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Table 1 The characteristics of the studies included in the systematic review of the association between TMAO and stroke

From: Gut microbiota-associated metabolite trimethylamine N-Oxide and the risk of stroke: a systematic review and dose–response meta-analysis

first author Year/ country Disease status Total Num. of participants Num. of categories/ num. Each group Design Sample source TMAO
μmol/ lit
Age range (y) Male % Main Results Adjustments
Zheng L et al. [16] 2019/ North Korea Community based general population 192 4/86 Nested case-control Serum TMAO CVD: 1.57 (0.79–2.29) μmol/L versus Control: 0.68 (0.23–1.40) μmol/L ≥ 35 35.41 The odds of CVD (defined as CHD+ stroke) at highest TMAO quartile was significantly higher than the lowest (OR 2.73 CI: 1.32–5.63) SBP, BMI, use of anti-HTN, smoking, drinking, T2DM, TC, TG, HDL-C, eGFR
Winther SA et al. [35] 2019/ Denmark Type1 Diabetes 1159 4/ 290 Cohort/ median 15 years follow-up Plasma TMAO 5.7 (3.8–9.9) 46 ± 13 58% The HR of relation between incident stroke and TMAO was 1.08 (0.93–1.27) P = 0.33 age, sex, DM duration, HbA1c, SBP, TC, smoking, UAER
Stubbs JR et al. [21] 2019/ Baseline data of EVOLVE trial of 22 countries Patients receiving maintenance hemodialysis 1243 5/ 248 Cross-sectional Serum TMAO 2.5–1103.1 54 ± 14 (50–60) 60% Higher prevalence of stroke in highest (11%) versus lowest (9%) TMAO quintiles; the HR/SHR of the plasma TMAO and stroke was OR:1.20 (CI: 0.88 to 1.64) age, sex, BMI, SBP, albumin, race, dialysis-duration, smoking, CVD, history of coronary intervention, stroke, MI, BUN
Rexidamu M et al. [20] 2019/ China Patients with first acute ischemic stroke 510 2/ 255 Case- control Serum TMAO Mean: 0.5–18.3 μM, Median: 5.8 (IQR: 3.3–10.0) 65 (IQR: 57–71) 53.3 Mean serum TMAO in patients stroke was higher than controls (P < 0.001). The odds of severe stroke with TMAO levels was 1.22 CI:1.08–1.32) (P < 0.001) Age, CRP, HCY and other factors
Liang Z et al. [36] 2018/ China Patients with arterial fibrillation 179 2 (68/111) Case-control Plasma TMAO Stroke versus non-stroke (8.25 ± 1.58 μM versus 2.22 ± 0.09) Stroke versus non stroke (68.0 ± 9.6; 64.1 ± 13.3) 58.10 Significantly higher plasma TMAO in stroke versus non-stroke; the odds ratio of association between TMAO and stroke was 4.934 (P < 0.001)
Wu C et al. [9] 2018/ China Patient’s with CAS 268 2 (117/ 151) Cohort / 30 day follow up for developing new lesions Plasma TMAO New lesions versus non-new lesions median 5.2 versus 3.2 μmol/L 64.4 56.7 Higher risk of new ischemic brain lesions in highest versus lowest TMAO quartiles (OR: 3.85 (1.37–7.56) (P < 0.001) Age, sex, symptomatic CAS%, CAS, SBP, FSG, LDL-C, HDL-C, hcys, % aortic arch III
Nie J et al. [7] 2018/ China Incident stroke and matched control, using data from the CSPPT 1244 2/ 622 Nested case-control Serum TMAO Stroke: 2.5 (1.6–4.0) control: 2.3 (1.4–3.7) (45–75) 47% Higher serum TMAO in patients with stroke compared with controls (2.5 versus 2.3 μmol/L) and higher odds of stroke in highest versus lowest TMAO tertile (OR:1.43 (1.02–2.01) P = 0.04 SBP, BMI, FSG, TC, eGFR, hcys, folate, smoking, time-averaged SBP in treatment period, choline, L carnitine
Haghikia A et al. [37] 2018/ Germany Patients with incident stroke 78 4/20 Cohort / 1 year follow-up Plasma TMAO 59 ± 14 69% Higher odds of incident CVD event (including stroke) in highest versus lowest TMAO quartile OR: 2.31; 95% CI, 1.25–4.23; P < 0.01 Age, sex, HTN, T2DM, LDL-C, smoking
Haghikia A et al. [37] 2018/ Germany Patients with incident stroke 593 4/148 Cohort / 1 year follow-up Plasma TMAO 67 ± 13 61% Higher odds of incident CVD event (including stroke) in highest versus lowest TMAO quartile OR: 3.3; 95% CI, 1.2–10.9; P = 0.04) age, sex, HTN, T2DM, LDL, smoking
Tang WHW et al. [32] 2017/ USA Patients with T2DM 1216 3 /401 Cohort / 5 years follow-up Plasma TMAO 4.4 (2.8–7.7) 64.4 ± 10.2 58% Significantly higher prevalence of stroke history in highest versus lowest TMAO tertiles (12% versus 5%; P = 0.002). Increased odds of major adverse cardiac risk including stroke in highest versus lowest TMAO tertiels (OR: 1.94 (1.23–3.05) P < 0.001) Age, gender, history of CVD, history of HF, SBP, LDL-C, HDL-C, smoking, BMI, hsCRP, HbA1C, eGFR.
Li X et al. [38] 2017/ USA Patinets with CVD (Cleveland acute coronary syndrome cohort) 530 2 (220/ 310) Cohort /7 years follow-up Plasma TMAO 4.28 (2.55–7.91) 62.4 ± 13.9 57.5 Higher plasma TMAO in patients with adverse cardiac events (including stroke) compared without (5.09 versus 3.73); P < 0.001 Age, gender, HDL-C, LDL-C, smoking, history of DM, HTN, CAD, CRP, eGFR, troponin T, STEMI, NSTEMI or unstable angina
Li X et al. [38] 2017/ USA Patients with CVD (Swiss ACS cohort) 1683 2 (190/ 1493) Cohort/ 7 years follow-up Plasma TMAO 2.87 (1.94–4.85) 63.9 ± 12.4 77.8 Higher plasma TMAO in patients with adverse cardiac events (including stroke) compared without (3.75 versus 2.80); P < 0.001 Age, gender, HDL-C, LDL-C, smoking, history of DM, HTN, revas-cularization or CAD, CRP, eGFR, troponin T, STEMI, NSTEMI or unstable angina
Guasch-Ferre M et al. [22] 2017/ USA Patients with CVD 980 4/ 245 Case-cohort Plasma TMAO 55–80 46.12 No significant association between HR of stroke in TMAO tertiels (P = 0.31) Age, sex, family history of CVD, smoking, BMI, PA, HTN, T2DM
Mafune A et al. [13] 2016/ Japan Patients underwent CVD surgeries 227 4/ 56–57 Cross-sectional Serum TMAO 0.09 to 141.2 68 70 No significant difference in prevalence of stroke between quartiles of TMAO (P = 0.49)
Yin J et al. [15] 2015/ China Patients with ischemic or TIA stroke 551 2 (322/ 231) Case- control Plasma TMAO Stroke versus controls (2.70; 1.91) 18–80 63.70 Plasma TMAO was lower in patients with stroke compared with controls (P < 0.001)
Tang WHW et al. [39] 2013/ USA Patients underwent CABG 4007 2 (513/3494) Cohort/ 3 years follow-up Plasma TMAO 3.7 (2.4–6.2) 63 64 Plasma TMAO was significantly higher in patients with adverse events (including stroke) compared with controls (P < 0.001); increased odds of events in forth quartiles versus first (1.43 (1.05–1.94)) Age, sex, smoking status, SBP, LDL-C, HDL-C, DM, hs-CRP, myeloperoxidase level, eGFR, WBC-count, BMI, medications (aspirin, statin, ACE inhibitor, ARB, or beta-blocker, extent of disease
  1. Abbreviations: ACEI Angiotensin converting enzyme inhibitor, ACS Acute coronary syndromes, ARB Angiotensin receptor blockers, BMI Body mass index, BUN Blood urea nitrogen, CABG Coronary artery bypass surgery, CAD Coronary artery disease, CAS Carotid artery stenosis, CI Confidence interval, CRP C-reactive protein, CSPPT China Stroke Primary Prevention Trial, CVD Cardiovascular disease, DM Diabetes mellitus, e-GFR Estimated glomerular filtration rate, EVOLVE valuation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events, FSG Fasting serum glucose, HbA1c Hemoglobin A1C, HCY Homocysteine, HDL-C High density lipoprotein cholesterol, HF Heart failure, HR Hazard ratio, HTN Hypertension, IQR Interquartile range, LDL-C Low density lipoprotein cholesterol, MI Myocardial infarction, NSTEMI non–ST-segment elevation myocardial infarction, OR Odds ratio, PA Physical Activity, SBP Systolic Blood Pressure, SHR Subdistribution Hazard Ratio, STEMI ST-Elevation Myocardial Infarction, TC Total cholesterol, T2DM Type two diabetes, TG Triglyceride, TIA transient ischemic attack, TMAO Trimethylamine N-oxide, UAER urinary albumin excretion, USA United States, WBC White blood cells