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Proteoglycan Remodeling Is Accelerated in Females with Angina Pectoris and Diffuse Myocardial Fibrosis: the iPOWER Study

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Abstract

Angina and no obstructive coronary artery disease (CAD) have an unfavorable prognosis, possibly due to diffuse myocardial fibrosis (DMF). In DMF the proteoglycans biglycan and versican are actively remodeled by matrix metalloproteinase. We investigated biglycan and versican in females with angina and possible DMF assessed by cardiac magnetic resonance (CMR). Seventy-one females with angina and no obstructive CAD were included. Asymptomatic females served as controls. Versican and biglycan were measured and CMR was performed measuring extracellular volume. Biglycan and versican levels were higher in symptomatic females compared with controls; 31.4 ng/mL vs. 16.4 ng/mL (p < 0.001) and 2.1 ng/mL vs. 1.8 ng/mL (p < 0.001) and moderately correlated to extracellular volume (r2 = 0.38, p<0.001 and r2 = 0.26, p = 0.015). Turnover of biglycan and versican was increased in angina females compared with controls and associated with extracellular volume, supporting a link between angina with no obstructive CAD and fibrotic remodeling.

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Abbreviations

BGM:

Biglycan

CAD:

Coronary artery disease

CAG:

Coronary angiography

CMD:

Coronary microvascular dysfunction

CMR:

Cardiac magnetic resonance

DMF:

Diffuse myocardial fibrosis

ECM:

Extracellular matrix

ELISA:

Enzyme-linked immunosorbent assays

iPOWER:

ImProve diagnOsis and treatment of Women with angina pEctoris and micRovessel disease

MOLLI:

Modified look-locker inversion recovery technique

NRI:

Net reclassification improvement

VCANM:

Versican

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Acknowledgements

The authors would like to thank the Danish Heart Foundation, the University of Copenhagen, The Innovation Foundation, and the Danish Research Fund (Den Danske Forskningsfond) for financial support and all collaborators in the iPOWER group. We also thank the Department of Cardiology at Bispebjerg Hospital and the Department of Radiology at Rigshospitalet where the examinations have taken place. A special thanks to the CMR technicians Birte Kjærulff, Jesper Kromann, Andrija Srkoc, and Torben Vaaben for assisting in scanning the participants. Finally, we thank all the participants for their time and willingness to contribute to the research.

Funding

This work was supported by The Danish Heart Foundation (grant number: 11-10-R87-B-A3628-22678), the Danish Research Fund (Den Danske Forskningsfond), and the University of Copenhagen.

Author information

Authors and Affiliations

  1. Department of Cardiology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark

    Naja Dam Mygind, Marie Mide Michelsen, Elena Suhrs, Kira Bang Bove & Eva Prescott

  2. Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Naja Dam Mygind, Niels Vejlstrup & Jens Kastrup

  3. Fibrosis Biology and Biomarkers, Nordic Bioscience A/S, Herlev, Denmark

    Signe Holm Nielsen, Federica Genovese & Morten Karsdal

  4. Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs Lyngby, Denmark

    Signe Holm Nielsen

  5. Department of Cardiology, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark

    Adam Pena

  6. Department of Cardiology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark

    Daria Frestad Bechsgaard

  7. Sanos Clinics A/S, Herlev, Denmark

    Henning Bay Nielsen

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  1. Naja Dam Mygind
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Contributions

NDM designed the study, included patients and participants, performed the CMR examinations, and made the manuscript draft ready for submission

SHN designed the study, performed biomarker analyses, and made the manuscript draft ready for submission

MMM helped in design of the study, included patients and participants. Reviewed the draft critically before submission

AP helped in design of the study, included patients and participants. Reviewed the draft critically before submission

ES helped in design of the study, included patients and participants. Reviewed the draft critically before submission

DFB helped in design of the study, included patients and participants. Reviewed the draft critically before submission

KB helped in design of the study, included patients and participants. Reviewed the draft critically before submission

FG helped in the design of the study with focus on biomarkers. Reviewed the draft critically before submission

HBN helped in the design of the study with focus on biomarkers. Reviewed the draft critically before submission

MK helped in the design of the study with focus on biomarkers. Reviewed the draft critically before submission

NV helped in the design of the study with focus on cardiac magnetic resonance. Reviewed the draft critically before submission

EP designed the study. Reviewed the draft critically before submission

JK designed the study. Reviewed the draft critically before submission

Corresponding author

Correspondence to Naja Dam Mygind.

Ethics declarations

Ethics Approval and Consent to Participate

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Danish Regional Committee on Biomedical Research Ethics (H-3-2012-005). Informed consent was obtained from all individual participants included in the study upon written and oral information.

Conflict of Interest

FG and MK are full-time employees at Nordic Bioscience and HBN is a full-time employee at ProScion. FG and MK hold stocks at Nordic Bioscience. All other authors have no conflict of interest.

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Associate Editor Joost Sluijter oversaw the review of this article

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Naja Dam Mygind and Signe Holm Nielsen share first authorship.

Eva Prescott and Jens Kastrup share last authorship.

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Mygind, N.D., Nielsen, S.H., Michelsen, M.M. et al. Proteoglycan Remodeling Is Accelerated in Females with Angina Pectoris and Diffuse Myocardial Fibrosis: the iPOWER Study. J. of Cardiovasc. Trans. Res. 14, 921–929 (2021). https://doi.org/10.1007/s12265-021-10106-y

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