I distinctly remember Mr Imran Khan stating more than once that the solution to the Kashmir problem should be a cricket match. If India were to win ,Kashmir would be hers, but in case Pakistan were the victors then ‘paradise on earth’ would be rightfully their territory. Those were the days when the Pakistani cricket team more or less had an edge on India. Pakistani batting then was not only rock solid but buttressed by arguably the finest pace attack on the planet. Mr Imran Khan, no minnow with the bat , was a terrific fast bowler. Somewhere down the line he mastered the reverse swing too. It would be interesting to know of his personal opinion in current times, bearing in mind that now its the Indian cricket team that bats deep with one of the most potent pace attack. Mr Imran Khan understandably refrains from attaching any form of cricket to Kashmir. Not test, not one day cricket nor the T20 form. To his credit Mr Imran Khan was right up there as one of the best all rounders in the world. So it comes as some surprise that such a fine cricketing brain is now batting in the murky world of Pakistani politics. I personally preferred him when he made those frank promulgations that smacked of simplicity in a man who played with a straight bat.


I am compelled to recollect those artless days; we also believed that saturated fat was a killer. The equation was simple, eat meat particularly red meat and you would kick up your cholesterol level. The spike in cholesterol in turn would clog your arteries, resulting in heart attacks and stroke. There was the famous “seven countries” data that set up the high cholesterol diet equals heart attack hypothesis. It was only much later we all found that that the “seven countries” data was full of holes. I have elaborated on the flaws in the past. Every randomised study on saturated fats has failed to show reduction in heart attacks by having a diet with reduced saturated fats. The Women’s Health Initiative followed 49,000m postmenopausal women for 8 years who had been on a low fat diet, but could not record reduction in the risk of death, heart attack or diabetes. The conclusion was no different when saturated fat was replaced by a vegetable oil (polyunsaturated fat). There were more heart attack and death in the intervention group. There have been 2 such randomised trials, both concluded that replacement with a vegetable oil somehow did not lower clinical events.


The “seven countries” data missed out on the fact that Scandinavian countries consuming greater fat had fewer heart attacks while Chile with a lower intake of fats suffered a greater number of heart problems. Scientists have repeatedly been flummoxed by the see saw correlation of fats and heart disease, and now most concede there is more to heart attacks then just a high fat diet. Neither can Kashmir be solved by a cricket match nor the simple high fat diet narrative fully explain increased risk of heart attack. Matters are more complicated than that, and therefore the emergence of a new fairly plausible theory.


Researchers from Cleveland Clinic have shown both in rats and humans that a chemical produced by bacteria present in the intestine is responsible for increased risk of heart attack. The predominant source is red meat, which carries carnitine. Carnitine operates as a fuel for intestinal bacteria that feeds on the red meat carnitine, burping out a chemical TMA (trimetyhyl amine). The TMA is metabolised by the liver to TMAO (trimethyl amine N oxide ) . TMAO is culprit chemical that not only is atherogenic but is also prothrombotic and inflammatory. TMAO is the MIRV or the Multiple Independent Reentry Vehicle missile capable of carrying multiple nuclear war heads. The Cleveland group have shown very elegantly that consuming red meat immediately raises fasting TMAO levels. Increased TMAO levels have been found to increase clinical cardiac events. TMAO shoots up in blood after a red meat steak but not after a vegetarian protein diet. Its carnitine in red meat that is the molecule which eventually is converted to a toxic chemical that triggers heart attacks. Carnitine is present in fish and chicken but in much smaller amounts. Carnitine by itself is harmless, but becomes dangerous when converted by gut bacteria to TMAO. Researchers also found that TMAO increased the risk of heart attack independent of other risk factors such as smoking, blood pressure, high cholesterol, or even less than 50% blocked coronary arteries ( Nature 2011;472:57-63). We are quite certain that carnitine is the culprit molecule. Hence one should be careful with all energy drinks and protein supplements containing carnitine.




Egg yolk also contains a chemical (lecithin)that is converted by bacteria in the gut into TMAO. Investigators have found that dietary choline from lecithin is metabolised by gut bacteria to TMA, which in turn is absorbed into the blood stream and metabolised in the liver to TMAO. Production of TMAO was surpassed by administration of broad spectrum antibiotics, which reappeared with withdrawal of the antibiotic. They also reported relationship between fasting plasma TMAO levels and cardiovascular event rate over a 3 year period in more than 400 participants undergoing coronary angiography. A dose dependant relationship was found between TMAO level and cardiac events ( N Engl J Med 2013;368:1575-84).


As recently as 2017 investigators reported more than 60% increased risk of cardiovascular events and death in people with raised TMAO. Researchers are now scrambling to figure out a method to cut down TMAO production. The easiest way would be to cut down on red meat. But its not as simple as that because most people would like to have their steak and eat it too. Gut microbes could be culled but the microbes manufacturing TMA are not identified. Administering broad spectrum antibiotics for months or years could be hazardous. Checking conversion of TMA to TMAO in the liver is another option being considered. Larger trials are needed to confirm whether reducing TMAO level cut heart attack risk. Probiotics may be developed that promote growth of gut bacteria that do need increase TMAO level.


We are however still in the initial years of the TMAO link with heart attack. So far the data has been consistent, but more research is needed before announcing blanket disapproval of certain diet. Beef, pork and mutton are in the cross hairs for now. But nutrition prescriptions continue to be bewilderingly erratic. Nothing seems to be as simple as it appears, very much like the Kashmir quagmire, where bulldozing your way through may feel direct and simple but has the potential to boomerang. It would be worth remembering that all those fancy protein supplements loaded with carnitine may not be a very prudent choice. But guess what the Cleveland Clinic scientists are experimenting with something as ordinary as orange peels to stop production of TMAO from TMA. What could be simpler than that.


N ENGL J MED 2013;368:1575-84

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