Elevated Soluble Fms-Like Tyrosine Kinase-1 and Placental-Like Growth Factor Levels Are Associated With Development and Mortality Risk in Heart Failure

Background— Vascular endothelial dysfunction may play an important role in the progression of heart failure (HF). We hypothesize that elevated levels of vascular markers, placental-like growth factor, and soluble Fms-like tyrosine kinase-1 (sFlt-1) are associated with adverse outcomes in patients with HF. We also assessed possible triggers of sFlt-1 elevation in animal HF models. Methods and Results— We measured plasma placental-like growth factor and sFlt-1 in 791 HF patients undergoing elective coronary angiogram. Median (interquartile range) placental-like growth factor and sFlt-1 levels were 24 (20–29) and 382 (277–953) pg/mL, respectively. After 5 years of follow-up, and after using receiver operator characteristic curves to determine optimal cutoffs, high levels of sFlt-1 (≥280 pg/mL; adjusted hazard ratio, 1.47; 95% confidence interval, 1.03–2.09; P =0.035) but not placental-like growth factor (≥25 pg/mL; adjusted hazard ratio, 1.26; 95% confidence interval, 0.94–1.71, P =0.12) were associated with adverse cardiovascular outcomes. In addition, significant elevation of sFlt-1 levels was observed in left anterior descending artery ligation and transverse aortic constriction HF mouse models after 4 and 8 weeks of follow-up, suggesting vascular stress and ischemia as triggers for sFlt-1 elevation in HF. Conclusions— Circulating sFlt-1 is generated as a result of myocardial injury and subsequent HF development. Elevated levels of sFlt-1 are associated with adverse outcomes in stable patients with HF.