Is increased plasma TMAO a compensatory response to hydrostatic and osmotic stress in cardiovascular diseases?

Recent clinical studies show a positive correlation between elevated plasma TMAO and increased cardiovascular risk. However, the mechanism of the increase and biological effects of TMAO in the circulatory system are obscure. Plasma TMAO level depends mostly on the following three factors. First, the liver produces TMAO from TMA, a gut bacteria metabolite of dietary choline and carnitine. Second, plasma TMAO increases after ingestion of dietary TMAO from fish and seafood. Finally, plasma TMAO depends on TMAO and TMA excretion by the kidneys. Ample evidence highlights protective functions of TMAO, including the stabilization of proteins and cells exposed to hydrostatic and osmotic stresses, for example in fish exposed to hydrostatic stress (deep water) and osmotic stress (salty water). Osmotic stress and hydrostatic stresses are augmented in cardiovascular diseases such as hypertension. In hypertensive subjects a diastole-systole change in hydrostatic pressure in the heart may exceed 220 mmHg with a frequency of 60-220/min. This produces environment in which hydrostatic pressure changes over 100,000 times per 24 h. Furthermore, cardiovascular diseases are associated with disturbances in water-electrolyte balance which produce changes in plasma osmolarity. Perhaps, the increase in plasma TMAO in cardiovascular diseases is analogous to increased level of plasma natriuretic peptide B, which is both a cardiovascular risk marker and a compensatory response producing beneficial effects for pressure/volume overloaded heart. In this regard, there is some evidence that a moderate increase in plasma TMAO due to TMAO supplementation may be beneficial in animal model of hypertension-related heart failure. Finally, increased plasma TMAO is present in humans consuming seafood-rich diet which is thought to be health-beneficial. We hypothesize that increased plasma TMAO serves as a compensatory response mechanism which protects cells from hydrostatic and osmotic stresses.