Atrial fibrillation is a disruption of normal heart rhythm. It becomes more prevalent with old age, and at its most severe end can contribute to cardiovascular mortality. Much of the incidence of atrial fibrillation is idiopathic, meaning the cause is obscure. Treatment tends to focus on the more severe cases and surgery to map the electrical connections in the heart and ablate regions that are causing issues, regardless of the underlying reasons as to why those regions might cause issues. Research suggests that the gut microbiome may play a role in idiopathic atrial fibrillation via generation of the metabolite TMAO, which is disruptive to the regulation of heart rhythm. Some people with idiopathic atrial fibrillation may be able to eliminate or dampen the severity of episodes by suitably altering their diet and thus adjusting the behavior and composition of the gut microbiome. A number of potential strategies for pharmaceutical inhibition of TMAO production exist, such as use of iodomethylcholine, but none of these compounds have been developed as drugs.
Gut microbiota-derived trimethylamine N-oxide (TMAO) plays a role in the pathogenesis of cardiovascular disease. The role of TMAO in the pathogenesis of atrial fibrillation (AF) remains uncertain. TMAO levels were quantified in plasma from serial subjects undergoing elective cardiac catheterizations (N=5,090) and shown to independently associate with prevalent AF following adjustment for risk factors (TMAO adjusted odds ratio 1.7).
Human cAMP response element modulator isoform IbΔC-X transgenic mice (CREM-IbΔC-X), a spontaneous mouse model of AF, supplemented with a TMAO diet developed AF sooner. C57BL/6J mice on and off a TMAO had more inducible AF via a transesophageal pacing study compared to chow controls. Dietary choline supplementation increased circulating TMAO levels and significantly accelerated AF onset in CREM-IbΔC-X mice. Iodomethylcholine (IMC), the gut microbial CutC/D inhibitor that suppresses choline to TMA(O) metabolic transformation, 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 inhibits muscarinic receptor 2 resulting in autonomic dysfunction that promotes AF. In summary, the gut microbial metabolite TMAO, independently associated with AF risk in subjects, enhances AF in multiple AF mouse models via autonomic dysfunction, and is a therapeutic target for prevention of AF.
