Association of moderately elevated trimethylamine N-oxide with cardiovascular risk: is TMAO serving as a marker for hepatic insulin resistance

To date, at least five prospective cohort studies have concluded that increased plasma levels of trimethylamine N-oxide (TMAO) predict increased risk for major adverse cardiovascular (CV) events in patients with pre-existing coronary heart disease.1–5 Moreover, though some epidemiology does not support a connection between plasma TMAO and CV risk,6 7 a recent meta-analysis of 11 prospective cohort studies concludes that higher plasma TMAO correlates with a 23% increase in risk for CV events (HR 1.23, 95% CI 1.07 to 1.42), as well as a 55% increase in all-cause mortality.8 The possibility that TMAO may be a mediating factor in this regard is raised by rodent studies in which plasma levels have been raised either by direct oral administration of TMAO, or by administration of very high doses (proportionately very much higher than would be employed in human supplementation) of its precursors phosphatidylcholine and carnitine; in these studies, in which the achieved plasma level of TMAO was at least an order of magnitude higher than commonly observed in humans, a proatherogenic effect was documented.9–14 In vitro studies, likewise employing supraphysiological concentrations of TMAO, have demonstrated effects suggesting proatherogenic potential.12 13 15–17 In case–control epidemiology, elevated TMAO has also been linked to substantially increased risk for type 2 diabetes and metabolic syndrome.18–20 Indeed, the correlations between TMAO and diabetes risk appear to be stronger than those for CV risk. Yet the notion that TMAO acts as a human vascular toxin at the plasma concentrations seen in people with reasonably normal renal function is difficult to square with other recent findings. Preformed TMAO is notably high in fish, in which it serves to maintain osmotic balance; levels tend to be higher in deep-sea fish, which must survive at higher pressures.21–24 This TMAO can be directly absorbed …