Prognostic value of growth differentiation factor-15 in heart failure among whole ejection fraction phenotypes

Abstract

Aims: The utility of growth differentiation factor-15 (GDF-15) in predicting long-term adverse outcomes in heart failure (HF) patients is not well established. This study explored the relationship between GDF-15 levels and adverse outcomes in HF patients across various ejection fraction (EF) phenotypes associated with coronary heart disease (CHD) and evaluated the added prognostic value of incorporating GDF-15 into the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score-based model.

Methods and results: This single-centre cohort study included 823 HF patients, categorized into 230 (27.9%) reduced EF (HFrEF), 271 (32.9%) mid-range EF (HFmrEF), and 322 (39.1%) preserved EF (HFpEF) groups. The median age was 68.0 years (range: 56.0-77.0), and 245 (29.8%) were females. Compared with the HFrEF and HFmrEF groups, the HFpEF group had a higher GDF-15 concentration (P = 0.002) and a higher MAGGIC risk score (P < 0.001). We examined the associations between GDF-15 levels and the risks of all-cause mortality and HF rehospitalization using Cox regression models. The C-index, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) metrics were employed to assess the incremental prognostic value. During the 9.4 year follow-up period, 425 patients died, and 484 were rehospitalized due to HF. Multivariate Cox regression analysis revealed that elevated GDF-15 levels were significantly associated with an increased risk of all-cause mortality [hazard ratio (HR) = 1.36, 95% confidence interval (CI): 1.20-1.54; P < 0.001] and HF rehospitalization (HR = 1.75, 95% CI: 1.57-1.95; P < 0.001) across all HF phenotypes. This association remained significant when GDF-15 was treated as a categorical variable (high GDF-15 group: all-cause death: HR = 1.73, 95% CI: 1.40-2.14; P < 0.001; HF rehospitalization: HR = 3.37, 95% CI: 2.73-4.15; P < 0.001). Inclusion of GDF-15 in the MAGGIC risk score-based model provided additional prognostic value for all HF patients (Δ C-index = 0.021, 95% CI: 0.002-0.041; IDI = 0.011, 95% CI: 0.001-0.025; continuous NRI = 0.489, 95% CI: 0.174-0.629) and HF rehospitalization (Δ C-index = 0.034, 95% CI: 0.005-0.063; IDI = 0.021, 95% CI: 0.007-0.032; continuous NRI = 0.307, 95% CI: 0.147-0.548), particularly in the HFpEF subgroup.

Conclusions: GDF-15 is identified as an independent risk factor for adverse outcomes in HF patients across the entire EF spectrum in the context of CHD. Integrating GDF-15 into the MAGGIC risk score-based model enhances its prognostic capability for adverse outcomes in the general HF population. This incremental prognostic effect was observed specifically in the HFpEF subgroup and not in other subgroups.

Keywords: Growth differentiation factor‐15; Heart failure with mid‐range ejection fraction; Heart failure with preserved ejection fraction; Heart failure with reduced ejection fraction; The Meta‐Analysis Global Group in Chronic Heart Failure risk score.

Figure 1

Association between GDF‐15 and adverse outcomes using a restricted cubic spline (RCS) regression model. Spline curves showing the association of GDF‐15 as a continuous variable with all‐cause mortality (A) and HF rehospitalization (B). The reference point is the median of GDF‐15. Spline curves were adjusted for heart rate, MAGGIC risk score, hypertension, previous myocardial infarction, previous PCI/CABG, stroke, chronic kidney disease, anaemia, atrial fibrillation, statin, diuretic, spironolactone, digoxin, calcium channel blocker, creatinine, LDL‐C, triglycerides, NT‐proBNP, and hs‐TnT. CABG, coronary artery bypass grafting; CI, confidence interval; GDF‐15, growth differentiation factor‐15; HF, heart failure; HR, hazard ratio; hs‐TnT, high‐sensitivity cardiac troponin T; LDL‐C, low‐density lipoprotein cholesterol; MAGGIC risk score, the Meta‐Analysis Global Group in Chronic Heart Failure risk score; NT‐proBNP, N‐terminal pro‐brain natriuretic peptide; PCI, percutaneous coronary intervention.

Figure 2

Kaplan–Meier survival curves for (A) all‐cause mortality and (B) HF rehospitalization in all HF patients. GDF‐15, growth differentiation factor‐15; HF, heart failure.