Impact of atrial fibrillation on soluble fms-like tyrosine kinase-1 and cardiovascular events in patients with suspected or known coronary artery disease: the EXCEED-J study
Authors: Wada H , Shinozaki T , Suzuki M , Sakagami S , Ajiro Y , Funada J , Matsuda M , Shimizu M , Takenaka T , Morita Y , Yonezawa K , Kotani K , Abe M , Akao M , Hasegawa K ,   The EXCEED-J Study Investigators
Published: October 2021

Abstract

Background
Soluble fms-like tyrosine kinase-1 (sFlt-1), a vascular endothelial growth factor (VEGF) antagonist, has been suggested as a marker of endothelial dysfunction. Circulating sFlt-1 levels are associated with adverse outcomes in patients with preeclampsia, chronic kidney disease, and heart failure. Atrial fibrillation (AF) and coronary artery disease (CAD) are both associated with endothelial dysfunction. However, whether sFlt-1 can predict cardiovascular (CV) events and whether AF modifies the relationship between sFlt-1 and CV events in patients with suspected or known CAD are unknown.

Methods
We performed a nationwide, multicenter, prospective cohort study to determine the prognostic value of sFlt-1 and other biomarkers in patients with suspected or known CAD undergoing elective angiography. Heparin-free fasting serum was collected from the peripheral vein to determine levels of sFlt-1, VEGF, placental growth factor, cystatin C, neutrophil gelatinase-associated lipocalin, N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin-I (hs-cTnI), and high-sensitivity C-reactive protein (hs-CRP). The primary outcome was 3-point major adverse CV events (3P-MACE) defined as a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. The secondary outcomes were all-cause death, CV death, and 5P-MACE defined as a composite of 3P-MACE, heart failure hospitalization, and coronary/peripheral artery revascularization.

Results
3311 patients were consecutively enrolled between Nov 2013 and May 2017. After excluding 56 ineligible patients, 3255 patients (324 AF and 2931 non-AF) were followed up over 3 years (follow-up rate, 99%). During the follow-up, 156 patients developed 3P-MACE, 215 died from any cause, 82 died from cardiovascular disease, and 1361 developed 5P-MACE. The sFlt-1 level was significantly higher in AF compared to non-AF patients (p&lt;0.001). Stepwise regression analysis revealed that the sFlt-1 level was independently associated with AF. After adjusting for potential clinical confounders, serum levels of sFlt-1, NT-proBNP, hs-cTnI and cystatin C, but not other biomarkers, were significantly associated with 3P-MACE in the entire cohort. These associations were still significant in non-AF patients, whereas only the sFlt-1 level was significantly associated with 3P-MACE in AF patients. Serum levels of sFlt-1, but not other biomarkers, were also significantly associated with CV death in AF patients. Among the biomarkers, only the hs-CRP level was significantly associated with all-cause death, and no biomarker was significantly associated with 5P-MACE in AF patients. Furthermore, sFlt-1 provided an incremental prognostic information for 3P-MACE to the model with potential clinical confounders in AF, but not in non-AF patients.

Conclusions
Serum levels of sFlt-1 were significantly associated with 3P-MACE in patients with suspected or known CAD. This association was pronounced in AF patients.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The EXCEED-J study is supported by Health Labour Sciences Research Grant (2013-2014), AMED (2015-2017, Grant Number JP17ek0210008) and Grant-in-Aid for Clinical Research from the National Hospital Organization (2018-2020).