Prospective Investigation of Cirrhotic Cardiomyopathy in Humans

Vanderbilt University Medical Center, Nashville TN

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY Cirrhotic cardiomyopathy (CCM) is a recognized but understudied and not well understood complication of cirrhosis. CCM is defined as subclinical diastolic or systolic dysfunction by echocardiography in patients with cirrhosis in the absence of overt coronary artery, valvular, or pericardial disease. Drs. Izzy (PI) and VanWagner (co-I) cofounded the multidisciplinary CCM consortium in 2018 that established diagnostic criteria for CCM in 2020 incorporating contemporary echocardiographic methods. Since then, mostly retrospective, and relatively small studies applying these criteria suggest CCM may be common affecting 24-45% of patients with cirrhosis and associated with adverse hepatic and cardiac outcomes and ~2-to 9-fold greater risk of death. Further, the pathophysiology of CCM in humans is not well understood, but preclinical evidence from our group and others implicates bile acids (BA) as a causal and potentially modifiable driver of CCM. Appreciating limitations of retrospective human and preclinical studies, the estimates for CCM prevalence and prognosis are concerning and motivate deeper and larger prospective investigation in humans to address unanswered questions highly relevant to clinical care and those of biologic importance. These include 1) what are the associations between CCM and all-cause mortality, cirrhosis-related outcomes, and adverse cardiac events, 2) what clinical factors associate with presence of CCM, and 3) do BA associate with adverse cardiac remodeling and features of CCM? Therefore, in this study we will conduct the first US based prospective investigation of CCM in humans with decompensated cirrhosis enrolled from two high-volume hepatology and liver transplant (LT) centers. Our study design will address limitations of prior studies by including a) larger sample size inclusive of both eligible and ineligible patients for LT, b) serial assessment every 6 months of clinical, laboratory, and echocardiographic data, and c) longitudinal ascertainment of hepatic, cardiac, and mortality outcomes. Our specific aims are to: 1) test the hypothesis that addition of CCM status to MELD-3.0 improves accuracy of risk stratification for 1-year all-cause mortality, 2) define clinical risk factors associated with CCM, and 3) test the hypotheses that higher circulating levels of total BA and altered composition of BA (ratio of conjugated primary BA [cholic and chenodeoxycholic acids] to secondary BA [ursodeoxycholic acid]) associate with the cardiac alterations seen in CCM. By providing foundational prospective data needed to advance the field of CCM, our study will exert a powerful and enduring scientific and clinical impact. We will refine clinical risk stratification for adverse outcomes in patients with end-stage liver disease and inform clinical screening and surveillance for CCM. Establishing a CCM risk profile and a BA-myocardial link are critical to designing future trials testing BA modifying therapies specific for CCM, particularly as pharmacotherapy for CCM are lacking. Our team of experts in hepatology, BA, cardiology, epidemiology, and biostatistics has the requisite resources to successfully complete the study, which will transform understanding of and the clinical approach to CCM.