Gut microbial trimethylamine N-oxide generation promotes risk of atrial fibrillation via muscarinic receptor–mediated autonomic dysfunction
Selvam Arjunan, Isaiah Pemberton, Xinmin S. Li, Naseer Sangwan, Lydia Akino, Emmanuel Opoku, Dmitriy Verbovetskiy, Ina Nemet, Hyun Su Kim, Haruko Masumiya, Zeneng Wang, Joseph A. Lupica, Melissa Y. Tian, Karis Mao, Deepthi P. Mallela, Maradumane L. Mohan, Sarah M. Schumacher, Julie H. Rennison, Sathyamangla V. Naga Prasad, Kenneth R. Laurita, Vamsi Chodisetty, Mina K. Chung, David R. Van Wagoner, John Barnard, Jonathan D. Smith, Oussama Wazni, Stanley L. Hazen, Robert A. Koeth
Selvam Arjunan, Isaiah Pemberton, Xinmin S. Li, Naseer Sangwan, Lydia Akino, Emmanuel Opoku, Dmitriy Verbovetskiy, Ina Nemet, Hyun Su Kim, Haruko Masumiya, Zeneng Wang, Joseph A. Lupica, Melissa Y. Tian, Karis Mao, Deepthi P. Mallela, Maradumane L. Mohan, Sarah M. Schumacher, Julie H. Rennison, Sathyamangla V. Naga Prasad, Kenneth R. Laurita, Vamsi Chodisetty, Mina K. Chung, David R. Van Wagoner, John Barnard, Jonathan D. Smith, Oussama Wazni, Stanley L. Hazen, Robert A. Koeth
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Research Article Cardiology Cell biology Clinical Research

Gut microbial trimethylamine N-oxide generation promotes risk of atrial fibrillation via muscarinic receptor–mediated autonomic dysfunction

Abstract

Gut microbiota–derived trimethylamine N-oxide (TMAO) plays a role in the pathogenesis of cardiovascular disease, but its role in the pathogenesis of atrial fibrillation (AF) remains uncertain. TMAO levels were quantified in plasma from serial subjects undergoing elective cardiac catheterizations and shown to independently associate with prevalent AF following adjustment for risk factors. Human cAMP response element modulator isoform IbΔC-X transgenic mice (CREM-IbΔC-X) supplemented with a TMAO diet developed AF sooner. C57BL/6J mice on and off a TMAO diet had more inducible AF via a transesophageal pacing study compared with chow-fed controls. Dietary choline supplementation increased circulating TMAO levels and significantly accelerated AF onset in CREM-IbΔC-X mice. Iodomethylcholine (IMC) reduced circulating TMAO levels and choline-induced AF onset. Cecal metagenomic analyses showed that choline supplementation induced changes in microbial communities associated with AF, while many of these changes were attenuated by IMC. Choline supplementation promoted overall adverse atrial remodeling with left atrial dilation. Optical mapping studies showed that mice supplemented with choline exhibited reduced conduction velocity, shortened action potential duration at 80% repolarization, and decreased wavelength. TMAO inhibited muscarinic receptor 2, resulting in autonomic dysfunction that promotes AF. In summary, TMAO, independently associated with AF risk in subjects, enhanced AF in multiple mouse models via autonomic dysfunction and is a therapeutic target for preventing AF.

Authors

Selvam Arjunan, Isaiah Pemberton, Xinmin S. Li, Naseer Sangwan, Lydia Akino, Emmanuel Opoku, Dmitriy Verbovetskiy, Ina Nemet, Hyun Su Kim, Haruko Masumiya, Zeneng Wang, Joseph A. Lupica, Melissa Y. Tian, Karis Mao, Deepthi P. Mallela, Maradumane L. Mohan, Sarah M. Schumacher, Julie H. Rennison, Sathyamangla V. Naga Prasad, Kenneth R. Laurita, Vamsi Chodisetty, Mina K. Chung, David R. Van Wagoner, John Barnard, Jonathan D. Smith, Oussama Wazni, Stanley L. Hazen, Robert A. Koeth

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Figure 8

Choline diet increases the LA size during diastolic and systolic function.

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Choline diet increases the LA size during diastolic and systolic functio...
(A) LA diastolic size in male and female CREM-IbΔC-X mice at 8 weeks of age on respective diets. (B) LA systolic size in male and female CREM-IbΔC-X mice at 8 weeks of age on respective diets. (C) Echocardiography of LA size in female and male CREM-IbΔC-X mice at 8 weeks of age on respective diets. In A and B, data represent mean ± SD. A Kruskal-Wallis test with Dunn’s post hoc analysis was used to determine the significant difference among the medians of 4 independent diet groups, and multiple paired comparison adjustments were performed. *P < 0.05, **P < 0.01, ****P < 0.00001.