A new classification of iron-deficient heart failure, sex-related differences in the management of atrial fibrillation and mitral regurgitation, and an update on the genetics of Brugada syndrome

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on heart failure, valvular heart disease, and arrhythmias contains the State of the Art Review article entitled ‘Identification of three mechanistic pathways for iron-deficient heart failure’ by Milton Packer from the Baylor University Medical Center in Dallas, TX, USA, and colleagues. The authors note that treatment of iron deficiency is playing a growing role in the management of heart failure (HF).1–3 Current understanding of iron-deficient HF is based on blood tests that are thought to reflect systemic iron stores, but the available evidence suggests greater complexity.4 The entry and egress of circulating iron is controlled by erythroblasts, which (in severe iron deficiency) will sacrifice erythropoiesis to supply iron to other organs, e.g. the heart. Marked hypoferraemia (typically with anaemia) can drive the depletion of cardiomyocyte iron, impairing contractile performance and explaining why a transferrin saturation less than ∼15%–16% predicts the ability of intravenous iron to reduce the risk of major HF events in long-term trials (Type 1 iron-deficient HF). However, HF may be accompanied by intracellular iron depletion within skeletal muscle and cardiomyocytes, which is disproportionate to the findings of systemic iron biomarkers. Inflammation- and deconditioning-mediated skeletal muscle dysfunction—a primary cause of dyspnoea and exercise intolerance in patients with HF—is accompanied by intracellular skeletal myocyte iron depletion, which can be exacerbated by even mild hypoferraemia, explaining why symptoms and functional capacity improve following intravenous iron, regardless of baseline haemoglobin or changes in haemoglobin (Type 2 iron-deficient HF). Additionally, patients with advanced HF show myocardial iron depletion due to both diminished entry of iron into and enhanced egress from the myocardium; the changes in iron proteins in the cardiomyocytes of these patients are opposite to those expected from systemic iron deficiency. Nevertheless, iron supplementation can prevent ventricular remodelling and cardiomyopathy produced by experimental injury in the absence of systemic iron deficiency (Type 3 iron-deficient HF). These observations, taken collectively, support the possibility of three different mechanistic pathways for the development of iron-deficient HF: one that is driven through systemic iron depletion and impaired erythropoiesis and two that are characterized by disproportionate depletion of intracellular iron in skeletal and cardiac muscle. These mechanisms are not mutually exclusive, and all pathways may be operative at the same time or may occur sequentially in the same patients. In a State of the Art Review article entitled ‘Alcoholic cardiomyopathy: an update’, Fernando Domínguez from the Hospital Universitario Puerta de Hierro Majadahonda in Madrid, Spain, and colleagues indicate that alcohol-induced cardiomyopathy (AC) is an acquired form of dilated cardiomyopathy (DCM) caused by prolonged and heavy alcohol intake in the absence of other causes.5 The amount of alcohol required to produce AC is generally considered as >80 g/day over 5 years, but there is still some controversy regarding this definition. This review on AC starts with a focus on pathogenesis, which involves different mechanisms. Firstly, the direct toxic effect of ethanol promotes oxidative stress in the myocardium and activation of the renin–angiotensin system. Moreover, acetaldehyde, the best-studied metabolite of alcohol, can contribute to myocardial damage impairing actin–myosin interaction and producing mitochondrial dysfunction. Genetic factors are also involved in the pathogenesis of AC, with DCM-causing genetic variants in patients with AC, especially titin-truncating variants. These findings support a double-hit hypothesis in AC, combining genetics and environmental factors. The synergistic effect of alcohol with concomitant conditions such as hypertension or liver cirrhosis can be another contributing factor leading to AC. There are no specific cardiac signs and symptoms in AC as compared with other forms of DCM. However, the natural history of AC differs from that of DCM and relies directly on alcohol withdrawal, as left ventricular ejection fraction recovery in abstainers is associated with an excellent prognosis. Thus, abstinence from alcohol is the most crucial step in treating AC, and specific therapies are available for this purpose. Otherwise, AC should be treated according to current guidelines of HF with reduced ejection fraction. Targeted therapies based on AC pathogenesis are currently being developed and could potentially improve AC treatment in the future (Figure 1). Clinical overview, pathogenesis, treatment, and prognosis of alcoholic cardiomyopathy. DCM, dilated cardiomyopathy; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; HTx, heart transplant; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; SD, standard deviation.5 Management of mitral regurgitation is quickly evolving.6–8 Presentation, outcome, and management of females with degenerative mitral regurgitation (DMR) are undefined. In a Clinical Research article entitled ‘Degenerative mitral regurgitation due to flail leaflet: sex-related differences in presentation, management, and outcomes’, Jean-Fançois Avierinos from the Aix-Marseille Université in France, and colleagues analysed sex-specific baseline clinical and echocardiographic characteristics at referral for DMR due to flail leaflets and subsequent management and outcomes.9 In the Mitral Regurgitation International Database (MIDA) international registry, females were compared with males regarding presentation at referral, management, and outcome (survival/HF), under medical treatment, post-operatively, and encompassing all follow-up. At referral, females (n = 650) vs. males (n = 1660) were older with more severe symptoms and higher MIDA score. Smaller cavity diameters belied higher cardiac dimension indexed to body surface area. Under conservative management, excess mortality vs. expected was observed in males [standardized mortality ratio (SMR) 1.45, P < .001] but was higher in females (SMR 2.00, P < .001). Female sex was independently associated with mortality [adjusted hazard ratio (HR) 1.29, P = .02], cardiovascular mortality (adjusted HR 1.58, P = .007), and HF (adjusted HR 1.36, P = .04) under medical management. Females vs. males were offered surgical correction less often (72% vs. 80%, P < .001); however, surgical outcome, adjusted for more severe presentation in females, was similar (P ≥ .09). Ultimately, overall outcome throughout follow-up was worse in females, who displayed persistent excess mortality vs. expected (SMR 1.31, P < .001), whereas males enjoyed normal life expectancy restoration (SMR 0.92, P = .036) (Figure 2). Comparison of severe degenerative mitral regurgitation presentation, management, and outcome between males and females. Females vs. males are referred less to tertiary care centres, at a later stage of severe degenerative mitral regurgitation (left), display more severe outcome under medical management (top middle), and are referred less to mitral repair with later indications (bottom middle) but have similar post-operative outcome when operated. They ultimately incur excess overall mortality under medical and surgical management combined, whereas normal life expectancy is restored in males (right). The black solid line denotes observed survival, dotted lines 95% confidence intervals, and the straight line expected survival. MIDA, Mitral Regurgitation International Database; SMR, standardized mortality ratio.9 The authors conclude that females with severe DMR are referred to tertiary centres at a more advanced stage, incur higher mortality and morbidity under conservative management, and are offered surgery less often and later after referral. Ultimately, these sex-related differences yield persistent excess mortality despite surgery in females with DMR, while males enjoy restoration of life expectancy, warranting imperative re-evaluation of sex-specific DMR management. The contribution is accompanied by an Editorial by Rebecca Hahn from Columbia University in New York, NY, USA.10 Hahn concludes that this is an impactful study which significantly strengthens the findings of other studies given the number of patients, duration of follow-up, and the extensive search for comorbid interactions. This study shows that sex determines management and outcomes for DMR throughout the duration of the follow-up period. This study is a call to action for the medical community on several fronts. Brugada syndrome (BrS) is an inherited arrhythmia with a higher disease prevalence and more lethal arrhythmic events in Asians than in Europeans.11 Genome-wide association studies (GWASs) have revealed its polygenic architecture mainly in European populations. In a Translational Research article entitled ‘Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci’, Taisuke Ishikawa from the Omics Research Center in Suita, Japan, and colleagues aimed to identify novel BrS-associated loci and to compare allelic effects across ancestries.12 A GWAS was conducted in Japanese participants, involving 940 cases and 1634 controls, followed by a cross-ancestry meta-analysis of Japanese and European GWASs (total of ∼3700 cases and 11 600 controls). The novel loci were characterized by fine-mapping, gene expression, and splicing quantitative trait associations in the human heart. The Japanese-specific GWAS identified one novel locus near ZSCAN20 (P = 1.0 × 10−8), and the cross-ancestry meta-analysis identified 17 association signals, including six novel loci. The effect directions of the 17 lead variants were consistent, and their allelic effects were highly correlated across ancestries. The genetic risk score derived from the BrS GWAS of European ancestry was significantly associated with the risk of BrS in the Japanese population [odds ratio (OR) 2.12; P = 1.2 × 10−61], suggesting a shared genetic architecture across ancestries. Functional characterization revealed that a lead variant in CAMK2D promotes alternative splicing, resulting in an isoform switch of calmodulin kinase II-δ, favouring a proinflammatory/prodeath pathway. The authors conclude that their study demonstrates novel susceptibility loci implicating potentially novel pathogenetic pathways underlying BrS. Despite differences in clinical expressivity and epidemiology, the polygenic architecture of BrS is substantially shared across ancestries. This manuscript is accompanied by an Editorial by Elijah Behr from the University of London, in the UK.13 Behr concludes that drug provocation testing to reveal concealed BrS can be non-specific depending on the clinical context of its use, and may be leading to false positives; yet it is currently the only available diagnostic method. An enhanced and optimized BrS polygenic risk score (PRS) offers a potentially more robust and novel approach to improving diagnostic accuracy as part of a clinical prediction model for patients with concealed BrS. Larger cohorts with long-term follow-up data will be required to assess whether a BrS PRS will impact upon risk stratification and fulfil its promise. Atrial fibrillation (AF) is a highly prevalent arrhythmia which needs careful management.14–21 In a Rapid Communications article entitled ‘Emergency department visit for atrial fibrillation: sex differences in treatment and outcomes in the Global RE-LY AF Registry’, Linda Johnson from McMaster University in Ontario, Canada, and colleagues indicate that studies of sex-based differences in AF suggest an influence of sex on cardiovascular death and stroke, although results are conflicting.22 Discrepant findings could reflect sex-based differences in access to care, but no studies have explored sex-based differences in treatment and outcomes among countries with differing income levels and gender parity. Such data are needed to understand if sex-based care gaps exist and are associated with differences in outcomes. This study explores how sex differences in AF treatment and outcomes vary between countries based on their economic status in the Global RE-LY AF Registry. From the prospective RE-LY registry [n = 15 400 patients presenting to an emergency department (ED) with AF in 47 countries between 2007 and 2011], the authors excluded patients without AF as the primary listed reason for ED presentation, or missing outcomes or CHADS2 score, resulting in a sample of ∼6600 patients. Outcomes were obtained at 1-year follow-up and included repeated hospitalization for AF, HF hospitalization, stroke or transient ischaemic attack (TIA), and death. The authors tested an extensively adjusted model including age, tobacco use, AF type, alcohol use, anticoagulation use, history of sleep apnoea, HF, diabetes, hypertension, stroke, chronic obstructive pulmonary disease, rheumatic heart disease, myocardial infarction, and severe valvular disease which showed higher risk of stroke or transient ischemic attack for women than for men [OR 1.42, 95% confidence interval (CI) 1.01–1.99, P = .045]. Female sex was not associated with rehospitalization for AF, hospitalization for HF, or death. This higher risk for stroke in women compared with men was numerically more prominent in upper-middle and high-income countries (P for interaction .51), and in the top two quartiles of Global Gender Gap score (P for interaction .17). The authors conclude that in the year after an ED visit for AF, females are less likely to receive rhythm control therapy, most notably in lower income countries or those with less gender parity. Despite this, there is no effect of female sex on AF or HF hospitalization or mortality. Female sex is associated with an increased risk of stroke/TIA, even after adjustment for comorbidities and anticoagulant use. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Programmed ventricular stimulation for risk stratification in hypertrophic cardiomyopathy patients’, Petros Arsenos from the National and Kapodistrian University of Athens in Greece and colleagues comment on the recent publication ‘Assessment of late gadolinium enhancement in hypertrophic cardiomyopathy improves risk stratification based on current guidelines’ by Jiaxin Wang from the Chinese Academy of Medical Sciences & Peking Union Medical College/National Center for Cardiovascular Diseases in Beijing, China, and colleagues.23,24 Wang et al. respond in a separate comment.25 The editors hope that this issue of the European Heart Journal will be of interest to its readers. Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, Daiichi Sankyo, Menarini outside the submitted work. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.