Author + information
- Jane A. Cannon, MB, ChB and
- John J.V. McMurray, MD∗ ()
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland, United Kingdom
- ↵∗Reprint requests and correspondence:
Dr. John J.V. McMurray, University of Glasgow, BHF Glasgow Cardiovascular Research Centre, 126 University Place, Glasgow, Scotland G12 8TA, United Kingdom.
There are few if any conditions that involve as many organs as heart failure (HF). Clinicians see lung, kidney, liver, brain, and skeletal muscle involvement on a day-to-day basis when managing patients with HF. For some years, the gut has also been implicated in HF. Specifically, it has been suggested that intestinal edema and ischemia may lead to increased gut permeability and entry of lipopolysaccharides produced by gram-negative bacteria into the circulation (1–3). These, in turn, are thought to activate cytokines and generate systemic inflammation that may contribute to pathophysiological progression of the HF syndrome. These mechanisms are believed to be most operative in patients with congestion and cachexia (1–3).
In this issue of the Journal, Tang et al. (4) reported new intestinal findings in HF. In a substantial observational study, these researchers found that plasma trimethylamine-N-oxide (TMAO) levels were increased in patients with HF undergoing coronary angiography (n = 720) compared with healthy controls (n = 300). TMAO, an amine oxide, is ultimately derived from foods containing l-carnitine (such as red meat) or phosphatidylcholine (lecithin), the main dietary source of choline (found in eggs). Choline is metabolized by gut bacteria to produce the intermediate compound trimethylamine (TMA), which freely enters the circulation and is then oxidized by hepatic flavin monooxygenases (in particular FMO3) to form TMAO. TMAO is excreted by the kidneys (5–7).
A potential role of TMAO in coronary artery disease has been proposed as a result of its action on cholesterol transport, macrophage activity, and possibly other atherogenic mechanisms (5,6). Now, Tang et al. (4) suggest a pathophysiological role of TMAO (and by implication intestinal microbiota) in HF. Not only were TMAO levels increased in patients with HF but higher levels were associated with adverse prognostic features (e.g., older age, diabetes, renal impairment, higher B-type natriuretic peptide concentrations) and reduced survival. Moreover, TMAO remained a predictor of mortality even when adjustments were made for other prognostic variables.
How should we interpret these findings, and can they be tied in to the original “gut hypothesis” of HF? From what we know about TMAO, the likely explanations for increased plasma levels in HF are increased TMA production in the bowel (reflecting diet and the composition of the intestinal microbiota), increased TMA entry from the bowel to blood (signaling intestinal barrier function), increased FMO activity, or decreased clearance of TMAO from the plasma compartment (or some combination of these). It would be of interest in future studies to know more about diet and use of drugs that might affect intestinal microbiota such as antibiotics and acid-suppressing agents.
There is prior evidence that gut flora may be altered in HF (1–3). Previous studies also described increased intestinal permeability in HF, although in the present study, high-sensitivity C-reactive protein levels were not greater in the higher TMAO group. Moreover, congestion and right-sided hemodynamics were not reported, and overall use of loop diuretics was low (although somewhat greater in the higher TMAO group) (1–3). In other words, the patients with higher TMAO levels did not fully fit the profile of those previously described as most likely to have increased intestinal permeability. Future studies might also report on liver function, hepatic congestion, or use of drugs that might have influenced FMO activity.
In addition, the strong correlation between TMAO concentration and kidney function raises the following question: given the importance of the kidney in eliminating TMAO, is higher TMAO level just a marker of renal impairment (7)? 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) (6,8).
More puzzling 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. Clearly, this is only the beginning of the story of TMAO in HF but one for which we should look forward to further installments.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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