LAUSR

Choline and choline-metabolites such as trimethylamine N-oxide (TMAO) have been investigated as cardiac biomarkers for many years (Danne et al. 2003, Danne and M€ ockel 2010). Hazen et al. (2011) demonstrated that three major metabolites of phosphatidylcholine (choline, TMAO, and betaine) predicted risk for cardiovascular disease in large clinical cohort of stable patients undergoing elective cardiac evaluations (Wang et al. 2011). Elevated levels of choline, TMAO and betaine were all observed to show dose-dependent associations with the presence of cardiovascular disease (CVD) and multiple individual CVD phenotypes including peripheral artery disease, coronary artery disease and history of myocardial infarction also after adjustment for traditional cardiac risk factors and medications usage. The group also demonstrated that dietary choline or TMAO promotes atherosclerosis in a mouse model and that when the gut flora was suppressed, dietary choline-enhanced atherosclerosis was inhibited. These findings suggested a ‘diet-microbe morbid union’ contributing to the pathogenesis of atherosclerosis (Rak and Rader 2011). Now a growing body of literature strongly supports the role of gut-microbe derived TMAO for cardiometabolic diseases and atherosclerosis. TMAO has proatherogenic and prothrombotic properties and is linked to coronary artery disease, diabetes and insulin resistance, heart failure and hypertension. Recent meta-analysis has confirmed TMAO as an independent biomarker of cardiovascular risk (Schiattarella et al. 2017). TMAO is primarily generated through gut-microbiome mediated conversion of dietary choline and carnitine to trimethylamine (TMA), which is converted to TMAO by hepatic flavin monooxygenase 3 (FMO3) and subsequently undergoes tissue distribution and renal elimination (Figure 1). The inhibition of TMAO production has been supposed as potential future treatment of atherosclerosis and enzymes related to the conversion of choline to TMA and subsequently to TMAO such as microbial TMA lyases and hepatic FMOs are considered as novel targets and the next frontier of drug discovery (Brown and Hazen 2017). The activation of the renin-angiotensin-aldosterone system (RAAS) plays a key role in the development and progression of cardiovascular disease, especially in arterial hypertension, heart failure and coronary artery disease. Angiotensinconverting-enzyme (ACE) inhibitors are a cornerstone in the prevention and treatment of cardiovascular disease and the most used and studied type of renin-angiotensin-aldosterone system (RAAS) blocker. Their benefits are due to their neurohormonal modulatory effects, which have vasodilatory, antiinflammatory, plaque-stabilizing, antithrombotic and anti-proliferative effects (L opez-Send on et al. 2004). Enalapril is an established inhibitor of the ACE and was introduced into the market in 1981. Enalapril is a prodrug which undergoes biotransformation to the active metabolite enalaprilat and is used for the treatment of arterial hypertension, diabetic kidney disease, heart failure and for secondary prevention of coronary artery disease. The current publication Konop et al. (2018) published in ‘Biomarkers’ is the first study suggesting that enalapril treatment (low and high-dose) for 2 weeks is associated with a significant decrease of plasma TMAO in Wistar rats fed with a standard laboratory diet. There was no significant difference in TMA stool level, TMA plasma levels and no significant difference between the groups in indoxyl plasma level and 24 h urine indoxyl excretion. Metagenomic analysis showed no effect on gut bacteria composition. This data suggests that the observed reduction of TMAO associated with enalapril treatment in the current study of Konop et al. (2018) was not based on effects on microbial composition or metabolism and therefore might represent a novel pathway of reducing circulating levels of proatherogenic TMAO. However microbial TMA lyases and hepatic FMOs were not specifically investigated in the current study and metabolic effects of enalapril may not be excluded. Enalapril-treated rats showed a higher fluid intake, higher 24 h urine excretion, lower sodium levels and a higher 24 h sodium output. As discussed in the paper ACE-inhibitors affect the mechanisms controlling cation and methylamine excretion such as the expression organic cation transporters (OCT1 and OCT2) in models of diabetic nephropathy (Thomas et al. 2003). Other experimental studies suggest that OCT2 is the key transporter for TMAO cellular uptake and OCT1/2 knockout mice demonstrate an increase of plasma TMAO levels (Teft et al. 2017). Therefore a potential link exists between organic cation transporters, ACE inhibitors and TMAO. This is interesting as