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)

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 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)

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)

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 (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)

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% at baseline; (ii) ≥10% absolute improvement in LVEF; and (iii) a second measurement of 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)

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 < 50%). (84, 85)

RV and right atrium dysfunction contribute to HFpEF pathophysiology. Also, RV dysfunction (lower RV systolic velocity and RV fractional area change) and impairment in RV-pulmonary artery coupling are more frequently found in HFpEF patients developing acute lung congestion with exercise. (86) Activation of the endothelin and adrenomedullin neurohormonal pathways is associated with pulmonary haemodynamic derangements, reduced RV functional reserve, reduced cardiac output, and more severe impairment of peak VO2 in HFpEF patients. (87) The most common causes of RVD are left-sided heart diseases (46%), pulmonary thromboembolic disease (18%), chronic lung disease/hypoxia (17%), and pulmonary arterial hypertension (11%). Average 1-year mortality in patients with RVD is high (>40%), highest among chronic lung disease patients. (88) The presence of RVD at CRT implantation predicts worsening LV remodelling and survival. (89)

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 < 0.001). Treatment benefits were robust in patients with LVEF < 60%, but not in those with LVEF > 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)

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 < 0.001), the secondary endpoints of total HF hospitalizations (HR, 0.70; 95% CI, 0.58–0.85; P < 0.001), the annual rate of decline in the estimated glomerular filtration rate (−0.55 vs. −2.28 mL/min/1.73 m² of body-surface area per year, P < 0.001), the risk of serious renal outcomes, (115) and the risk and total number of inpatient and outpatient worsening HF events, which starts early after the initiation of treatment and remains during the duration of treatment. (116) These beneficial effects were also observed to a similar extent in patients pre-treated with ARNI (117) and were independent of baseline diabetes status and across the continuum of HbA1c, (118) and in patients with and without CKD and regardless of the severity of kidney impairment at baseline. (119)

In the SUGAR-DM-HF study, empagliflozin reduced LV volumes measured by CV magnetic resonance in patients with HFrEF and type 2 diabetes or prediabetes. (120) The mechanistic trial EMPA-TROPISM (ATRU-4) showed the beneficial effect of empagliflozin in improving LV volumes, LV mass, LV systolic function, functional capacity, and quality of life in non-diabetic patients with HFrEF (121) (ref). Taken the evidence together, SGLT-2 inhibitors reduce all-cause and CV mortality and improve renal outcomes in patients with HFrEF, supporting the role of dapagliflozin and empagliflozin as a new standard of care for patients with HFrEF. (119, 122)

Sotagliflozin, another SGLT-2 inhibitor that displays also gastrointestinal SGLT-1 inhibition and thus reduces intestinal glucose absorption, was investigated in patients with type 2 diabetes after a recent hospitalization for worsening heart failure (SOLOIST-WHF). Patients were included independent of their ejection fraction, and 78% of patients had an ejection fraction <50%. The primary endpoint of CV death, total hospitalizations, and urgent visits for HF was significantly reduced in patients treated with sotagliflozin (HR, 0.67; 95% CI, 0.52–0.85; P < 0.001). The results were consistent among subgroups and especially also in patients with an EF > 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 < 0.001). It has to be mentioned that both sotagliflozin trials had to be stopped earlier than planned because of loss of funding from the sponsor.

The activator of soluble guanylate cyclase (sGC) vericiguat was investigated in the VICTORIA study in 5050 patients with recently decompensated chronic HF and LVEF < 45%. (125, 126) Vericiguat significantly reduced the primary outcome of CV death or first HF hospitalisation (HR, 0.90; 95% CI, 0.82–0.98; P = 0.02). While vericiguat significantly reduced HF hospitalisations (HR, 0.90; 95% CI, 0.81–1.00), CV deaths were not significantly diminished. Adverse events were largely similar among the vericiguat and placebo groups. An analysis comparing HRs and absolute RR in three large recent HFrEF trials demonstrated that while the HR suggests a smaller treatment effect in VICTORIA than in the DAPA-HF and PARADIGM-HF trials, a comparison of 12-month event rates for the primary outcome pointed to a comparable benefit across the three trials. (127, 128) Given the significant interaction of vericiguat effects according to baseline NT-proBNP levels, a post hoc analysis showed an association of vericiguat benefit on the primary outcome in patients with NTproBNP levels up to 8000 pg/mL, with greatest benefit in patients with NTproBNP <4000 pg/mL (HR, 0.77, 95% CI, 0.68–0.88). (129)

Vericiguat was evaluated In HFpEF patients in the VITALITY trial, (128) showing no benefit in quality of life and exercise tolerance. (130) Similarly, in the CAPACITY trial, the sGC stimulator praliciguat was well-tolerated but did neither affect the primary efficacy endpoint of pVO₂ nor other predefined outcome parameters. (131)

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)

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)

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.

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) 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.

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 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)