Figures of the Heart Failure Association: Prof. Lars H. Lund, Chair of the HFA Committee on Registries, Surveys and Epidemiology and HFA Board Member (from 2016)

Lars H. Lund has a broad background in heart failure (HF), with research activities over the entire spectrum from molecule to patient to big data registries. He is committed to meeting the critical unmet needs in HF today1: (i) in HF with reduced ejection fraction (HFrEF): improving implementation of existing evidence-based therapy2; (ii) in HF with mid-range (HFmrEF) and preserved ejection fraction (HFpEF): testing and establishing existing HF therapy for the subset of patients who may benefit (especially patients with HFmrEF)3; (iii) in HF with truly preserved ejection fraction: to test novel treatment approaches, targeting e.g. systemic microvascular inflammation4, 5 and improving trial design by targeting patients with a modifiable HF phenotype6, 7; and (iv) in advanced and acute HF: developing and testing novel inotropes.8, 9 Lars grew up in Sweden and was a competitive tennis player in his youth. He went to the US to combine university studies and competitive tennis on an athletic scholarship at College of Charleston in South Carolina. He studied broadly in the liberal arts before moving on to medical school at Duke University in North Carolina. Medical school was a truly immersive experience and mind-opening in terms of dedication both to patients and academic rigour (though leaving no time for tennis, alas). During medical school, Lars also underwent PhD studies in molecular biology at Duke University and at Karolinska Institutet in Stockholm, his home town, focusing on the regulation of gene and protein expression. After medical school, Lars pursued internship and residency in internal medicine, and subsequently clinical and research training in HF physiology, at Columbia University in New York. After spending 16 years in the US, Lars returned to Stockholm, Karolinska Institutet and Karolinska University Hospital. At Karolinska, Lars has built a comprehensive clinical and research programme in HF. He has lead the programme in advanced and acute HF collaborating broadly with surgeons, interventionists, and intensivists to build a HF team leading the expansion of interventions such as durable and short-term mechanical circulatory support. In keeping with the recognition of emerging unmet needs in HF, he has also established a large outpatient referral clinic for HFpEF in addition to cardiomyopathies and advanced HF. In his research programme, Lars mentors a large number of PhD students, post-docs and fellows and collaborates broadly across the globe. He has been a leader in establishing clinical physiology and biomarker-based risk prediction models and scores that are important for clinical phenotyping and mandatory in the selection of patients for scarce or expensive interventions such as heart transplantation or left ventricular assist devices (LVADs)10, 11; he leads the research programme in the Swedish Heart Failure Registry (SwedeHF, https://www.ucr.uu.se/rikssvikt-en/) where he has advanced our understanding of how proven HFrEF therapy is implemented in the real world and where he has extensively characterized HFmrEF12; he has established several large cohorts of patients with HFmrEF and HFpEF, including KaRen13 and PROMIS-HFpEF,4 where he has described multiple novel aspects of HFpEF, such as an inflammatory biomarker profile, important derangements in the left atrium, and the importance or coronary microvascular dysfunction measured by coronary flow reserve4; and he has built a large clinical research operation serving on steering or executive committees in several important phase II and III programmes as well as enrolling in multiple trials, with a focus on a large comprehensive phase II HF trial centre. With his extensive research experience anchored in ongoing and extensive clinical practice, Lars has become a global leader in HF, as a board member of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC), among the most frequently searched and viewed speakers at the annual HFA congress, an author of the International Society for Heart and Lung Transplantation (ISHLT) guidelines on heart transplantation14 and European Association for Cardio-Thoracic Surgery (EACTS) consensus document on long-term mechanical circulatory support,15 Associate Editor of the European Journal of Heart Failure and Journal of Cardiac Failure, on the Editorial Board of Circulation and Circulation: Heart Failure, co-director of research in the SwedeHF, and principal investigator of the ESC EURObservational Research Programme (EORP) and HFA HF III Registry, and prior Director of the ISHLT Adult Heart Transplant Registry. Lars has initiated the world's first registry based randomized trial in HF – the Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure With Preserved Ejection Fraction (SPIRRIT-HFpEF, NCT02901184).16 He leads several phase II clinical trials targeting novel inotropic mechanisms to improve contractility and cardiac output as well as systemic microvascular inflammation in HFpEF. He is the founder of the biotech company AnaCardio. The biggest enigma and something very relevant currently is the persistently poor understanding of HFpEF. Even though ejection fraction is inexact and may change over time, I am a proponent of using ejection fraction for characterizing HF (at least until we have something better).17, 18 I believe that the mid-range ejection fraction category ‘belongs’ mostly to HFrEF. Outcomes are as expected better in HFmrEF than in HFrEF, but otherwise, demographics, clinical characteristics,3, 12, 19 and response to conventional HF therapy is similar in HFrEF and HFmrEF.3, 20, 21 In contrast, HF with truly preserved ejection fraction is something different – it is more heterogeneous22; in some cases caused by e.g. comorbidity-driven systemic inflammation and coronary microvascular dysfunction4, 5, 23; in others caused by specific cardiomyopathies such as transthyretin amyloidosis; or in some simply reflecting age- and/or comorbidity-related deconditioning and frailty. Understanding the role of comorbidities as drivers of symptoms vs. as drivers of a true HFpEF syndrome may reveal novel treatment targets and improve trial design in HFpEF.13, 24 The biggest challenge for the HF clinician is to care for patients and interact with referring doctors in cardiology, internal medicine and primary care, such that all the tremendously effective evidence-based HFrEF therapy is implemented! Angiotensin-converting enzyme inhibitors and beta-blockers are reasonably well used in HFrEF but already at the next step of the treatment algorithm, namely mineralocorticoid receptor antagonists, use across the Western world is only about one-third of eligible patients.25 Making things even more challenging, HFrEF therapy is now increasingly complex.26 Sacubitril/valsartan is and sodium–glucose co-transporter 2 (SGLT2) inhibitors soon will be standard of care in HFrEF, and then in select patients the HF team must consider the potential for If inhibition, soluble guanylate cyclase stimulators, digoxin, intravenous iron, coronary artery bypass grafting, percutaneous mitral valve intervention, catheter ablation for atrial fibrillation, implantable haemodynamic monitoring, heart transplantation, LVAD as bridge to transplant or destination therapy, palliative care, and in the future, if trials are positive, myosin activators, and potassium binders to treat hyperkalaemia and enable renin–angiotensin–aldosterone inhibitor use. At the same time, the population is aging, more patients are surviving acute coronary syndromes, HF is increasing in prevalence, and costs of HF care are increasing dramatically. In this context, the HF team must be adept at selection and prioritization for therapy,10 while the generalist needs to focus more on proper referral rather than the impossible task of mastering the nuanced indications for all these interventions.2, 27 This is a critical question that spans the entire spectrum of health care organizations and stakeholders, and relates indeed the challenges discussed above. The HFA is exemplary in its comprehensive approach to increasing HF awareness, with the world leading HF congress and the flagship journal, the European Journal of Heart Failure, as well as broad educational activities involving all stakeholders including patients, such as HF awareness day, guidelines, webinars, post-graduate courses, and very importantly, the ESC HFA and EORP HF registry, which is now in its third version (HF III, https://www.escardio.org/Research/Registries- the incredible success of neurohormonal inhibition as a therapeutic concept; why conventional inotropes were harmful. With the introduction of neprilysin inhibition, we have learned that not all compensation is harmful but that instead, the natriuretic peptide system can be harnessed to improve symptoms and outcomes; and finally now with the SGLT2 inhibitors, we are learning that beneficial mechanisms in HF may extend beyond neurohormonal inhibition and modulation – incredibly exciting but also complex times! My biggest mistake could be insufficient focus, I will never know. During my PhD training I focused on specific molecules involved in the regulation of gene and protein expression, and I often wonder if I could have done more in my career by focusing intensely on narrow aspects of molecular cardiology or perhaps oncology or infectious diseases, other major unmet needs. Instead, I engaged early in broad aspects of HF research and clinical care, such as mechanisms of contraction–relaxation, biomarkers and functional measures in HFpEF, HF characterization and phenotyping using cohorts and registries, and more recently optimizing design of trials in HF by optimizing eligibility criteria7 and stream-lining trial design using the registry-based randomized controlled trial concept.16 Broad engagement in research and clinical practice in HF is tremendously rewarding, and I feel like every time I see a patient I apply something I have learned from my own research; but sometimes I regret not choosing a narrow focus dedicated to a single scientific question. Andrew J.S. Coats IRCCS San Raffaele Pisana Rome, Italy email protected