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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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Front. Med.    2022, Vol. 16 Issue (2) : 295-305    https://doi.org/10.1007/s11684-021-0857-2
RESEARCH ARTICLE
FMO3--TMAO axis modulates the clinical outcome in chronic heart-failure patients with reduced ejection fraction: evidence from an Asian population
Haoran Wei1, Mingming Zhao2,3, Man Huang1, Chenze Li1,4, Jianing Gao3, Ting Yu1, Qi Zhang3, Xiaoqing Shen1, Liang Ji3, Li Ni1, Chunxia Zhao1, Zeneng Wang5, Erdan Dong2,3, 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
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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.
Keywords chronic heart failure      trimethylamine-N-oxide      flavin monooxygenase 3      single nucleotide polymorphism     
Corresponding Author(s): Lemin Zheng,Dao Wen Wang   
About author:

Mingsheng Sun and Mingxiao Yang contributed equally to this work.
Just Accepted Date: 08 May 2021   Online First Date: 21 June 2021    Issue Date: 26 April 2022
 Cite this article:   
Haoran Wei,Mingming Zhao,Man Huang, et al. FMO3--TMAO axis modulates the clinical outcome in chronic heart-failure patients with reduced ejection fraction: evidence from an Asian population[J]. Front. Med., 2022, 16(2): 295-305.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0857-2
https://academic.hep.com.cn/fmd/EN/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  Baseline characteristics of the HFrEF cohort stratified by TMAO levels (n=915)
Fig.1  The Kaplan–Meier curves for primary outcome with metabolites stratified by tertiles. The Kaplan–Meier curves for primary outcome with (A) trimethylamine-N-oxide (TMAO), (B) carnitine, and (C) choline stratified by tertiles. The P value was calculated by log-rank test.
Variables Tertile 1 Tertile 2 Tertile 3 P for Trend
≤1.574 1.574–3.770 >3.770
Unadjusted 1 0.84 (0.63–1.12) 1.47 (1.13–1.91)** <0.001
Adjusted model 1 1 0.83 (0.62–1.10) 1.34 (1.02–1.75)* 0.002
Adjusted model 2 1 0.87 (0.65–1.19) 1.34 (1.02–1.75)* 0.005
Adjusted model 3 1 0.92 (0.68–1.23) 1.33 (1.01–1.74)* 0.018
Tab.2  The hazard ratios (HRs) for the primary outcome according to the tertile of plasma TMAO level
Fig.2  Hazard ratio (95% CI) of the plasma TMAO levels for the primary outcome among patient subgroups. Comparison of hazard ratios and P values of tertile 3 to tertile 1. Sex, age, smoking status, systolic blood pressure (SBP), diabetes mellitus, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), hemoglobin, left ventricular ejection fraction (LVEF), estimated glomerular filtration rate (eGFR), and N-terminal pro B type natriuretic peptide (NT-proBNP) were adjusted in this model. LVEDD, left ventricular end-diastolic dimension. Thirteen patients have missed LVEDD data.
Fig.3  Association between plasma TMAO and the flavin-containing monooxygenase 3 (FMO3) polymorphisms. The P value was calculated by ANOVA. *P<0.05.
Fig.4  The Kaplan–Meier curves for the primary outcome with plasma TMAO levels among genotypes (A–C). The P value was calculated by log-rank test.
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