title: Trimethylamine-N-oxide in the Healthy and Diseased Heart
Creators: name: Naghipour, Saba
Publisher: name: Griffith University
Year: 2023
Subjects: subject: cardiovascular disease
subject: mitochondria
subject: diabetes
subject: trimethylamine-N-oxide (TMAO)

description: Cardiovascular disease (CVD) remains the greatest cause of death globally, despite ongoing efforts to prevent disease and optimise clinical therapies. The development of CVD is largely dependent on lifestyle risk factors prevalent in modern societies, including poor diet and exercise habits, smoking status, low socioeconomic status, and psychosocial stresses. A lifestyle of chronic unhealthy eating habits, together with these factors, drives common metabolic disorders such as type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS), both strongly contributing to the risk of CVD. Over recent decades, a growing body of literature identifies and supports a key role for the gut microbiome in the aetiology of our most common chronic diseases, including CVD. Indeed, dietary factors not only governs overall energy balance, but influences the gut microbiome. In particular, the gut microbial metabolite trimethylamine-N-oxide (TMAO) has been identified as a potential player in the linkages between diet, the gut microbiome, and CVD development and outcomes. Elevations in circulating TMAO have been observed in chronic (often comorbid) disorders such as obesity, T2DM, heart failure and chronic kidney disease, as well as in advanced age. Additionally, studies using in vitro and in vivo models indicate that TMAO may well promote CVD, enhancing atherosclerotic disease via stimulatory effects on inflammation and oxidative stress. Despite considerable ongoing investigations, some fundamental questions remain unaddressed. Critically, the TMAO concentrations commonly used to induce and study such pathological outcomes are generally many-fold higher than observed in human disorders, and animal models of disease. In addition, it is not clear whether TMAO can induce pathology in otherwise healthy people, in the absence of co-morbidities. Findings are conflicting in this regard, thus it remains to be established whether TMAO actively drives disease or represents a potentially useful biomarker secondary to evolving cardiometabolic disease. In terms of cardiovascular influences, most in vitro and in vivo studies focus on vascular and inflammatory effects, with much less information available regarding both myocardial and also mitochondrial effects of TMAO. The latter mitochondrial dysfunction is broadly implicated in common cardiometabolic diseases. Given these unknowns, and gaps in the literature regarding TMAO in CVD, this doctoral project sought to establish whether extracellular concentrations of TMAO observed in mild and severe cardiovascular or related metabolic diseases are sufficient to independently impact the heart, its vessels, and myocardial mitochondria. Questions addressed include whether cardiovascular effects are evident with acute elevations in TMAO or require chronic changes; do such effects emerge in otherwise healthy hearts or are they more evident in extant disease; and, what are the relationships between TMAO concentrations, cardiometabolic risk factors, diet, and gut microbiome profile. […]