Statins and Muscles

     A number of readers have asked me about the recent article in the NY Times which quoted an online article in the Journal of the American College of Cardiology which discussed the adverse effects of statin use on skeletal muscle.

     To begin with, there is a molecule called Co-enzyme Q (or Q-10) which lines the inside of the membrane of mitochondria. A mitochondrion is an organelle inside a cell where ATP, the source of the cell's energy is generated. There are many mitochondria in muscle cells, for obvious reasons. The electron chain to create ATP must pass through Co-Q, so that in the absence of Co-Q the cell can generate no energy. Finally, one side effect of the use of statins is the reduction of the amount of Co-Q in the body. Another side effect of statins is muscle aches and occasionally elevation of CPK, which indicates muscle damage.

     The study involved a study of overweight men and women, who did no exercise, and satisfied the criteria for the metabolic syndrome. They first did a stress test and underwent a muscle biopsy. Then one-half of the subjects were given a daily dose of a statin, and both groups underwent supervised exercise for 45 minutes five times a week. After 12 weeks, repeat stress testing and muscle biopsies were done.

     Now we already have evidence that exercise and statins lower cholesterol, and lower the death rate in patients with dyslipidemia. There also was an article in this year's Lancet (Feb. 2, p. 394) that showed that in veterans with dyslipidemia both exercise and statins  lower cholesterol levels and reduce mortality, and the effect of exercise plus statin was greater than either modality alone.
After the 12 weeks, the non-medicated group had increased their physical fitness, but the medicated group did not. The energy enzyme levels in muscle mitochondria increased in the non-drug group and decreased in the drug group.

     What does this all mean? Since we do not know the precise mechanism(s) by which exercise lowers the death rate, the study cannot be interpreted. One would have to look at the death rate or heart attack rate of both groups, and since this is a group with no history of a heart attack, we would probably have to wait five years to detect a possible difference in outcomes. In other words, we know that exercise is beneficial for cardiac health, and the fact that statin use apparently prevents an increase in aerobic fitness does not mean that exercise plus statin use is no better than either treatment alone.

     Just as lack of exercise and elevated cholesterol are separate risk factors for heart attacks, and together they are synergistic in increasing one's risk, so are statin use and exercise synergistic in preventing such an event.

Cholesterol, Statins, Zetia,Niacin, ASCVD, and MI's

This blog was stimulated by several recent articles and studies about statins, zetia, Niacin, ASCVD, and MI's. We must not lose sight of the fact that virtually all researchers have concluded that an MI is triggered by the rupture of an atheromatous plaque in a coronary artery, although the actual rupture has not, I think, ever been seen dynamically. Nevertheless, when a coronary artery is found clotted off at autopsy, and the clot is adjacent to and newer than the plaque, and the surrounding tissue is necrosed, then the conclusion is probably correct.

The first fact to notice at such an autopsy is that the atheromatous-clotted artery, as a rule, has a larger diameter anatomically before and after the clot than does another coronary artery. In other words, the probability of a rupture-to-clot process does not seem to depend vitally on the pre-clot diameter, although there is, of course, some influence. Just recall how many times an artery with 97%-99% stenosis is not occluded, but is stented instead.

So we then come to the question: what causes (or prevents) the plaque in a coronary artery from rupturing, clotting off the artery, and causing an MI? Clearly there must be some degree of inflammation which sets the plaque up to be susceptible to the shearing force of coronary blood flow. So we can have some equation that the probability of clot formation varies as (C)x(probability of plaque)x(?thickness of plaque)x(probability of rupture), where C is a factor to indicate that an MI has occurred before; if C=1 we are dealing with primary prevention, and if C is greater than one, we are dealing with secondary prevention.

Since we have plenty of data on secondary prevention, I am going to concentrate on primary prevention. Now CRP, a measure of inflammation, has been variously correlated with the risk of MI as has 81 mg/day of ASA, with no clear-cut primary prevention shown by either lowering CRP or by daily ASA. But in experimental physics we have a saying: If you are arguing about the significance of data, then the data is not significant, similar to the last data point in a particle physics experiment.

We do know that diabetes, cigarette smoking and hypertension are synergistic with cholesterol levels in causing a plaque as well as a clot. This shows at least two mechanisms at work, since it is difficult to imagine that hypertension increases local plaque inflammation. Similarly Zetia, which lowers cholesterol, does not seem to increase coronary artery diameter, but these studies did not look at MI or CVA as an endpoint, so we don't know if Zetia affects plaque inflammation and rupture. A curious observation is that if your "native" cholesterol is 200, your risk of an MI is greater than if Crestor was used to lower your native cholesterol from 240 to 200. This clearly indicates to me that statins have an additional preventive effect, probably lowering inflammation of the plaque, over and above lowering cholesterol and/or reducing the size of the plaque. Similarly Niacin, which raises HDL, has a beneficial effect beyond its size effect, and probably lowers inflammation as well. And patients (usually female) with cholesterols over 300 and 85+ years old without and ASCVD are outside our explanations and models.

But to me, the most amazing drug is C2H5OH, or ethanol. In matched pairs, people who drink "moderately" (= 1 drink/day for men, and one every other day for women) have a lower heart attack rate and LARGER DIAMETER CORONARY ARTERIES AT AUTOPSY than do non-drinkers. This result holds for numerous studies with whiskey, beer, slivovitz (plum brandy), scotch, etc,in homogeneous populations (e.g.native-born Japanese males in Hawaii) and seems to be a pure alcohol effect. We have known this since 1974 (see article in JAMA). No one knows the mechanism by which this occurs, but I assume constant research is going on. Since young people already have atheromatous plaques, then if we want to reduce heart disease in our older population, it seems to me we should encourage a glass of wine with dinner starting with high school seniors. There is no argument in the literature about this effect, as there is about lowering CRP, adding ASA, or lowering salt in the diet.

With regard to lowering salt in the diet, there were two long articles (one pro and one con) about this subject published years ago in Lancet. The con argument was that just as eating sugar will not make you a diabetic, so will eating salt (with normal kidney function) not give you hypertension. I have a more fundamental ethical objection to imposing salt reduction. In hospitals and research clinics, when an experiment is performed on human subjects, it must be passed by the Institutional Review Board, and each subject must be warned of possible negative side effects and given a chance to withdraw. No such board will review the law if low salt diets are mandated, and I am concerned that 10 years down the road we may learn that we have done irreversible harm to the subjects, our fellow citizens, or to the children in school cafeterias.