Low LDL-Cholesterol levels predict higher mortality in heart failure with reduced ejection fraction: validating the "lipid paradox" in a real-world cohort
B Murat, F Aydin, S MuratAbstract
Background
Hyperlipidemia is a well-established risk factor for coronary artery disease; however, in patients with heart failure (HF), lower cholesterol levels are often associated with worse outcomes, a phenomenon known as the "lipid paradox."
Purpose
We aimed to investigate the prognostic value of low-density lipoprotein cholesterol (LDL-C) levels on long-term survival in patients with heart failure with reduced ejection fraction (HFrEF).
Methods
We conducted a retrospective study of 605 patients with HFrEF. Patients were stratified into three groups based on baseline LDL-C levels: <70 mg/dL (n=128), 70–100 mg/dL (n=213), and >100 mg/dL (n=264). The primary outcome was 5-year all-cause mortality. Secondary outcomes included cardiovascular mortality and composite endpoints of mortality or HF hospitalization. Multivariable Cox proportional hazards regression was performed to adjust for confounders, including age, comorbidities, and NT-proBNP levels.
Results
Patients in the lowest LDL-C group (<70 mg/dL) had significantly higher baseline NT-proBNP levels [median 7759 vs. 1810 pg/mL, p<0.001] and lower hemoglobin [11.8 vs. 12.9 g/dL, p<0.001] than patients in the highest LDL-C group (>100 mg/dL) (table 1). Unadjusted survival analysis revealed an inverse relationship between LDL-C and mortality: the 5-year mortality rate was highest in the <70 mg/dL group (65.6%) compared with the 70–100 mg/dL (51.2%) and >100 mg/dL (47.7%) groups (p=0.003). Similarly, 1-year mortality was nearly double in the lowest LDL-C group compared with the highest (40.6% vs. 20.8%, p<0.001). In multivariable analysis adjusting for age, sex, and NT-proBNP, higher LDL-C levels showed a trend toward a protective effect, although the "lipid paradox" was partly explained by disease severity markers. The ROC analysis for the multivariable model demonstrated moderate discrimination for 5-year mortality (AUC = 0.691) (Figure 1).
Conclusion
In patients with HFrEF, low LDL-C levels are strongly associated with increased all-cause and heart failure-specific mortality. This inverse relationship suggests that low cholesterol may serve as a surrogate marker for malnutrition, cachexia, and advanced disease severity rather than a therapeutic target in this population. Clinicians should view very low LDL-C in HFrEF as a "red flag" for poor prognosis.For image description, please refer to the figure legend and surrounding text.Figure 1For image description, please refer to the figure legend and surrounding text.