Growth Differentiation Factor 15 Is Associated With Major Amputation and Mortality in Patients With Peripheral Artery Disease

BACKGROUND: Peripheral artery disease (PAD) is one of the most common clinical presentations of atherosclerosis, and its prevalence is still increasing. Despite improvement of health care, morbidity and mortality risks remain high, including the risk of amputation. GDF15 (growth differentiation factor 15) is a member of the transforming growth factor family that is involved in apoptosis and inflammation; therefore, GDF15 is a potential biomarker to identify patients at high risk of adverse clinical outcomes. METHODS AND RESULTS: Circulating GDF15 levels were measured using a multiplex immunoassay in patients with critical limb ischemia and PAD from 2 different patient cohorts that included patients with clinically manifest PAD: the JUVENTAS (Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra‐Arterial Supplementation) trial (n=160, 67 major events; critical limb ischemia) and the Athero‐Express Biobank (n=386, 64 major events; PAD). Kaplan–Meier curves demonstrated that high levels of GDF15 were associated with increased risk of major events, defined as major amputation (at or above the ankle joint) and all‐cause mortality, in both cohorts (highest versus lowest, JUVENTAS: hazard ratio: 4.01 [95% confidence interval, 2.05–7.84; P<0.0001]; Athero‐Express: hazard ratio: 3.27 [95% confidence interval, 1.64–6.54; P=0.0008]). In the JUVENTAS trial, this was more pronounced in women. Cox proportional multivariable regression models with median follow‐up of 3 years, corrected for common confounders, showed hazard ratios of 1.70 (95% confidence interval, 1.18–2.69; P=0.0053) and 1.57 (95% confidence interval, 1.02–2.41; P=0.041) per 2.78‐fold increase of GDF15 in JUVENTAS and Athero‐Express, respectively. CONCLUSIONS: High GDF15 levels are associated with increased risk of major amputation and/or death in PAD patients. GDF15 levels could be of additive value to identify patients who are at high risk of amputation or death and could help guide treatment choices.