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

Abstract

BackgroundPeripheral 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 ResultsCirculating 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.ConclusionsHigh 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.

Hepcidin and GDF-15 are potential biomarkers of Iron Deficiency Anaemia in Chronic Kidney Disease Patients in South Africa

“…Another important nding in this study is the negative correlation of GDF-15 with haemoglobin in both CKD patients and controls. This nding is consistent with reports by others (44,49,50), but is in disagreement with ndings in non-CKD populations, where GDF-15 was positively correlated with haemoglobin (51)(52)(53). The difference in ndings between our study and others could be explained by racial differences and diversity of ethnicity in the studied population.…”

The association between serum growth differentiation factor 15 levels and lower extremity atherosclerotic disease is independent of body mass index in type 2 diabetes

“…The results from previous studies have shown that increased circulating GDF15 levels were closely associated with the development and progression of various cardiovascular diseases (including myocardial ischaemia/reperfusion, heart failure, atherosclerosis, and acute coronary syndrome), and were shown to be a strong and independent predictor of mortality and disease progression in patients with atherosclerosis and coronary artery disease [5][6][7][8][9][10][31][32][33][34][35][36]. In diabetic patients, higher levels of lipids and chronic inflammation may directly damage the cardiovascular system [37].…”

Prediction of Cardiovascular Clinical Outcomes with Novel Biomarker: the Focus on Growth Differentiation Factor 15

“…In the JUVENTAS (Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-Arterial Supplementation) trial in patients with established peripheral artery disease elevated levels of GDF-15 were found a predictor of critical limb ischemia, increased risk of major amputation and all-cause mortality [27]. Elevated GDF-15 associated with a lack of reverse remodeling and increased mortality after transcatheter aortic valve replacement procedure and improves risk prediction of CV mortality rate adding to traditional score model [28].…”