Associations of Angiopoietins With Heart Failure Incidence and Severity

https://doi.org/10.1016/j.cardfail.2021.04.001Get rights and content

Highlights

  • Angiopoietin levels may predict an individual's likelihood to develop heart failure.

  • Angiopoietin levels may help to prognosticate for individuals who have heart failure.

  • This study may highlight a pathway that could be potentially targetable in individuals with heart failure.

Abstract

Background

Angiopoietin-1 and 2 (Ang1, Ang2) are important mediators of angiogenesis. Angiopoietin levels are perturbed in cardiovascular disease, but it is unclear whether angiopoietin signaling is causative, an adaptive response, or merely epiphenomenon of disease activity.

Methods and Results

In a cohort free of cardiovascular disease at baseline (Multi-Ethnic Study of Atherosclerosis [MESA]), relationships between angiopoietins, cardiac morphology, and subsequent incidence of heart failure or cardiovascular death were evaluated. In cohorts with pulmonary arterial hypertension or left heart disease, associations between angiopoietins, invasive hemodynamics, and adverse clinical outcomes were evaluated. In MESA, Ang2 was associated with a higher incidence of heart failure or cardiovascular death (hazard ratio 1.21 per standard deviation, P < .001). Ang2 was associated with increased right atrial pressure (pulmonary arterial hypertension cohort) and increased wedge pressure and right atrial pressure (left heart disease cohort). Elevated Ang2 was associated with mortality in the pulmonary arterial hypertension cohort.

Conclusions

Ang2 was associated with incident heart failure or death among adults without cardiovascular disease at baseline and with disease severity in individuals with existing heart failure. Our finding that Ang2 is increased before disease onset and that elevations reflect disease severity, suggests Ang2 may contribute to heart failure pathogenesis.

Section snippets

Methods

This work uses 3 cohorts to evaluate the relationship between angiopoietins and heart failure. Serum angiopoietin levels were measured in each cohort. The Multi-Ethnic Study of Atherosclerosis (MESA) Angiogenesis cohort was used to evaluate relationships between angiopoietins, cardiac morphology, and the risk of incident heart failure or cardiovascular death in individuals without CVD at the time Ang1 and Ang2 were measured. A pulmonary arterial hypertension (PAH) cohort was used to evaluate

MESA Cohort

The MESA–Angiogenesis cohort included 1383 participants selected randomly from the parent MESA cohort. In addition, 155 MESA participants outside the MESA–Angiogenesis cohort experienced incident heart failure or cardiovascular death; these participants were included in longitudinal case-cohort analyses only. In the current study, 1358 participants in the MESA-Angiogenesis cohort (81 cases, 1277 noncases) and 154 additional cases outside the cohort had all available covariates and were included

Discussion

To our knowledge, this study is the first to demonstrate that an elevation in Ang2 is associated with a higher risk of heart failure or cardiovascular death in individuals without heart disease at baseline. We also confirm and expand previous observations suggesting that Ang2 is associated with more severe disease in individuals with existing heart failure. Taken together, this suggests Ang2 elevation precedes heart disease, is unlikely to merely represent a reaction to existing disease, and

Conclusions

This study corroborates previous data identifying increased Ang2 as a biomarker for heart failure severity. Our results suggest increased Ang2 predicts increased risk of mortality in PAH and increased risk of incident heart failure or cardiovascular mortality in individuals without CVD. Because Ang2 is increased before disease onset in the MESA cohort, and increases reflect disease severity in right and left heart failure, Ang2 could be a contributor to heart failure pathogenesis and not merely

Disclosure

All authors report no direct conflict of interest related to this manuscript. Dr Leary receives research support from the NHLBI, PHA, AHA, Chest Foundation, Lung LLC, Bayer, and Actelion; salary support from the Cystic Fibrosis Therapeutic Development network; and honoraria from Bayer. Dr Tedford has consulting relationships with Medtronic, Aria CV Inc., Acceleron, Arena Pharmaceuticals, and United ​Therapeutics. Dr Tedford is on a steering committee for Medtronic and Abbott, and a research

Acknowledgments

The authors thank the MESA investigators, staff, and participants for their valuable contributions. A full list of participating investigators and institutions can be found at http://www.mesa-nhlbi.org.

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    Presented at the online symposium: “What's new in clinical research in pulmonary hypertension: lessons from the best abstracts,” October 21, 2020, at the 2020 American Thoracic Society Annual Conference.

    This research was supported by contracts from the National Heart, Lung, and Blood Institute 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, R01-HL-086719, K24-HL-103844, and R01-HL-071759, and by grants UL1-TR-000040, UL1-TR-001079 and UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS). The American Heart Association Mentored Award in Population Research supported the MESA-Angiogenesis Ancillary Study.

    ⁎⁎

    These authors contributed equally to this work.

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