Trimethylamine N-oxide in cardiovascular disease: Pathophysiology and the potential role of statins

Cardiovascular diseases are one of the leading causes of mortality and morbidity worldwide, with the total number of cases increasing to 523 million in 2019. Despite the advent of new drugs, cardiovascular mortality has increased at an alarming rate of 53.7 % from 12.1 million deaths in 1990. Recently, the role of gut microbiome metabolites, such as Trimethylamine N-Oxide (TMAO), in the pathogenesis of cardiovascular disease (CVD) has attracted significant attention. The gut microbiome is critical in various physiological processes including metabolism, immune function, and inflammation. Elevated TMAO levels are associated with atherosclerosis, heart failure, arrhythmia, and atrial fibrillation. TMAO accelerates atherosclerosis by promoting vascular inflammation and reducing reverse cholesterol transport, which leads to lipid accumulation and vessel narrowing. Previous research has indicated that a Mediterranean diet rich in fiber and phytochemicals can reduce TMAO levels by limiting precursors and fostering beneficial gut microbiota. Prebiotics and probiotics also decrease TMAO, while drugs such as meldonium, aspirin, and antibiotics have shown promise. However, recent studies have demonstrated major potential for the use of statins in reducing TMAO levels. Statin therapy can significantly reduce TMAO levels independent of their cholesterol-lowering effects. This reduction may involve direct interactions with the gut microbiome, changes in cholesterol metabolism, and changes in bile acid composition. This review aims to comprehensively evaluate the therapeutic potential of statins in reducing TMAO levels to improve CV outcomes.