Characterizing Heart Failure With Preserved Ejection Fraction in End-Stage Liver Disease and Liver Transplant Outcomes

Abstract

Background: Heart failure with preserved ejection fraction (HFpEF) and its risk factors are increasingly recognized in patients with end-stage liver disease (ESLD).

Objectives: The aim of this study was to characterize HFpEF and identify relevant risk factors in patients with ESLD. Additionally, the prognostic impact of high-probability HFpEF on post-liver transplantation (LT) mortality was investigated.

Methods: Patients with ESLD prospectively enrolled from the Asan LT Registry between 2008 and 2019 were divided into groups with low (scores of 0 and 1), intermediate (scores of 2-4), and high (scores of 5 and 6) probability using the Heart Failure Association-PEFF diagnostic score for HFpEF. Gradient-boosted modeling in machine learning was further used to appraise the apparent importance of risk factors. Finally, post-LT all-cause mortality was followed for 12.8 years (median 5.3 years); there were 498 deaths after LT.

Results: Among the 3,244 patients, 215 belonged to the high-probability group, commonly those with advanced age, female sex, anemia, dyslipidemia, renal dysfunction, and hypertension. The highest risk factors for the high-probability group, according to gradient-boosted modeling, were female sex, anemia, hypertension, dyslipidemia, and age >65 years. Among patients with Model for End-Stage Liver Disease scores of >30, those with high, intermediate, and low probability had cumulative overall survival rates of 71.6%, 82.2%, and 88.9% at 1 year and 54.8%, 72.1%, and 88.9% at 12 years after LT (log-rank P = 0.026), respectively.

Conclusions: High-probability HFpEF was found in 6.6% of patients with ESLD with poorer long-term post-LT survival, especially those with advanced stages of liver disease. Therefore, identifying HFpEF using the Heart Failure Association-PEFF score and addressing modifiable risk factors can improve post-LT survival.

Keywords: cirrhotic cardiomyopathy; diastolic dysfunction; end-stage liver disease; heart failure with preserved ejection fraction; liver transplantation.

Graphical abstract

Figure 1

Proportion and Venn Diagram of the Group With High Probability for HFpEF (A) Bar graphs represent the percentages of patients in the high-probability group for each heart failure with preserved ejection fraction (HFpEF) risk factor. (B) Venn diagram of high-probability group of HFpEF (light blue) with hypertension, female sex, anemia, and age >65 years. GFR = glomerular filtration rate.

Figure 2

Clinical Profiles and Phenotypes Associated With High Probability for HFpEF (A) The essential risk factors for high probability of developing HFpEF, assessed using the Shapley additive explanations (SHAP) score: the y-axis indicates the features in order of importance from top to bottom. On the x-axis, the SHAP value indicates the change in log odds. Gradient color indicates the original value for that variable, and each point represents a sample from the test set. (B) The relative contribution of variables to the risk for high-probability HFpEF ranked according to their chi-square values from the multivariate-adjusted model. Abbreviations as in Figure 1.

Figure 3

Association of Liver Disease Severity With HFA-PEFF Score (A) Boxplot shows median and IQR, and whiskers represent 95% CIs. (B) The cubic spline curve between Model for End-Stage Liver Disease score (MELDs) and Heart Failure Association (HFA)–PEFF score, indicating that worsening liver disease severity is associated with the occurrence of heart failure with ejection fraction (HFpEF).

Figure 4

Post–LT Kaplan-Meier Survival Curves (A) Survival probability stratified by HFA-PEFF category in all patients (n = 3,244). (B) In patients with MELDs of >30 (n = 457), the HFA-PEFF score classification showed a more significant difference between survival rates. The post–liver transplantation (LT) cumulative survival rate at 12 years was significantly lower in the high-probability group than in the low-probability group. Abbreviations as in Figure 3.

Central Illustration

Prevalence and Risk Factors of HFpEF in End-Stage Liver Disease Among patients with end-stage liver disease (n = 3,244), 6.6% had high probability of developing heart failure with preserved ejection fraction (HFpEF) and had worse post–liver transplantation (LT) survival outcomes. HFA = Heart Failure Association; MELD = Model for End-Stage Liver Disease.