The role of splanchnic congestion and the intestinal microenvironment in the pathogenesis of advanced heart failure

Abstract

Purpose of review: Right-sided heart failure (HF), which is often present in the setting of advanced HF, is associated with cardiac cachexia, the cardiorenal syndrome, and adverse outcomes. Improved understanding of venous congestion of the splanchnic circulation, which may play a key role in the pathogenesis of right-sided HF, could lead to novel therapeutics to ameliorate HF. Here we provide an overview of right-sided HF, splanchnic hemodynamics, fluid homeostasis, and the intestinal microenvironment. We review recent literature to describe pathophysiologic mechanisms and possible therapeutics.Recent findings: Several possible mechanisms centered around upregulation of sodiumhydrogen exchanger-3 (NHE3) may form a causal link between right ventricular (RV) dysfunction, splanchnic congestion, and worsening HF. These include: (1) an anaerobic environment in enterocytes, resulting in reduced intracellular pH; (2) increased sodium absorption by the gut via NHE3; (3) decreased pH at the intestinal brush border thus altering the gut microbiome profile; (4) increased bacterial synthesis of trimethylamine N-oxide; and (5) decreased bacterial synthesis of short-chain fatty acids causing abnormal intestinal barrier function.Summary: Splanchnic congestion in the setting of right-sided HF may serve an important role in the pathogenesis of advanced HF, and further exploration of these mechanisms may lead to new therapeutic advances.

TMAO: how gut microbiota contributes to heart failure

“…24 In addition, visceral venous congestion caused by right HF may also lead to decreased blood flow to intestinal epithelial cells, resulting in cell hypoxia, anaerobic metabolism, and overexpression of the sodium/hydrogen exchanger 3, thereby increasing sodium transport and lowering the lumen pH. 25 All these factors eventually contribute to a shifting composition of the gut microbiota, which is mainly manifested by a reduction in Bacteroides and Bifidobacteria and an increase in Firmicutes and Proteobacteria. 26 Moreover, increased concentrations of enteropathogenic Candida such as Salmonella, Shigella, and Campylobacter were found in fecal samples from chronic HF (CHF) patients.…”

Inhibition of sodium-proton-exchanger subtype 3-mediated sodium absorption in the gut: A new antihypertensive concept

“…Lachnospiraceae and Ruminococcaceae have been identified as the most metabolically active bacteria of the human microbiota and play a dominant role in the trimethylamine-N-oxide (TMAO) production [60] . Several studies suggest an existence of a positive feedback mechanism between TMAO and NHE3 expression [55] , [61] and found serum TMAO to be associated with chronic upregulation of blood pressure via prolonging the hypertensive effect of angiotensin II [62] . Hence, reduction in aforementioned bacteria species caused by NHE3-deficiency could have positive impact on blood pressure.…”

Trimethylamine N‐oxide and outcomes in patients hospitalized with acute heart failure and preserved ejection fraction

“…[5][6][7][8][9] Hypoperfusion and congestion of the intestine lead to a decrease in blood flow to intestinal epithelial cells, resulting in cell hypoxia, anaerobic metabolism, and overexpression of sodium/hydrogen exchanger 3. 9,10 This enhances sodium absorption, and hydrogen ions are exchanged into the gut lumen, decreasing the local pH of the gut and altering the composition of the intestinal microbiota. [9][10][11] An imbalance in the gut microbiota leads to an increase in harmful metabolites produced by gut bacteria.…”

“…9,10 This enhances sodium absorption, and hydrogen ions are exchanged into the gut lumen, decreasing the local pH of the gut and altering the composition of the intestinal microbiota. [9][10][11] An imbalance in the gut microbiota leads to an increase in harmful metabolites produced by gut bacteria. Trimethylamine N-oxide (TMAO) is a molecular metabolite that is derived from the gut microbiota.…”

“…Choline, betaine, and l ‐carnitine, which are included in red meat, eggs, fish, and dairy products, are converted to trimethylamine via certain gut microbial enzymes and then metabolized by the liver to TMAO. This promotes atherosclerosis and is associated with increased morbidity and mortality in coronary artery disease 10,12,13 . TMAO also directly affects the heart by inducing myocardial hypertrophy and fibrosis, 14 inflammation, 15 and mitochondrial dysfunction of the myocardium, 16 which may affect development and prognosis of HF 9 .…”