IntroductionDetecting early cardiac involvement in Fabry disease (FD) is important because therapy may alter disease progression. Cardiovascular magnetic resonance (CMR) can detect T1 lowering, representing myocardial sphingolipid storage. In many diseases, early mechanical dysfunction may be detected by abnormal global longitudinal strain (GLS). We explored the relationship of early mechanical dysfunction and sphingolipid deposition in FD.MethodsAn observational study of 221 FD and 77 healthy volunteers (HVs) who underwent CMR (LV volumes, mass, native T1, GLS, late gadolinium enhancement), ECG and blood biomarkers, as part of the prospective multicentre Fabry400 study.ResultsAll FD had normal LV ejection fraction (EF 73%±8%). Mean indexed LV mass (LVMi) was 89±39 g/m2 in FD and 55.6±10 g/m2 in HV. 102 (46%) FD participants had left ventricular hypertrophy (LVH). There was a negative correlation between GLS and native T1 in FD patients (r=−0.515, p<0.001). In FD patients without LVH (early disease), as native T1 reduced there was impairment in GLS (r=−0.285, p<0.002). In the total FD cohort, ECG abnormalities were associated with a significant impairment in GLS compared with those without ECG abnormalities (abnormal: −16.7±3.5 vs normal: −20.2±2.4, p<0.001).ConclusionsGLS in FD correlates with an increase in LVMi, storage and the presence of ECG abnormalities. In LVH-negative FD (early disease), impairment in GLS is associated with a reduction in native T1, suggesting that mechanical dysfunction occurs before evidence of sphingolipid deposition (low T1).Trial registration number NCT03199001; Results.

Background: Cardiac response to enzyme replacement therapy (ERT) in Fabry disease is typically assessed by measuring left ventricular mass index using echocardiography or cardiovascular magnetic resonance, but neither quantifies myocardial biology. Low native T1 in Fabry disease represents sphingolipid accumulation; late gadolinium enhancement with high T2 and troponin elevation reflects inflammation. We evaluated the effect of ERT on myocardial storage, inflammation, and hypertrophy. Methods: Twenty patients starting ERT (60% left ventricular hypertrophy–positive) were compared with 18 patients with early disease and 18 with advanced disease over 1 year at 3 centers. Cardiovascular magnetic resonance (left ventricular mass index, T1, T2, global longitudinal strain, and late gadolinium enhancement) and biomarkers (high-sensitive troponin-T and NT-proBNP [N-terminal Pro-B-type natriuretic peptide]) at baseline (pre-ERT) and 12 months were performed. Early disease controls were stable, treatment-naïve patients (mainly left ventricular hypertrophy–negative); advanced disease controls were stable, established ERT patients (mainly left ventricular hypertrophy–positive). Results: Over 1 year, early disease controls increased maximum wall thickness and left ventricular mass index (9.8±2.7 versus 10.2±2.6 mm; P =0.010; 65±15 versus 67±16 g/m 2 ; P =0.005) and native T1 fell (981±58 versus 959±61 ms; P =0.002). Advanced disease controls increased T2 in the late gadolinium enhancement area (57±6 versus 60±7 ms; P =0.023) with worsening global longitudinal strain (−13.2±3.4 versus −12.1±4.8; P =0.039). Newly treated patients had a small reduction in maximum wall thickness (14.8±5.9 versus 14.4±5.7 mm; P =0.028), stable left ventricular mass index (93±42 versus 92±40 g/m 2 ; P =0.186) and a reduction in T1 lowering (917±49 versus 931±54 ms; P =0.017). Conclusions: Fabry myocardial phenotype development is different at different disease stages. After 1 year of ERT initiation, left ventricular hypertrophy–positive patients have a detectable, small reduction in left ventricular mass and storage.

Aims Cardiac involvement in Fabry disease (FD) occurs prior to left ventricular hypertrophy (LVH) and is characterized by low myocardial native T1 with sphingolipid storage reflected by cardiovascular magnetic resonance (CMR) and electrocardiogram (ECG) changes. We hypothesize that a pre-storage myocardial phenotype might occur even earlier, prior to T1 lowering. Methods and results FD patients and age-, sex-, and heart rate-matched healthy controls underwent same-day ECG with advanced analysis and multiparametric CMR [cines, global longitudinal strain (GLS), T1 and T2 mapping, stress perfusion (myocardial blood flow, MBF), and late gadolinium enhancement (LGE)]. One hundred and fourteen Fabry patients (46 ± 13 years, 61% female) and 76 controls (49 ± 15 years, 50% female) were included. In pre-LVH FD (n = 72, 63%), a low T1 (n = 32/72, 44%) was associated with a constellation of ECG and functional abnormalities compared to normal T1 FD patients and controls. However, pre-LVH FD with normal T1 (n = 40/72, 56%) also had abnormalities compared to controls: reduced GLS (−18 ± 2 vs. −20 ± 2%, P &lt; 0.001), microvascular changes (lower MBF 2.5 ± 0.7 vs. 3.0 ± 0.8 mL/g/min, P = 0.028), subtle T2 elevation (50 ± 4 vs. 48 ± 2 ms, P = 0.027), and limited LGE (%LGE 0.3 ± 1.1 vs. 0%, P = 0.004). ECG abnormalities included shorter P-wave duration (88 ± 12 vs. 94 ± 15 ms, P = 0.010) and T-wave peak time (Tonset – Tpeak; 104 ± 28 vs. 115 ± 20 ms, P = 0.015), resulting in a more symmetric T wave with lower T-wave time ratio (Tonset – Tpeak)/(Tpeak – Tend) (1.5 ± 0.4 vs. 1.8 ± 0.4, P &lt; 0.001) compared to controls. Conclusion FD has a measurable myocardial phenotype pre-LVH and pre-detectable myocyte storage with microvascular dysfunction, subtly impaired GLS and altered atrial depolarization and ventricular repolarization intervals.

BACKGROUND: Cardiovascular magnetic resonance can demonstrate myocardial processes in Fabry disease (FD), such as low native T1 (sphingolipid storage) and late gadolinium enhancement (LGE, scar). Recently, high T2 (edema) has been observed in the basal inferolateral wall along with troponin elevation. We hypothesized that edema and myocyte injury would be chronically associated and have electrical, mechanical, and disease associations in FD. METHODS:A prospective international multicenter study was conducted on 186 consecutive FD patients (45.2±1.1 years, 58% females). Additionally, 28 patients with hypertrophic cardiomyopathy, 30 with chronic myocardial infarction and 59 healthy volunteers were included. All study participants underwent comprehensive cardiovascular magnetic resonance with T1 and T2 mapping, cines, and LGE imaging. RESULTS:LGE in the basal inferolateral wall in FD had T2 elevation (FD 58.2±5.0 ms versus hypertrophic cardiomyopathy 55.6±4.3 ms, chronic myocardial infarction 53.7±3.4 ms and healthy volunteers 48.9±2.5 ms, P<0.001), but when LGE was present there was also global T2 elevation (53.1±2.9 versus 50.6±2.2 ms, P<0.001). Thirty-eight percent of FD patients had high troponin. The strongest predictor of increased troponin was high basal inferolateral wall T2 (odds ratio, 18.2 [95% CI, 3.7-90.9], P<0.0001). Both T2 and troponin elevations were chronic over 1 year. High basal inferolateral wall T2 was associated with baseline global longitudinal strain impairment (P=0.005) and electrocardiographic abnormalities (long PR, complete bundle branch block, left ventricular hypertrophy voltage criteria, long QTc, and T-wave inversion, all P<0.05) and predicted clinical worsening after 1 year (Fabry stabilization index >20%, P=0.034). CONCLUSIONS:LGE in Fabry has chronic local T2 elevation that is strongly associated with chronic troponin elevation. In addition, there is slight global T2 elevation. Both are associated with ECG and mechanical changes and clinical worsening over 1 year.