==== Front Health Sci Rep Health Sci Rep 10.1002/(ISSN)2398-8835 HSR2 Health Science Reports 2398-8835 John Wiley and Sons Inc. Hoboken 10.1002/hsr2.211 HSR2211 Research Letter Research Letter Angiopoietin‐2 and hemocompatibility‐related adverse events during percutaneous left ventricular assist device supports Imamura et alImamura Teruhiko https://orcid.org/0000-0002-7294-7637 1 teimamu@med.u-toyama.ac.jp Nakamura Makiko 1 Yokoyama Shigeki 2 Doi Toshio https://orcid.org/0000-0002-0764-1519 2 Fukahara Kazuaki 2 Kinugawa Koichiro 1 1 Second Department of Internal Medicine University of Toyama Toyama Japan 2 Department of Cardiovascular Surgery University of Toyama Toyama Japan * Correspondence Teruhiko Imamura, 2630 Sugitani, Toyama 930‐0194, Japan. Email: teimamu@med.u-toyama.ac.jp 03 12 2020 12 2020 3 4 10.1002/hsr2.v3.4e21110 6 2020 05 11 2020 10 11 2020 © 2020 The Authors. Health Science Reports published by Wiley Periodicals LLC.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. source-schema-version-number2.0cover-dateDecember 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.5 mode:remove_FC converted:03.12.2020 Imamura T , Nakamura M , Yokoyama S , Doi T , Fukahara K , Kinugawa K . Angiopoietin‐2 and hemocompatibility‐related adverse events during percutaneous left ventricular assist device supports . Health Sci Rep . 2020 ;3 :e211 10.1002/hsr2.211 Teruhiko Imamura and Makiko Nakamura contributed equally to this work. ==== Body 1 INTRODUCTION Despite considerable improvement in survival in heart failure patients receiving left ventricular assist devices (LVADs), hemocompatibility‐related adverse events (HRAEs) including bleeding and thromboembolic evens remain as unsolved issues. 1 , 2 Inappropriate activation of the inflammatory and angiogenesis cascade including angiopoietin‐2 (Ang‐2) seems to have a considerable association with the development of arteriovenous malformation and gastrointestinal bleeding during LVAD supports. 3 Ang‐2 is considerably associated with the plasma B‐type natriuretic peptide (BNP) levels in the heart failure cohort. Furthermore, Ang‐2 is inappropriately elevated relative to BNP levels in some LVAD patients. 4 However, its prognostic impact on HRAEs remains uninvestigated. In this study, we investigated the prognostic impact of Ang‐2 level relative to BNP (Ang‐2/BNP) obtained immediately after percutaneous LVAD implantation on future occurrences of HRAE. 2 METHODS 2.1 Patient selection In this prospective study, consecutive patients who received percutaneous LVAD between August 2018 and February 2019 were included. Indication of percutaneous LVAD therapy is determined by the attending cardiologists. In brief, candidates had cardiogenic shock refractory to guideline‐directed medical therapy. All participants gave informed consents, and the institutional ethical review board approved this study beforehand. We affirm that this manuscript is an honest, accurate, and transparent account of the study being reported, that no important aspects of the study have been omitted, and that any discrepancies from the study as planned. The original data are available when required and considered to be appropriate. 2.2 Variables collection In addition to the baseline characteristics data, Ang‐2/BNP was measured from patients' plasma within 3 days following LVAD implantation, using Human Angiopoietin‐2 Quantikine ELISA Kit. 2.3 Outcomes A primary endpoint was set as any occurrence of HRAEs during LVAD supports. HRAEs consist of gastrointestinal bleeding, symptomatic stroke with image findings, and device thrombosis medically or surgically managed, according to the INTERMACS definition. 2 Death, device explantation, or 30‐day follow‐up was censored. 2.4 Statistical analyses Statistical analyses were performed using SPSS Statistics 22 (SPSS Inc, Armonk, Illinois). Continuous variables were expressed as median and interquartile. The impact of Ang‐2/BNP on HRAE was investigated as a primary concern. Receiver operating characteristics analysis was performed to calculate a cutoff of Ang‐2/BNP for the occurrence of HRAE. Kaplan–Meier analyses and log‐rank tests were performed to compare freedom from HRAE between high Ang‐2/BNP and low Ang‐2/BNP groups. Cox proportional hazard ratio regression analyses were performed to investigate the impact of high Ang‐2/BNP on the occurrence of HRAE by adjusting for age, which is another well‐known risk factor of HRAE. 3 RESULTS 3.1 Baseline characteristics In total, 21 patients (median 71 years old, 14 males) were included (Table 1). Ang‐2 (median 5.0 pg/mL) and BNP (median 437 pg/mL) were measured within 3 days following LVAD implantation. Median Ang‐2/BNP was 1.7 (0.9, 2.5). TABLE 1 Baseline characteristics N = 21 Age, years 71 (59, 83) Male sex 14 (67%) Etiology Acute coronary syndrome 12 (57%) Takotsubo syndrome 1 (5%) Ischemic cardiomyopathy 1 (5%) Hypertrophic cardiomyopathy 1 (5%) Dilated cardiomyopathy 6 (28%) Serum Ang‐2, pg/mL 5.0 (2.7, 6.3) Plasma BNP, pg/mL 437 (264, 732) Ang‐2/BNP 1.7 (0.9, 2.5) Note: Variables are expressed as median and interquartile or number and percentage. Abbreviations: Ang‐2, angiopoietin‐2; BNP, B‐type natriuretic peptide. 3.2 Ang‐2/BNP and clinical outcomes During 6‐day (2, 15) LVAD support on median, there were seven HRAEs: four gastrointestinal bleedings, one ischemic stroke, two hemorrhagic strokes, and no device thrombosis. A cutoff of Ang‐2/BNP to predict future HRAE was calculated as 2.7 with sensitivity of 0.57 and specificity of 1.00. Four patients had Ang‐2/BNP > 2.7: two patients had cerebral bleedings and the other two had gastrointestinal bleedings. Freedom from HRAE was significantly stratified by the Ang‐2/BNP of 2.7 (66% vs 0%, P = .005; Figure 1). Ang‐2/BNP was a significant risk factor of future HRAE with an unadjusted hazard ratio of 7.53 (95% confidence interval 1.37‐41.3) and an adjusted hazard ratio of 25.6 (95% confidence interval 2.58‐255). FIGURE 1 Freedom from HRAE. *P < .05 by log‐rank test; † P < .05 by Cox proportional hazard ratio regression analyses For individual HRAEs, Ang‐2/BNP cutoff of 2.7 had sensitivity of 0.50 and specificity of 0.88 to predict gastrointestinal bleedings and sensitivity of 0.67 and specificity of 0.89 to predict strokes. 4 DISCUSSION 4.1 Ang‐2 and BNP The inflammatory system has a considerable association with advanced heart failure: Ang‐2 and BNP have a strong correlation in the heart failure cohort. 5 Our team recently demonstrated that Ang‐2 was inappropriately elevated relative to the BNP level during LVAD supports compared to the heart failure cohort, 4 probably due to the stimulation of Ang‐2 activity via hematological instability. 6 This is a rationale of why we used Ang‐2/BNP as a variable instead of Ang‐2 alone. The detailed mechanism of the variety of Ang‐2/BNP levels among each individual remains unknown. 4.2 Ang‐2/BNP and HRAE The association between Ang‐2 and gastrointestinal bleeding during LVAD supports is receiving great concern. Inflammatory and angiogenesis cascade including Ang‐2 might stimulate a formation of arteriovenous malformation and increase the risk of gastrointestinal bleeding. 3 In this study, we demonstrated that the inappropriately elevated Ang‐2 level predicted future bleedings. In other words, Ang‐2 is inappropriately activated immediately following LVAD implantation in such high‐risk patients. Elevated Ang‐2/BNP level was associated with also the occurrence of stroke with high specificity. The detailed mechanism requires further investigations, but our team previously hypothesized the association among right ventricular failure, chronic inflammation, and stroke during LVAD supports. 7 As a major marker of inflammation, Ang‐2 might have a critical role in the occurrence of stroke. 4.3 Limitations and future concerns We should state that the study is a proof of concept, and the finding should be validated in larger scale studies. We adjusted for age alone, given its considerable impact on HRAE and small sample size, 2 and we cannot deny any other confounders. We showed an association between Ang‐2/BNP and HRAEs, but the causality remains unknown with a lack of detailed data explaining it. We observed just for 30 days, given that the devices were percutaneous ones, and the applicability of our findings to other durable LVADs remains uncertain. Nevertheless, our findings would give us a clue to risk‐stratify patients for the future occurrence of HRAE during LVAD supports. Furthermore, any therapeutic intervention to improve the elevated Ang‐2, including omega‐3 fatty acid or any other more specific agents, 8 might reduce the risk of HRAE. 5 CONCLUSION Elevated Ang‐2 level soon after percutaneous LVAD implantation was associated with future HRAEs. The clinical implication to intervene in Ang‐2 would be a future concern. FUNDING Teruhiko Imamura receives grant support from JSPS KAKENHI: JP20K17143, which had no involvements in conducting the study and preparing the draft. AUTHOR CONTRIBUTIONS Conceptualization: Teruhiko Imamura Formal analysis: Teruhiko Imamura Funding acquisition: Koihciro Kinugawa Writing – original draft: Teruhiko Imamura, Makiko Nakamura Writing – review and editing: Shigeki Yokoyama, Toshio Doi, Kazuaki Fukahara   All authors have read and approved the final version of the manuscript.   Teruhiko Imamura has full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis. TRANSPARENCY STATEMENT Teruhiko Imamura affirms that this manuscript is an honest, accurate, and transparent account of the study being reported, that no important aspects of the study have been omitted, and that any discrepancies from the study as planned have been explained. DATA AVAILABILITY STATEMENT The data that support the findings of this study are available from the corresponding author upon reasonable request. ==== Refs REFERENCES 1 Mehra MR . The burden of haemocompatibility with left ventricular assist systems: a complex weave . Eur Heart J . 2019 ;40 (8 ):673 ‐677 .28329374 2 Uriel N , Colombo PC , Cleveland JC , et al. Hemocompatibility‐related outcomes in the MOMENTUM 3 trial at 6 months: a randomized controlled study of a fully magnetically levitated pump in advanced heart failure . Circulation . 2017 ;135 (21 ):2003 ‐2012 .28385948 3 Tabit CE , Chen P , Kim GH , et al. Elevated angiopoietin‐2 level in patients with continuous‐flow left ventricular assist devices leads to altered angiogenesis and is associated with higher nonsurgical bleeding . Circulation . 2016 ;134 (2 ):141 ‐152 .27354285 4 Nakamura M , Imamura T , Hori M , et al. Regulation of angiopoietin‐2 before and after mechanical circulatory support therapy . ASAIO J . 2020 ; (in press). 10.1097/MAT.0000000000001189 . 5 Link A , Poss J , Rbah R , et al. Circulating angiopoietins and cardiovascular mortality in cardiogenic shock . Eur Heart J . 2013 ;34 (22 ):1651 ‐1662 .23349297 6 Tabit CE , Coplan MJ , Chen P , Jeevanandam V , Uriel N , Liao JK . Tumor necrosis factor‐alpha levels and non‐surgical bleeding in continuous‐flow left ventricular assist devices . J Heart Lung Transplant . 2018 ;37 (1 ):107 ‐115 .28651907 7 Imamura T , Nguyen A , Kim G , et al. Optimal haemodynamics during left ventricular assist device support are associated with reduced haemocompatibility‐related adverse events . Eur J Heart Fail . 2019 ;21 (5 ):655 ‐662 .30592363 8 Imamura T , Nguyen A , Rodgers D , et al. Omega‐3 therapy is associated with reduced gastrointestinal bleeding in patients with continuous‐flow left ventricular assist device . Circ Heart Fail . 2018 ;11 (10 ):e005082.30354397