SCIENTIFIC JOURNAL of the Hungarian Society of Cardiology

The year in cardiovascular medicine 2021: heart failure and cardiomyopathies

█ Current opinion

Johann Bauersachs1*, Rudolf A. de Boer2, JoAnn Lindenfeld3 and Biykem Bozkurt4
1Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany;
2Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands;
3Vanderbilt Heart and Vascular Institute, Vanderbilt University Medical Center, Nashville, TN, USA; and
4Winters Center for Heart Failure, Cardiology, Baylor College of Medicine and Michael E. DeBakey VA Medical Center, Houston TX, USA
Received 16 September 2021; revised 27 October 2021; accepted 16 November 2021; online publish-ahead-of-print 3 January 2022


In the year 2021, the universal definition and classi­fication of heart failure (HF) was published that defines HF as a clinical syndrome with symptoms and/or signs caused by a cardiac abnormality and corroborated by elevated natriuretic peptide levels or objective evidence of cardiogenic congestion. This definition and the classification of HF with reduced ejection fraction (HFrEF), mildly reduced, and HF with pre-served ejection fraction (HFpEF) is consistent with the 2021 ESC Guidelines on HF. Among several other new recommendations, these guidelines give a Class I indication for the use of the sodium-glucose co-transporter 2 (SGLT2) inhibitors dapagliflozin and empagliflozin in HFrEF patients. As the first evidence-based treatment for HFpEF, in the EMPEROR-Preserved trial, empagliflozin reduced the composite endpoint of cardiovascular death and HF hospitalizations. Several reports in 2021 have provided novel and detailed analyses of device and medical therapy in HF, especially regarding sacubitril/valsartan, SGLT2 inhibitors, mineralocorticoid receptor antagonists, ferric carboxymal-tose, soluble guanylate cyclase activators, and cardiac myosin activators. In patients hospitalized with COVID-19, acute HF and myocardial injury is quite frequent, whereas myocarditis and long-term damage to the heart are rather uncommon.



Heart failure (HF) remains a major challenge for patients and healthcare systems worldwide. For patients suffering from HF with reduced ejection fraction (HFrEF), se­veral evidence-based treatments are available and have markedly improved prognosis and quality of life; however, a subset of these patients displays a rapid progression of HF despite best care. A recent special article called to action for global approaches to novel drug solutions for these patients (1), but also for patients with HF with preserved EF (HFpEF), for whom until recently there was not a single evidence-based treatment.
In this article, we summarize important progress that has been made in 2021 regarding the diagnosis and treatment of HF with a special focus on articles published in 2021 in the European Heart Journal and the European Journal of Heart Failure.

Definition and classification of heart failure

With the recognition of the need for standardization of an HF definition, the Universal Definition and Classification of Heart Failure was developed, which defined HF as a clinical syndrome with current or prior symptoms and or signs caused by a structural and/or functional cardiac abnormality and corroborated by elevated natriuretic peptide (NP) levels or objective evidence of cardiogenic pulmonary or systemic congestion by diagnostic modalities (Figure 1) (2). It also provided revised definitions for stages of HF, categorized as ‘At-Risk for HF’ (former Stage A) for patients at risk for HF but without current or prior symptoms or signs of HF and without structural cardiac changes or elevated biomarkers of heart disease; Pre-HF (former Stage B) for patients without current or prior symptoms or signs of HF but evidence of structural heart disease, abnormal cardiac function, elevated NP levels or elevated cardiac troponin levels; ‘Heart Failure’ (former Stage C for symptomatic patients, ‘Advanced HF’ (former Stage D) for patients with severe symptoms and/or signs of HF (Figure 1). Ejection fraction categories were classified as HFrEF: left ventricular (LV) EF ≤40% (Figure 1); HF with mildly reduced EF (HFmrEF): LVEF 41–49%; HFpEF: LVEF >50%; and HF with improved EF (HFimpEF): HF with a baseline LVEF ≤40%, a ≥10 point increase from baseline LVEF, and a second measurement of LVEF >40%. The EF categories used in the recent 2021 ESC HF Guidelines were consistent with these classifications (3). In the Universal Definition of HF, there was also an emphasis on trajectories of HF and to use “persistent HF” instead of “stable HF” for patients with ongoing symptoms/signs and “HF in remission” instead of “recovered HF” for patients with resolution of symptoms and signs of HF or with the resolution of previous structural/functional heart disease (2) (Figure 1). Though a simple definition of HF predominantly depending on NPs was proposed as an alternative (4), limitations of such an approach due to variability of NP levels by age, sex, body mass, renal function, and atrial fibrillation; and lack of specificity and lack of evidence in linking treatments to a biomarker-based approach were identified as significant barriers to a simply biomarker-based approach in definition of HF (4).


The HF Atlas survey reports a wide-ranging incidence of HF and HF hospitalizations across Europe with considerable heterogeneity in the resources for management and the data quality providing data to allow the development of strategies to improve inequalities (5). Exposure to ambient air pollutants increases the risk of HF in a dose-dependent fashion, and there was a particularly high risk of HF among persons with genetic higher susceptibility to HF (Figure 2) (6). Air pollution probably should be considered in risk scores to predict HF.

A recent European registry report demonstrated that dilated cardiomyopathy (DCM), not skeletal myopathy, is the major determinant of prognosis in patients with dystrophin gene mutations.7 Finally, cancer and HF occur more commonly together that predicted by risk models, and a recent study suggests that statins reduce the risk of both and have a greater risk reduction with more prolonged use (8)

Diagnostics and risk stratification

For HFrEF, the main diagnostic criterion remains LVEF ≤40% (3). However, there is more controversy in the other categories, HFmrEF and HFpEF. Pieske et al. (9) formulated, on behalf of the ESC, new diagnostic criteria, including echo parameters, NPs, and if a definitive diagnosis cannot be made, to turn to stress testing and/or invasive haemodynamics.

There is increasing appreciation that classical diagnostics fall short in complex multifactorial diseases with various aetiologies and precipitants, and seve­ral studies have addressed whether an agnostic approach, where large data sets are queried by compu­ter algorithms, may be superior in making a specific diagnosis. Such techniques are referred to as machine learning (ML) and artificial intelligence (AI). Peyster et al. (10) used an automated image analysis to detect rejection after heart transplantation and described a “Computer-Assisted Cardiac Histologic Evaluation (CACHE)-Grader” pipeline that was non-inferior to the rejection grading provided by independent pathologists. Another field of research for which AI provides an attractive tool is the categorization of patients who received a general diagnosis of HF. Verdonschot et al. (11) studied 795 consecutive DCM patients with data on aetiology and co-morbidities, imaging studies and endomyocardial biopsies, and identified four distinct phenogroups. Woolley et al. (12) using an algorithm based on 363 biomarkers to phenotype, 429 patients with HFpEF identified four clusters with different clinical parameters and important differences in prognosis.

Artificial intelligence/machine learning might be particularly useful for a diagnosis of HF. Kwon et al. (13) evaluated data from 34 103 patients who underwent echocardiography and electrocardiogram (ECG) and created an ML algorithm that could detect HFpEF. Segar et al. (14) employed ML models to aid in predicting race-specific risk for incident HF.

In the near future, we will be faced with many more potential utility of AI/ML models, as there is a clear need for individualized approaches and decision-making (15). It will be essential, however, to provide recommendations as to what input is (minimally) required for models, and the models must be prospectively tested in independent settings. Furthermore, treatment decisions based on the models must be tested in a randomized blinded fashion (16).

Imaging and biomarkers

A state-of-the-art diagnosis of HF remains challenging. The ESC guidelines (3) recommend using an array of signs and symptoms, supplemented with imaging and biomarkers studies. The imaging primarily relies on echocardiography and CMR, and NPs and high sensitivity troponins are the preferred biomarkers. However, sophisticated classification of patients in various categories using imaging and biomarkers may enhance adequate phenotyping (11, 17) and imaging of non-cardiac tissues such as fat may have relevance to HF phenotyping, too (18, 19). Furthermore, next-generation genetic analyses has been shown to have a consequence for prognosis (20) and diagnosis (21) of HF. In addition, a recent article highlighted the indications of endomyocardial biopsies (22).

Specific situations

Acute heart failure

The 2021 ESC guidelines did not significantly change recommendations for acute HF, although the use of opioids was downgraded to a Class III recommendation (3). Evidence continues to accrue supporting the use of urinary sodium in assessing outcomes in acute HF (23, 24).

Cardiogenic shock

Mortality remains high in cardiogenic shock, and randomized trials assessing therapies remain rare but a single-centre trial randomized patients with cardiogenic shock to either milrinone or dobutamine and showed no differences in any of the primary or secondary outcomes (25). In the follow-up of the IMPRESS trial in cardiogenic shock, there was no difference in mortality comparing intra-aortic balloon pumps vs. the Impella device at 5 years (26). A biomarker composite outperformed other risk scores for cardiogenic shock using 4 biomarkers [Cystatin C, Lactate, interleukin-6, and N-terminal pro brain natriuretic peptide (NT-proBNP)] (27). A recent consensus statement outlines important suggestions for optimizing cardiogenic shock trials (28).

Ventricular assist devices and heart transplantation

A single entry registry confirms that HeartMate III (HMIII) outcomes are better than historical controls confirming randomized trials (29). The stroke rate with HMIII is less than with the Heartware ventricular assist device (HVAD) – one of several reasons the HVAD has been withdrawn from use (30). Disappointingly, left ventri­cular assist devices (LVAD) use does not reduce myocardial fibrosis nor does a new risk score improve the prediction of right ventricular failure post-LVAD, but on the bright side, elderly patients have benefits in quality of life and exercise capacity with LVADs (31–33). There is substantial inter-observer variability in the diagnosis of cellular rejection in myocardial biopsies but automated computation image analysis may allow improved standardization as described in the section on Diagnostics and Imaging. Non-invasive prediction of rejection in cardiac transplant recipients has been elusive, but studies using peripheral blood cell-free DNA show promising early results (34).

Pregnancy/patients with peripartum cardiomyopathy

Women with a known cardiomyopathy or at risk for HF planning pregnancy, or presenting with HF during or after pregnancy are in need of individualized pre-, during, and post-pregnancy assessment and counseling (35).

Patients with peripartum cardiomyopathy are at risk for det­ri­mental outcomes (36, 37) but often do recover from HFrEF. Recent publications investigated the value of ECG abnormalities for predicting echocardiographic results and the role of hypertensive disorders during pregnancy (38, 39).

Hypertrophic cardiomyopathy/amyloidosis

In the health status analysis of EXPLORER-HCM, mavacamten markedly improved the health status of patients with symptomatic obstructive hypertrophic cardio­myopathy (HCM) compared with placebo (40). Gaps in evidence for risk stratification for sudden cardiac death in HCM were summarized by Pelliccia et al. (41). In a study by Marston et al. (42) using Sarcomeric Human Cardiomyopathy Registry, patients with childhood-onset HCM were reported more likely to have sarcomeric disease, carry a higher risk of life-threatening ventricular arrhythmias, and have a greater need for advanced HF therapies. In the German Cardiac Society position statement, Yilmaz et al. (43) outline a diagnostic algorithm to detect cardiac amyloidosis, to accurately determine its extent, and to reliably identify the underlying subtype of amyloidosis, thereby enabling subsequent targeted treatment.


Heart failure often complicates the treatment of cancer, and a recent paper proposes definitions of cardiovascular (CV) toxicities (44). Classically, chemotherapy and radiotherapy have been identified as risk factors, but in the recent decade, immunotherapy with immune checkpoint inhibitors (ICIs) is becoming the mainstay of cancer treatment. However, ICIs also carry a risk for CV side effects. D’Souza et al. (45) reported on this risk in a Danish registry and show that ICI is associated with a 1.8% 1-year risk for (peri-)myocarditis, and with an almost 10% risk for any CV complication. Given the increasing use of ICI, this issue will require clinical guidance and further study, as ICIs have an impact on seve­ral cells and tissues (46, 47). There are initial reports providing guidance as to treat ICI-induced myocarditis (48, 49).
This field extends the increasing awareness that incident cancer is more common in patients with prevalent HF (50) and that cancer and HF may be connected more closely than anticipated before. In support of this, Ren et al. (8) demonstrated that the use of statins reduces incident cancer. Finally, a special article by Zannad et al. (51) discusses aspects of cancer research that may be applicable to HF research, with the aim of streamlining the clinical trial process and decreasing the time and cost required to bring safe, effective, treatments to HF patients.


New algorithm of the 2021 ESC Guidelines on heart failure for the pharmacological treatment of heart failure with reduced ejection fraction

The 2021 ESC Guidelines on HF provide a Class I recommendation for pharmacological treatment of all HFrEF patients with a combination of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor-neprilysin inhibitor (ARNI), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and a sodium–glucose co-transporter 2 (SGLT2) inhibitor (dapagliflozin or\and empagliflozin) (Figure 1B) (3). The guideline still recommends the use of ARNI as a replacement for ACE inhibitor; however, an ARNI may also be considered as a first-line therapy instead of an ACE inhibitor. It is recommended that these four disease-modifying drugs are initiated within a short time frame (3, 52). Potential advantages of another algorithm for the sequencing of these drugs have been suggested by McMurray and Packer (53) with beta-blockade and SGLT2 inhibition as first-line therapies. However, albeit appealing from a pathophysiological standpoint such a new sequence is not yet evidence-based.

A recent consensus document of the HFA of the ESC identified nine patient profiles that may be relevant for treatment implementation in patients with HFrEF taking into account heart rate, atrial fibrillation, symptomatic low blood pressure, estimated glomerular filtration rate, or hyperkalaemia. Using such a personalized approach may lead to a better and more comprehensive therapy for each individual patient (54).

Angiotensin-converting enzyme inhibition

While ACE inhibitors are a standard for the prevention and treatment of HF for many years, the impact of these drugs as preventive therapy for HF in patients with Duchenne muscular dystrophy was unclear. A large French registry showed that prophylactic treatment of patients without LV dysfunction with an ACE inhibitor was able to prevent the transition to HF and improve survival in Duchenne muscular dystrophy (55).

Angiotensin receptor-neprilysin inhibitors (PARAGON, PARADIGM, PARALLAX, PARADISE-MI, LIFE)

In an analysis of the PARADIGM-HF trial, initiation of sacubitril/valsartan, even when titrated to target dose, did not lead to greater discontinuation or down-titration of other guideline-directed medical therapies and was associated with fewer discontinuations of MRA (56). In real-world patients with HFrEF, sacubitril/valsartan was effective, safe, and well tolerated (57–60). Sacubitril–valsartan was found to be useful in treating resistant hypertension in HFpEF in the PARAGON-HF trial when compared with valsartan (61). In the PROVE-HF trial, in patients with HFrEF, 32% improved their EF to >35% by 6 months and 62% to >35% by 12 months after initiation of sacubitril/valsartan therapy (62). In patients with asymptomatic LV systolic dysfunction late after myocardial infarction, treatment with sacubitril/valsartan did not have a significant reverse remodelling effect compared with valsartan (63, 64). In the PARADISE-MI trial (65), sacubitril/valsartan did not significantly reduce the rate of CV death, HF hospitalization, or outpatient HF requiring treatment in patients with LVEF ≤40% and/or pulmonary congestion following acute myocardial infarction, compared with ramipril (results presented at the ACC). In the Sacubitril/Valsartan in Patients with Advanced Heart Failure with Reduced Ejection Fraction in the Advanced Heart Failure (LIFE-HF) trial, which enrolled NYHA Class IV patients and LVEF ≤35%, sacubitril/valsartan did not improve the clinical composite endpoints (presented at ACC 2021). PARALLAX trial will determine if sacubitril/valsartan improves NT-proBNP levels, exercise capacity, quality of life, and symptom burden in HF patients with EF >40% (66).

In the new 2021 ESC Guidelines on HF (3), sacubitril/valsartan is recommended as a replacement for an ACE inhibitor in patients with HFrEF as a Class I recom­mendation. Initiation of sacubitril/valsartan in ACE inhibitor naive patients with HFrEF on the other hand is suggested as a Class IIb recommendation (3).

Sodium–glucose co-transporter 2 inhibitors (EMPEROR-Reduced, EMPEROR-Preserved, DAPA-HF, SOLOIST)

Sodium–glucose co-transporter 2 inhibitors are rapidly becoming the panacea for the entire spectrum of cardiometabolic and renal disease. In trials in type 2 diabetes mellitus (T2DM), a beneficial effect was observed for CV endpoints in general, while the effects on incident HF were overwhelmingly positive. These effects were validated in patients with prevalent HFrEF, first in DAPA-HF and a year later in the EMPEROR-Reduced trial. Numerous subanalyses from these trials were published in 2021.

First, besides the striking effects on hard endpoints, it is more and more recognized that functional status and symptoms are important to patients with HFrEF (67). Both in DAPA-HF and EMPEROR-Reduced, these were improved (68, 69), although a smaller dedicated trial with empagliflozin did not improve functional status (70). Further, a series of subanalyses showed no interaction of SGLT2 inhibitors with common HF drugs, such as MRAs, and most importantly, also not with sacubitril/valsartan (71, 72). Furthermore, the equal effects of the drugs were ascertained by analysing the effects across countries and ethnicities (73). Another striking observation was that dapagliflozin was associated with a lower incidence of new-onset diabetes (74). Collectively, to date, we have not seen any analysis suggesting a differential or lesser effect of SGLT2 inhibitors in HFrEF. We therefore must start to learn how to employ these drugs practically (52, 75).

Different from HFrEF, the efficacy of SGLT2 inhibitors in HFpEF remained to be proven. However, the EMPEROR-Preserved study presented during ESC 2021 demonstrated that empagliflozin reduced the primary combined endpoint of CV death and HF hospitalization in almost 6000 patients with HFpEF (Figure 3). These data are extremely important and provide hope for millions of HFpEF patients for whom there were no evidence-based therapies. Over a median follow-up of 26 months, the primary outcome event occurred in 13.8% of the patients in the empagliflozin group and in 17.1% in the placebo group [hazard ratio (HR): 0.79; 95% confidence interval (CI): 0.69–0.90; P <0.001]. Empagliflozin was very effective in reducing HF hospitalization, but all-cause mortality was not reduced. The effects of empagliflozin were consistent in patients with or without diabetes (76, 77). Shortly, the result of the second mortality trial in HFpEF with the SGLT2 inhibitor dapagliflozin, DELIVER, will be presented (78).

Sodium–glucose co-transporter 2 inhibitors were also evaluated in patients with acute HF or immediately after acutely decompensated HF. The SOLOIST trial (79), with the mixed SGLT 1/2 inhibitor sotagliflozin, enrolled 1244 patients with T2DM and recent worsening HF and showed a beneficial effect of the study drug, initiated before or shortly after discharge, with regard to a significantly lower total number of CV deaths and HF hospitalizations and urgent visits for HF. The ongoing EMPULSE trial will provide more data in the acute HF arena (80).

Sodium–glucose co-transporter 2 inhibitors do not stop to amaze us in renal disease. After the publication of the hallmark trials CREDENCE and DAPA-CKD (81), in 2021, the SCORED trial (82) came out, demonstrating in patients with T2DM and chronic kidney disease, allocated to sotagliflozin or placebo, a reduction of 37% in the primary endpoint of CV death and HF events (HR: 0.74; 95% CI: 0.63–0.88; P < 0.001). However, sotagliflozin was associated with adverse events such as di­arrhoea, genital mycotic infections, volume depletion, and diabetic ketoacidosis.

Mineralocorticoid receptor antagonists (FIDELIO, FIGARO, HOMAGE)

Mineralocorticoid receptor antagonists are first-line therapies for HFrEF and may also be considered in HFmrEF (3). Novel non-steroidal MRA such as finerenone differ from steroidal MRA regarding tissue distribution, MR binding, recruitment of cofactors, and downstream gene expression (83). In FIDELIO-DKD, finerenone improved CV and kidney outcomes in patients with chronic kidney disease and T2D regardless of baseline HF status (G. Filippatos, 2021, submitted for publication). In FIGARO-DKD, finerenone reduced the primary composite endpoint of death from CV causes, non-fatal myocardial infarction, non-fatal stroke, or HF hospitalization with the benefit driven primarily by a lower incidence of HF hospitalization (84). In HOMAGE, in patients with, or at high risk for, coronary disease and raised NP levels, no interaction between baseline serum galectin-3 and changes in procollagen collagen biomarkers induced by spironolactone treatment was observed. However, blood pressure and NT-proBNP were reduced by spironolactone (85).

Activators of soluble guanylate-cyclase (VICTORIA)

The novel activator of soluble guanylate cyclase, vericiguat, in a subanalysis of the VICTORIA trial, did not reduce new-onset atrial fibrillation. However, pre-existing atrial fibrillation did not affect the beneficial effect of vericiguat on the primary composite outcome (time to CV death or first HF hospitalization) or its components (86). Similarly, beneficial effects of vericiguat were consistent across the full range of renal function (87).

Cardiac myosin activators

A substudy of the pivotal trial of the myosin activator omecamtiv mecarbil (GALACTIC-HF) in patients with HFrEF found that the drug reduced the primary endpoint of HF hospitalization and CV death more as EF declined with a 17% decrease in the lowest quartile (EF ≤ 22%) and no benefit in the highest quartile (EF ≥33%) (88).

Ferric carboxymaltose (AFFIRM-AHF; IRON-CRT)

Iron deficiency is related to worse outcomes in HF. The AFFIRM-AHF study demonstrated that in patients with LVEF <50% and iron deficiency after a hospitalization for acute HF, iv. treatment with ferric carboxymaltose did not only reduce HF hospitalizations but also results in clinically meaningful beneficial effects on quality of life (89). In HFrEF patients with iron deficiency and a persistently reduced LVEF <45% after cardiac resynchronization therapy (IRON-CRT) study, iv. ferric carboxymaltose FCM improved cardiac structure and function, as well as quality of life (90).

Iron deficiency also contributes to resistance to endo­genous erythropoietin, an important cause of anaemia in HF (91).


In a small clinical trial, CDR132L, an antisense oligonuc­leotide drug directed against miR-132 was well tolerated and seemed to be associated with cardiac functional improvement in HF patients (92–94).

In 50 patients with idiopathic chronic DCM and parvovirus B19 persistence, i.v. immunoglobulin therapy did not significantly improve LV systolic function or functional capacity beyond standard medical therapy (95).

Device and interventional therapies

Cardiac resynchronization therapy

In patients with HF, atrial fibrillation and a narrow QRS mortality and HF hospitalizations were reduced by atrio­ventricular junctional ablation and cardiac resynchronization therapy (CRT) compared with pharmacological treatment alone; this beneficial effect was similar in patients with LVEF ≤35% and >35% (96). Guidelines for CRT and suggestions for optimized implementation have recently been published (97, 98). The controversy about whether adding an ICD to CRT provide additional mortality benefit, especially in non-ischaemic HF continues (99).

Percutaneous mitral valve repair

The US Valvular Disease Guidelines as well as the 2021 ESC Guidelines on valvular heart disease recently upgraded the recommendation for transcatheter mitral valve repair (TEER) for secondary (functional) mitral regurgitation (SMR) to a IIA recommendation for patients who meet COAPT criteria (100, 101). A joint position statement from the ESC supports this recommendation (102). The 3-year results of the COAPT trial demonstrate the ongoing benefit of TEER (103). An important secondary analysis from COAPT demonstrates that residual 3–4+ SMR is the strongest risk factor for poor outcomes in both the TEER group and in the medical therapy group (104). In patients with atrial fibrillation, TEER was associated with a lower risk of stroke (105). Subgroups of MITRA-FR mimicking COAPT patients did not show a benefit of TEER, although a subgroup of COAPT mimicking MITRA-FR patients did show a benefit in HF hospitalizations (106, 107).

Implantable haemodynamic monitors

The GUIDE-HF trial evaluated haemodynamic guided management to reduce HF hospitalizations and mortality in patients with NYHA II-IV and all ejection fractions. The overall analysis was negative but when COVID-19 was accounted for there was a significant reduction in HF hospitalization in NYHA II-III patients with either a previous HF hospitalization or elevated NPs (108).

Specific management

Telemedicine and remote monitoring

In a comprehensive review, Bekfani and colleagues discuss unmet needs in the management of patients with HF, how remote monitoring might contribute to future solutions and provide an overview of current and novel remote monitoring technologies (109). A great variety of innovative remote monitoring technologies and algorithms including patient self-managed testing, wearable devices, technologies integrated into clinically indicated therapeutic devices, such as pacemakers and defibrillators, and landmark clinical trials of remote monitoring were reviewed.


In an Expert Panel consensus document on Cardiac Rehabilitation for Patients with Heart Failure, Bozkurt et al. (110) provide an overview of efficacy and safety evidence of exercise training and cardiac rehabilitation in HFrEF and HFpEF, recommendations on practical approaches to exercise training and cardiac rehabilitation in patients with HF and examine the reasons and solutions for underutilization of cardiac rehabilitation in HF patients. In the REHAB-HF trial, in a diverse population of older patients who were hospitalized for acute decompensated HF, an early, transitional, tailored, prog­ressive rehabilitation intervention that included multiple physical function domains resulted in greater improvement in physical function than usual care. This is an important study demonstrating the safety and efficacy of initiation of progressive rehabilitation initiated during and early post-hospitalization in HF patients regardless of LVEF (111).

Heart failure during the COVID-19 pandemic

Incident acute HF was recognized as a complication in 2%, and myocardial injury in 10% of all patients hospitalized with COVID-19 (112). Elevated admission NT-proBNP levels were associated with higher mortality (113) and cardiac myocyte-specific microRNAs were upregulated in critically ill COVID-19 patients indicating cardiac involvement (114). Declining overall admission rates for HF (115) and higher out-of-hospital mortality rates (116) during lockdown were recognized as alarming issues, reflecting lack of access to care among patients with established HF. Randomized trials demon­strated the safety of continuation of ACE inhibitors or ARB among patients hospitalized with COVID-19 (117–119). Dapagliflozin treatment did not significantly reduce organ dysfunction or death, but was well tole­rated in patients hospitalized with COVID-19 (DARE-19 trial) (120). Myocarditis emerged as a rare complication of COVID-19 mRNA vaccinations, especially in young men (121). Benefit–risk assessment for COVID-19 vaccination was favourable for all age and sex groups; and almost all patients with myocarditis had resolution of symptoms and signs (121). Long-term complications of SARS-CoV-2 infection include persistent sinus tachycardia, postural orthostatic tachycardia syndrome, atrial arrhythmia, and cardiomyopathy (122). Among athletes recovering from COVID-19, several CMR studies reported varying rates and degrees of cardiac abnormalities suggestive of myocarditis (123, 124). Screening by troponin, ECG, echocardiography, and additional CMR and/or stress echocardiography if abnormal, resulted in only 0.6% of the athletes being restricted to return to sports, and none had cardiac events (125). Though myocardial injury is common in COVID-19, and SARS-CoV-2 RNA can be detected in the heart, myocarditis is an uncommon pathologic diagnosis occurring in 4.5% of highly selected cases undergoing autopsy or endomyocardial biopsy (126). During convalescence after severe COVID-19 infection with troponin elevation, myo­carditis-like injury can be detected by CMR, however, with limited extent and minimal functional consequence (Figure 4) (127).


The authors wish to thank Dr. T. König for editorial assistance.

Conflict of interest: J.B. received honoraria for lectures/consulting from Novartis, Vifor, Bayer, Servier, Abiomed, Pfizer, Boehringer Ingelheim, AstraZeneca, Cardior, Daichii Sankyo, CVRx, BMS, MSD, Amgen, Corvia, not related to this article; and research support for the department from Zoll, CVRx, Vifor, Abiomed, not related to this article. In addition, J.B. is Scientific Advisory Board Member of Cardior and has a patent PCT/EP2007/008772 with royalties paid, and a patent PCT/EP2009/051986 with royalties paid both on microRNA and downstream targets for diagnostic and therapeutic purposes. The UMCG, which employs R.A.d.B. has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc., Novo Nordisk, and Roche. R.A.d.B. received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche. J.L. received honoraria for consultation from Abbott, Alleviant, AstraZeneca, Boehringer Ingelheim, Boston Scientific, CVRx, Edwards Lifesciences, Merck, Vwave and grant function from AstraZeneca, Volumetrix, Sensible Medical. B.B. received honoraria for consultation/advisory committee participation from Bayer, scPharmaceuticals, Vifor Pharma, Amgen, Relpysa, Baxter; and served in the Clinical Events Committee for Guide-HF Trial Abbott Pharmaceuticals and Data Safety Monitoring Board for Anthem Trial by Liva Nova Pharmaceuticals; none related to this article.

Reproduced from: Bauersachs et al. European Heart Journal (2022) 43, 367–376, by permission of Oxford University Press on behalf of the European Society of Cardiology

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1. Figtree GA, Broadfoot K, Casadei B, et al. A call to action for new global approaches to cardiovascular disease drug solutions. Eur Heart J 2021; 42: 1464–1475.

2. Bozkurt B, Coats AJS, Tsutsui H, et al. Universal definition and classification of heart failure: a report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure: endorsed by the Canadian Heart Failure Society, Heart Failure Association of India, Cardiac Society of Australia and New Zealand, and Chinese Heart Failure Association. Eur J Heart Fail 2021; 23: 352–380.

3. McDonagh TA, Metra M, Adamo M, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021; 42: 3599–3726.

4. Cleland JGF, Pfeffer MA, Clark AL, Januzzi JL, McMurray JJV, Mueller C, et al. The struggle towards a Universal Definition of Heart Failure – how to proceed? Eur Heart J 2021; 42: 2331–2343.

5. Seferovic PM, Vardas P, Jankowska EA, et al. The heart failure association atlas: heart failure epidemiology and management statistics 2019. Eur J Heart Fail 2021; 23: 906–914.

6. Wang M, Zhou T, Song Y, Li X, et al. Joint exposure to various ambient air pollutants and incident heart failure: a prospective analysis in UK Biobank. Eur Heart J 2021; 42: 1582–1591.

7. Restrepo-Cordoba MA, Wahbi K, Florian AR, et al. Prevalence and clinical outcomes of dystrophin-associated dilated cardiomyopathy without severe skeletal myopathy. Eur J Heart Fail 2021; 23: 1276–1286.

8. Ren Q-W, Yu S-Y, Teng T-HK, et al. Statin associated lower cancer risk and related mortality in patients with heart failure. Eur Heart J 2021; 42: 3049–3059.

9. Pieske B, Tschöpe C, de Boer RA, et al. How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J 2019; 40: 3297–3317.

10. Peyster EG, Arabyarmohammadi S, Janowczyk A, et al. An automated computational image analysis pipeline for histological grading of cardiac allograft rejection. Eur Heart J 2021; 42: 2356–2369.

11. Verdonschot JAJ, Merlo M, Dominguez F, et al. Phenotypic clustering of dilated cardiomyopathy patients highlights important pathophysiological differences. Eur Heart J 2021; 42: 162–174.

12. Woolley RJ, Ceelen D, Ouwerkerk W, et al. Machine learning based on biomarker profiles identifies distinct subgroups of heart failure with preserved ejection fraction. Eur J Heart Fail 2021; 23: 983–991.

13. Kwon J-M, Kim K-H, Eisen HJ, et al. Artificial intelligence assessment for early detection of heart failure with preserved ejection fraction based on electrocardiographic features. Eur Heart J Digital Health 2021; 2: 106–116.

14. Segar MW, Jaeger BC, Patel KV, et al. Development and validation of machine learning-based race-specific models to predict 10-year risk of heart failure: a multicohort analysis. Circulation 2021; 143: 2370–2383.

15. Hamdani N, Costantino S, Mugge A, et al. Leveraging clinical epigenetics in heart failure with preserved ejection fraction: a call for individualized therapies. Eur Heart J 2021; 42: 1940–1958.

16. Fraser AG, Tschope C, de Boer RA. Diagnostic recommendations and phenotyping for heart failure with preserved ejection fraction: knowing more and understanding less? Eur J Heart Fail 2021; 23: 964–972.

17. Raafs AG, Verdonschot JAJ, Henkens M, et al. The combination of carboxy-terminal propeptide of procollagen type I blood levels and late gadolinium enhancement at cardiac magnetic resonance provides additional prognostic information in idiopathic dilated cardiomyopathy – a multilevel assessment of myocardial fibrosis in dilated cardiomyopathy. Eur J Heart Fail 2021; 23: 933–944.

18. Sorimachi H, Obokata M, Takahashi N, et al. Pathophysiologic importance of visceral adipose tissue in women with heart failure and preserved ejection fraction. Eur Heart J 2021; 42: 1595–1605.

19. Withaar C, Meems LMG, de Boer RA. Fighting HFpEF in women: taking aim at belly fat. Eur Heart J 2021; 42: 1606–1608.

20. Assmus B, Cremer S, Kirschbaum K, Culmann D, Kiefer K, Dorsheimer L, et al. Clonal haematopoiesis in chronic ischaemic heart failure: prognostic role of clone size for DNMT3A- and TET2-driver gene mutations. Eur Heart J 2021; 42: 257–265.

21. Garnier S, Harakalova M, Weiss S, et al. Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23. Eur Heart J 2021; 42: 2000–2011.

22. SeferovićPM, Tsutsui H, McNamara DM, et al. Heart Failure Association of the ESC, Heart Failure Society of America and Japanese Heart Failure Society Position statement on endomyocardial biopsy. Eur J Heart Fail 2021; 23: 854–871.

23. Tersalvi G, Dauw J, Gasperetti A, et al. The value of urinary sodium assessment in acute heart failure. Eur Heart J Acute Cardiovasc Care 2021; 10: 216–223.

24. Biegus J, Zymliński R, Fudim M, et al. Spot urine sodium in acute heart failure: differences in prognostic value on admission and discharge. ESC Heart Fail 2021; 8: 2597–2602.

25. Mathew R, Di Santo P, Jung RG, et al. Milrinone as compared with dobutamine in the treatment of cardiogenic shock. N Engl J Med 2021; 385: 516–525.

26. Karami M, Eriksen E, Ouweneel DM, et al. Long-term 5-year outcome of the randomized IMPRESS in severe shock trial: percutaneous mechanical circulatory support vs. intra-aortic balloon pump in cardiogenic shock after acute myocardial infarction. Eur Heart J Acute Cardiovasc Care 2021; 10: 1009–1015.

27. Ceglarek U, Schellong P, Rosolowski M, et al. The novel cystatin C, lactate, interleukin-6, and N-terminal pro-B-type natriuretic peptide (CLIP)-based mortality risk score in cardiogenic shock after acute myocardial infarction. Eur Heart J 2021; 42: 2344–2352.

28. Arrigo M, Price S, Baran DA, et al. Optimising clinical trials in acute myocardial infarction complicated by cardiogenic shock: a statement from the 2020 Critical Care Clinical Trialists Workshop. Lancet Respir Med 2021; 9: 1192–1202.

29. Schmitto JD, Mariani S, Li T, et al. Five-year outcomes of patients supported with HeartMate 3: a single-centre experience. Eur J Cardiothorac Surg 2021; 59: 1155–1163.

30. Cho S-M, Mehaffey JH, Myers SL, et al. Cerebrovascular events in patients with centrifugal–flow left ventricular assist devices: a propensity score matched analysis from the intermacs registry. Circulation 2021; 144: 763–772.

31. Kassner A, Oezpeker C, Gummert J, et al. Mechanical circulatory support does not reduce advanced myocardial fibrosis in patients with end-stage heart failure. Eur J Heart Fail 2021; 23: 324–334.

32. Rivas-Lasarte M, Kumar S, Derbala MH, et al. Prediction of right heart failure after left ventricular assist implantation: external validation of the EUROMACS right-sided heart failure risk score. Eur Heart J Acute Cardiovasc Care 2021; 10: 723–732.

33. Emerson D, Chikwe J, Catarino P, et al. Contemporary left ventricular assist device outcomes in an aging population: an STS INTERMACS analysis. J Am Coll Cardiol 2021; 78: 883–894.

34. Agbor-Enoh S, Shah P, Tunc I, et al. Cell-free DNA to detect heart allograft acute rejection. Circulation 2021; 143: 1184–1197.

35. Sliwa K, van der Meer P, Petrie MC, et al. Risk stratification and management of women with cardiomyopathy/ heart failure planning pregnancy or presenting during/after pregnancy: a position statement from the Heart Failure Association of the European Society of Cardiology Study Group on Peripartum Cardiomyopathy. Eur J Heart Fail 2021; 23: 527–540.

36. Sliwa K, Petrie MC, van der Meer P, et al. Clinical presentation, management, and 6-month outcomes in women with peripartum cardiomyopathy: an ESC EORP registry. Eur Heart J 2020; 41: 3787–3797.

37. Farhan HA, Yaseen IF. Peripartum cardiomyopathy in Iraq: initial registry–based data and 6 month outcomes. ESC Heart Fail 2021; 8: 4048–4054.

38. Mbakwem AC, Bauersachs J, Viljoen C, et al. Electrocardiographic features and their echocardiographic correlates in peripartum cardiomyopathy: results from the ESC EORP PPCM registry. ESC Heart Fail 2021; 8: 879–889.

39. Jackson AM, Petrie MC, Frogoudaki A, et al. Hypertensive disorders in women with peripartum cardiomyopathy: insights from the ESC EORP PPCM Registry. Eur J Heart Fail 2021. 1002/ejhf.2264

40. Spertus JA, Fine JT, Elliott P, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): health status analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2021; 397: 2467–2675.

41. Pelliccia F, Gersh BJ, Camici PG. Gaps in evidence for risk stratification for sudden cardiac death in hypertrophic cardiomyopathy. Circulation 2021; 143: 101–103.

42. Marston NA, Han L, Olivotto I, et al. Clinical characteristics and outcomes in childhood-onset hypertrophic cardiomyopathy. Eur Heart J 2021; 42: 1988–1996.

43. Yilmaz A, Bauersachs J, Bengel F, et al. Diagnosis and treatment of cardiac amyloidosis: position statement of the German Cardiac Society (DGK). Clin Res Cardiol 2021; 110: 479–506.

44. Herrmann J, Lenihan D, Armenian S, et al. Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement. Eur Heart J 2021.
https: //

45. D’Souza M, Nielsen D, Svane IM, et al. The risk of cardiac events in patients receiving immune checkpoint inhibitors: a nationwide Danish study. Eur Heart J 2021; 42: 1621–1631.

46. Totzeck M, Lutgens E, Neilan TG. Are we underestimating the potential for cardiotoxicity related to immune checkpoint inhibitors? Eur Heart J 2021; 42: 1632–1635.

47. de Wit S, de Boer RA. From studying heart disease and cancer simultaneously to reverse cardio-oncology. Circulation 2021; 144: 93–95.

48. Michel L, Helfrich I, Hendgen-Cotta UB, et al. Targeting early stages of cardiotoxicity from anti-PD1 immune checkpoint inhibitor therapy. Eur Heart J 2021: ehab430.

49. Lehmann LH, Cautela J, Palaskas N, et al. Clinical strategy for the diagnosis and treatment of immune checkpoint inhibitor-associated myocarditis: a narrative review. JAMA Cardiol 2021; 6: 1329–1337.

50. de Boer RA, Hulot J-S, Tocchetti CG, et al. Common mechanistic pathways in cancer and heart failure. A scientific roadmap on behalf of the Translational Research Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur J Heart Fail 2020; 22: 2272–2289.

51. Zannad F, Cotter G, Alonso Garcia A, et al. What can heart failure trialists learn from oncology trialists? Eur Heart J 2021; 42: 2373–2383.

52. Bauersachs J. Heart failure drug treatment: the fantastic four. Eur Heart J 2021; 42: 681–683.

53. McMurray JJV, Packer M. How should we sequence the treatments for heart failure and a reduced ejection fraction? a redefinition of evidence-based medicine. Circulation 2021; 143: 875–877.

54. Rosano GMC, Moura B, Metra M, et al. Patient profiling in heart failure for tailoring medical therapy. A consensus document of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2021; 23: 872–881.

55. Porcher R, Desguerre I, Amthor H, et al. Association between prophylactic angiotensin-converting enzyme inhibitors and overall survival in Duchenne muscular dystrophy-analysis of registry data. Eur Heart J 2021; 42: 1976–1984.

56. Bhatt AS, Vaduganathan M, Claggett BL, et al. Effect of sacubitril/valsartan vs. enalapril on changes in heart failure therapies over time: the PARADIGM-HF trial. Eur J Heart Fail 2021; 23: 1518–1524.

57. Tsutsui H, Momomura SI, Saito Y, Ito H, Yamamoto K, Sakata Y, et al. Efficacy and safety of sacubitril/valsartan in Japanese patients with chronic heart failure and reduced ejection fraction-results from the PARALLEL-HF study. Circ J 2021; 85: 584–594.

58. Proudfoot C, Studer R, Rajput T, et al. Real-world effectiveness and safety of sacubitril/valsartan in heart failure: a systematic review. Int J Cardiol 2021; 331: 164–171.

59. Giovinazzo S, Carmisciano L, Toma M, et al. Sacubitril/valsartan in real-life European patients with heart failure and reduced ejection fraction: a systematic review and meta-analysis. ESC Heart Fail 2021; 8: 3547–3556.

60. Volpe M, Bauersachs J, Bayes-Genis A, et al. Sacubitril/valsartan for the management of heart failure: a perspective viewpoint on current evidence. Int J Cardiol 2021; 327: 138–145.

61. Jackson AM, Jhund PS, Anand IS, et al. Sacubitril-valsartan as a treatment for apparent resistant hypertension in patients with heart failure and preserved ejection fraction. Eur Heart J 2021; 42: 3741–3752.

62. Felker GM, Butler J, Ibrahim NE, et al. Implantable cardioverter-defibrillator eligibility after initiation of sacubitril/valsartan in chronic heart failure: insights From PROVE-HF. Circulation 2021; 144: 180–182.

63. Docherty KF, Campbell RT, Brooksbank KJM, et al. Effect of neprilysin inhibition on left ventricular remodeling in patients with asymptomatic left ventricular systolic dysfunction late after myocardial infarction. Circulation 2021; 144: 199–209.

64. Docherty KF, Campbell RT, Brooksbank KJM, et al. Rationale and methods of a randomized trial evaluating the effect of neprilysin inhibition on left ventricular remodelling. ESC Heart Fail 2021; 8: 129–138.

65. Jering KS, Claggett B, Pfeffer MA, et al. Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI): design and baseline characteristics. Eur J Heart Fail 2021; 23: 1040–1048.

66. Shah SJ, Cowie MR, Wachter R, al. Baseline characteristics of patients in the PARALLAX trial: insights into quality of life and exercise capacity in heart failure with preserved ejection fraction. Eur J Heart Fail 2021; 23: 1541–1551.

67. Spertus JA. Quality of life in EMPEROR-Reduced: emphasizing what is important to patients while identifying strategies to support more patient-centred care. Eur Heart J 2021; 42: 1213–1215.

68. Kosiborod MN, Jhund PS, Docherty KF, 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: 90–99.

69. Butler J, Anker SD, Filippatos G, et al. Empagliflozin and health-related quality of life outcomes in patients with heart failure with reduced ejection fraction: the EMPEROR-Reduced trial. Eur Heart J 2021; 42: 1203–1212.

70. Abraham WT, Lindenfeld J, Ponikowski P, et al. Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction, with and without type 2 diabetes. Eur Heart J 2021; 42: 700–710.

71. Solomon SD, Jhund PS, Claggett BL, et al. Effect of dapagliflozin in patients with HFrEF treated with sacubitril/valsartan: the DAPA-HF trial. JACC Heart Fail 2020; 8: 811–818.

72. Packer M, Anker SD, Butler J, et al. 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; 42: 671–680.

73. Lam CSP, Ferreira JP, Pfarr E, Sim D, Tsutsui H, Anker SD, et al. Regional and ethnic influences on the response to empagliflozin in patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial. Eur Heart J 2021; 42: 4442–4451.

74. Inzucchi SE, Docherty KF, Køber L, et al. Dapagliflozin and the incidence of type 2 diabetes in patients with heart failure and reduced ejection fraction: an exploratory analysis from DAPA-HF. Diabetes Care 2021; 44: 586–594.

75. McMurray JJV, Solomon SD, Docherty KF, Jhund PS. The Dapagliflozin and Prevention of Adverse outcomes in Heart Failure trial (DAPA-HF) in context. Eur Heart J 2021; 42: 1199–1202.

76. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021; 385: 1451–1461.

77. Anker SD, Butler J, Filippatos GS, et al. Evaluation of the effects of sodium–glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR-Preserved Trial. Eur J Heart Fail 2019; 21: 1279–1287.

78. Solomon SD, de Boer RA, DeMets D, et al. Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial. Eur J Heart Fail 2021; 23: 1217–1225.

79. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2021; 384: 117–128.

80. Tromp J, Ponikowski P, Salsali A, et al. Sodium–glucose co-transporter 2 inhibition in patients hospitalized for acute decompensated heart failure: rationale for and design of the EMPULSE trial. Eur J Heart Fail 2021; 23: 826–834.

81. Heerspink HJL, Sjostrom CD, Jongs N, et al. Effects of dapagliflozin on mortality in patients with chronic kidney disease: a pre-specified analysis from the DAPA-CKD randomized controlled trial. Eur Heart J 2021; 42: 1216–1227.

82. Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med 2021; 384: 129–139.

83. Agarwal R, Kolkhof P, Bakris G, et al. Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine. Eur Heart J 2021; 42: 152–161.

84. Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med 2021; 385: 2252–2263.

85. Cleland JGF, Ferreira JP, Mariottoni B, et al. The effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure: the heart ‘OMics’ in AGEing (HOMAGE) randomized clinical trial. Eur Heart J 2021; 42: 684–696.

86. Ponikowski P, Alemayehu W, Oto A, et al. Vericiguat in patients with atrial fibrillation and heart failure with reduced ejection fraction: insights from the VICTORIA trial. Eur J Heart Fail 2021; 23: 1300–1312.

87. Voors AA, Mulder H, Reyes E, et al. Renal function and the effects of vericiguat in patients with worsening heart failure with reduced ejection fraction: insights from the VICTORIA (Vericiguat Global Study in Subjects with HFrEF) trial. Eur J Heart Fail 2021; 23: 1313–1321.

88. Teerlink JR, Diaz R, Felker GM, et al. Effect of ejection fraction on clinical outcomes in patients treated with omecamtiv mecarbil in GALACTIC-HF. J Am Coll Cardiol 2021; 78: 97–108.

89. Jankowska EA, Kirwan BA, Kosiborod M, Butler J, Anker SD, McDonagh T, et al. The effect of intravenous ferric carboxymaltose on health-related quality of life in iron-deficient patients with acute heart failure: the results of the AFFIRM-AHF study. Eur Heart J 2021; 42: 3011–3020.

90. Martens P, Dupont M, Dauw J, et al. The effect of intravenous ferric carboxymaltose on cardiac reverse remodelling following cardiac resynchronization therapy-the IRON-CRT trial. Eur Heart J 2021: ehab411.

91. Tkaczyszyn M, Comin-Colet J, Voors AA, et al. Iron deficiency contributes to resistance to endogenous erythropoietin in anaemic heart failure patients. Eur J Heart Fail 2021; 23: 1677–1686.

92. Täubel J, Hauke W, Rump S, 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; 42: 178–188.

93. Devaux Y, Badimon L. CDR132L: another brick in the wall towards the use of miRNAs to treat cardiovascular disease. Eur Heart J 2021; 42: 202–204.

94. Baker AH, Giacca M. Antagonism of miRNA in heart failure: first evidence in human. Eur Heart J 2021; 42: 189–191.

95. Hazebroek MR, Henkens MTHM, Raafs AG, et al. Intravenous immunoglobulin therapy in adult patients with idiopathic chronic cardiomyopathy and cardiac parvovirus B19 persistence: a prospective, double-blind, randomized, placebo-controlled clinical trial. Eur J Heart Fail 2021; 23: 302–309.

96. Brignole M, Pentimalli F, Palmisano P, et al. AV junction ablation and cardiac resynchronization for patients with permanent atrial fibrillation and narrow QRS: the APAF-CRT mortality trial. Eur Heart J 2021; 42: 4731–4739.

97. Glikson M, Nielsen JC, Kronborg MB, et al. 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Europace. 2021: euab232.

98. Mullens W, Auricchio A, Martens P, et al. Optimized implementation of cardiac resynchronization therapy: a call for action for referral and optimization of care: A joint position statement from the Heart Failure Association (HFA), European Heart Rhythm Association (EHRA), and European Association of Cardiovascular Imaging (EACVI) of the European Society of Cardiology. Eur J Heart Fail 2020; 22: 2349–2369.

99. Schrage B, Lund LH, Melin M, Benson L, et al. Cardiac resynchronization therapy with or without defibrillator in patients with heart failure. Europace 2021: euab233.

100. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Thorac Cardiovasc Surg 2021; 162: e183–e353.

101. Vahanian A, Beyersdorf F, Praz F, et al. 2021 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2021: ehab395.

102. Coats AJS, Anker SD, Baumbach A, et al. The management of secondary mitral regurgitation in patients with heart failure: a joint position statement from the Heart Failure Association (HFA), European Association of Cardiovascular Imaging (EACVI), European Heart Rhythm Association (EHRA), and European Association of Percutaneous

103. Mack MJ, Lindenfeld J, Abraham WT, et al. 3-year outcomes of transcatheter mitral valve repair in patients with heart failure. J Am Coll Cardiol 2021; 77: 1029–1040.

104. Kar S, Mack MJ, Lindenfeld J, et al. Relationship between residual mitral regurgitation and clinical and quality-of-life outcomes after transcatheter and medical treatments in heart failure: COAPT trial. Circulation 2021; 144: 426–437.

105. Gertz ZM, Herrmann HC, Lim DS, et al. Implications of atrial fibrillation on the mechanisms of mitral regurgitation and response to MitraClip in the COAPT trial. Circ Cardiovasc Interv 2021; 14: e010300.

106. Iung B, Messika-Zeitoun D, Boutitie F, et al. Characteristics and outcome of COAPT-eligible patients in the MITRA-FR trial. Circulation 2020; 142: 2482–2484.

107. Lindenfeld J, Abraham WT, Grayburn PA, et al. Association of effective regurgitation orifice area to left ventricular end-diastolic volume ratio with transcatheter mitral valve repair outcomes: a secondary analysis of the COAPT trial. JAMA Cardiol 2021; 6: 427–436.

108. Lindenfeld J, Zile MR, Desai AS, et al. Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial. Lancet 2021; 398: 991–1001.

109. Bekfani T, Fudim M, Cleland JGF, Jorbenadze A, von Haehling S, Lorber A, et al. A current and future outlook on upcoming technologies in remote monitoring of patients with heart failure. Eur J Heart Fail 2021; 23: 175–185.

110. Bozkurt B, Fonarow GC, Goldberg LR, et al. Cardiac rehabilitation for patients with heart failure: JACC expert panel. J Am Coll Cardiol 2021; 77: 1454–1469.

111. Kitzman DW, Whellan DJ, Duncan P, Pastva AM, Mentz RJ, Reeves GR, et al. Physical rehabilitation for older patients hospitalized for heart failure. N Engl J Med 2021; 385: 203–216.

112. Harrison SL, Buckley BJR, Rivera-Caravaca JM, et al. Cardiovascular risk factors, cardiovascular disease, and COVID-19: an umbrella review of systematic reviews. Eur Heart J Qual Care Clin Outcomes 2021; 7: 330–339.

113. Yoo J, Grewal P, Hotelling J, S, et al. Admission NT-proBNP and outcomes in patients without history of heart failure hospitalized with COVID-19. ESC Heart Fail 2021; 8: 4278–4287.

114. Garg A, Seeliger B, Derda AA, et al. Circulating cardiovascular microRNAs in critically ill COVID-19 patients. Eur J Heart Fail 2021; 23: 468–475.

115. Charman SJ, Velicki L, Okwose NC, et al. Insights into heart failure hospitalizations, management, and services during and beyond COVID-19. ESC Heart Fail 2021; 8: 175–182.

116. Butt JH, Fosbøl EL, Gerds TA, et al. All-cause mortality and location of death in patients with established cardiovascular disease before, during, and after the COVID-19 lockdown: a Danish Nationwide Cohort Study. Eur Heart J 2021; 42: 1516–1523.

117. Bauer A, Schreinlechner M, Sappler N, et al. Discontinuation versus continuation of renin-angiotensin-system inhibitors in COVID-19 (ACEI-COVID): a prospective, parallel group, randomised, controlled, open-label trial. Lancet Respir Med 2021; 9: 863–872.

118. Lopes RD, Macedo AVS, de Barros ESPGM, et al. Effect of discontinuing vs continuing angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on days alive and out of the hospital in patients admitted with COVID-19: a randomized clinical trial. JAMA 2021; 325: 254–264.

119. Cohen JB, Hanff TC, William P, et al. Continuation versus discontinuation of renin–angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial. Lancet Respir Med 2021; 9: 275–284.

120. Kosiborod MN, Esterline R, Furtado RHM, et al. Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol 2021; 9: 586–594.

121. Bozkurt B, Kamat I, Hotez PJ. Myocarditis with COVID-19 mRNA vaccines. Circulation 2021; 144: 471–484.

122. Huang C, Huang L, Wang Y, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet 2021; 397: 220–232.

123. Rajpal S, Tong MS, Borchers J, et al. Cardiovascular magnetic resonance findings in competitive athletes recovering from COVID-19 infection. JAMA Cardiol 2021; 6: 116–118.

124. Clark DE, Parikh A, Dendy JM, et al. COVID-19 myocardial pathology evaluation in athletes with cardiac magnetic resonance (COMPETE CMR). Circulation 2021; 143: 609–612.

125. Martinez MW, Tucker AM, Bloom OJ, et al. Prevalence of inflammatory heart disease among professional athletes with prior COVID-19 infection who received systematic return-to-play cardiac screening. JAMA Cardiol 2021; 6: 745–752.

126. Kawakami R, Sakamoto A, Kawai K, et al. Pathological evidence for SARS-CoV-2 as a cause of myocarditis: JACC review topic of the week. J Am Coll Cardiol 2021; 77: 314–325.

127. Kotecha T, Knight DS, Razvi Y, et al. Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance. Eur Heart J 2021; 42: 1866–1878.