Elevated bile acids are associated with left ventricular structural changes in biliary atresia
Manpreet Virk, Muhammad Umair M. Mian, Dalia Bashir, John K. Wilkes, Tobias Schlingman, Saúl Flores, Curtis Kennedy, Fong Lam, Ayse Akcan‐Arikan, Trung Nguyen, Krupa R. Mysore, Nhu Thao Nguyen Galván, Jorge Coss‐Bu, Saul J. Karpen, Sanjiv Harpavat, Moreshwar S. Desai
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.