Improved Understanding and Novel Treatment of Heart Failure with Preserved Ejection Fraction

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1 U N I V E R S I T Y O F C O P E N H A G E N F A C U L T Y O F H E A L T H A N D M E D I C A L S C I E N C E S B R I D G E - T R A N S L A T I O N A L E X C E L L E N C E P R O G R A M ME P R O J E C T S Y N O P S I S T E M P L A T E Project title Mentor 1 Mentor 2 Framework Project synopsis Improved Understanding and Novel Treatment of Heart Failure with Preserved Ejection Fraction Finn Gustafsson, MD, DMSc, Professor of Cardiology, The Heart Centre, Rigshospitalet (finn.gustafsson@regionh.dk) Morten B Thomsen, PhD, Associate Professor, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen (mbthom@sund.ku.dk) This project will be executed within a translational framework, bridging experimental physiology and clinical medicine. In this environment, the postdoctoral scientist will be seeped in a milieu of academic, translational, physiological and clinical expertise, where the foundations for a successful translational career will be laid. The two mentors have long-standing national and international experience with cardiac hemodynamics, electrophysiology and disease. The project will thus encompass both pre-clinical and clinical aspects to understand an important aspect of heart failure, with the overarching goal to identify rational targets to alleviate heart failure symptoms to the future benefit of the patients. The post-doctoral scientist will work with animal models of disease using advanced hemodynamic and electrophysiological techniques, histology, gene-targeting therapies and on human materials and data. Heart Failure with preserved Ejection Fraction (HFpEF, previously known as diastolic heart failure) is an increasingly common form of cardiac disease associated with female sex, ageing, obesity, and hypertension, for which no treatment has proven effective. Mainly, this is a consequence of inadequate understanding of pathophysiology of the disease. The project will use established and new animal models to study specific components of the HFpEF syndrome (e.g. chronotropic incompetence, diastolic stiffness) and risk factors (e.g. diabetes, physical activity). Thereafter, specific therapies relating to intracellular calcium homeostasis will be tested. The project will connect the clinical data to the animal model, ensure pre-clinical target development and bridge the gap back to the clinical setting laying the foundation for clinical development.

2 Profile of potential fellow PAGE 2 OF 2 PhD in cardiovascular medicine or physiology An interest in working the animal models of disease Publication and teaching experience Understanding of medical challenges, but not necessarily an MD background Ambitious, motivated and with a positive, can-do attitude

3 U N I V E R S I T Y O F C O P E N H A G E N F A C U L T Y O F H E A L T H A N D M E D I C A L S C I E N C E S B R I D G E - T R A N S L A T I O N A L E X C E L L E N C E P R O G R A M ME M E N T O R C V T E M P L A T E Name Title Current department(s) Current position(s) Education/training Scientific career profile Finn Gustafsson MD, PhD, DMSci Department of Cardiology, Rigshospitalet; Department of Clinical Medicine, University of Copenhagen Clinical professor, consultant cardiologist 2010: DMSci, University of Copenhagen 2007: Certified specialist in Cardiology, Rigshospitalet, Copenhagen : Clinical fellow, Toronto General Hospital (Heart Failure and Transplant) : Resident Internal Medicine and Cardiology 2000: PhD, Department of Medical Physiology, Panum Institute, University of Copenhagen : Internship 1994: MD, University of Copenhagen As a heart failure (HF) specialist my main clinical interest is to understand the underlying pathophysiology of the diseases I treat. Attempting to obtain this I have conducted research in HF using several modalities from experimental animal models, invasive hemodynamic clinical studies, epidemiology and randomized trials. In the last five years a large part of my research activities has been devoted to characterizing patients with HF and preserved ejection fraction (HFpEF) hemodynamically, not just at rest but during exercise. This is performed using Swan-Ganz catheter-based pressure and flow measurements under resting and exercise conditions. This way we have tested the effect of various pharmacological interventions (such as PDE-5 inhibition) and structural interventions (creating of an interatrial shunt to unload the left atrium). The majority of the work has been undertaken in collaboration with David Kaye in Melbourne and Dan Burkhoff, Columbia University, NY, USA. I completed my phd in experimental physiology (microvascular control) and I have recently been involved in development of a pig HF model used to study novel aspects of neurohormonal activation. My research group routinely conducts advanced hemodynamic studies, endomyocardial biopsies, echocardiography and other indispensable investigations in the field of clinical HF research. Collaborators within the University of Copenhagen include Professor Jens Peter Gøtze and Professor Caroline Kistorp and at Odense University Hospital Professor Jacob Møller. Outside Denmark I work closely with Professor Heather Ross, Toronto, Canada and Professor Stuart Russell, Duke University, USA. I am associate editor for Circulation: Heart Failure and on the editorial board for European Journal of Heart Failure.

4 Bibliometric summary Contributions to mentoring, training, supervision PAGE 2 OF 2 Number of publications: 250, number of first authorships or last authorships: 83, number of citations: 6068, h-index (Web of Science): main publications since Jung MH Gustafsson F: Effect of increasing pump speed during exercise on peak oxygen consumption in heart failure patients supported with continuousflow left ventricular assist device (CF-LVAD). A double-blind randomized study. European Journal of Heart Failure 2014;16: Søndergaard L Gustafsson F: Transcatheter treatment of heart failure with preserved or mildly reduced ejection fraction using a novel interatrial implant to lower left atrial pressure. European Journal of Heart Failure 2014;16: Hasenfuß G, Gustafsson F,..Kaye DM: A transcatheter intracardiac shunt device for heart failure with preserved ejection fraction (REDUCE LAP-HF): a multicentre, open-label, single-arm, phase 1 trial. Lancet 2016; 387: Køber L,..Gustafsson F,.., Pehrson S: Defibrillator Implantation in Non- Ischemic Systolic Heart Failure. New England Journal of Medicine 2016; 375: Jung M,..Gustafsson F: Pump Speed Modulations and Sub-maximal Exercise Tolerance in LVAD Patients- A Double Blind Randomized Trial. Journal of Heart and Lung Transplantation 2017; 36: Wolsk E,, Gustafsson F: The influence of age on hemodynamic parameters during rest and exercise in healthy individuals. JACC HF 2017; 5: Lund L,,Gustafsson F. Screening for heart transplantation and left ventricular assist device - results from the ScrEEning for advanced Heart Failure treatment (SEE-HF) study. European Journal of Heart Failure 2018; 20: Wolsk E,,Gustafsson F: Resting and exercise hemodynamics in relation to 6-minute walk test in patients with heart failure and preserved ejection fraction. European Journal of Heart Failure 2018; 20: Gustafsson F,,Garbade J: Six-month outcomes after treatment of advanced heart failure with a full magnetically levitated continuous flow left ventricular assist device: report from the ELEVATE registry. European Heart Journal 2018: 39: Balling L,, Gustafsson F: Hemodynamic effect of short-term infusion of a vasopressin V1A/V2 receptor antagonist conivaptan in patients with chronic heart failure during submaximal exercise. American Heart Journal 2018; 203: I have a large experience in mentoring pre- and postgraduate students in both clinical medicine and research. My role as a mentor is support and help when things are difficult not to direct and manage. Success to me is an independent, capable mentee, who is ready and inspired to be a mentor her/himself. I have supervised 9 completed phd projects and I am currently supervisor for 7 phd students. I have one post-doc employed and I have started the advanced HF fellow program at my institution. I have organized Scandinavian Academies on advanced HF as well as numerous courses on HF.

5 U N I V E R S I T Y O F C O P E N H A G E N F A C U L T Y O F H E A L T H A N D M E D I C A L S C I E N C E S B R I D G E - T R A N S L A T I O N A L E X C E L L E N C E P R O G R A M ME M E N T O R C V T E M P L A T E Name Title Current department(s) Current position(s) Education/training Scientific career profile Bibliometric summary Morten B Thomsen PhD Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen. Associate Professor Education: 2005: PhD in Cardiology, Maastricht University, The Netherlands. 2000: MSc in Human Biology, University of Copenhagen, Denmark. 1997: BSc in Biology, University of Aarhus, Denmark. Training: : Post-Doctoral Research Scientist at the Center for Molecular Therapeutics, Department of Pharmacology, Columbia University, New York, USA : Research scientist at the Department of Medical Physiology, Heart-Lung Centre Utrecht, University Medical Centre Utrecht, The Netherlands. I am a translational, integrative physiologist, primarily focusing on the cardiovascular system. My goal is to discover new diagnostic and treatment modalities using advanced basic science techniques that can be driven to clinical use to the benefit of the patients. As an example, I discovered and developed a new algorithm for forecasting ventricular arrhythmias in susceptible animals and later in patients. This technology is now in clinical development. My lab uses advanced electrophysiological techniques in intact conscious or anesthetized animals, in isolated organs and in single cells. We use advanced disease models (surgical and genetic) and we can follow structural and mechanical remodeling in the heart using specialized echocardiography. The research group is embedded in the department s section for Heart, Renal and Circulation research, with 10 principal investigators in newly renovated, very functional laboratories. Main collaborators include Drs. Kirstine Calloe (Univ. Copenhagen), Christian Alkjaer (Univ. Aarhus), Ana Gomez (Univ. Paris-Saclay) and Martin Young (Univ. Alabama). I am the deputy Editor in Chief of Physiological Reports and serve on the editorial board of several scientific journals. 45 peer-reviewed publications since 2003; 16 as first author; 6 as second author; 11 as last and corresponding author; 1,178 citations; h-index 18.

6 Contributions to mentoring, training, supervision PAGE 2 OF 2 1. Thomsen MB, Nielsen MS, Aarup A et al. Uremia increases QRS duration after β-adrenergic stimulation in mice. Physiol Rep, 2018;6(3):e Speerschneider T, Grubb S... Thomsen MB. Ventricular repolarization time, location of pacing stimulus and current pulse amplitude [...] in mice. Acta Physiol (Oxf), 2017;219(3): Grubb S, Aistrup GL... Thomsen MB. Preservation of Cardiac Function by Prolonged Action Potentials in Mice Deficient of KChIP2. Am J Physiol Heart Circ Physiol, 2015;309:H Soltysinska E, Speerschneider T... Thomsen MB. Sinoatrial Node Dysfunction Induces Cardiac Arrhythmias in Diabetic Mice. Cardiovasc Diabetol, 2014;13(1): Speerschneider T, Grubb S... Thomsen MB. Development of Heart Failure is Independent of KChIP2 Expression. J Physiol, 2013;591(23): Thomsen MB, Wang C... Pitt GS. The accessory subunit KChIP2 modulates the cardiac L-type calcium current. Circ Res, 2009;104(12): Hinterseer M, Thomsen MB... Kaab S. Beat-To-Beat Variability of QT intervals is increased in patients with drug-induced long-qt syndrome: a case control pilot study. Eur Heart J, 2008;29(2): Thomsen MB, Oros A... Vos MA. Proarrhythmic electrical remodelling is associated with increased beat-to-beat variability of repolarisation. Cardiovasc Res, 2007;73(3): Thomsen MB, Volders P... Vos MA. Beat-to-beat variability of repolarization determines proarrhythmic outcome in dogs susceptible to drug-induced torsades de pointes. J Am Coll Cardiol, 2006;48(6): Thomsen MB, Verduyn SC... Vos MA. Increased short-term variability of repolarization predicts d-sotalol-induced torsades de pointes in dogs. Circulation. 2004;110(16): Mentoring talents means providing the means facilitating the personal, academic and scientific development a trainee requires becoming an independent, successful researcher, fulfilling shared ambitions. It takes time and one-on-one training, which I prioritize. I have supervised 3 PhD students and 4 master students since They are all now successfully pursuing clinical, academic or industrial careers. I am a course leader for general anatomy and physiology for medical students. I teach in this course and in several other courses including cardiovascular physiology, pharmacology and internal medicine. I have organized several PhD courses and run an interest group on cardiac physiology under the auspices of the Scandinavian Physiological Society.