Friday, January 22, 2010

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.

Friday, January 8, 2010

Mental Stress and Physical Discomfort

I have observed time and time again, that when your mind is stressed your body will start to hurt, or you will have some physical symptom. Mental stress almost always comes from doing something emotionally in a family situation, or physically in a non-work situation, that you do not want to do. As a rule, this is also connected with the thought of feeling guilty if you do not do the particular act, whether you want to or not. Boredom, for instance, is low-level anger,triggered because you do not want to be where you are (music concert, college class, visiting in-laws, etc. ), and typically occurs when you are doing something in a group/social situation where you feel you "have" to be. As you get older, you do fewer of these unwanted things, (a) because society puts less pressure on you, and (b) you feel more entitled to spoil yourself and be kind to yourself without feeling guilty or "selfish".

Your entire gut from the back of your throat to the top of your rectum is under autonomic control, i.e. the brain signals the spinal cord and the spinal cord signals the gut for digestion, peristalsis, and defecation. It is totally out of your voluntary control. Many of my working women, when they go away to a hotel on a business trip, are incapable of moving their bowels until they get home. Many men cannot relax enough to urinate when another man is standing at the neighboring stall. Many men also cannot get an erection when they are in bed with their wives if they have unconscious anger towards her. Most of my patients with irritable bowel syndrome have some degree of chronic stress or are suppressing anger or anxiety.

At the first and every annual visit thereafter I ask all my patients, male and female, the same two questions: (a) Do you look forward to going to work in the AM? and (b) Do you look forward to coming home at night? If I am seeing a non-working spouse, I ask a similar questions about the feelings when the other spouse leaves for work in the AM and returns home in the PM. I also ask teenagers if they look forward to going to high school (many girls and few boys do).

When it comes to school, many students see it as a form of jail. It is less of a problem with girls than boys, because girls seem to buy into the system at an earlier age. Hence, for instance, girls always have neater handwriting than boys do, because boys don't care. This persists into adulthood: in the hospital charts I can usually distinguish male student notes from female student notes by their penmanship. But it is not a matter of lack of fine motor control, or else men could not become watchmakers. As I often tell parents, many boys don't have ADD, but rather DGD (Don't Give a Damn) disease about school, especially when it comes to homework. Of course Adderall, Ritalin, coffee, and most other CNS stimulants help everyone focus better and do better on SAT's.

Men have a slight advantage in that most of their stress is work-connected, and therefore has finite boundaries. Women, however, feel responsible for the happiness of the whole family, and often feel guilty and responsible if any family member is unhappy. In general, I have found that if a daughter gets a divorce, the father feels sorry for her, and the mother wonders what she (the mother) did that was wrong in raising her. Often, if the husband has a problem with his mother, the wife takes care of all the social interactions with her mother-in-law, even when the wife has problems with her as well. Men seem to get a free ride away from many of the emotional stresses in the family: as Jerry Steinfeld infamously put it "We men are expected to be shallow.".

True love is overwhelming, and therefore makes parents and governments alike equally nervous, because they realize they are powerless to control it. Forget about Romeo and Juliet, or how Lancelot's and Guinevere's mutual love wrecked King Arthur's Court. If Julius Caesar had not been in love with Cleopatra, the history of the Roman world would have been different. Similarly with Marc Antony and Cleopatra, and King George of England and Wallis Simpson.

I leave the question of King David, Bathsheba and Uriah the Hittite to biblical historians, and just note it in passing. When teenagers fall in love, they see only the immediate present and their utter happiness, while the parents look 20 years down the road, and worry if their new in-law will fit properly into their society, both economic and social. For my married patients who are totally in love, the rest of the world always takes second place, and those who are not completely in love never quite "get it". Those totally in love seem to awaken every morning and say to themselves: "How can I spoil my loved one and myself today?", and never feel selfish about so thinking.

The anger at being "forced" socially to do what one doesn't want to do builds up slowly, but is more present than we allow ourselves to recognize. Every time you say to yourself I "should" do something, it is really the outside world, society, or your family (usually your parents) saying it. Men can partially discharge the anger through physical outlets, physical aggression or getting drunk, but women are more likely to suppress the anger, since anger is not a socially acceptable emotion for most women, and was probably discouraged from early childhood on, until the suppression of anger became automatic and internalized. The female child also starts to feel de-legitimized and ego-dystonic by being told that she should not feel a certain emotion. Suppressed anger almost always leads to depression. This is probably why almost all surveys show that single women are happier than married women, since married women are burdened by more social "shoulds".

Since many fatigue and pain states have an emotional basis, the next time you feel tired, or yawn, or feel bored, or have pain, or a GI upset, or a sore back, etc., try asking yourself: "What is stressing me? What am I doing or planning to do that I don't really want to do?". Then tell yourself that you are not being selfish if you protect your mental and emotional peace, and refuse to do or stop doing the unwanted action. If someone else is involved, and he/she really cares about you, they would want you to do what you want to do, wouldn't they?