Elevated bile acids are associated with left ventricular structural changes in biliary atresia

Abstract

Background: In children with biliary atresia (BA), pathologic structural changes within the heart, which define cirrhotic cardiomyopathy, are associated with adverse perioperative outcomes. Despite their clinical relevance, little is known about the pathogenesis and triggers of pathologic remodeling. Bile acid excess causes cardiomyopathy in experimental cirrhosis, but its role in BA is poorly understood.

Methods: Echocardiographic parameters of left ventricular (LV) geometry [LV mass (LVM), LVM indexed to height, left atrial volume indexed to BSA (LAVI), and LV internal diameter (LVID)] were correlated with circulating serum bile acid concentrations in 40 children (52% female) with BA listed for transplantation. A receiver-operating characteristic curve was generated to determine optimal threshold values of bile acids to detect pathologic changes in LV geometry using Youden index. Paraffin-embedded human heart tissue was separately analyzed by immunohistochemistry for the presence of bile acid-sensing Takeda G-protein-coupled membrane receptor type 5.

Results: In the cohort, 52% (21/40) of children had abnormal LV geometry; the optimal bile acid concentration to detect this abnormality with 70% sensitivity and 64% specificity was 152 µmol/L (C-statistics=0.68). Children with bile acid concentrations >152 µmol/L had ∼8-fold increased odds of detecting abnormalities in LVM, LVM index, left atrial volume index, and LV internal diameter. Serum bile acids positively correlated with LVM, LVM index, and LV internal diameter. Separately, Takeda G-protein-coupled membrane receptor type 5 protein was detected in myocardial vasculature and cardiomyocytes on immunohistochemistry.

Conclusion: This association highlights the unique role of bile acids as one of the targetable potential triggers for myocardial structural changes in BA.

FIGURE 1

Circulating bile acid concentrations and echocardiographic aberrations: figure depicts LV mass index [LVMI (g/ht^2.7)], LV mass (LVM) z score, left atrial volume index (LAVI) mL/m², left ventricular internal diameter (LVID) z score, fractional shortening (%FS), and relative wall thickness (RWT) between groups with bile acid concentrations <152 μmol/L and > 152 μmol/L. Data above the dotted line represents abnormal values. Note the increased LVMI, LVM (z score), LAVI and LVID (z score) in patients with bile acid concentrations above 152 μmol/L. Statistics: Mann–Whitney U, *p <0.05.

FIGURE 2

Detection of TGR5 protein in the human myocardium: immunohistochemistry was performed in paraffin-embedded human heart tissue using a polyclonal antibody directed against human TGR5 (1:200 dilution; Sigma Aldrich). Note the presence of brown TGR5 staining in the vascular endothelium within the heart (A) (red arrow); note that there is no staining seen in IgG-incubated control (B) (20× magnification; scale bar=100 μ). (C) Depicts brown TGR5 staining of heart muscles (red arrow), again note no staining with IgG control (D) (40× magnification; scale=50 μ). (E) Depicts staining within the cardiomyocytes, while no staining seen in IgG control (F) (100× magnification; scale=10 μ). On the right inset is TGR5 staining (red arrow) in human placental trophoblasts (G) (40× magnification; scale=50 μ) and human splenic monocytes (H) (100× magnification; scale=10 μ), both serving as positive controls for the detection of TGR5 with the primary antibody.