Gut Flora Metabolite Seen to Predict Mortality in HF

October 29, 2014

CLEVELAND, OH — Fasting plasma levels of a metabolite generated by intestinal microbes were significantly higher in a cohort of patients with heart failure than in subjects without heart failure, report investigators this week[1]. Moreover, the 5-year mortality risk of those with heart failure went up sharply with greater baseline concentrations of the metabolite, trimethylamine-N-oxide (TMAO), which is produced by the gut flora from dietary carnitine and other nutrients, the group observed.

TMAO capacity as a risk predictor was independent of traditional heart-failure risk factors, renal function, and biomarkers such as natriuretic peptides and high-sensitivity C-reactive protein (hs-CRP).

"The present study is the first demonstration of an association between elevated TMAO levels and poor prognosis in patients with HF," according to the authors, led by Dr WH Wilson Tang (Cleveland Clinic, OH), publishing in the November 4, 2014 issue of the Journal of the American College of Cardiology.

Proatherogenic TMAO

The same group previously published separate studies pointing to both carnitine and choline in the diet, with major sources including red meat and egg yolks, respectively, as fuel for the production of TMAO by gut bacteria[2,3]. The studies also provided evidence that elevated plasma TMAO levels, but not intake of the dietary substrates necessarily, are proatherogenic and predicted risk of MI, stroke, or death.

The current findings, Tang told heartwire , represent probably "the first time we've linked blood levels of a microbiome-generated product of dietary nutrients to heart-failure progression." They also point to an evolution in the so-called gut hypothesis of heart-disease pathophysiology, which proposed inflammation secondary to translocation of intestinal bacteria to the bloodstream as one cause of vascular disease. The new line of research, he said, suggests that the culprit may instead be the release of bacterial metabolites such as TMAO into the circulation.

An accompanying editorial called it "puzzling" that TMAO levels would have the observed relationship with HF prognosis[4]. "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," write Drs Jane A Cannon and John JV McMurray (University of Glasgow, Scotland).

Also, they wondered, "Given the importance of the kidney in eliminating TMAO, is higher TMAO level just a marker of renal impairment? Other questions arise—for example, what is the role of comorbidities, such as diabetes, in elevating TMAO levels? Diabetes was considerably more common in the higher-TMAO group, and metformin has been reported to increase TMAO levels (and intestinal microbiota have been postulated to play a role in the development of diabetes)."

Heart Disease: A Result of "Diet-Microbiome Interplay"?

"This is a very understudied area," Tang observed. "What we eat is obviously a huge exposure to the outside world, and it's filtered through these microbes." The current research points to "diet-microbiome interplay" as a cause of vascular disease and perhaps end-organ diseases like heart failure and renal failure and raises the prospect of interventions that "modulate" the microbiome for prevention of heart-failure development and progression.

Tang et al prospectively compared a cohort of 720 patients with stable heart failure but no recent acute coronary syndromes undergoing elective coronary angiography with 300 "apparently healthy subjects without known cardiac disease." The median baseline TMAO level for the HF patients was 5.0 µmol, significantly higher than the 3.5 µmol for the comparator group.

The hazard ratio (HR) for all-cause mortality over five years in the HF cohort, for baseline TMAO levels in the highest vs lowest quartiles, was:

  • 3.42 (95% CI 2.24–5.23) in an unadjusted model.

  • 2.20 (95% CI 1.42–3.43) in a model adjusted for age, sex, systolic blood pressure, LDL and HDL cholesterol, smoking, diabetes, and natriuretic peptides.

  • 1.85 (95% CI 1.14–3.00) in a model further adjusted for estimated glomerular filtration rate and hs-CRP.

Rising TMAO as a continuous variable was associated with an adjusted mortality HR of 1.18 (95% CI 1.06–1.31) per standard deviation.

"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 group writes.

Also intriguing, Tang said, is the wide variation in intestinal flora among individuals. "We are just walking culture dishes," and people may have a lot of TMAO depending on their gut concentrations of TMAO-producing bacteria or the amount of meat in their diet, levels of which seem to track with adverse outcomes.

The current findings, along with other research, Tang said, point to a potential for upstream heart-failure therapies. "We start eating from the day we are born, and the gut flora develops in the first year of our life. It is quite plastic, quite easily affected by lifestyle. This may have a potential [as a target for] preventing the development and progression of heart failure."

"Tang has received investigator-initiated research grant support from Abbott Laboratories, with no personal financial payments," according to the report, which also had disclosures for the other authors. Cannon and McMurray report that they have no relevant financial relationships.

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