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This issue opens with the ‘2020 ESC Guidelines for the management of adult congenital heart disease: The Task Force for the management of adult congenital heart disease of the European Society of Cardiology (ESC)’, authored by Helmut Baumgartner from the University Hospital Muenster in Germany and colleagues from the ESC Scientific Document Group.1 The population of adults with congenital heart disease (CHD) has risen dramatically over the last 60 years, in large part due to the success of cardiac surgery and paediatric cardiac care. In most western civilizations, >85% of babies born with CHD can now be expected to survive to adulthood.1–3 These Guidelines address the many challenges regarding the management of adults with congenital heart disease. The authors note that since the previous version of the Guidelines on the management of grown-up CHD was published in 2010, new evidence has accumulated for this patient group, particularly on percutaneous interventional techniques and risk stratification with regard to timing of surgery and catheter intervention, as well as medical treatment. This has made a revision of the recommendations necessary. Since adult patients with CHD now present in increasing numbers at advanced ages, including the elderly, the term grown-up CHD no longer appears appropriate and has therefore been replaced with adult CHD throughout the document. This is also in accordance with the international literature.
The next article is from the ‘Year in Cardiovascular Medicine’ series. In ‘The year in cardiovascular medicine 2020: valvular heart disease’, Javier Bermejo from the Universidad Complutense de Madrid and CIBERCV in Spain, and colleagues note that valvular heart disease is one of the most rapidly changing disciplines in cardiovascular medicine.4 During the past year, important basic research has provided new insight on disease mechanisms and identified new potential targets for pharmacological treatment (Figure 1). Despite the unequivocal impact of COVID-19, the results of landmark clinical trials with percutaneous devices have become available. Aspects of adjuvant medical therapies after device implantation have also been clarified. Technical improvements in next-generation valvular medical devices are taking place in parallel, showing promising preliminary clinical results. As the risk related to intervention procedures and their consequences is becoming lower, new opportunities for an earlier treatment arise.
Proposed framework for classifying coexisting mitral regurgitation and severe LV systolic dysfunction. This framework is based on ancillary analyses of randomized clinical trials and prospective validation is pending. ERO: effective regurgitant orifice. EDV: end-diastolic volume. TMVr: transcatheter mitral valve repair. (from Bermejo J, Postigo A, Baumgartner H. The year in cardiovascular medicine 2020: valvular heart disease. See pages 647–656).
The issue continues with a focus on Heart Failure and Cardiomyopathies. In the Special Article entitled ‘The year in cardiovascular medicine 2020: heart failure and cardiomyopathies’, Héctor Bueno from the Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid, Spain, and colleagues,5 again from the ‘Year in Cardiovascular Medicine’ series, highlights that 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 and HF with preserved ejection fraction (HFpEF), or monitoring cardiotoxicity; and a new definition of HF with recovered left ventricular ejection fraction (LVEF) was released. Benefits of renin–angiotensin–aldosterone system inhibitors and beta-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 co-transporter 2 (SGLT2) inhibitors empagliflozin and sotagliflozin in patients with HF arereported. The EMPEROR Reduced trial in patients with HF with reduced EF (HFrEF) with or without type 2 diabetes (T2DM) demonstrated a significant reduction of cardiovascular death and HF hospitalizations (HFHs) in patients randomized to empaglifozin. In patients with T2DM and HF across the whole EF spectrum after a recent HFH, the SOLOIST trial showed a reduction of the primary endpoint of cardiovascular deaths, total HFHs, and urgent visits for HF in patients randomized to sotaglifozin. In addition, in patients with kidney disease with or without diabetes mellitus (DAPA-CKD), dapagliflozin prevented 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 HF decompensation (Figure 2).
During 2020, we learned new options to better stratify patients with heart failure and preserved left ventricular ejection fraction (HFpEF) (A), the clinical benefit of three new drugs to improve prognosis of patient with heart failure and reduced left ventricular ejection fraction (HFrEF): empagliflozin, vericiguat, and omecamtiv mecarbil (B), the potential benefit of a broader utilization of recommended drugs for HFrEF in patients with left ventricular ejection fraction >40% (C), and the potential added clinical benefit of a comprehensive use of recommended drugs for HFrEF (D) in a year marked by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic (central cartoon). (from Bueno H, Moura B, Lancellotti P, Bauersachs J. The year in cardiovascular medicine 2020: heart failure and cardiomyopathies. See pages 657–680)
As noted above, SGLT2s initially proposed for the treatment of T2DM have then been found to improve the outcomes of HFrEF.6 The question remains, however, of whether the nominally ‘standard’ heart failure drug treatment in the SGLT2 inhibitor trials corresponded to a ‘real’ modern guideline-directed medical therapy.7 In a Fast Track clinical research article entitled ‘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’,8 Milton Packer from the Baylor University Medical Center at Dallas, Texas, USA, and colleagues evaluated the influence of background treatment with sacubitril/valsartan on the effects of SGLT2 inhibition with empagliflozin in patients with HFrEF. The EMPEROR-Reduced trial randomized 3730 patients with HF and an EF ≤40% to placebo or empagliflozin (10 mg/day), in addition to recommended treatment for HF, for a median of 16 months. About 20% of patients were receiving sacubitril/valsartan at baseline. Patients receiving a neprilysin inhibitor were particularly well treated, as evidenced by lower systolic pressures, heart rates, N-terminal probrain natriuretic protein (NT-proBNP), and greater use of cardiac devices (all P < 0.001) when compared with those not receiving sacubitril/valsartan. Nevertheless, when compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for HF by 23% in the patients not taking a neprilysin inhibitor (P = 0.0008) and by 36% in the patients taking a neprilysin inhibitor (P = 0.009); interaction P = 0.31. In addition, empagliflozin significantly and similarly slowed the rate of decline in estimated glomerular filtration rate (eGFR) in patients not taking and in patients taking a neprilysin inhibitor. Combined inhibition of an SGLT2 and neprilysin caused minimal incremental changes in blood pressure and was well tolerated.
The authors conclude that the effects of empagliflozin to favourably affect the clinical course of HF and kidney function are not diminished in intensively treated patients who are receiving concurrent therapy with sacubitril/valsartan. In contrast, combined treatment with both SGLT2 and neprilysin inhibitors can be expected to yield substantial additional benefits. The manuscript is accompanied by an Editorial by Johann Bauersachs from the Medizinische Hochschule Hannover in Germany.9 In his commentary, the author concludes that the totality of evidence now suggests that patients with HFrEF should be treated early with a combination of the four drugs [an angiotensin receptor–neprilysin inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor] to fully benefit from substantial and sustained reductions of mortality and HFHs. The important task now is to ensure access to this evidence-based therapy for all HFrEF patients.
In a clinical research article entitled ‘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’, John Cleland from the University of Glasgow, and colleagues investigated the effects of spironolactone on fibrosis and cardiac function in people at increased risk of developing HF10 in a randomized, open-label, blinded-endpoint trial comparing spironolactone (50 mg/day) or control for up to 9 months in people with, or at high risk of coronary artery disease and raised plasma BNPs. The primary endpoint was the interaction between baseline serum galectin-3 and changes in serum procollagen type-III N-terminal pro-peptide (PIIINP) in participants assigned to spironolactone or control. Procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP), reflecting synthesis and degradation of type-I collagen, were also measured. In 527 participants, changes in PIIINP were similar for spironolactone and control, but those receiving spironolactone had greater reductions in PICP and the PICP/CITP ratio. No interactions with serum galectin-3 were observed.
The authors conclude that galectin-3 does not identify greater reductions in serum concentrations of collagen biomarkers in response to spironolactone. However, spironolactone may influence type-I collagen metabolism. The manuscript is accompanied by an Editorial by Bertram Pitt and James Brian Byrd from the University of Michigan School of Medicine in Ann Arbor, Michigan, USA.11 The authors conclude that while the major use of MRAs currently is in patients with HFrEF, it is reasonable to predict that on the basis of HOMAGE and other recent findings, in the near future the use of MRAs will be expanded, using new means to identify inappropriate mineralocorticoid receptor activation, to prevent rather than to treat HF, resistant hypertension, and chronic kidney disease.
While SGLT2 inhibition has consistently been found to improve the outcome of patients with HFrEF regardless of the diabetic status, its effects on symptoms in patients with HFrEF or HHpEF are poorly known. The EMPERIAL programme was designed to prospectively evaluate the effect of the SGLT2 inhibitor empagliflozin on exercise ability and symptom burden in HF through two conceptually identical randomized trials, enrolling patients with HFrEF or HFpEF, with or without T2DM. Thus, in the clinical research article entitled ‘Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction, with and without type 2 diabetes’, William Abraham from the the Ohio State University in Columbus, Ohio, USA and colleagues enrolled patients with HFrEF (≤40%, n = 312, EMPERIAL-Reduced) or HFpEF (>40%, n = 315, EMPERIAL-Preserved) who were randomized to empagliflozin 10 mg or placebo for 12 weeks.12 The primary endpoint was the 6-min walk test distance change to week 12. Key secondary endpoints included the Kansas City Cardiomyopathy Questionnaire Total Symptom Score and the Chronic Heart Failure Questionnaire. Empaglifozin failed to improve the primary endpoint and the secondary endpoints.
Abraham et al. conclude that the primary outcome for both trials was neutral. Nevertheless, they found hypothesis-generating improvements in exploratory analyses of secondary endpoints with empagliflozin in HFrEF. The manuscript is accompanied by an Editorial by Mark C. Petrie from the University of Glasgow, and colleagues.13 The authors note that the 6-min walk distance does not appear to be the optimum ‘patient-centred’ outcome. Indeed, the 6-min distance can be affected by many HF-related comorbidities such as arthritis, previous stroke, obesity, and lung disease, and is therefore not an optimal measure of improvement in patients’ HF status. The impact of these comorbidites may be even more relevant in HFpEF where comorbidities are more prevalent and more severe.
The issue is further complemented by one Discussion Forum contribution, a manuscript entitled ‘On risk stratification and its paradoxes: the physician as a risk factor?’ by Pedro Brugada from the Free University of Brussels (UZ Brussel) VUB in Belgium.14
The editors hope that this issue of the European Heart Journal will be of interest to its readers.
With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.
