Association between LDL-C levels and outcomes in patients with heart failure with preserved ejection fraction: a real-world study

Background Although the correlation between elevated low-density lipoprotein cholesterol (LDL-C) levels and heightened cardiovascular risk is well-established, its association with long-term prognosis in patients with heart failure with preserved ejection fraction (HFpEF) remains incompletely understood. Purpose This study aimed to investigate, in patients with HFpEF: 1) the association between LDL-C levels at the time of first HFpEF diagnosis and clinical outcomes; and 2) the interaction of different comorbidity patterns on this association. Methods Using electronic medical record data, this real-world study examined the relationship between baseline LDL-C levels and 3-year all-cause mortality in hospitalized patients with HFpEF. Multivariable-adjusted Cox model was used to calculated hazard ratio (HR) and 95% confidence interval (CI). Hierarchical clustering of 15 conditions was employed to identify patient subgroups, and the association of LDL-C with 3-year all-cause mortality was examined within each identified patterns. Results A total of 44,249 patients (average 70.8 years old) were enrolled and categorized into five groups based on baseline LDL-C levels: <70 mg/dL, 70-100 mg/dL, 100-130 mg/dL, 130-160 mg/dL, and >160 mg/dL. During 3-year follow-up, the all-cause mortality rates were 21.1%, 17.1%, 15.6%, 14.4%, and 15.4% in these groups, respectively. In Cox regression analysis, a U-shaped association was observed between baseline LDL-C and 3-year mortality. Compared to patients with LDL-C 100-130 mg/dL, both lower (<70 mg/dL) and higher (130-160 and >160 mg/dL) LDL-C levels were associated with increased mortality risk (HR 1.14 [95%CI: 1.06-1.22]; HR 1.08 [95%CI: 1.00-1.17]; HR 1.29 [95%CI: 1.17-1.41], respectively). Hierarchical clustering identified six distinct patterns: Cardiostructural-Rhythmic (Pattern 1, n = 297, 0.67%), Immune-Hematic-Respiratory (Pattern 2, n = 2,388, 5.40%), Cardiometabolic (Pattern 3, n = 3,546, 8.01%), Combined (Pattern 4, n = 1,894, 4.28%), Non-Clustered (Pattern 5, n = 1,958, 4.42%), and No Multimorbidity (Pattern 6, n = 34,166, 77.2%). Compared with No Multimorbidity patients, those in other five identified patterns were associated with a 60% (Pattern 1), 104% (Pattern 2), 10% (Pattern 3), 98% (Pattern 4), and 31% (Pattern 5) higher risk of 3-year all-cause mortality, respectively. In Pattern 2, LDL-C < 70 mg/dL (versus 100-130 mg/dL) was associated with a 28% increased risk of 3-year mortality (HR 1.28 [95%CI: 1.04-1.57]), while higher LDL-C levels showed no such association. Conversely, in Pattern 3, no significant difference in risk was observed for patients with lower LDL-C levels, but LDL-C >160 mg/dL was associated with increased mortality (HR 1.43 [95%CI: 1.06-1.94]). Conclusion A U-shaped association between LDL-C levels and 3-year mortality was observed in the overall HFpEF population. Notably, this association was modified by the presence of different comorbidity patterns.