title: Soluble Flt-1 links microvascular disease with heart failure in CKD.
abstract: Chronic kidney disease (CKD) is associated with an increased risk of heart failure (HF). Elevated plasma concentrations of soluble Flt-1 (sFlt-1) have been linked to cardiovascular disease in CKD patients, but whether sFlt-1 contributes to HF in CKD is still unknown. To provide evidence that concludes a pathophysiological role of sFlt-1 in CKD-associated HF, we measured plasma sFlt-1 concentrations in 586 patients with angiographically documented coronary artery disease and renal function classified according to estimated glomerular filtration rate (eGFR). sFlt-1 concentrations correlated negatively with eGFR and were associated with signs of heart failure, based on New York Heart Association functional class and reduced left ventricular ejection fraction (LVEF), and early mortality. Additionally, rats treated with recombinant sFlt-1 showed a 15 % reduction in LVEF and a 29 % reduction in cardiac output compared with control rats. High sFlt-1 concentrations were associated with a 15 % reduction in heart capillary density (number of vessels/cardiomyocyte) and a 24 % reduction in myocardial blood volume. Electron microscopy and histological analysis revealed mitochondrial damage and interstitial fibrosis in the hearts of sFlt-1-treated, but not control rats. In 5/6-nephrectomised rats, an animal model of CKD, sFlt-1 antagonism with recombinant VEGF121 preserved heart microvasculature and significantly improved heart function. Overall, these findings suggest that a component of cardiovascular risk in CKD patients could be directly attributed to sFlt-1. Assessment of patients with CKD confirmed that sFlt-1 concentrations were inversely correlated with renal function, while studies in rats suggested that sFlt-1 may link microvascular disease with HF in CKD.
authors.affiliation: Department of Internal Medicine D, University Hospital Münster, Albert Schweitzer Campus 1, Gebäude A1, 48149, Münster, Germany, giodimarco@gmail.com.
authors.forename: Giovana S
authors.initials: GS
authors.lastname: Di Marco
authors.forename: Dominik
authors.initials: D
authors.lastname: Kentrup
authors.forename: Stefan
authors.initials: S
authors.lastname: Reuter
authors.forename: Anna B
authors.initials: AB
authors.lastname: Mayer
authors.forename: Lina
authors.initials: L
authors.lastname: Golle
authors.forename: Klaus
authors.initials: K
authors.lastname: Tiemann
authors.forename: Manfred
authors.initials: M
authors.lastname: Fobker
authors.forename: Christiane
authors.initials: C
authors.lastname: Engelbertz
authors.forename: Günter
authors.initials: G
authors.lastname: Breithardt
authors.forename: Eva
authors.initials: E
authors.lastname: Brand
authors.forename: Holger
authors.initials: H
authors.lastname: Reinecke
authors.forename: Hermann
authors.initials: H
authors.lastname: Pavenstädt
authors.forename: Marcus
authors.initials: M
authors.lastname: Brand
mesh_terms: D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006333:Heart Failure / Q000209:etiology*; D006801:Humans; D008297:Male; D055806:Microvessels / Q000473:pathology; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000150:complications* / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood* / Q000378:metabolism
chemical_list: C501162:FLT1 protein, human; C501164:Flt1 protein, rat; D040281:Vascular Endothelial Growth Factor Receptor-1