Trimethylamine-N-oxide (TMAO) is the main diet-induced metabolite produced by the gut microbiota, and it is mainly eliminated through renal excretion. TMAO has been correlated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) and related complications, such as cardiovascular mortality or major adverse cardiovascular events (MACE). Meta-analyses have postulated that high circulating TMAO levels are associated with an increased risk of cardiovascular events and all-cause mortality, but the link between TMAO and CVD remains not fully consistent. The results of prospective studies vary depending on the target population and the outcome studied, and the adjustment for renal function tends to decrease or reverse the significant association between TMAO and the outcome studied, strongly suggesting that the association is substantially mediated by renal function. Importantly, one Mendelian randomization study did not find a significant association between genetically predicted higher TMAO levels and cardiometabolic disease, but another found a positive causal relationship between TMAO levels and systolic blood pressure, which—at least in part—could explain the link with renal function. The mechanisms by which TMAO can increase this risk are not clearly elucidated, but current evidence indicates that TMAO induces cholesterol metabolism alterations, inflammation, endothelial dysfunction, and platelet activation. Overall, there is no fully conclusive evidence that TMAO is a causal factor of ASCVD, and, especially, whether TMAO induces or just is a marker of hypertension and renal dysfunction requires further study.

Recent evidence, including massive gene-expression analysis and a wide-variety of other multi-omics approaches, demonstrates an interplay between gut microbiota and the regulation of plasma lipids. Gut microbial metabolism of choline and l-carnitine results in the formation of trimethylamine (TMA) and concomitant conversion into trimethylamine-N-oxide (TMAO) by liver flavin monooxygenase 3 (FMO3). The plasma level of TMAO is determined by the genetic variation, diet and composition of gut microbiota. Multiple studies have demonstrated an association between TMAO plasma levels and the risk of atherothrombotic cardiovascular disease (CVD). We aimed to review the molecular pathways by which TMAO production and FMO3 exert their proatherogenic effects. TMAO may promote foam cell formation by upregulating macrophage scavenger receptors, deregulating enterohepatic cholesterol and bile acid metabolism and impairing macrophage reverse cholesterol transport (RCT). Furthermore, FMO3 may promote dyslipidemia by regulating multiple genes involved in hepatic lipogenesis and gluconeogenesis. FMO3 also impairs multiple aspects of cholesterol homeostasis, including transintestinal cholesterol export and macrophage-specific RCT. At least part of these FMO3-mediated effects on lipid metabolism and atherogenesis seem to be independent of the TMA/TMAO formation. Overall, these findings have the potential to open a new era for the therapeutic manipulation of the gut microbiota to improve CVD risk.

Cardiovascular diseases are the leading cause of death worldwide. Aging and/or metabolic stress directly impact the cardiovascular system. Over the last few years, the contributions of altered nicotinamide adenine dinucleotide (NAD+) metabolism to aging and other pathological conditions closely related to cardiovascular diseases have been intensively investigated. NAD+ bioavailability decreases with age and cardiometabolic conditions in several mammalian tissues. Compelling data suggest that declining tissue NAD+ is commonly related to mitochondrial dysfunction and might be considered as a therapeutic target. Thus, NAD+ replenishment by either genetic or natural dietary NAD+-increasing strategies has been recently demonstrated to be effective for improving the pathophysiology of cardiac and vascular health in different experimental models, as well as human health, to a lesser extent. Here, we review and discuss recent experimental evidence illustrating that increasing NAD+ bioavailability, particularly by the use of natural NAD+ precursors, may offer hope for new therapeutic strategies to prevent and treat cardiovascular diseases.

The atherogenicity of low-density lipoprotein (LDL) and triglyceride-rich lipoproteins (TRLs) may be more significant than LDL cholesterol levels. Clinical trials which have led to increased high-density lipoprotein (HDL) cholesterol have not always seen reductions in cardiovascular disease (CVD). Furthermore, genetic variants predisposing individuals to high HDL cholesterol are not associated with a lower risk of suffering a coronary event, and therefore HDL functionality is considered to be the most relevant aspect. Virgin olive oil (VOO) is thought to play a protective role against CVD. This review describes the effects of VOO and phenol-enriched VOOs on lipoprotein atherogenicity and HDL atheroprotective properties. The studies have demonstrated a decrease in LDL atherogenicity and an increase in the HDL-mediated macrophage cholesterol efflux capacity, HDL antioxidant activity, and HDL anti-inflammatory characteristics after various VOO interventions. Moreover, the expression of cholesterol efflux-related genes was enhanced after exposure to phenol-enriched VOOs in both post-prandial and sustained trials. Improvements in HDL antioxidant properties were also observed after VOO and phenol-enriched VOO interventions. Furthermore, some studies have demonstrated improved characteristics of TRL atherogenicity under postprandial conditions after VOO intake. Large-scale, long-term randomized clinical trials, and Mendelian analyses which assess the lipoprotein state and properties, are required to confirm these results.

Objective—: The ability of HDL (high-density lipoprotein) to promote macrophage cholesterol efflux is considered the main HDL cardioprotective function. Abdominal aortic aneurysm (AAA) is usually characterized by cholesterol accumulation and macrophage infiltration in the aortic wall. Here, we aim to evaluate the composition of circulating HDL particles and their potential for promoting macrophage cholesterol efflux in AAA subjects. Approach and Results—: First, we randomly selected AAA and control subjects from Spain. The AAA patients in the Spanish cohort showed lower plasma apoA-I levels concomitantly associated with low levels of plasma HDL cholesterol and the amount of preβ-HDL particles. We determined macrophage cholesterol efflux to apoB-depleted plasma, which contains mature HDL, preβ-HDL particles and HDL regulatory proteins. ApoB-depleted plasma from AAA patients displayed an impaired ability to promote macrophage cholesterol efflux. Next, we replicated the experiments with AAA and control subjects derived from Danish cohort. Danish AAA patients also showed lower apoA-I levels and a defective HDL-mediated macrophage cholesterol efflux. Conclusions—: AAA patients show impaired HDL-facilitated cholesterol removal from macrophages, which could be mechanistically linked to AAA.