Reduction of vascular leakage by imatinib is associated with preserved microcirculatory perfusion and reduced renal injury markers in a rat model of cardiopulmonary bypass

Koning, Nick J.; Lange, Fellery de; Meurs, Matijs van; Jongman, Rianne M.; Ahmed, Yunus; Schwarte, Lothar A.; Amerongen, Geerten P. van Nieuw; Vonk, Alexander B.A.; Niessen, Hans W.M.; Baufreton, Christophe; Boer, Christa

doi:10.1016/j.bja.2017.11.095

Cited by 26 publications

(43 citation statements)

References 48 publications

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“…33 Moreover, it was shown recently that strategies aiming to preserve microcirculatory perfusion during CPB may require an additional direct action on endothelial cell receptors involved in barrier signaling. 17,34 Limitations of the Study A limitation of this study is that it was performed in a relatively small cohort with a single center design. Moreover, all microvascular parameters were measured sublingually as the sublingual microcirculatory network provides an easily accessible site to investigate changes in microcirculatory perfusion.…”

Section: Discussionmentioning

confidence: 99%

Microvascular Alterations During Cardiac Surgery Using a Heparin or Phosphorylcholine-Coated Circuit

Dekker

Veerhoek

Leeuwen

et al. 2020

Journal of Cardiothoracic and Vascular Anesthesia

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Objective: Heparin biocompatible coating frequently is used to reduce inflammation and blood coagulation during cardiopulmonary bypass (CPB) in cardiac surgery. Whether heparin coating is protective or damaging to the vascular endothelium is unclear. The authors investigated whether heparin-coated (HC) circuits are associated with better preservation of microcirculatory perfusion and glycocalyx dimensions compared with nonheparin phosphorylcholine-coated (PC) circuits. Design: Prospective, randomized blinded study. Setting: Tertiary university hospital. Participants: A total of 26 adults undergoing elective coronary artery bypass graft surgery with CPB. Interventions: PC (n = 13) versus HC circuits (n = 13). Measurements and Main Results: Sublingual microcirculatory perfusion was measured before, during, and after CPB using sidestream dark field imaging and analyzed for perfused vessel density and perfused boundary region, an inverse parameter for glycocalyx dimensions. Onset of CPB was associated with an increase in perfused boundary region in the PC group that continued until the third postoperative day (2.0 § 0.2 to 2.5 § 0.2 mm; p = 0.018). This was paralleled by increased plasma syndecan-1 levels in the PC group. Contrastingly, both parameters remained unaltered in the HC group compared with baseline levels. CPB decreased perfused vessel density in both groups (CPB v pre-CPB: PC: 17 § 2 to 13 § 2 mm/mm 2 , p = 0.006; HC: 16 § 2 to 11 § 2 mm/mm 2 , p = 0.003) and remained equally altered in the first 3 postoperative days. Conclusion: The use of an HC circuit is associated with better preservation of the endothelial glycocalyx compared with PC circuits, whereas microcirculatory perfusion was disturbed equally in both groups. Hence, CPB-induced microcirculatory perfusion disturbances seem to be coating independent.

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Section: Discussionmentioning

confidence: 99%

Microvascular Alterations During Cardiac Surgery Using a Heparin or Phosphorylcholine-Coated Circuit

Dekker

Veerhoek

Leeuwen

et al. 2020

Journal of Cardiothoracic and Vascular Anesthesia

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“…All animals were anaesthetised as previously reported 2,8 with isoflurane 4.0% in oxygen 100% (Ivax Farma, Haarlem, The Netherlands) in a plastic box. After tracheal intubation with a 16G catheter (Venflon Pro, Becton Dickinson, Helsingborg, Sweden), lungs were mechanically ventilated (UMV-03, UNO Roestvaststaal BV, Zevenaar, The Netherlands) with a PEEP of 2e4 cm H 2 O, ventilatory frequency of 60e65 bpm, tidal volumẽ 10 ml kg À1 with isoflurane 1.5e2.0% in oxygen-enriched air (40% O 2 /60% N 2 ).…”

Section: Anaesthesia and Surgical Preparationmentioning

confidence: 99%

“…The left cremaster muscle was isolated under warm saline superfusion, spread out on a heated platform (34 C), and covered with gas impermeable plastic film (Saran wrap) as previously described. 2,8,16 Heparin (500 IU kg À1 , LEOPharma, Amsterdam, The Netherlands) was administered followed by cannulation of the right femoral artery with a 20G catheter (Arterial Cannula, Becton Dickinson) for arterial inflow of the CPB circuit. The right jugular vein was catheterised with a 20G catheter (Venflon Pro, Becton Dickinson) for administration of vasculotide or PBS as control.…”

Section: Anaesthesia and Surgical Preparationmentioning

confidence: 99%

“…The protocol for CPB was performed as previously described. 2,8 In summary, the CPB circuit consisted of an open venous reservoir, a roller pump (Pericor SF70, Verder, Haan, Germany), and an oxygenator-heat exchanger with a three-layer hollow fibre membrane for gas exchange (Ing. M. Humbs, Valley, Germany).…”

Section: Cardiopulmonary Bypassmentioning

confidence: 99%

“…We recently showed that CPB is associated with endothelial hyperpermeability 7 and is paralleled by vascular leakage and expression of pulmonary and renal injury markers. 8 A therapeutic strategy aimed at reducing vascular leakage during CPB might therefore improve microcirculatory perfusion and limit postoperative organ dysfunction after CPB.…”

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confidence: 99%

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Vasculotide, an angiopoietin-1 mimetic, reduces pulmonary vascular leakage and preserves microcirculatory perfusion during cardiopulmonary bypass in rats

Dekker¹,

Meurs

Leeuwen³

et al. 2018

British Journal of Anaesthesia

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Background: Cardiopulmonary bypass (CPB) during cardiac surgery impairs microcirculatory perfusion and is paralleled by vascular leakage. The endothelial angiopoietin/Tie2 system controls microvascular leakage. This study investigated whether targeting Tie2 with the angiopoietin-1 mimetic vasculotide reduces vascular leakage and preserves microcirculatory perfusion in a rat CPB model. Methods: Rats were subjected to 75 min of CPB after treatment with vasculotide or phosphate buffered solution as control or underwent a sham procedure. Microcirculatory perfusion and leakage were assessed with intravital microscopy (n¼10 per group) and Evans blue dye extravasation (n¼13 per group), respectively. Angiopoietin-1,-2, and Tie2 protein and gene expression were determined in plasma, kidney, and lung. Results: CPB immediately impaired microcirculatory perfusion [5 (4e8) vs 10 (7e12) vessels per recording, P¼0.002] in untreated CPB rats compared with sham, which persisted after weaning from CPB. CPB increased circulating angiopoeietin-1,-2, and soluble Tie2 concentrations and reduced Tie2 messenger ribonucleic acid (mRNA) expression in kidney and lung. Moreover, CPB increased Evans blue dye leakage in kidney [12 (8e25) vs 7 (1e12) mg g À1 , P¼0.04] and lung [and 23 (13e60) vs 6 (4e16) mg g À1 , P¼0.001] compared with sham. Vasculotide treatment preserved microcirculatory perfusion during and after CPB. Moreover, vasculotide treatment reduced Evans blue dye extravasation in lung compared with CPB control [18 (6e28) mg g À1 vs 23 (13e60) mg g À1 , P¼0.04], but not in kidney [10 (3e23) vs 12 (8e25) mg g À1 , P¼0.38].

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COVID-19-driven endothelial damage: complement, HIF-1, and ABL2 are potential pathways of damage and targets for cure

2020

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COVID-19 pandemia is a major health emergency causing hundreds of deaths worldwide. The high reported morbidity has been related to hypoxia and inflammation leading to endothelial dysfunction and aberrant coagulation in small and large vessels. This review addresses some of the pathways leading to endothelial derangement, such as complement, HIF-1α, and ABL tyrosine kinases. This review also highlights potential targets for prevention and therapy of COVID-19-related organ damage and discusses the role of marketed drugs, such as eculizumab and imatinib, as suitable candidates for clinical trials.

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Reduction of vascular leakage by imatinib is associated with preserved microcirculatory perfusion and reduced renal injury markers in a rat model of cardiopulmonary bypass

Cited by 26 publications

References 48 publications

Microvascular Alterations During Cardiac Surgery Using a Heparin or Phosphorylcholine-Coated Circuit

Microvascular Alterations During Cardiac Surgery Using a Heparin or Phosphorylcholine-Coated Circuit

Vasculotide, an angiopoietin-1 mimetic, reduces pulmonary vascular leakage and preserves microcirculatory perfusion during cardiopulmonary bypass in rats

COVID-19-driven endothelial damage: complement, HIF-1, and ABL2 are potential pathways of damage and targets for cure

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