Elevated placental growth factor (PlGF) predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy

Background and Aim. Placental growth factor (PlGF) is up-regulated in early and advanced atherosclerotic lesions, acts as a primary inflammatory instigator of atherosclerotic plaque instability, and may be an independent biomarker of adverse outcome in patients with acute coronary syndromes. In diabetic nephropathy the relative cardiovascular mortality and morbidity is increased and therefore, this study investigated the prognostic value of PlGF in a large cohort of type 1 diabetic patients with and without diabetic nephropathy. Research Design and Methods. In a prospective, observational follow-up study 190 type 1 diabetic patients with overt diabetic nephropathy (116 men, age (mean (SD)) 41 ± 10 years, duration of diabetes 28 ± 8 years, glomerular filtration rate (GFR) 76 ± 33 mL/min/1.73 m²) and a matched control group of 174 patients with normoalbuminuria (104 men, age 43 ± 10 years, duration of diabetes 27 ± 9) were followed for 10 years (range: 0-10.3). The primary endpoint was a composite endpoint of cardiovascular death, hospitalization for myocardial infarction or stroke, coronary artery bypass grafting or percutanous coronary intervention, ischaemic amputation or peripheral bypass-surgery. Plasma PlGF was determined by an enzyme linked immunosorbent assay at baseline. Results. During 10 years of follow-up 74 patients (39%) with diabetic nephropathy reached the primary endpoint versus only 18 (10%) of normoalbuminuric patients, log rank test; p<0.001. During follow-up 16 (25%) patients in the lowest, 24 (39%) in the middle and 34 (52%) patients in the upper tertile reached the primary cardiovascular endpoint, p=0.007. Hazard ratios in the second and third tertile as compared with the first tertile were 1.76 (0.92-3.38) and 2.64 (1.41-4.91) (p=0.009). Cox regression analyses including PlGF concentration as a continuous variable revealed an unadjusted hazard ratio of the primary endpoint for each 1 ng /L increase in PlGF of 1.10 (1.03-1.16), p=0.002; covariate adjusted hazard ratio 1.07 (1.00-1.14), p=0.03. Conclusions. Increased PlGF is a new independent predictor of cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy.