Trimethylamine N-oxide, The Important Therapeutic Target for Heart Failure

Review Article

Austin J Cardiovasc Dis Atherosclerosis. 2023; 10(1): 1053.

Trimethylamine N-oxide, The Important Therapeutic Target for Heart Failure

Guo R, Song Y, Xu Y, and Hua S*

College of traditional Chinese Medicine, Tianjin University of traditional Chinese Medicine, China

*Corresponding author: Hua SShengyu Hua, College of traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China

Received: January 11, 2023; Accepted: February 27, 2023; Published: March 06, 2023

Abstract

Heart Failure (HF) is a common cause of morbidity and mortality and is characterized by high morbidity and mortality. The pathophysiology of HF is complex, and it is important to elucidate the molecular mechanism of HF, identify key agents, and conduct further research to discover new therapeutic targets to decrease the incidence and economic burden associated with HF. In 2011, a metabolomic-based study identified that Trimethylamine N-Oxide (TMAO) could predict Cardiovascular Diseases (CVDs) risk. In subsequent studies, TMAO has been found to influence the pathological processes of various CVDs significantly. This review clarifies the effect of TMAO on heart failure from three aspects: the production of Trimethylamine (TMA) and TMAO, TMAO in the pathological process of HF and TMAO can be the therapeutic target for HF, hoping to provide reference for clinical treatment of HF and research on HF.

Keywords: TMAO; Heart failure; cardiovascular diseases

Abbreviations: HF: Heart Failure; TMAO: Trimethylamine N-Oxide; CVDs: Cardiovascular Diseases; TMA: Trimethylamine; FMOs: Flavin-Containing Monooxygenases; FMO3: FMO Isoform 3; DMB: 3,3- Dimethyl-1-Butanol; NF- κB: Nuclear Factor-k-Gene Binding; TGF-β1: Transforming Growth Factor beta-1; VECs: Vascular Endothelial Cells; NLRP3: Leucine-Rich Repeat Protein 3; FMD: Fasting-Mimicking Diet; CKD: Chronic Kidney Disease; TCM: Traditional Chinese Medicine; BBR: Berberine; B - GB: Ginkgolide B

Introduction

As the end stage of various Cardiovascular Ddiseases (CVDs), Heart Failure (HF) is a group of clinical syndromes caused by abnormal cardiac structural and functional changes due to various factors, leading to ventricular systolic and diastolic dysfunctions [1]. It is a common cause of morbidity and mortality. Although an increasing number of medical scientists and researchers have focused on therapeutic targets for HF and great progress has been made in the treatment strategy and new drug research, the incidence of HF is still very high, and the number of patients with HF is increasing. According to statistics, there are 5.7 million people over the age of 20 years with HF in the United States, and the number of adults with HF is expected to rise to 8 million by 2030 [2]. Overall, the prognosis of patients with HF remains poor, and readmission and mortality rates remain high. In a study, 83% of the patients were admitted to the hospital at least once a year, and 43% were admitted at least four times a year [3]. All-cause mortality ranged from 21.6% to 36.5% and 6.9% to 15.6% in patients with acute HF and chronic HF, Respectively [4]. The pathophysiology of HF is complex, including hemodynamic abnormalities, neuroendocrine system activation, cardiac remodeling, and inflammatory response [5]. The investigation of the mechanisms underlying the pathological progression of HF is still ongoing. It is important to elucidate the molecular mechanism of HF, identify key agents, and conduct further research to discover new therapeutic targets to decrease the incidence and economic burden associated with HF.

Recent studies have identified the importance of gut microbiota in the pathophysiology of HF [6-13]. Reduced cardiac output and altered systemic circulation due to HF can cause intestinal hypoperfusion, intestinal mucosal ischemia, and edema [12]. This increases the likelihood of intestinal barrier damage and permeability, promotes microbial translocation, leads to microbial metabolites entering the blood circulation, increases proinflammatory mediators, and finally leads to chronic inflammation in patients with HF [7,13]. Increased intestinal permeability leads to bacterial translocation across the intestinal barrier, increasing endotoxin and other bacterial wall compounds, which may exacerbate the pathophysiological progression of HF [9,14]. Higher levels of enteropathogenic candida, including Campylobacter spp, Shigella spp, and Yersinia enterocolitica, have been observed in patients with CHF [15].

In 2011, a metabolomic-based study identified metabolites of the dietary lipid phosphatidylcholine, including choline, Trimethylamine N-Oxide (TMAO), and betaine, in an independent large clinical cohort. This research also demonstrated that they could predict CVD risk. The germ-free mice in these studies confirmed that dietary choline and gut microbiota significantly affect TMAO production, macrophage cholesterol accumulation, and foam cell formation. This discovery that gut microbiota-dependent metabolism of dietary phosphatidylcholine contributes to the pathogenesis of CVD opened another way for diagnosing and treating CVDs [16]. In subsequent studies, researchers found that TMAO is associated with a variety of CVDs, such as atherosclerosis [17], hypertension [18], type 2 diabetes [19], myocardial infarction [20], and HF [21]. TMAO has been found to influence the pathological processes of various CVDs significantly. This review aims to discuss the generation of Trimethylamine (TMA) and TMAO, the effect of TMAO in the course of HF, and the potential of TMAO as an important therapeutic target for HF, to have significant references for clinical work.

Production of TMA and TMAO

TMA nutritional precursors, including choline, betaine, croton betaine, trimethyl lysine, G-butyl betaine, phosphatidylcholine, glycerol phosphate choline, and TMAO [22], can be transformed to TMA by particular gut microbial enzymes. Red meat, fish, eggs and products made from cow's milk are rich in these components. Most TMA enter the circulatory system and are subsequently oxidized to TMAO by flavin-containing monooxygenases (FMOs) [23-25]. In the five functional enzymes in the host, FMO isoform 3 (FMO3) is the crux in this process, with the highest conversion efficiency [26]. In most cases, the kidneys clear TMAO, and the remaining TMAO is reduced to TMA. This process is finished by TMAO reductase in the intestines [27].

It has been shown that changes in the gut microbiota caused by HF can result in changes in TMAO. Nine human gut strains, including Firmicutes and Proteobacteria, were able to produce TMA [28]. Corresponding to these findings, in patients with HF, the increased proportion of gut strains is consistent with the nine human gut strains capable of producing TMA, suggesting that, changes in the gut microbiota can affect TMAO levels. This process is achieved by adjusting the intestinal TMA synthesis.

However, the inherent causes may also significantly affect TMAO levels in humans. Human genes directly influence gut microbiota and can affect immune pathways and metabolic phenotypes [29,30]. In some chronic diseases, such as type 2 diabetes, disease susceptibility can be partly because of genetics that changes the gut microbiome [31]. In an overall analysis of genome-wide gut microbial hosts, microbiota and genetic factors accounted for about 10% of the variation in gut microbiota [32]. On the basis of the significant role of genetics in the gut microbiota, genetics could be thought to play a role in TMAO production.

TMAO in the Pathological Process of HF

Plasma TMAO level is significantly higher in patients with HF with a preserved ejection fraction [33]. Rats induced by cross-sectional aortic coarctation are excellent animal models of HF. In this model, circulating TMAO levels were significantly higher than in the sham-operated group [34]. In an animal study, mice fed with TMAO or choline exhibited more severe left ventricular dilatation, pulmonary edema, and myocardial fibrosis; the circulating brain natriuretic peptide levels were higher than those in control mice. In patients with HF, higher plasma TMAO levels are associated with poorer prognosis [35]. The effect of TMAO on HF progression is significant [36].

TMAO Exacerbates Myocardial Hypertrophy and Fibrosis

In an animal study, TMAO induced cardiac hypertrophy and fibrosis via Smad3 signaling, and a specific inhibitor of Smad3 blocked this effect [37]. 3,3-Dimethyl-1-Butanol (DMB), an inhibitor of TMAO biosynthesis, can prevent myocardial hypertrophy, fibrosis, and inflammation by negatively influencing the p65 Nuclear Factor-k-Gene Binding (NF-κB) and Transforming Growth Factor Beta-1 (TGF- β1)/Smad3 signaling pathways [38]. TMAO can also reprogram skin fibroblasts, adipocyte progenitors, and Vascular Endothelial Cells (VECs) into myofibroblasts via TMAO receptor protein R-like endoplasmic reticulum kinase. Under TGF-β1 stimulation, FMO3 expression can be observed in skin fibroblasts [39].

Citation: Guo R, Song Y, Xu Y, Hua S. Trimethylamine N-oxide, The Important Therapeutic Target for Heart Failure. Austin J Cardiovasc Dis Atherosclerosis. 2023; 10(1): 1053.