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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/m2 (66.0-184.0) vs 99.0 g/m2 (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 (VO2) 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 VO2 (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.

In patients with Fabry disease (FD), cardiovascular involvement is the main cause of death and reduction of quality of life. Left ventricular hypertrophy mimicking hypertrophic cardiomyopathy is the main feature of FD cardiac involvement although glycolipid storage occurs in all cardiac cellular types. Accumulation of lysosomal globotriasylceramide represents the main mechanism of cardiac damage in early stages, but secondary pathways of cellular and tissue damage, triggered by lysosomal storage, and including altered energy production, inflammation and cell death, contribute to cardiac damage and disease progression. These mechanisms appear prominent in more advanced stages, hampering and reducing the efficacy of FD-specific treatments. Therefore, additional cardiovascular therapies are important to manage cardiovascular symptoms and reduce cardiovascular events. Although new therapies targeting lysosomal storage are in development, a better definition and comprehension of the complex pathophysiology of cardiac damage in FD, may lead to identify new therapeutic targets beyond storage and new therapeutic strategies.

In the past few years, the wide application of cardiac magnetic resonance (CMR) significantly changed the approach to the study of cardiac involvement in Fabry Disease (FD). The possibility to perform non-invasive tissue characterization, including new sequences such as T1/T2 mapping, offered a powerful tool for differential diagnosis with other forms of left ventricular hypertrophy. In patients with confirmed diagnosis of FD, CMR is the most sensitive non-invasive technique for early detection of cardiac involvement and it provides new insight into the evolution of cardiac damage, including gender-specific features. Finally, CMR multiparametric detection of subtle changes in cardiac morphology, function and tissue composition is potentially useful for monitoring the efficacy of specific treatment over time. This paper aims to provide a comprehensive review of current knowledge regarding the application of CMR in FD cardiac involvement and its clinical implication.

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 chi(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.

Aims Fabry cardiomyopathy is characterized by glycosphingolipid storage and increased myocardial trabeculation has also been demonstrated. This study aimed to explore by cardiac magnetic resonance whether myocardial trabecular complexity, quantified by endocardial border fractal analysis, tracks phenotype evolution in Fabry cardiomyopathy. Methods and results Study population included 20 healthy controls (12 males, age 32 +/- 9) and 45 Fabry patients divided into three groups: 15 left ventricular hypertrophy (LVH)-negative patients with normal T1 (5 males, age 28 +/- 13; Group 1); 15 LVH-negative patients with low T1 (9 males, age 33 +/- 9.6; Group 2); 15 LVH-positive patients (11 males, age 53.5 +/- 9.6; Group 3). Trabecular fractal dimensions (Dfs) (total, basal, mid-ventricular, and apical) were evaluated on cine images. Total Df was higher in all Fabry groups compared to controls, gradually increasing from controls to Group 3 (1.27 +/- 0.02 controls vs. 1.29 +/- 0.02 Group 1 vs. 1.30 +/- 0.02 Group 2 vs. 1.34 +/- 0.02 Group 3; P<0.001). Group 3 showed significantly higher values of all Dfs compared to the other Groups. Both basal and total Dfs were significantly higher in Group 1 compared with controls (basal: 1.30 +/- 0.03 vs. 1.26 +/- 0.04, P =0.010; total: 1.29 +/- 0.02 vs. 1.27 +/- 0.02, P=0.044). Total Df showed significant correlations with: (i) T1 value (r=-0.569; P<0.001); (ii) LV mass (r=0.664, P<0.001); (iii) trabecular mass (r=0.676; P <0.001); (iv) Mainz Severity Score Index (r=0.638; P<0.001). Conclusion Fabry cardiomyopathy is characterized by a progressive increase in Df of endocardial trabeculae together with shortening of T1 values. Myocardial trabeculation is increased before the presence of detectable sphingolipid storage, thus representing an early sign of cardiac involvement.

AIMS: Fabry cardiomyopathy is characterized by glycosphingolipid storage and increased myocardial trabeculation has also been demonstrated. This study aimed to explore by cardiac magnetic resonance whether myocardial trabecular complexity, quantified by endocardial border fractal analysis, tracks phenotype evolution in Fabry cardiomyopathy. METHODS AND RESULTS: Study population included 20 healthy controls (12 males, age 32±9) and 45 Fabry patients divided into three groups: 15 left ventricular hypertrophy (LVH)-negative patients with normal T1 (5 males, age 28±13; Group 1); 15 LVH-negative patients with low T1 (9 males, age 33±9.6; Group 2); 15 LVH-positive patients (11 males, age 53.5±9.6; Group 3). Trabecular fractal dimensions (Dfs) (total, basal, mid-ventricular, and apical) were evaluated on cine images. Total Df was higher in all Fabry groups compared to controls, gradually increasing from controls to Group 3 (1.27±0.02 controls vs. 1.29±0.02 Group 1 vs. 1.30±0.02 Group 2 vs. 1.34±0.02 Group 3; P<0.001). Group 3 showed significantly higher values of all Dfs compared to the other Groups. Both basal and total Dfs were significantly higher in Group 1 compared with controls (basal: 1.30±0.03 vs. 1.26±0.04, P =0.010; total: 1.29±0.02 vs. 1.27±0.02, P=0.044). Total Df showed significant correlations with: (i) T1 value (r=-0.569; P<0.001); (ii) LV mass (r=0.664, P<0.001); (iii) trabecular mass (r=0.676; P <0.001); (iv) Mainz Severity Score Index (r=0.638; P<0.001). CONCLUSION: Fabry cardiomyopathy is characterized by a progressive increase in Df of endocardial trabeculae together with shortening of T1 values. Myocardial trabeculation is increased before the presence of detectable sphingolipid storage, thus representing an early sign of cardiac involvement. Published on behalf of the European Society of Cardiology.

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Aims: Right ventricular hypertrophy (RVH) is a common finding in Anderson–Fabry disease (AFD), but the prognostic role of right ventricular (RV) involvement has never been assessed. The aim of our study was to evaluate the prognostic significance of RVH and RV systolic function in AFD. Methods and results: Forty-five AFD patients (56% male patients) with extensive baseline evaluation, including assessment of RVH and RV systolic function, were followed-up for an average of 51.2 ± 11.4 months. RV systolic function was assessed by standard and tissue Doppler echocardiography. Cardiovascular events were defined as new-onset atrial fibrillation (AF), sustained ventricular arrhythmias, heart failure, or pacemaker/implantable cardioverter defibrillator implantation; renal events were defined as progression to dialysis and/or renal transplantation or significant worsening of glomerular filtration rate; and cerebrovascular events were defined as transient ischaemic attack or stroke. Fourteen patients (31.1%) presented RVH, while RV systolic function was normal in all cases. During the follow-up period, 13 patients (28.8%, 11 male) experienced 18 major events, including two deaths. Cardiovascular events occurred in eight patients (17.7%). The most common event was pacemaker/implantable cardioverter defibrillator implantation (six patients, 13.3%), followed by AF (three cases, 6.6%). Only one case of worsening New York Heart Association class (from II to III and IV) was observed. Ischaemic stroke occurred in three cases (6.6%). Renal events were recorded in three patients (6.6%). At univariate analysis, several variables were associated with the occurrence of events, including RVH (HR: 7.09, 95% CI: 2.17 to 23.14, P = 0.001) and indexes of RV systolic function (tricuspid annular plane systolic excursion HR: 0.77, 95% CI: 0.62 to 0.96, P = 0.02; and RV tissue Doppler systolic velocity HR: 0.76, 95% CI: 0.61 to 0.93, P = 0.01). At mul