Intestinal Trimethylamine-N-Oxide in Heart Failure
Background Altered intestinal function is prevalent in patients with heart failure (HF), but its role in adverse outcomes is unclear.
Objectives This study investigated the potential pathophysiological contributions of intestinal microbiota in HF.
Methods We examined the relationship between fasting plasma trimethylamine-N-oxide (TMAO) and all-cause mortality over a 5-year follow-up in 720 patients with stable HF.
Results The median TMAO level was 5.0 μM, which was higher than in subjects without HF (3.5 μM; p < 0.001). There was modest but significant correlation between TMAO concentrations and B-type natriuretic peptide (BNP) levels (r = 0.23; p < 0.001). Higher plasma TMAO levels were associated with a 3.4-fold increased mortality risk. Following adjustments for traditional risk factors and BNP levels, elevated TMAO levels remained predictive of 5-year mortality risk (hazard ratio [HR]: 2.2; 95% CI: 1.42 to 3.43; p < 0.001), as well as following the addition of estimated glomerular filtration rate to the model (HR: 1.75; 95% CI: 1.07 to 2.86; p < 0.001).
Conclusions High TMAO levels were observed in patients with HF, and elevated TMAO levels portended higher long-term mortality risk independent of traditional risk factors and cardiorenal indexes.
There is increasing recognition that the gastrointestinal system represents an often overlooked contributor to the pathogenesis of heart failure (HF) syndrome and its adverse complications. Normally, intestinal barrier function is maintained by a well-balanced intestinal microbial community, intact tight junctions in the mucosa, normal mucosal immunity, and normal sodium and water homeostasis. With HF and associated splanchnic circulation congestion, bacterial translocation can occur due to altered intestinal barrier function, bacterial overgrowth, and impaired host defense, leading to endotoxemia that in turn can contribute to systemic inflammation. Several of these features of altered intestinal function have been observed in patients with HF. Meanwhile, progressive venous congestion in subsets of patients with significant congestive signs and symptoms may lead to unwanted consequences of abdominal congestion, including adverse impact on drug absorption and pharmacokinetics, and renal glomerular and tubular dysfunction resulting from raised intra-abdominal pressures.
Intestinal microbiota are implicated in the regulation of multiple host metabolic pathways that contribute to phenotypes such as obesity and insulin resistance. Our group has recently described a mechanistic link between intestinal microbe-dependent generation of trimethylamine-N-oxide (TMAO) and increased risk for future cardiovascular events (death, myocardial infarction, and stroke) by a pathway involving dietary nutrients such as phosphatidylcholine, choline, and carnitine. In chronic systolic HF, the relationship between the intestinal microbiota-generated metabolite TMAO and both cardiorenal indexes and long-term clinical prognosis has not been examined. We sought to investigate the relationship between fasting plasma TMAO levels and long-term clinical prognosis in patients with stable HF undergoing cardiac evaluation, particularly in relation with established prognostic markers (B-type natriuretic peptide [BNP] and estimated glomerular filtration rate [eGFR]).
Abstract and Introduction
Background Altered intestinal function is prevalent in patients with heart failure (HF), but its role in adverse outcomes is unclear.
Objectives This study investigated the potential pathophysiological contributions of intestinal microbiota in HF.
Methods We examined the relationship between fasting plasma trimethylamine-N-oxide (TMAO) and all-cause mortality over a 5-year follow-up in 720 patients with stable HF.
Results The median TMAO level was 5.0 μM, which was higher than in subjects without HF (3.5 μM; p < 0.001). There was modest but significant correlation between TMAO concentrations and B-type natriuretic peptide (BNP) levels (r = 0.23; p < 0.001). Higher plasma TMAO levels were associated with a 3.4-fold increased mortality risk. Following adjustments for traditional risk factors and BNP levels, elevated TMAO levels remained predictive of 5-year mortality risk (hazard ratio [HR]: 2.2; 95% CI: 1.42 to 3.43; p < 0.001), as well as following the addition of estimated glomerular filtration rate to the model (HR: 1.75; 95% CI: 1.07 to 2.86; p < 0.001).
Conclusions High TMAO levels were observed in patients with HF, and elevated TMAO levels portended higher long-term mortality risk independent of traditional risk factors and cardiorenal indexes.
Introduction
There is increasing recognition that the gastrointestinal system represents an often overlooked contributor to the pathogenesis of heart failure (HF) syndrome and its adverse complications. Normally, intestinal barrier function is maintained by a well-balanced intestinal microbial community, intact tight junctions in the mucosa, normal mucosal immunity, and normal sodium and water homeostasis. With HF and associated splanchnic circulation congestion, bacterial translocation can occur due to altered intestinal barrier function, bacterial overgrowth, and impaired host defense, leading to endotoxemia that in turn can contribute to systemic inflammation. Several of these features of altered intestinal function have been observed in patients with HF. Meanwhile, progressive venous congestion in subsets of patients with significant congestive signs and symptoms may lead to unwanted consequences of abdominal congestion, including adverse impact on drug absorption and pharmacokinetics, and renal glomerular and tubular dysfunction resulting from raised intra-abdominal pressures.
Intestinal microbiota are implicated in the regulation of multiple host metabolic pathways that contribute to phenotypes such as obesity and insulin resistance. Our group has recently described a mechanistic link between intestinal microbe-dependent generation of trimethylamine-N-oxide (TMAO) and increased risk for future cardiovascular events (death, myocardial infarction, and stroke) by a pathway involving dietary nutrients such as phosphatidylcholine, choline, and carnitine. In chronic systolic HF, the relationship between the intestinal microbiota-generated metabolite TMAO and both cardiorenal indexes and long-term clinical prognosis has not been examined. We sought to investigate the relationship between fasting plasma TMAO levels and long-term clinical prognosis in patients with stable HF undergoing cardiac evaluation, particularly in relation with established prognostic markers (B-type natriuretic peptide [BNP] and estimated glomerular filtration rate [eGFR]).