Visceral Congestion in Heart Failure: Right Ventricular Dysfunction, Splanchnic Hemodynamics, and the Intestinal Microenvironment
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Purpose of Review
Visceral venous congestion of the gut may play a key role in the pathogenesis of right-sided heart failure (HF) and cardiorenal syndromes. Here, we review the role of right ventricular (RV) dysfunction, visceral congestion, splanchnic hemodynamics, and the intestinal microenvironment in the setting of right-sided HF. We review recent literature on this topic, outline possible mechanisms of disease pathogenesis, and discuss potential therapeutics.
There are several mechanisms linking RV–gut interactions via visceral venous congestion which could result in (1) hypoxia and acidosis in enterocytes, which may lead to enhanced sodium–hydrogen exchanger 3 (NHE3) expression with increased sodium and fluid retention; (2) decreased luminal pH in the intestines, which could lead to alteration of the gut microbiome which could increase gut permeability and inflammation; (3) alteration of renal hemodynamics with triggering of the cardiorenal syndrome; and (4) altered phosphate metabolism resulting in increased pulmonary artery stiffening, thereby increasing RV afterload. A wide variety of therapeutic interventions that act on the RV, pulmonary vasculature, intestinal microenvironment, and the kidney could alter these pathways and should be tested in patients with right-sided HF.
The RV–gut axis is an important aspect of HF pathogenesis that deserves more attention. Modulation of the pathways interconnecting the right heart, visceral congestion, and the intestinal microenvironment could be a novel avenue of intervention for right-sided HF.
KeywordsHeart failure Right ventricle Venous congestion Intestine Sodium–hydrogen exchanger 3 Microbiome
National Institutes of Health R01 HL107577 and R01 HL 127028, and American Heart Association no. 16SFRN28780016 and no. 15CVGPSD27260148.
Compliance with Ethical Standards
Conflict of Interest
V.B.P. and A.S. each declare no potential conflicts of interest.
S.J.S. has received grant support from Actelion, AstraZeneca, Corvia, and Novartis; and consulting fees from Actelion, AstraZeneca, Bayer, Boehringer-Ingelheim, Cardiora, Ironwood, Merck, Novartis, Pfizer, and Sanofi.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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- 4.Bosch L, Lam CSP, Gong L, Chan SP, Sim D, Yeo D, et al. Right ventricular dysfunction in left-sided heart failure with preserved versus reduced ejection fraction. Eur J Heart Fail. 2017. https://doi.org/10.1002/ejhf.873.
- 10.• Valentova M, von Haehling S, Bauditz J, Doehner W, Ebner N, Bekfani T, et al. Intestinal congestion and right ventricular dysfunction: a link with appetite loss, inflammation, and cachexia in chronic heart failure. Eur Heart J. 2016;37(21):1684–91. This is a recent article that found that visceral (intestinal) congestion is the strongest factor associated with cardiac cachexia in heart failure patients. CrossRefPubMedGoogle Scholar
- 15.Heianza Y, Ma W, Manson JE, Rexrode KM, Qi L. Gut microbiota metabolites and risk of major adverse cardiovascular disease events and death: a systematic review and meta-analysis of prospective studies. J Am Heart Assoc. 2017;6(7):e004947.Google Scholar
- 21.Sanduzzi Zamparelli M, Compare D, Coccoli P, Rocco A, Nardone OM, Marrone G, et al. The metabolic role of gut microbiota in the development of nonalcoholic fatty liver disease and cardiovascular disease. Int J Mol Sci. 2016;17(8):E1225.Google Scholar
- 38.Natarajan N, Hori D, Flavahan S, Steppan J, Flavahan NA, Berkowitz DE, et al. Microbial short chain fatty acid metabolites lower blood pressure via endothelial G-protein coupled receptor 41. Physiol Genomics. 2016;48(11):826-834.Google Scholar
- 40.Senthong V, Wang Z, Li XS, Fan Y, Wu Y, Tang WH, et al. Intestinal microbiota-generated metabolite trimethylamine-N-oxide and 5-year mortality risk in stable coronary artery disease: the contributory role of intestinal microbiota in a COURAGE-like patient cohort. J Am Heart Assoc 2016;5(6):e002816.Google Scholar
- 46.•• Zhu W, Gregory JC, Org E, Buffa JA, Gupta N, Wang Z, et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell. 2016;165(1):111–24. This paper describes the mechanistic link between the gut-derived microbial metabolite TMAO, enhanced platelet reactivity, and thrombosis risk. CrossRefPubMedPubMedCentralGoogle Scholar
- 49.Dong T, Aronsohn A, Gautham Reddy K, Te HS. Rifaximin decreases the incidence and severity of acute kidney injury and hepatorenal syndrome in cirrhosis. Dig Dis Sci. 2016.Google Scholar
- 71.Khan SS, Cuttica MJ, Beussink-Nelson L, Kozyleva A, Sanchez C, Mkrdichian H, et al. Effects of ranolazine on exercise capacity, right ventricular indices, and hemodynamic characteristics in pulmonary arterial hypertension: a pilot study. Pulm Circ. 2015;5(3):547–56.CrossRefPubMedPubMedCentralGoogle Scholar
- 72.Shah SJ, Blair JE, Filippatos GS, Macarie C, Ruzyllo W, Korewicki J, et al. Effects of istaroxime on diastolic stiffness in acute heart failure syndromes: results from the hemodynamic, echocardiographic, and neurohormonal effects of istaroxime, a novel intravenous inotropic and lusitropic agent: a randomized controlled trial in patients hospitalized with heart failure (HORIZON-HF) trial. Am Heart J. 2009;157(6):1035–41.CrossRefPubMedGoogle Scholar
- 74.Kapur NK, Bader YH. Percutaneous circulatory assist devices for right ventricular failure. Interv. Cardiol Clin. 2013;2(3):445–56.Google Scholar
- 76.Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study. Circ Heart Fail. 2011;4(1):8–17.CrossRefPubMedGoogle Scholar
- 77.Bonderman D, Ghio S, Felix SB, Ghofrani HA, Michelakis E, Mitrovic V, et al. Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study. Circulation. 2013;128(5):502–11.CrossRefPubMedGoogle Scholar
- 79.• Spencer AG, Labonte ED, Rosenbaum DP, Plato CF, Carreras CW, Leadbetter MR, et al. Intestinal inhibition of the Na+/H+ exchanger 3 prevents cardiorenal damage in rats and inhibits Na+ uptake in humans. Sci Transl Med. 2014;6(227):227ra36. Spencer et al. describe the protective beneficial effect of gut NHE3 inhibition on cardiorenal damage in rats. CrossRefPubMedGoogle Scholar
- 82.Ghosh P. The stress polarity pathway: AMPK ‘GIV’-es protection against metabolic insults. Aging (Albany NY). 2017;9(2):303–14.Google Scholar