The Notch Ligands DLL1 and Periostin Are Associated with Symptom Severity and Diastolic Function in Dilated Cardiomyopathy
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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.
KeywordsDilated cardiomyopathy Diastolic dysfunction Delta-like Notch ligand 1 (DLL1) Delta-like 1 homologue (DLK1) Periostin (POSN) Notch pathway Myocardial remodeling
Delta-like Notch ligand 1
Delta-like 1 homologue
Heart failure with reduced ejection fraction
New York Heart Association
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 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).
- 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
- 5.Burchfield, J. S., Xie, M., & Hill, J. A. (2013). Pathological ventricular remodeling. Mechanisms: Part 1 of 2, 128, 388–400.Google Scholar
- 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.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
- 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
- 17.D’Souza, B., Meloty-Kapella, L., & Weinmaster, G. (2010). Canonical and Non-Canonical Notch Ligands., 92, 73–129.Google Scholar
- 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
- 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.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.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.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
- 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.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.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
- 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.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
- 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