Leveraging clinical epigenetics in heart failure with preserved ejection fraction: a call for individualized therapies Nazha Hamdani 1,2,3,4, Sarah Costantino 5, Andreas Mügge 2,3, Djamel Lebeche 6,7,8, Carsten Tschöpe 9,10,11, Thomas Thum 12,13,14, and Francesco Paneni 5,15,16* 1 Institute of Physiology, Ruhr University, Bochum, Germany; 2 Molecular and Experimental Cardiology, Ruhr University, Bochum, Germany; 3 Department of Cardiology, St-Josef Hospital, Ruhr University, Bochum, Germany; 4 Clinical Pharmacology, Ruhr University, Bochum, Germany; 5 Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, Schlieren CH-8952, Switzerland; 6 Department of Medicine, Icahn School of Medicine at Mount Sinai, Cardiovascular Research Institute, New York, NY 10029, USA; 7 Department of Medicine, Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; 8 Department of Medicine, Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; 9 Berlin Institute of Health Center for Regenerative Therapies and Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany; 10 German Center for Cardiovascular Research (DZHK), Partner site Berlin, Berlin, Germany; 11 Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK), Berlin, Germany; 12 Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany; 13 REBIRTH Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany; 14 Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover 30625, Germany; 15 University Heart Center, Cardiology, University Hospital Zurich, Zürich, Switzerland; 16 Department of Research and Education, University Hospital Zurich, Zürich, Switzerland *Corresponding author. Tel: +41-44-6355096, Fax: +41-44-6356827, Email: [email protected] Described as the ‘single largest unmet need in cardiovascular medicine’, heart failure with preserved ejection fraction (HFpEF) remains an untreatable disease currently representing 65% of new heart failure diagnoses. HFpEF is more frequent among women and associates with a poor prognosis and unsustainable healthcare costs. Moreover, the variability in HFpEF phenotypes amplifies complexity and difficulties in the approach. In this perspective, unveiling novel molecular targets is imperative. Epigenetic modifications—defined as changes of DNA, histones, and non-coding RNAs (ncRNAs)—represent a molecular framework through which the environment modulates gene expression. Epigenetic signals acquired over the lifetime lead to chromatin remodelling and affect transcriptional programmes underlying oxidative stress, inflammation, dysmetabolism, and maladaptive left ventricular remodelling, all conditions predisposing to HFpEF. The strong involvement of epigenetic signalling in this setting makes the epigenetic information relevant for diagnostic and therapeutic purposes in patients with HFpEF. The recent advances in high-throughput sequencing, computational epigenetics, and machine learning have enabled the identification of reliable epigenetic biomarkers in cardiovascular patients. Contrary to genetic tools, epigenetic biomarkers mirror the contribution of environmental cues and lifestyle changes and their reversible nature offers a promising opportunity to monitor disease states. The growing understanding of chromatin and ncRNAs biology has led to the development of several Food and Drug Administration approved ‘epidrugs’ (chromatin modifiers, mimics, anti-miRs) able to prevent transcriptional alterations underpinning left ventricular remodelling and HFpEF. In the present review, we discuss the importance of clinical epigenetics as a new tool to be employed for a personalized management of HFpEF. Role of environmental factors and epigenetic processing in the pathogenesis of HFpEF.