Trimethylamine oxide cuts heart failure death

Oily fish is claimed to cut the risk of cardiovascular disease. Indeed, populations with a high fish diet do have a lower heart disease risk. Why though, remained a mystery. Now researchers think that one molecule - trimethylamine oxide -TMAO - might be the key. But it has a chequered history, because previous work had labelled it a metabolic bad boy. Turns out though that that was incorrect: the finger had been pointed at the wrong molecule. And, as Chris Smith heard, Marcin Ufnal has instead discovered that TMAO is powerfully protective against heart failure, an effect it achieves by acting as a diuretic to reduce the workload on the heart and prevent fibrous tissue from stiffening the muscle…

Marcin - So our interest in trimethylamine oxide started a few years ago, when a paper was published in the New England Journal of Medicine that people who suffer from cardiovascular diseases have a high level of trimethylamine oxide. And we were wondering, how is it possible? Seafood has a lot of trimethylamine oxide, and at the same time, if you eat seafood it's good for your health. So in the next series of experiments, we found out that trimethylamine oxide actually is beneficial. Whereas what is harmful is its precursor trimethylamine, and trimethylamine is changed into trimethylamine oxide by our liver.

Chris - What is the trimethylamine oxide doing in the seafood then?

Marcin - Trimethylamine oxide is called osmolite. So it protects cells of animals from high osmotic pressure and deep sea animals from hydrostatic pressure in deep waters.

Chris - Is there potentially then a role for it in human health? Because there are certain tissues in our body which do from time to time or periodically moment to moment experience extremely high pressures. And relevant to the cardiovascular system, I'm thinking every time my heart beats, especially if I'm running around, it's going to develop extremely high pressure in the muscle cells. So could this have a role in protecting the muscle cells then from those high pressures?

Marcin - Well, actually this was our hypothesis, but our experiments show that actually it's not the correct pathway and the beneficial effect of trimethylamine oxide seem to be associated with osmotic pressure. And in our case, this was like a rat model of heart failure. They accumulate too much water and too much salt. So giving trimethylamine oxide, we increased excretion with urine of salt and water. So actually trimethylamine oxide works as a diuretic.

Chris - Talk us through the experiments you actually did then to prove that that was the case in your rats.

Marcin - We performed two experiments in rats with hypertension, and in two models of heart failure. And in both experiments, we treated rats with trimethylamine oxide for one year. The rats were given this trimethylamine oxide with drinking water. We tried to give them a dose that would be similar to the dose of trimethylamine oxide that would be consumed if you were just eating seafood all the time.

Chris - And then you're following up the rats to see if there is an obvious morbidity and mortality outcome difference in the animals that eat the normal rat chow versus the animals supplemented with what would be rat seafood?

Marcin - Yeah, and it was really striking for us. Rats that were receiving trimethylamine oxide all survived, whereas in a control group, only 66% survived. Also other parameters, such as blood pressure, were lower in animals on trimethylamine oxide.

Chris - How did you link the outcome - this dramatic reduction in mortality that's a third down that's very considerable - how did you link that to it being the trimethylamine oxide, the TMAO? And what mechanism do ascribe to it to cause that dramatic reduction in mortality?

Marcin - In both of these experiments we observed increased urine output. And we were wondering whether this might be related with the final outcome. So we designed another experiment in which we looked at the effect of trimethylamine oxide on urination. And we found that rats that were treated with trimethylamine oxide acutely with higher doses had significantly increased urine output, significantly increased excretion of water and excretion of sodium, which was very similar to what we observe after administering drugs that are called diuretics.

Chris - What did this do to the heart itself? Because we know that if you look at heart tissue in people with heart failure, there are various changes that happen over a period of time, which is alleviated by taking drugs like diuretics to reduce the amount of load on the heart, but there are other changes that happen - the heart remodels itself to compensate, doesn't it, so do your rats also respond in the same way to the TMAO when you give it?

Marcin - Yeah. These rats had lower fibrosis. So in general, when you have a failing heart, the cardiomyocytes, the muscle tissue is substituted by other tissue - by fibroblasts. And in our rats that were treated with trimethylamine oxide, we had lower fibrosis and we also had better parameters, haemodynamic parameters of the heart.

Chris - Do you think that this could translate to humans then? Obviously it suggests that the reason people who have a very seafood rich diet, and I'm thinking people in Japan, people who are Inuit, people who have a correspondingly low level of heart disease might be our natural experiments already happening. But do you think that this could be a therapy for humans?

Marcin - I hope it could be a supplement for a diet that does not have it. We could start with doses that will be just similar to doses that are taken by people who eat a lot of seafood.