96
JACC VOL. 66, NO. 1, 2015
Letters
JULY 7, 2015:91–9
and plaque destabilizing apoptosis of intimal macro-
associated with a worse prognosis independent of
phages and smooth muscle cells. Indeed, both
traditional cardiorenal indices and risk factors. We
4-phenylbutyrate and taurodeoxycholate are re-
believe that the observed associations are hypothesis
ported to exert antiatherosclerotic activity in rodent
generating and call for further rigorous mechanistic
studies and to suppress induction of CD36 and
investigations. Our reported association between
scavenger receptor A in macrophages. In notable
elevated TMAO levels and an adverse prognosis
contrast, TMAO has been found to have a proa-
among subjects with heart failure was recently vali-
therogenic effect in mice and to up-regulate CD36
dated in independent cohorts of patients, including
and scavenger receptor A expression in macrophages
among subjects with chronic systolic heart failure
(5). Although it is quite conceivable that TMAO has
(left ventricular ejection fraction #35%) with well-
some idiosyncratic adverse countervailing effect
characterized
on foam cells that outweighs the benefit of its
as well as in a Norwegian cohort with similar
inhibitory influence on ER stress, it should be noted
observations (2). There are also emerging data to
that only 1 research group to date has reported a
demonstrate the potential interplay between TMAO
proatherogenic role for TMAO; this observation
and other neurohormonal systems that are implicated
needs independent confirmation before it can be
in the pathogenesis of heart failure and other car-
accepted as established fact.
diovascular diseases (3). Thus, a rapidly growing body
echocardiographic
assessments
(1),
of evidence suggests that elevated TMAO levels are *Mark F. McCarty, BA James J. DiNicolantonio, PharmD
strikingly linked to an adverse prognosis in heart
*Catalytic Longevity
determine whether the observed associations are
7831 Rush Rose Drive
causal, which may point toward important potential
Apt. 316
nutritional or other preventive efforts that might
Carlsbad, California 92009
mitigate the observed risk.
failure patients, and further studies are warranted to
E-mail: [email protected]
We agree that the role of dietary choices and
http://dx.doi.org/10.1016/j.jacc.2014.12.077
nutritional exposure as mechanistic underpinnings
Please note: Mark McCarty is the owner of a small nutraceutical company, some of whose products contain carnitine. Dr. DiNicolantonio works for a company that sells L-carnitine, but he does not directly profit from its sale.
of heart failure pathophysiology has been speculated for several decades. However, unlike many commentaries, we are very careful not to make any unfounded speculations regarding any single di-
REFERENCES 1. Tang WH, Wang Z, Fan Y, et al. Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure. J Am Coll Cardiol 2014;64:1907–14. 2. McCarty MF. L-carnitine consumption, its metabolism by intestinal microbiota, and cardiovascular health. Mayo Clin Proc 2013;88:786–9. 3. Rizos I. Three-year survival of patients with heart failure caused by dilated cardiomyopathy and L-carnitine administration. Am Heart J 2000;139: S120–3. 4. Colin-Ramirez
E,
Castillo-Martinez
L,
Orea-Tejeda
A,
Zheng
Y,
Westerhout CM, Ezekowitz JA. Dietary fatty acids intake and mortality in patients with heart failure. Nutrition 2014;30:1366–71. 5. Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013; 19:576–85.
etary source of TMAO production as the sole culprit. The challenge in investigations of this topic is largely due to the difficulties in objective quantification in a rigorous scientific manner. Epidemiological studies are limited in their precision and accuracy to measure dietary composition. In our own published data, systemic levels of L-carnitine, choline, as well as betaine portend poorer long-term prognosis when there is a concomitant increase in circulating TMAO levels. Moreover, we recently discovered the contributory role of g-butyrobetaine, an intermediate metabolite of
L -carnitine
that is
vital to carnitine metabolism in vegetarians/vegans, which may potentially siphon oral L -carnitine avail-
REPLY: Trimethylamine-N-Oxide and
ability upstream from the gastrointestinal tract (4).
Heart Failure
These
novel
observations
further
illustrate
the
complex interplay between dietary nutrients, gut We thank Mr. McCarty and Dr. DiNicolantonio for
microbial metabolism, and host homeostasis, above
their interest and their opinions regarding our dis-
and beyond a simplistic explanation to justify or
covery of a previously unappreciated role for the
refute any therapeutic approaches. It is true that
potential involvement of a specific gut microbiota–
some species of fish have a high TMAO content,
dependent pathway leading to higher circulating
whereas many others do not. A similar situation is
trimethylamine N-oxide (TMAO) levels that were
observed with the content of specific molecular
JACC VOL. 66, NO. 1, 2015
Letters
JULY 7, 2015:91–9
species of omega-3 fatty acids in fish; many have
independent validation. It is not surprising that the
very little.
latest
American
Heart
Association
The issue regarding
L -carnitine
supplementation
College
of
Cardiology/American
guidelines
systematically
re-
itself being beneficial in the setting of chronic heart
viewed the current evidence and do not recom-
failure is far from being substantiated scientifically.
mend the use of otherwise unregulated nutritional
Indeed, we find the characterization and analyses of
supplements, including carnitine, in the treatment
Mr. McCarty and Dr. DiNicolantonio quite misleading.
of chronic heart failure with systolic dysfunction
Although there may be short-term myocardial effects
due to lack of benefit. We believe that the growing
and theoretical benefits, the majority of human
body of data demonstrating mechanistic links be-
studies in this area were performed more than 2
tween the gut microbiota–dependent TMAO pathway
decades ago and predominantly in the acute post-
and
infarction setting (4). Careful review of
L -carnitine
impairment in animal models, coupled with the in-
supplementation studies in chronic heart failure
dependent clinical studies now reporting strong as-
revealed that all were short of duration and in
sociations
patients not even receiving contemporary therapies
adverse prognosis are a call for concern. The po-
(such as angiotensin-converting enzyme inhibitors
tential long-term adverse risk of high-dose, long-
and beta-blockers) (4). The study that was quoted as
term
demonstrating the benefits of L -carnitine included 80
intervention simply cannot be overlooked and re-
subjects not taking beta-blockers (with open-label L -
quires further investigation. In our humble opinion,
both
atherosclerosis
between
L -carnitine
and
elevated
renal
TMAO
supplementation
as
functional
levels
and
nutritional
carnitine use after 3 months) and reported 7 deaths in
the cardioprotective benefits are not firmly estab-
3 years of follow-up (annualized mortality rate of
lished, yet the risks are foreseeable and quantifiable
3.3%, surprisingly low for a population in New York
in some individuals.
Heart Association functional class III to IV). Results did not demonstrate any significant effects on car-
*W.H. Wilson Tang, MD Stanley L. Hazen, MD, PhD
dioprotection as it relates to preventing reinfarction
*Department of Cellular and Molecular Medicine
(p ¼ 0.45) or future development of heart failure
Lerner Research Institute
(p ¼ 0.21) with L -carnitine supplementation (4). When
Cleveland Clinic
the studies with
JACC VOL. 66, NO. 1, 2015
Letters
JULY 7, 2015:91–9
and plaque destabilizing apoptosis of intimal macro-
associated with a worse prognosis independent of
phages and smooth muscle cells. Indeed, both
traditional cardiorenal indices and risk factors. We
4-phenylbutyrate and taurodeoxycholate are re-
believe that the observed associations are hypothesis
ported to exert antiatherosclerotic activity in rodent
generating and call for further rigorous mechanistic
studies and to suppress induction of CD36 and
investigations. Our reported association between
scavenger receptor A in macrophages. In notable
elevated TMAO levels and an adverse prognosis
contrast, TMAO has been found to have a proa-
among subjects with heart failure was recently vali-
therogenic effect in mice and to up-regulate CD36
dated in independent cohorts of patients, including
and scavenger receptor A expression in macrophages
among subjects with chronic systolic heart failure
(5). Although it is quite conceivable that TMAO has
(left ventricular ejection fraction #35%) with well-
some idiosyncratic adverse countervailing effect
characterized
on foam cells that outweighs the benefit of its
as well as in a Norwegian cohort with similar
inhibitory influence on ER stress, it should be noted
observations (2). There are also emerging data to
that only 1 research group to date has reported a
demonstrate the potential interplay between TMAO
proatherogenic role for TMAO; this observation
and other neurohormonal systems that are implicated
needs independent confirmation before it can be
in the pathogenesis of heart failure and other car-
accepted as established fact.
diovascular diseases (3). Thus, a rapidly growing body
echocardiographic
assessments
(1),
of evidence suggests that elevated TMAO levels are *Mark F. McCarty, BA James J. DiNicolantonio, PharmD
strikingly linked to an adverse prognosis in heart
*Catalytic Longevity
determine whether the observed associations are
7831 Rush Rose Drive
causal, which may point toward important potential
Apt. 316
nutritional or other preventive efforts that might
Carlsbad, California 92009
mitigate the observed risk.
failure patients, and further studies are warranted to
E-mail: [email protected]
We agree that the role of dietary choices and
http://dx.doi.org/10.1016/j.jacc.2014.12.077
nutritional exposure as mechanistic underpinnings
Please note: Mark McCarty is the owner of a small nutraceutical company, some of whose products contain carnitine. Dr. DiNicolantonio works for a company that sells L-carnitine, but he does not directly profit from its sale.
of heart failure pathophysiology has been speculated for several decades. However, unlike many commentaries, we are very careful not to make any unfounded speculations regarding any single di-
REFERENCES 1. Tang WH, Wang Z, Fan Y, et al. Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure. J Am Coll Cardiol 2014;64:1907–14. 2. McCarty MF. L-carnitine consumption, its metabolism by intestinal microbiota, and cardiovascular health. Mayo Clin Proc 2013;88:786–9. 3. Rizos I. Three-year survival of patients with heart failure caused by dilated cardiomyopathy and L-carnitine administration. Am Heart J 2000;139: S120–3. 4. Colin-Ramirez
E,
Castillo-Martinez
L,
Orea-Tejeda
A,
Zheng
Y,
Westerhout CM, Ezekowitz JA. Dietary fatty acids intake and mortality in patients with heart failure. Nutrition 2014;30:1366–71. 5. Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013; 19:576–85.
etary source of TMAO production as the sole culprit. The challenge in investigations of this topic is largely due to the difficulties in objective quantification in a rigorous scientific manner. Epidemiological studies are limited in their precision and accuracy to measure dietary composition. In our own published data, systemic levels of L-carnitine, choline, as well as betaine portend poorer long-term prognosis when there is a concomitant increase in circulating TMAO levels. Moreover, we recently discovered the contributory role of g-butyrobetaine, an intermediate metabolite of
L -carnitine
that is
vital to carnitine metabolism in vegetarians/vegans, which may potentially siphon oral L -carnitine avail-
REPLY: Trimethylamine-N-Oxide and
ability upstream from the gastrointestinal tract (4).
Heart Failure
These
novel
observations
further
illustrate
the
complex interplay between dietary nutrients, gut We thank Mr. McCarty and Dr. DiNicolantonio for
microbial metabolism, and host homeostasis, above
their interest and their opinions regarding our dis-
and beyond a simplistic explanation to justify or
covery of a previously unappreciated role for the
refute any therapeutic approaches. It is true that
potential involvement of a specific gut microbiota–
some species of fish have a high TMAO content,
dependent pathway leading to higher circulating
whereas many others do not. A similar situation is
trimethylamine N-oxide (TMAO) levels that were
observed with the content of specific molecular
JACC VOL. 66, NO. 1, 2015
Letters
JULY 7, 2015:91–9
species of omega-3 fatty acids in fish; many have
independent validation. It is not surprising that the
very little.
latest
American
Heart
Association
The issue regarding
L -carnitine
supplementation
College
of
Cardiology/American
guidelines
systematically
re-
itself being beneficial in the setting of chronic heart
viewed the current evidence and do not recom-
failure is far from being substantiated scientifically.
mend the use of otherwise unregulated nutritional
Indeed, we find the characterization and analyses of
supplements, including carnitine, in the treatment
Mr. McCarty and Dr. DiNicolantonio quite misleading.
of chronic heart failure with systolic dysfunction
Although there may be short-term myocardial effects
due to lack of benefit. We believe that the growing
and theoretical benefits, the majority of human
body of data demonstrating mechanistic links be-
studies in this area were performed more than 2
tween the gut microbiota–dependent TMAO pathway
decades ago and predominantly in the acute post-
and
infarction setting (4). Careful review of
L -carnitine
impairment in animal models, coupled with the in-
supplementation studies in chronic heart failure
dependent clinical studies now reporting strong as-
revealed that all were short of duration and in
sociations
patients not even receiving contemporary therapies
adverse prognosis are a call for concern. The po-
(such as angiotensin-converting enzyme inhibitors
tential long-term adverse risk of high-dose, long-
and beta-blockers) (4). The study that was quoted as
term
demonstrating the benefits of L -carnitine included 80
intervention simply cannot be overlooked and re-
subjects not taking beta-blockers (with open-label L -
quires further investigation. In our humble opinion,
both
atherosclerosis
between
L -carnitine
and
elevated
renal
TMAO
supplementation
as
functional
levels
and
nutritional
carnitine use after 3 months) and reported 7 deaths in
the cardioprotective benefits are not firmly estab-
3 years of follow-up (annualized mortality rate of
lished, yet the risks are foreseeable and quantifiable
3.3%, surprisingly low for a population in New York
in some individuals.
Heart Association functional class III to IV). Results did not demonstrate any significant effects on car-
*W.H. Wilson Tang, MD Stanley L. Hazen, MD, PhD
dioprotection as it relates to preventing reinfarction
*Department of Cellular and Molecular Medicine
(p ¼ 0.45) or future development of heart failure
Lerner Research Institute
(p ¼ 0.21) with L -carnitine supplementation (4). When
Cleveland Clinic
the studies with
