FMO3--TMAO axis modulates the clinical outcome in chronic heart-failure patients with reduced ejection fraction: evidence from an Asian population

doi:10.1007/s11684-021-0857-2

Frontiers of Medicine

2022, Vol. 16

Issue (2): 295-305 https://doi.org/10.1007/s11684-021-0857-2

本期目录

FMO3--TMAO axis modulates the clinical outcome in chronic heart-failure patients with reduced ejection fraction: evidence from an Asian population

Haoran Wei¹, Mingming Zhao^2,³, Man Huang¹, Chenze Li^1,⁴, Jianing Gao³, Ting Yu¹, Qi Zhang³, Xiaoqing Shen¹, Liang Ji³, Li Ni¹, Chunxia Zhao¹, Zeneng Wang⁵, Erdan Dong^2,³, Lemin Zheng³(

), Dao Wen Wang¹(

)

¹. Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
². Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides; Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China
³. The Institute of Cardiovascular Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China
⁴. Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
⁵. Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA

全文: PDF(864 KB) HTML

Abstract：

The association among plasma trimethylamine-N-oxide (TMAO), FMO3 polymorphisms, and chronic heart failure (CHF) remains to be elucidated. TMAO is a microbiota-dependent metabolite from dietary choline and carnitine. A prospective study was performed including 955 consecutively diagnosed CHF patients with reduced ejection fraction, with the longest follow-up of 7 years. The concentrations of plasma TMAO and its precursors, namely, choline and carnitine, were determined by liquid chromatography-mass spectrometry, and the FMO3 E158K polymorphisms (rs2266782) were genotyped. The top tertile of plasma TMAO was associated with a significant increment in hazard ratio (HR) for the composite outcome of cardiovascular death or heart transplantation (HR=1.47, 95% CI=1.13–1.91, P=0.004) compared with the lowest tertile. After adjustments of the potential confounders, higher TMAO could still be used to predict the risk of the primary endpoint (adjusted HR=1.33, 95% CI=1.01–1.74, P=0.039). This result was also obtained after further adjustment for carnitine (adjusted HR=1.33, 95% CI=1.01–1.74, P=0.039). The FMO3 rs2266782 polymorphism was associated with the plasma TMAO concentrations in our cohort, and lower TMAO levels were found in the AA-genotype. Thus, higher plasma TMAO levels indicated increased risk of the composite outcome of cardiovascular death or heart transplantation independent of potential confounders, and the FMO3 AA-genotype in rs2266782 was related to lower plasma TMAO levels.

Key words： chronic heart failure trimethylamine-N-oxide flavin monooxygenase 3 single nucleotide polymorphism

收稿日期: 2020-10-24 出版日期: 2022-04-26

Corresponding Author(s): Lemin Zheng,Dao Wen Wang

作者简介:

Peng Lu, Renxing Wang, and Yue Xing contributed equally to this work.

引用本文:

. [J]. Frontiers of Medicine, 2022, 16(2): 295-305.
Haoran Wei, Mingming Zhao, Man Huang, Chenze Li, Jianing Gao, Ting Yu, Qi Zhang, Xiaoqing Shen, Liang Ji, Li Ni, Chunxia Zhao, Zeneng Wang, Erdan Dong, Lemin Zheng, Dao Wen Wang. FMO3--TMAO axis modulates the clinical outcome in chronic heart-failure patients with reduced ejection fraction: evidence from an Asian population. Front. Med., 2022, 16(2): 295-305.

链接本文:

https://academic.hep.com.cn/fmd/CN/10.1007/s11684-021-0857-2
https://academic.hep.com.cn/fmd/CN/Y2022/V16/I2/295

	ALL (n=915)	Tertile 1≤1.574 (n=306)	Tertile 2 1.574–3.770 (n=304)	Tertile 3>3.770 (n=305)	P value
Demographic characteristics
?Age (year)	57.1±14.1	55.1±13.9	56.1±13.8	60.2±14.0	<0.001
?Male (%)	69.9	67.3	72.4	70.2	0.400
?Smoker (%)	41.4	41.2	38.5	44.6	0.310
?Drinker (%)	26.8	24.3	29.3	26.9	0.364
?SBP (mmHg)	122 (110–138)	120 (107–137)	124 (110–137)	123 (110–140)	0.085
?DBP (mmHg)	80 (69–90)	78 (69–88)	88 (73–102)	79 (68–89)	0.483
?Heart rate (beat per min)	86 (75–102)	90 (76–104)	88 (73–102)	84 (74–100)	0.079
?NYHA class II/III/IV	24.6/44.8/30.6	25.2/40.8/34.0	28.6/46.7/24.7	20.0/46.9/33.1	0.021
Medical history (%)
?Hypertension	77.4	79.7	75.3	77	0.420
?Diabetes	28.7	28.1	22	36.1	0.001
?Dyslipidemia	16.7	16.7	17.1	16.4	0.970
?Coronary artery disease	29.5	29.1	26.3	33.1	0.180
Laboratory measurements
?Fasting glucose (mmol/L)	5.74 (5.02–7.27)	5.77 (5.00–7.36)	5.64 (5.02–6.62)	5.89 (5.07–7.57)	0.518
?Total cholesterol (mmol/L)	3.74 (3.13–4.52)	3.76 (3.10–4.55)	3.83 (3.23–4.50)	3.63 (3.02–4.44)	0.287
?Triglycerides (mmol/L)	1.08 (0.79–1.55)	1.08 (0.80–1.49)	1.06 (0.84–1.64)	1.08 (0.75–1.55)	0.128
?LDL cholesterol (mmol/L)	2.37 (1.87–2.95)	2.37 (1.87–3.02)	2.42 (1.98–2.94)	2.28 (1.79–2.93)	0.440
?HDL cholesterol (mmol/L)	0.88 (0.71–1.10)	0.89 (0.68–1.12)	0.91 (0.73–1.11)	0.86 (0.71–1.05)	0.259
?NT-proBNP (ng/L)	3804 (1745–8584)	3348 (1566–7904)	3159 (1516–7980)	5038 (2197–9168)	<0.001
?hsCRP (mg/L)	5.55 (2.08–15.58)	8.10 (3.20–23.80)	4.20 (1.80–11.00)	4.90 (1.70–21.90)	0.382
?eGFR (mL/min/1.73 m²)	71.1 (54.7–85.5)	72.6 (57.1–88.3)	74.8 (59.5–89.0)	62.8 (45.8–80.0)	<0.001
?Hemoglobin (g/L)	134 (119–147)	133 (118–145)	135 (123–148)	133 (117–147)	0.198
Echocardiography
?LVEDD (mm)	64 (58–49)	63 (58–69)	64 (59–70)	64 (58–70)	0.260
?LVEF (%)	31 (25–36)	31 (25–36)	31 (26–35)	30 (25–36)	0.641
Medication (%)
?Diuretics	84.9	84	82.2	88.5	0.082
?ACEI/ARB	85.5	82	91.4	83	0.001
?Beta-blocker	64.2	62.4	65.5	64.6	0.722
?Spironolactone	81.5	80.1	80.9	83.6	0.501

Tab.1

Fig.1

Tab.2

Fig.2

Fig.3

Fig.4

1	MD Huffman, JD Berry, H Ning, AR Dyer, DB Garside, X Cai, ML Daviglus, DM Lloyd-Jones. Lifetime risk for heart failure among white and black Americans: cardiovascular lifetime risk pooling project. J Am Coll Cardiol 2013; 61(14): 1510–1517 https://doi.org/10.1016/j.jacc.2013.01.022 pmid: 23500287
2	N Sato. Epidemiology of heart failure in Asia. Heart Fail Clin 2015; 11(4): 573–579 https://doi.org/10.1016/j.hfc.2015.07.009 pmid: 26462097
3	Z Wang, E Klipfell, BJ Bennett, R Koeth, BS Levison, B Dugar, AE Feldstein, EB Britt, X Fu, YM Chung, Y Wu, P Schauer, JD Smith, H Allayee, WH Tang, JA DiDonato, AJ Lusis, SL Hazen. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011; 472(7341): 57–63 https://doi.org/10.1038/nature09922 pmid: 21475195
4	WH Tang, Z Wang, BS Levison, RA Koeth, EB Britt, X Fu, Y Wu, SL Hazen. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 2013; 368(17): 1575–1584 https://doi.org/10.1056/NEJMoa1109400 pmid: 23614584
5	WH Tang, Z Wang, Y Fan, B Levison, JE Hazen, LM Donahue, Y Wu, SL Hazen. Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis. J Am Coll Cardiol 2014; 64(18): 1908–1914 https://doi.org/10.1016/j.jacc.2014.02.617 pmid: 25444145
6	Z Wang, WH Tang, JA Buffa, X Fu, EB Britt, RA Koeth, BS Levison, Y Fan, Y Wu, SL Hazen. Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. Eur Heart J 2014; 35(14): 904–910 https://doi.org/10.1093/eurheartj/ehu002 pmid: 24497336
7	V Senthong, XS Li, T Hudec, J Coughlin, Y Wu, B Levison, Z Wang, SL Hazen, WH Tang. Plasma trimethylamine N-oxide, a gut microbe-generated phosphatidylcholine metabolite, is associated with atherosclerotic burden. J Am Coll Cardiol 2016; 67(22): 2620–2628 https://doi.org/10.1016/j.jacc.2016.03.546 pmid: 27256833
8	XS Li, S Obeid, R Klingenberg, B Gencer, F Mach, L Räber, S Windecker, N Rodondi, D Nanchen, O Muller, MX Miranda, CM Matter, Y Wu, L Li, Z Wang, HS Alamri, V Gogonea, YM Chung, WH Tang, SL Hazen, TF Lüscher. Gut microbiota-dependent trimethylamine N-oxide in acute coronary syndromes: a prognostic marker for incident cardiovascular events beyond traditional risk factors. Eur Heart J 2017; 38(11): 814–824 https://doi.org/10.1093/eurheartj/ehw582 pmid: 28077467
9	BJ Bennett, TQ de Aguiar Vallim, Z Wang, DM Shih, Y Meng, J Gregory, H Allayee, R Lee, M Graham, R Crooke, PA Edwards, SL Hazen, AJ Lusis. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab 2013; 17(1): 49–60 https://doi.org/10.1016/j.cmet.2012.12.011 pmid: 23312283
10	M Warrier, DM Shih, AC Burrows, D Ferguson, AD Gromovsky, AL Brown, S Marshall, A McDaniel, RC Schugar, Z Wang, J Sacks, X Rong, TA Vallim, J Chou, PT Ivanova, DS Myers, HA Brown, RG Lee, RM Crooke, MJ Graham, X Liu, P Parini, P Tontonoz, AJ Lusis, SL Hazen, RE Temel, JM Brown. The TMAO-generating enzyme flavin monooxygenase 3 is a central regulator of cholesterol balance. Cell Rep 2015; 10(3): 326–338 https://doi.org/10.1016/j.celrep.2014.12.036 pmid: 25600868
11	RC Schugar, DM Shih, M Warrier, RN Helsley, A Burrows, D Ferguson, AL Brown, AD Gromovsky, M Heine, A Chatterjee, L Li, XS Li, Z Wang, B Willard, Y Meng, H Kim, N Che, C Pan, RG Lee, RM Crooke, MJ Graham, RE Morton, CD Langefeld, SK Das, LL Rudel, N Zein, AJ McCullough, S Dasarathy, WHW Tang, BO Erokwu, CA Flask, M Laakso, M Civelek, SV Naga Prasad, J Heeren, AJ Lusis, SL Hazen, JM Brown. The TMAO-producing enzyme flavin-containing monooxygenase 3 regulates obesity and the beiging of white adipose tissue. Cell Rep 2017; 20(1): 279 https://doi.org/10.1016/j.celrep.2017.06.053 pmid: 28683320
12	SB Koukouritaki, MT Poch, ET Cabacungan, DG McCarver, RN Hines. Discovery of novel flavin-containing monooxygenase 3 (FMO3) single nucleotide polymorphisms and functional analysis of upstream haplotype variants. Mol Pharmacol 2005; 68(2): 383–392 https://doi.org/10.1124/mol.105.012062 pmid: 15858076
13	A Türkanoğlu Özçelik, B Can Demirdöğen, S Demirkaya, O Adalı. Flavin containing monooxygenase 3 genetic polymorphisms Glu158Lys and Glu308Gly and their relation to ischemic stroke. Gene 2013; 521(1): 116–121 https://doi.org/10.1016/j.gene.2013.03.010 pmid: 23510775
14	CW Yancy, M Jessup, B Bozkurt, J Butler, DE Jr Casey, MH Drazner, GC Fonarow, SA Geraci, T Horwich, JL Januzzi, MR Johnson, EK Kasper, WC Levy, FA Masoudi, PE McBride, JJ McMurray, JE Mitchell, PN Peterson, B Riegel, F Sam, LW Stevenson, WH Tang, EJ Tsai, BL Wilkoff; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 62(16): e147–e239 https://doi.org/10.1016/j.jacc.2013.05.019 pmid: 23747642
15	RA Koeth, Z Wang, BS Levison, JA Buffa, E Org, BT Sheehy, EB Britt, X Fu, Y Wu, L Li, JD Smith, JA DiDonato, J Chen, H Li, GD Wu, JD Lewis, M Warrier, JM Brown, RM Krauss, WH Tang, FD Bushman, AJ Lusis, SL Hazen. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013; 19(5): 576–585 https://doi.org/10.1038/nm.3145 pmid: 23563705
16	Y Zhu, E Jameson, M Crosatti, H Schäfer, K Rajakumar, TD Bugg, Y Chen. Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota. Proc Natl Acad Sci USA 2014; 111(11): 4268–4273 https://doi.org/10.1073/pnas.1316569111 pmid: 24591617
17	RA Koeth, BS Levison, MK Culley, JA Buffa, Z Wang, JC Gregory, E Org, Y Wu, L Li, JD Smith, WHW Tang, JA DiDonato, AJ Lusis, SL Hazen. γ-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO. Cell Metab 2014; 20(5): 799–812 https://doi.org/10.1016/j.cmet.2014.10.006 pmid: 25440057
18	CE Cho, MA Caudill. Trimethylamine-N-oxide: friend, foe, or simply caught in the cross-fire? Trends Endocrinol Metab 2017; 28(2): 121–130 https://doi.org/10.1016/j.tem.2016.10.005 pmid: 27825547
19	JR Stubbs, JA House, AJ Ocque, S Zhang, C Johnson, C Kimber, K Schmidt, A Gupta, JB Wetmore, TD Nolin, JA Spertus, AS Yu. Serum trimethylamine-N-oxide is elevated in CKD and correlates with coronary atherosclerosis burden. J Am Soc Nephrol 2016; 27(1): 305–313 https://doi.org/10.1681/ASN.2014111063 pmid: 26229137
20	T Shafi, NR Powe, TW Meyer, S Hwang, X Hai, ML Melamed, T Banerjee, J Coresh, TH Hostetter. Trimethylamine N-oxide and cardiovascular events in hemodialysis patients. J Am Soc Nephrol 2017; 28(1): 321–331 https://doi.org/10.1681/ASN.2016030374 pmid: 27436853
21	M Westerterp, AE Bochem, L Yvan-Charvet, AJ Murphy, N Wang, AR Tall. ATP-binding cassette transporters, atherosclerosis, and inflammation. Circ Res 2014; 114(1): 157–170 https://doi.org/10.1161/CIRCRESAHA.114.300738 pmid: 24385509
22	E Kathirvel, K Morgan, G Nandgiri, BC Sandoval, MA Caudill, T Bottiglieri, SW French, TR Morgan. Betaine improves nonalcoholic fatty liver and associated hepatic insulin resistance: a potential mechanism for hepatoprotection by betaine. Am J Physiol Gastrointest Liver Physiol 2010; 299(5): G1068–G1077 https://doi.org/10.1152/ajpgi.00249.2010 pmid: 20724529
23	LJ Wang, HW Zhang, JY Zhou, Y Liu, Y Yang, XL Chen, CH Zhu, RD Zheng, WH Ling, HL Zhu. Betaine attenuates hepatic steatosis by reducing methylation of the MTTP promoter and elevating genomic methylation in mice fed a high-fat diet. J Nutr Biochem 2014; 25(3): 329–336 https://doi.org/10.1016/j.jnutbio.2013.11.007 pmid: 24456734
24	GB Lim. Gut flora—pathogenic role in chronic heart failure. Nat Rev Cardiol 2016; 13(2): 61 https://doi.org/10.1038/nrcardio.2015.200 pmid: 26701213
25	WH Tang. We are not alone: understanding the contributions of intestinal microbial communities and the congested gut in heart failure. JACC Heart Fail 2016; 4(3): 228–229 https://doi.org/10.1016/j.jchf.2015.12.004 pmid: 26874394
26	E Pasini, R Aquilani, C Testa, P Baiardi, S Angioletti, F Boschi, M Verri, F Dioguardi. Pathogenic gut flora in patients with chronic heart failure. JACC Heart Fail 2016; 4(3): 220–227 https://doi.org/10.1016/j.jchf.2015.10.009 pmid: 26682791
27	DM Shih, Z Wang, R Lee, Y Meng, N Che, S Charugundla, H Qi, J Wu, C Pan, JM Brown, T Vallim, BJ Bennett, M Graham, SL Hazen, AJ Lusis. Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis. J Lipid Res 2015; 56(1): 22–37 https://doi.org/10.1194/jlr.M051680 pmid: 25378658
28	J Miao, AV Ling, PV Manthena, ME Gearing, MJ Graham, RM Crooke, KJ Croce, RM Esquejo, CB Clish, Morbid Obesity Study Group; D Vicent, SB Biddinger. Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis. Nat Commun 2015; 6(1): 6498 https://doi.org/10.1038/ncomms7498 pmid: 25849138
29	H Yamazaki, M Shimizu. Survey of variants of human flavin-containing monooxygenase 3 (FMO3) and their drug oxidation activities. Biochem Pharmacol 2013; 85(11): 1588–1593 https://doi.org/10.1016/j.bcp.2013.03.020 pmid: 23567996
30	DM Lambert, OA Mamer, BR Akerman, L Choinière, D Gaudet, P Hamet, EP Treacy. In vivo variability of TMA oxidation is partially mediated by polymorphisms of the FMO3 gene. Mol Genet Metab 2001; 73(3): 224–229 https://doi.org/10.1006/mgme.2001.3189 pmid: 11461189
31	A Morandi, C Zusi, M Corradi, F Olivieri, C Piona, E Fornari, C Maffeis. Minor diplotypes of FMO3 might protect children and adolescents from obesity and insulin resistance. Int J Obes 2018; 42(6): 1243–1248 https://doi.org/10.1038/s41366-018-0100-7 pmid: 29795455
32	Z Shan, T Sun, H Huang, S Chen, L Chen, C Luo, W Yang, X Yang, P Yao, J Cheng, FB Hu, L Liu. Association between microbiota-dependent metabolite trimethylamine-N-oxide and type 2 diabetes. Am J Clin Nutr 2017; 106(3): 888–894 https://doi.org/10.3945/ajcn.117.157107 pmid: 28724646

[1]

Supplemental_materials

Download

Viewed

Full text

Abstract

Cited

Shared

Discussed