Acid Inhibitors and Vitamin B-12

     There were many news articles published after a report printed in the Journal of the American Medical Association ( JAMA volume 310, no. 22, pp 2435-2442, December 11, 2013) about the link between stomach acid suppressors and a deficiency of Vitamin B-12.

     Vitamin B-12 is unusual in that it is only found in animal cells, since it is needed to make animal DNA, but not vegetable DNA. Furthermore, the stomach secretes a chemical, called intrinsic factor, which attaches to the Vitamin B-12 molecule and facilitates its absorption by the intestine. As we get older, the stomach secretes less intrinsic factor, so elderly people are more likely to develop a deficiency, which can lead to a reversible anemia, and irreversible neurological defects. 

     Studies in Sweden have shown that if you  swallow enough Vitamin B-12, say 1 mg/day, then you will absorb sufficient vitamin to avoid a deficiency, even in the complete absence of intrinsic factor. So all that a patient on a proton pump acid inhibitor or an H-2 blocker to suppress stomach acid needs to do is to take 1mg/day of Vitamin B-12. The B-12 level should still be checked, but this OTC dose should be sufficient to prevent any problem.

Statins Part 2

     Recently, the American Heart Association and the American College of Cardiology came out with new recommendations for the use of statins. As always, there was no minority report, and some physicians quit the advisory panel because they could not agree with the final recommendations. The important point is that the new recommendations look at patients as more than just their cholesterol numbers.

     The recommendations are quite simple. There is a recommendation for the use of statin therapy based on the patient's medical condition, and there is NO target number to which the total cholesterol or LDL cholesterol should be lowered. Also, Zetia is never recommended since there is no evidence that Zetia, despite lowering cholesterol, can lower the heart attack or stroke risk. There is something that statins do, perhaps related to their anti-inflammatory effect, that does lower these two risks.

     The first recommendation is an emphasis on the Mediterranean diet, which involves increasing one's intake of vegetables, fruits, and whole grains, low fat dairy products, poultry, fish, legumes and nuts, and limiting the intake of sweets, saturated fats, and trans fats.

     High intensity statin therapy is recommended for individuals who have ASCVD and are younger than 75 years, and for those who have had a heart attack. The importance, again, is in prescribing statins, and not aiming for a target number for total cholesterol or LDL cholesterol. Just giving a statin seems to be sufficient to give protection.

     If high intensity statins cannot be tolerated because of muscle cramps, etc., then the dose should be lowered, but in this high risk group, a statin is mandatory.

     If your LDL cholesterol is 190 or higher, then again high dose statin therapy is recommended for any age group.

     If you have diabetes, then moderate intensity statin therapy is recommended between the ages of 40 and 74.

     Using tables which are available in the literature, if your 10 year ASCVD risk is 7.5% or more, and you are between the ages of 40 and 75, then you should be given moderate or high dose statin therapy.

     The overall message is that if you are at risk for a heart attack you should be taking a statin at as high a dose that can be tolerated. Again, the target numbers for cholesterol and LDL cholesterol are no longer used (except that an LDL cholesterol of over 190 should be treated). No longer should an attempt be made to get the LDL down to 70 or 100, etc.

   

   

   

Calcium

     There have been many studies and much written about calcium supplements as well as calcium plus Vitamin D and the amount of calcium in one's diet. There was an excellent review article about these matters recently published in the New England Journal of Medicine (NEJM vol. 369, pp 1537-1543, October 17, 2013) and I thought I would summarize the article here.

     First let me say that the interaction between Vitamin D and calcium is not completely understood. It is also not true that calcium supplements can  reduce age-related bone loss and the susceptibility to fracture, assuming that one has a diet adequate in the RDA of calcium. (One study did show that taking 800 IU of Vitamin D would achieve this goal.) There is therefore insufficient evidence to recommend calcium supplements in community-dwelling adults.

     The RDA of elemental calcium is 1000 mg/day for women up to age 50, and 1200 mg/day thereafter. For men, the RDA is 1000 mg/day up to age 70 and 1200 mg/day thereafter. Most people receive at least this much in their diet. The largest calcium contribution comes from milk and milk products such as yogurt and cheese. The best vegetable for calcium is raw kale, and the best fish is sardines, followed by pink salmon. Another source of calcium is fortified cereals.  Diets containing less than 700 mg/day of calcium can lead to bone loss.

     The recommended upper limits of ingested calcium is 2500 mg/day in women up to age 50 and 2000 mg/day thereafter. For men The same limits apply at the same ages.

     The most common supplements are calcium carbonate (Tums is an example of this) and calcium citrate. Calcium carbonate requires stomach acid to be absorbed, so this pill should be taken with meals, while calcium citrate may be taken at any time. The most common side effect of calcium is constipation and bloating. Some studies show that additional calcium increases your risk of developing kidney stones, and other studies show that it reduces your risk.

     It is important to note that bone meal, oyster shells and dolomite may contain lead, and therefore should not be consumed by pregnant women.

     There was one study showing that calcium supplements can increase one's risk for prostate cancer, and a larger study showing that it did not. There have been studies showing that calcium supplements increase your cardiovascular risk, as well as studies showing that it does not increase your risk, and there has been a good deal of discussion about these conflicting studies. I generally feel that if you have to argue  about the significance of data or a result, then the result is not significant.

   

 

   

   

Exercise is Good For You

     A very interesting meta-analysis was published online in the British Medical Journal by H. Naci (BMJ 2013:347:f5577) this month. It compared the benefits of drug therapy vs.exercise in the secondary prevention of new or worsening conditions in 4 diseases: coronary heart disease, stroke, heart failure, and adult-onset Type II diabetes. They disallowed studies in which both drugs and exercise were prescribed and  because a head-to-head study of exercise vs. drug therapy was the desired goal.

     It is well-known and documented that exercise has health benefits. There is an enhanced quality of life, fewer hospital admissions, and enhanced all-cause mortality in those who exercise. The study here reviewed meta-analyses to try to compare the benefits of drug therapy vs. exercise in mortality.

     The author reviewed 4 sets of patients: those receiving a statin for elevated cholesterol, those receiving a diuretic for chronic heart failure, those receiving anti-coagulation because of a stroke, and those receiving metformin or a similar drug for pre-diabetes. Over 339,000 patients in over 350 meta-analyses were reviewed.  The results can be simply summarized, but should not be taken as a reason to stop medication.

     No difference was found in mortality for secondary prevention of heart disease between drugs and exercise in patients with elevated cholesterol.

     No difference was found in mortality or progression to full diabetes between drug therapy and exercise.

     There was a slight advantage in exercise rather than anticoagulation or anti-platelet therapy in patients with a stroke.

     But diuretics were definitely superior to exercise in patients with chronic heart failure.

     The conclusion would seem to be that if you have any of these four conditions, be sure to start exercising if you are not already doing so, For further details, the full report is available online, whether or not you are a subscriber to the British Medical Journal.

   

   

   

   

Anti-inflammatories, Heart Attacks, and GI Bleeding

          This blog is based on an article that recently appeared in Lancet, vol. 382, pp779-789, Sept. 6, 2013. The article was a meta-analysis (and see my previous blogs on the problems inherent inj meta-analyses) of over 700 studies that looked at the relationship between anti-inflammatory drugs, heart attacks, and GI bleeding. (Recall that Vioxx was taken off the market because of an increase in heart attacks and strokes.)

     A little biochemistry is in order. There are two enzymes released by platelets that synthesize prostaglandins, called COX-1 and COX-2 for short. COX-2 prostaglandins mediate pain and inflammation, and COX-1 prostaglandins protect against GI bleeding, especially in the stomach. Aspirin blocks the production of both enzymes irreversibly, which is why aspirin is used to prevent strokes and reduce pain and inflammation,  and can cause GI bleeding. The studies looked at NSAIDs such as ibuprofen (Advil, Motrin), naproxen (Naprosen, Aleve), and diclofenac. These NSAIDS block both COX-1 and COX-2. The studies also looked at anti-inflammatory drugs such as Celebrex that only blocked COX-2,(called coxibs), and therefore did not increase the risk of GI bleeding.

     The study showed that all NSAIDs increased the risk for GI bleeding, but in no case were acid-blockers such as Prilosec and Prevacid used, which would have decreased the risk. The surprising result was that not only did coxibs increase the risk of heart attacks by one-third, but that all the NSAIDs except Aleve did as well, so that Aleve is the safest from a vascular point of view. Unfortunately, naproxen also had the highest risk of GI bleeding.

     Thus the safest anti-pain and anti-inflammatory drug would appear to be Aleve, but an acid-blocking drug should be taken with it to reduce the risk of GI bleeding.

Men, Testosterone, and Estrogen

     There was an article published recently in the New England Journal of Medicine ( Vol 369, pp1011-1022, Sept. 12 2012) about the effect on men of testosterone and estrogen suppression. It was only a 12 week study, but the results are interesting. I will summarize the study here.

     Firstly, I should mention that the male production of testosterone decreases slowly with age. This actually means that even an "normal" level of testosterone at age 60 is abnormal in the sense that it is diminished from the level at age 20. All men have an enzyme that converts some testosterone to estradiol, an estrogen, and this conversion provides 80% of the circulating estradiol. (I should also mention here that in addition to estrogen and progesterone, all women secrete testosterone.) There are also studies showing that one of the causes of diminished sexual drive in menopausal women is a reduction in their testosterone level, so that estrogen replacement alone may not be enough to restore their sex drive. This was shown initially by a female OB-GYN in Canada.

     The experiment reported in the NEJM showed the effects of chemical castration which eliminated testosterone production. Some of the men also received a drug to inhibit the production of estrogen when the testosterone level was allowed to rise. The results of this climical study can be summarized as follows:

     Testosterone directly regulates lean mass,  muscular strength and sexual function. Testosterone deficiency decreases lean mass, muscle strength, muscle size and sexual function. Low estradiol also contributes to loss of libido and sexual function. Interestingly enough, low estradiol also contributes to increased abdominal fat, and possibly to osteoporosis as well.

     The increase in abdominal fat is medically worrisome, because this increase is associated with resistance to insulin (i.e. to pre-diabetes) as well as the metabolic syndrome. But the solution to low estradiol should not be estrogen replacement, because that was tried with men with prostate cancer and they developed severe cardiovascular problems. 

     The message I take from this study is that after replacing testosterone when necessary, then the estradiol level should be measured. If that level is still low, then the testosterone dose should be increased to normalize the estradiol level and thereby decrease the risk of the patient's developing the metabolic syndrome. It is also trivial to add that menopausal women should have their testosterone level measured. 

    

Mammograms and Breast Cancer

     There has been much confusion and differing recommendations about how often women should get mammograms. Different groups and different countries have different recommendations, all of which are backed by "data". It is very confusing to read all the recommendations and then try to make a decision for oneself.

     The conflict arises, in part, from the difference between making recommendations for one million people and making a recommendation for one individual. If a mammogram shows breast cancer, then the payoff for the individual is 100% in that the breast cancer was detected.All  recommendations from different groups rest, in part, on prior assumptions, so that two groups can look at the same data and arrive at different conclusions.

     Right now the British recommend one mammogram every 3 years between the ages of 50 and 70. The American College of Radiology and the American Cancer society recommend annual mammograms from age 40.  Finally, the US Preventive Services Task Force recommends biannual screenings between the ages of 40 to 74, and the American College of Obstetricians and Gynecologists is not sure if screenings should be annual or biennial. And none of the groups has a  firm recommendation on the benefits of breast self-examination. I should also mention that to my knowledge, no one has compared the possible benefit of a screening mammogram every 6 months vs. once a year.

     The patient should make the decision, of course. With varying recommendations, one will generally pick the one that suits their needs the best. The only caveat is: if a mammogram shows cancer will you blame yourself for not having had one sooner?

     The bugbear is the damage caused by false positive mammograms and unnecessary biopsies. But the people making the recommendations do not, as a rule, discuss false positives with their patients. And the majority of patients would probably risk a negative biopsy in their search for a true one. It
 seems to me that once again we should yield to the patients' views, after outlining the recommendations of the different groups. And I do with that there had been a study comparing semi-annual memmograms with annual mammograms in high risk patients.

Coffee, Chocolate and Your Heart

     There have been three studies released recently, dealing with the effects of coffee, coffee and tea, and chocolate on the heart. The studies variously showed a small reduction in both systolic and diastolic blood pressure or a reduced risk of heart failure. Once again, these studies are suggestive, but larger and more complete studies are necessary to reach a firm conclusion. And let us not lose sight of the fact that none of the studies showed the consumption of coffee or tea or chocolate to have a deleterious effect on heart function or blood pressure. The benefit of chocolate is presumed to be the result of flavanol in the chocolate; this compound increases the formation of nitrous oxide and thereby dilates the arteries ( much as Viagra does).

     One study was done by Dr. Karen Ried of the University of Melbourne, Australia. This was a review of 20 short term studies involving over 900 volunteers. The studies lasted 2 weeks, 8 weeksa, or 18 weeks.They ate 100 gm of chocolate daily, and averaged a 3mm drop in systolic pressure and a 2mm drop in diastolic. One study showed a drop of 4mm and 3 mm, respectively. This is the same effect you would see from daily exercise or a heart-healthy diet. The control group showed no such decrease. The article also mentioned the Kuma Indians of South America who average 4 cups of cocoa a day and have remarkably good blood pressure.

     Another study was a meta-analysis of 5 studies. There was a j-shaped curve relating the consumption of coffee to heart failure. The biggest "protection" against heart failure came with those who averaged 3 to 5 cups of coffee a day. The results of this study might make one reconsider the recommendations against coffee consumption in certain patients.

     The final study was a French retrospective analysis of over 175,000 patients ranging in age from 16 to 95 years with regard to their consumption of tea or coffee. They subdivided the patients into 3 groups: no coffee or tea, one to four cups a day, and more than four cups daily. In those drinking 1-4 cups a day, there was a small decrease in systolic blood pressure, in pulse pressure, and in pulse rate. The effect was small, but it is suggestive.

     To me the take away message from these studies is that there is no evidence that the consumption of tea, coffee or chocolate is detrimental, and it may in fact be beneficial.



    

NSAID pain pills and heart disease

     Recently there was an electronic pre-publication ahead of print by Lancet, the British medical magazine. The article (and the accompanying editorial) discussed the result of a meta-analysis (and see my prior blogs for the errors inherent in meta-analyses) of 639 randomized trials of Cox-inhibitors (such as Celebrex) and NSAIDs (ibuprofen or Motrin/Advil, naproxen or Aleve, and diclofenac or Voltaren) to see if their use (a) caused increased upper GI bleeding and/or (b) increased vascular events (heart attack, heart failure, stroke). You may recall that Vioxx, a cox-inhibitor, was taken off the market because of an increased incidence of cardiac events.

     The results were first announced as an increase in relative risk, which always looks worse than the increase in absolute risk. The studies looked at the effect of either a standard dose of a coxib, or a high dose (150mg diclofenac, 2400mg ibuprofen, 1000mg naproxen). The studies looked at major vascular events (heart attack or stroke), heart failure, overall mortality, and upper GI complications.

     There was an increase in major vascular events of 33% with the use of  Celebrex and Voltaren. There was also an increased risk with Motrin, but it did not reach clinical significance. There was no increased risk with Aleve. OTOH, the use of Aleve was associated with the greatest risk of upper GI bleeding compared with the other three drugs. And only coxibs showed a statistically significant rise in all-cause mortality.
In the case of vascular events and upper GI bleeding, the greatest risk factors were age, and conditions (diabetes, hypertension, GERD) that pre-dispose to a problem.

     Now for the absolute numbers, which illustrate the real risk. Using a coxib or diclofenac was associated with 3 additional vascular events per 1,000 person years, one of which was fatal. If a patient had a 2% annual risk of a vascular event, then a coxib would add 7 additional events per 1000 patient years (2 of which would be fatal), Voltaren would add 8 (2 fatal), and Advil would add 9 (3 fatal).

     In patients with a 0.5% annual risk of upper GI complications, coxibs and diclofenac would add 4 more events per 1000 patient years, ibuprofen 15 more events, and naproxen 16 more.

     All four drugs showed a statistically significant increase in hospitalizations due to heart failure.

     Once again, we see that the absolute risk seems less serious than the relative risk, as is almost always the case. Also, no studies were done at a lower dose of the drugs, and no studies were done to see if the addition of a PPI or other acid inhibitor lessened the risk of upper GI complications.

     The data thus shows a small but statistically significant risk with some of these drugs to cause problems.
These problems occurred more frequently in high risk groups, and you should discuss with your doctor which group you fall into. To my mind, the data is barely significant, and the use of these drugs is a judgment call, and one has to compare quality of life to statistical risk.

Coenzyme Q-10

     After I mentioned the effect of statins on muscles and referred to coenzyme Q-10, I have received a number of questions about this ubiquitous molecule,  so I thought I would answer a few of them here.

     Coenzyme Q-10 is contained in animal foods that we eat, but over 90% of this molecule is synthesized in the body. Curiously enough, it shares a common molecule with the synthetic process for cholesterol. The subscript "10" refers to the number of side chains. This is important, because lab rats synthesize and use Co-Q-9, which is chemically different, so the results with lab rats should not be extrapolated to human use. Your tissue level of CoQ decreases with age, chronic heart failure, diabetes, some cancers, and HIV, but adding CoQ to the diet has not been shown to benefit any of these conditions. It will, however, help protect the heart from the side effects of doxorubicin, an anti-cancer drug, and does help the immune system of lab rats.

     As I mentioned in my earlier blog, CoQ is a vital molecule for the electron transport chain that lets the cell generate aerobic (requiring oxygen) energy, which accounts for over 90% of the body's requirement. No other molecule in the body can do this job.The molecule was discovered in 1957, and is found in the membranes of many cell organelles, especially in mitochondria, the energy factories of the body. The molecule is fat-soluble,  and also has anti-oxidant properties as well as the ability to regenerate other antioxidants such as Vitamin E.

     Because the molecule is fat soluble, absorption is best when taken with food. A typical dose is 150 to 300 mg/day. It was found that it may help some migraneurs, and when taken with magnesium citrate and Vitamin B2 (riboflavin) help prevent migraine attacks in some patients. Because it shares a common molecule with the synthesis of cholesterol, statins, which reduce the level of cholesterol, also reduce the level of CoQ. Oddly enough, some beta-blockers also reduce the tissue level of CoQ.

     There are few studies that show any unequivocal benefit from taking CoQ-10. It does improve the immune system of lab rats, but not of humans. It also seems to protect lab rats from the damages of external radiation.The two interventional studies, one on patients with heart failure  and one on patients with breast cancer failed to show a significant benefit. Studies to see if CoQ supplementation increased the lifetime of lab rats led to contradictory results.
However, a meta-analysis (and see my previous blog for my critique of such studies) did show that Co-Q-10 lowered the blood pressure in humans, by as much as 15mm systolic and 10 mm diastolic, which is a very powerful result. No study has shown that Co-Q supplementation reverses the decrease of CoQ caused by statins.

     In summary, coenzyme Q-10 is a vital molecule for energy generation, and we are busily looking for a clinical use for supplemental doses.  I am looking forward to a double-blind study to validate its benefit in patients with hypertension, as well as  to see if it can prevent the muscle aches  and muscle breakdown that can develop with the use of statins.

   

   

Pancreatic Cancer, Pancreatitis, and Diabetes.

     There was an article last week (Friday, May 31) on the front page of the business section of the NY Times quoting an interview with a doctor who claims that he has evidence that a diabetes drug, Januvia, can predispose the users to pancreatic cancer, based on animal studies.

     First, let me say a few words about all drug/animal studies. Animals have very different biochemical milieus than do humans, and the results of animal studies may not apply to humans. As an example of the difference, every animal but man and the guinea pig have the necessary enzymes to synthesize ascorbic acid, or Vitamin C. So already their chemistry is different. It is not automatic that a drug that has effect A on animals will have effect A on humans, and vice versa.

     Several decades ago, Congress passed a law with the Delaney clause, saying that any food additive that caused tumors in animals could not be added to food for humans. Shortly thereafter it was found that saccharine caused tumors in mouse bladders. Since saccharine was the only synthetic sweetener then available, Congress immediately passed a law exempting saccharine. So even the lawmakers don't believe the animal-human link.

     The changes that Dr. Peter Butler found were "pre-cancerous" lesions in rats, and no one knows how many precancerous lesions progress or what the time frame is. Post-marketing surveys have found no increased incidence of pancreatic cancers in users of Januvia, but there is argument as to whether or not there is an increased incidence of pancreatitis. As I have said before, if you have to argue about the significance of data, it almost certainly is not significant.

     What are the risk factors for pancreatic cancer? Age, obesity, chronic pancreatitis, and diabetes. The link with diabetes is tricky, because often pancreatic cancer first makes its presence known by causing diabetes. No one has shown that alcohol consumption is a risk factor for pancreatic cancer, even though it is a risk factor for chronic pancreatitis, and chronic pancreatitis is "linked" to pancreatic cancer, but not shown to cause it if you parse the observational data. OTOH extrapolating from diet studies, the Mediterranean diet should be protective.

     In summary, since diabetes itself is a risk factor for pancreatic cancer, the proper study would be to compare two groups of diabetics, one of whom takes Januvia while the other does not. And these patients should have the same diet vis-a-vis red meat and vegetables. I wonder if chronic pancreatitis is a risk factor for pancreatic cancer in lab rats? If it is not, then such a result would invalidate the  extrapolation from lab rats to humans.

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.

Does Marijuana Prevent Diabetes?

     An article in this month's (May 2013) American Journal of Medicine shows that current users of marijuana have better glucose control than do former users, who in turn have better glucose control than do abstainers. This study was a retrospective one, and needs to be validated by a forward study. This will probably never happen, for obvious reasons, much as retrospective studies showing that cigarette smokers have a lower incidence of Parkinson's disease were never followed up.

     The use of marijuana was based on interviews with the 4657 members of the study; of this group 579 were current users and 1975 were prior users. Fasting glucose and insulin levels were measured, and the degree of insulin resistance was calculated. Diabetics and pre-diabetics both have insulin resistance.

     This study was triggered by prior studies showing  that marijuana users have a lower incidence of  both obesity and diabetes, but there have been no similar studies of THC users. Current marijuana users in this study were seen to have lower levels of fasting insulin, and were less likely to be insulin resistant. They also had higher levels of HDL cholesterol and smaller waist sizes. Past users (more than 30 days before the study questionnaire) also had a lower incidence of insulin resistance than did non-users, but not as low as did current users.

     The results of this study need to be followed up, but given the current federal law classifying marijuana as a Class I drug, meaning "no significant medical benefit", it is difficult to envision a prospective study being done.  One possibility might be in the state of Washington or Colorado, where marijuana was recently legalized. OTOH, perhaps the federal law could be changed to make it legal to treat diabetes and the metabolic syndrome with THC and to do a study of its effect.

   

   

The New Arabian Coronavirus.

     A new respiratory virus which has killed 18 of the 31 infected cases has arisen in Saudi Arabia, where teams of Arabian physicians, members of the World Health Organization, and infectious disease specialists from the United States are all investigating jointly. This virus is a coronavirus, the same type (but genetically different) of the virus that originated in Chinses poultry and became the SARS virus when it infected man. The disease has developed in clusters of people. In one Arabian cluster of 15 people infected with the virus, 9 died.  The most recent infection detected was in a man in France who inhabited the same hospital room as a person who returned from Dubai to France and was found to have the virus.

     The virus has a predilection for elderly people with underlying chronic medical conditions that might impair their ability to fight disease. There is some evidence for people-to-people transmission, but this connection  is weak and not 100%. For instance, only one doctor taking care of a patient has  developed the disease. But since there are 4 clusters of the disease, this is evidence for weak person-to-person transmission.

     At this point, we do not know the (presumed) animal reservoir of the disease. This disease has the potential to mutate and become much more infective and transmissible, which could create a weak epidemic or a strong pandemic. There is no antiviral currently on the market that treats this
infection, and efforts are just starting to sequence its genome and to develop a vaccine. There is not much more to say, except to recommending avoiding travels to areas in the Middle East where this new coronavirus has been found, as well as avoiding travels to areas of China and Taiwan where the new bird flu, InfluenzaA-N7H9 has been detected.

     I strongly recommend following ProMED,com, the daily e-mailing of the International Society of Infectious Disease (ISID) for up to date information on both viruses.

The New Asian Bird Flu

     I thought I would share some facts with you about the new strain of influenza A H7N9, that has arisen in China and probably comes from birds, although we are not 100% certain of that. There has, as yet, been no evidence of people-to-people transmission (unlike SARS which infected health care workers). Furthermore, although this flu strain is resistant to amantadine, it is susceptible to oral oseltamovir  (Tamiflu).

     As of the end of April, there have been 126 confirmed cases in China, and 24 or 19% died. Older people are more susceptible to both catching the flu and succumbing to it, especially if they have a chronic health problem. Cases have been found in eight contiguous provinces in eastern China as well as in Beijing, Shanghai and Taiwan. China is making prodigious efforts to learn all it can about the flu and the birds' contribution to it. The flu has been found in some chickens and ducks, but the flu virus is harmless to poultry, and birds  who are infected with the virus show no signs of being ill.

     Thankfully, in the over 1500 close contacts of sick patients there has been no evidence of the flu, so unless it mutates there is no risk of an epidemic or pandemic. Except for one pigeon, the virus has only been found in chickens and ducks for sale in marketplaces; farms seem to be exempt. Relatively few poultry are carrying the virus, and 20% of the people with the virus report no exposure to birds. Chinese physicians and technicians are making herculean efforts to track and to find the virus, as well as sequencing its genome, and are examining pigs as well as poultry.

     China has invited members from the World Health Organization as well as from our own Center for Disease Control to come and assist in their work. In addition, the CDC is monitoring patients here in the US for cases of Influenza A/H7N9, but so far have found no cases. There is not even the suggestion of facts or cases being hidden by China, so whatever you read should be accepted.

     In summary, the virus is mild and relatively rare in poultry,  but has a case fatality rate of 20% in humans, and while we think that poultry is the reservoir, we are not yet sure.

   

Red Meat, Carnitine, and ASCVD

     There was a recent article published in Nature Medicine that was picked up by the wire services and made its way into the mainstream media, including both the NY Times and the Wall Street Journal. Many readers have asked me to comment on the report. In what follows, again please remember that correlation or association is not causation.

     The article cited studies of 2950 patients undergoing cardiac evaluation, and found that increasing levels of carnitine correlated positively with the risk for stroke and heart attacks. Gut bacteria can convert carnitine to a compound called TMAO, and levels of this compound have been correlated with atherosclerosis in the past.In mice, TMAO inhibits the breakdown of cholesterol. Due to the absence of meat in their diet, vegetarians have much lower levels of carnitine than do meat eaters.
Based on other studies, TMAO may promote the growth of plaques in arteries, but the data is not solid. At this point, we do not know if there is a third molecule derived from TMAO that is also correlated with cardiovascular events.

     L-carnitine (carnitine is a stereo isomer and comes in both an l (left-handed) and d (right-handed) form, but as is usual with the human body, our enzymes recognize only the l form of amino acids. L-carnitine is a facilitator for the cell's use of fatty acids to obtain energy with the help of vitamin C via the citric acid cycle. The body can make carnitine as well as obtain it from food, which is not surprising since it is a necessary part of the energy cycle, and children born without the  ability to use carnitine suffer severe metabolic problems.

     The body has other uses for carnitine, and I will discuss a few. It has been shown in clinical studies that administering l-carnitine to patients with angina reduces the amount of cardiac medicine they need, and increases their chest pain-free exercise ability. The amount of carnitine in cells decreases with age,  which thereby diminishes osteocalcin which in turn promotes osteoporosis.
Oddly enough, one study suggested that carnitine can improve sperm quality in infertile men, and can also reduce the size of a variocele.

     Carnitine reduces fat mass and increases muscle mass, which is why bodybuilders take so much of it. Carnitine supplements appear to improve neurotransmitter functioning in the brain of elcerly patients. It was also found that l-carnitine levels were lower in children with asthma, and administering l-carnitine to these asthmatic children improved their pulmonary function tests.  L-carnitine is also a peripheral antagonist of thyroid hormone action.

     To summarize, increased l-carnitine levels in patients with increased TMAO levels was positively correlated with cardiovascular events, and further studies are definitely needed.

Interpreting Medical Clinical Studies

     It occurred to me that with so many reports of clinical studies quoted in the news, I should review this topic, or, rather, supplement my earlier blog which discussed  the difference between absolute and relative risk, or the validity of a verbal report as compared to a published journal article, among other topics.

     Let me begin by re-emphasizing that correlation is not causation, so that if people with disease A do or do not ingest substance B on a regular basis, this does not necessarily mean that you can reduce your risk of disease A by ingesting or refraining from substance B. However it is fair to say that if every study shows a correlation,(such as between smoking and lung cancer) then there probably is a causal relationship, bearing in mind that it is still possible that there is a common denominator of which we are unaware that links A and B. The classic example is the correlation between coffee drinking and coronary artery disease, where the confounding effect was that coffee drinkers were more likely to be smokers.

     There are two classic errors that can occur in a clinical study. A type I error is when the scientist mistakenly believes that the intervention has an effect on the incidence of the disease. A type II error is when the scientist mistakenly believes that the intervention has no effect. Most studies are designed to minimize and accurately define the chance of a type I error, and a positive study is generally statistically accepted if the probability of a type I error is less than 5%. This means that there is one chance in twenty that the conclusion is wrong, which is why I tell my patients to wait for a second prospective study. The chance of a type I error can never be zero.  A type II error is directly related to the square root of the number of people in the study, so that by including enough patients, the likelihood of a type II error can be made as small as you like (at an additional expense and inconvenience to the observer).

     There are two types of studies: retrospective and prospective. A retrospective study interviews people with disease A and compares the results with a matched set of individuals (matched as to age, sex, race, and/or other qualities as closely as possible). The study then tries to find differences in their past history between the two groups: did they go to graduate school, do they exercise, do they take Vitamin E, or whatever the scientist feels like studying. It is statistically fairer and more rigorously accurate if you specify in advance what action you are studying, rather than just do a blanket survey for differences. By the laws of chance, you are guaranteed to make a type I error if you survey all interventions. To be called an accurate marksman you must specify which leaf on the tree you are trying to hit before you fire a bullet into its branches and see that you hit a leaf.

     A prospective study can be defined so as to accurately calculate the chance of a type I or type II error. In this study, we take a matched set of patients, do intervention B on one set, and compare the incidence of disease A in both sets after a fixed time period, which may be as long as five years for a dietary intervention, and as short as 30 days if we are looking for the occurrence of a second heart attack after the first one. In this case we have definitely defined both the intervention and the disease for which we are looking.

     Most of the medical news with which we are bombarded has to do with retrospective studies, and we are assailed with the information that intervention A is good or bad for you based on them. A retrospective study should only be used to suggest a hypothesis, which then should be tested by a prospective study. Any retrospective study is filled with pitfalls, beginning with relying on the subject's memory of what he or she did or didn't do, e.g. the number of aspirin you took per week, on the average, over the past five years.  And then we have headlines such as "more coffee drinkers get pancreatic cancer" (subsequently shown to be untrue). But since every retrospective study shows that adult females who drink two or more cups of coffee a day have a lower incidence of adult onset diabetes, there probably is a causative link between the two.

     Be especially wary of the statement that more people who live in a certain area have more or less than the nationwide incidence of a disease. By the laws of statistics, the population of most counties or cities will have either more or less than the national average of almost everything. We don't even have consistent results comparing the lifespans of taller and shorter people, or right-handed people to left-handed people.

     When I read about the results of a retrospective study, I say to myself "Very interesting. I wonder what a prospective study would show". It has been my experience that most retrospective conclusions are not validated by the ensuing prospective study, and very often a second prospective study does not agree with the first. Lancet had back-to-back articles with opposite conclusions as to whether or not a low salt diet prevented hypertension.

     One last point. Often it is noticed that people with a certain medical problem (e.g. ASCVD) have an abnormal test (such as the CRP). We then jump to the erroneous conclusion that lowering the CRP will reduce the incidence of coronary artery disease, which conclusion has never been validated. My analogy to this is that pulling down on the metal floor indicator in the lobby of an office building will not bring the elevator down.

   

Drug Reps and Doctors

     Several non-physician readers have asked me questions about the relationship between drug reps and doctors, and between drug companies and doctors, so I thought I would set the record straight.

     Firstly, the major cost decision is when the doctor decides that the patient needs a new drug, e.g. a statin to lower cholesterol. The variation in price between two brands (or two generics) is generally less than 10%. The major cost comes from the doctor's deciding to prescribe the drug, and the drug rep has little or no control over that. Whether the doctor prescribes Lipitor, or Crestor, or simvastatin depends on many facts, mostly upon what the doctor has read. If he/she feels there is no difference among the statins on the market, then the decision is almost a random one. The point here is that the best a drug rep can hope for is to get the doctor to prescribe a particular brand of a statin, and the price difference between brand A and brand B is as I have said, not large. Again, let me emphasize that the medical decision that the patient needs a certain class of drugs is the major decision influencing the cost to the patient. For instance, if the patient has atrial fibrillation, then anticoagulation to reduce the risk of a stroke is usually mandatory.

     The drug reps are strictly limited by the FDA as to what information can be told to or given to the doctors. The rules are so strict that if a drug rep has highlighted a sentence in a journal article, then he/she can only hold the article up for me to read. It is forbidden to give me the article with highlighting because the FDA fears that drawing my attention to the highlighted sentence might unduly influence me. Another rule is that the drug company can only give as a  gift an an article that a non-doctor has no use for. They can give me reflex hammers or tuning forks or pocket eye charts, but no coffee cups or ballpoint pens(!). And if I have a question about the side effects, etc. of a drug, every company has a doctor's hotline whereby I can request information from the company directly. Alternatively, I can file a request for more information with the drug rep.

     The drug reps can invite the doctors to a dinner where another doctor is lecturing on the drug rep's drug. The slides are supplied by the drug company and the company's lawyers restrict the words the doctor can use. The doctor who gives the talk is paid for his/her speech but the other doctors are paid nothing, but the dinner is free.And doctors can no longer bring along their wives to the dinner, unless the wife also works in the office as an office manager, etc.

     There is a service that sells to the drug companies a list of all the doctors in a given area along with the number of prescriptions of the company's product a doctor prescribes in one or three months. The speakers at the dinner are chosen from doctors who are the heaviest prescribers of the medicine on which they are asked to speak, so paying them for the talk is  a post hoc decision, and does not induce the doctor to prescribe a drug that he/she  already heavily prescribes. The drug company only hopes the lecture will influence other doctors to prescribe more of the drug. After the talk, the doctors are free to ask questions to the speaker.

     Doctors who write published articles must post a disclaimer at the end of the article, listing all the drug companies for which they have given speeches, or been a consultant for, or received any remuneration from, so that readers are immediately made aware of any possible conflict of interest.

Calcium Supplements, Good or Bad?

     There have been several articles recently published in medical journals (JAMA, New England Journal of Medicine, British Medical Journal) about the possible risks associated with taking calcium supplements. The study groups are respected researchers, and include our own National Institute of Health. The studies addressed only  the question of calcium supplements, and not the impact on health of  a diet that was high in calcium.

     I must state in advance that one problem with the results of the studies, besides their contradictory results, is that we have no good explanation for their results. While this does not mean the results are not valid and true, this lack of reasoning as to cause and effect makes it more difficult to believe in the result. It is also puzzling why the two main studies found different effects in men and women, and the results of one contradicted the results of the other.

      The amount of calcium in your blood is very closely controlled by the body, and it is the ionized calcium, Ca++, a divalent cation that is the active form. Calcium exists in your blood both free as a cation and bound to serum proteins, and the aforementioned studies did not measure calcium levels. Because magnesium also exists as a divalent cation it often precipitates out in laboratory processes  along with calcium, which led to the belief that the use of a supplement that contained magnesium as well as calcium was beneficial; no such result has ever been shown to be valid. However, since calcium is mildly constipating and magnesium is a mild laxative, combining the two elements into one pill makes theoretical clinical sense. Strontium is also a divalent cation, and unfortunately can be taken up by your bones along with calcium, which explains  some of the bone marrow cancers induced by the radioactive strontium fallout from an atomic explosion.

     The calcium levels are controlled by parathyroid hormone, which also activates Vitamin D into its useful form and thereby promotes the uptake of calcium by your bones both directly and indirectly. As a rule, the amount of calcium in your diet does not affect the level of calcium in your bloodstream. It is generally agreed that the calcium in your diet should contain between 600mg to 1200mg of calcium daily, along with 400 Units of Vitamin D, in order to maintain bone strength and prevent osteoporosis because activated Vitamin D promotes the absorption of calcium from your gut. We also know that ingesting too much calcium if you have chronic kidney disease can promote calcification of the arteries in your body, probably because kidney failure induces a state of secondary hyperparathyroidism, but a further discussion of this condition is beyond the scope of this article. Parathyroid hormone also increases the absorption of phosphate from your intestine which makes clinical sense since the largest mineral constituent of your bones is hydroxylapatite, which contains both calcium and phosphorous.

     Now as to the studies. The question asked was whether or not taking calcium supplements (1000 mg or more in men and 1400 mg or more in women) had a benefit on the patient's health. One study showed an increase in overall mortality, and cardiovascular mortality as well as in heart attacks,  but not in stroke. This increase in mortality was shown to exist in men, but not in women. Another study, published at about the same time, showed a similar increase in overall and cardiovascular mortality in women, but not in men(!).In each study the control group was same-sex patients who did not take calcium supplements.

     So what are we to believe? There even are no clear-cut studies showing that calcium supplements prevent osteoporotic fracture; in fact some studies show an opposite result. (But taking extra Vitamin D at a dose of 800 mg/day does seem to prevent such fractures.) It is difficult to recommend calcium supplements in view of the above quoted data. It would be useful to have  a study that measured calcium levels in people having heart attacks were it not for the fact that no one knows whether or not a MI acutely affects calcium levels. And it would seem heartless to tell the patients to read all three studies and to make up their own minds. I think that because no study showed by clear-cut evidence that taking calcium supplements was beneficial for one's health, then the recommendation of the doctor should come down on not recommending calcium supplements, thereby combining two tenets of medicine: "first, do no harm" and "less is more".

How Well Does the Flu Vaccine Work?

     I belong to the International Society for Infectious Diseases, or ISID, whose home page is www.isid.org. It is a consortium of physicians and public health workers who are interested in aspects of public health that are related to possible epidemics, among other things. Any worker can post a finding thru their ProMed-mail post, located at http://www.promedmail.org. In fact, it was a Dutch physician who had been working in China when the SARS pneumonia broke out who first announced it to the world when he returned to the Netherlands using this e-mail posting system. (Up to that point the Chinese government was minimizing the severity of the problem, in a replay of Ibsen's "Enemy of the People".)

     There are discussions now posted in ProMED mail  about the effectiveness of the present 3-strain flu vaccine in 2010-2011, with estimates of effectiveness ranging from 30% to 70%, and I refer you to their web site for further information.

     These results should not be that surprising. There have already been two (U.S.) government studies showing that the efficacy of the current vaccine falls below protective levels after about 4 to 6 months. It therefore follows that the best protection would be to get a flu vaccine every six months, even though no insurance company or HMO or MCR will pay for it. There was an even more recent study demonstrating that a vaccine of four times the standard dose will provide satisfactory protection for one year.

     I leave it to my readers to discuss these results with their primary care physicians. I myself plan to get a second flu shot six months after my last one, and pay for it of course. One caveat: we do not manufacture sufficient amounts of flu vaccine to give everyone in the U.S. two flu shots per year, and it is not clear what the government's response will be to requests for a second dose of flu vaccine.

 

The Mediterranean Diet

     The cardiovascular benefits of the Mediterranean Diet (or MD)  have been in the news lately. The newspaper stories  were based on an article published in The New England Journal of Medicine (issue of February 25, 2013, by R. Estruch et.al.). But since even the New York Times did not give a fully accurate description of the MD or the study and its results, I thought I would do so here.

     To quote from the article: "The MD  is characterized by a high intake of olive oil, fruit, nuts, vegetables and cereals; a moderate intake of fish and poultry; a low intake of dairy products, red meats, processed meats;  and sweets and wine consumed in moderation with meals". Over 7,000 male and female adults in Spain were admitted to the study, and all were given periodic instruction and review by nutritionists about the MD. The adults, who ranged in age from 55 to 80, were split into three groups: one group was given extra olive oil (1 liter per week), one group was given extra nuts (30 grams of mixed walnuts, hazelnuts and almonds per week), and the third group was given periodic reinforcements about the design and benefits of a low fat diet.

     There were no restrictions placed on the total caloric intake, and no advice about increasing physical activity. In addition, although none of the study patients had any evidence of cardiovascular disease, all were at risk for developing this problem: they either had adult-onset diabetes, or they had three or more of the following risk factors: smoking, hypertension,elevated LDL cholesterol, low HDL cholesterol, overweight or obesity, or a family history of premature heart disease. The primary endpoint was heart attack, stroke or death from cardiovascular disease.

     The two MD groups increased their fish consumption by 0.3 servings/week, increased their legume consumption by 0.4 servings per week,  and they increased their consumption of olive oil to 50 or 32 grams per day. No change in physical activity was observed. In the 5 year follow, there were 288 events noted: 96 with extra olive oil, 83 with extra nuts, and 109 in the control group who were encouraged about a low fat diet. Only the reduction in stroke risk reached statistical significance, and the calculated benefit was 3 major cardiovascular events per 1000 person-years.

     I think  it would be fair to say that any intervention in a group at elevated risk for cardiovascular disease would be beneficial, but it is scientifically difficult to extrapolate the above results to normal, healthy individuals with no health risks, especially if they live in a country with a low mortality rate, such as Japan.

     Added note: The hard copy was just published in The New England Journal of Medicine, vol. 368, pp 1279-1290, April 4, 2013, by R. Estruch et. al.
   

Unhealthy America

     A recent report from the National Research Council and the Institute of Medicine made headlines when it pointed out how unhealthy Americans are compared with 16 other wealthy, developed nations: Australia, Canada, and all the nations of Europe. This report is nicely summarized in the Journal of the American Medical Association (JAMA February 27, 2013, vol. 309, pp 771-772) The following is a precis of this report. I might add that no cause was found for our lowest ranking in health and highest ranking in death rates.

     Until age 75, we have the highest death rate, compared with those other countries, but if we reach age 75 then we have a higher life expectancy.

     We have higher rates of disease and injury especially in motor vehicle accidents involving alcohol.

     US infants are least likely to reach their first birthdays, compared to the other 16 countries.

     We have lower birth weights, and mortality rates up to age 5 are also higher.

     US teenagers die at a higher rate from motor vehicle crashes and homicides.

     US teenagers also have the highest pregnancy rate and the highest prevalence of sexually transmitted diseases. They are also the least likely to practice safe sex.

     We have the highest incidence of AIDS.

     We also have the highest obesity rates and the highest rate of adult-onset diabetes, as well as the second highest rate of death from ischemic heart disease.

     US patients are more likely to return to the emergency room and to be readmitted after hospital discharge.

     We are less likely to smoke and drink, but we are more likely to abuse drugs and not fasten seat belts.

     We have the highest child poverty rate.
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     Even our wealthiest white citizens have a higher mortality than matched adults in other countries.

And no one reason or cause seems to explain our unhealthiness, especially since we pay more per capita on health care than do any of the other industrialized democracies.

   

 

Statins

     Statins have been in the news lately, so I thought I might write a few words about them. Statins chemically mimic an enzyme in the liver (HMG-Co-A) that is used in the first step of making cholesterol, and when the liver tries to use the statin, then overall less cholesterol is produced, and your serum levels fall. The body makes most of its cholesterol between midnight and dawn, which is why the earliest statins, which had a short half-life, were prescribed to be taken at bedtime. But the later statins such as Lipitor and Crestor have a much longer half-life, so they  may be taken at any time during the day, and food does not significantly affect their absorption.

     There is absolutely no question, based on numerous clinical studies, that statins definitely provide secondary protection against a heart attack or a  stroke. That is, if you have had a heart attack or a (non-hemorrhagic) stroke, taking a statin will lower your risk of having a second one. Whether or not you should also take aspirin should be decided by you and your doctor, and adding a regime of exercise provides an additional benefit above and beyond the benefit from taking the statin. All statins appear to give equivalent results.

     The question of primary prevention is a little more complicated. There is no satisfactory study showing that a person with no risks for heart disease other than elevated  cholesterol benefits from taking a statin. Many doctors will prescribe a statin for a patient with a risk factor for coronary artery disease or a stroke: smokers, diabetics, patients with ASCVD, and patients with significant narrowing of a carotid artery. There is evidence for decreased mortality when a patient with documented ASCVD takes a statin, even in the absence of a heart attack.

     I have found the most troublesome side-effect to be leg cramps, which are sometimes severe enough to awaken patients at night. Often the leg pains can be helped by reducing the dose of the statin or switching to another brand. The statins can also raise liver enzymes, and some patients report difficulty with mental concentration. There is some weak data that statin use can slightly increase your risk of developing adult-onset diabetes, but it may also reduce your risk of getting cancer (see my earlier blog about this). The muscle cramps and occasional myositis may be related to the fact that all statins lower the level of Coenzyme Q-10.

     Statins are one of the few drugs where the ingestion of grapefruit juice should probably be avoided. A chemical in grapefruit inhibits the P450 enzyme that degrades statins, so the use of grapefruits can raise the level of the statin in your blood and your liver.

     Let me close by summarizing the results of the JUPITER study. This study showed that in patients who had an elevated CRP (a marker of inflammation) who also took a statin had a lower incidence of heart attacks, coronary artery surgery, and strokes. Strangely enough, there was no decrease in the indicence of deaths from coronary artery disease, but there were 20% fewer deaths from all causes, mainly cancer.

     There are many, many clinical trials of statins in various medical conditions being conducted, and you can expect to see future stories about their benefits, side effects, or, occasionally, a null result. There was also a recent retrospective study showing that patients that lowered their LDL cholesterol through diet had an increased rate of cardiac events and deaths, so it may well be that the beneficial effect of statins is due more
to their anti-inflammatory effect than to their lowering cholesterol.


   

Stress and the Broken Heart

     Gilbert and Sullivan were correct to have Ko-Ko sing in "The Mikado" that "a little tomtit" died of a broken heart. There is a broken heart syndrome well-known to cardiologists, who also refer to it as stress cardiomyopathy or takotsubo cardiomyopathy. Sudden stress, usually of an emotional nature, can cause sudden cardiac death, angina, and acute congestive heart failure. I will first discuss the effects of acute stress on the heart, and then the far-reaching effects of chronic stress on the heart and the circulatory system.

     The broken-heart syndrome, which usually affects women, is thought to be due to the effects of an acute surge of adrenalin on the heart. Such an acute surge can cause reversible spasm of the coronary arteries, ballooning of the left ventricle, and a stunning of the cardiac muscle syncytium. The precise mechanism is not known, but the effect is real, and has been observed many times. Cardiac enzyme tests for a heart attack are normal, but an echocardiogram will show a ballooning and dysfunction of a portion of the left ventricle, thereby causing acute heart failure. Coronary artery catheterization shows no sign of blockage, and the EKG changes are not those shown by a heart attack. Such an attack which can be manifested by acute chest pain and shortness of breath can look like an anxiety attack, but a cardiac exam will typically show signs of heart failure. In some cases, cardiac arrhythmias can also occur. Recovery with proper treatment tends to be rapid, typically within one week. The interval between the emotional shock (often caused by the death of a spouse) and the cardiac event is variable, and any severe emotional shock can be the trigger. There is even one (apocryphal?) story of a woman having such an attack after winning the lottery.

     Chronic stress caused by  anxiety or depression or problems at home or at work can also cause deleterious chemical changes in the bloodstream, with eventual effects on the circulation of coronary as well as peripheral arteries, and a possible fatiguing of the cardiac muscle. We know that the stress caused by these mental conditions can cause elevated adrenalin  and cortisol levels, as well as an elevated pulse rate and white blood count. This effect also raises blood pressure and makes the blood more liable to clot. There is a concomitant elevation of fatty acids, cholesterol and triglycerides. Whether or not chronic stress can lead to heart disease is not known, but, as indicated, chronic stress elevates all the chemicals in our bloodstream that we would prefer to be lower to protect against cardiac disease.

     Unfortunately, there is as yet little or no clinical data to show that lowering stress decreases the risk of developing a cardiac problem; even the type A hypothesis has not been well proven. And I doubt (but who knows?) that the effect of a daily glass of wine on lowering the risk of a heart attack is due to its relieving of stress. Since marijuana mellows most users, it will be interesting to examine the heart attack rates in Colorado and Washington State in 10 years, to see if there is any effect on the incidence of cardiac events that could be attributed to the chronic smoking of marijuana.

Do Antioxidants Block Cancer Treatment?

     This blog is based on a suppositional paper written by Dr. James Watson, of DNA fame, and published in Open Biology. He argues that the presence of antioxidants in cancer cells blocks anticancer treatments. The only clinical evidence of which I am aware that supports his thesis is the study of Finnish male smokers which showed that those who took antioxidant supplements had a higher incidence of lung cancer, and there also are several studies of cancer cells in vitro that seem to demonstrate a similar effect of antioxidants.

     Dr. Watson's paper is long and highly technical, so I will summarize the key points here and try to interpret them for the reader who is not heavily involved in cancer research. I might just begin by remarking that no interventional diet study involving the addition of antioxidants to the daily diet (beta carotene, Vitamin E, selenium, Vitamin A, and Vitamin C) has been shown to prolong the human life span. I will also touch on the possible reason for the benefit of aspirin in cancer prevention and why tests are now being done to see if the diabetes drug metformin has anti-cancer properties.

     Most agents used to kill organ (non bone-marrow) cancers, including Xrays and chemotherapy, work by generating ROS, or reactive oxygen species (such as OH-) which block key steps in the cell cycle and thereby hasten apoptosis, or cell self-destruction. The presence of ROS also generates a hypoxic environment in the cell, which drives a conversion of the cell from an epithelial to a mesenchymal type. But at the same time, in self-protection, the presence of ROS causes the cell to generate antioxidants, which render the cell resistant if not immune to both ionizing radiation and chemotherapy. In addition, mesenchymal cells are more prone to travel and metastasize. So the presence of ROS is both an accelerator and a brake.

     The presence of the Myc gene  activator can drive cancer cells forward, as can the presence of inflammatory cytokines such as interleukin-6. It is therefore theorized than the cancer-preventing property of daily aspirin (most convincingly demonstrated in colon cancer) derives from its anti-inflammatory and cytokine suppressing effect. And it has been shown that the turning off of Myc drives cancer cells towards apoptosis.

     Now in mouse models of cancer, the anti-diabetic drug metformin preferentially killed mesenchymal stem cells, which cells are the most resistant to chemotherapy and the most prone to metastasize. The reason for this is probably its blocking of oxidative phosphorylation. There are currently a number of ongoing studies where metformin is being added to standard anticancer chemotherapies in humans to look for an enhanced killing effect.

     To summarize Dr. Watson's thesis, and again I refer the interested reader to his paper, anticancer chemotherapy and Xrays generate ROS. The presence of ROS has a two-fold effect: it drives the cancer cell  towards apoptosis, or cell death, and at the same time it induces antioxidants which render the cell resistant to further anticancer treatment as well as inducing a transformation to a mesenchymal stem cell. It is not known if the antioxidants themselves drive this change in addition to inducing resistance to treatment.

     Based on this theory, and the limited data to date, it would seem prudent to avoid adding antioxidants to your diet which in theory would increase the antioxidant levels in every cell in your body by diffusion. Remember the study of Vitamin E, touted as an oxidant, which showed (in two different studies) that an increase in the intake of Vitamin E increased the rate of cardiac events and heart attacks.

   

   

   

   

BMI, Overweight, and Longevity

     A recent article in the Journal of the American Medical Association (JAMA, 2013;309: 71-82) created quite a stir when it concluded that adults who were overweight but not obese had a 6% lower all-cause mortality rate. Nutritionists rushed to say that this did not mean that you should gain weight, although if the study had shown the reverse I am sure they would have unanimously recommended weight loss. This was not the first study to reach this conclusion, so I thought I should review it here, along with examining exactly what the BMI purports to measure since all obesity labels were based on the BMI (Basal Metabolic Index) results.
 
     The BMI was first defined by Quetelet in the 1800's as a surrogate number for estimating the amount of body fat. It is defined as mass(kg)/height (m) x height, i.e. the mass divided by the square of one's height. Since your mass increases with your total body volume, it scales with the cube of your height, so it is immediately obvious that only dividing by the square of the height will overestimate the total body fat of taller individuals. Similarly, muscular athletes have very little total body fat, but since muscle has mass, the BMI will  overestimate their total body fat as well. It is trivial to note that since most elderly patients have some degree of osteoporosis and therefore lighter bones, the BMI will mistakenly classify some of them as underweight.
I should also mention here that in 1998 the U.S. lowered its cutoff for the lower limit of overweight from a BMI of 27.8 to 25.0, in accordance with the WHO standards, thereby immediately reclassifying millions of Americans as overweight who the day before the change had "normal" weight. In addition, doctors in the US do not agree on the healthy lower limit of the BMI  for adult women, and the WHO does not have the classification of "underweight". And the 0.5 to 1.0 inches in height that you lose with age increases your BMI without you actually gaining any weight.

     The consensus in the US is that a BMI of 18.5 to 25 is normal weight, 25 to 30 is overweight, and greater than 30 is obese. Using these definitions, there have already been two published studies, one of diabetic patients and one of patients with ASCVD, and both demonstrated that overweight patients had a lower death rate than both normal weight and obese patients. No one has an explanation for these results, nor have I even seen theories that attempt to explain them. The JAMA study looked at 97 studies of all-cause mortality, encompassing 270,000 deaths and over 2,800,000 subjects, so it is fairly comprehensive.
We are left with the paradox that being overweight by BMI standards statistically increases your risk for high blood pressure, diabetes, ASCVD, stroke and some cancers, yet overall it is protective of mortality.

     In a previous blog I listed the 11 countries in order of longevity. I will repeat the list here adding the mean BMI of each country. Except for Japan, #1 and with the lowest BMI, there is no clear pattern:
Japan---22, Switzerland---25, Australia---26, Italy 23.5, Israel---25, Iceland---26, Spain---24.5, France---23.5, Canada---25.5, Singapore---22, and New Zealand---26.6.

     So once again we are left with "a beautiful theory ruined by an ugly fact" to quote a Nobel scientist. Perhaps we should re-normalize the BMI values and re-define normal weight. Or perhaps we should have a separate classification of "healthy BMI" and "unhealthy BMI". Or, more likely, there is a confounding fact of which we are unaware which would explain the results, but so far there are no candidates. It does make me feel better with my BMI of 27 because at 6'2" I doubt that I could get down to 185 pounds, even if I wanted to. I think we underestimate the genetic effects on us of our parents' diseases, especially parents of the same sex.