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Soluble Flt-1 links microvascular disease with heart failure in CKD

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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.

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Acknowledgments

The authors thank Katrin Beul and Richard Holtmeier for their excellent technical assistance. This work was supported by the Bundesministerium für Bildung und Forschung [01GI0701], Deutsche Forschungsgemeinschaft [BR2262/3-1, SFB656 C3/C7 and Br1589/8-2], Else-Kröner Fresenius Stiftung [P38/09//A55/09], KfH Kuratorium für Dialyse und Nierentransplantation, and Stifterverband für die Deutsche Wissenschaft/Simon-Claussen-Stiftung [H1405409999915626].

Conflict of interest

H. R. has received speaker honoraria from B.R.A.H.M.S., Bristol-Myers Squibb, Cordis, Daiichi-Sankyo, Medtronic, The Medicine Company, Novartis and Sanofi-Aventis.

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Authors and Affiliations

  1. Department of Internal Medicine D, University Hospital Münster, Albert Schweitzer Campus 1, Gebäude A1, 48149, Münster, Germany

    Giovana S. Di Marco, Dominik Kentrup, Stefan Reuter, Anna B. Mayer, Lina Golle, Eva Brand, Hermann Pavenstädt & Marcus Brand

  2. Department of Cardiology, Isar Heart Center, Sonnenstr. 24-26, 80331, Munich, Germany

    Klaus Tiemann

  3. Centre for Laboratory Medicine, University Hospital Münster, Albert Schweitzer Campus 1, 48149, Münster, Germany

    Manfred Fobker

  4. Division of Vascular Medicine, Department of Cardiovascular Medicine, University Hospital Münster, Albert Schweitzer Campus 1, 48149, Münster, Germany

    Christiane Engelbertz, Günter Breithardt & Holger Reinecke

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Di Marco, G.S., Kentrup, D., Reuter, S. et al. Soluble Flt-1 links microvascular disease with heart failure in CKD. Basic Res Cardiol 110, 30 (2015). https://doi.org/10.1007/s00395-015-0487-4

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