Fatigue as a determinant of quality of life across heart failure phenotypes

Abstract Introduction Fatigue is a common and distressing symptom in heart failure with reduced ejection fraction (HFrEF), characterized by persistent physical, cognitive, and emotional tiredness that limits daily activities and reduces health-related quality of life (HRQoL). However, it remains understudied in HF with mildly reduced and preserved ejection fraction (HFmrEF and HFpEF), resulting in limited knowledge of its prevalence, characteristics, and association with HRQoL across HF phenotypes. Purpose The purpose of the study was to describe fatigue and its relationship with HRQoL in patients with HF across the phenotypes HFrEF, HFmrEF and HFpEF. Methods This cross-sectional study was conducted at the cardiology clinics of two hospitals in Sweden between 2019 - 2024. Inclusion criteria were age ≥18 years and confirmed diagnosis of HF. Fatigue and HRQoL was measured using the The Multidimensional Fatigue Inventory 20-items (MFI-20; including general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue) and Euroqol questionnaire EQ-5D (EQ-5D-3L). Patients were identified by a HF nurse during a planned visit at an outpatient clinic, or before being discharged from a cardiology ward. Patients completed the self- administered questionnaires on one occasion. Descriptive statistics were used, and differences between HF phenotypes were examined using ANOVA, Kruskal-Wallis or X² tests, as appropriate. Associations between fatigue and HRQoL were assessed with Pearson correlation, and odds ratios were estimated using multivariable logistic regression. Result A total of 242 patients with HF were included; 65% had HFrEF, 16% HFmrEF, and 19% had HFpEF. Overall fatigue levels were high, with a mean total MFI-20 score of 63.2 ±16.7 (range 20-100), and did not differ significantly between HF phenotypes (P=0.13). Physical fatigue was the most pronounced dimension across all patients (mean 14.5±4.1; range 4-20). Patients with HFpEF reported higher general fatigue than those with HFrEF (15.4±3.5 vs. 13.6±3.9; P=0.03), and significantly lower HRQoL (median 0.813 0.712–0.874 vs. 0.868 0.767–0.935; P= 0.01). Higher levels of fatigue were strongly associated with lower HRQoL (r= -0.68, n=232, P= .001). In multivariable logistic regression analyses, fatigue emerged as the strongest predictor of poor HRQoL; higher MFI-20 scores were associated with significantly lower odds of reporting better HRQoL (OR=0.89; 95% CI 0.85-0.92; P 0.001). Conclusion High levels of fatigue were reported across all HF phenotypes and emerged as the strongest independent predictor of poor HRQoL, outweighing traditional clinical markers such as EF and New York Heart Association (NYHA) class. These findings highlight the need for targeted interventions—particularly those addressing physical fatigue— to improve HRQoL. Reducing fatigue may lead to meaningful improvements in HRQoL.