- Email: [email protected]
Trimethylamine N-Oxide in Seafood
2916
JACC VOL. 68, NO. 25, 2016
Letters
DECEMBER 27, 2016:2911–9
(p > 0.050 for all comparisons). An association between the response to therapy (decrease in E/E
0
>10%) and inclusion in the highest tertile of baseline SENCR was observed (odds ratio [95% confidence interval]: 0.067 [0.005 to 0.823]; p ¼ 0.035; area under the curve [95% CI]: 0.763 [0.558 to 0.967]).
study was supported by Eli Lilly, the Netherlands, which has a partnership with Takeda, the manufacturer of pioglitazone. Metformin tablets and matching placebos were kindly provided by Merck, the Netherlands. Dr. Thum filed patents about the diagnostic use of lncRNAs in cardiovascular diseases. Dr. Thum is founder of Cardior Pharmaceutics GmbH. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Llorente-Cortes and Thum contributed equally to this work.
In a validation cohort of 30 men with wellcontrolled T2DM (mean 55.0 5.7 years of age, glycosylated hemoglobin 7.0 1.0%), SENCR was associated with the percentage change in E/E 0 ( b ¼ –0.708, p ¼ 0.007). Furthermore, pre-treatment SENCR levels were higher in the responder group (responder ¼ 2.10 0.44 arbitrary units; nonresponder ¼ 1.53 0.27 arbitrary units; p ¼ 0.014). We suggest for the first time that circulating lncRNAs are blood-based biomarkers for therapeutic guidance of cardiovascular conditions. We demonstrate that: 1) pre-treatment levels of circulating SENCR are associated with the rate of change in dia-
REFERENCES 1. van der Meer RW, Rijzewijk LJ, de Jong HW, et al. Pioglitazone improves cardiac function and alters myocardial substrate metabolism without affecting cardiac triglyceride accumulation and high-energy phosphate metabolism in patients with well-controlled type 2 diabetes mellitus. Circulation 2009;119:2069–77. 2. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a metaanalysis of randomized trials. JAMA 2007;298:1180–8. 3. Boon RA, Jae N, Holdt L, Dimmeler S. Long noncoding RNAs: from clinical genetics to therapeutic targets? J Am Coll Cardiol 2016;67:1214–26. 4. Kumarswamy R, Bauters C, Volkmann I, et al. Circulating long noncoding RNA, LIPCAR, predicts survival in patients with heart failure. Circ Res 2014; 114:1569–75.
stolic function; 2) levels of circulating SENCR before therapy allow distinction of responders from nonresponders; and 3) SENCR is a better predictor of the response to therapy than are other traditional clinical
Trimethylamine N-Oxide in Seafood
variables. Thus, assessment of lncRNA levels could constitute a major breakthrough in the development
Rotten or Forgotten?
of personalized medicine to guide medical therapy, with important implications in terms of adverse effects and treatment costs.
We read the paper by Senthong et al. (1) with great interest. The research article was accompanied by
*David de Gonzalo-Calvo, PhD Franziska Kenneweg, MSc Claudia Bang, PhD Rocío Toro, MD, PhD Rutger W. van der Meer, MD, PhD Luuk J. Rijzewijk, MD Johannes W.A. Smit, MD, PhD Hildo J. Lamb, MD, PhD *Vicenta Llorente-Cortes, PhD Thomas Thum, MD, PhD
an editorial comment by Schmid-Schönbein (2).
*Cardiovascular Research Center (CSIC-ICCC)
directly involved in development of atherosclerosis
Biomedical Research Institute Sant Pau (IIB Sant Pau)
therefore seems like a paradox, as intake of seafood
Av. Sant Antoni Maria Claret 167
is generally accepted as cardioprotective.
Pavelló del Convent
During
recent
years,
trimethylamine
N-oxide
(TMAO) has emerged as a putative risk factor linking development of atherosclerosis to intake of socalled unhealthy foods (beef, egg) containing the TMAO precursors carnitine and choline. However, seafood is an important dietary source of free TMAO, in addition to the TMAO precursors carnitine and choline, a fact that appears to be commonly overlooked. To us, the hypothesis that TMAO is
In fish and marine invertebrates, TMAO exerts
08025 Barcelona
important osmoregulatory functions, and the mole-
Spain
cule can be found in high concentrations in these
E-mail: [email protected] OR [email protected]
organisms (3). TMAO from fish may be absorbed
http://dx.doi.org/10.1016/j.jacc.2016.10.014
directly from the gastrointestinal tract and give rise
Please note: The authors are part of the Cardiolinc network. The authors thank Ignasi Gich, MD, PhD (IIB Sant Pau, Barcelona, Spain) and Pablo Martínez Camblor, PhD (Geisel School of Medicine, Hanover, New Hampshire) for their excellent statistical support. This work was supported by the Merck Health Foundation (Merck Serono Research Award in Cardiometabolism 2014), Fundación Pública Andaluza Progreso y Salud (PI-0011/2014), Instituto de Salud Carlos III (FIS PI14/01729), ERC Consolidator grant LongHeart, DFG Th903/10-1, the IFB-Tx (BMBF), the 7th FP-funded EU project HOMAGE and the Foundation Leducq; and cofinanced by the European Fund for Regional Development (E.F.R.D.) and Fundació Marató TV3 (201521 10). The PIRAMID
to plasma levels that are orders of magnitude higher than after beef or egg intake (4). Indeed, TMAO has previously been suggested as a marker of seafood consumption (5). In contrast, TMAO derived from carnitine and choline is produced in the liver, by oxidation of trimethylamine (TMA) produced by gut bacteria. Hepatic oxidation of TMA to TMAO may
JACC VOL. 68, NO. 25, 2016
Letters
DECEMBER 27, 2016:2911–9
be regarded as a detoxifying mechanism, and humans
lacking
monooxygenase
the 3)
converting experience
enzyme the
fish
virtually none. As physicians seeing patients who
(flavin
often take fish oil supplements, we often advise
odor
them that “Blubber is blubber—and oil extracted
syndrome. Whereas TMAO is odorless, the volatile
from the blubber of a fish can have fatty acid
compound TMA has the smell of spoiled fish.
composition nearly identical to bacon fat! So you
Taken together, TMAO—contrary to TMA—does not
have to read the label and count up the omega-3
smell bad, and its ingestion via seafood should
fatty acids!” We simply reject the hypothesis and
probably not be regarded as fishy business.
oversimplification that anything and everything derived from the sea and ingested in any quantity
*Jørgen Valeur, MD, PhD Bjarne Landfald, MSc, PhD Arnold Berstad, MD, PhD Jan Raa, MSc, PhD *Unger-Vetlesen’s Institute
must be “heart healthy.” We also respectfully point out that nowhere in our studies do we argue for or against any specific food types that are beneficial or harmful, nor do we issue any statements regarding odor. Rather, we focus
Lovisenberg
scientifically on the exact components (phosphati-
Diaconal Hospital
dylcholine, carnitine) as chemical precursors for
NO-0440 Oslo
certain microbial metabolic pathways that have been
Norway
mechanistically
E-mail: [email protected]
observations have now been validated in multiple
http://dx.doi.org/10.1016/j.jacc.2016.08.077
independent cohorts with distinct population char-
Please note: The authors have reported that they have no relationships relevant to the content of this paper to disclose.
acteristics,
REFERENCES 1. Senthong V, Li XS, Hudec T, et al. Plasma trimethylamine N-oxide, a gut microbe-generated phosphatidylcholine metabolite, is associated with atherosclerotic burden. J Am Coll Cardiol 2016;67:2620–8. 2. Schmid-Schönbein GW. Can fishy odor be a risk factor for coronary artery
linked
including
with
our
atherogenesis.
detailed
Our
angiographic
evaluation. There is no doubt that many factors (e.g., quantity, quality and preparation methods, underlying comorbid conditions of host) can influence whether fish or any other food types are truly beneficial. Our central hypothesis focuses on the potential contribution of dietary-induced gut micro-
disease? J Am Coll Cardiol 2016;67:2629–30.
bial metabolism to atherogenesis, not fish per se.
3. Seibel BA, Walsh PJ. Trimethylamine oxide accumulation in marine animals: relationship to acylglycerol storage. J Exp Biol 2002;205:297–306.
TMAO-rich fish in patients who have been associated
4. Cho CE, Taesuwan S, Malysheva OV, et al. Trimethylamine-N-oxide (TMAO) response to animal source foods varies among healthy young men and is influenced by their gut microbiota composition: a randomized controlled trial. Mol Nutr Food Res 2016 Jul 5 [E-pub ahead of print]. 5. Eisert R, Oftedal OT, Lever M, Ramdohr S, Breier BH, Barrell GK. Detection of food intake in a marine mammal using marine osmolytes and their analogues as dietary biomarkers. Marine Ecology Progress Series 2005;300: 213–28.
REPLY: Trimethylamine N-Oxide in Seafood
Nevertheless, the benefits of large quantities of with elevated TMAO levels (e.g., chronic kidney disease) have not been demonstrated, and in fact protein restriction in a renal diet actually limits rather than encourages the amount ingested. We believe that better understanding of the mechanistic pathways leading to this dynamic host-microbial interplay requires precise quantification with such mechanistic biomarkers serving as a therapeutic target rather than merely considering the benefit and harm of broad
Rotten or Forgotten?
food groups.
We thank Dr. Valeur and colleagues for making their case for cardioprotective effects of seafood and the
*W.H. Wilson Tang, MD Stanley L. Hazen, MD PhD
apparent “paradox” that they viewed as challenging
*Center for Clinical Genomics
our central hypothesis. Indeed, circulating levels do
Department of Cellular and Molecular Medicine
rise when certain species of fish or seafood are
Lerner Research Institute
ingested (especially deep sea fish in which trime-
Heart and Vascular Institute
thylamine N-oxide [TMAO] is generated and serves
Cleveland Clinic
as a form of antifreeze, but others do not have high
9500 Euclid Avenue
levels), and humans have very efficient clearance
Desk J3-4
mechanisms via the kidneys. However, similar to
Cleveland, Ohio 44195
omega-3 polyunsaturated fatty acids, not all fish
E-mail: [email protected]
have the same amounts of TMAO—and many have
http://dx.doi.org/10.1016/j.jacc.2016.09.969
2917
JACC VOL. 68, NO. 25, 2016
Letters
DECEMBER 27, 2016:2911–9
(p > 0.050 for all comparisons). An association between the response to therapy (decrease in E/E
0
>10%) and inclusion in the highest tertile of baseline SENCR was observed (odds ratio [95% confidence interval]: 0.067 [0.005 to 0.823]; p ¼ 0.035; area under the curve [95% CI]: 0.763 [0.558 to 0.967]).
study was supported by Eli Lilly, the Netherlands, which has a partnership with Takeda, the manufacturer of pioglitazone. Metformin tablets and matching placebos were kindly provided by Merck, the Netherlands. Dr. Thum filed patents about the diagnostic use of lncRNAs in cardiovascular diseases. Dr. Thum is founder of Cardior Pharmaceutics GmbH. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Llorente-Cortes and Thum contributed equally to this work.
In a validation cohort of 30 men with wellcontrolled T2DM (mean 55.0 5.7 years of age, glycosylated hemoglobin 7.0 1.0%), SENCR was associated with the percentage change in E/E 0 ( b ¼ –0.708, p ¼ 0.007). Furthermore, pre-treatment SENCR levels were higher in the responder group (responder ¼ 2.10 0.44 arbitrary units; nonresponder ¼ 1.53 0.27 arbitrary units; p ¼ 0.014). We suggest for the first time that circulating lncRNAs are blood-based biomarkers for therapeutic guidance of cardiovascular conditions. We demonstrate that: 1) pre-treatment levels of circulating SENCR are associated with the rate of change in dia-
REFERENCES 1. van der Meer RW, Rijzewijk LJ, de Jong HW, et al. Pioglitazone improves cardiac function and alters myocardial substrate metabolism without affecting cardiac triglyceride accumulation and high-energy phosphate metabolism in patients with well-controlled type 2 diabetes mellitus. Circulation 2009;119:2069–77. 2. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a metaanalysis of randomized trials. JAMA 2007;298:1180–8. 3. Boon RA, Jae N, Holdt L, Dimmeler S. Long noncoding RNAs: from clinical genetics to therapeutic targets? J Am Coll Cardiol 2016;67:1214–26. 4. Kumarswamy R, Bauters C, Volkmann I, et al. Circulating long noncoding RNA, LIPCAR, predicts survival in patients with heart failure. Circ Res 2014; 114:1569–75.
stolic function; 2) levels of circulating SENCR before therapy allow distinction of responders from nonresponders; and 3) SENCR is a better predictor of the response to therapy than are other traditional clinical
Trimethylamine N-Oxide in Seafood
variables. Thus, assessment of lncRNA levels could constitute a major breakthrough in the development
Rotten or Forgotten?
of personalized medicine to guide medical therapy, with important implications in terms of adverse effects and treatment costs.
We read the paper by Senthong et al. (1) with great interest. The research article was accompanied by
*David de Gonzalo-Calvo, PhD Franziska Kenneweg, MSc Claudia Bang, PhD Rocío Toro, MD, PhD Rutger W. van der Meer, MD, PhD Luuk J. Rijzewijk, MD Johannes W.A. Smit, MD, PhD Hildo J. Lamb, MD, PhD *Vicenta Llorente-Cortes, PhD Thomas Thum, MD, PhD
an editorial comment by Schmid-Schönbein (2).
*Cardiovascular Research Center (CSIC-ICCC)
directly involved in development of atherosclerosis
Biomedical Research Institute Sant Pau (IIB Sant Pau)
therefore seems like a paradox, as intake of seafood
Av. Sant Antoni Maria Claret 167
is generally accepted as cardioprotective.
Pavelló del Convent
During
recent
years,
trimethylamine
N-oxide
(TMAO) has emerged as a putative risk factor linking development of atherosclerosis to intake of socalled unhealthy foods (beef, egg) containing the TMAO precursors carnitine and choline. However, seafood is an important dietary source of free TMAO, in addition to the TMAO precursors carnitine and choline, a fact that appears to be commonly overlooked. To us, the hypothesis that TMAO is
In fish and marine invertebrates, TMAO exerts
08025 Barcelona
important osmoregulatory functions, and the mole-
Spain
cule can be found in high concentrations in these
E-mail: [email protected] OR [email protected]
organisms (3). TMAO from fish may be absorbed
http://dx.doi.org/10.1016/j.jacc.2016.10.014
directly from the gastrointestinal tract and give rise
Please note: The authors are part of the Cardiolinc network. The authors thank Ignasi Gich, MD, PhD (IIB Sant Pau, Barcelona, Spain) and Pablo Martínez Camblor, PhD (Geisel School of Medicine, Hanover, New Hampshire) for their excellent statistical support. This work was supported by the Merck Health Foundation (Merck Serono Research Award in Cardiometabolism 2014), Fundación Pública Andaluza Progreso y Salud (PI-0011/2014), Instituto de Salud Carlos III (FIS PI14/01729), ERC Consolidator grant LongHeart, DFG Th903/10-1, the IFB-Tx (BMBF), the 7th FP-funded EU project HOMAGE and the Foundation Leducq; and cofinanced by the European Fund for Regional Development (E.F.R.D.) and Fundació Marató TV3 (201521 10). The PIRAMID
to plasma levels that are orders of magnitude higher than after beef or egg intake (4). Indeed, TMAO has previously been suggested as a marker of seafood consumption (5). In contrast, TMAO derived from carnitine and choline is produced in the liver, by oxidation of trimethylamine (TMA) produced by gut bacteria. Hepatic oxidation of TMA to TMAO may
JACC VOL. 68, NO. 25, 2016
Letters
DECEMBER 27, 2016:2911–9
be regarded as a detoxifying mechanism, and humans
lacking
monooxygenase
the 3)
converting experience
enzyme the
fish
virtually none. As physicians seeing patients who
(flavin
often take fish oil supplements, we often advise
odor
them that “Blubber is blubber—and oil extracted
syndrome. Whereas TMAO is odorless, the volatile
from the blubber of a fish can have fatty acid
compound TMA has the smell of spoiled fish.
composition nearly identical to bacon fat! So you
Taken together, TMAO—contrary to TMA—does not
have to read the label and count up the omega-3
smell bad, and its ingestion via seafood should
fatty acids!” We simply reject the hypothesis and
probably not be regarded as fishy business.
oversimplification that anything and everything derived from the sea and ingested in any quantity
*Jørgen Valeur, MD, PhD Bjarne Landfald, MSc, PhD Arnold Berstad, MD, PhD Jan Raa, MSc, PhD *Unger-Vetlesen’s Institute
must be “heart healthy.” We also respectfully point out that nowhere in our studies do we argue for or against any specific food types that are beneficial or harmful, nor do we issue any statements regarding odor. Rather, we focus
Lovisenberg
scientifically on the exact components (phosphati-
Diaconal Hospital
dylcholine, carnitine) as chemical precursors for
NO-0440 Oslo
certain microbial metabolic pathways that have been
Norway
mechanistically
E-mail: [email protected]
observations have now been validated in multiple
http://dx.doi.org/10.1016/j.jacc.2016.08.077
independent cohorts with distinct population char-
Please note: The authors have reported that they have no relationships relevant to the content of this paper to disclose.
acteristics,
REFERENCES 1. Senthong V, Li XS, Hudec T, et al. Plasma trimethylamine N-oxide, a gut microbe-generated phosphatidylcholine metabolite, is associated with atherosclerotic burden. J Am Coll Cardiol 2016;67:2620–8. 2. Schmid-Schönbein GW. Can fishy odor be a risk factor for coronary artery
linked
including
with
our
atherogenesis.
detailed
Our
angiographic
evaluation. There is no doubt that many factors (e.g., quantity, quality and preparation methods, underlying comorbid conditions of host) can influence whether fish or any other food types are truly beneficial. Our central hypothesis focuses on the potential contribution of dietary-induced gut micro-
disease? J Am Coll Cardiol 2016;67:2629–30.
bial metabolism to atherogenesis, not fish per se.
3. Seibel BA, Walsh PJ. Trimethylamine oxide accumulation in marine animals: relationship to acylglycerol storage. J Exp Biol 2002;205:297–306.
TMAO-rich fish in patients who have been associated
4. Cho CE, Taesuwan S, Malysheva OV, et al. Trimethylamine-N-oxide (TMAO) response to animal source foods varies among healthy young men and is influenced by their gut microbiota composition: a randomized controlled trial. Mol Nutr Food Res 2016 Jul 5 [E-pub ahead of print]. 5. Eisert R, Oftedal OT, Lever M, Ramdohr S, Breier BH, Barrell GK. Detection of food intake in a marine mammal using marine osmolytes and their analogues as dietary biomarkers. Marine Ecology Progress Series 2005;300: 213–28.
REPLY: Trimethylamine N-Oxide in Seafood
Nevertheless, the benefits of large quantities of with elevated TMAO levels (e.g., chronic kidney disease) have not been demonstrated, and in fact protein restriction in a renal diet actually limits rather than encourages the amount ingested. We believe that better understanding of the mechanistic pathways leading to this dynamic host-microbial interplay requires precise quantification with such mechanistic biomarkers serving as a therapeutic target rather than merely considering the benefit and harm of broad
Rotten or Forgotten?
food groups.
We thank Dr. Valeur and colleagues for making their case for cardioprotective effects of seafood and the
*W.H. Wilson Tang, MD Stanley L. Hazen, MD PhD
apparent “paradox” that they viewed as challenging
*Center for Clinical Genomics
our central hypothesis. Indeed, circulating levels do
Department of Cellular and Molecular Medicine
rise when certain species of fish or seafood are
Lerner Research Institute
ingested (especially deep sea fish in which trime-
Heart and Vascular Institute
thylamine N-oxide [TMAO] is generated and serves
Cleveland Clinic
as a form of antifreeze, but others do not have high
9500 Euclid Avenue
levels), and humans have very efficient clearance
Desk J3-4
mechanisms via the kidneys. However, similar to
Cleveland, Ohio 44195
omega-3 polyunsaturated fatty acids, not all fish
E-mail: [email protected]
have the same amounts of TMAO—and many have
http://dx.doi.org/10.1016/j.jacc.2016.09.969
2917