JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 64, NO. 18, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jacc.2014.04.088
EDITORIAL COMMENT
Gut Feelings About Heart Failure*
Jane A. Cannon, MB, CHB, John J.V. McMurray, MD
T
here are few if any conditions that involve as
A potential role of TMAO in coronary artery dis-
many organs as heart failure (HF). Clinicians
ease has been proposed as a result of its action on
see lung, kidney, liver, brain, and skeletal
cholesterol
transport,
macrophage
activity,
and
muscle involvement on a day-to-day basis when
possibly other atherogenic mechanisms (5,6). Now,
managing patients with HF. For some years, the gut
Tang et al. (4) suggest a pathophysiological role of
has also been implicated in HF. Specifically, it has
TMAO (and by implication intestinal microbiota) in
been suggested that intestinal edema and ischemia
HF. Not only were TMAO levels increased in patients
may lead to increased gut permeability and entry
with HF but higher levels were associated with
of lipopolysaccharides produced by gram-negative
adverse prognostic features (e.g., older age, diabetes,
bacteria into the circulation (1–3). These, in turn, are
renal impairment, higher B-type natriuretic peptide
thought to activate cytokines and generate systemic
concentrations) and reduced survival. Moreover,
inflammation that may contribute to pathophysiolog-
TMAO remained a predictor of mortality even
ical progression of the HF syndrome. These mecha-
when adjustments were made for other prognostic
nisms are believed to be most operative in patients
variables.
How should we interpret these findings, and can
with congestion and cachexia (1–3).
they be tied in to the original “gut hypothesis” of HF?
SEE PAGE 1908
From what we know about TMAO, the likely expla-
In this issue of the Journal, Tang et al. (4) reported
nations for increased plasma levels in HF are
new intestinal findings in HF. In a substantial
increased TMA production in the bowel (reflecting
observational study, these researchers found that
diet and the composition of the intestinal micro-
plasma trimethylamine-N-oxide (TMAO) levels were
biota), increased TMA entry from the bowel to blood
increased in patients with HF undergoing coronary
(signaling intestinal barrier function), increased FMO
angiography (n ¼ 720) compared with healthy con-
activity, or decreased clearance of TMAO from the
trols (n ¼ 300). TMAO, an amine oxide, is ultimately
plasma compartment (or some combination of these).
derived from foods containing
(such as
It would be of interest in future studies to know more
red meat) or phosphatidylcholine (lecithin), the
about diet and use of drugs that might affect in-
main dietary source of choline (found in eggs).
testinal microbiota such as antibiotics and acid-
Choline is metabolized by gut bacteria to produce the
suppressing agents.
L -carnitine
(TMA),
There is prior evidence that gut flora may be
which freely enters the circulation and is then
altered in HF (1–3). Previous studies also described
oxidized by hepatic flavin monooxygenases (in
increased intestinal permeability in HF, although in
particular FMO3) to form TMAO. TMAO is excreted
the present study, high-sensitivity C-reactive protein
by the kidneys (5–7).
levels were not greater in the higher TMAO group.
intermediate
compound
trimethylamine
Moreover, congestion and right-sided hemodynamics
were not reported, and overall use of loop diuretics
*Editorials published in the Journal of the American College of Cardiology
was low (although somewhat greater in the higher
reflect the views of the authors and do not necessarily represent the
TMAO group) (1–3). In other words, the patients
views of JACC or the American College of Cardiology.
From the British Heart Foundation Cardiovascular Research Centre,
University of Glasgow, Glasgow, Scotland, United Kingdom. Both authors
with higher TMAO levels did not fully fit the
profile of those previously described as most likely
have reported that they have no relationships relevant to the contents of
to have increased intestinal permeability. Future
this paper to disclose.
studies might also report on liver function, hepatic
1916
Cannon and McMurray
JACC VOL. 64, NO. 18, 2014
Gut Feelings About HF
NOVEMBER 4, 2014:1915–6
congestion, or use of drugs that might have influ-
proatherogenic mechanism could account for an in-
enced FMO activity.
crease in mortality in such a short time frame, espe-
In addition, the strong correlation between TMAO
cially in patients with nonobstructive coronary
concentration and kidney function raises the following
disease. As we know, the majority of deaths in such
question: given the importance of the kidney in elim-
patients will have likely been due to pump failure or
inating TMAO, is higher TMAO level just a marker
an arrhythmia, not coronary events. Clearly, this
of renal impairment (7)? Other questions arise—for
is only the beginning of the story of TMAO in HF
example, what is the role of comorbidities, such as
but one for which we should look forward to further
diabetes, in elevating TMAO levels? Diabetes was con-
installments.
siderably more common in the higher TMAO group,
and metformin has been reported to increase TMAO
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
levels (and intestinal microbiota have been postulated
John J.V. McMurray, University of Glasgow, BHF
to play a role in the development of diabetes) (6,8).
Glasgow Cardiovascular Research Centre, 126 Uni-
More puzzling is just how TMAO by itself might
relate to prognosis. It is probably unlikely that a
versity Place, Glasgow, Scotland G12 8TA, United
Kingdom. E-mail: [email protected].
REFERENCES
1. Niebauer J, Volk HD, Kemp M, et al. Endotoxin
and immune activation in chronic heart failure:
a prospective cohort study. Lancet 1999;353:
4. Tang WHW, Wang Z, Fan Y, et al. Prognostic
value of elevated levels of intestinal microbegenerated metabolite trimethylamine-N-oxide
trimethylamine-N-oxide in end-stage renal disease
patients undergoing haemodialysis. Nephrol Dial
Transplant 2006;21:1300–4.
1838–42.
in patients with heart failure: refining the gut hypothesis. J Am Coll Cardiol 2014;64:1908–14.
8. Huo T, Cai S, Lu X, Sha Y, Yu M, Li F. Metabo-
2. Verbrugge FH, Dupont M, Steels P, et al.
Abdominal contributions to cardiorenal dysfunction in congestive heart failure. J Am Coll Cardiol
2013;62:485–95.
3. Sandek A, Bjarnason I, Volk HD, et al. Studies on
bacterial endotoxin and intestinal absorption
function in patients with chronic heart failure. Int J
Cardiol 2012;157:80–5.
5. Tang WH, Wang Z, Levison BS, et al. Intestinal
microbial metabolism of phosphatidylcholine and
cardiovascular risk. N Engl J Med 2013;368:1575–84.
nomic study of biochemical changes in the serum
of type 2 diabetes mellitus patients after the
treatment of metformin hydrochloride. J Pharm
Biomed Anal 2009;49:976–82.
6. Loscalzo J. Gut microbiota, the genome, and diet
in atherogenesis. N Engl J Med 2013;368:1647–9.
7. Bain MA, Faull R, Fornasini G, Milne RW,
Evans AM. Accumulation of trimethylamine and
KEY WORDS biomarkers, heart failure,
prognosis