W H Wilson Tang1, Zeneng Wang2, Kevin Shrestha3, Allen G Borowski3, Yuping Wu4, Richard W Troughton5, Allan L Klein3, Stanley L Hazen6. 1. Center for Cardiovascular Diagnostics and Prevention, Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland, Ohio; Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address: tangw@ccf.org. 2. Center for Cardiovascular Diagnostics and Prevention, Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland, Ohio. 3. Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio. 4. Department of Mathematics, Cleveland State University, Cleveland, Ohio. 5. Department of Medicine, Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand. 6. Center for Cardiovascular Diagnostics and Prevention, Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland, Ohio; Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio.
Abstract
BACKGROUND: Trimethylamine-N-oxide (TMAO) has been linked to increased cardiovascular risk. We aimed to determine the prognostic value of TMAO and its dietary precursors, choline and betaine, in heart failure (HF). METHODS AND RESULTS: In 112 patients with chronic systolic HF with comprehensive echocardiographic evaluation, we measured plasma TMAO, choline, and betaine by mass spectrometry. Median (interquartile range) TMAO levels, choline, and betaine levels were 5.8 (3.6-12.1) μmol/L, 10.9 (8.4-14.0) μmol/L, and 43.8 (37.1-53.0) μmol/L, respectively, and were correlated with each other (all P < .0001 for both). TMAO levels were significantly higher in patients with diabetes mellitus (9.4 [4.9-13.2] vs 4.8 [3.4-9.8] μmol/L; P = .005) and in subjects with New York Heart Association functional class III or greater (7.0 [4.7-14.8] vs 4.7 [3.4-11.3] μmol/L; P = .02). Elevated TMAO, choline, and betaine levels were each associated with higher plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and more advanced left ventricular diastolic dysfunction, but not systolic dysfunction or inflammatory and endothelial biomarkers. Higher choline (hazard ratio [HR] 1.64, 95% CI 1.22-2.20; P = .001), betaine (HR 1.51, 95% CI 1.10-2.08; P = .01), and TMAO (HR 1.48, 95% CI 1.10-1.96; P = .01) predicted increased risk for 5-year adverse clinical events (death/transplantation). Only higher TMAO levels predicted incident adverse clinical events independently from age, estimated glomerular filtration rate, mitral E/septal Ea, and NT-proBNP levels (HR 1.46, 95% CI 1.03-2.14; P = .03). CONCLUSION: Elevated plasma TMAO, choline, and betaine levels are each associated with more advanced left ventricular diastolic dysfunction and portend poorer long-term adverse clinical outcomes in chronic systolic HF. However, only higher plasma TMAO was associated with poor prognosis after adjustment for cardiorenal indices.
BACKGROUND:Trimethylamine-N-oxide (TMAO) has been linked to increased cardiovascular risk. We aimed to determine the prognostic value of TMAO and its dietary precursors, choline and betaine, in heart failure (HF). METHODS AND RESULTS: In 112 patients with chronic systolic HF with comprehensive echocardiographic evaluation, we measured plasma TMAO, choline, and betaine by mass spectrometry. Median (interquartile range) TMAO levels, choline, and betaine levels were 5.8 (3.6-12.1) μmol/L, 10.9 (8.4-14.0) μmol/L, and 43.8 (37.1-53.0) μmol/L, respectively, and were correlated with each other (all P < .0001 for both). TMAO levels were significantly higher in patients with diabetes mellitus (9.4 [4.9-13.2] vs 4.8 [3.4-9.8] μmol/L; P = .005) and in subjects with New York Heart Association functional class III or greater (7.0 [4.7-14.8] vs 4.7 [3.4-11.3] μmol/L; P = .02). Elevated TMAO, choline, and betaine levels were each associated with higher plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and more advanced left ventricular diastolic dysfunction, but not systolic dysfunction or inflammatory and endothelial biomarkers. Higher choline (hazard ratio [HR] 1.64, 95% CI 1.22-2.20; P = .001), betaine (HR 1.51, 95% CI 1.10-2.08; P = .01), and TMAO (HR 1.48, 95% CI 1.10-1.96; P = .01) predicted increased risk for 5-year adverse clinical events (death/transplantation). Only higher TMAO levels predicted incident adverse clinical events independently from age, estimated glomerular filtration rate, mitral E/septal Ea, and NT-proBNP levels (HR 1.46, 95% CI 1.03-2.14; P = .03). CONCLUSION: Elevated plasma TMAO, choline, and betaine levels are each associated with more advanced left ventricular diastolic dysfunction and portend poorer long-term adverse clinical outcomes in chronic systolic HF. However, only higher plasma TMAO was associated with poor prognosis after adjustment for cardiorenal indices.
Authors: Zhili Shao; Zeneng Wang; Kevin Shrestha; Akanksha Thakur; Allen G Borowski; Wendy Sweet; James D Thomas; Christine S Moravec; Stanley L Hazen; W H Wilson Tang Journal: J Am Coll Cardiol Date: 2012-03-27 Impact factor: 24.094
Authors: Anja Sandek; Ingvar Bjarnason; Hans-Dieter Volk; Roger Crane; Jonathan B Meddings; Josef Niebauer; Paul R Kalra; Sabine Buhner; Ralph Herrmann; Jochen Springer; Wolfram Doehner; Stephan von Haehling; Stefan D Anker; Mathias Rauchhaus Journal: Int J Cardiol Date: 2010-12-28 Impact factor: 4.164
Authors: W H Wilson Tang; Zeneng Wang; Yiying Fan; Bruce Levison; Jennie E Hazen; Lillian M Donahue; Yuping Wu; Stanley L Hazen Journal: J Am Coll Cardiol Date: 2014-10-27 Impact factor: 24.094
Authors: W H Wilson Tang; Zeneng Wang; Bruce S Levison; Robert A Koeth; Earl B Britt; Xiaoming Fu; Yuping Wu; Stanley L Hazen Journal: N Engl J Med Date: 2013-04-25 Impact factor: 91.245
Authors: Wai Hong Wilson Tang; Wilson Tong; Kevin Shrestha; Zeneng Wang; Bruce S Levison; Brian Delfraino; Bo Hu; Richard W Troughton; Allan L Klein; Stanley L Hazen Journal: Eur Heart J Date: 2008-08-06 Impact factor: 29.983
Authors: W H Wilson Tang; Frederick Van Lente; Kevin Shrestha; Richard W Troughton; Gary S Francis; Wilson Tong; Maureen G Martin; Allen G Borowski; Sue Jasper; Randall C Starling; Allan L Klein Journal: J Card Fail Date: 2008-05-27 Impact factor: 5.712
Authors: Zeneng Wang; Elizabeth Klipfell; Brian J Bennett; Robert Koeth; Bruce S Levison; Brandon Dugar; Ariel E Feldstein; Earl B Britt; Xiaoming Fu; Yoon-Mi Chung; Yuping Wu; Phil Schauer; Jonathan D Smith; Hooman Allayee; W H Wilson Tang; Joseph A DiDonato; Aldons J Lusis; Stanley L Hazen Journal: Nature Date: 2011-04-07 Impact factor: 49.962
Authors: Robert A Koeth; Zeneng Wang; Bruce S Levison; Jennifer A Buffa; Elin Org; Brendan T Sheehy; Earl B Britt; Xiaoming Fu; Yuping Wu; Lin Li; Jonathan D Smith; Joseph A DiDonato; Jun Chen; Hongzhe Li; Gary D Wu; James D Lewis; Manya Warrier; J Mark Brown; Ronald M Krauss; W H Wilson Tang; Frederic D Bushman; Aldons J Lusis; Stanley L Hazen Journal: Nat Med Date: 2013-04-07 Impact factor: 53.440
Authors: Carlee I Oakley; Julian A Vallejo; Derek Wang; Mark A Gray; LeAnn M Tiede-Lewis; Tilitha Shawgo; Emmanuel Daon; George Zorn; Jason R Stubbs; Michael J Wacker Journal: Am J Physiol Heart Circ Physiol Date: 2020-04-03 Impact factor: 4.733
Authors: Sarah M Skye; Weifei Zhu; Kymberleigh A Romano; Chun-Jun Guo; Zeneng Wang; Xun Jia; Jennifer Kirsop; Bridget Haag; Jennifer M Lang; Joseph A DiDonato; W H Wilson Tang; Aldons J Lusis; Federico E Rey; Michael A Fischbach; Stanley L Hazen Journal: Circ Res Date: 2018-10-26 Impact factor: 17.367