Cardiac Involvement in Anderson-Fabry Disease: Preliminary Data from a Multidisciplinary Referral Center

BackgroundAnderson-Fabry disease (AFD) is a rare X-linked lysosomal disorder due to GLA gene mutations, causing deficient α-galactosidase A activity and accumulation of globotriaosylceramide in multiple organs. Cardiac involvement significantly affects morbidity and mortality, manifesting as left ventricular hypertrophy(LVH), arrhythmias, conduction issues, or heart failure(HF). Early detection through multiparametric assessment, including ECG, echocardiography, cardiac magnetic resonance(CMR) and biomarkers, is crucial for guiding treatment and monitoring progression. AimsTodescribe the clinical, imaging, and laboratory characteristics of a cohort of AFD patients from a tertiary referral center; evaluate the diagnostic performance of cardiac biomarkers, particularly high-sensitivity troponin I(hs-cTnI), for detecting cardiac involvement; characterize the subgroup of patients carrying the late-onset, cardiac-predominant N215S mutation. Materials & methodsThis retrospective observational study included patients with genetically confirmed AFD followed at PadovaUniversityHospital. Clinical, imaging, and biochemical data were collected from medical records, including demographic data, clinical presentation, comorbidities, and therapy. Cardiological assessment included echocardiography, ECG and CMR. Biomarkers(Lyso-Gb3, hs-cTnI, NT-proBNP) were collected. Outcomes considered during follow-up were adverse cardiac events, including HF, arrhythmias and mortality. Results64 AFD patients were included(31%male, median age48), most diagnosed through familial screening(40 63%). At first evaluation in our Center, 29(45%) were asymptomatic, while 24(38%) showed predominant cardiac involvement. At echocardiography, median interventricular septum thickness was 9mm(8-14), left ventricular ejection fraction was 63%(60-66). Among patients with CMR, 10/25(40%) showed reduced native T1 and 12/24 (50%) had late gadolinium enhancement (LGE). Median hs-cTnI, available in 60 patients at first evaluation, was 2.4(1.9-31)ng/L. To identify cardiac involvement based on echocardiographic criteria, hs-cTnI<LoD showed 92% sensitivity(CI74–99%), 80% specificity(CI63–92%), 93% negative predictive value(NPV CI80–99%), 77% positive predictive value(PPV CI58–90%), and 85% accuracy(CI73–93%). At the 99th percentile sex-specific upper reference limit(99th%URL), specificity and PPV improved(97%, 94%), but sensitivity and NPV decreased(64%,79%). When defining cardiac involvement based on all available characteristics (including CMR and biopsy data) diagnostic performance of hs-cTnI improved. Data were consistent when excluding variants of uncertain pathogenicity. Echocardiographic parameters worsened progressively across increasing hs-cTnI cutoffs. Over a median follow-up of 63 months between diagnosis date and last evaluation, 10(16%) reached a composite cardiovascular endpoint, with significantly lower event-free survival in patients with hs-cTnI≥LoD(p=0.021) and ≥99th%(p=0.04). The N215S subcohort (n=24) included 18(75%) patients identified by familial screening, 39% of whom showed cardiac involvement at first evaluation in our Center, and 6(25%) index cases. LVH was present in 11(48%), median hs-cTnI was 5(2.2–52) ng/L and 15(65%) had hs-cTnI>LoD. ConclusionsIn this single-center cohort, multimodal cardiac assessment revealed a broad spectrum of cardiac involvement, from subclinical changes to overt cardiac disease, underscoring the utility of comprehensive imaging, including CMR, for accurate assessment. The N215S subcohort demonstrated predominantly cardiac presentation. Hs-cTnI proved a valuable diagnostic biomarker to identify cardiac involvement: levels below the LoD reliably excluded cardiac involvement, while values above the 99th% confirmed disease with high specificity/PPV. Progressively increasing hs-cTnI values, even below the sex-specific 99th%URL, were associated with worsening structural and functional echocardiographic abnormalities