Novel Endotypes in Heart Failure: Effects on Guideline-Directed Medical Therapy

Jasper Tromp, Wouter Ouwerkerk, Biniyam Demissei, Stefan D. Anker, John G. F. Cleland, K. Dickstein, Gerasimos S. Filippatos, Pim van der Harst, Hans L. Hillege, Chim C. Lang, Marco Metra, Leong Loke Ng, Piotr Ponikowski, Nilesh J. Samani, Dirk Jan van Veldhuisen, Faiez Zannad, Aelko H. Zwinderman, Adriaan A. Voors, Peter van der Meer (Lead / Corresponding author)

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Abstract

Aims: We sought to determine subtypes of patients with heart failure (HF) with a distinct clinical profile and treatment response, using a wide range of biomarkers from various pathophysiological domains. Methods and results: We performed unsupervised cluster analysis using 92 established cardiovascular biomarkers to identify mutually exclusive subgroups (endotypes) of 1802 patients with HF and reduced ejection fraction (HFrEF) from the BIOSTAT-CHF project. We validated our findings in an independent cohort of 813 patients. Based on their biomarker profile, six endotypes were identified. Patients with endotype 1 were youngest, less symptomatic, had the lowest N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and lowest risk for all-cause mortality or hospitalization for HF. Patients with endotype 4 had more severe symptoms and signs of HF, higher NT-proBNP levels and were at highest risk for all-cause mortality or hospitalization for HF [hazard ratio (HR) 1.4; 95% confidence interval (CI) 1.1-1.8]. Patients with endotypes 2, 3, and 5 were better uptitrated to target doses of beta-blockers (P < 0.02 for all). In contrast to other endotypes, patients with endotype 5 derived no potential survival benefit from uptitration of angiotensin-converting enzyme-inhibitor/angiotensin-II receptor blocker and beta-blockers (Pinteraction <0.001). Patients with endotype 2 (HR 1.29; 95% CI 1.10-1.42) experienced possible harm from uptitration of beta-blockers in contrast to patients with endotype 4 and 6 that experienced benefit (Pinteraction for all <0.001). Results were strikingly similar in the independent validation cohort. Conclusion: Using unsupervised cluster analysis, solely based on biomarker profiles, six distinct endotypes were identified with remarkable differences in characteristics, clinical outcome, and response to uptitration of guideline directed medical therapy.

Original languageEnglish
Article numberehy712
Pages (from-to)4269-4276
Number of pages8
JournalEuropean Heart Journal
Volume39
Issue number48
Early online date13 Dec 2018
DOIs
Publication statusPublished - 21 Dec 2018

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    Tromp, J., Ouwerkerk, W., Demissei, B., Anker, S. D., Cleland, J. G. F., Dickstein, K., Filippatos, G. S., van der Harst, P., Hillege, H. L., Lang, C. C., Metra, M., Ng, L. L., Ponikowski, P., Samani, N. J., van Veldhuisen, D. J., Zannad, F., Zwinderman, A. H., Voors, A. A., & van der Meer, P. (2018). Novel Endotypes in Heart Failure: Effects on Guideline-Directed Medical Therapy. European Heart Journal, 39(48), 4269-4276. [ehy712]. https://doi.org/10.1093/eurheartj/ehy712