Contributions of mitochondrial dysfunction to baroreflex and cardiac dysregulation in hepatic encephalopathy

Abstract

Hepatic encephalopathy (HE) is a common neurocognitive complication of acute and chronic liver failure and is associated with 50–90% mortality without liver transplantation. Despite a highly challenging clinical problem, systematic evaluations of the cellular mechanisms of HE‐related mortality are still lacking. Clinical studies showed that the degree of baroreflex dysregulation is related to the severity of HE. At the cellular level, oxidative stress resulting from mitochondrial dysfunction in brain stem nuclei in the baroreflex circuit, including nucleus tractus solitarii (NTS) and rostral ventrolateral medulla (RVLM), and in the heart are known to result baroreflex dysregulation and cardiac dysfunction. This study investigated whether the same mechanism underlies the high mortality in HE. An azoxymethane (AOM)‐induced acute liver failure model of HE employing C57BL/6 mouse was used. Diffusion tensor imaging (DTI) or magnetic resonance spectroscopy (MRS) of the brain stem was performed, together with blood pressure, heart rate and indices of baroreflex recorded by radiotelemetry. Animals died within 24–30 h after AOM (100 μg/g, ip) injection. DTI further revealed that the connectivity between the NTS and nucleus ambiguus (NA), the origin of the vagal innervation of the heart, was progressively disrupted though sustained, concurrent with impaired but persistent cardiac vagal baroreflex. On the other hand, the connectivity between NTS and RVLM was progressively disrupted until its disappearance, coincidental with the abolition of baroreflex‐mediated sympathetic vasomotor tone that signifies brain death clinically. Results from 31P MRS obtained from mouse brain stem showed reduced ratio between phosphocreatine and γATP, indicating mitochondrial dysfunction in HE. Furthermore, there was a decrease in cardiac contractility, alongside an elevation of reactive oxygen species and necrotic cell death and a reduction in ATP level in the NTS or RVLM. Our results showed that impairment of baroreflex and cardiac function takes place during the progression towards death in HE, and bioenergetic failure, oxidative stress and necrotic cell death are the culprits.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.