Association of growth differentiation factor-8 with prognosis in heart failure: the PREHOSP-CHF Study

Background Skeletal muscle wasting and cardiac cachexia is one of the critical problems in patients with HF (heart failure), and are associated with poor prognosis. Growth differentiation factor-8 (GDF-8, also called myostatin), a cytokine from the transforming growth factor-β (TGF-β) family, is known as a strong inhibitor of skeletal muscle growth, and reported as a direct mediator of skeletal muscle atrophy in mice with heart failure. Purpose To investigate the association of GDF-8 with prognosis in patients with HF. Methods The PREHOSP-CHF study is a multicenter prospective cohort study to determine the predictive value of angiogenesis-related biomarkers in HF. A total of 1,024 patients (mean age 75.5±12.6 years; 58.7% male) admitted to acute decompensated HF were included in the analyses. Serum levels of GDF-8, as well as N-terminal pro B-type natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin-I (hs-cTnI), high sensitivity C reactive protein (hs-CRP), were measured at the time of discharge. Patients were followed over two years. Results Of 1,024 patients, median value of GDF-8 was 1560 pg/ml (interquartile range 1097-2316 pg/ml). When we divided the patients into 4 groups based on the quartile of GDF-8, patients with lowest quartile of GDF-8 were significantly older, frequently female, and had lower body mass index (BMI). Prevalence of anemia was higher, and prevalence of dyslipidemia was lower in patients with lowest quartile of GDF-8, but prevalence of other comorbidities was similar between the 4 groups. Prevalence of prior HF hospitalization and HF with reduced ejection fraction was also similar between the 4 groups, but patients with lowest quartile of GDF-8 showed significantly higher New York Heart Association class. Levels of NT-proBNP and hs-CRP, but not hs-cTnI, were higher in patients with lowest quartile of GDF-8. During the median follow-up of 720 days, all-cause death, cardiovascular death, and HF hospitalization occurred in 211, 113, and 309 patients, respectively. Patients with lowest quartile of GDF-8 showed significantly higher incidence of all-cause death and cardiovascular death, but not that of HF hospitalization (Figure 1). In multivariate analysis including NT-proBNP, hs-cTnI, and hs-CRP, GDF-8 was not significantly associated with the incidence of all-cause death, cardiovascular death, or HF hospitalization, However, when we stratified the patient into high (≥22 kg/m2, N=473) and low (<22 kg/m2, N=551) BMI group, lower levels of GDF-8 were significantly and independently associated with the incidence of all-cause death in patients with low BMI (Figure 2). Conclusions Among patients with HF, those with low GDF-8 showed significantly higher incidence of all-cause death and cardiovascular death. Furthermore, low levels of GDF-8 might be a independent risk for the incidence of all-cause death in HF patients with low BMI.