PROJECT SUMMARY/ABSTRACT Therapies aimed at preventing development of cirrhosis-related complications are lacking. Statins have been shown to improve liver function and attenuate portal hypertension although definitive studies are lacking. Our investigative team has deep expertise in cirrhosis and portal hypertension including clinical, translational, and laboratory aspects of disease. Our aims in this proposal are: Aim 1. To conduct a prospective, multicenter, observational study of patients with compensated cirrhosis that will serve as the foundation for discovery of novel mechanistic and therapeutic targets. We will consolidate a longitudinal database to (a) provide unique information on the natural history and outcomes of cirrhosis and (b) support translational research (proposed in Aim 3). This robust multicenter dataset will be used for the development and validation of an artificial intelligence-derived algorithm for prediction of decompensation combining extensive clinical, laboratory and radiographic data, including magnetic resonance elastography and electrocardiogram. Aim 2. To perform a multicenter prospective randomized phase 3 clinical trial of simvastatin versus placebo to improve outcomes in patients with compensated cirrhosis. This aim will test the hypothesis that simvastatin is superior to placebo for reducing complications of cirrhosis and overall mortality. This phase 3 efficacy trial will randomize patients to Simvastatin 20 mg or placebo daily with median follow up of 36 months. The primary endpoint will be development of varices, decompensating events or death analyzed as ordinal outcomes based six prognostic stages. Secondary endpoints will include fibrosis regression, incidence of hepatocellular carcinoma, and cardiovascular complications. Aim 3. To identify novel pathogenic targets in cirrhosis progression through 2 Sub-aims: Sub-Aim 3a. To investigate the rate of telomere attrition in cirrhosis progression and decompensation. Telomere shortening has been observed in advanced cirrhosis and preclinical studies have shown reduced fibrosis with telomere length restoration. However, the rate of telomere attrition in cirrhosis and its association with disease progression remain unknown. Our proposal will serve as the basis for future studies assessing new therapies aimed at telomere length preservation in cirrhosis and effects of statins. Sub-Aim 3b. To measure circulating markers of neutrophil extracellular traps (NETs) and its correlation to development of hepatic decompensation. Anticoagulation has been shown to reduce hepatic decompensation in a small trial of patients with cirrhosis. Our group has recently shown that NETs drive intrahepatic thrombosis, and inhibition of NETs reduces portal pressure in preclinical studies. Thus, the results of this sub-aim will serve as the foundation for future human studies investigating novel therapies aimed at disrupting NETs in the liver. Our center and team have substantial expertise in clinical trials and therapeutics for advanced liver disease and are thus well poised to conduct these studies.

PROJECT NARRATIVE This study will investigate the natural history of cirrhosis. The success of this proposed research will result in new treatments for patients with cirrhosis.