miR-181c level predicts response to exercise training in patients with heart failure and preserved ejection fraction: an analysis of the OptimEx-Clin trial

Author:

Gevaert Andreas B12ORCID,Witvrouwen Isabel12,Van Craenenbroeck Amaryllis H34,Van Laere Steven J5,Boen Jente R A16,Van de Heyning Caroline M12,Belyavskiy Evgeny78,Mueller Stephan910,Winzer Ephraim11,Duvinage André910,Edelmann Frank78,Beckers Paul J2,Heidbuchel Hein12,Wisløff Ulrik12,Pieske Burkert78,Adams Volker11,Halle Martin910ORCID,Van Craenenbroeck Emeline M12,

Affiliation:

1. Research Group Cardiovascular Diseases, GENCOR Department, University of Antwerp, Campus Drie Eiken D.T.228, Universiteitsplein 1, 2610 Antwerp, Belgium

2. Department of Cardiology, Antwerp University Hospital (UZA), Edegem, Belgium

3. Research Group Nephrology and Renal Transplantation, Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit Leuven, Leuven, Belgium

4. Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium

5. Translational Cancer Research Unit, Center for Oncological Research (CORE), University of Antwerp, Antwerp, Belgium

6. Research Group Physiopharmacology, GENCOR Department, University of Antwerp, Antwerp, Belgium

7. Department of Internal Medicine and Cardiology, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Berlin, Germany

8. DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany

9. Department of Prevention and Sports Medicine, University Hospital Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

10. DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany

11. Heart Center Dresden – University Hospital, Department of Internal Medicine and Cardiology, Technische Universität Dresden, Dresden, Germany

12. Cardiac Exercise Research Group at Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway

Abstract

Abstract Aims In patients with heart failure with preserved ejection fraction (HFpEF), exercise training improves the quality of life and aerobic capacity (peakV·O2). Up to 55% of HF patients, however, show no increase in peakV·O2 despite adequate training. We hypothesized that circulating microRNAs (miRNAs) can distinguish exercise low responders (LR) from exercise high responders (HR) among HFpEF patients. Methods and results We selected HFpEF patients from the Optimizing Exercise Training in Prevention and Treatment of Diastolic HF (OptimEx) study which attended ≥70% of training sessions during 3 months (n = 51). Patients were defined as HR with a change in peakV·O2 above median (6.4%), and LR as below median (n = 30 and n = 21, respectively). Clinical, ergospirometric, and echocardiographic characteristics were similar between LR and HR. We performed an miRNA array (n = 377 miRNAs) in 14 age- and sex-matched patients. A total of 10 miRNAs were upregulated in LR, of which 4 correlated with peakV·O2. Validation in the remaining 37 patients indicated that high miR-181c predicted reduced peakV·O2 response (multiple linear regression, β = −2.60, P = 0.011), and LR status (multiple logistic regression, odds ratio = 0.48, P = 0.010), independent of age, sex, body mass index, and resting heart rate. Furthermore, miR-181c decreased in LR after exercise training (P-group = 0.030, P-time = 0.048, P-interaction = 0.037). An in silico pathway analysis identified several downstream targets involved in exercise adaptation. Conclusions Circulating miR-181c is a marker of the response to exercise training in HFpEF patients. High miR-181c levels can aid in identifying LR prior to training, providing the possibility for individualized management.

Funder

European Research Council under the European Union's Seventh Framework Programme

Deutsche Forschungsgemeinschaft through the TUM International Graduate School of Science and Engineering

Flanders Research Foundation

Publisher

Oxford University Press (OUP)

Subject

Cardiology and Cardiovascular Medicine,Epidemiology

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