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

• Type of Material: Article
• Authors: Muhammad Hammadah, Cleveland Clinic; Vasiliki Georgiopoulou, Emory University; Andreas Kalogeropoulos, Emory University; Malory Weber, Cleveland Clinic; Xi Wang, Cleveland Clinic; Michael A. Samara, Minneapolis Heart Institute; Yuping Wu, Cleveland State University; Javed Butler, Emory University; W. H. Wilson Tang, Cleveland Clinic
• Language: English
• Date: 2016-01-01
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 American Heart Association, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/CIRCHEARTFAILURE.115.002115
• Title of Journal or Parent Work: Circulation: Heart Failure
• ISSN: 1941-3289
• Volume: 9
• Issue: 1
• Start Page: e002115
• End Page: e002115
• Grant/Funding Information: This research was supported by grants from the National Institutes of Health and the Office of Dietary Supplements (R01HL103866, P20HL113452).; The GeneBank study was supported by NIH grants P01HL076491, P01HL098055, R01HL103931, and the Cleveland Clinic Clinical Research Unit of the Case Western Reserve University CTSA (UL1TR 000439-06).
• Keywords: mice; ligation; ANGIOGENESIS; placenta growth factor; Science & Technology; HYPERTROPHY; PREECLAMPSIA; animal; ACUTE MYOCARDIAL-INFARCTION; Cardiac & Cardiovascular Systems; heart failure; CARDIOMYOPATHY; Life Sciences & Biomedicine; Cardiovascular System & Cardiology; VEGF; HYPERTENSION
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, General

Abstract

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.