproteins (LDL--the "bad" cholesterol), and high-density lipoproteins (HDL--the "good" cholesterol).

Despite the labels, all do important things. The problem arises, according to conventional wisdom, when LDL levels become too high, and the elimination function performed by HDL breaks down. The excess LDL is not passed back through the liver, it clogs blood vessels, and it begins to coagulate and clump within them. But why should it? Furthermore, why is it that the majority of heart attack victims have normal cholesterol levels?

Those are key questions. Increasingly, the focus is shifting away from the cholesterol itself and onto chronic inflammation of the arterial walls.

Inflammation is a killer. It can weaken blood vessels until they rupture, causing a heart attack (or stroke), regardless of cholesterol levels. It can also result in the weakened sites latching onto passing cholesterol molecules in the body's attempt to repair the damage, thereby initiating the process that ends with a cholesterol blockage.

Thirty years ago, at Harvard Medical School, research pioneer Dr. Kilmer McCully was looking for a better marker for heart attack risk by linking high levels of the inflammation-causing amino acid homocysteine to the disease. McCully's views were out of the mainstream at that time, and it would take until the late '90s for the profession to catch up, as homocysteine finally came under broad scrutiny.

Inflammation theory got another big boost in 2003, when a massive longitudinal study at Boston's Brigham and Women's Hospital was published in the New England Journal of Medicine. It showed that the presence of a compound called C-reactive protein (CRP), a substance manufactured by the liver in response to the presence of inflammation in the body, was the best predictor of heart attack and stroke risk.

In this context, we can return to a consideration of statins. Suppose that their efficacy in reducing the risk of heart attack is due not to the fact that they inhibit cholesterol production, but to their powerful anti-inflammatory properties. That's precisely the conclusion reached by Dr. Duane Graveline, a flight surgeon and original NASA scientist/astronaut, who has been studying the subject for years.

Well, what does it matter? one might reasonably ask. If the drugs decrease the risk of heart attack, what's not to like?

As with all drugs, the answer is that there are trade-offs involved. No one knows the extent of them yet. The inhibition of mevalonate, for example, involves more than just cholesterol suppression, since it's a precursor of other substances with important biological functions.

What is known is a list of side effects associated with statins. According to Swedish researcher Dr. Ulle Ravnskov, these include fatigue, muscle soreness/weakness, peripheral neuropathy of the legs, short temper, aggressive behavior, and (rare) muscle problems leading to kidney failure. Pregnant women should avoid statins because of the likelihood of birth defects in their newborns.

Perhaps most disturbing is the possibility that statins may interfere with cognition. While reports linking the drugs to such disorders as transient global amnesia and other Alzheimer's-like symptoms are anecdotal at the moment, there is real cause for concern.

In a landmark 2001 study by Dr. Frank Pfrieger et al, of France's Centre de Neurochimie, the group discovered a link between brain cholesterol metabolism and nerve cell development, learning and memory. Cholesterol proved to be the heretofore elusive factor responsible for the development of synapses, the contact sites between adjacent neurons in the brain. We can't think properly without cholesterol.

Now, here's the rub. Cholesterol circulating in the bloodstream is unavailable to the brain; both LDL and HDL are too large to pass the blood/brain barrier. Cholesterol needed by the brain must be manufactured on-site.

Statins, however, do pass the barrier and enter the brain, where, it is reasonable to assume, they exercise their proven ability to inhibit cholesterol production. A scary possibility.

Dr. Graveline suggests that dosage levels be reconsidered. The relatively high dosages of statins required to lower cholesterol may not be necessary if the drugs' protective qualities are actually due to their anti-inflammatory action. A smaller, and far less risky, dose may work just fine.

And who knows, future generations may marvel that we spent so much time and money developing ever more sophisticated cholesterol inhibitors when all we really needed was the simplest, least expensive anti-inflammatory of them all, aspirin.

Posted 01-23-2007 5:10 PM by DougHornig