The Notch Ligands DLL1 and Periostin Are Associated with Symptom Severity and Diastolic Function in Dilated Cardiomyopathy

Abstract

In dilated cardiomyopathy (DCM), adverse myocardial remodeling is essential, potentially involving Notch signaling. We hypothesized that secreted Notch ligands would be dysregulated in DCM. We measured plasma levels of the canonical Delta-like Notch ligand 1 (DLL1) and non-canonical Notch ligands Delta-like 1 homologue (DLK1) and periostin (POSN) in 102 DCM patients and 32 matched controls. Myocardial mRNA and protein levels of DLL1, DLK1, and POSN were measured in 25 explanted hearts. Our main findings were: (i) Circulating levels of DLL1 and POSN were higher in patients with severe DCM and correlated with the degree of diastolic dysfunction and (ii) right ventricular tissue expressions of DLL1, DLK1, and POSN were oppositely associated with cardiac function indices, as high DLL1 and DLK1 expression corresponded to more preserved and high POSN expression to more deteriorated cardiac function. DLL1, DLK1, and POSN are dysregulated in end-stage DCM, possibly mediating different effects on cardiac function.

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Abbreviations

DCM:

Dilated cardiomyopathy

DLL1:

Delta-like Notch ligand 1

DLK1:

Delta-like 1 homologue

POSN:

Periostin

HF:

Heart failure

ECM:

Extracellular matrix

HFrEF:

Heart failure with reduced ejection fraction

NYHA:

New York Heart Association

LV:

Left ventricle

RV:

Right ventricle

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Acknowledgements

We thank all the study participants.

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Correspondence to Hilde M. Norum.

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The authors declare that they have no conflicts of interest.

Human and Animal Rights

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. No animal studies were carried out by the authors for this article.

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Informed consent was obtained from all patients for being included in the study.

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This work received funding from the Raagholt Foundation and the Norwegian Order of Odd Fellows (HMN).

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Associate Editor Daniel P. Judge oversaw the review of this article

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Norum, H.M., Broch, K., Michelsen, A.E. et al. The Notch Ligands DLL1 and Periostin Are Associated with Symptom Severity and Diastolic Function in Dilated Cardiomyopathy. J. of Cardiovasc. Trans. Res. 10, 401–410 (2017). https://doi.org/10.1007/s12265-017-9748-y

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Keywords

  • Dilated cardiomyopathy
  • Diastolic dysfunction
  • Delta-like Notch ligand 1 (DLL1)
  • Delta-like 1 homologue (DLK1)
  • Periostin (POSN)
  • Notch pathway
  • Myocardial remodeling