Mechanisms and outcomes of heart failure: from HFpEF, HFmrEF, and HFrEF to transplantation

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts As in most human activities, be it in sports, politics, or business, scientists and the journals they publish their work in are rated continuously. Numerous indices are used to do so such as the impact factor, immediacy index, impact quotient, Eigen factor, Altimetric score, and h-index. As pointed out in the Editor’s Page entitled ‘Measuring the unmeasurable: assessing the quality of science and scientists’,1 they all measure different aspects and thus never fully grasp the value of the work. Indeed, science is like art and, as such, unmeasurable. Nevertheless, we all want measures and, as long as we know what they provide us with, measuring the unmeasurable is appropriate. The recent ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure2 defined three forms of heart failure, i.e. heart failure with reduced ejection fraction or HFrEF, with mid-range ejection fraction or HFmrEF, and with preserved ejection fraction or HFpEF (Figure 1). Definition of three forms of heart failure according to the ESC Guidelines.2 The prevalence, mortality, and differential management3 of these three types of patients are still unclear. In their article ‘Mortality associated with heart failure with preserved vs. reduced ejection fraction in a prospective international multi-ethnic cohort study’, Robert Neil Doughty and colleagues from the University of Auckland in New Zealand determined and compared characteristics and outcomes of 2039 patients with HFpEF (28%), HFmrEF (12%), and HFrEF (59%).4 Compared with patients with HFrEF, patients with HFpEF were older, more commonly female, and more likely to be hypertensive, but less likely to have coronary artery disease. Patients with HFpEF had a lower adjusted risk of death than those with HFrEF. Plasma N-terminal pro brain natriuretic peptide (NT-proBNP) was similarly related to mortality in all three groups. These interesting results are further put into perspective in an interesting Editorial by Scott Solomon from the Brigham and Women’s Hospital in Boston, Massachusetts, USA.5 Next to coronary artery disease, cardiomyopathies are an important cause of heart failure. They differ substantially in structure, function, and their genetics.6–10 The Cardiomyopathy Registry of the EURObservational Research Programme is a prospective, observational, multinational registry of 3208 patients with hypertrophic (HCM), dilated (DCM), arrhythmogenic right ventricular (ARVC), and restrictive (RCM) cardiomyopathy, as reported in the article entitled ‘The Cardiomyopathy Registry of the EURObservational Research Programme of the European Society of Cardiology: baseline data and contemporary management of adult patients with cardiomyopathies’ by Philippe Charron and colleagues from the EORP Cardiomyopathy Registry Investigators.11 Demographic and clinical differences between cardiomyopathy subtypes were observed for age at diagnosis, history of familial disease, history of sustained ventricular arrhythmia, use of magnetic resonance imaging, as well as the use of genetic testing and of defibrillators. As compared with probands, relatives had a lower age at diagnosis, but a similar rate of symptoms and defibrillators. Patients from Southern Europe more frequently had a familial disease, were more frequently diagnosed during family screening, and more frequently had a rare underlying disease. This registry therefore provides contemporary observational data on characteristics and management of patients with cardiomyopathies in Europe and unravels potential gaps in existing recommendations.12 Heart failure is accompanied by major neuroendocrine activation including natriuretic peptides.13 In an EHJ Brief Communication entitled ‘The heart regulates the endocrine response to heart failure: cardiac contribution to circulating neprilysin’,14 Mattia Arrigo and colleagues from the Hopital Lariboisiere in Paris studied the regulation of the natriuretic peptide pathway in heart failure in patients undergoing implantation of the CARMAT total artificial heart. Ventricular removal was associated with an immediate drop in circulating natriuretic peptides, a nearly total disappearance of circulating glycosylated proBNP and furin activity, and a marked decrease in soluble neprilysin, while from week 1 onwards, natriuretic peptides remained unchanged. In contrast, partial recoveries in glycosylated proBNP, furin activity, and soluble neprilysin were observed (Figure 2). In patients with preserved systolic function, soluble neprilysin concentrations in the coronary sinus and systemic vessels were similar, while in those with reduced function, soluble neprilysin concentration and activity were around three-fold higher in the coronary sinus compared with systemic vessels. Thus, the heart plays a pivotal role as a regulator of the endocrine response in systolic dysfunction, not only by releasing natriuretic peptides, but also by contributing to circulating neprilysin, which determines the bioavailability of other numerous vasoactive peptides. Circulating mediators in patients with advanced heart failure with reduced cardiac systolic function undergoing TAH implantation. BNP, B-type natriuretic peptide; MR-proANP, mid-regional pro-atrial natriuretic peptide; proBNP T71-glycosylation, pro-B-type natriuretic peptide glycosylation at threonine 71; sNEP, soluble neprilysin (from Arrigo M, Vodovar N, Nougué H, Sadoune M, Pemberton CJ, Ballan P, Ludes P-O, Gendron N, Carpentier A, Cholley B, Bizouarn P, Cohen-Solal A, Singh JP, Szymonifka J, Latremouille C, Samuel J-L, Launay JM, Pottecher J, Richards AM, Truong QA, Smadja DM, Mebazaa A. The heart regulates the endocrine response to heart failure: cardiac contribution to circulating neprilysin. See pages 1794–1798). Heart transplantation is the last resort in the management of patients with heart failure, and results in complete denervation of the donor heart with loss of afferent and efferent nerve connections. The majority of patients remain completely denervated during the first 6–12 months following transplantation, while some hearts are reinnervated, an issue addressed in a review entitled ‘Re-innervation post-cardiac transplantation’ by Avishay Grupper and colleagues from the Mayo Clinic Minnesota in Rochester, Minnesota, USA.15 Evidence of reinnervation is usually found during the second year after transplantation, and involves the myocardial muscle, sinoatrial node, and coronary vessels, but remains incomplete and regionally limited many years post-transplant. Restoration of cardiac innervation can improve exercise capacity as well as blood flow regulation in the coronary arteries, and hence improve quality of life. As yet, there is no evidence that the reinnervation process is associated with the occurrence of allograft-related events or survival. The importance of the myocardial microcirculation in cardiac conditions is under-regognized,16 but is most probably impaired in infarction,17 and different forms of heart failure,18 inflammatory diseases,19 and may even involve other organs such as the retinal circulation.20 So far it has been challenging to interrogate the microcirculation. Capillary rarefaction constitutes one of the earliest changes of allograft vasculopathy in cardiac allograft recipients, but its identification with coronary flow reserve or intracoronary resistance measurements is hampered because of non-selective interrogation of the capillary bed. In their manuscript ‘Identification of capillary rarefaction using intracoronary wave intensity analysis with resultant prognostic implications for cardiac allograft patients’, Javier Escaned and colleagues from Hospital Clinico Universitario San Carlos in Madrid, Spain investigated the potential of wave intensity analysis to assess capillary rarefaction in 52 allograft patients to predict changes of allograft vasculopathy.21 A significant relationship was noted of capillary density with coronary flow reserve and the backward decompression wave. Patients with a smaller backward decompression wave had an increased risk of developing angiographic allograft vasculopathy (Figure 3). Additionally, the index backward decompression wave was lower in those who went on to have a clinical change of allograft vasculopathy events as well as more severe disease. Thus, in cardiac transplant patients, wave intensity analysis is able to quantify the early changes of allograft vasculopathy and predicts angiographic and clinical outcomes. The clinical implications of the novel findings are discussed in an Editorial by Nico Bruining from Erasmus MC in Rotterdam, The Netherlands.22 Schematic representations of the process of cardiac allograft vasculopathy and the ability of coronary wave intensity analysis to predict rate and severity of angiographic and clinical outcomes. In the first few months following transplantation, more severe capillary rarefaction occurs in those patients who ultimately go on to develop angiographically and clinical severe allograft vasculopathy. This change is quantifiable using wave intensity analysis where the size of the backward decompression wave identifies capillary rarefaction, and therefore predicts the rate and severity of angiographic and clinical disease and could guide screening rates (from Broyd CJ, Hernández-Pérez F, Segovia J, Echavarría-Pinto M, Quirós-Carretero A, Salas C, Gonzalo N, Jiménez-Quevedo P, Nombela-Franco L, Salinas P, Núñez-Gil I, Del Trigo M, Goicolea J, Alonso-Pulpón L, Fernández-Ortiz A, Parker K, Hughes A, Mayet J, Davies J, Escaned J. Identification of capillary rarefaction using intracoronary wave intensity analysis with resultant prognostic implications for cardiac allograft patients. See pages 1807--1814). Inflammation is involved not only in atherosclerosis,23,24 but also in myocardial remodelling, not only in myocarditis,25,26 but also in conditions with neurohumoral activation.27 Chemokine-mediated monocyte infiltration into the damaged myocardium initiates inflammation during cardiac remodelling. In their Basic Science article entitled ‘CXCL1–CXCR2 axis mediates angiotensin II-induced cardiac hypertrophy and remodelling through regulation of monocyte infiltration’, Hui-Hua Li and colleagues from the Institute of Cardiovascular Diseases in Dalian, China investigated the role of the chemokine CXCL1 and its receptor CXCR2 in angiotensin II-induced cardiac remodelling. Angiotensin II was administrated to wild-type mice treated with CXCL1 neutralizing antibody or the CXCR2 inhibitor SB265610, to CXCR2 knockout or bone marrow reconstituted chimeric mice. Microarray revealed that CXCL1 was the most highly up-regulated in the wild-type heart at day 1 after angiotensin II infusion, and CXCR2 expression and CXCR2+ immune cells were time-dependently increased. Administration of CXCL1 neutralizing antibody prevented angiotensin II-induced hypertension, cardiac dysfunction, hypertrophy, fibrosis, and macrophage accumulation compared with the IgG control. Furthermore, angiotensin II-induced remodelling and inflammatory responses were also significantly attenuated in CXCR2 knockout mice and in wild-type mice treated with SB265610 or transplanted with CXCR2-deficienct bone marrow cells. Co-culture experiments in vitro further confirmed that CXCR2 deficiency inhibited macrophage migration and activation, and attenuated angiotensin II-induced myocyte hypertrophy and fibroblast differentiation through multiple signalling pathways. Finally, the circulating CXCL1 level and CXCR2+ monocytes were increased in patients with heart failure. Thus, angiotensin II-induced infiltration of monocytes in the heart is largely mediated by CXCL1–CXCR2 signalling which aggravates cardiac remodelling. Inhibition of CXCL1 and/or CXCR2 may represent new therapeutic targets in hypertensive heart diseases. The manuscript is accompanied by an Editorial by Ernesto L. Schiffrin from the Jewish General Hospital in Montreal, QC Canada.28 Vesicles released from cells and in particular from stem cells exert a variety of biological functions.29,30 In a Basic Science article entitled ‘Acellular therapeutic approach for heart failure: in vitro production of extracellular vesicles from human cardiovascular progenitors’, Nisa Karen Elaine Renault and colleagues from the Paris Centre de Recherche Cardiovasculaire at the Hôpital Européen Georges Pompidou in Paris, France report that extracellular vesicles secreted by embryonic stem cell-derived cardiovascular progenitor cells recapitulate the therapeutic effects of their parent cells in a mouse model of chronic heart failure.31 The authors objectives were to investigate whether extracellular vesicles released by more readily available cell sources are therapeutic, whether their effectiveness is influenced by the differentiation state of the secreting cell, and through which mechanisms they act. Extracellular vesicles secreted by induced pluripotent stem cell (iPSC)-derived cardiovascular progenitor cells and iPSC-derived cardiomyocytes were isolated by ultracentrifugation and characterized. Myocardial infarction was induced in nude mice, and those with left ventricular ejection fraction (LVEF) ≤45% received either transcutaneous echo-guided injections of human iPSC-cardiomyocytes in the peri-infarct myocardium, extracellular vesicles secreted by human iPSC-progenitor cells or saline. In vitro, extracellular vesicles were internalized by target cells, increased endothelial cell survival and migration in a dose-dependent manner, and stimulated tube formation. Extracellular vesicles were rich in microRNA, and most of the 16 highly abundant, evolutionarily conserved microRNAs are associated with tissue repair pathways. In vivo, extracellular vesicles outperformed cell injections and improved cardiac function. Gene profiling revealed that extracellular vesicle-treated hearts were enriched for tissue reparative pathways. Thus, iPSC-progenitor cell-derived extracellular vesicles are effective in experimental heart failure, in part through their specific microRNA signature and stimulation of cardioprotective pathways. The potential use of such vesicles in cardiac conditions is discussed in an Editorial by Joseph C. Wu from Stanford University in California, USA.29 Patients with heart failure often develop atrial fibrillation, which is an important cause of ischaemic stroke.32,33 In their clinical review ‘Cardiac diagnostic work-up of ischaemic stroke’, Hayang Yang and colleagues from the Academic Medical Center at the University of Amsterdam in the Netherlands remind us that cardioembolic sources account for 20–30% of ischaemic strokes.34 As many of their causes can, thanks to new diagnostic and therapeutic developments, be identified and managed, proper work-up of such patients is important due to their prognostic and therapeutic implications. In particular, detection of atrial fibrillation, patent foramen ovale, and aortic as well as carotid plaques is important. Herein, they propose a cardiac diagnostic work-up scheme for patients with ischaemic stroke from definite cardioembolic sources and embolic strokes of undetermined source. The editors hope that this issue of the European Heart Journal will be of interest to its readers.