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

  • Hilde M. NorumEmail author
  • Kaspar Broch
  • Annika E. Michelsen
  • Ida G. Lunde
  • Tove Lekva
  • Aurelija Abraityte
  • Christen P. Dahl
  • Arnt E. Fiane
  • Arne K. Andreassen
  • Geir Christensen
  • Svend Aakhus
  • Pål Aukrust
  • Lars Gullestad
  • Thor Ueland
Original Article


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.


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



Dilated cardiomyopathy


Delta-like Notch ligand 1


Delta-like 1 homologue




Heart failure


Extracellular matrix


Heart failure with reduced ejection fraction


New York Heart Association


Left ventricle


Right ventricle



We thank all the study participants.

Compliance with Ethical Standards

Conflict of Interest

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.

Informed Consent

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

Sources of Funding

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

Supplementary material

12265_2017_9748_MOESM1_ESM.docx (27 kb)
ESM 1 (DOCX 27 kb)


  1. 1.
    Mozaffarian, D., Benjamin, E. J., Go, A. S., Arnett, D. K., Blaha, M. J., Cushman, M., et al. (2016). Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation, 133, e38–360.CrossRefPubMedGoogle Scholar
  2. 2.
    Baldasseroni, S., Opasich, C., Gorini, M., Lucci, D., Marchionni, N., Marini, M., et al. (2002). Left bundle-branch block is associated with increased 1-year sudden and total mortality rate in 5517 outpatients with congestive heart failure: a report from the Italian network on congestive heart failure. American Heart Journal, 143, 398–405.CrossRefPubMedGoogle Scholar
  3. 3.
    Felker, G. M., Thompson, R. E., Hare, J. M., Hruban, R. H., Clemetson, D. E., Howard, D. L., et al. (2000). Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. New England Journal of Medicine, 342, 1077–1084.CrossRefPubMedGoogle Scholar
  4. 4.
    Kadish, A., Dyer, A., Daubert, J. P., Quigg, R., Estes, N. A., Anderson, K. P., et al. (2004). Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. New England Journal of Medicine, 350, 2151–2158.CrossRefPubMedGoogle Scholar
  5. 5.
    Burchfield, J. S., Xie, M., & Hill, J. A. (2013). Pathological ventricular remodeling. Mechanisms: Part 1 of 2, 128, 388–400.Google Scholar
  6. 6.
    Spinale, F. G., Coker, M. L., Heung, L. J., Bond, B. R., Gunasinghe, H. R., Etoh, T., et al. (2000). A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation, 102, 1944–1949.CrossRefPubMedGoogle Scholar
  7. 7.
    Masci, P. G., Doulaptsis, C., Bertella, E., Del Torto, A., Symons, R., Pontone, G., et al. (2014). Incremental prognostic value of myocardial fibrosis in patients with non-ischemic cardiomyopathy without congestive heart failure. Circulation: Heart Failure, 7, 448–456.Google Scholar
  8. 8.
    Ponikowski, P., Voors, A. A., Anker, S. D., Bueno, H., Cleland, J. G., Coats, A. J., et al. (2016). 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC. European Heart Journal, 37, 2129–2200.CrossRefPubMedGoogle Scholar
  9. 9.
    Borlaug, B. A., & Paulus, W. J. (2011). Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. European Heart Journal, 32, 670–679.CrossRefPubMedGoogle Scholar
  10. 10.
    Hansen, A., Haass, M., Zugck, C., Krueger, C., Unnebrink, K., Zimmermann, R., et al. (2001). Prognostic value of Doppler echocardiographic mitral inflow patterns: implications for risk stratification in patients with chronic congestive heart failure. Journal of the American College of Cardiology, 37, 1049–1055.CrossRefPubMedGoogle Scholar
  11. 11.
    Roura, S., Planas, F., Prat-Vidal, C., Leta, R., Soler-Botija, C., Carreras, F., et al. (2007). Idiopathic dilated cardiomyopathy exhibits defective vascularization and vessel formation. European Journal of Heart Failure, 9, 995–1002.CrossRefPubMedGoogle Scholar
  12. 12.
    de la Pompa, J. L., & Epstein, J. A. (2012). Coordinating tissue interactions: Notch signaling in cardiac development and disease. Developmental Cell, 22, 244–254.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Oie, E., Sandberg, W. J., Ahmed, M. S., Yndestad, A., Laerum, O. D., Attramadal, H., et al. (2010). Activation of Notch signaling in cardiomyocytes during post-infarction remodeling. Scandinavian Cardiovascular Journal, 44, 359–366.CrossRefPubMedGoogle Scholar
  14. 14.
    Pei, H., Song, X., Peng, C., Tan, Y., Li, Y., Li, X., et al. (2015). TNF-alpha inhibitor protects against myocardial ischemia/reperfusion injury via Notch1-mediated suppression of oxidative/nitrative stress. Free Radical Biology and Medicine, 82, 114–121.CrossRefPubMedGoogle Scholar
  15. 15.
    Nemir, M., Metrich, M., Plaisance, I., Lepore, M., Cruchet, S., Berthonneche, C., et al. (2014). The Notch pathway controls fibrotic and regenerative repair in the adult heart. European Heart Journal, 35, 2174–2185.CrossRefPubMedGoogle Scholar
  16. 16.
    Croquelois, A., Domenighetti, A. A., Nemir, M., Lepore, M., Rosenblatt-Velin, N., Radtke, F., et al. (2008). Control of the adaptive response of the heart to stress via the Notch1 receptor pathway. Journal of Experimental Medicine, 205, 3173–3185.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    D’Souza, B., Meloty-Kapella, L., & Weinmaster, G. (2010). Canonical and Non-Canonical Notch Ligands., 92, 73–129.Google Scholar
  18. 18.
    D'Souza, B., Miyamoto, A., & Weinmaster, G. (2008). The many facets of Notch ligands. Oncogene, 27, 5148–5167.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Norum, H. M., Gullestad, L., Abraityte, A., Broch, K., Aakhus, S., Aukrust, P., et al. (2016). Increased serum levels of the Notch ligand DLL1 are associated with diastolic dysfunction, reduced exercise capacity, and adverse outcome in chronic heart failure. Journal of Cardiac Failure, 22, 218–223.CrossRefPubMedGoogle Scholar
  20. 20.
    Rodriguez, P., Higueras, M. A., Gonzalez-Rajal, A., Alfranca, A., Fierro-Fernandez, M., Garcia-Fernandez, R. A., et al. (2012). The non-canonical NOTCH ligand DLK1 exhibits a novel vascular role as a strong inhibitor of angiogenesis. Cardiovascular Research, 93, 232–241.CrossRefPubMedGoogle Scholar
  21. 21.
    Cheng, C. W., Wang, C. H., Lee, J. F., Kuo, L. T., & Cherng, W. J. (2012). Levels of blood periostin decrease after acute myocardial infarction and are negatively associated with ventricular function after 3 months. Journal of Investigative Medicine, 60, 523–528.CrossRefPubMedGoogle Scholar
  22. 22.
    Broch, K., Andreassen, A. K., Ueland, T., Michelsen, A. E., Stueflotten, W., Aukrust, P., et al. (2015). Soluble ST2 reflects hemodynamic stress in non-ischemic heart failure. International Journal of Cardiology, 179, 378–384.CrossRefPubMedGoogle Scholar
  23. 23.
    Lang, R. M., Bierig, M., Devereux, R. B., Flachskampf, F. A., Foster, E., Pellikka, P. A., et al. (2005). Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. Journal of the American Society of Echocardiography, 18, 1440–1463.CrossRefPubMedGoogle Scholar
  24. 24.
    Galderisi, M., Henein, M. Y., D'Hooge, J., Sicari, R., Badano, L. P., Zamorano, J. L., et al. (2011). Recommendations of the European Association of Echocardiography: how to use echo-Doppler in clinical trials: different modalities for different purposes. European Journal of Echocardiography, 12, 339–353.CrossRefPubMedGoogle Scholar
  25. 25.
    Levey, A. S., Bosch, J. P., Lewis, J. B., Greene, T., Rogers, N., & Roth, D. (1999). A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification animal studies of Diet in Renal Disease Study Group. Annals of Internal Medicine, 130, 461–470.CrossRefPubMedGoogle Scholar
  26. 26.
    Aukrust, P., Aandahl, E. M., Skalhegg, B. S., Nordoy, I., Hansson, V., Tasken, K., et al. (1999). Increased activation of protein kinase A type I contributes to the T cell deficiency in common variable immunodeficiency. Journal of Immunology, 162, 1178–1185.Google Scholar
  27. 27.
    Stylianou, E., Aukrust, P., Müller, F., Nordøy, I., & Frøland, S. S. (2001). Complex effects of interferon-α on the cytokine network in HIV infection—possible contribution to immunosuppression. Cytokine, 14, 56–62.CrossRefPubMedGoogle Scholar
  28. 28.
    Nagueh, S. F., Appleton, C. P., Gillebert, T. C., Marino, P. N., Oh, J. K., Smiseth, O. A., et al. (2009). Recommendations for the evaluation of left ventricular diastolic function by echocardiography. European Journal of Echocardiography, 10, 165–193.CrossRefPubMedGoogle Scholar
  29. 29.
    Edelmann, F., Schmidt, A. G., Gelbrich, G., Binder, L., Herrmann-Lingen, C., Halle, M., et al. (2010). Rationale and design of the 'aldosterone receptor blockade in diastolic heart failure' trial: a double-blind, randomized, placebo-controlled, parallel group study to determine the effects of spironolactone on exercise capacity and diastolic function in patients with symptomatic diastolic heart failure (Aldo-DHF). European Journal of Heart Failure, 12, 874–882.CrossRefPubMedGoogle Scholar
  30. 30.
    Nagueh, S. F., Smiseth, O. A., & Appleton, C. P. (2016). Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Journal of the American Society of Echocardiography, 29.Google Scholar
  31. 31.
    Doughty, R. N., Klein, A. L., Poppe, K. K., Gamble, G. D., Dini, F. L., Moller, J. E., et al. (2008). Independence of restrictive filling pattern and LV ejection fraction with mortality in heart failure: an individual patient meta-analysis. European Journal of Heart Failure, 10, 786–792.CrossRefPubMedGoogle Scholar
  32. 32.
    Pabois, A., Pagie, S., Gérard, N., Laboisse, C., Pattier, S., Hulin, P., et al. (2016). Notch signaling mediates crosstalk between endothelial cells and macrophages via Dll4 and IL6 in cardiac microvascular inflammation. Biochemical Pharmacology, 104, 95–107.CrossRefPubMedGoogle Scholar
  33. 33.
    O'Meara, E., de Denus, S., Rouleau, J. L., & Desai, A. (2013). Circulating biomarkers in patients with heart failure and preserved ejection fraction. Current Heart Failure Reports, 10, 350–358.CrossRefPubMedGoogle Scholar
  34. 34.
    Chan, M. M., Santhanakrishnan, R., Chong, J. P., Chen, Z., Tai, B. C., Liew, O. W., et al. (2016). Growth differentiation factor 15 in heart failure with preserved vs. reduced ejection fraction. European Journal of Heart Failure, 18, 81–88.CrossRefPubMedGoogle Scholar
  35. 35.
    Gandhi, P. U., Gaggin, H. K., Sheftel, A. D., Belcher, A. M., Weiner, R. B., Baggish, A. L., et al. (2014). Prognostic usefulness of insulin-like growth factor-binding protein 7 in heart failure with reduced ejection fraction: a novel biomarker of myocardial diastolic function? American Journal of Cardiology, 114, 1543–1549.CrossRefPubMedGoogle Scholar
  36. 36.
    Gandhi, P. U., Gaggin, H. K., Redfield, M. M., Chen, H. H., Stevens, S. R., Anstrom, K. J., et al. (2016). Insulin-like growth factor-binding protein-7 as a biomarker of diastolic dysfunction and functional capacity in heart failure with preserved ejection fraction: results from the RELAX Trial. JACC Heart Fail, 4, 860–869.CrossRefPubMedGoogle Scholar
  37. 37.
    Fedak, P. W., Moravec, C. S., McCarthy, P. M., Altamentova, S. M., Wong, A. P., Skrtic, M., et al. (2006). Altered expression of disintegrin metalloproteinases and their inhibitor in human dilated cardiomyopathy. Circulation, 113, 238–245.CrossRefPubMedGoogle Scholar
  38. 38.
    Sun, D., Li, H., & Zolkiewska, A. (2008). The role of Delta-like 1 shedding in muscle cell self-renewal and differentiation. Journal of Cell Science, 121, 3815–3823.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Liu, Y., Korte, F. S., Moussavi-Harami, F., Yu, M., Razumova, M., Regnier, M., et al. (2012). Transcription factor CHF1/Hey2 regulates EC coupling and heart failure in mice through regulation of FKBP12.6. American Journal of Physiology: Heart and Circulatory Physiology, 302, H1860–H1870.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Tkatchenko, T. V., Moreno-Rodriguez, R. A., Conway, S. J., Molkentin, J. D., Markwald, R. R., & Tkatchenko, A. V. (2009). Lack of periostin leads to suppression of Notch1 signaling and calcific aortic valve disease. Physiological Genomics, 39, 160–168.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Tanabe, H., Takayama, I., Nishiyama, T., Shimazaki, M., Kii, I., Li, M., et al. (2010). Periostin associates with Notch1 precursor to maintain Notch1 expression under a stress condition in mouse cells. PloS One, 5, e12234.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Zhao, S., Wu, H., Xia, W., Chen, X., Zhu, S., Zhang, S., et al. (2014). Periostin expression is upregulated and associated with myocardial fibrosis in human failing hearts. Journal of Cardiology, 63, 373–378.CrossRefPubMedGoogle Scholar
  43. 43.
    Katsuragi, N., Morishita, R., Nakamura, N., Ochiai, T., Taniyama, Y., Hasegawa, Y., et al. (2004). Periostin as a novel factor responsible for ventricular dilation. Circulation, 110, 1806–1813.CrossRefPubMedGoogle Scholar
  44. 44.
    Martos, R., Baugh, J., Ledwidge, M., O’Loughlin, C., Conlon, C., Patle, A., et al. (2007). Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction. Circulation, 115, 888–895.CrossRefPubMedGoogle Scholar
  45. 45.
    Maeng, Y. S., Choi, Y. J., & Kim, E. K. (2015). TGFBIp regulates differentiation of EPC (CD133(+) C-kit(+) Lin(−) cells) to EC through activation of the Notch signaling pathway. Stem Cells, 33, 2052–2062.CrossRefPubMedGoogle Scholar
  46. 46.
    Mochizuki, K., He, S., & Zhang, Y. (2011). Notch and inflammatory T-cell response: new developments and challenges. Immunotherapy, 3, 1353–1366.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Sekine, C., Nanki, T., & Yagita, H. (2014). Macrophage-derived delta-like protein 1 enhances interleukin-6 and matrix metalloproteinase 3 production by fibroblast-like synoviocytes in mice with collagen-induced arthritis. Arthritis & Rhematology, 66, 2751–2761.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Hilde M. Norum
    • 1
    • 2
    • 3
    Email author
  • Kaspar Broch
    • 4
  • Annika E. Michelsen
    • 1
    • 2
  • Ida G. Lunde
    • 5
    • 6
  • Tove Lekva
    • 1
  • Aurelija Abraityte
    • 1
    • 2
    • 5
  • Christen P. Dahl
    • 1
    • 4
    • 5
  • Arnt E. Fiane
    • 7
  • Arne K. Andreassen
    • 4
  • Geir Christensen
    • 5
    • 6
  • Svend Aakhus
    • 4
    • 8
  • Pål Aukrust
    • 1
    • 2
    • 9
    • 10
    • 11
  • Lars Gullestad
    • 2
    • 4
  • Thor Ueland
    • 1
    • 2
    • 11
  1. 1.Research Institute of Internal MedicineOslo University HospitalOsloNorway
  2. 2.Faculty of MedicineUniversity of OsloOsloNorway
  3. 3.Department of Research and Development, Division of Emergencies and Critical CareOslo University HospitalOsloNorway
  4. 4.Department of CardiologyOslo University HospitalOsloNorway
  5. 5.Center for Heart Failure ResearchUniversity of OsloOsloNorway
  6. 6.Institute for Experimental Medical ResearchOslo University Hospital, UllevålOsloNorway
  7. 7.Department of Cardiothoracic SurgeryOslo University HospitalOsloNorway
  8. 8.Department of Circulation and Imaging, Faculty of MedicineNorwegian University of Science and TechnologyTrondheimNorway
  9. 9.Section of Clinical Immunology and Infectious DiseasesOslo University HospitalOsloNorway
  10. 10.K.G. Jebsen Inflammation Research CenterUniversity of OsloOsloNorway
  11. 11.K.G. Jebsen Thrombosis Research and Expertise CenterUniversity of TromsøTromsøNorway

Personalised recommendations