What is the issue with fish, TMAO and heart disease?

The metabolite TMAO has emerged as a putative factor in the development of CHD with over 1,000 scientific publications this decade reporting associations with a variety of serious health conditions of the cardiovascular system and beyond. The relationship may extend beyond a role for TMAO as simply a marker for CHD, and an understanding of how TMAO directly promotes atherosclerosis such as the CD36 pathway are known (3) .

What is the issue with fish, TMAO and heart disease?

1) Some fish have pre-formed TMAO (but not all)

While not all fish have significant tissue levels of TMAO, some do. In a study of 89 species of fish in Hong Kong, TMAO was not detected in most freshwater fish (4). Human studies do indicate that eating some species of fish may acutely raise blood TMAO levels. Whether the acute rise and fall of a single meal of fish promotes atherosclerosis or endothelial (artery wall lining) dysfunction in humans is not known but it has been reported in an animal model (5).

In an article in Forbes on the issue of TMAO and dietary fish, Stanley Hazen, MD, chair of the Department of Cellular and Molecular medicine at the Cleveland Clinic and an American Heart Association Distinguished Scientist 2017, was quoted as indicating that "some forms of fish that have very high levels of TMAO, such as deep sea fish in Arctic waters, which use TMAO as anti-freeze and have extraordinarily high TMAO levels. Surface fish, like trout, tend to have very low TMAO (6)."

In an email exchange I had with Wilson Tang, MD, the Director of Cleveland Clinic’s Center for Clinical Genomics, Research Director, and staff cardiologist, he indicated that:

“As far as I’ve been able to find, there is no comprehensive analysis of TMAO content in common fish/seafood used in the North American diet. However, its generally accepted that TMAO levels tend to increase as the habitat depth of the fish deepens and the water temperature becomes colder.

Wild-caught freshwater lake and river fish are the least likely to have high concentrations of TMAO. This includes trout and perch. Saltwater fishes however are more likely to have higher levels, including, shark, rays, mollusks, and crustaceans.  Various types of cod including Chilean seabass, a cold-water cod fish, have high levels. One exception is the generally freshwater tilapia. Tilapia species may have higher TMAO due to the food it is eating. Farm raised fish tend to have higher TMAO than their wild-caught counterparts. TMAO and TMAO precursors are common nutrients in farm-raised fish diets.” 

2) The TMAO/Fish Debate Exists in the Medical Literature

An interesting exchange of opinions on fish and TMAO occurred in response to an article in 2016 linking elevated TMAO levels to CHD in humans (7). Researchers in Oslo, Norway wrote in a letter to the journal that “the hypothesis that TMAO is directly involved in development of atherosclerosis therefore seems like a paradox, as intake of seafood is generally accepted as cardioprotective”. They suggested that ingesting TMAO directly from seafood should not be regarded as “fishy business”.

Drs. Tang and Hazen of the Cleveland Clinic got the final word in on this issue in their response in the same journal. They wrote that they rejected the idea that “anything and everything derived from the sea and ingested in any quantity must be heart healthy” and even equated the oil extracted from blubber to bacon fat! They pointed out that the “benefits of large quantities of TMAO-rich fish in patients who have been associated with elevated TMAO levels (e.g. chronic kidney disease) have not been demonstrated”.

Finally, in a review article last year the group of Cleveland Clinic researchers commented on the issue of fish and TMAO (8). They wrote that “a paradox concerning TMAO is the high levels of this metabolite in fish and the associations of diets high in fish to be beneficial for cardiovascular health. Clearly, fish intake (especially deep-sea fish) is associated with detectable increase in urinary TMAO excretion…transient (usually in a few hours’ time) before returning to its steady state”. The study in mice relating fish intake and atherosclerosis to indicate that the matter of fish and health is not resolved (5). They concluded that there was “no study that directly demonstrates the beneficial effects of fish intake in patients with advanced chronic kidney disease, a population in which TMAO clearance is likely impaired.”

There are some take home points:

1) The majority of fish do not have TMAO in their flesh

2) The similarities, if any, of a transient rise in preformed TMAO from those species of fish versus the regular exposure to TMAO metabolized by daily meat and egg consumption needs to be considered.

3) A blood test is widely available for TMAO. I have measured this metabolite in several thousands of patients. When the TMAO level is elevated I advise my patients to limit or eliminate red meat, egg yolks, deep water fish, and supplements with L-carnitine and choline. I recheck the level in a month and it usually drops to normal. If someone regularly eats fish I would advise having the TMAO level checked, along with a blood mercury level which is often markedly elevated in patients in my clinic eating fish several times a week and using the level to determine if it would be advisable to adjust their diet.