Search

Aims: The Italian Fabry Disease Cardiovascular Registry (IFDCR) comprises 50 Italian centres with specific expertise in managing cardiovascular manifestations and complications of patients with Fabry disease (FD). The primary aim of the IFDCR is to examine and improve the clinical care and outcomes of patients with FD by addressing several knowledge gaps in the epidemiology, natural history, genotype-phenotype correlations, diagnosis, and management of this condition, with particular focus on cardiovascular manifestations and complications., Methods and Results: The IFDCR is an international, longitudinal, multicentre, non-interventional, observational study. Consecutive patients aged ≥2 years with a diagnosis of FD will be included in the study. The recruitment period consists of two parts: the retrospective enrolment period, from January 1981 to December 2023, and the prospective enrolment period, spanning from January 2024 to December 2031. The registry collects baseline and follow-up data, including the enrolment setting, patient demographics, family history, symptoms, clinical manifestations, electrocardiogram, cardiovascular imaging, laboratory assessment, medical therapy, genetic testing results, and outcomes., Conclusions: The IFDCR is a national, multicentre, registry that includes patients with FD. It holds detailed and multiparametric data across the patient pathway and clinical manifestations, acting as a powerful tool for improving the quality of care and conducting high-impact research., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

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 results in an exacerbation of 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. The present review aims to redefine the role of cardiologists across the main decision nodes in contemporary AFD clinical care and drug discovery., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

As a slowly progressive form of hypertrophic cardiomyopathy (HCM), Anderson-Fabry disease (FD) resembles the phenotype of the most common sarcomeric forms, although significant differences in presentation and long-term progression may help determine the correct diagnosis. A variety of electrocardiographic and imaging features of FD cardiomyopathy have been described at different times in the course of the disease, and considerable discrepancies remain regarding the assessment of disease severity by individual physicians. Therefore, we here propose a practical staging of FD cardiomyopathy, in hopes it may represent the standard for cardiac evaluation and facilitate communication between specialized FD centres and primary care physicians. We identified 4 main stages of FD cardiomyopathy of increasing severity, based on available evidence from clinical and imaging studies: non-hypertrophic, hypertrophic - pre-fibrotic, hypertrophic - fibrotic, and overt dysfunction. Each stage is described and discussed in detail, following the principle that speaking a common language is critical when managing such complex patients in a multi-disciplinary and sometimes multi-centre setting., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: There is limited evidence on the risk stratification of cardiovascular outcomes in patients with Fabry disease (FD)., Objectives: This study sought to classify FD patients into disease stages, based on the extent of the cardiac damage evaluated by echocardiography, and to assess their prognostic impact in a multicenter cohort., Methods: Patients with FD from 5 Italian referral centers were categorized into 4 stages: stage 0, no cardiac involvement; stage 1, left ventricular (LV) hypertrophy (LV maximal wall thickness >12 mm); stage 2, left atrium (LA) enlargement (LA volume index >34 mL/m 2 ); stage 3, ventricular impairment (LV ejection fraction <50% or E/e' ≥15 or TAPSE <17 mm). The study endpoint was the composite of all-cause death, hospitalization for heart failure, new-onset atrial fibrillation, major bradyarrhythmias or tachyarrhythmias, and ischemic stroke., Results: A total of 314 patients were included. Among them, 174 (56%) were classified as stage 0, 41 (13%) as stage 1, 57 (18%) as stage 2 and 42 (13%) as stage 3. A progressive increase in the composite event rate at 8 years was observed with worsening stages of cardiac damage (log-rank P < 0.001). On multivariable Cox regression analysis, the staging was independently associated with the risk of cardiovascular events (HR: 2.086 per 1-stage increase; 95% CI: 1.487-2.927; P < 0.001). Notably, cardiac staging demonstrated a stronger and additive prognostic value, as compared with the degree of LV hypertrophy., Conclusions: In FD patients, a novel staging classification of cardiac damage, evaluated by echocardiography, is strongly associated with cardiovascular outcomes and may be helpful to refine risk stratification., Competing Interests: Funding Support and Author Disclosures Dr Lillo has received advisory board fees from Amicus Therapeutics, Sanofi Genzyme, Takeda, and Shire. Dr Biagini has received speaker fees from Amicus Therapeutics, Sanofi Genzyme, Takeda, and Bristol Myers Squibb. Dr Pieroni has received speaker and/or advisory board fees from Sanofi Genzyme, Pfizer, and Bristol Myers Squibb. Dr Crea has received personal fees from Amgen, AstraZeneca, Abbott, Menarini, Chiesi, and Daiichi-Sankyo. Dr Limongelli has received advisory board fees from Amicus Therapeutics; and has received an unrestricted grant from Sanofi. Dr Olivotto has received research grants from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Shire, Bayer, Amicus, Chiesi, and Menarini International; and has received speaker and/or advisory board fees from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Shire, Tenaya, and Rocket Pharma. Dr Graziani has received research grants from Takeda and Pfizer; and has received advisory board fees from Amicus Therapeutics, Sanofi Genzyme, and Shire. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: A small but significant reduction in left ventricular (LV) mass after 18 months of migalastat treatment has been reported in Fabry disease (FD). This study aimed to assess the effect of migalastat on FD cardiac involvement, combining LV morphology and tissue characterisation by cardiac magnetic resonance (CMR) with cardiopulmonary exercise testing (CPET)., Methods: Sixteen treatment-naïve patients with FD (4 women, 46.4±16.2 years) with cardiac involvement (reduced T1 values on CMR and/or LV hypertrophy) underwent ECG, echocardiogram, troponin T and NT-proBNP (N-Terminal prohormone of Brain Natriuretic Peptide) assay, CMR with T1 mapping, and CPET before and after 18 months of migalastat., Results: No change in LV mass was detected at 18 months compared to baseline (95.2 g/m 2 (66.0-184.0) vs 99.0 g/m 2 (69.0-121.0), p=0.55). Overall, there was an increase in septal T1 of borderline significance (870.0 ms (848-882) vs 860.0 ms (833.0-875.0), p=0.056). Functional capacity showed an increase in oxygen consumption (VO 2 ) at anaerobic threshold (15.50 mL/kg/min (13.70-21.50) vs 14.50 mL/kg/min (11.70-18.95), p=0.02), and a trend towards an increase in percent predicted peak VO 2 (72.0 (63.0-80.0) vs 69.0 (53.0-77.0), p=0.056) was observed. The subset of patients who showed an increase in T1 value and a reduction in LV mass (n=7, 1 female, age 40.5 (28.6-76.0)) was younger and at an earlier disease stage compared to the others, and also exhibited greater improvement in exercise tolerance., Conclusion: In treatment-naïve FD patients with cardiac involvement, 18-month treatment with migalastat stabilised LV mass and was associated with a trend towards an improvement in exercise tolerance. A tendency to T1 increase was detected by CMR. The subset of patients who had significant benefits from the treatment showed an earlier cardiac disease compared to the others., Trial Registration Number: NCT03838237., Competing Interests: Competing interests: AC: honoraria for presentations and board meetings from Amicus Therapeutics, Sanofi Genzyme and Shire; research grant from Amicus Therapeutics. MP: speaker and advisory board honoraria and travel support from Sanofi Genzyme, Amicus Therapeutics and Shire. FP: honoraria from Sanofi Genzyme, Shire and Amicus Therapeutics. MS: honoraria for speaking fees for symposia and meetings and for advisory board attendance from Sanofi Genzyme and Shire International. AB: travel sponsor from Genzyme, Shire and Amicus. CL: travel sponsor from Genzyme, Shire and Amicus. MR: travel sponsor from Genzyme, Shire and Amicus. RM: travel sponsor, honoraria and expert witness with Sanofi Genzyme and Amicus. IM: travel sponsor from Genzyme, Shire and Amicus. IO: advisory board for Amicus, Cytokinetics, Tenaya and BMS; research grant from Amicus, Genzyme, Shire, BMS, Cytokinetics, Menarini International, Bayer and Boston Scientific. IT: travel sponsor from Genzyme, Shire and Amicus. KC: full-time employee of Siemens Medical Solutions USA. FG: travel sponsor from Genzyme, Shire and Amicus; honoraria speaker for Takeda-Shire and Genzyme. ML: honoraria for presentations from Shire., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The hypertrophic cardiomyopathy phenotype encompasses a heterogeneous spectrum of genetic and acquired diseases characterized by the presence of left ventricular hypertrophy in the absence of abnormal cardiac loading conditions. This "umbrella diagnosis" includes the "classic" hypertrophic cardiomyopathy (HCM), due to sarcomere protein gene mutations, and its phenocopies caused by intra- or extracellular deposits, such as Fabry disease (FD) and cardiac amyloidosis (CA). All these conditions share a wide phenotypic variability which results from the combination of genetic and environmental factors and whose pathogenic mediators are poorly understood so far. Accumulating evidence suggests that inflammation plays a critical role in a broad spectrum of cardiovascular conditions, including cardiomyopathies. Indeed, inflammation can trigger molecular pathways which contribute to cardiomyocyte hypertrophy and dysfunction, extracellular matrix accumulation, and microvascular dysfunction. Growing evidence suggests that systemic inflammation is a possible key pathophysiologic process potentially involved in the pathogenesis of cardiac disease progression, influencing the severity of the phenotype and clinical outcome, including heart failure. In this review, we summarize current knowledge regarding the prevalence, clinical significance, and potential therapeutic implications of inflammation in HCM and two of its most important phenocopies, FD and CA., (© 2023. The Author(s).)

Background: Fabry disease is a rare, multisystemic disorder caused by GLA gene variants that lead to alpha galactosidase A deficiency, resulting in accumulation of glycosphingolipids and cellular dysfunction. Fabry-associated clinical events (FACEs) cause significant morbidity and mortality, yet the long-term effect of Fabry therapies on FACE incidence remains unclear., Methods: This posthoc analysis evaluated incidence of FACEs (as a composite outcome and separately for renal, cardiac and cerebrovascular events) in 97 enzyme replacement therapy (ERT)-naïve and ERT-experienced adults with Fabry disease and amenable GLA variants who were treated with migalastat for up to 8.6 years (median: 5 years) in Phase III clinical trials of migalastat. Associations between baseline characteristics and incidence of FACEs were also evaluated., Results: During long-term migalastat treatment, 17 patients (17.5%) experienced 22 FACEs and there were no deaths. The incidence rate of FACEs was 48.3 events per 1000 patient-years overall. Numerically higher incidence rates were observed in men versus women, patients aged >40 years versus younger patients, ERT-naïve versus ERT-experienced patients and men with the classic phenotype versus men and women with all other phenotypes. There was no statistically significant difference in time to first FACE when analysed by patient sex, phenotype, prior treatment status or age. Lower baseline estimated glomerular filtration rate (eGFR) was associated with an increased risk of FACEs across patient populations., Conclusions: The overall incidence of FACEs for patients during long-term treatment with migalastat compared favourably with historic reports involving ERT. Lower baseline eGFR was a significant predictor of FACEs., Competing Interests: Competing interests: DAH reports advisory board participation, consulting fees and honoraria for Takeda, Sanofi, Amicus Therapeutics, Inc., Idorsia, Freeline and Protalix. DGB reports advisory board participation, consulting fees, speakers’ bureau fees and honoraria from Amicus Therapeutics, Inc. and Sanofi/Genzyme. RG reports consulting fees from Abeona, Amicus Therapeutics, Inc., Chiesi, Denali, Inventiva, JCR, Novartis, PTC, Protalix, RegenxBio and Sobi; speakers’ bureau fees from BioMarin, Amicus Therapeutics, Inc., Chiesi, Idorsia, Janssen, Novartis, Pfizer, PTC, Sanofi and Takeda; research funding from Allievex, Avrobio, Azafaros, JCR, Lysogene, Paradigm, PassageBio, RegenxBio, Sanofi, Sigilon, Takeda and Ultragenyx. RJH reports consulting fees from Alexion, Amicus Therapeutics, Inc., Avrobio, Chiesi, Sangamo, Sanofi/Genzyme and Takeda; advisory fees from Alexion, Amicus Therapeutics, Inc. and Sanofi/Genzyme; speakers’ bureau fees from Alexion and Sanofi/Genzyme and grants/research funding from Alexion, Amicus Therapeutics, Inc., Idorsia, Protalix, Sangamo, Sanofi/Genzyme and Takeda. EK reports consulting fees from Amicus Therapeutics, Inc. KN reports advisory board participation for Amicus Therapeutics, Inc., Takeda and Sanofi/Genzyme; consulting fees from Amicus Therapeutics, Inc. and Takeda and research funding from Amicus Therapeutics, Inc., Takeda, Sanofi/Genzyme, Idorsia and Avrobio. IO reports advisory board participation for Amicus Therapeutics, Inc., Bristol Myers Squibb, Bayer, Astra Zeneca and Cytokinetics; contracted research for Amicus Therapeutics, Inc., Menarini International, Shire-Takeda, Bristol Myers Squibb, Boston Scientific and Sanofi/Genzyme and speaker’s bureau fees from Boston Scientific, Bristol Myers Squibb and Sanofi/Genzyme. UF-R reports advisory board participation from Amicus Therapeutics, Inc., Freeline, Sanofi/Genzyme and Takeda; speakers’ fees and travel support from Amicus Therapeutics, Inc., Sanofi/Genzyme and Takeda and research funding from Sanofi/Genzyme and Takeda. NSa reports speakers’ bureau fees from Amicus Therapeutics, Inc., Takeda, JCR and Sanofi and research funding from JCR and Sanofi. NSk was an employee and stockholder in Amicus Therapeutics, Inc. at the time of drafting this manuscript and determining the analysis plan. GS-P reports advisory board participation for Amicus Therapeutics, Inc. and Sanofi, research grants/funding from Amicus Therapeutics, Takeda, Idorsia and Freeline and honoraria from Amicus Therapeutics, Inc. and Sanofi. RT reports advisory board participation, consulting fees and honoraria for Takeda, Sanofi, Amicus Therapeutics, Inc. and Chiesi. WRW reports advisory board participation for Sanofi/Genzyme, Takeda, Chiesi, Alexion/Astra Zeneca and BioMarin; research funding from Amicus Therapeutics, Inc. and Takeda; consulting fees from Amicus Therapeutics, Inc. and Spark; contracted clinical study research from Amicus Therapeutics, Inc., Alexion/Astra Zeneca, BioMarin, Chiesi, Freeline, Orphazyme, Pfizer, Protalix, Sangamo, Sanofi/Genzyme, Takeda and 4D Molecular Therapeutics., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Little is known about prevalence and predictors of myocardial infarction with non-obstructive coronary arteries (MINOCA) in Fabry disease (FD) and hypertrophic cardiomyopathy (HCM). We assessed and compared the prevalence and predictors of MINOCA in a large cohort of HCM and FD patients., Methods: In this multicenter, retrospective study we enrolled 2870 adult patients with HCM and 267 with FD. The only exclusion criterion was documented obstructive coronary artery disease. MINOCA was defined according to guidelines. For each patient we collected clinical, ECG and echocardiographic data recorded at initial evaluation., Results: Overall, 36 patients had MINOCA during a follow-up period of 4.5 ± 11.2 years. MINOCA occurred in 16 patients with HCM (0.5%) and 20 patients with FD (7.5%; p &lt; 0.001). The difference between the 2 groups was highly significant, also after adjustment for the main clinical, ECG and echocardiographic variables (OR 6.12; 95%CI 2.80-13.3; p &lt; 0.001). In the FD population MINOCA occurred in 17 out of 96 patients with left ventricle hypertrophy (LVH, 17.7%) and in 3 out of 171 patients without LVH (1.7%; OR 12.0; 95%CI 3.43-42.3; p &lt; 0.001). At multivariable analysis, voltage criteria for LVH at ECG (OR 7.3; 95%CI 1.93-27.7; p = 0.003) and maximal LV wall thickness at echocardiography (OR 1.15; 95%CI 1.05-1.27; p = 0.002) maintained an independent association with MINOCA. No major significant differences were found in clinical, ECG and echocardiographic findings between HCM patients with or without MINOCA., Conclusions: MINOCA was rare in HCM patients, and 6-fold more frequent in FD patients. MINOCA may be considered a red flag for FD and aid in the differential diagnosis from HCM., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Bradyarrhythmias are an established red flag for storage cardiac conditions including Anderson-Fabry disease (AFD). The prevalence of bradyarrhythmias requiring a pacemaker (PM) and their timing in AFD is unresolved., Methods: We evaluated the prevalence and predictors of PM requirement in a large AFD cohort, investigating the occurrence of bradyarrhythmias as initial versus late manifestation. We retrospectively evaluated 82 consecutive AFD patients referred to our multidisciplinary referral center from 1994 to 2020 with a median follow-up of 6.9 years, identifying those requiring pacing. Univariable analysis was performed to identify cardiac features associated with PM implantation., Results: Five of 82 (6%) AFD patients required PM implantation (5/39, i.e., 13% of those with cardiac involvement), always in the context of advanced cardiomyopathy. In none, bradyarrhythmias were the presenting feature. Indications included sick sinus syndrome in three patients, advanced atrioventricular block in two patients. QRS prolongation during follow-up strongly correlated with the onset of bradyarrhythmias., Conclusion: Severe bradyarrhythmias are relatively frequent in patients with AFD cardiomyopathy, but do not represent a mode of presentation, occurring late in the disease course and always in the context of advanced cardiac involvement. Monitoring QRS variations over time may help to identify patients requiring pacing., (© 2022 Wiley Periodicals LLC.)

Objectives: To evaluate the role of the ECG in the differential diagnosis between Anderson-Fabry disease (AFD) and hypertrophic cardiomyopathy (HCM)., Methods: In this multicentre retrospective study, 111 AFD patients with left ventricular hypertrophy were compared with 111 patients with HCM, matched for sex, age and maximal wall thickness by propensity score. Independent ECG predictors of AFD were identified by multivariate analysis, and a multiparametric ECG score-based algorithm for differential diagnosis was developed., Results: Short PR interval, prolonged QRS duration, right bundle branch block (RBBB), R in augmented vector left (aVL) ≥1.1 mV and inferior ST depression independently predicted AFD diagnosis. A point-by-point ECG score was then derived with the following diagnostic performances: c-statistic 0.80 (95% CI 0.74 to 0.86) for discrimination, the Hosmel-Lemeshow χ 2 6.14 (p=0.189) for calibration, sensitivity 69%, specificity 84%, positive predictive value 82% and negative predictive value 72%. After bootstrap resampling, the mean optimism was 0.025, and the internal validated c-statistic for the score was 0.78., Conclusions: Standard ECG can help to differentiate AFD from HCM while investigating unexplained left ventricular hypertrophy. Short PR interval, prolonged QRS duration, RBBB, R in aVL ≥1.1 mV and inferior ST depression independently predicted AFD. Their systematic evaluation and the integration in a multiparametric ECG score can support AFD diagnosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Various electrocardiographic (ECG) indices have been shown to be useful for early recognition and staging of cardiac involvement in Fabry Disease (FD). However, many of them lack acceptable sensitivity and specificity. We assessed the value of automated ECG measures to discriminate between pre-hypertrophic FD and healthy individuals., Methods and Results: Normal ECGs from 1496 healthy individuals (57.4% male, age 37.4 ± 13 years) were compared to those of 142 FD patients without LVH (37.3% male, age 41.5 ± 18 years). All ECGs were analyzed centrally and a total of 429 automated ECG measures per individual were included for step-wise analysis. The Cramer V statistic was first used to pick out those parameters which were helpful in discriminating between the two groups and a final selection was made by using two models, namely the FLD (Fisher Linear Discrimination) and the Logistic model, to optimise diagnostic performance for the detection of cardiac involvement in FD patients vs. specificity in healthy individuals. The three-step statistical analysis identified 9 ECG parameters as most significant for the discrimination between the groups. The combined discriminant score yielded 64% sensitivity and 97% specificity for correct classification of FD patients in the test sample with a logistic area under curve of the ROC analysis of 0.97., Conclusion: The combination of automated ECG measures identified via a stepwise statistical approach may be useful for detection of FD patients in the pre-hypertrophic stage. These data are promising for screening purposes in the very early stages of FD cardiomyopathy and warrant prospective confirmation., Competing Interests: Declaration of Competing Interest MN, PN, IO: Travel, Advisory board and Speakers fees and Research support from Sanofi-Genzyme and Takeda. PR, NJ, DS and PMF: none declared., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Fabry disease (FD) is a rare X-linked inherited lysosomal storage disorder caused by deficient α-galactosidase A activity that leads to an accumulation of globotriasylceramide (Gb3) in affected tissues, including the heart. Cardiovascular involvement usually manifests as left ventricular hypertrophy, myocardial fibrosis, heart failure, and arrhythmias, which limit quality of life and represent the most common causes of death. Following the introduction of enzyme replacement therapy, early diagnosis and treatment have become essential to slow disease progression and prevent major cardiac complications. Recent advances in the understanding of FD pathophysiology suggest that in addition to Gb3 accumulation, other mechanisms contribute to the development of Fabry cardiomyopathy. Progress in imaging techniques have improved diagnosis and staging of FD-related cardiac disease, suggesting a central role for myocardial inflammation and setting the stage for further research. In addition, with the recent approval of oral chaperone therapy and new treatment developments, the FD-specific treatment landscape is rapidly evolving., Competing Interests: Funding Support and Author Disclosures Dr. Pieroni has received advisory board honoraria from Amicus Therapeutics and Sanofi Genzyme; and has received speaker honoraria from Amicus Therapeutics, Sanofi Genzyme, and Shire. Dr. Moon has received advisory board honoraria and speaker honoraria from Sanofi Genzyme and Shire; and has received an investigator-led research grant from Sanofi Genzyme. Dr. Arbustini has received travel support from Sanofi Genzyme, Shire, and Amicus Therapeutics. Dr. Barriales-Villa has received an unrestricted educational grant from Sanofi Genzyme; and has received advisory board/speaker’s fees from Amicus Therapeutics, Sanofi Genzyme, and Pfizer. Dr. Camporeale has received honoraria for presentations and board meetings from Amicus Therapeutics, Sanofi Genzyme, and Shire; and has received a research grant from Amicus Therapeutics. Dr. Vujkovac has received speaker honoraria and travel support from Sanofi Genzyme and Takeda. Dr. Elliott has received an unrestricted educational grant from Pfizer; and has received advisory board and/or speaker’s fees from Myokardia, Cytokinetics, Sanofi Genzyme, Shire, Alnylam, and Pfizer. Dr. Hagege has received support from Amicus, Gilead, Myokardia, Novartis, and Sanofi Genzyme. Dr. Kuusisto has received advisory board attendance fees from Sanofi Genzyme; and has received speaker honoraria and travel support from Sanofi Genzyme, Shire, and Amicus. Dr. Linhart has been a consultant for Amicus Therapeutics, Sanofi Genzyme, and Takeda; and has received speaker honoraria and travel support from Sanofi Genzyme and Takeda. Dr. Nordbeck has received honoraria for lecturing and advisory board participation from Amicus Therapeutics, Genzyme/Sanofi, Greenovation, Idorsia, and Shire/Takeda. Dr. Olivotto has received grants from Myokardia, Sanofi Genzyme, Shire, Bayer, Amicus, and Menarini International; and has received board and/or speaker’s fees from Myokardia, Cytokinetics, Sanofi Genzyme, and Shire. Dr. Pietila-Effati has received advisory board attendance and speaker honoraria, and travel support from Sanofi Genzyme; and has been a consultant for Shire. Dr. Namdar has received research support, advisory board attendance, and speaker honoraria, and travel support from Sanofi Genzyme; and has received research support from Shire HGT., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Results from the 18-month randomized treatment period of the phase 3 ATTRACT study demonstrated the efficacy and safety of oral migalastat compared with enzyme replacement therapy (ERT) in patients with Fabry disease who previously received ERT. Here, we report data from the subsequent 12-month, migalastat-only, open-label extension (OLE) period. ATTRACT (Study AT1001-012; NCT01218659) was a randomized, open-label, active-controlled study in patients aged 16-74 years with Fabry disease, an amenable GLA variant, and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m 2 . During the OLE, patients who received migalastat 150 mg every other day (QOD) during the randomized period continued receiving migalastat (Group 1 [MM]); patients who received ERT every other week discontinued ERT and started migalastat treatment (Group 2 [EM]). Outcome measures included eGFR, left ventricular mass index (LVMi), composite clinical outcome (renal, cardiac or cerebrovascular events), and safety. Forty-six patients who completed the randomized treatment period continued into the OLE (Group 1 [MM], n = 31; Group 2 [EM], n = 15). eGFR remained stable in both treatment groups. LVMi decreased from baseline at month 30 in Group 1 (MM) in patients with left ventricular hypertrophy at baseline. Only 10% of patients experienced a new composite clinical event with migalastat treatment during the OLE. No new safety concerns were reported. In conclusion, in patients with Fabry disease and amenable GLA variants, migalastat 150 mg QOD was well tolerated and demonstrated durable, long-term stability of renal function and reduction in LVMi., Competing Interests: Declaration of competing interest UFR has served on advisory boards for Amicus Therapeutics, Shire, Freeline, and Sanofi Genzyme, as a speaker for Amicus Therapeutics and Sanofi Genzyme, and has received research funding from Shire, Amicus Therapeutics, and Sanofi Genzyme. DH has received honoraria and research funding from Amicus Therapeutics, Shire, Sanofi Genzyme, Protalix, and Actelion. GSP has served on advisory boards for Amicus Therapeutics and Greenovation, as a speaker for Sanofi Genzyme, and has received research funding from Amicus Therapeutics, Idorsia, and Shire. SS has served as an investigator for Amicus Therapeutics. K Nedd received fees from Sanofi Genzyme and Shire-Takeda. IO has received research funding from and served as a speaker for Shire, Sanofi Genzyme, and MyoKardia. DO has served on advisory boards for Sanofi Genzyme. TH has nothing to disclose. TO has received research funding from DSP, Sanofi Genzyme, and Avrobio. NS, JY, and JAB are employees of and hold stock in Amicus Therapeutics. K Nicholls has served on advisory boards for Amicus Therapeutics, Sanofi Genzyme, and Shire, as a speaker for Amicus Therapeutics, and has received research funding from Sanofi Genzyme and Shire., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To report a novel finding in patients with Fabry disease, that is, the observation by adaptive optics ophthalmoscopy of intracellular lipidic deposits in retinal vessels., Methods: Observational two-center case series. Eighteen patients with genetically proven Fabry disease underwent flood-illumination adaptive optics ophthalmoscopy imaging (rtx1; Imagine Eyes, Orsay, France) of retinal vessels., Results: Fourteen patients (78% of all patients; 7 of the 10 women and 7 of the 8 men) showed paravascular punctuate or linear opacities in both eyes. In the least-affected patients, these were seen only in the wall of precapillary arterioles as discrete spots of 5 µm to 10 µm large, whereas in those more severely affected, capillaries and first-order vessels were also involved with diffuse opacification of the wall. These deposits sometime showed a striated pattern, suggesting colocalization with vascular smooth muscle cells., Conclusion: Adaptive optics ophthalmoscopy of retinal vessels may be of interest for patients with Fabry disease, providing noninvasive, gradable evaluation of microvascular involvement.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants in the α-galactosidase A (GLA) gene that leads to reduced or undetectable α-galactosidase A enzyme activity and progressive accumulation of globotriaosylceramide and its deacylated form globotriaosylsphingosine in cells throughout the body. FD can be multisystemic with neurological, renal, cutaneous and cardiac involvement or be limited to the heart. Cardiac involvement is characterized by progressive cardiac hypertrophy, fibrosis, arrhythmias, heart failure and sudden cardiac death. The cardiac management of FD requires specific measures including enzyme replacement therapy or small pharmacological chaperones in patients carrying amenable pathogenic GLA gene variants and more general management of cardiac symptoms and complications. In this paper, we summarize current knowledge of FD-related heart disease and expert consensus recommendations for its management., (© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Importance: Diagnostic screening for Anderson-Fabry cardiomyopathy (AFC) is performed in the presence of specific clinical red flags in patients with hypertrophic cardiomyopathy (HCM) older than 25 years. However, left ventricular outflow tract obstruction (LVOTO) has been traditionally considered an exclusion criteria for AFC., Objective: To examine a series of patients diagnosed with HCM and severe basal LVOTO undergoing myectomy in whom the diagnosis of AFC was suspected by the cardiac surgeon intraoperatively and confirmed by histological and genetic examinations., Design, Setting, and Participants: This retrospective analysis of patients undergoing surgical septal reduction strategies was conducted in 3 European tertiary referral centers for HCM from July 2013 to December 2016. Patients with a clinical diagnosis of obstructive HCM referred for surgical management of LVOTO were observed for at least 18 months after the procedure (mean [SD] follow-up, 33 [14] months)., Main Outcomes and Measures: Etiology of patients with HCM who underwent surgical myectomy., Results: From 2013, 235 consecutive patients with a clinical diagnosis of HCM underwent septal myectomy. The cardiac surgeon suspected a storage disease in 3 patients (1.3%) while inspecting their heart samples extracted from myectomy. The mean (SD) age at diagnosis for these 3 patients was 42 (4) years; all were male. None of the 3 patients presented with extracardiac features suggestive of AFC. All patients showed asymmetrical left ventricular hypertrophy, with maximal left ventricular thickness in the basal septum (19-31 mm), severe basal LVOTO (70-120 mm Hg), and left atrial dilatation (44-57 mm). Only 1 patient presented with late gadolinium enhancement on cardiovascular magnetic resonance at the right ventricle insertion site. The mean (SD) age at surgical procedure was 63 (5) years. On tactile sensation, the surgeon felt a spongy consistency of the surgical samples, different from the usual stony-elastic consistency typical of classic HCM, and this prompted histological examinations. Histology showed evidence of intracellular storage, and genetic analysis confirmed a GLA A gene mutation (p.Asn215Ser) in all 3 patients., Conclusions and Relevance: Screening for AFC should be performed even in the absence of red flags in patients with HCM older than 25 years.

Background: Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant ( amenable ) forms of α-Gal to facilitate normal lysosomal trafficking., Methods: The main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed., Results: Fifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had non-amenable mutant forms of α-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m 2 (-11.0 to -2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated., Conclusions: Migalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations., Trial Registration Number: NCT00925301; Pre-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Aims: Male patients with Anderson-Fabry disease (AFD) often exhibit cardiac involvement, characterized by LV hypertrophy (LVH), associated with severe coronary microvascular dysfunction (CMD). Whether CMD is present in patients without LVH, particularly when female, remains unresolved. The aim of the study was to investigate the presence of CMD by positron emission tomography (PET) in AFD patients of both genders, with and without evidence of LVH., Methods and Results: We assessed myocardial blood flow following dipyridamole infusion (Dip-MBF) with 13N-labelled ammonia by PET in 30 AFD patients (age 51 ± 13 years; 18 females) and in 24 healthy controls. LVH was defined as echocardiographic maximal LV wall thickness ≥13 mm. LVH was present in 67% of patients (n = 20; 10 males and 10 females). Dip-MBF was reduced in all patients compared with controls (1.8 ± 0.5 and 3.2 ± 0.5 mL/min/g, respectively, P < 0.001). For both genders, flow impairment was most severe in patients with LVH (1.4 ± 0.5 mL/min/g in males and 1.9 ± 0.5 mL/min/g in females), but was also evident in those without LVH (1.8 ± 0.3 mL/min/g in males and 2.1 ± 0.4 mL/min/g in females; overall P = 0.064 vs. patients with LVH). Analysis of variance (ANOVA) for the 17 LV segments showed marked regional heterogeneity of MBF in AFD (F = 4.46, P < 0.01), with prevalent hypoperfusion of the apical region. Conversely, controls showed homogeneous LV perfusion (F = 1.25, P = 0.23)., Conclusions: Coronary microvascular function is markedly impaired in AFD patients irrespective of LVH and gender. CMD may represent the only sign of cardiac involvement in AFD patients, with potentially important implications for clinical management.

Objective: Fabry's disease (FD) is an X-linked lysosomal storage disease. Distal extremity pain can be an early finding and renal, cardiac, and cerebrovascular complications may lead to complications and mortality. Treatment is now available for these patients, who may not be diagnosed correctly for years if the neuropathic nature of the pain is not recognized. The aim of our study was to describe early clinical features in a cohort of patients with FD and to emphasize the importance of distal extremity pain for early diagnosis., Methods: The medical charts of 35 patients with FD followed in a single center were reviewed. When data were incomplete, a detailed pain questionnaire was sent to patients. Nonresponders were contacted by telephone., Results: Distal extremity pain was present in the majority of cases (25 of 35). The mean age at diagnosis of FD was 43.5 years (range 5-77 years). Distal extremity pain was more prevalent in males than females and occurred mostly in childhood or adolescence. When present at onset, the disease progressed with subsequent organ system involvement. Misdiagnoses were frequent and included growing pains, juvenile idiopathic arthritis, connective tissue disease, and gout., Conclusion: Clinical manifestations of FD, including episodes of severe pain in the feet and hands, often start in childhood. Distal extremity pain may be the only symptom for a considerable period of time. Patients may be wrongly labeled as having rheumatologic conditions, resulting in long diagnostic and therapeutic delays. Rheumatologists should be aware of the clinical aspects of FD and include it in the differential diagnosis of distal extremity pain in childhood and adolescence., (Copyright © 2011 by the American College of Rheumatology.)

Heart failure with preserved ejection fraction (HFpEF) is a major driver of cardiac morbidity and mortality in developed countries, due to ageing populations and the increasing prevalence of comorbidities. While heart failure with reduced ejection fraction is dominated by left ventricular impairment, HFpEF results from a complex interplay of cardiac remodelling, peripheral circulation, and concomitant features including age, hypertension, obesity, and diabetes. In an important subset, however, HFpEF is subtended by specific diseases of the myocardium that are genetically determined, have distinct pathophysiology, and are increasingly amenable to targeted, innovative treatments. While each of these conditions is rare, they collectively represent a relevant subset within HFpEF cohorts, and their prompt recognition has major consequences for clinical practice, as access to dedicated, disease-specific treatments may radically change the quality of life and outcome. Furthermore, response to standard heart failure treatment will generally be modest for these individuals, whose inclusion in registries and trials may dilute the perceived efficacy of treatments targeting mainstream HFpEF. Finally, a better understanding of the molecular underpinnings of monogenic myocardial disease may help identify therapeutic targets and develop innovative treatments for selected HFpEF phenotypes of broader epidemiological relevance. The field of genetic cardiomyopathies is undergoing rapid transformation due to recent, groundbreaking advances in drug development, and deserves greater awareness within the heart failure community. The present review addressed existing and developing therapies for genetic causes of HFpEF, including hypertrophic cardiomyopathy, cardiac amyloidosis, and storage diseases, discussing their potential impact on management and their broader implications for our understanding of HFpEF at large. [ABSTRACT FROM AUTHOR]