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A compound released by gut microbes as they digest red meat appears linked to heart failure (HF) and its prognosis, a study showed.

Fasting plasma levels of trimethylamine-N-oxide (TMAO) were higher among HF patients than in healthy controls (median 5.0 versus 3.5 mM, P<0.001), of the Cleveland Clinic, and colleagues found.

in HF, independent of traditional risk factors and estimated glomerular filtration rate as a measure of renal function, the researchers reported in the November issue of the Journal of the American College of Cardiology.

The gut has been implicated in HF for years, although the original hypothesis was that intestinal edema and ischemia allowed things to leak into the system that cause inflammation, and , both of the University of Glasgow, noted in an accompanying editorial.

The new findings on TMAO are " but one for which we should look forward to further installments," they wrote.

"From what we know about TMAO, the likely explanations for increased plasma levels in HF are increased trimethylamine production in the bowel (reflecting diet and the composition of the intestinal microbiota), increased trimethylamine entry from the bowel to blood (signaling intestinal barrier function), increased flavin monooxygenase activity, or decreased clearance of TMAO from the plasma compartment (or some combination of these).

"More puzzling," they added," is just how TMAO by itself might relate to prognosis. It is probably unlikely that a proatherogenic mechanism could account for an increase in mortality in such a short time frame, especially in patients with nonobstructive coronary disease. As we know, the majority of deaths in such patients will have likely been due to pump failure or an arrhythmia, not coronary events."

Dietary Implications

TMAO, while generated by gut microbes, ultimately comes from foods containing L-carnitine (such as red meat) or phosphatidylcholine (lecithin) -- the main dietary source of choline (found in eggs), Cannon and McMurray noted.

A diet that cuts down on such foods "would essentially be the Mediterranean diet," Hazen told 乌鸦传媒, although "following a heart-healthy diet that's low in cholesterol, low in saturated fat, will achieve the same end in terms of lowering the phosphatidylcholine and the carnitine intake as well."

Prior research by Hazen's group linked the compound to atherosclerosis and to risk of coronary artery and peripheral artery disease.

While the new findings can't establish a causal link with heart failure, there are implications for diet and perhaps for drug treatment targets, Hazen suggested.

"These studies suggest diet may play a bigger role in heart failure than we previously appreciated," he said. "We know that salt intake plays a big role in heart failure outcomes, but beyond that we don't have very good dietary information ....

"New interventions designed to limit this pathway, and that may be in the form of a drug that blocks the microbial pathway, are an area for future research as well."

The Findings

The study included 720 stable cardiac disease patients with a history of HF prospectively enrolled at the Cleveland Clinic from 2001 to 2007 where they were getting elective, non-urgent coronary angiography. None had a recent acute coronary syndrome.

Plasma levels of TMAO in the top versus bottom quartile (over 8.5 mM versus less than 3.0 mM) were associated with a 3.4-fold difference in mortality risk among HF patients. After adjustment for traditional risk factors and BNP levels, the hazard ratio remained at 2.2; additional adjustment for estimated glomerular filtration rate attenuated it to 1.75, but that risk was still significant at P<0.001.

Each standard-deviation increment in TMAO level was associated with 18% higher mortality risk at 5 years after adjustment for traditional cardiac risk factors (HR 1.18, P<0.01).

The association with all-cause mortality was similar for ischemic and nonischemic patients with HF, as well as other clinical subgroups.

Notably, TMAO significantly improved net reclassification (by 11% according to the net reclassification index and by 16% on an integrated discrimination measure, both P<0.001) when added atop traditional cardiovascular risk factors. There was also a nonsignificant trend for a better area under the curve (P=0.096).

TMAO and B-type natriuretic peptide (BNP) levels had a "modest but significant" correlation (r=0.23, P<0.001).

"It is intriguing that in the setting of elevated natriuretic peptide levels, which often represent significant myocardial disease progression, a relatively low fasting TMAO level was associated with far lower mortality risk than that seen with elevated levels of both markers," the researchers wrote.

Limitations included a single blood draw for TMAO without dietary history as well as the single-center design and possible selection bias for ischemic cardiomyopathy and a low rate of advanced cardiorenal or advanced HF.

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