RETRACTED: Wiesinger et al. An Innovative Tool for Evidence-Based, Personalized Treatment Trials in Mucopolysaccharidosis. Pharmaceutics 2023, 15, 1565.

The journal retracts the article, An Innovative Tool for Evidence-Based, Personalized Treatment Trials in Mucopolysaccharidosis [...].

The Prevalence of and Predisposing Factors for Late Atrial Arrhythmias after Transcatheter Closure of Secundum Atrial Septal Defects in Children.

BACKGROUND: A 24 h Holter study in children after transcatheter secundum ASD (ASD II) closure was conducted to detect the prevalence of defects and/or device-related late atrial arrhythmias (LAAs). ASD II closure with an Amplatzer septal occluder (ASO) is an established procedure. Little is known about LAAs after device implantation. METHODS: The eligible participants were children who had undergone ASO implantation, with a follow-up of ≥5 years, as well as one pre- and at least one post-procedural Holter ECG. RESULTS: In total, 161 patients (mean age: 6.2 ± 4.3 years), with a mean follow-up of 12.9 ± 3.1 years (range 5-19), were included. A median of four Holter ECGs per patient were available. LAAs occurred before intervention in four patients (2.5%), and it was peri-interventional in four patients (2.5%), sustained in three patients (1.9%), and developed in three patients (1.9%). In patients with pre- and peri-interventional LAAs, the Qp/Qs ratio was higher (6.4 ± 3.9 vs. non-AA: 2.0 ± 1.1 (p = 0.002)) and the IAS/ASO ratio was lower (1.18 ± 0.27 vs. non-AA: 1.7 ± 0.4 (p < 0.001)). The patients with LAAs differed from those without LAAs in their Qp/Qs (6.8 ± 3.5 vs. 2.0 ± 1.3; p < 0.0001) and IAS/ASO ratios (1.14 ± 0.19 vs. 1.73 ± 0.45; p < 0.001). The patients with LAAs had a Qp/Qs ratio ≥2.94:1, and those who developed LAAs had an IAS/ASO ratio <1.15. CONCLUSIONS: LAAs occurred in 1.9% of patients and were sustained in another 1.9% of patients but persisted in those with large shunt defects and large occluders in relation to the atrial septal length. The predisposing factors for LAAs after ASD closure were a high Qp/Qs ratio, pre-existing atrial arrhythmias, and a low IAS/ASO ratio.

An Innovative Tool for Evidence-Based, Personalized Treatment Trials in Mucopolysaccharidosis.

Mucopolysaccharidosis (MPS) is a group of rare metabolic diseases associated with reduced life expectancy and a substantial unmet medical need. Immunomodulatory drugs could be a relevant treatment approach for MPS patients, although they are not licensed for this population. Therefore, we aim to provide evidence justifying fast access to innovative individual treatment trials (ITTs) with immunomodulators and a high-quality evaluation of drug effects by implementing a risk-benefit model for MPS. The iterative methodology of our developed decision analysis framework (DAF) consists of the following steps: (i) a comprehensive literature analysis on promising treatment targets and immunomodulators for MPS; (ii) a quantitative risk-benefit assessment (RBA) of selected molecules; and (iii) allocation phenotypic profiles and a quantitative assessment. These steps allow for the personalized use of the model and are in accordance with expert and patient representatives. The following four promising immunomodulators were identified: adalimumab, abatacept, anakinra, and cladribine. An improvement in mobility is most likely with adalimumab, while anakinra might be the treatment of choice for patients with neurocognitive involvement. Nevertheless, a RBA should always be completed on an individual basis. Our evidence-based DAF model for ITTs directly addresses the substantial unmet medical need in MPS and characterizes a first approach toward precision medicine with immunomodulatory drugs.

Evaluating Cardiac Lateralization by MRI to Simplify Estimation of Cardiopulmonary Impairment in Pectus Excavatum.

BACKGROUND: The severity of pectus excavatum is classified by the Haller Index (HI) and/or Correction Index (CI). These indices measure only the depth of the defect and, therefore, impede a precise estimation of the actual cardiopulmonary impairment. We aimed to evaluate the MRI-derived cardiac lateralization to improve the estimation of cardiopulmonary impairment in Pectus excavatum in connection with the Haller and Correction Indices. METHODS: This retrospective cohort study included a total of 113 patients (mean age = 19.03 ± 7.8) with pectus excavatum, whose diagnosis was verified on cross-sectional MRI images using the HI and CI. For the development of an improved HI and CI index, the patients underwent cardiopulmonary exercise testing to assess the influence of the right ventricle's position on cardiopulmonary impairment. The indexed lateral position of the pulmonary valve was utilized as a surrogate parameter for right ventricle localization. RESULTS: In patients with PE, the heart's lateralization significantly correlated with the severity of pectus excavatum (p ≤ 0.001). When modifying HI and CI for the individual's pulmonary valve position, those indices are present with greater sensitivity and specificity regarding the maximum oxygen-pulse as a pathophysiological correlate of reduced cardiac function (χ2 10.986 and 15.862, respectively). CONCLUSION: The indexed lateral deviation of the pulmonary valve seems to be a valuable cofactor for HI and CI, allowing for an improved description of cardiopulmonary impairment in PE patients.

Left atrial strain correlates with severity of cardiac involvement in Anderson-Fabry disease.

OBJECTIVES: Cardiac involvement in Anderson-Fabry disease (AFD) results in myocardial lipid depositions. An early diagnosis can maximize therapeutic benefit. Thus, this study aims to investigate the potential of cardiac MRI (CMR) based parameters of left atrial (LA) function and strain to detect early stages of AFD. METHODS: Patients (n = 58, age 40 (29-51) years, 31 female) with genetically proven AFD had undergone CMR including left ventricular (LV) volumetry, mass index (LVMi), T1, and late gadolinium enhancement, complemented by LA and LV strain measurements and atrial emptying fractions. Patients were stratified into three disease phases and compared to age and sex-matched healthy controls (HC, n = 58, age 41 [26-56] years, 31 female). RESULTS: A total of 19 early-, 20 intermediate-, and 19 advanced-phase patients were included. LV and LA reservoir strain was significantly impaired in all AFD phases, including early disease (both p < 0.001). In contrast, LA volumetry, T1, and LVMi showed no significant differences between the early phase and HC (p > 0.05). In the intermediate phase, LVMi and T1 demonstrated significant differences. In advanced phase, all parameters except active emptying fractions differed significantly from HC. ROC curve analyses of early disease phases revealed superior diagnostic confidence for the LA reservoir strain (AUC 0.88, sensitivity 89%, specificity 75%) over the LV strain (AUC 0.82). CONCLUSIONS: LA reservoir strain showed impairment in early AFD and significantly correlated with disease severity. The novel approach performed better in identifying early disease than the established approach using LVMi and T1. Further studies are needed to evaluate whether these results justify earlier initiation of therapy and help minimize cardiac complications. KEY POINTS: • Parameters of left atrial function and deformation showed impairments in the early stages of Anderson-Fabry disease and correlated significantly with the severity of Anderson-Fabry disease. • Left atrial reservoir strain performed superior to ventricular strain in detecting early myocardial involvement in Anderson-Fabry disease and improved diagnostic accuracies of approaches already using ventricular strain. • Further studies are needed to evaluate whether earlier initiation of enzyme replacement therapy based on these results can help minimize cardiac complications from Anderson-Fabry disease.

Biventricular strain assessment indicates progressive impairment of myocardial contractility in phenotypically negative patients with Fabry's disease.

PURPOSE: The accumulation of sphingolipids in Fabry's disease (FD) leads to left ventricular (LV) hypertrophy and shortened T1 in cardiac magnetic resonance (CMR). Early detection of myocardial involvement is essential for the timely initiation and efficacy of enzyme replacement therapy. However, there is a diagnostic gap between the onset of accumulation and detectable myocardial changes. This study aimed to evaluate the diagnostic value of biventricular strain assessment in early FD. METHODS: Genetically proven FD patients (n = 58) and healthy volunteers (HV, n = 62) who had undergone 3 T CMR were retrospectively identified and stratified into 3 groups according to disease severity. Biventricular volumetry, global longitudinal strains (GLS), indexed biventricular masses (RVMi/LVMi), and T1 were evaluated. Group comparisons were performed by ANOVA and diagnostic accuracy was evaluated by ROC-analysis. RESULTS: The study population included 19 group I, 20 group II and 19 group III patients. LV volumetry and T1 showed no significant difference between early FD patients and HV (all p > 0.760). However, RVMi was increased, while RV-GLS and LV-GLS were significantly impaired (p = 0.024 and < 0.001, respectively). Biventricular strains accurately discriminated early FD patients and HV with RV-GLS being non-inferior to LV-GLS (AUC for both 0.83, p > 0.05). Adding strains to the established approach using T1 and LVMi further increased diagnostic accuracy (AUC 0.99, p < 0.05). CONCLUSIONS: Biventricular strains may help detect altered myocardial deformation patterns in phenotypically negative FD patients. These findings may lead to an earlier initiation of therapy, which in turn may slow hypertrophy and the associated long-term risks.

The Inflammation in the Cytopathology of Patients With Mucopolysaccharidoses- Immunomodulatory Drugs as an Approach to Therapy.

Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases (LSDs), characterized by the accumulation of glycosaminoglycans (GAGs). GAG storage-induced inflammatory processes are a driver of cytopathology in MPS and pharmacological immunomodulation can bring improvements in brain, cartilage and bone pathology in rodent models. This manuscript reviews current knowledge with regard to inflammation in MPS patients and provides hypotheses for the therapeutic use of immunomodulators in MPS. Thus, we aim to set the foundation for a rational repurposing of the discussed molecules to minimize the clinical unmet needs still remaining despite enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT).

Twenty years of the Fabry Outcome Survey (FOS): insights, achievements, and lessons learned from a global patient registry.

BACKGROUND: Patient registries provide long-term, real-world evidence that aids the understanding of the natural history and progression of disease, and the effects of treatment on large patient populations with rare diseases. The year 2021 marks the 20th anniversary of the Fabry Outcome Survey (FOS), an international, multicenter, observational registry (NCT03289065). The primary aims of FOS are to broaden the understanding of Fabry disease (FD), an X-linked lysosomal storage disorder, and to improve the clinical management of affected patients. Here, we review the history of FOS and the analyses and publications disseminated from the registry, and we discuss the contributions FOS studies have made in understanding FD. RESULTS: FOS was initiated in April 2001 and, as of January 2021, 4484 patients with a confirmed diagnosis and patient informed consent have been enrolled from 144 centers across 26 countries. Data from FOS have been published in nearly 60 manuscripts on a wide variety of topics relevant to FD. Analyses of FOS data have investigated the long-term effectiveness and safety of enzyme replacement therapy (ERT) with agalsidase alfa and its effects on morbidity and mortality, as well as the benefits of prompt and early treatment with agalsidase alfa on the progression of cardiomyopathy and the decline in renal function associated with FD. Based on analyses of FOS data, ERT with agalsidase alfa has also been shown to improve additional signs and symptoms of FD experienced by patients. FOS data analyses have provided a better understanding of the natural history of FD and the specific populations of women, children, and the elderly, and have provided practical tools for the study of FD. FOS has also provided methodology and criteria for assessing disease severity which contributed to the continuous development of medical practice in FD and has largely improved our understanding of the challenges and needs of long-term data collection in rare diseases, aiding in future rare disease real-world evidence studies. CONCLUSION: FOS over the last 20 years has substantially increased the scientific knowledge around improved patient management of FD and continues to expand our understanding of this rare disease.

Treatment of Fabry Disease management with migalastat-outcome from a prospective 24 months observational multicenter study (FAMOUS).

AIMS: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A (GLA/AGAL), resulting in the lysosomal accumulation of globotriaosylceramide (Gb3). Patients with amenable GLA mutations can be treated with migalastat, an oral pharmacological chaperone increasing endogenous AGAL activity. In this prospective observational multicentre study, safety as well as cardiovascular, renal, and patient-reported outcomes and disease biomarkers were assessed after 12 and 24 months of migalastat treatment under 'real-world' conditions. METHODS AND RESULTS: A total of 54 patients (26 females) (33 of these [61.1%] pre-treated with enzyme replacement therapy) with amenable mutations were analysed. Treatment was generally safe and well tolerated. A total of 153 events per 1000 patient-years were detected. Overall left ventricular mass index decreased after 24 months (all: -7.5 ± 17.4 g/m2, P = 0.0118; females: -4.6 ± 9.1 g/m2, P = 0.0554; males: -9.9 ± 22.2 g/m2, P = 0.0699). After 24 months, females and males presented with a moderate yearly loss of estimated glomerular filtration rate (-2.6 and -4.4 mL/min/1.73 m2 per year; P = 0.0317 and P = 0.0028, respectively). FD-specific manifestations/symptoms remained stable (all P > 0.05). A total of 76.9% of females and 50% of males suffered from pain, which has not improved under treatment. FD-specific disease scores (Disease Severity Scoring System and Mainz Severity Score Index) remained stable during treatment. AGAL activities and plasma lyso-Gb3 values remained stable, although some male patients presented with increasing lyso-Gb3 levels over time. CONCLUSIONS: Treatment with migalastat was generally safe and resulted in most patients in an amelioration of left ventricular mass. However, due to the heterogeneity of FD phenotypes, it is advisable that the treating physician monitors the clinical response regularly.

A single center experience in 90 cases with nonimmune hydrops fetalis: diagnostic categories ‒ mostly aneuploidy and still often idiopathic.

OBJECTIVES: The prognosis of nonimmune hydrops fetalis (NIHF) is still poor with a high mortality and morbidity rate despite progress in perinatal care. This study was designed to investigate etiology and outcome of NIHF. METHODS: A retrospective review of 90 NIHF cases from 2007 to 2019 was conducted at University Medical Center of the Johannes Gutenberg University, Mainz, Germany. Demographics, genetic results, prenatal and postnatal outcomes including one year survival as well as autopsy data were extracted. Etiology of hydrops was classified using 13 previously established categories. In 4 patients observed between 2016 and 2019, we used a next-generation-sequencing (NGS) panel for genetic evaluation. RESULTS: Ninety NIHF cases were identified, with a median gestational age (GA) at diagnosis of 14 weeks. There were 25 live-born infants with a median GA of 34 weeks at birth, 15 patients survived to one year. There was aneuploidy in more than one third of the cases. All 90 cases were subclassified into etiologic categories with chromosomal 35, idiopathic 15, syndromic 11, cardiovascular 9, inborn errors of metabolism 6, lymphatic dysplasia 3, thoracic 3, infections 3, gastrointestinal 3 and hematologic 2. The NGS panel was used in 4 cases and 4 diagnoses were made. CONCLUSIONS: In 90 cases with NIHF we identified an aneuploidy in more than one third of the cases. Improved techniques, such as possibly specific genetic analysis, could reduce the high rate of unexplained cases of NIHF.

Addressing the need for patient-friendly medical communications: adaptation of the 2019 recommendations for the management of MPS VI and MPS IVA.

BACKGROUND: Patients are the most important stakeholders in the care of any disease and have an educational need to learn about their condition and the treatment they should receive. Considering this need for patient-focused materials, we present a directed approach for mucopolysaccharidosis (MPS) VI and MPS IVA, a pair of rare, inherited diseases that affects multiple organs and parts of the body. Independent guidelines on the treatment of these diseases were recently published, providing evidence- and expertise-driven recommendations to optimize patient management. However, while healthcare providers may have the training and knowledge to understand these guidelines, patients and their caregivers can find the technical content challenging. Hence, we aimed to develop plain language summaries (PLS) of the MPS VI and MPS IVA guidelines with patients as the primary audience. RESULTS: A review of the guidelines by an expert team identified six domains of information relevant to patients: The multidisciplinary team, regular tests and check-ups, disease-modifying and supportive treatments, general anesthetics, ear-nose-throat/respiratory care, and surgeries. This information was adapted into a series of infographics specific to either MPS VI or MPS IVA, designed to appeal to patients and clearly present information in a concise manner. CONCLUSIONS: The use of patient-friendly materials, like the infographics we have developed, has the potential to better inform patients and engage them in their care. We issue a "call to arms" to the medical community for the development of similar PLS materials in rare diseases intended to inform and empower patients.

Evaluation of the long-term treatment effects of intravenous idursulfase in patients with mucopolysaccharidosis II (MPS II) using statistical modeling: data from the Hunter Outcome Survey (HOS).

BACKGROUND: Mucopolysaccharidosis II (MPS II; Hunter syndrome) is a rare, life-limiting lysosomal storage disease caused by deficient iduronate-2-sulfatase activity. Enzyme replacement therapy (ERT) with intravenous (IV) idursulfase can stabilize or improve many somatic manifestations, but there remains a need for further analysis of long-term treatment outcomes. Using data from patients with MPS II enrolled in the Hunter Outcome Survey (HOS), mixed modeling was performed to evaluate and predict the effects of IV idursulfase treatment on selected clinical parameters for up to 8 years following treatment start. The modeling population comprised male patients followed prospectively in HOS who had received IV idursulfase for at least 5 years and who had data available for two or more time points (at least one post-ERT). Age at ERT start and time since ERT start were included as covariates. RESULTS: In total, 481 patients were eligible for inclusion in at least one model. At 8 years post-ERT start, improvement from baseline was predicted for each age group (< 18 months, 18 months to < 5 years and ≥ 5 years at treatment start) in the following parameters: mean urinary glycosaminoglycan levels (percentage changes of > -75% in each group), mean left ventricular mass index (decreases of ~ 1 g/m2) and mean palpable liver size (decreases of > 2 cm). Improvements in mean 6-min walk test distance (increase of > 50 m) and stabilization in percent predicted forced vital capacity and forced expiratory volume in 1 s (decreases of ~ 4 and ~ 9 percentage points, respectively) at 8 years post-ERT start were predicted for patients aged ≥ 5 years at ERT start (these assessments are unsuitable for patients aged < 5 years). Predicted changes over time were similar across the three age groups; however, overall outcomes were most favorable in children aged < 18 months at ERT start. CONCLUSIONS: These findings suggest that the previously reported positive effects of IV idursulfase on the somatic manifestations of MPS II are predicted to be maintained for at least 8 years following ERT initiation and highlight the value of statistical modeling to predict long-term treatment outcomes in patients with rare diseases.

Rapid detection by hydrops panel of Noonan syndrome with PTPN11 mutation (p.Thr73Ile) and persistent thrombocytopenia.

BACKGROUND: Nonimmune hydrops fetalis (NIHF) is still a challenging diagnosis. The differential diagnosis is extensive and the success of identifying a cause depends on the thoroughness of efforts to establish a diagnosis. For the early diagnosis of NIHF, a virtual gene panel diagnostic tool was developed. The female premature baby in question was delivered via emergency cesarean at 30 + 1 weeks of gestational age (GA) due to rapidly developing NIHF to a healthy mother. The family history was noncontributory. METHODS: DNA of the family was extracted and sequenced by the virtual hydrops panel with whole-exome sequencing. RESULTS: The hydrops panel revealed Noonan syndrome (NS) with a germline mutation in PTPN11 c.218C>T (p.Thr73Ile). CONCLUSION: The diagnosis of our patient was rapidly confirmed by the hydrops panel. The variant of c.218C>T (p.Thr73Ile) has not yet been described in literature relating to NIHF. Only a few case reports of this variant are known. This particular mutation is associated with Noonan syndrome, congenital heart defect and persistent thrombocytopenia. Few reveal juvenile myelomonocytic leukemia.

Treatment of Fabry's Disease With Migalastat: Outcome From a Prospective Observational Multicenter Study (FAMOUS).

Fabry's disease (FD) is an X-linked lysosomal storage disorder caused by the deficient activity of the lysosomal enzyme α-galactosidase A (α-Gal A) leading to intracellular accumulation of globotriaosylceramide (Gb3). Patients with amenable mutations can be treated with migalastat, a recently approved oral pharmacologic chaperone to increase endogenous α-Gal A activity. We assessed safety along with cardiovascular, renal, and patient-reported outcomes and disease biomarkers in a prospective observational multicenter study after 12 months of migalastat treatment under "real-world" conditions. Fifty-nine (28 females) patients (34 (57.6%) pretreated with enzyme replacement therapy) with amenable mutations were recruited. Migalastat was generally safe and well tolerated. Females and males presented with a reduction of left ventricular mass index (primary end point) (-7.2 and -13.7 g/m2 , P = 0.0050 and P = 0.0061). FD-specific manifestations and symptoms remained stable (all P > 0.05). Both sexes presented with a reduction of estimated glomerular filtration rate (secondary end point) (-6.9 and -5.0 mL/minute/1.73 m2 ; P = 0.0020 and P = 0.0004, respectively), which was most prominent in patients with low blood pressure (P = 0.0271). α-Gal A activity increased in male patients by 15% from 29% to 44% of the normal wild-type activity (P = 0.0106) and plasma lyso-Gb3 levels were stable in females and males (P = 0.3490 and P = 0.2009). Reevaluation of mutations with poor biochemical response revealed no marked activity increase in a zero activity background. We conclude that therapy with migalastat was generally safe and resulted in an amelioration of left ventricular mass. In terms of impaired renal function, blood pressure control seems to be an unattended important goal.

Diagnosis and Care of Infants and Children with Pompe Disease.

Pompe disease is a rare metabolic myopathy caused by deficiency of lysosomal α-glucosidase. Reduced enzyme activity results in abnormal intra- and extralysosomal glycogen deposition as well as impaired cellular function and autophagy. Age at manifestation and severity of disease depend on residual enzyme activity. Enzyme replacement therapy (ERT) is available since 2006. In infantile onset Pompe disease, the most severe form, markedly prolonged survival has resulted in a new phenotype with symptoms and problems not encountered previously. In addition, it became apparent that antibody formation against the recombinant human enzyme may adversely affect the response to ERT. This review summarizes new knowledge gained in the last years concerning care of pediatric patients with Pompe disease and gives recommendations for diagnostics, treatment, and follow-up.

Cardio- Renal Outcomes With Long- Term Agalsidase Alfa Enzyme Replacement Therapy: A 10- Year Fabry Outcome Survey (FOS) Analysis.

PURPOSE: Following the publication of 5-year agalsidase alfa enzyme replacement therapy (ERT) outcomes data from the Fabry Outcome Survey (FOS), 10-year data were analyzed. PATIENTS AND METHODS: FOS (ClinicalTrials.gov identifier: NCT03289065) data (April 2001 to August 2018) were retrospectively analyzed. Estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) were analyzed after treatment start (baseline) for patients with ≥3 measurements, including baseline and year 10. RESULTS: Median (range) age (years) of the evaluable treated renal cohort at treatment start was 48.8 (17.9-67.3) for females (n=62), 34.4 (18.0-66.8) for males (n=90). With eGFR ≥60 mL/min/1.73 m2 at baseline, mean (95% CI) rate of eGFR change (eGFR/year) over 10 years was relatively stable in females (n=52; -0.55 [-1.12, +0.01]) and slightly declined in males (n=79; -1.99 [-2.45, -1.54]). With impaired kidney function (eGFR <60 mL/min/1.73 m2) at baseline, mean (95% CI) eGFR/year was stable in females (n=10; -0.14 [-1.43, +1.15]) and slightly declined in males (n=11; -2.79 [-4.01, -1.56]) over 10 years. Median (range) age (years) of the evaluable treated cardiac cohort at treatment start was 46.7 (3.7-67.3) for females (n=34), 28.2 (4.0-54.2) for males (n=35). With left ventricular hypertrophy (LVH; LVMI >48 g/m2.7 in females, >50 g/m2.7 in males) at baseline, mean (95% CI) LVMI/year slightly increased over 10 years in females (n=18; +1.51 [+0.91, +2.12]) and males (n=14; +0.87 (+0.19, +1.55). Without LVH at baseline, mean (95% CI) LVMI/year was stable in females (n=16; +0.52 [-0.13, +1.17]) and males (n=21; +0.57 [+0.02, +1.13]) over 10 years. CONCLUSION: Agalsidase alfa-treated patients with 10-year FOS data and preserved kidney function and/or normal LVMI at baseline remained largely stable; those with decreased kidney function or LVH at baseline experienced modest declines in renal function and/or increases in LVMI.

Intermediate outcomes of transcatheter pulmonary valve replacement with the Edwards Sapien 3 valve - German experience.

Background: After encouraging results with the Edwards Sapien and XT valves, this study aimed to review procedural data and early outcomes for the Sapien 3 valves for transcatheter pulmonary valve replacement (TPVR). Methods: We performed a multicenter, retrospective analysis of cases who underwent a Sapien 3 TPVR between 2015 and 2017 in 7 centers in Germany with a follow-up of up to 2 years. Results: 56 patients could be enrolled (weight 58,5 ± 25,0 kg; 53% Tetralogy of Fallot, 45% native RVOT). Most procedures were two-stage procedures (82,1%) with 100% prestenting. Valve sizes were 20 mm (n = 1), 23 mm (n = 15), 26 mm (n = 27), 29 mm (n = 13). Procedural success rate was 96.4%. Two patients underwent surgical valve implantation after balloon rupture during TPVR. Follow-up data were available up to 24-month post TPVR. The rate of patients with ? moderate and severe pulmonary regurgitation decreased to 0% after TPVR, peak systolic gradient decreased from 24,2 (SD±20,9) mmHg to 7,1 mmHg (SD±5,0). There were no endocarditis, severe tricuspid valve impairment or stent fractures. Conclusions: With the Edwards Sapien 3 valve, the patient pool for TPVR can be substantially extended. Continued data collection is necessary to verify long-term results.

Early detection of organ involvement in Fabry disease by biomarker assessment in conjunction with LGE cardiac MRI: results from the SOPHIA study.

BACKGROUND: Initiation of enzyme replacement therapy (ERT) early in the Fabry disease course may facilitate better outcomes than in patients with advanced disease. Early diagnosis is often hindered by the heterogeneous nature of signs and symptoms, and by the presentation of atypical phenotypes. METHODS: The Sophisticated Assessment of Disease Burden in Patients with Fabry Disease study (SOPHIA; ClinicalTrials.gov, NCT01210196) evaluated clinical and diagnostic assessments for early detection of Fabry-related organ pathology in ERT-naïve patients with mild FD symptoms. Assessments included cardiac magnetic resonance imaging with late gadolinium enhancement (LGE-CMR), echocardiography, 24-h Holter electrocardiography, and biomarkers of FD and fibrosis. RESULTS: 35 patients with mean (SD) baseline age of 45.0 (10.2) years were included and assessed at baseline, 12 months, and (optionally) at 24 months. At baseline, LGE-CMR and elevated procollagen III N-terminal propeptide, sphingosine-1-phosphate, and globotriaosylsphingosine were the most prevalent indicators of early Fabry-related pathology. LGE was already present in 58.8% of patients with normal left ventricular mass index. 15.2% of patients showed grade 1 diastolic dysfunction. QRS duration increased from baseline to last observation, particularly in patients with severe baseline fibrosis. Fibrosis progressed from baseline to last observation, especially in patients with baseline LGE ≥ 2.50 mL (3.65 [1.14] mL vs 6.74 [1.10] mL). Statistically significant correlations were found between LGE volume and high-sensitivity troponin T, and between LGE volume and fragments of urinary collagen alpha-1 (I), (III), and (VII), and collagen alpha-3 (V). CONCLUSIONS: Fibrosis may become apparent before left ventricular hypertrophy occurs. LGE-CMR imaging is superior to conventional echocardiography for detecting early cardiomyopathy in FD and, in conjunction with biomarker tests, may help detect early organ involvement in mild FD.

Evaluating enzyme replacement therapies for Anderson-Fabry disease: commentary on a recent report.

Anderson-Fabry disease (AFD) is a rare lysosomal storage disorder. Randomized controlled clinical trials (RCTs) are preferred as the highest category of evidence, but limited availability of robust evidence in rare diseases may necessitate the use of less rigorous evidence. An analysis of cohort studies of enzyme replacement therapies for AFD published in 2017 by El Dib and coworkers made treatment recommendations that contradict previously published findings from RCTs and a systematic Cochrane review. Our commentary outlines concerns regarding selection criteria and statistical methods with their analysis.