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. 2019 Apr 11;23(1):117.
doi: 10.1186/s13054-019-2418-5.

Microcirculatory perfusion disturbances following cardiac surgery with cardiopulmonary bypass are associated with in vitro endothelial hyperpermeability and increased angiopoietin-2 levels

Nicole A M Dekker  1   2   3 , Anoek L I van Leeuwen  4   5   6 , Willem W J van Strien  4 , Jisca Majolée  5 , Robert Szulcek  5   7 , Alexander B A Vonk  5   6 , Peter L Hordijk  5 , Christa Boer  4 , Charissa E van den Brom  4   5
Affiliations

Microcirculatory perfusion disturbances following cardiac surgery with cardiopulmonary bypass are associated with in vitro endothelial hyperpermeability and increased angiopoietin-2 levels

Nicole A M Dekker et al. Crit Care. .

Abstract

Background: Endothelial hyperpermeability following cardiopulmonary bypass (CPB) contributes to microcirculatory perfusion disturbances and postoperative complications after cardiac surgery. We investigated the postoperative course of renal and pulmonary endothelial barrier function and the association with microcirculatory perfusion and angiopoietin-2 levels in patients after CPB.

Methods: Clinical data, sublingual microcirculatory data, and plasma samples were collected from patients undergoing coronary artery bypass graft surgery with CPB (n = 17) before and at several time points up to 72 h after CPB. Renal and pulmonary microvascular endothelial cells were incubated with patient plasma, and in vitro endothelial barrier function was assessed using electric cell-substrate impedance sensing. Plasma levels of angiopoietin-1,-2, and soluble Tie2 were measured, and the association with in vitro endothelial barrier function and in vivo microcirculatory perfusion was determined.

Results: A plasma-induced reduction of renal and pulmonary endothelial barrier function was observed in all samples taken within the first three postoperative days (P < 0.001 for all time points vs. pre-CPB). Angiopoietin-2 and soluble Tie2 levels increased within 72 h after CPB (5.7 ± 4.4 vs. 1.7 ± 0.4 ng/ml, P < 0.0001; 16.3 ± 4.7 vs. 11.9 ± 1.9 ng/ml, P = 0.018, vs. pre-CPB), whereas angiopoietin-1 remained stable. Interestingly, reduced in vitro renal and pulmonary endothelial barrier moderately correlated with reduced in vivo microcirculatory perfusion after CPB (r = 0.47, P = 0.005; r = 0.79, P < 0.001). In addition, increased angiopoietin-2 levels moderately correlated with reduced in vitro renal and pulmonary endothelial barrier (r = - 0.46, P < 0.001; r = - 0.40, P = 0.005) and reduced in vivo microcirculatory perfusion (r = - 0.43, P = 0.01; r = - 0.41, P = 0.03).

Conclusions: CPB is associated with an impairment of in vitro endothelial barrier function that continues in the first postoperative days and correlates with reduced postoperative microcirculatory perfusion and increased circulating angiopoietin-2 levels. These results suggest that angiopoietin-2 is a biomarker for postoperative endothelial hyperpermeability, which may contribute to delayed recovery of microcirculatory perfusion after CPB.

Trial registration: NTR4212 .

Keywords: Angiopoietin-2; Capillary permeability; Cardiopulmonary bypass; Endothelium; Microcirculation.

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Conflict of interest statement

Ethics approval and consent to participate

The Glycar study was approved in the Netherlands by the Human Subjects Committee of the Amsterdam University Medical Centers under committee’s reference number 13.291 (Clinical trial registration: NTR4212). Written informed consent was obtained from all patients before inclusion.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Prolonged postoperative impairment of renal and pulmonary endothelial barrier. Human renal and pulmonary microvascular endothelial cells were exposed to plasma from patients undergoing cardiopulmonary bypass collected before onset of CPB (pre-CPB), after weaning from CPB (post-CPB), and 24 h (+ 24 h) and 72 h (+ 72 h) after surgery. Renal (a) and pulmonary (c) endothelial resistance after plasma exposure over time and quantification of renal (b) and pulmonary (d) endothelial resistance after 3 h. Data represent mean or mean ± SD. One-way ANOVA with Bonferroni post-hoc analysis, *P < 0.05 versus pre-CPB; and repeated measures ANOVA, #P < 0.05. CPB, cardiopulmonary bypass; SD, standard deviation
Fig. 2
Fig. 2
Post-CPB plasma induces renal and pulmonary endothelial gap formation. Quantification of renal (a) and pulmonary (b) intercellular gap formation and representative images of endothelial cells after exposure of plasma from patients before CPB (pre-CPB, middle panels) and 72 h after CPB (72 h post-CPB, right panels). Endothelial cells were stained for VE-cadherin (adherens junctions; green), actin (stress fibers; white), and DAPI (nuclei; blue) after 3 h of plasma exposure. Red arrows indicate examples of endothelial gaps. Scale bar represents 50 μm. Data represent mean number of gaps per endothelial cell ± SD quantified from n = 5 images per time point from 6 patients. One-way ANOVA with Bonferroni post-hoc analysis, *P < 0.05 versus pre-CPB. CPB, cardiopulmonary bypass; SD, standard deviation
Fig. 3
Fig. 3
Changes in circulating angiopoietin and soluble Tie2 levels after cardiopulmonary bypass. Circulating levels of angiopoietin-1 (a), angiopoietin-2 (b), ratio angiopoietin-2/1 (c), and soluble Tie2 (d) before onset of CPB (pre-CPB), after weaning from CPB (post-CPB), 24 h (+ 24 h) and 72 h (+ 72 h) after surgery corrected for hematocrit levels. Data represent mean + SD. One-way ANOVA with Bonferroni post-hoc analysis, *P < 0.05 versus pre-CPB. CPB, cardiopulmonary bypass; SD, standard deviation
Fig. 4
Fig. 4
Reduced in vitro renal and pulmonary endothelial barrier are associated with reduced in vivo microcirculatory perfusion and increased angiopoietin-2 levels. Association between circulating angiopoietin-2 levels and renal (a) and pulmonary (b) endothelial barrier after plasma exposure, microcirculatory perfusion (c), and lactate levels (d). Association between renal (e) and pulmonary (f) endothelial barrier function after plasma exposure and microcirculatory perfusion. Data are presented with a linear regression with 95% CI and tested with a Pearson’s correlation test. CPB, cardiopulmonary bypass; CI, confidence interval
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