Free fatty acids: independent predictors of long-term adverse cardiovascular outcomes in heart failure patients

Abstract

Background: The association between plasma free fatty acid (FFA) and the outcomes in the heart failure (HF) patients remains unclear.

Methods: A cohort study among HF patients was performed. Plasma FFA was analyzed as both a continuous and a categorical variable (grouped by tertiles) to assess its association with composite cardiovascular (CV) death and HF hospitalization (CV death & HHP), CV death alone, and all-cause mortality (ACM) using Cox regression models. Subgroup analyses of HF patients with preserved ejection fraction (HFpEF) and mildly reduced/reduced ejection fraction (HFmrEF/HFrEF) were performed. This work also assessed the effectiveness of combining FFA and NT-pro BNP biomarkers for risk stratification by calculating the concordance index (C-index).

Results: Among the 4,109 HF patients, FFA levels exceeding 0.4-0.42 mmol/L were associated with increased risks of the three outcomes. Patients in the highest FFA tertile faced greater risks than those in the lowest tertile. Adjusted hazard ratios were 1.32 (95% CI: 1.11-1.58) for CV death & HHP, 1.45 (95% CI: 1.16-1.82) for CV death, and 1.39 (95% CI: 1.15-1.68) for ACM, with a maximum follow-up of 8 years (median: 25 months). Subgroup analyses revealed that elevated FFA levels consistently predicted worse outcomes in both HFmrEF/HFrEF and HFpEF patients. The C-index for predicting outcomes was significantly greater when NT-pro BNP and FFA were combined than when NT-pro BNP was used alone (P < 0.01).

Conclusion: Increased plasma FFA concentrations were independently associated with greater risks of CV death & HHP, CV death, and ACM among HF patients, irrespective of the ejection fraction. The combination of FFA and NT-pro BNP biomarkers significantly improved risk stratification in HF patients.

Keywords: Adverse cardiovascular outcomes; All-cause mortality; Free fatty acids; Heart failure; Long-term follow-up.

Fig. 1

Flowchart of the study subject inclusion process

Fig. 2

RCS curves modeling the relationships between plasma FFA levels and the three long-term adverse outcomes, including CV death & HHP (a), CV death (b), and ACM (c). A) Analysis of the entire heart failure patient population; B) analysis of the HFrEF cohort, which included HFmrEF individuals; C) analysis of the HFpEF cohort. The point where the dashed line intersects the X-axis represents the plasma FFA level corresponding to the inflection point of the RCS curve. The adjusted covariates in the Cox multiple regression models included age, sex, BMI, smoking status, alcohol consumption, major comorbidities (type 2 diabetes, hypertension, atrial fibrillation, and coronary artery disease), serum creatinine, NT-proBNP, hs-CRP, and the prescription of ACE inhibitors/ARBs/ARNIs, β-blockers, MRAs, and SGLT2 inhibitors at discharge

Fig. 3

Kaplan-Meier curves depicting the incidence of cardiovascular death and heart failure hospitalization (A), cardiovascular death (B), and all-cause mortality (C) in patients with normal versus elevated FFA levels (defined as > 0.45 mmol/L in female patients and > 0.60 mmol/L in male patients). (Note: Ref: the reference group; adj. HR: adjusted hazard ratio)

Fig. 4

Forest plots displaying the results of stratified analyses and interaction tests. In the whole cohort, the overall HRs for the three adverse outcomes were derived from a Cox proportional hazards regression model, representing the risk associated with an increase of one standard deviation (SD) in the continuous variable. P_int: P for interaction. BMI: body mass index; CAD: coronary artery disease; HBP: hypertension; HF: heart failure; HFpEF: heart failure with preserved ejection fraction. T2DM: Type 2 diabetes mellitus; eGFR: estimated glomerular filtration rate; hs-CRP: high-sensitivity C-reactive protein; LDL-C: low-density lipoprotein cholesterol

Fig. 5

Receiver operating characteristic (ROC) curves and the corresponding area under the curve (AUC) values for different models predicting cardiovascular death and heart failure hospitalization (A), cardiovascular death (B), and all-cause mortality (C). (Note: CV death & HHP: cardiovascular death and heart failure hospitalization; CV death: cardiovascular death; ACM: all-cause mortality.)