Authors

• Héctor Bueno — Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain — ORCID: 0000-0003-0277-7596
• Brenda Moura — Cardiology Department, Porto, Portugal — ORCID: 0000-0001-6158-7368
• Patrizio Lancellotti — Department of Cardiology, CHU SartTilman, University of Liège Hospital, Liège, Belgium — ORCID: 0000-0002-0804-8194
• Johann Bauersachs — Department of Cardiology and Angiology, Hannover, Germany — ORCID: 0000-0002-9341-117X

DOI

Full Text

## Introduction Heart failure (HF) prevalence remains high worldwide with significant sex-related and regional differences in its presentation, management, and outcomes. In 2020, advances in biomarkers and imaging techniques were reported for the diagnosis and prognosis of diastolic dysfunction, HF with preserved ejection fraction or monitoring cardiotoxicity; a new definition of HF with recovered left ventricular ejection fraction (LVEF) was released. Benefits of renin–angiotensin–aldosterone system inhibitors and β-blockers may extend to patients with an LVEF up to 55%. Sacubitril–valsartan improved LV remodelling, biomarker levels, and rates of sudden cardiac death. Two studies investigating the sodium-glucose cotransporter 2 inhibitors empagliflozin and sotagliflozin in patients with HF were reported: the EMPEROR-Reduced trial in patients with HF with reduced EF with or without type 2 diabetes (T2DM) demonstrated a significant reduction in cardiovascular (CV) death and HF hospitalisations (HFH). In patients with T2DM and HF across the whole EF spectrum after a recent HFH, the SOLOIST trial showed a reduction in the primary endpoint of CV deaths, total HFH, and urgent visits for HF. In addition, in patients with kidney disease with or without diabetes mellitus (DAPA-CKD), dapagliflozin prevented the deterioration of renal function. Two novel drugs, the activator of soluble guanylate cyclase vericiguat and the myosin activator omecamtiv mecarbil, in the large outcome trials VICTORIA and GALACTIC-HF predominantly reduced HFH in high-risk patients with worsening HF. In the AFFIRM-AHF trial, intravenous ferric carboxymaltose reduced HFH in patients with iron deficiency after an HF decompensation. Year 2020 will be remembered as the year of coronavirus disease of 2019 (COVID-19). The pandemia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a massive impact on global health and economy. When this article is published, >80 million people will have been infected and >1.75 million will have died of the disease. Many others will have died or worsen of their diseases, many with cardiovascular (CV) disease, as an indirect effect of the fear to seek assistance or the collapse of healthcare systems. Yet, advances in science and medical care continued developing during the year. This article reviews important advances in the field of heart failure (HF) presented in 2020. ## Epidemiology More than 64 million people are living with HF in the world, with an estimated prevalence of 1–2% among adults in developed countries, most often with several comorbidities. (1) The incidence of HF may be stabilizing globally, with decreases in higher-income countries, (2) but increases in lower-income countries, and a shift towards HF with preserved ejection fraction (HFpEF), and increasing due to population ageing and the increase in obesity. (1) Age, traditional risk factors for HF, a sedentary lifestyle, and social deprivation are associated with incident HF. (3) Actually, lifestyle and social determinants of health are attracting more attention in the epidemiology and care of patients with HF. (4) In patients with new-onset HF, the most common first events are cardiac events (36%), recurrent HF (28%), and death (29%). (5) Non-traditional risk factors, such as pacemaker implantation may play a role in the development of HF: within the first 2 years after implantation in patients without known HF, the incidence of fatal and non-fatal HF is 10.6%, six times higher than for age- and gender-matched individuals without HF and pacemaker. (6) Mortality rates of HF seem to be declining less rapidly than previously in the general population. (1) Among patients with cardiac resynchronization therapy (CRT), a gradual decrease in sudden cardiac death risk has been observed since the early 2000s (7) with implications for the role of implantable defibrillators and the design of comprehensive HF care models. Significant regional differences in the management of acute HF have been identified, including timing and types of treatments used, (8) and rates and time trends of readmission. (2, 9, 10) However, the importance of distinguishing worsening/chronic HF from new-onset HF in patients with first hospitalization has been highlighted, as patients with worsening/chronic HF have a significantly greater comorbidity burden and higher adjusted risks of mortality and HF readmission. (10, 11) ## Clinical aspects ## Diagnostics and risk stratification ## Imaging Imaging is pivotal in the diagnosis and risk stratification of patients with HF. The European Society of Cardiology (ESC) Heart Failure Association (HFA) has recently highlighted in a position statement the central role of full echocardiographic examination in patients admitted for acute heart failure (AHF). (12) Once the patient is stabilized, the added value of routine cardiac magnetic resonance (CMR) over echocardiography alone to help diagnose the causes of HF not related to ischaemic heart disease has been questioned. (13) Selective rather than routine CMR for identifying specific HF aetiologies is more cost effective. Noteworthy, CMR could serve to better define HFpEF phenotypes and to select patient specific therapies, such as MRA may be for HFpEF patients with myocardial fibrosis. (14-17) The diagnosis of HFpEF remains challenging especially in patients with coexisting conditions that account for dyspnoea. Diastolic dysfunction, left atrial enlargement, elevated left atrial pressure, and pulmonary hypertension are common in these patients. (18, 19) The 2016 diastolic dysfunction grading algorithm proposed by the European Association of Cardiovascular Imaging has shown improved prognostic value compared to the 2009 one. (20) However, the high number of patients with doubtful classification renders clinical decision making challenging. (21) The analysis of LA mechanics, LA strain, and left ventricular (LV) global longitudinal strain (22) allows to better classify the degree of diastolic dysfunction and improves individual risk stratification. Two algorithms (H2FPEF and ESC HFA-PEFF) may facilitate HFpEF diagnosis. These two scores have equivalent predictive power of incident HF hospitalization or death among patients without a clinical diagnosis of HF. (23) Although LV ejection fraction (LVEF) is key for HF classification, it remains a crude estimate of LV function. Intriguingly, 17% of patients with initially preserved LV systolic function show a decrease in LVEF below 40% at 6 months follow-up, which is associated with more cardiac events. (24) Parameters of LV mechanics (LV strain, multilayer strain and myocardial work) provide incremental prognostic information over LVEF. (22, 25) The benefit of treatment [i.e. sacubitril/valsartan (SV)] on LV remodelling is also better captured by LV strain. (26) Myocardial mechanics is linked to coronary microvascular dysfunction in patients with hypertensive HF. (27, 28) In AHF, cardiac sympathetic nerve dysfunction, as evaluated by 123I-metaiodobenzylguanidine imaging, is associated with poor outcome irrespective of LVEF. (29) ## Biomarkers Biomarkers are key for diagnosis and prognostic evaluation in patients with HF. Circulating biomarkers related to extracellular matrix regulation were abnormal in patients with HFpEF, displayed prognostic value, and were influenced favourably by SV in PARAGON-HF. (30) In HF with reduced LVEF (HFrEF), absolute NT-proBNP, hs-TnT, and sST2 levels predict outcomes independent of age, sex, and LVEF category. (31) Differential circulating levels of biomarkers associated with ageing in patients with HF have been reported, with increasing levels of proteins associated with extracellular matrix organization, inflammatory processes, and tumour cell regulation and lower expression of tumour proliferation functions. (32) In AHF, a specific challenge is to identify infection as a trigger of AHF. Procalcitonin (PCT) has emerged as an alternative for C-reactive protein in diagnosing bacterial infection. In a recent randomized, multicentre, open study, a strategy of PCT-guided initiation of antibiotic therapy was more effective than standard care in improving clinical outcomes. (33) Omics phenotyping is likely the next frontier to unravel disease mechanisms and heterogeneity. (34) As a recent example, incorporating a panel of three metabolite-based biomarkers into a risk score improved the prognostic utility of NT-proBNP by predicting long-term CV death. (35) ## Heart failure during the COVID-19 pandemic The role of the angiotensin-converting enzyme (ACE) receptor 2 in the infection of human cells by SARS-CoV-2 and in the pathophysiology of COVID-19, (36) and the poor prognosis of cardiac patients with COVID-19 (37) raised the concern of a potential deleterious effect of the treatment with ACE inhibitors and angiotensin receptor blockers (ARB). These drugs may either decrease acute lung damage, prevent angiotensin-II-mediated pulmonary inflammation or increase the SARS-CoV-2 pulmonary damage by the up-regulation of ACE2 receptors. (38, 39) Observational studies refuted the hypothesis of a deleterious effect of ACEI/ARB. (40-43) The BRACE CORONA trial found no worse outcomes in patients with COVID-19 allocated to continuation or interruption of their chronic ACEI/ARB treatment (presented at the ESC Congress, data not published). The incidence of AHF or decompensation of chronic HF among patients with Covid-19 is high and with poor prognosis. (44) Indirect effects of the pandemic included the reduction in HF hospitalizations during local outbreaks (45-47) with increases in their hospital mortality, (45, 47) and major challenges for the management and Follow-up of HF patients, and the conduct of clinical trials. Recommendations to overcome these challenges have been released. (48-50) ## Sex and heart failure Women account for half of patients with HF with a lower incidence rate until the age of 75 years, a higher proportion of HFpEF, probably related to the higher prevalence of obesity and diabetes mellitus. (1) Women with HF present a greater symptom burden and poorer quality of life as compared with men. (51) Significant sex-related differences have been described in Europe in the management of acute and chronic HF (8, 52) including a lower use of guideline-directed medical therapies—which seem to be mostly explained by older age and comorbidity rather than by sex itself—with lower crude rates of death and HF hospitalization in women. The lack of sex-related differences in the clinical effect of HF therapies (53, 54) does not justify these differences, although the possibility has been suggested that women with HF might benefit from treatment to a higher level of LVEF than previously considered. (54) A different perspective of the gender gap in HF is the lower proportion of female authors in HF practice guidelines and trials, ranging between 11% and 24% only, with modest increases over time in European and US guidelines references but not in HF trials. Importantly, HF trials with a woman first or senior author are associated with a higher proportion of enrolled female participants. (55) ## Comorbidities Comorbidities are important because they impact the clinical presentation, management, and outcomes of HF patients. The burden of comorbidities is higher in older patients, women and those with HFpEF, (56-58) which are often ignored. (59) Particularly relevant conditions in HF patients include atrial fibrillation, (60) which has complex interrelations with HF needing more research. (61, 62) One example is the lack of increase in mortality risk associated with elevated heart rate in patients with HFrEF and atrial fibrillation, as compared to sinus rhythm. (60, 63) Renal disease is one other, with renal function often changing during the course of the disease or as a response to HF therapies. Clinical responses, including worsening renal function and pseudo-worsening renal function, and their pathophysiological correlates, i.e. tubular function (diuretic response) beyond estimated glomerular filtration rate (eGFR), need to be understood to be properly managed, adapting therapies to the changing situation. (64, 65) ## Specific situations ## Acute heart failure In patients with acute HFrEF, istaroxime, an inhibitor of the sarcolemmal Na+/K+ pump activating the SERCA2a pump, improved cardiac function without major adverse effects in a small mechanistic trial. (66) Cimlanod, a nitroxyl donor infused over 48 h, was reasonably well tolerated at a lower dose whereas higher doses caused unacceptable hypotension. There was improvement of NT-ProBNP but not on dyspnoea (presented at HFA Discoveries, data not published). A number of position papers have summarized the role of imaging (12) or the management of AHF in specific situations, such as acute coronary syndromes (67) or atrial fibrillation. (68) ## Cardiogenic shock While its incidence seems to be decreasing, cardiogenic shock still conveys a high mortality risk. (69) A new clinical classification, (70) and two position papers (71, 72) on cardiogenic shock have been published this year. The SWEdish evaluation of left Ventricular Assist Device (SweVAD) will examine the impact of mechanical circulatory support vs. guideline-directed medical therapy on survival in a population of AHF patients ineligible for heart transplant. (73) ## Peripartum cardiomyopathy Peripartum cardiomyopathy (PPCM) is the first cause of HF in women during/after pregnancy (74-76) The ESC EORP registry on PPCM enrolled >700 women with this condition from 49 countries. It showed that PPCM affects women from any region or ethnicity. Within 6 months after diagnosis, the average rates of maternal mortality, readmission, and neonatal mortality were, respectively, 6%, 10%, and 5%, with marked regional variations. Recovery of LVEF occurred in 46% of women. (77) The management of these patients is reviewed in a recent paper. (78) ## HF with recovered left ventricular ejection fraction This year, a working definition of HF with recovered left ventricular ejection fraction (HFrecEF) has been proposed. This includes: (i) documentation of a decreased LVEF 40%. (79) Reverse LV remodelling is associated with improved myocyte and LV chamber contractility and better clinical outcomes. However, a significant proportion of patients with HFrecEF develop recurrences of LV dysfunction and HF. Despite improvements in structural and functional abnormalities, many of the multilevel molecular changes occurring during LV remodelling remain dysregulated in reverse remodelled hearts. Therefore, guideline-directed medical and device therapy for patients with HFrecEF should be continued indefinitely with close clinical follow-up. (79) ## HF in cancer patients The role of CV imaging in cancer patients receiving cardiotoxic therapies has been highlighted in a position statement by the HFA (12) and in the European Society for Medical Oncology guidelines. (80) The role of focus echocardiography (81) and CMR (82) has also been recently discussed. In daily practice, caution should, however, be given if using late gadolinium enhancement or qualitative T2-weighted STIR imaging-only approach for the exclusion of checkpoint inhibitor-associated myocarditis. (83) Imaging is cornerstone for monitoring cardiotoxicity and identifying subtle impairment of myocardial function occurring prior crossing the traditionally defined threshold of LV systolic dysfunction (LVEF 40%), highest among chronic lung disease patients. (88) The presence of RVD at CRT implantation predicts worsening LV remodelling and survival. (89) ## Pharmacotherapies ## Angiotensin receptor–neprilysin inhibitors (paragon, paradigm, parallax) Angiotensin receptor–neprilysin inhibitor (ARNI) showed, in a sub-analysis of PARADIGM-HF, a reduction in sudden cardiac death risk regardless of the use of implantable cardiac defibrillators. (90) Reduction in ventricular volumes and increase in LVEF have been observed with standard echocardiography in patients after 6 months on SV, but improvement in global longitudinal strain is apparent after 3 months. (26) In a small cohort of patients with end stage renal disease, SV showed efficacy and safety. (91) The LIFE Trial, comparing SV to valsartan in NYHA Class IV HFREF patients, although prematurely interrupted because of the COVID 19 pandemia, will still provide information about ARNI as a treatment option for advanced HF patients. (92) The PARALLAX trial tested the efficacy of SV vs. optimal individualised background therapy in HFpEF patients and found a reduction in NT-proBNP from baseline to 12 weeks but no effect on six-minute walk distance from baseline to 24 weeks (presented at ESC 2020—data not published). In the PARAGON Trial in patients with HFpEF, SV did not result in a lower rate of total hospitalizations for HF and death. Of the 12 pre-specified subgroup analyses, sex and LVEF appeared to modify the effect of SV vs. valsartan on the primary composite outcome. Although no benefit was apparent in men, there was a significant reduction in HF hospitalizations in women. (93) Also, patients seemed to derive more benefit from SV when started early after hospitalization. (94) Baseline and mean achieved systolic blood pressure of 120–129 mm Hg identified the lowest risk HFpEF patients, but the blood pressure-lowering effects of SV did not account for its effects on outcomes, regardless of sex. (95) Compared with valsartan, SV reduced the risk of renal events and slowed the decline in estimated glomerular filtration rate. (96) Reduction in serum uric acid was also associated with improved outcomes. (97) A meta-analysis assessing the efficacy of different renin–angiotensin–aldosterone system (RAAS) antagonists in clinical trials performed in HFpEF patients (PEP-CHF, CHARM-preserved, I-PRESERVE, TOPCAT, PARAGON-HF) showed no statistical difference in all-cause and CV mortality among RAAS antagonists and placebo, but a significantly decreased risk in HF hospitalizations in patients allocated to receive ARNI compared with controls (OR, 0.73, 95% CI, 0.61–0.87) and ARB (OR 0.80, 95% CI, 0.71–0.91). (98) A patient-level data analysis from the PARADIGM-HF and PARAGON-HF trials (SV vs. enalapril in HFrEF and SV vs. valsartan in HFpEF, respectively), and the CHARM-Alternative and CHARM-Preserved trials (candesartan vs. placebo) showed that, compared with RAAS inhibitors, SV improved outcomes across the range of LVEF, with a risk reduction (RR) of 0.54 [95% confidence interval (CI) 0.45–0.65] for the recurrent primary endpoint compared with putative placebo (P 60%. (99) These results are in line with prior post hoc analyses from the TOPCAT study and β-blocker trials suggesting that the cut-off of LVEF for a beneficial treatment effects is 55%. These analyses show that in the sparsely studied population of patients with an LVEF of 40–55%, several HF treatments might provide benefit (**Figure 1**). (100) FIGURE 1. Results from different trials testing a number of drugs commonly used to treat heart failure, pointing to an extended benefit up to a left ventricular ejection fraction of 55%. For patients with left ventricular ejection fraction >55%, a population group usually presenting several comorbidities, there is still no evidence of a drug improving prognosis. Reprinted from Böhm et al. (100) (from Bueno H, Moura B, Lancellotti P, Bauersachs J. The year in cardiovascular medicine 2020: heart failure and cardiomyopathies. Eur Heart J. 2021 Feb 11;42(6):657-670. https://doi.org/10.1093/eurheartj/ehaa1061, by permission of OUP on behalf of the ESC) ## Sodium-glucose cotransporter 2 inhibitors (EMPEROR-Reduced, DAPA-HF, SOLOIST, VERTIS, SUGAR-DM-HF, EMPA-TROPISM [ATRU-4]) In patients with type 2 diabetes, the sodium-glucose cotransporter 2 (SGLT-2) inhibitors empagliflozin and dapagliflozin reduce the risk of HF hospitalization regardless of baseline CV risk or history of HF. (101, 102) In The VERTIS trial, ertugliflozin did neither significantly reduce CV events, nor the combined endpoint of CV death/HF hospitalization (103) but reduced HF hospitalizations. (104) In patients with HFrEF, DAPA-HF has demonstrated a significant reduction in CV mortality and HF events. (105, 106) This robust effect was analysed in more detail in several seminal papers published in 2020. The benefit of dapagliflozin was independent of the diabetes status, occurring across all levels of HbA1C, (107) as well as of baseline renal function or blood pressure, patient age, or background HF therapy. (108–111) Dapagliflozin improved symptoms, physical function, and quality of life (112) and was shown to be a cost-effective treatment for HFrEF in the UK, German, and Spanish healthcare systems. (113) Dapagliflozin also reduces the rate of decline in renal function in HFrEF patients. (111) as well as in patients with chronic kidney disease, as shown in the DAPA-CKD trial, where treatment with dapagliflozin reduced the risk of worsening renal function, end-stage kidney disease, or death. (111) This protective effect was observed in patients with or without diabetes. (111, 114) Empagliflozin also showed marked beneficial effects in HFrEF patients independently from diabetes status, with a significant reduction in the primary composite endpoint of CV death and HF events (hazard ratio (HR), 0.75; 95% CI, 0.65–0.86; P 2 of body-surface area per year, P 50%. (123) Sotagliflozin was also investigated in patients with type 2 diabetes, chronic kidney disease, and elevated CV risk (SCORED); (124) primary endpoint (changed during the study to a composite of CV death, total HF hospitalizations and urgent visits for HF) was significantly reduced in patients treated with sotagliflozin (HR, 0.67; 95% CI, 0.52–0.85; P 2 nor other predefined outcome parameters. (131) ## Cardiac myosin activators and inhibitors ## Omecantiv mecarbil (GALACTIC-HF, EXPLORER-HCM) Omecamtiv mecarbil, a cardiac myosin activator that enhances cardiomyocyte contraction, given twice daily on the basis of plasma levels of the drug, significantly reduced the primary endpoint of HF hospitalisation and CV death in patients with HFrEF and a recent HF event (HR, 0.92; 95% CI, 0.86–0.99; P = 0.03) but had no impact on any of the secondary outcomes (CV death, change in symptom score, first HF hospitalization, and death from any cause). (132) A similar compound, danicamtiv, increased stroke volume, improved global longitudinal and circumferential strain, decreased LA minimal volume index, and increased LA function index when compared to placebo in a small phase 2a trial in 40 patients with stable HFrEF. (133) On the other hand, mavacamten, a myosin inhibitor, significantly improved the combined primary endpoint of increase in peak oxygen consumption (pVO2) and reduction in NYHA class in a phase 3 trial in patients with obstructive hypertrophic cardiomyopathy. Also, outflow tract obstruction and health status were improved. (134) ## Other therapies ## Ferric carboxymaltose (AFFIRM-AHF) In iron-deficient patients hospitalized for acute HF (AFFIRM-AHF), (135) intravenous ferric carboxymaltose compared to placebo was associated with a trend to reduced total HF hospitalizations and CV death (rate ratio 0.79, 95% CI 0.62–1.01, P = 0·059). In a pre-specified sensitivity analysis considering the impact of the COVID-19 pandemic, a statistically significant difference in favour of ferric carboxymaltose was reported for the primary endpoint was reported, but not in CV death risk. (136) ## MicroRNA-132 inhibition In a first clinical trial limited by a small number of HF patients, the antisense oligonucleotide drug directed against miR-132, CDR132L, (137) was well tolerated and showed first hints for a cardiac functional improvement. (138) ## Comprehensive disease-modifying pharmacological therapies Using data from the EMPHASIS-HF, PARADIGM-HF, and DAPA-HF trials lifetime gains in survival have been estimated with comprehensive therapy (SV, β-blocker, MRA, and SGLT-2 inhibitor) vs. RAAS and β-blockers in patients with chronic HFrEF. (11, 139) The HR for the composite endpoint of CV death or hospitalisation for HF was 0.38 (95% CI 0.30–0.47). Favourable results were also calculated for CV death alone, hospitalization for HF alone, and all-cause mortality. Comprehensive therapy could prolong overall survival 6.3 years in average in a 55-year-old patient. These results support the combination use of SV, β-blockers, mineralocorticoid receptor antagonists, and SGLT-2 inhibitors as a new therapeutic standard. ## Device/interventional therapies ## Secondary (or functional) mitral regurgitation (COAPT) Secondary (or functional) mitral regurgitation (SMR) occurs frequently in HFrEF and is associated with progressive symptoms and worse prognosis. If SMR is treated by edge-to-edge repair, patients with optimal result at discharge and 12-month follow-up displayed best outcomes. (140) ## Cardiac resynchronization therapy (STOP-CRT) Cardiac resynchronization therapy (STOP-CRT) is an integral part of treatment in patients with HFrEF, especially with left bundle branch block and wide QRS. In a selected cohort of patients with LVEF >50% during CRT and neurohormonal blockade, the STOP-CRT study investigated the feasibility and safety of neurohormonal blocker withdrawal. The incidence of adverse LV remodelling or clinical outcomes was low after discontinuation of betablockade/RAAS inhibition. However, comorbidities prompted the continuation of neurohormonal blockers in many patients. (141) In patients with HFrEF who are ineligible for CRT, baroreflex activation therapy (BAT) may be useful in addition to optimal drug therapy. In the BeAT-HF study, BAT was safe and significantly improved symptoms, quality of life, exercise capacity, and NT-proBNP. (142) On the basis of these data, BAT was approved in the USA, while ongoing follow-up in the BeAT-HF study will assess effects on hard outcomes. ## Specific management issues ## Telemedicine and remote monitoring The role of telemedicine and remote monitoring in the management of HF patients is still controversial. An observational study in three European countries showed that pulmonary artery pressure-guided HF management is feasible and safe and associated with better outcomes haemodynamic and clinical outcomes. (143) Also, preliminary results testing non-invasive remote physiological monitoring from a wearable sensor showed promising results in the early detection of impending HF rehospitalisation. (144) However, different modes of remote monitoring failed to show a benefit in improving treatment, quality of life, (145) or clinical outcomes. (146) Moreover, remote monitoring with a cardiac implanted electronic device increased clinical activity for patients with HF and AF, with no associated reduction in mortality, and conversely, greater risk of CV hospitalisation amongst patients with persistent/permanent AF. (147) In the COVID-19 era, remote monitoring is a useful tool for managing HF patients. (148) ## Self-care and palliative care Self-care is essential in the management of chronic HF. Practical advice for key activities and priorities for self-care is given in an HFA manuscript. (149) At the end of the HF pathway, palliative care should be introduced early, focusing on symptom management, (150) regardless of prognosis, but actually only a minority in Europe receive it. (151) Providing palliative care substantially reduces hospitalizations, with no clear adverse effect on survival. (152)

Literature

1. Groenewegen A, Rutten FH, Mosterd A, Hoes AW. Epidemiology of heart failure. Eur J Heart Fail. 2020;22:1342–56. https://doi.org/10.1002/ejhf.1858
2. Sulo G, Igland J, Øverland S, Egeland GM, Roth GA, Vollset SE, et al. Heart failure in Norway, 2000-2014: analysing incident, total and readmission rates using data from the Cardiovascular Disease in Norway (CVDNOR) Project. Eur J Heart Fail. 2020;22:241–8. https://doi.org/10.1002/ejhf.1609
3. Uijl A, Koudstaal S, Direk K, Denaxas S, Groenwold RHH, Banerjee A, et al. Risk factors for incident heart failure in age- and sex-specific strata: a population-based cohort using linked electronic health records. Eur J Heart Fail. 2019;21:1197–206. https://doi.org/10.1002/ejhf.1350
4. White-Williams C, Rossi LP, Bittner VA, Driscoll A, Durant RW, Granger BB, et al.; On behalf of theAmerican Heart Association Council on Cardiovascular and Stroke Nursing. Council on Clinical Cardiology; and Council on Epidemiology and Prevention. Addressing social determinants of health in the care of patients with heart failure: a scientific statement from the American Heart Association. Circulation. 2020;141:e841–63. [Jun]. https://doi.org/10.1161/CIR.0000000000000767
5. Velagaleti RS, Larson MG, Enserro D, Song RJ, Vasan RS. Clinical course after a first episode of heart failure: insights from the Framingham Heart Study. Eur J Heart Fail. 2020;22:1768–76. https://doi.org/10.1002/ejhf.1918
6. Tayal B, Fruelund P, Sogaard P, Riahi S, Polcwiartek C, Atwater BD, et al. Incidence of heart failure after pacemaker implantation: a nationwide Danish Registry-based follow-up study. Eur Heart J. 2019;40:3641–8. https://doi.org/10.1093/eurheartj/ehz584
7. Barra S, Providência R, Narayanan K, Boveda S, Duehmke R, Garcia R, et al. Time trends in sudden cardiac death risk in heart failure patients with cardiac resynchronization therapy: a systematic review. Eur Heart J. 2020;41:1976–86. https://doi.org/10.1093/eurheartj/ehz773
8. Motiejūnaitė J, Akiyama E, Cohen-Solal A, Maggioni AP, Mueller C, Choi DJ, et al. The association of long-term outcome and biological sex in patients with acute heart failure from different geographic regions. Eur Heart J. 2020;41:1357–64. https://doi.org/10.1093/eurheartj/ehaa071
9. Parizo JT, Kohsaka S, Sandhu AT, Patel J, Heidenreich PA. Trends in readmission and mortality rates following heart failure hospitalization in the Veterans Affairs Health Care System from 2007 to 2017. JAMA Cardiol. 2020;5:1042–7. https://doi.org/10.1001/jamacardio.2020.2028
10. Butt JH, Fosbøl EL, Gerds TA, Andersson C, McMurray JJV, Petrie MC, et al. Readmission and death in patients admitted with new-onset versus worsening of chronic heart failure: insights from a nationwide cohort. Eur J Heart Fail. 2020;22:1777–85. https://doi.org/10.1002/ejhf.1800
11. Jhund PS. The recurring problem of heart failure hospitalisations. Eur J Heart Fail. 2020;22:249–50. https://doi.org/10.1002/ejhf.1721
12. Čelutkienė J, Lainscak M, Anderson L, Gayat E, Grapsa J, Harjola VP, et al. Imaging in patients with suspected acute heart failure: timeline approach position statement on behalf of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2020;22:181–95. https://doi.org/10.1002/ejhf.1678
13. Paterson DI, Wells G, Erthal F, Mielniczuk L, O’Meara E, White J, et al. OUTSMART HF: a randomized controlled trial of routine versus selective cardiac magnetic resonance for patients with nonischemic heart failure (IMAGE-HF 1B). Circulation. 2020;141:818–27. https://doi.org/10.1161/CIRCULATIONAHA.119.043964
14. Quarta G, Gori M, Iorio A, D’Elia E, Moon JC, Iacovoni A, et al. Cardiac magnetic resonance in heart failure with preserved ejection fraction: myocyte, interstitium, microvascular, and metabolic abnormalities. Eur J Heart Fail. 2020;22:1065–75. https://doi.org/10.1002/ejhf.1961
15. Pezel T, Viallon M, Croisille P, Sebbag L, Bochaton T, Garot J, et al. Imaging interstitial fibrosis, left ventricular remodeling, and function in stage A and B heart failure. JACC Cardiovasc Imaging. 2020;•••: [cited 2020 December 24]. https://doi.org/10.1016/j.jcmg.2020.05.036
16. Emrich T, Hahn F, Fleischmann D, Halfmann MC, Düber C, Varga‐Szemes A, et al. T1 and T2 mapping to detect chronic inflammation in cardiac magnetic resonance imaging in heart failure with reduced ejection fraction. ESC Heart Fail. 2020;7:2544–52. https://doi.org/10.1002/ehf2.12830
17. Chamsi-Pasha MA, Zhan Y, Debs D, Shah DJ. CMR in the evaluation of diastolic dysfunction and phenotyping of HFpEF: current role and future perspectives. JACC Cardiovasc Imaging. 2020;13:283–96. https://doi.org/10.1016/j.jcmg.2019.02.031
18. Putko BN, Savu A, Kaul P, Ezekowitz J, Dyck JR, Anderson TJ, et al. Left atrial remodelling, mid-regional pro-atrial natriuretic peptide, and prognosis across a range of ejection fractions in heart failure. Eur Heart J Cardiovasc Imaging. 2021;•••: [cited 2020 December 24]. https://doi.org/10.1093/ehjci/jeaa041
19. Guazzi M, Ghio S, Adir Y. Pulmonary hypertension in HFpEF and HFrEF: JACC review topic of the week. J Am Coll Cardiol. 2020;76:1102–11. https://doi.org/10.1016/j.jacc.2020.06.069
20. Lin TT, Wang YC, Juang JM, Hwang JJ, Wu CK. Application of the newest European Association of Cardiovascular Imaging Recommendation regarding the long-term prognostic relevance of left ventricular diastolic function in heart failure with preserved ejection fraction. Eur Radiol. 2020;30:630–9. https://doi.org/10.1007/s00330-019-06261-1
21. Romano G, Magro S, Agnese V, Mina C, Di Gesaro G, Falletta C, et al. Echocardiography to estimate high filling pressure in patients with heart failure and reduced ejection fraction. ESC Heart Fail. 2020;7:2268–77. https://doi.org/10.1002/ehf2.12748
22. Tanacli R, Hashemi D, Neye M, Motzkus LA, Blum M, Tahirovic E, et al. Multilayer myocardial strain improves the diagnosis of heart failure with preserved ejection fraction. ESC Heart Fail. 2020;7:3240–5. https://doi.org/10.1002/ehf2.12826
23. Selvaraj S, Myhre PL, Vaduganathan M, Claggett BL, Matsushita K, Kitzman DW, et al. Application of diagnostic algorithms for heart failure with preserved ejection fraction to the community. JACC Heart Fail. 2020;8:640–53. https://doi.org/10.1016/j.jchf.2020.03.013
24. Yoshihisa A, Sato Y, Kanno Y, Takiguchi M, Yokokawa T, Abe S, et al. Prognostic impacts of changes in left ventricular ejection fraction in heart failure patients with preserved left ventricular ejection fraction. Open Heart. 2020;7:e001112. https://doi.org/10.1136/openhrt-2019-001112
25. Wang CL, Chan YH, Wu VC, Lee HF, Hsiao FC, Chu PH. Incremental prognostic value of global myocardial work over ejection fraction and global longitudinal strain in patients with heart failure and reduced ejection fraction. Eur Heart J Cardiovasc Imaging. 2021;•••:. https://doi.org/10.1093/ehjci/jeaa162
26. Mazzetti S, Scifo C, Abete R, Margonato D, Chioffi M, Rossi J, et al. Short-term echocardiographic evaluation by global longitudinal strain in patients with heart failure treated with sacubitril/valsartan. ESC Heart Fail. 2020;7:964–72. https://doi.org/10.1002/ehf2.12656
27. Zhou W, Brown JM, Bajaj NS, Chandra A, Divakaran S, Weber B, et al. Hypertensive coronary microvascular dysfunction: a subclinical marker of end organ damage and heart failure. Eur Heart J. 2020;41:2366–75. https://doi.org/10.1093/eurheartj/ehaa191
28. Escaned J, Lerman LO. Coronary microcirculation and hypertensive heart failure. Eur Heart J. 2020;41:2376–8. https://doi.org/10.1093/eurheartj/ehaa437
29. Seo M, Yamada T, Tamaki S, Watanabe T, Morita T, Furukawa Y, et al. Prognostic significance of cardiac I-123-metaiodobenzylguanidine imaging in patients with reduced, mid-range, and preserved left ventricular ejection fraction admitted for acute decompensated heart failure: a prospective study in Osaka Prefectural Acute. Eur Heart J Cardiovasc Imaging. 2021;•••: [cited 2020 December 24]. https://doi.org/10.1093/ehjci/jeaa025
30. Cunningham JW, Claggett BL, O’Meara E, Prescott MF, Pfeffer MA, Shah SJ, et al. Effect of sacubitril/valsartan on biomarkers of extracellular matrix regulation in patients with HFpEF. J Am Coll Cardiol. 2020;76:503–14. https://doi.org/10.1016/j.jacc.2020.05.072
31. Aimo A, Januzzi JL, Vergaro G, Richards AM, Lam CSP, Latini R, et al. Circulating levels and prognostic value of soluble ST2 in heart failure are less influenced by age than N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T. Eur J Heart Fail. 2020;22:2078–88. https://doi.org/10.1002/ejhf.1701
32. Ferreira JP, Ouwerkerk W, Santema BT, van Veldhuisen DJ, Lang CC, Ng LL, et al. Differences in biomarkers and molecular pathways according to age for patients with HFrEF. Cardiovasc Res. 2020;•••:. https://doi.org/10.1093/cvr/cvaa279
33. Möckel M, Boer RA, Slagman AC, Haehling S, Schou M, Vollert JO, et al. Improve management of acute heart failure with ProcAlCiTonin in EUrope: results of the randomized clinical trial IMPACT EU Biomarkers in Cardiology (BIC) 18. Eur J Heart Fail. 2020;22:267–75. https://doi.org/10.1002/ejhf.1667
34. Bayes-Genis A, Liu PP, Lanfear DE, de Boer RA, González A, Thum T, et al. Omics phenotyping in heart failure: the next frontier. Eur Heart J. 2020;41:3477–84. https://doi.org/10.1093/eurheartj/ehaa270
35. McGranaghan P, Düngen HD, Saxena A, Rubens M, Salami J, Radenkovic J, et al. Incremental prognostic value of a novel metabolite-based biomarker score in congestive heart failure patients. ESC Heart Fail. 2020;7:3029–39. https://doi.org/10.1002/ehf2.12928
36. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271–280.e8. https://doi.org/10.1016/j.cell.2020.02.052
37. Inciardi RM, Adamo M, Lupi L, Cani DS, Di Pasquale M, Tomasoni D, et al. Characteristics and outcomes of patients hospitalized for COVID-19 and cardiac disease in Northern Italy. Eur Heart J. 2020;41:1821–9. https://doi.org/10.1093/eurheartj/ehaa388
38. Sama IE, Ravera A, Santema BT, van Goor H, ter Maaten JM, Cleland JGF, et al. Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors. Eur Heart J. 2020;41:1810–7. https://doi.org/10.1093/eurheartj/ehaa373
39. Tomasoni D, Italia L, Adamo M, Inciardi RM, Lombardi CM, Solomon SD, et al. COVID-19 and heart failure: from infection to inflammation and angiotensin II stimulation. Searching for evidence from a new disease. Eur J Heart Fail. 2020;22:957–66. https://doi.org/10.1002/ejhf.1871
40. de Abajo FJ, Rodríguez-Martín S, Lerma V, Mejía-Abril G, Aguilar M, García-Luque A, et al. Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study. Lancet. 2020;395:1705–14. https://doi.org/10.1016/S0140-6736(20)31030-8
41. Bean DM, Kraljevic Z, Searle T, Bendayan R, Kevin O, Pickles A, et al. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are not associated with severe COVID-19 infection in a multi-site UK acute hospital trust. Eur J Heart Fail. 2020;22:967–74. https://doi.org/10.1002/ejhf.1924
42. Reynolds HR, Adhikari S, Pulgarin C, Troxel AB, Iturrate E, Johnson SB, et al. Renin-angiotensin-aldosterone system inhibitors and risk of Covid-19. N Engl J Med. 2020;382:2441–8. https://doi.org/10.1056/NEJMoa2008975
43. Mancia G, Rea F, Ludergnani M, Apolone G, Corrao G. Renin-angiotensin-aldosterone system blockers and the risk of Covid-19. N Engl J Med. 2020;382:2431–40. https://doi.org/10.1056/NEJMoa2006923
44. Rey JR, Caro-Codón J, Rosillo SO, Iniesta ÁM, Castrejón-Castrejón S, Marco-Clement I, et al. Heart failure in Covid-19 patients: prevalence, incidence and prognostic implications. Eur J Heart Fail. 2020;•••:. https://doi.org/10.1002/ejhf.1990
45. Bromage DI, Cannatà A, Rind IA, Gregorio C, Piper S, Shah AM, et al. The impact of COVID-19 on heart failure hospitalization and management: report from a Heart Failure Unit in London during the peak of the pandemic. Eur J Heart Fail. 2020;22:978–84. https://doi.org/10.1002/ejhf.1925
46. Andersson C, Gerds T, Fosbøl E, Phelps M, Andersen J, Lamberts M, et al. Incidence of new-onset and worsening heart failure before and after the COVID-19 epidemic lockdown in Denmark: a nationwide cohort study. Circ Heart Fail. 2020;13:e007274. https://doi.org/10.1161/CIRCHEARTFAILURE.120.007274
47. Cannatà A, Bromage DI, Rind IA, Gregorio C, Bannister C, Albarjas M, et al. Temporal trends in decompensated heart failure and outcomes during COVID-19: a multisite report from heart failure referral centres in London. Eur J Heart Fail. 2020;•••: [cited 2020 December 24]. https://doi.org/10.1002/ejhf.1986
48. Zhang Y, Coats AJS, Zheng Z, Adamo M, Ambrosio G, Anker SD, et al. Management of heart failure patients with COVID-19: a joint position paper of the Chinese Heart Failure Association & National Heart Failure Committee and the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2020;22:941–56. https://doi.org/10.1002/ejhf.1915
49. D’Amario D, Restivo A, Canonico F, Rodolico D, Mattia G, Francesco B, et al. Experience of remote cardiac care during the COVID-19 pandemic: the V-LAPTM device in advanced heart failure. Eur J Heart Fail. 2020;22:1050–2. https://doi.org/10.1002/ejhf.1900
50. Anker SD, Butler J, Khan MS, Abraham WT, Bauersachs J, Bocchi E, et al. Lindenfeld JAnn, McMurray JJV, Mehra M, Metra M, Packer M, Pieske B, Pocock SJ, Ponikowski P, Rosano GMC, Teerlink JR, Tsutsui H, Van Veldhuisen DJ, Verma S, Voors AA, Wittes J, Zannad F, Zhang J, Seferovic P, Coats AJS. Conducting clinical trials in heart failure during (and after) the COVID-19 pandemic: an Expert Consensus Position Paper from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J. 2020;41:2109–17. https://doi.org/10.1093/eurheartj/ehaa461
51. Truby LK, O’Connor C, Fiuzat M, Stebbins A, Coles A, Patel CB, et al. Sex differences in quality of life and clinical outcomes in patients with advanced heart failure: insights from the PAL-HF trial. Circ Heart Fail. 2020;13:e006134. https://doi.org/10.1161/CIRCHEARTFAILURE.119.006134
52. Lainščak M, Milinković I, Polovina M, Crespo‐Leiro MG, Lund LH, Anker SD, et al. Sex- and age-related differences in the management and outcomes of chronic heart failure: an analysis of patients from the ESC HFA EORP Heart Failure Long-Term Registry. Eur J Heart Fail. 2020;22:92–102. https://doi.org/10.1002/ejhf.1645
53. Rossello X, Ferreira JP, Pocock SJ, McMurray JJV, Solomon SD, Lam CSP, et al. Sex differences in mineralocorticoid receptor antagonist trials: a pooled analysis of three large clinical trials. Eur J Heart Fail. 2020;22:834–44. https://doi.org/10.1002/ejhf.1740
54. Dewan P, Jackson A, Lam CSP, Pfeffer MA, Zannad F, Pitt B, et al. Interactions between left ventricular ejection fraction, sex and effect of neurohumoral modulators in heart failure. Eur J Heart Fail. 2020;22:898–901. https://doi.org/10.1002/ejhf.1776
55. Reza N, Tahhan AS, Mahmud N, DeFilippis EM, Alrohaibani A, Vaduganathan M, et al. Representation of women authors in international heart failure guidelines and contemporary clinical trials. Circ Heart Fail. 2020;13:e006605. https://doi.org/10.1161/CIRCHEARTFAILURE.119.006605
56. Pandey A, Vaduganathan M, Arora S, Qamar A, Mentz RJ, Shah SJ, et al. Temporal trends in prevalence and prognostic implications of comorbidities among patients with acute decompensated heart failure: the ARIC study community surveillance. Circulation. 2020;142:230–43. https://doi.org/10.1161/CIRCULATIONAHA.120.047019
57. Khan MS, Samman Tahhan A, Vaduganathan M, Greene SJ, Alrohaibani A, Anker SD, et al. Trends in prevalence of comorbidities in heart failure clinical trials. Eur J Heart Fail. 2020;22:1032–42. https://doi.org/10.1002/ejhf.1818
58. Bhatt AS, Ambrosy AP, Dunning A, DeVore AD, Butler J, Reed S, et al. The burden of non-cardiac comorbidities and association with clinical outcomes in an acute heart failure trial—insights from ASCEND-HF. Eur J Heart Fail. 2020;22:1022–31. https://doi.org/10.1002/ejhf.1795
59. Aimo A, Barison A, Castiglione V, Emdin M. The unbearable underreporting of comorbidities in heart failure clinical trials. Eur J Heart Fail. 2020;22:1043–4. https://doi.org/10.1002/ejhf.1846
60. Docherty KF, Shen L, Castagno D, Petrie MC, Abraham WT, Böhm M, et al. Relationship between heart rate and outcomes in patients in sinus rhythm or atrial fibrillation with heart failure and reduced ejection fraction. Eur J Heart Fail. 2020;22:528–38. https://doi.org/10.1002/ejhf.1682
61. Al-Khatib SM, Benjamin EJ, Albert CM, Alonso A, Chauhan C, Chen PS, et al. Advancing research on the complex interrelations between atrial fibrillation and heart failure: a report from a US National Heart, Lung, and Blood Institute Virtual Workshop. Circulation. 2020;141:1915–26. https://doi.org/10.1161/CIRCULATIONAHA.119.045204
62. Packer M. Do most patients with obesity or type 2 diabetes, and atrial fibrillation, also have undiagnosed heart failure? A critical conceptual framework for understanding mechanisms and improving diagnosis and treatment. Eur J Heart Fail. 2020;22:214–27. https://doi.org/10.1002/ejhf.1646
63. Bauersachs J, Veltmann C. Heart rate control in heart failure with reduced ejection fraction: the bright and the dark side of the moon. Eur J Heart Fail. 2020;22:539–42. https://doi.org/10.1002/ejhf.1733
64. Mullens W, Damman K, Testani JM, Martens P, Mueller C, Lassus J, et al. Evaluation of kidney function throughout the heart failure trajectory—a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2020;22:584–603. https://doi.org/10.1002/ejhf.1697
65. Cox ZL, Hung R, Lenihan DJ, Testani JM. Diuretic strategies for loop diuretic resistance in acute heart failure: the 3T trial. JACC Heart Fail. 2020;8:157–68. https://doi.org/10.1016/j.jchf.2019.09.012
66. Carubelli V, Zhang Y, Metra M, Lombardi C, Felker GM, Filippatos G, et al. Treatment with 24 hour istaroxime infusion in patients hospitalised for acute heart failure: a randomised, placebo-controlled trial. Eur J Heart Fail. 2020;22:1684–93. https://doi.org/10.1002/ejhf.1743
67. Harjola VP, Parissis J, Bauersachs J, Brunner‐La Rocca HP, Bueno H, Čelutkienė J, et al. Acute coronary syndromes and acute heart failure: a diagnostic dilemma and high-risk combination. A statement from the Acute Heart Failure Committee of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2020;22:1298–314. https://doi.org/10.1002/ejhf.1831
68. Gorenek B, Halvorsen S, Kudaiberdieva G, Bueno H, Van Gelder IC, Lettino M, et al. Atrial fibrillation in acute heart failure: a position statement from the Acute Cardiovascular Care Association and European Heart Rhythm Association of the European Society of Cardiology. Eur Heart J Acute Cardiovasc Care. 2020;9:348–57. https://doi.org/10.1177/2048872619894255
69. Aissaoui N, Puymirat E, Delmas C, Ortuno S, Durand E, Bataille V, et al. Trends in cardiogenic shock complicating acute myocardial infarction. Eur J Heart Fail. 2020;22:664–72. https://doi.org/10.1002/ejhf.1750
70. Hanson ID, Tagami T, Mando R, Kara Balla A, Dixon SR, Timmis S, et al. SCAI shock classification in acute myocardial infarction: insights from the National Cardiogenic Shock Initiative. Catheter Cardiovasc Interv. 2020;96:1137–42. https://doi.org/10.1002/ccd.29139
71. Zeymer U, Bueno H, Granger CB, Hochman J, Huber K, Lettino M, et al. Acute Cardiovascular Care Association position statement for the diagnosis and treatment of patients with acute myocardial infarction complicated by cardiogenic shock: a document of the Acute Cardiovascular Care Association of the European Society of Car. Eur Heart J Acute Cardiovasc Care. 2020;9:183–97. https://doi.org/10.1177/2048872619894254
72. Chioncel O, Parissis J, Mebazaa A, Thiele H, Desch S, Bauersachs J, et al. Epidemiology, pathophysiology and contemporary management of cardiogenic shock—a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2020;22:1315–41. https://doi.org/10.1002/ejhf.1922
73. Karason K, Lund LH, Dalén M, Björklund E, Grinnemo K, Braun O, et al. the SweVAD Investigators. Randomized trial of a left ventricular assist device as destination therapy versus guideline-directed medical therapy in patients with advanced heart failure. Rationale and design of the SWEdish evaluation of left Ventricular Assist Device (SweVAD) trial. Eur J Heart Fail. 2020;22:739–50. https://doi.org/10.1002/ejhf.1773
74. Phan D, Duan L, Ng A, Shen AJ, Lee MS. Characteristics and outcomes of pregnant women with cardiomyopathy stratified by etiologies: a population-based study. Int J Cardiol. 2020;305:87–91. https://doi.org/10.1016/j.ijcard.2019.12.027
75. Bauersachs J, König T, Meer P, Petrie MC, Hilfiker‐Kleiner D, Mbakwem A, et al. Pathophysiology, diagnosis and management of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Study Group on peripartum cardiomyopathy. Eur J Heart Fail. 2019;21:827–43. https://doi.org/10.1002/ejhf.1493
76. Sliwa K, Bauersachs J, Coats AJS. The European Society of Cardiology Heart Failure Association Study Group on Peripartum Cardiomyopathy—what has been achieved in 10 years. Eur J Heart Fail. 2020;22:1060–4. https://doi.org/10.1002/ejhf.1912
77. Sliwa K, Petrie MC, van der Meer P, Mebazaa A, Hilfiker-Kleiner D, Jackson AM, et al. Clinical presentation, management, and 6-month outcomes in women with peripartum cardiomyopathy: an ESC EORP registry. Eur Heart J. 2020;41:3787–97. https://doi.org/10.1093/eurheartj/ehaa455
78. Davis MB, Arany Z, McNamara DM, Goland S, Elkayam U. Peripartum cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75:207–21. https://doi.org/10.1016/j.jacc.2019.11.014
79. Wilcox JE, Fang JC, Margulies KB, Mann DL. Heart Failure With recovered left ventricular ejection fraction: JACC Scientific Expert Panel. J Am Coll Cardiol. 2020;76:719–34. https://doi.org/10.1016/j.jacc.2020.05.075
80. Curigliano G, Lenihan D, Fradley M, Ganatra S, Barac A, Blaes A, et al. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol. 2020;31:171–90. https://doi.org/10.1016/j.annonc.2019.10.023
81. Keramida K, Farmakis D, López Fernández T, Lancellotti P. Focused echocardiography in cardio-oncology. Echocardiography. 2020;37:1149–58. https://doi.org/10.1111/echo.14800
82. Harries I, Liang K, Williams M, Berlot B, Biglino G, Lancellotti P, et al. Magnetic resonance imaging to detect cardiovascular effects of cancer therapy. JACC CardioOncology. 2020;2:270–92. https://doi.org/10.1016/j.jaccao.2020.04.011
83. Zhang L, Awadalla M, Mahmood SS, Nohria A, Hassan MZO, Thuny F, et al. Cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis. Eur Heart J. 2020;41:1733–43. https://doi.org/10.1093/eurheartj/ehaa051
84. Border WL, Sachdeva R, Stratton KL, Armenian SH, Bhat A, Cox DE, et al. Longitudinal changes in echocardiographic parameters of cardiac function in pediatric cancer survivors. JACC CardioOncology. 2020;2:26–37. https://doi.org/10.1016/j.jaccao.2020.02.016
85. López-Sendón J, Álvarez-Ortega C, Zamora Auñon P, Buño Soto A, Lyon AR, Farmakis D, et al. Classification, prevalence, and outcomes of anticancer therapy-induced cardiotoxicity: the CARDIOTOX registry. Eur Heart J. 2020;41:1720–9. https://doi.org/10.1093/eurheartj/ehaa006
86. Reddy YNV, Obokata M, Wiley B, Koepp KE, Jorgenson CC, Egbe A, et al. The haemodynamic basis of lung congestion during exercise in heart failure with preserved ejection fraction. Eur Heart J. 2019;40:3721–30. https://doi.org/10.1093/eurheartj/ehz713
87. Obokata M, Kane GC, Reddy YNV, Melenovsky V, Olson TP, Jarolim P, et al. The neurohormonal basis of pulmonary hypertension in heart failure with preserved ejection fraction. Eur Heart J. 2019;40:3707–17. https://doi.org/10.1093/eurheartj/ehz626
88. Padang R, Chandrashekar N, Indrabhinduwat M, Scott CG, Luis SA, Chandrasekaran K, et al. Aetiology and outcomes of severe right ventricular dysfunction. Eur Heart J. 2020;41:1273–82. https://doi.org/10.1093/eurheartj/ehaa037
89. Patel D, Trulock K, Kumar A, Kiehl E, Toro S, Moennich LA, et al. Baseline right ventricular dysfunction predicts worse outcomes in patients undergoing cardiac resynchronization therapy implantation. J Card Fail. 2020;26:227–32. https://doi.org/10.1016/j.cardfail.2019.12.004
90. Rohde LE, Chatterjee NA, Vaduganathan M, Claggett B, Packer M, Desai AS, et al. Sacubitril/valsartan and sudden cardiac death according to implantable cardioverter-defibrillator use and heart failure cause: a PARADIGM-HF analysis. JACC Heart Fail. 2020;8:844–55. https://doi.org/10.1016/j.jchf.2020.06.015
91. Lee S, Oh J, Kim H, Ha J, Chun KH, Lee CJ, et al. Sacubitril/valsartan in patients with heart failure with reduced ejection fraction with end-stage of renal disease. ESC Heart Fail. 2020;7:1125–9. https://doi.org/10.1002/ehf2.12659
92. Mann DL, Greene SJ, Givertz MM, Vader JM, Starling RC, Ambrosy AP, et al. Sacubitril/valsartan in advanced heart failure with reduced ejection fraction: rationale and design of the lIFE trial. JACC Heart Fail. 2020;8:789–99. https://doi.org/10.1016/j.jchf.2020.05.005
93. McMurray JJV, Jackson AM, Lam CSP, Redfield MM, Anand IS, Ge J, et al. Effects of sacubitril-valsartan versus valsartan in women compared with men with heart failure and preserved ejection fraction: insights from PARAGON-HF. Circulation. 2020;141:338–51. https://doi.org/10.1161/CIRCULATIONAHA.119.044491
94. Vaduganathan M, Claggett BL, Desai AS, Anker SD, Perrone SV, Janssens S, et al. Prior heart failure hospitalization, clinical outcomes, and response to sacubitril/valsartan compared with valsartan in HFpEF. J Am Coll Cardiol. 2020;75:245–54. https://doi.org/10.1016/j.jacc.2019.11.003
95. Selvaraj S, Claggett BL, Böhm M, Anker SD, Vaduganathan M, Zannad F, et al. Systolic blood pressure in heart failure with preserved ejection fraction treated with sacubitril/valsartan. J Am Coll Cardiol. 2020;75:1644–56. https://doi.org/10.1016/j.jacc.2020.02.009
96. Mc Causland FR, Lefkowitz MP, Claggett B, Anavekar NS, Senni M, Gori M, et al. Angiotensin-neprilysin inhibition and renal outcomes in heart failure with preserved ejection fraction. Circulation. 2020;142:1236–45. https://doi.org/10.1161/CIRCULATIONAHA.120.047643
97. Selvaraj S, Claggett BL, Pfeffer MA, Desai AS, Mc Causland FR, McGrath MM, et al. Serum uric acid, influence of sacubitril/valsartan, and cardiovascular outcomes in heart failure with preserved ejection fraction: PARAGON-HF. Eur J Heart Fail. 2020;22:2093–101. https://doi.org/10.1002/ejhf.1984
98. Kuno T, Ueyama H, Fujisaki T, Briasouli A, Takagi H, Briasoulis A. Meta-analysis evaluating the effects of renin-angiotensin-aldosterone system blockade on outcomes of heart failure with preserved ejection fraction. Am J Cardiol. 2020;125:1187–93. https://doi.org/10.1016/j.amjcard.2020.01.009
99. Vaduganathan M, Jhund PS, Claggett BL, Packer M, Widimský J, Seferovic P, et al. A putative placebo analysis of the effects of sacubitril/valsartan in heart failure across the full range of ejection fraction. Eur Heart J. 2020;41:2356–62. https://doi.org/10.1093/eurheartj/ehaa184
100. Böhm M, Bewarder Y, Kindermann I. Ejection fraction in heart failure revisited—where does the evidence start? Eur Heart J. 2020;41:2363–5. https://doi.org/10.1093/eurheartj/ehaa281
101. Seferović PM, Fragasso G, Petrie M, Mullens W, Ferrari R, Thum T, et al. Sodium-glucose co-transporter 2 inhibitors in heart failure: beyond glycaemic control. The position paper of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2020;22:1495–503. https://doi.org/10.1002/ejhf.1954
102. Seferović PM, Coats AJS, Ponikowski P, Filippatos G, Huelsmann M, Jhund PS, et al. European Society of Cardiology/Heart Failure Association position paper on the role and safety of new glucose-lowering drugs in patients with heart failure. Eur J Heart Fail. 2020;22:196–213. https://doi.org/10.1002/ejhf.1673
103. Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383:1425–35. https://doi.org/10.1056/NEJMoa2004967
104. Cosentino F, Cannon CP, Cherney DZI, Masiukiewicz U, Pratley R, Dagogo-Jack S, et al. On behalf of the VERTIS CV Investigators. Efficacy of ertugliflozin on heart failure-related events in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease: results of the VERTIS CV trial. Circulation. 2020;142:2205–15. https://doi.org/10.1161/CIRCULATIONAHA.120.050255
105. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995–2008. https://doi.org/10.1056/NEJMoa1911303
106. McMurray JJV, DeMets DL, Inzucchi SE, Køber L, Kosiborod MN, Langkilde AM, et al. A trial to evaluate the effect of the sodium-glucose co-transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction (DAPA-HF). Eur J Heart Fail. 2019;21:665–75. https://doi.org/10.1002/ejhf.1432
107. Petrie MC, Verma S, Docherty KF, Inzucchi SE, Anand I, Belohlávek J, et al. Effect of dapagliflozin on worsening heart failure and cardiovascular death in patients with heart failure with and without diabetes. JAMA. 2020;323:1353–68. https://doi.org/10.1001/jama.2020.1906
108. Docherty KF, Jhund PS, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. Effects of dapagliflozin in DAPA-HF according to background heart failure therapy. Eur Heart J. 2020;41:2379–92. https://doi.org/10.1093/eurheartj/ehaa183
109. Martinez FA, Serenelli M, Nicolau JC, Petrie MC, Chiang CE, Tereshchenko S, et al. Efficacy and safety of dapagliflozin in heart failure with reduced ejection fraction according to age: insights from DAPA-HF. Circulation. 2020;141:100–11. https://doi.org/10.1161/CIRCULATIONAHA.119.044133
110. Serenelli M, Böhm M, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. Effect of dapagliflozin according to baseline systolic blood pressure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF). Eur Heart J. 2020;41:3402–18. https://doi.org/10.1093/eurheartj/ehaa496
111. Jhund PS, Solomon SD, Docherty KF, Heerspink HJL, Anand IS, Böhm M, et al. Efficacy of dapagliflozin on renal function and outcomes in patients with heart failure with reduced ejection fraction: results of DAPA-HF. Circulation. 2021;•••: [cited 2020 December 24]. https://doi.org/10.1161/CIRCULATIONAHA.120.050391
112. Kosiborod MN, Jhund PS, Docherty KF, Diez M, Petrie MC, Verma S, et al. Effects of dapagliflozin on symptoms, function, and quality of life in patients with heart failure and reduced ejection fraction: results from the DAPA-HF trial. Circulation. 2020;141:90–9. https://doi.org/10.1161/CIRCULATIONAHA.119.044138
113. McEwan P, Darlington O, McMurray JJV, Jhund PS, Docherty KF, Böhm M, et al. Cost-effectiveness of dapagliflozin as a treatment for heart failure with reduced ejection fraction: a multinational health-economic analysis of DAPA-HF. Eur J Heart Fail. 2020;22:2147–56. https://doi.org/10.1002/ejhf.1978
114. Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383:1436–46. https://doi.org/10.1056/NEJMoa2024816
115. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413–24. https://doi.org/10.1056/NEJMoa2022190
116. Packer M, Anker SD, Butler J, Filippatos GS, Ferreira JP, Pocock S, et al. Effect of empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial. Circulation. 2021;•••: [cited 2020 December 24]. https://doi.org/10.1161/CIRCULATIONAHA.120.051783
117. Packer M. Influence of neprilysin inhibition on the efficacy and safety of empagliflozin in patients with chronic heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial. Eur Heart J. 2021. Forthcoming. https://doi.org/10.1093/eurheartj/ehz553
118. Anker SD, Butler J, Filippatos G, Khan MS, Marx N, Lam CSP, et al. Effect of empagliflozin on cardiovascular and renal outcomes in patients with heart failure by baseline diabetes status—results from the EMPEROR-Reduced trial. Circulation. 2021;•••:. https://doi.org/10.1161/CIRCULATIONAHA.120.051824
119. Zannad F, Ferreira JP, Pocock SJ, Anker SD, Butler J, Filippatos G, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396:819–29. https://doi.org/10.1016/S0140-6736(20)31824-9
120. Lee MMY, Brooksbank KJM, Wetherall K, Mangion K, Roditi G, Campbell RT, et al. Effect of empagliflozin on left ventricular volumes in patients with type 2 diabetes, or prediabetes, and heart failure with reduced ejection fraction (SUGAR-DM-HF). Circulation. 2021;•••: [cited 2020 December 24]. https://doi.org/10.1161/CIRCULATIONAHA.120.052186
121. Santos-Gallego CG, Vargas-Delgado AP, Requena JA, Garcia-Ropero A, Mancini D, Pinney S, et al. Randomized trial of empagliflozin in non-diabetic patients with heart failure and reduced ejection fraction. J Am Coll Cardiol. 2021;•••:. https://doi.org/10.1016/j.jacc.2020.11.008
122. Butler J, Zannad F, Filippatos G, Anker SD, Packer M. Totality of evidence in trials of sodium-glucose co-transporter-2 inhibitors in the patients with heart failure with reduced ejection fraction: implications for clinical practice. Eur Heart J. 2020;41:3398–401. https://doi.org/10.1093/eurheartj/ehaa731
123. Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021;•••: [cited 2020 December 24]. https://doi.org/10.1056/NEJMoa2030183
124. Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease. N Engl J Med. 2021;•••: [cited 2020 December 24]. https://doi.org/10.1056/NEJMoa2030186
125. Pieske B, Patel MJ, Westerhout CM, Anstrom KJ, Butler J, Ezekowitz J, et al. Baseline features of the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial. Eur J Heart Fail. 2019;21:1596–604. https://doi.org/10.1002/ejhf.1664
126. Armstrong PW, Pieske B, Anstrom KJ, Ezekowitz J, Hernandez AF, Butler J, et al. Vericiguat in patients with heart failure and reduced ejection fraction. N Engl J Med. 2020;382:1883–93. https://doi.org/10.1056/NEJMoa1915928
127. Butler J, Anstrom KJ, Armstrong PW, For the VICTORIA Study Group. Comparing the benefit of novel therapies across clinical trials: insights from the VICTORIA trial. Circulation. 2020;142:717–9. https://doi.org/10.1161/CIRCULATIONAHA.120.047086
128. Butler J, Lam CSP, Anstrom KJ, Ezekowitz J, Hernandez AF, O’Connor CM, et al. Rationale and design of the VITALITY-HFpEF trial. Circ Heart Fail. 2019;12:e005998. https://doi.org/10.1161/CIRCHEARTFAILURE.119.005998
129. Ezekowitz JA, O’Connor CM, Troughton RW, Alemayehu WG, Westerhout CM, Voors AA, et al. N-terminal Pro-B-type natriuretic peptide and clinical outcomes: vericiguat heart failure with reduced ejection fraction study. JACC Heart Fail. 2020;8:931–9. https://doi.org/10.1016/j.jchf.2020.08.008
130. Armstrong PW, Lam CSP, Anstrom KJ, Ezekowitz J, Hernandez AF, O’Connor CM, et al. Effect of vericiguat vs placebo on quality of life in patients with heart failure and preserved ejection fraction: the VITALITY-HFpEF randomized clinical trial. JAMA. 2020;324:1512–21. [Oct]. https://doi.org/10.1001/jama.2020.15922
131. Udelson JE, Lewis GD, Shah SJ, Zile MR, Redfield MM, Burnett J, et al. Rationale and design for a multicenter, randomized, double-blind, placebo-controlled, phase 2 study evaluating the safety and efficacy of the soluble guanylate cyclase stimulator praliciguat over 12 weeks in patients with heart failure with preserved eje. Am Heart J. 2020;222:183–90. https://doi.org/10.1016/j.ahj.2020.01.009
132. Teerlink JR, Diaz R, Felker GM, McMurray JJV, Metra M, Solomon SD, et al. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. N Engl J Med. 2021;•••: [cited 2020 December 24]. https://doi.org/10.1056/NEJMoa2025797
133. Voors AA, Tamby JF, Cleland JG, Koren M, Forgosh LB, Gupta D, et al. Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: experimental data and clinical results from a phase 2a trial. Eur J Heart Fail. 2020;22:1649–58. https://doi.org/10.1002/ejhf.1933
134. Olivotto I, Oreziak A, Barriales-Villa R, Abraham TP, Masri A, Garcia-Pavia P, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;396:759–69. https://doi.org/10.1016/S0140-6736(20)31792-X
135. Ponikowski P, Kirwan BA, Anker SD, Dorobantu M, Drozdz J, Fabien V, et al. Rationale and design of the AFFIRM-AHF trial: a randomised, double-blind, placebo-controlled trial comparing the effect of intravenous ferric carboxymaltose on hospitalisations and mortality in iron-deficient patients admitted for acute heart failure. Eur J Heart Fail. 2019;21:1651–8. https://doi.org/10.1002/ejhf.1710
136. Ponikowski P, Kirwan BA, Anker SD, McDonagh T, Dorobantu M, Drozdz J, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet. 2020;•••: [cited 2020 December 24]. https://doi.org/10.1016/S0140-6736(20)32339-4
137. Batkai S, Genschel C, Viereck J, Rump S, Bär C, Borchert T, et al. CDR132L improves systolic and diastolic function in a large animal model of chronic heart failure. Eur Heart J. 2021;•••: [cited 2020 December 24]. https://doi.org/10.1093/eurheartj/ehaa791
138. Täubel J, Hauke W, Rump S, Viereck J, Batkai S, Poetzsch J, et al. Novel antisense therapy targeting microRNA-132 in patients with heart failure: results of a first-in-human Phase 1b randomized, double-blind, placebo-controlled study. Eur Heart J. 2021;•••: [cited 2020 December 24]. https://doi.org/10.1093/eurheartj/ehaa898
139. Vaduganathan M, Claggett BL, Jhund PS, Cunningham JW, Pedro Ferreira J, Zannad F, et al. Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials. Lancet. 2020;396:121–8. https://doi.org/10.1016/S0140-6736(20)30748-0
140. Reichart D, Kalbacher D, Rübsamen N, Tigges E, Thomas C, Schirmer J, et al. The impact of residual mitral regurgitation after MitraClip therapy in functional mitral regurgitation. Eur J Heart Fail. 2020;22:1840–8. https://doi.org/10.1002/ejhf.1774
141. Nijst P, Martens P, Dauw J, Tang WHW, Bertrand PB, Penders J, et al. Withdrawal of neurohumoral blockade after cardiac resynchronization therapy. J Am Coll Cardiol. 2020;75:1426–38. https://doi.org/10.1016/j.jacc.2020.01.040
142. Zile MR. Lindenfeld JAnn, Weaver FA, Zannad F, Galle E, Rogers T, Abraham WT. Baroreflex activation therapy in patients with heart failure with reduced ejection fraction. J Am Coll Cardiol. 2020;76:1–13. https://doi.org/10.1016/j.jacc.2020.05.015
143. Angermann CE, Assmus B, Anker SD, Asselbergs FW, Brachmann J, Brett ME, et al. Pulmonary artery pressure-guided therapy in ambulatory patients with symptomatic heart failure: the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF). Eur J Heart Fail. 2020;22:1891–901. [Jun]. https://doi.org/10.1002/ejhf.1943
144. Stehlik J, Schmalfuss C, Bozkurt B, Nativi-Nicolau J, Wohlfahrt P, Wegerich S, et al. Continuous wearable monitoring analytics predict heart failure hospitalization: the LINK-HF multicenter study. Circ Heart Fail. 2020;13:e006513. https://doi.org/10.1161/CIRCHEARTFAILURE.119.006513
145. Rahimi K, Nazarzadeh M, Pinho-Gomes AC, Woodward M, Salimi-Khorshidi G, Ohkuma T, et al. Home monitoring with technology-supported management in chronic heart failure: a randomised trial. Heart. 2020;106:1573–8. [Oct]. https://pubmed.ncbi.nlm.nih.gov/32580977/
146. Galinier M, Roubille F, Berdague P, Brierre G, Cantie P, Dary P, et al. Telemonitoring versus standard care in heart failure: a randomised multicentre trial. Eur J Heart Fail. 2020;22:985–94. https://doi.org/10.1002/ejhf.1906
147. Zakeri R, Morgan JM, Phillips P, Kitt S, Ng GA, McComb JM, et al. REM‐HF Investigators. Impact of remote monitoring on clinical outcomes for patients with heart failure and atrial fibrillation: results from the REM-HF trial. Eur J Heart Fail. 2020;22:543–53. https://doi.org/10.1002/ejhf.1709
148. Abraham WT, Fiuzat M, Psotka MA, O’Connor CM. Heart failure collaboratory statement on remote monitoring and social distancing in the landscape of COVID-19. JACC Heart Fail. 2020;8:692–4. https://doi.org/10.1016/j.jchf.2020.06.006
149. Jaarsma T, Hill L, Bayes-Genis A, Brunner La Rocca HP, Castiello T, Čelutkienė J, et al. Self-care of heart failure patients: practical management recommendations from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2021;•••: [cited 2020 December 24]. https://doi.org/10.1002/ejhf.2008
150. Hill L, Geller TP, Baruah R, Beattie JM, Boyne J, De Stoutz N, et al. Integration of a palliative approach into heart failure care: a European Society of Cardiology Heart Failure Association position paper. Eur J Heart Fail. 2020;•••:. https://doi.org/10.1002/ejhf.1994
151. Sobanski PZ, Alt-Epping B, Currow DC, Goodlin SJ, Grodzicki T, Hogg K, et al. Palliative care for people living with heart failure: European Association for Palliative Care Task Force expert position statement. Cardiovasc Res. 2020;116:12–27. https://doi.org/10.1093/cvr/cvz200
152. Sahlollbey N, Lee CKS, Shirin A, Joseph P. The impact of palliative care on clinical and patient-centred outcomes in patients with advanced heart failure: a systematic review of randomized controlled trials. Eur J Heart Fail. 2020;•••: [cited 2020 December 24]. https://doi.org/10.1002/ejhf.1783