Treatment of heart failure across the spectrum of left ventricular ejection fraction and an update on cardiac amyloidosis and ischaemic cardiomyopathy

With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article. For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This issue opens with two Special Articles of the series the Year in Cardiovascular Medicine. The first article is the ‘The year in cardiovascular medicine 2021: heart failure and cardiomyopathies’ by Johann Bauersachs from the Medizinische Hochschule Hannover, and colleagues.1 In 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 (HFrEF), mildly reduced, and preserved ejection fraction (HFpEF) are 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 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 carboxymaltose, soluble guanylate cyclase activators, and cardiac myosin activators. The second article from this series is ‘The year in cardiovascular medicine 2021: interventional cardiology’ by Javier Escaned from the Hospital Clinico Universitario San Carlos in Madrid, Spain, and colleagues.2 Since last year’s report, the authors have witnessed substantial progress in all aspects of interventional cardiology. Of note, the practice of interventional cardiology took place amidst successive waves of the COVID-19 pandemic, which continues to be a major burden for all healthcare professionals around the globe. In this review, the authors revisit the developments in percutaneous coronary intervention (PCI), structural heart interventions, and adjunctive pharmacotherapy. The issue continues with a focus on HF and cardiomyopathies. Ischaemic cardiomyopathy (ICM) is the most frequent cause of HFrEF; its management is complex and widely debated.3,4 In a Viewpoint article entitled ‘Myocardial revascularization in ischaemic cardiomyopathy: routine practice vs. scientific evidence’, Raffaele De Caterina from Pisa University Hospital and University of Pisa in Italy, and colleagues indicate that patients with extensive coronary artery disease and ICM have an unfavourable prognosis.5 Current ESC guidelines recommend myocardial revascularization in ICM patients with suitable coronary anatomy, using either coronary artery bypass graft (CABG) or PCI. Real-world data indicate that PCI has become the revascularization strategy of choice in ICM, with usage rates now nearly three times higher than CABG. The authors summarize the scientific evidence for revascularization with either CABG or PCI in patients with ICM, the guiding principles to support its continued use, and the disturbing discordance between current clinical practice and scientific evidence. Subject phenotypes and the most common genotype in subjects enrolled in THAOS in continental Western Europe. Data are from all European countries included in THAOS. Shown are: the total number of subjects from each country in THAOS, the proportions of each phenotype, and the most common mutation in each country (with its percentage of all subjects in that country). Not shown are: Belgium, three subjects with cardiac + neurological phenotype (genotypes: Val30Met, Glu54Leu, and Glu74Leu); and Cyprus, one subject with neurological phenotype (genotype: Val30Met). Note that the most common form of ATTR amyloidosis in Germany and Italy was ATTRwt (41.6% and 34.2% of all subjects, respectively).14 Transthyretin amyloidosis (ATTR amyloidosis) is a heterogeneous disorder with cardiac, neurological, and mixed phenotypes.6–13 In a Clinical Research article entitled ‘Transthyretin cardiac amyloidosis in continental Western Europe: an insight through the Transthyretin Amyloidosis Outcomes Survey (THAOS)’, Thibaud Damy from the GRC Amyloid Research Institute in Créteil, France, and colleagues describe the phenotypic and genotypic profile of this disease in continental Western Europe as it appears from the Transthyretin Amyloidosis Survey (THAOS).14 THAOS is an ongoing, worldwide, longitudinal, observational survey established to study differences in presentation, diagnosis, and natural history in ATTR amyloidosis subjects. At data cut-off, 1411 symptomatic subjects from nine continental Western European countries were enrolled in THAOS [1286 hereditary (ATTRm) amyloidosis; 125 wild-type ATTR (ATTRwt) amyloidosis]. Genotypes and phenotypes varied notably by country. Four mutations (Val122Ile, Leu111Met, Thr60Ala, and Ile68Leu) and ATTRwt were associated with a mainly cardiac phenotype showing symmetric left ventricular (LV) hypertrophy, normal diastolic LV dimensions and volume, and mildly depressed LV ejection fraction (LVEF). Morphological and functional abnormalities on echocardiogram were significantly more severe in subjects with cardiac, compared with a mixed phenotype characterized by higher median interventricular septal thickness (18 vs. 16 mm; P = 0.0006) and greater prevalence of LVEF <50% (38 vs. 17%; P = 0.0008). Subjects with cardiac mutations or ATTRwt (or cardiac or mixed phenotype) had a lower survival rate than subjects with other genotypes (or the neurological phenotype) (P < 0.0001, for both). The authors conclude that ATTR amyloidosis genotypes and phenotypes are highly heterogeneous in continental Western Europe. A geographic map of the different disease profiles and awareness that a subset of subjects have a dominant cardiac phenotype, mimicking hypertrophic cardiomyopathy, at presentation can facilitate the clinical recognition of this underdiagnosed disease. This manuscript is accompanied by an Editorial by Enrico Ammirati from the Niguarda Hospital in Milan, Italy and Omar AbouEzzeddine from the Mayo Clinic, Rochester, MN, USA.15 The authors conclude that ATTR is a broad spectrum of diseases with diverse genotypes, heterogeneous phenotypes, and variable geographic distribution. Current registries under-represent patients with ATTRwt and ATTRm with cardiac genotypes. The advent of non-invasive, scintigraphy-based diagnostic techniques has increased recognition of ATTR cardiomyopathy. Future registries ought to incorporate more patients with ATTR and track cardiac and systemic biomarkers to improve phenotypic classification, disease staging, and risk stratification. Finally, in this exciting era of therapeutic advances, studying the impact of novel disease-modifying agents on clinical course and outcomes is crucial. In another Clinical Research article entitled ‘Primary care heart failure service identifies a missed cohort of heart failure patients with reduced ejection fraction’, Matthew Kahn from the Liverpool Heart and Chest Hospital NHS Foundation Trust in the UK, and colleagues explored whether a missed cohort of patients in the community with HF and LV systolic dysfunction (LVSD) could be identified and receive treatment optimization through a primary care HF (PCHF) service.16 A PCHF service is a partnership between Inspira Health, National Health Service Cardiologists, and Medtronic. The PCHF service uses retrospective clinical audit to identify patients requiring a prospective face-to-face consultation with a consultant cardiologist for clinical review of their HF management within primary care. The service is delivered via five phases: (i) interrogation of general practitioner (GP) systems; (ii) clinical audit of medical records; (iii) patient invitation; (iv) consultant reviews; and (v) follow-up. A total of 78 GP practices (864 194 population) have participated. The service found that within primary care, 27% of HF patients identified for a cardiologist consultation were eligible for complex device therapy, 45% required optimization of medicines, and 47% of patients audited required diagnosis codes adding to their GP record. The authors conclude that a PCHF service can identify a missed cohort of patients with HF and LVSD, enabling the optimization of prognostic medication and an increase in device prescription. The contribution is accompanied by an Editorial by Lars Lund from the Karolinska Institutet in Stockholm, Sweden, and colleagues.17 The authors conclude that the PCHF service resulted in an increase by ∼40% of the number of patients receiving optimal care. Although no clinical outcomes were reported, it is not unreasonable to expect that this translated into improved outcomes. Medical records-based screening has the potential to identify previously unrecognized HF diagnoses and HF undertreatment. Screening is widely accepted in other areas of medicine and should be further studied in HF. Influence of ejection fraction on the effect of empagliflozin on time to cardiovascular death or hospitalization for heart failure. Ejection fraction is analysed as a continuous variable, based on the assumption that the relationship is linear. Analysis of the influence of ejection fraction using cubic splines yielded a pattern similar to that observed in our six subgroups, showing a consistent risk reduction in patients with an ejection fraction <65% and an attenuated effect at the highest ejection fractions. Shaded areas represent 95% confidence intervals.22 SGLT2 inhibitors have emerged as a key treatment of HF.18–21 In a Clinical Research article entitled ‘Effect of empagliflozin in patients with heart failure across the spectrum of left ventricular ejection fraction’, Javed Butler from the University of Mississippi School of Medicine in Jackson, MS, USA, and colleagues assessed the influence of EF on the effect of the SGLT2 inhibitor empagliflozin on HF outcomes.22 A pooled analysis was performed on both the EMPEROR-Reduced and EMPEROR-Preserved trials (9718 patients), and patients were grouped based on EF: <25, 25–34, 35–44, 45–54, 55–64, and ≥65%. Outcomes assessed included (i) time to first hospitalization for HF or cardiovascular mortality; (ii) time to first HF hospitalization; (iii) total (first and recurrent) hospitalizations for HF; and (iv) health status assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). The risk of cardiovascular death and hospitalization for heart failure declined progressively as EF increased from <25% to ≥65%. Empagliflozin reduced the risk of cardiovascular death or HF hospitalization, mainly by reducing HF hospitalizations. Empagliflozin reduced the risk of HF hospitalization by ∼30% in all EF subgroups, with an attenuated effect in patients with an EF ≥65%. Hazard ratios were: EF <25%, 0.73; EF 25–34%, 0.63; EF 35–44%, 0.72; EF 45–54%, 0.66; EF 55–64%, 0.70; and EF ≥65%, 1.05. Other HF outcomes, including KCCQ, showed a similar response pattern. Sex did not influence the responses to empagliflozin. The authors conclude that the magnitude of the effect of empagliflozin on HF outcomes is clinically meaningful and similar in patients with EF <25% to <65% but is attenuated in patients with an EF ≥65%. The manuscript is accompanied by an Editorial by John McMurray and Toru Kondo from the University of Glasgow in the UK.23 The authors note that the two most novel aspects of the new ESC guidelines on HF were the strong recommendation given to SGLT2 inhibitors as a treatment for HFrEF (EF ≤40%) and the first ever recommendation of any therapy for the renamed HFmrEF (EF >40% to <50%). Use of all the major neurohumoral-modulating therapies was proposed in the latter patients, although the recommendation was much weaker than for patients with HFrEF because it was based on retrospective analyses of trials which suggested benefit of these treatments in certain patients with an EF >40%, i.e. probably those with some degree of LV systolic dysfunction. The precise upper EF threshold above which there is no benefit remains uncertain and a source of debate. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Respectful language and putting the person first with obesity’, Simar Singh Bajaj from Harvard University in Cambridge, MA, USA, and colleagues comment on the recent publication ‘Obesity modifies the energetic phenotype of dilated cardiomyopathy’ by Jennifer J. Rayner from the University of Oxford in the UK.24,25 Rayner et al. respond in a separate comment.26 The editors hope that this issue of the European Heart Journal will be of interest to its readers.