Abstract
Aim: Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite synthesized in host organisms from specific food constituents, such as choline, carnitine and betaine. During the last decade, elevated TMAO levels have been proposed as biomarkers to estimate the risk of cardiometabolic diseases. However, there is still no consensus about the role of TMAO in the pathogenesis of cardiovascular disease since regular consumption of TMAO-rich seafood (i.e., a Mediterranean diet) is considered to be beneficial for the primary prevention of cardiovascular events. Therefore, the aim of this study was to investigate the effects of long-term TMAO administration on mitochondrial energy metabolism in an experimental model of right ventricle heart failure.Methods: TMAO was administered to rats at a dose of 120 mg/kg in their drinking water for 10 weeks. Then, a single subcutaneous injection of monocrotaline (MCT) (60 mg/kg) was administered to induce right ventricular dysfunction, and treatment with TMAO was continued (experimental groups: Control; TMAO; MCT; TMAO+MCT). After 4 weeks, right ventricle functionality was assessed by echocardiography, mitochondrial function and heart failure-related gene and protein expression was determined.Results: Compared to the control treatment, the administration of TMAO (120 mg/kg) for 14 weeks increased the TMAO concentration in cardiac tissues up to 14 times. MCT treatment led to impaired mitochondrial function and decreased right ventricular functional parameters. Although TMAO treatment itself decreased mitochondrial fatty acid oxidation-dependent respiration, no effect on cardiac functionality was observed. Long-term TMAO administration prevented MCT-impaired mitochondrial energy metabolism by preserving fatty acid oxidation and subsequently decreasing pyruvate metabolism. In the experimental model of right ventricle heart failure, the impact of TMAO on energy metabolism resulted in a tendency to restore right ventricular function, as indicated by echocardiographic parameters and normalized organ-to-body weight indexes. Similarly, the expression of a marker of heart failure severity, brain natriuretic peptide, was substantially increased in the MCT group but tended to be restored to control levels in the TMAO+MCT group.Conclusion: Elevated TMAO levels preserve mitochondrial energy metabolism and cardiac functionality in an experimental model of right ventricular heart failure, suggesting that under specific conditions TMAO promotes metabolic preconditioning-like effects.
Highlights
Impaired energy metabolism is one of the cornerstones of heart failure pathophysiology (Rosca and Hoppel, 2013)
Compared to those in the MCT control group, the direct right ventricular (RV) pressure measurement was decreased by 22%, the RV diastolic and systolic areas were decreased by up to 27%, and the RV fractional area change was increased by 25% in the trimethylamine N-oxide (TMAO)+MCT group
None of the measured parameters in the TMAO+MCT group were significantly different from those in the control group. These results indicate that chronically elevated TMAO levels in plasma and cardiac tissue do not affect cardiac functionality, while long-term TMAO administration preserves myocardial mechanical function in monocrotalineinduced heart failure
Summary
Impaired energy metabolism is one of the cornerstones of heart failure pathophysiology (Rosca and Hoppel, 2013). During the progression of heart failure, overall cardiac oxidative metabolism decreases, resulting in energy starvation (Sabbah, 2020). One of the risk factors that lead to disturbances in energy metabolism and further progression of cardiovascular diseases is unhealthy dietary patterns. High intake of fat, red meat and processed food, as in Western diet, is shown to damage myocardial oxidative capacity, leading to impaired mitochondrial energy metabolism (Neves et al, 2014). It has been shown that chronic heart failure is characterized by substantial alterations in gut microbiome composition and reduced microbial variety (Kummen et al, 2018; Mayerhofer et al, 2020). Previous studies suggest a link between the human gut microbiome and the homeostasis of energy metabolism, a clear causal relationship between them remains elusive
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