Circulating Angiokines Are Associated With Reverse Remodeling and Outcomes in Chronic Heart Failure

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ABSTRACT

Background

We sought to determine whether circulating modifiers of endothelial function are associated with cardiac structure and clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF).

Methods

We measured 25 proteins related to endothelial function in 99 patients from the GUIDE-IT study. Protein levels were evaluated for association with echocardiographic parameters and the incidence of all-cause death and hospitalization for heart failure (HHF).

Results

Higher concentrations of angiopoietin 2 (ANGPT2), vascular endothelial growth factor receptor 1 (VEGFR1) and hepatocyte growth factor (HGF) were significantly associated with worse function and larger ventricular volumes. Over time, decreases in ANGPT2 and, to a lesser extent, VEGFR1 and HGF, were associated with improvements in cardiac size and function. Individuals with higher concentrations of ANGPT2, VEGFR1 or HGF had increased risks for a composite of death and HHF in the following year (HR 2.76 (95% CI 1.73–4.40) per 2-fold change in ANGPT2; HR 1.76 (95% CI 1.11–2.79) for VEGFR1; and HR 4.04 (95% CI 2.19–7.44) for HGF).

Conclusions

Proteins related to endothelial function associate with cardiac size, cardiac function and clinical outcomes in patients with HFrEF. These results support the concept that endothelial function may be an important contributor to the progression to and the recovery from HFrEF.

Graphical Abstract

Take-Home Visual Graphic: Changes in circulating angiokines are associated with reverse remodeling and outcomes in chronic heart failure.

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Section snippets

Clinical Perspective

A decrease in cardiac capillary density has been associated with worsening heart failure. We identified associations between concentrations of proteins known to affect endothelial function with cardiac size and function in patients with HFrEF. Of measured factors, we found ANGPT2, VEGFR1 and HGF concentrations to be closely associated with ventricular remodeling and to be associated with future hospitalization and death due to HFrEF. Our work suggests that endothelial remodeling is an important

Lay Summary

Prior work has shown that failing hearts have a reduced density of blood vessels. We hypothesized that circulating proteins that regulate blood vessel growth and function might be altered in patients with heart failure. We measured protein levels in a group of patients from the GUIDE-IT study that had multiple assessments of heart size and function. We found that higher concentrations of ANGPT2, VEGFR1 and HGF in the blood are related to larger hearts with worse function. In hearts that

Methods

Trial design and outcomes for the GUIDE-IT study have been reported previously.29,30 Briefly, GUIDE-IT was a multicenter trial that randomized 894 patients with left ventricular ejection fraction (LVEF) ≤ 40% to NT-proBNP-guided management or usual care. A follow-up of 24 months after enrollment was planned; however, GUIDE-IT was stopped early because of futility. 268 participants from GUIDE-IT also participated in a prespecified echocardiographic substudy.31 These participants underwent

Patient Population

There were 99 participants from the GUIDE-IT Echo substudy who had available plasma for Angiome profiling. Cohort characteristics are presented in Table 1. The average age was 60.9 ± 11.2 years (mean ± SD); 29.3% (29/99) of patients were female; and 48.5% (48/99) of participants had ischemic cardiomyopathy. Mean LVEF at the time of enrollment was 28.2 ± 10.0%, with improvement in mean LVEF over 12 months to 34.5 ± 11.9%. Median follow-up was 18.7 months (IQR 15.0–23.8 months). Overall, 7.1%

Discussion

Much of the biology of reverse cardiac remodeling has focused on changes to the cardiomyocyte. For example, decreases in cardiomyocyte size, increased β-adrenergic receptor density and improved calcium handling have all been reported with reverse remodeling.38 Importantly, the fetal gene-expression program that is induced in failing myocytes is attenuated, likely reflected clinically by decreased NT-proBNP concentrations during reverse remodeling.31 Other work has suggested that restoration of

Conclusion

We found that circulating regulators of endothelial homeostasis and function have varying concentrations in patients with HfrEF and have dynamics that are closely associated with differences in cardiac structure and function. Of the factors assayed, ANGPT2, VEGFR1 and HGF concentrations were most robustly related to cardiac morphologic and functional parameters and were highly associated with the need for HHF and with death. Our work suggests that dynamic changes in circulating modulators of

Disclosures

JH completed work for this manuscript while supported by grant T32HL069749; DJM serves as a consultant for CVRx, Cytokinetics and Novonordisk and receives grant funding from NovoNordisk and the NIH; ABN receives funding from Genentech, HTG Molecular Diagnostics, MedImmune/AstraZeneca, Medpacto, Promega Corporation, and Seattle Genetics and consulting or personal fees from Eli Lilly, GSK, Promega Corporation, Leap Therapeutics, and Adjuvolt Therapeutics; ILP serves on the advisory board for

Author Contributions

RK, AN and GMF designed and conceptualized the study. RK and GMF obtained funding. Statistical analysis was performed by RK, JH and EY. The original manuscript was written and edited by RK, JH and GMF. Overall study supervision was provided by RK and GMF.

Acknowledgments

We thank all the patients and sites who generously participated in the GUIDE-IT study. We also thank Christopher Kontos and Michael Dee Gunn for helpful comments and discussion; Gayle Passmore for regulatory assistance; Andrew Shepple for assistance with sample transfer; and Mark Starr and Chris Brady for technical assistance.

Funding Sources

This work was funded by a grant from the Translating Duke Health Initiative (RK, GMF), a Duke University Strong Start Physician Scientist Award (RK), the Walker P. Inman Endowment (RK), NHLBI R01 HL146849 (RK), and NHLBI R01 HL157277 (RK). GUIDE-IT was funded by the NHLBI, and the embedded biorepository and echo substudies used for these analyses were funded by Roche Diagnostics (Rotkreutz, Switzerland).

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