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Over the past several decades, public health experts and physicians have pinned a hefty portion of the blame for heart disease on saturated fat. That’s not without reason. The long-chain saturated fatty acids found in foods like steak, butter, and coconut oil raise artery-clogging low–density lipoprotein (LDL) cholesterol, a cause of atherosclerotic cardiovascular disease. At the same time, diets high in red meat have been strongly associated with heart disease and mortality.
But a problem has emerged: meta-analyses of dietary recall studies suggest that saturated fat intake may not be as tightly linked to cardiovascular disease and mortality risk as was previously thought. Cholesterol content likewise doesn’t appear to adequately explain the hazards of a red meat–rich diet.
Now, researchers are homing in on another possible culprit: a dietary metabolite linked to red meat called trimethylamine N-oxide, or TMAO. Three recent meta-analyses confirmed that high blood levels of TMAO are associated with increased risks of cardiovascular disease and all-cause mortality. One of the studies, published in the Journal of the American Heart Association in 2017, found a more than 60% heightened risk of both major adverse cardiovascular events and death from all causes in people with elevated TMAO. Other research has associated higher TMAO levels with heart failure and chronic kidney disease.
Research suggests that TMAO is part of an additional biological pathway through which red meat raises heart disease risk, said JoAnn Manson, MD, DrPH, a professor of medicine at Harvard Medical School in Boston, who coauthored the 2017 analysis. The body makes TMAO from foods with choline and l-carnitine, nutrients that are abundant in meat, poultry, fish, dairy, and egg yolks. Liver enzymes produce TMAO from its precursor, a gas called trimethylamine (TMA) that’s formed when gut bacteria break down these nutrients.
Red meat is particularly high in l-carnitine. A team of Cleveland Clinic scientists, in collaboration with colleagues at the Children’s Hospital Oakland Research Institute in California, recently studied the role of red meat and saturated fat in gut microbiome-related TMAO generation. Red meat consumption raised some participants’ plasma TMAO levels substantially more than white meat or nonmeat protein consumption. (All the participants had eggs and dairy as part of their meals.)
Not only did red meat increase the amount of l-carnitine available for TMAO synthesis, it also appeared to shift the gut microbiome, fueling more bacteria for the task. And for still unknown reasons, it also reduced the kidneys’ ability to excrete TMAO in urine. The effects were reversed when the participants were crossed over to white-meat and nonmeat diets.
“A chronic red meat–ingestion diet—there are many, many studies that connect that to heightened mortality risk and cardiovascular risk, and we think that a partial reason for that is because of this carnitine-TMAO connection,” said Stanley Hazen, MD, PhD, section head of preventive cardiology at the Cleveland Clinic.
Incidentally, the saturated fat content of the meals made no difference to TMAO levels in the study, which Hazen published this year in the European Heart Journal. “The TMAO pathway seems to be independent of the saturated fat story,” he said.
What TMAO generation does depend on is bacteria. According to work by Hazen and colleagues, without the right gut microbes, humans and mice can’t produce TMA, which the liver requires to make TMAO. That relationship with gut bugs could be TMAO’s Achilles’ heel.
One of the first hints of a link between TMAO and heart disease came in 2011, when Hazen’s team went looking for metabolites that foretold cardiovascular events. In a large clinical study, circulating levels of TMAO, choline, and betaine—all metabolites of the dietary lipid phosphatidylcholine—predicted the risk of cardiovascular disease after adjusting for traditional risk factors and medications.
When researchers fed atherosclerosis-prone mice chow supplemented with choline or TMAO, arterial plaques increased more than in mice fed regular chow. In the same series of experiments, published in Nature, the researchers also discovered that gut bacteria were required to form TMAO and TMAO-accelerated atherosclerosis in mice. As some of the first research to implicate the gut microbiome in promoting heart disease, the findings were groundbreaking.
Two years later, in 2013, Hazen and colleagues went on to show that humans, too, need gut microbes to produce TMAO from choline and that blood levels of the metabolite predict future risk of heart attack, stroke, or death. The same month, they linked another nutrient—l-carnitine—and gut flora to TMAO production. People with high levels of both l-carnitine and TMAO were more likely to have cardiovascular disease at the time of the study and increased risks of future cardiovascular events.
Hazen’s work was “the first to demonstrate clearly this unique relationship among food, bacterial metabolism, and human metabolism,” said cardiologist Joseph Loscalzo, MD, PhD, chair of the department of medicine at Harvard University–affiliated Brigham and Women’s Hospital in Boston, who was not involved with the research.
Multiple studies involving animals and humans—many conducted at the Cleveland Clinic—now suggest that TMAO is atherogenic, prothrombotic, and inflammatory, making it a “triple threat to the cardiovascular system,” said Kim Williams, MD, chief of cardiology at Rush University Medical Center in Chicago.
The exact mechanisms haven’t been sorted out, but the metabolite appears to create and upset arterial plaques and increase blood clots through a variety of pathways, like reducing cholesterol clearance; increasing cholesterol-laden foam cells and proinflammatory cytokines; and enhancing platelet reactivity.
But not everyone is convinced that TMAO contributes to heart disease. A major criticism of the theory centers around fish, which can contain high concentrations of TMAO and TMA. If TMAO causes disease, and fish contains it, why is fish consumption associated with heart health? Loscalzo said this paradox might be explained by the healthful components in fish, particularly omega-3 fatty acids, offsetting the negative effects of TMAO, although the question is far from answered. But to Hazen, the paradox may not even exist: the vast majority of fish, including commonly eaten varieties like bass, catfish, trout, and walleye, don’t contain TMAO, he said. The top offenders are certain deep-sea varieties, like cod, haddock, and halibut. The TMAO content of other fish, including salmon, depends on the where and when they’re caught, according to Hazen.
Some experts chalk up the associations to reverse causality: decreased kidney function associated with atherosclerosis leading to a buildup of TMAO. This would make the metabolite a marker, not a mediator, of disease.
But Hazen said the reverse causality argument ignores many facts. For example, TMAO predicts future development of heart disease and adverse events even in subjects with completely normal kidney function. He puts TMAO front and center with blood cholesterol in the pathogenesis of cardiovascular disease. The metabolite appears to ramp up sensitivity to LDL cholesterol. “Not everyone with high cholesterol develops heart disease,” he said. “Conversely, some people with low cholesterol develop atherosclerosis and heart disease, and we think a big controller of that is TMAO.”
Clinical trials and larger prospective studies could convince more people. Manson is using data from the Nurses’ Health Study (NHS) and the Vitamin D and Omega-3 Trial (VITAL) cohorts to examine how dietary changes over time affect blood levels of TMAO, l-carnitine, and choline and how those shifts predict the risk of cardiovascular events in a large group of women and men.
For now, there’s no official guidance on whether to test TMAO levels or in whom. (As a coinventor of the TMAO blood test offered by Quest Diagnostics, Hazen and the Cleveland Clinic are eligible to receive royalties from its use.) There’s also no consensus on whether the metabolite should be reduced and to what level—or how. (One study suggests that low-dose aspirin partially reduces elevated TMAO.) As such, far fewer physicians offer TMAO screening compared with routine cholesterol testing.
But it could be a matter of time before that changes. “These studies raise interesting questions about clinical trial design that could give us more definitive answers about the implications for therapy and for diet modification,” Loscalzo said. “As the story evolves, I think [TMAO] will have clinical impact in the not too distant future.”
Hazen intends to be ready when that time comes. He’s searching for drugs that could reduce TMAO levels. One option might be to block liver enzymes from converting TMA to TMAO, much like statins tamp down cholesterol production in the liver. But people with the rare metabolic disorder trimethylaminuria, who naturally can’t convert TMA into TMAO, give off a strong fishy odor, something scientists want to avoid inducing intentionally. Another alternative would be to augment renal clearance of the metabolite.
However, it might make the most sense to go after TMA production by “drugging” the microbiome. To that end, Hazen recently developed a family of drugs that in mice block microbial production of TMA from choline and, in turn, reduce TMAO, preventing heightened platelet reactivity and thrombosis without increasing bleeding risks. With the recent discovery of the intestinal bacteria that convert l-carnitine into TMA in a 2-step process, researchers can now begin to develop an inhibitor for this pathway, too. Meanwhile, scientists at the Medical College of Wisconsin are also investigating probiotics to reduce TMAO levels in patients with coronary artery disease.
But what about the most obvious approach, dietary modification? For Williams, a self-described “plant-based cardiologist,” the existing evidence solidly places TMAO among what he says are the known animal-product contributors to heart disease: saturated fat, dietary cholesterol, heme iron, and ruminant trans fat. Williams cited the mortality-reducing effects of a “provegetarian” food pattern, and said the research on TMAO is yet another reason to stop eating animals in all forms, or at the very least eliminate red meat. Bolstering his argument, a recent meta-analysis of randomized clinical trials found the most favorable blood lipid changes when red meat-heavy diets were substituted with high-quality plant protein diets.
Researchers at Stanford University are already studying the effects of plant-based meat alternatives on TMAO levels in a clinical trial. But short of going full-on herbivore, people can substantially reduce TMAO levels within as little as a month by eliminating or reducing red meat, according to the European Heart Journal trial that compared protein sources.
However, Cleveland Clinic cardiologist W. H. Wilson Tang, MD, who coauthored the study with Hazen, had reservations about recommending that everyone do so. In the trial, people eating red-meat heavy diets had a range of responses, with some participants’ TMAO levels shooting up far less than others’.
As for animal products in general, white meat, eggs, or dairy may not influence TMAO levels to the same degree as red meat or deep-sea fish. Before issuing blanket prescriptions for patients to dramatically alter their diets to reduce TMAO, Tang said more studies are needed to determine who would benefit the most. He’s currently leading a pilot trial involving 90 people that will determine the proportion of participants with persistently elevated TMAO levels and their response to a low-TMAO Mediterranean diet.
In Tang’s view, it could be a mistake to focus too much on any single dietary component, even red meat. It’s more important to understand how the foods we eat influence and interact with our intestinal microbes and renal clearance system, both of which are highly individualized. In fact, the gut microbiome is increasingly being seen as an important heart disease player. Red meat is only a part of the cardiovascular disease story, Tang argues—and one that may not even matter for some people.
Hazen used to be avid red-meat eater, but he said it’s now a “very, very rare item on the plate.” Yet he, too, is wary of insisting that others make the same drastic change. “Diet is a personal choice,” he said. “We beat up patients over their eating habits. I don’t think that is productive.” Although he believes that patients should be educated about the risks associated with eating a red meat–heavy diet, which could nudge them toward a plant-based one, he thinks it’s unrealistic to expect everyone to act on the information. “That’s why I want to develop a drug: so that you can have your steak and eat it, too,” he said.
In the meantime, Hazen and Tang’s discoveries have kicked off an interest in dietary metabolites as marker-mediators of disease, Manson said. Her team recently received funding to expand their study in the NHS and VITAL cohorts beyond TMAO. They’re now looking at how dietary patterns affect roughly 400 other plasma metabolites. Ultimately, she wants to use the findings to develop metabolomic risk scores for future coronary heart disease development. As she puts it, “this is really just the tip of the iceberg.”
Animal products and dietary supplements are well-known sources of choline and l-carnitine, but the TMAO-precursors can also show up in these unexpected places:
Processed foods that contain phosphatidylcholine, also known as lecithin
Protein supplementation products
Some fruits and vegetables
Abbasi J. TMAO and Heart Disease: The New Red Meat Risk? JAMA. Published online May 22, 2019321(22):2149–2151. doi:10.1001/jama.2019.3910
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