Intestinal barrier dysfunction is associated with elevated right atrial pressure in patients with advanced decompensated heart failure

Abstract

We prospectively performed serial differential sugar absorption test in 29 consecutively consented patients with advanced decompensated heart failure admitted to the heart failure intensive care unit for hemodynamically-guided therapy. We observed that intestinal barrier function was significantly impaired in our study cohort, and increased intestinal permeability was associated with elevated right atrial pressure and poorer prognosis yet without any association with systemic levels of the gut microbial metabolite, trimethylamine N-oxide (TMAO) or intestinal fatty acid binding protein that were thought to be indicative of intestinal abnormalities.

Recently, connections between the gut and heart failure (HF) have been discovered.¹ In the setting of HF, intestinal wall edema due to systemic congestion and reduced intestinal blood flow can lead to disruption of the mucosal barrier and increased permeability, which have been reported in patients with stable HF, and was further associated with higher levels of inflammatory biomarkers.² However, the relationship between intestinal permeability and HF prognosis remains unclear. This study aimed to investigate whether alterations to intestinal permeability was associated with changes in hemodynamic status, intestinal biomarkers (intestinal fatty acid binding protein [I-FABP]), gut microbial metabolites, and worsening outcomes in acute decompensated HF (ADHF).

We prospectively enrolled 29 ADHF patients who required hemodynamic monitoring by pulmonary artery catheterisation at the HF intensive care unit at Cleveland Clinic and consented to participating in the study. Exclusion criteria included inflammatory bowel disease, hematologic diseases, acute coronary syndrome within the preceding 30 days, active infection, administration of antibiotics or probiotics within 1 month of study enrolment, end-stage renal failure requiring hemodialysis, and a history of any bariatric procedure. This study complies with the Declaration of Helsinki, and was approved by the Cleveland Clinic Institutional Review Board. All patients provided written informed consent.

The differential sugar absorption test (DST) was used to evaluate intestinal permeability by quantifying L-rhamnose and lactulose disaccharide in the urine after oral administration, as previously reported (online supplementary for methods, Figure S1).³ Three hours after their evening meal, patients emptied their bladder and took a test solution containing 5 g lactulose, 5 g rhamnose, and 5 g sucrose, with up to 100 ml of deionised water—an approximate osmolality of 1,500 mOsm/L. To avoid possible interference, patients were forbidden to drink any soft drinks, alcohol, fruit juice, or milk during the test. Total urine volume was measured and analysed for lactulose and rhamnose using liquid chromatographymass spectrometry. The ratio of lactulose to rhamnose recovery in urine (LR ratio) was used as a measure of intestinal permeability.^{4, 5} The DST was performed twice for each patient.

Baseline blood samples were collected prior to therapy and sugar drink administration. Serum I-FABP levels were determined by human FABP2/I-FABP enzyme-linked immunosorbent assay. ⁶ Trimethylamine-N-oxide (TMAO), choline, and betaine levels in plasma were determined using stable isotope dilution high-performance liquid chromatography with online electrospray ionisation tandem mass spectrum as previously described.⁷ Descriptive statistics are reported. Logistic regression models were used to determine the association of LR ratio to adverse clinical events, a composite of all-cause death, and need for heart transplantation or left ventricular assist device implantation, while adjusting for age, sex, and creatinine. Statistical significance was assumed with a two-sided P-value of <.05.

The mean age was 58.9 ± 10.4 years, 76% were male, and the mean left ventricular ejection fraction was 21.7% ± 9.8%. The median LR ratio was 0.08 (interquartile range, 0.05-0.13). Although patients with high LR ratios had significantly lower hemoglobin levels, there were no significant differences between the groups with respect to other variables, including I-FABP and TMAO (online supplementary Table S). We observed no significant correlations between LR ratios and age and plasma glucose levels. LR ratios correlated with invasively-measured right atrial pressure (RAP) (ρ = 0.43, P = .027) and echocardiographic-estimated RAP (ρ = 0.46, P = .013), whereas other hemodynamic parameters, N-terminal pro-B type natriuretic peptide, and TMAO were not significantly correlated with LR ratios (Table I). Increased RAP can potentiate intestinal edema, leading to intestinal insult and compromised barrier function. ⁸ However, identifying and evaluating the extent of intestinal congestion in HF remains a challenge. Although biomarkers are considered as possible candidate to evaluate intestinal congestion, ⁶ many of them are readily diffused across the intestinal membranes, and do not correlate with the DST. ⁹ During a median follow-up of 56 days, 17 patients experienced adverse clinical events. Patients with a high LR ratio had significantly higher events than those with a low LR ratio (P = .035) (Figure I). In addition, the LR ratio was independently associated with an increased risk of adverse outcomes (adjusted odds ratio: 7.93, 95% confidence interval: 1.04 to 60.6, P = .046). We noted several limitations to our current study. First, our investigation was a single-center study, which recruited a relatively small number of patients that required catheterization in an intensive care unit setting. Due to this small sample size and specific criteria, we did not overlook selection bias, which may have inflated the proportion of severe HF patients and potentially confounded our results. The lack of associations between increased intestinal permeability and TMAO, I-FABP or NT-proBNP may be due to this fact. Another potential limitation is the absence of individual dietary history before hospital admission to further validate the efficacy of the DST. To mitigate this, DSTs were performed twice for each patient; however, it is possible that the interval was too short for the assessment of euvolemic state. In addition, it is difficult to determine whether patients with low LR ratio have some level of intestinal barrier disruption without comparisons to healthy controls.

Table I.

Associations between LR ratio and clinical parameters

	Spearman’s rho	P
Age, years	0.10	.60
Glucose, mg/dl	−0.10	.59
NT-proBNP, pg/ml	−0.04	.83
RAP, mm Hg	0.43	.027
PCWP, mm Hg	−0.30	.18
Cardiac output, l/min	−0.06	.79
Cardiac index, l/min/m2	0.14	.48
Estimated RAP by echo, mm Hg	0.46	.013

LR, lactulose/L-rhamnose; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure

Figure I.

Prevalence of adverse clinical events between high and low LR ratios. Abbreviation: LR, lactulose/L-rhamnose.

In conclusion, in patients with ADHF, intestinal barrier function, as measured by DST, was significantly impaired, and increased intestinal permeability was associated with elevated RAP and poorer prognosis yet without any association with systemic TMAO levels.