New light shed on Anderson–Fabry, peripartum, and early-onset cardiomyopathies

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on heart failure and congenital heart disease contains the State of the Art Review article ‘Anderson–Fabry disease management: role of the cardiologist’ by Maurizio Pieroni from the San Donato Hospital in Arezzo, Italy, and colleagues.1 The authors note that Anderson–Fabry disease (AFD) is a lysosomal storage disorder characterized by glycolipid accumulation in cardiac cells, associated with a peculiar form of hypertrophic cardiomyopathy (HCM). Up to 1% of patients with a diagnosis of HCM indeed have AFD. With the availability of targeted therapies for sarcomeric HCM and its genocopies, a timely differential diagnosis is essential. Specifically, the therapeutic landscape for AFD is rapidly evolving and offers increasingly effective, disease-modifying treatment options. However, diagnosing AFD may be difficult, particularly in the non-classic phenotype with prominent or isolated cardiac involvement and no systemic red flags. For many AFD patients, the clinical journey from initial clinical manifestations to diagnosis and appropriate treatment remains challenging, due to late recognition or utter neglect. Consequently, late initiation of treatment does not resolve cardiac involvement, representing the main cause of morbidity and mortality, irrespective of gender. Optimal management of AFD patients requires a dedicated multidisciplinary team, in which the cardiologist plays a decisive role, ranging from the differential diagnosis to the prevention of complications and the evaluation of timing for disease-specific therapies. This review aims to redefine the role of cardiologists across the main decision nodes in contemporary AFD clinical care and drug discovery. Iron deficiency is becoming an important therapeutic target in the treatment of heart failure (HF).2–5 In a Clinical Research article entitled ‘Intravenous iron for heart failure, iron deficiency definitions, and clinical response: the IRONMAN trial’, John Cleland from the University of Glasgow in the UK, and colleagues evaluate what is the relationship between blood tests for iron deficiency, including anaemia, and the response to intravenous iron in patients with HF.6 In the IRONMAN trial, 1137 patients with HF, ejection fraction ≤45%, and either serum ferritin <100 μg/L or transferrin saturation (TSAT) < 20% were randomized to intravenous ferric derisomaltose (FDI) or usual care. Relationships were investigated between baseline anaemia severity, ferritin, and TSAT, and changes in haemoglobin from baseline to 4 months, Minnesota Living with HF (MLwHF) score and 6-min walk distance achieved at 4 months, and clinical events, including HF hospitalization (recurrent) or cardiovascular death. The rise in haemoglobin after administering FDI, adjusted for usual care, was greater for lower baseline TSAT (Pinteraction < .0001) and ferritin (Pinteraction = .028) and more severe anaemia (Pinteraction = .014). MLwHF scores at 4 months were somewhat lower (better) with FDI for more anaemic patients (overall Pinteraction = .14; physical Pinteraction = .085; emotional Pinteraction = .043) but were not related to baseline TSAT or ferritin. Blood tests did not predict difference in achieved walking distance for those randomized to FDI compared with controls. The absence of anaemia or a TSAT ≥20% was associated with lower event rates and little evidence of benefit from FDI. More severe anaemia or TSAT <20%, especially when ferritin was ≥100 μg/L, was associated with higher event rates and greater absolute reductions in events with FDI, albeit not statistically significant. Cleland and colleagues conclude that this hypothesis-generating analysis suggests that anaemia or TSAT <20% with ferritin >100 μg/L might identify patients with HF who obtain greater benefit from intravenous iron. This interpretation requires confirmation. The contribution is accompanied by an Editorial by Peter van der Meer and Niels Grote Beverborg from the University Medical Center Groningen in the Netherlands.7 The authors note that while the field of iron deficiency holds promise, it has not fully met its anticipated potential. It still appears poised to significantly impact the prognosis of a substantial number of patients, yet the data are not as convincing as expected, and questions remain to be answered. The current study provides one step forward in solving the puzzle. Hopefully an individual patient data meta-analyses of all conducted trials can answer the question of whether we should treat patients with intravenous iron, and, perhaps even more importantly, which patients? There are no established clinical tools to predict left ventricular (LV) recovery in women with peripartum cardiomyopathy (PPCM).8,9 In a Clinical Research article entitled ‘A novel score to predict left ventricular recovery in peripartum cardiomyopathy derived from the ESC EORP Peripartum Cardiomyopathy Registry’, Alice Jackson from the University of Glasgow in the UK, and colleagues indicate that using data from women enrolled in the ESC EORP PPCM Registry, their aim was to derive a prognostic model to predict LV recovery at 6 months and develop the ‘ESC EORP PPCM Recovery Score’—a tool for clinicians to estimate the probability of LV recovery.10 From 2012 to 2018, a total of 752 women from 51 countries were enrolled. Eligibility included (i) a peripartum state, (ii) signs or symptoms of HF, (iii) LV ejection fraction (LVEF) ≤ 45%, and (iv) exclusion of alternative causes of HF. The model was derived using data from participants in the registry and internally validated using bootstrap methods. The outcome was LV recovery (LVEF ≥50%) at 6 months. An integer score was created. Overall, 465 women had a 6-month echocardiogram. LV recovery occurred in 216 (46.5%). The final model included baseline LVEF, baseline LV end-diastolic diameter, human development index (a summary measure of a country’s social and economic development), duration of symptoms, QRS duration, and pre-eclampsia. The model was well calibrated and had good discriminatory ability (C-statistic 0.79). The model was internally validated (optimism-corrected C-statistic 0.78) (Figure 1). Graphical summary of the main study findings. The human development index (HDI) is a summary measure (between zero and one) of a country’s social and economic development and can be found at: https://hdr.undp.org/data-center/human-development-index#/indicies/HDI. CI, confidence interval; EORP, EURObservational Research Programme; ESC, European Society of Cardiology; LV, left ventricular: LVEF, left ventricular ejection fraction; PPCM, peripartum cardiomyopathy10 The authors conclude that this study proposes a model which accurately predicts LV recovery at 6 months in women with PPCM. The corresponding ESC EORP PPCM Recovery Score can be easily applied in clinical practice to predict the probability of LV recovery for an individual to guide tailored counselling and treatment. The contribution is accompanied by an Editorial by Carmen Basic and Maria Schaufelberger from the University of Gothenburg in Sweden.11 The authors conclude their contribution by indicating that this is a call for action. Hopefully several research groups will test the model by Jackson and co-workers or further develop this predictive model to identify early those women with a low recovery probability in order to initiate appropriate actions, as this has an impact not only on the affected woman, but also on the child and her whole family. Finally, it is important to remember that prognostic models can only provide general guidance and should be interpreted in conjunction with the healthcare provider’s clinical expertise. Childhood-onset cardiomyopathies are rare and poorly characterized.12–15 In a Clinical Research article entitled ‘Cardiomyopathies in children and adolescents: aetiology, management, and outcomes in the European Society of Cardiology EURObservational Research Programme Cardiomyopathy and Myocarditis Registry’, Juan Pablo Kaski from the University College London Institute of Cardiovascular Science and Great Ormond Street Hospital NHS Foundation Trust in London, UK, and colleagues examined the baseline characteristics and 1-year follow-up of children with cardiomyopathy in the first European Cardiomyopathy Registry.16 Prospective data were collected on individuals aged from 1 up to 18 years enrolled in the European Society of Cardiology EURObservational Research Programme Cardiomyopathy and Myocarditis long-term registry. A total of 633 individuals with hypertrophic (HCM; 61%), dilated (DCM; 32%), restrictive (RCM; 4.4%), and arrhythmogenic right ventricular cardiomyopathy (ARVC; 1.6%) were enrolled by 23 referral centres in 14 countries. Median age at diagnosis was 4.0 years; 98% of patients were receiving cardiac medication; 13% had an implantable cardioverter-defibrillator; and 47% had familial disease. Genetic testing was performed in 68% of patients with a pathogenic or likely pathogenic variant reported in 60%. Rare disease phenocopies were reported in 28% of patients and were most frequent in patients under 10 years. Over a median follow-up of 12.5 months, 3.3% of patients died (2.6% from HCM, 3% from DCM, 16% from RCM). HF events were most frequent in RCM patients (36.0%). The findings confirm the heterogeneous aetiology of childhood cardiomyopathies and show a high frequency of familial disease. Outcomes differ by cardiomyopathy subtype, highlighting a need for disease-specific evaluation and treatment. This manuscript is accompanied by an Editorial by Jolanda Sabatino from the ‘Magna Graecia’ University of Catanzaro, Giovanni Di Salvo from the University of Padua, Italy, and Werner Budts from the University Hospitals Leuven in Belgium.17 The authors conclude by indicating that the establishment of the first European Paediatric Cardiomyopathy and Myocarditis Registry, as part of the EORP effort, signifies a relevant advancement in comprehending cardiomyopathies that occur in infancy. The insights from the registry have the potential to bring about a change in how paediatric cardiomyopathies are approached. This might lead to a new age where early detection becomes the crucial element for better outcomes, thereby guaranteeing the well-being of affected children and their families. The burden of congenital heart disease (CHD) keeps increasing thanks to a substantial prolongation of life expectancy generating new challenges.18–23 Cardiopulmonary fitness in CHD decreases faster than in the general population, resulting in impaired health-related quality of life (HRQoL). In a Clinical Research article entitled ‘Early hybrid cardiac rehabilitation in congenital heart disease: the QUALIREHAB trial’, Pascal Amedro from the Bordeaux University Hospital in Pessac Cedex, France, and colleagues point out that as the standard of care seems insufficient to encourage and maintain fitness, an early hybrid cardiac rehabilitation programme could improve HRQoL in CHD.24 The QUALIREHAB multicentre, randomized, controlled trial evaluated and implemented a 12-week centre- and home-based hybrid cardiac rehabilitation programme, including multidisciplinary care and physical activity sessions. Adolescent and young adult CHD patients with impaired cardiopulmonary fitness were randomly assigned to either the intervention (i.e. cardiac rehabilitation) or the standard of care. The primary outcome was the change in HRQoL from baseline to 12-month follow-up in an intention-to-treat analysis. The secondary outcomes were the change in cardiovascular parameters, cardiopulmonary fitness, and mental health. The expected number of 142 patients were enrolled in the study (mean age 17.4, 52% female). Patients assigned to the intervention had a significant positive change in HRQoL total score (mean difference 3.8; P = .038), body mass index (mean difference −0.7 kg/m2, P = .022), level of physical activity (mean difference 2.5; P = .044, and disease knowledge (mean difference 2.7; P = .007). The per-protocol analysis confirmed these results with a higher magnitude of differences. Acceptability, safety, and short-term effects of the intervention were good to excellent (Figure 2). The long-term beneficial effect of the 12-week centre-based and home-based hybrid cardiac rehabilitation programme on adolescents and young adults with CHD was observed on HRQoL (primary outcome), BMI, physical activity, and disease knowledge, opening up the possibility for the QUALIREHAB programme to be rolled out to the adult population of CHD and non-congenital cardiac disease. BMI, body mass index; CHD, congenital heart disease; HRQoL, health-related quality of life.24 The authors conclude that QUALIREHAB improves HRQoL, body mass index, physical activity, and disease knowledge in youths with CHD, opening up the possibility for this programme to be rolled out to the adult population of CHD and non-congenital cardiac disease. The contribution is accompanied by an Editorial by Keri Shafer and Anne Marie Valente from Harvard Medical School in Boston, MA, USA.25 The authors note that this study achieves an important improvement in HRQoL in patients with CHD characterized by severe physical limitations. Perhaps by focusing on the improvement made in social functioning and disease knowledge we can better understand the benefits. Each subject was provided with multiple opportunities to connect and inquire about their heart condition, a unique aspect of this trial. Additionally, social determinants of health were addressed by reducing transportation insecurity and improving access to care, i.e. the fitness programme came to them. Similar to the Black Barbershop study, this study design met patients in their own communities. By doing so in all aspects of CHD care, we have an opportunity to see improvements in many other areas of health. Using these data, future research could focus both on higher intensity exercise training programmes together with a comprehensive approach to supporting CHD patients in their fitness and health improvement. Interventions that couple patient education and social support may be especially useful in this cohort. The authors are congratulated on accomplishing just that in this important and often overlooked population. The issue continues with a Rapid Communications contribution entitled ‘Hepatocellular carcinoma in survivors after Fontan operation: a case–control study’, by Yuli Kim from the Hospital of the University of Pennsylvania in Philadelphia, PA, USA, and colleagues.26 The authors point out that liver injury is universal in patients who have undergone Fontan palliation for complex congenital heart disease and results in fibrosis and cirrhosis. Fontan-associated liver disease (FALD) can be rarely complicated by hepatocellular carcinoma (HCC), the risk factors for which are not fully elucidated. The authors aim to identify clinical characteristics associated with the development of HCC in adult single ventricle patients with Fontan circulation. Out of a total of 3251 adult Fontan patients followed across all 18 centres, the estimated prevalence of HCC was 1.8%. Median age of HCC diagnosis was 31 years. One-year survival after HCC diagnosis was 81%. Desaturation [adjusted odds ratio (aOR) 2.4, P = .02], history of Fontan revision (aOR 2.3, P = .02), and thrombocytopenia (aOR 2.3, P = .02) were associated with increased odds of HCC. The authors conclude that hepatocellular carcinoma is diagnosed in up to 2% of adult Fontan patients. Those with more advanced Fontan-associated liver disease represented by abnormal liver biochemistries and signs of circulatory failure may be at increased risk. Until more clearly defined risk factors are identified, the authors recommend abdominal ultrasounds and alpha-foetoprotein determination every 6 months for adult Fontan patients in accordance with guidelines for HCC screening. Systemic right ventricular (sRV) dysfunction is highly prevalent and is associated with substantial morbidity and mortality in patients with complete transposition of the great arteries with atrial switch surgery (D-TGA/AS) and in those with congenitally corrected transposition of the great arteries (ccTGA). In a Rapid Communications contribution ‘Angiotensin receptor–neprilysin inhibitor vs. placebo in congenital systemic right ventricular heart failure: the PARACYS-RV trial’, Marie-A. Chaix from the Université de Montréal in Canada, and colleagues note that there is no recommended evidence-based therapy proven to halt disease progression or improve survival for sRV dysfunction. Recent open-label studies support the safety of sacubitril combined with valsartan in this setting, and highlight the need for randomized trials.27 In their contribution, Chaix et al. present the results of the Prospective comparison of Angiotensin Receptor-neprilysin inhibitor vs. plAcebo in patients with Congenital sYStemic Right Ventricular heart failure (PARACYS-RV) trial. This randomized, double-blind, placebo-controlled, crossover trial was designed to compare sacubitril/valsartan with placebo in adults (≥18 years) with moderate to severe sRV dysfunction, biventricular physiology, and New York Heart Association (NYHA) functional class II–III symptoms. The study protocol (NCT05117736) was previously published. The trial was prematurely interrupted upon a unanimous decision by the steering committee owing to the high rate of worsening HF events. Analysis of unblinded data revealed a clear association between these events and interruption of sacubitril/valsartan, either after the run-in phase was followed by placebo or during the 2-week sacubitril/valsartan washout period prior to crossover to placebo. The authors conclude that premature interruption of PARACYS-RV precludes firm conclusions regarding the efficacy of sacubitril/valsartan in patients with sRV dysfunction and NYHA Class II–III symptoms. Despite the small sample size, sacubitril/valsartan was associated with favourable trends regarding the two primary outcomes (maximal total exercise duration and N-terminal probrain natriuretic peptide). These promising results, along with encouraging observational studies, support the need for conclusive trials. Future trials should avoid crossovers to placebo and discontinuation of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers without substitution. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘The obesity paradigm on outcome in heart failure with reduced ejection fraction’, Wolfram Doehner from the Charité-Universitätsmedizin Berlin, Germany and colleagues comment on the recent publication ‘Anthropometric measures and adverse outcomes in heart failure with reduced ejection fraction: revisiting the obesity paradox’ by Jawad H. Butt from the University of Glasgow, UK, and colleagues.28,20 Butt et al. respond in a separate comment.30 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, the With thanks to and for with of this