Walid Zenini, MD, Naziha Soltani, MD
Department of Cardiology, Centre Hospitalier de Narbonne, Narbonne, France
Clinical History
A 65-year-old woman with genetically confirmed Fabry disease (GLA mutation c.718C>T, p.Arg240Ter; α-galactosidase A enzymatic activity at diagnosis: 0.3 nmol/hr/mg; reference >3.8 nmol/hr/mg) and a positive family history (affected mother and one sibling) was referred for routine follow-up cardiovascular magnetic resonance (CMR). She had been receiving enzyme replacement therapy with agalsidase beta (Fabrazyme, 1 mg/kg intravenously every two weeks) for five years without infusion reactions. She had no cardiovascular risk factors or other relevant comorbidities, and was entirely asymptomatic with no chest pain, dyspnea, syncope, or palpitations.
A baseline CMR performed two years earlier had demonstrated mild concentric LV hypertrophy, predominantly septal, with a small area of late gadolinium enhancement (LGE) in the basal inferolateral wall. Resting electrocardiogram (ECG) at that time was normal and remains normal on current evaluation. Cardiac troponin was not measured at either time point, as it was not part of the routine clinical assessment for this indication at our center.
CMR Findings
CMR was performed on a 1.5T SIGNA Voyager system (GE Healthcare, Chicago, Illinois, USA) using a standardized Fabry disease protocol: cine balanced steady-state free precession (bSSFP) sequences, native T1 mapping (MOdified Look Locker Inversion recovery (MOLLI) 5(3)3), native T2 mapping, post-contrast T1 mapping for extracellular volume (ECV). Cine bSSFP sequences demonstrated preserved biventricular systolic function (Movie 1).
  |
| Movie 1. Cine bSSFP sequences in two and three-chamber views demonstrating concentric LV hypertrophy with preserved ejection fraction. |
Quantitative LV measurements: left ventricular end-diastolic volume index (LVEDVi) 58 mL/m2, left ventricular ejection fraction (LVEF) 70%, LV mass index 62 g/m2, maximal septal wall thickness 14 mm, all stable compared to the prior CMR. Native T1 and T2 mapping demonstrated marked regional heterogeneity (Figures 1–2). The basal inferolateral segment showed elevated native T1 (1189 ms), elevated T2 (62 ms), and markedly elevated ECV (55%) (Figure 3), indicating replacement fibrosis with superimposed active myocardial inflammation. Institutional reference ranges at 1.5T: native septal T1 950 ± 50 ms (lower normal limit ~890 ms); native T2 50 ± 5 ms (upper limit 55 ms); ECV 25 ± 3% (upper limit 31%).
 |
| Figure 1. Native T1 map (short-axis, basal level) demonstrating elevated T1 in the basal inferolateral segment (1189 ms, arrow) in comparison to the preserved septal T1 (950 ms). |
 |
| Figure 2. Native T2 map (short-axis, basal level) demonstrating elevated T2 in the basal inferolateral segment (62 ms, arrow) consistent with myocardial inflammation accompanying fibrosis, with normal septal T2 (48 ms). |
 |
| Figure 3. ECV color map (short axis, basal level) demonstrating elevated ECV in the basal inferolateral segment (55%, arrow), with normal septal ECV (24%). T1 polar map demonstrating the regional distribution of native T1 values across all myocardial segments, with inferolateral elevation clearly delineated against the preserved septal values. |
T1 polar map analysis confirmed the regional distribution of these abnormalities, with inferolateral elevation clearly delineated against the preserved septal values (Figure 4). In contrast, the interventricular septum showed native T1 (950 ms, within normal range), T2 (48 ms, normal), and ECV (24%, normal).
 |
| Figure 4. T1 polar map demonstrating the regional distribution of native T1 values across all myocardial segments, with inferolateral elevation clearly delineated against the preserved septal values. |
The prior CMR two years earlier had documented a similar septal native T1 value; native T2 mapping and ECV were not performed at that examination. LGE imaging confirmed persistent mid-wall, non-ischemic enhancement in the basal inferolateral segment, the characteristic topography of Fabry cardiomyopathy, unchanged in extent from the prior CMR (Figure 5). No new regions of enhancement were identified.
 |
| Figure 5. Basal short axis phase sensitive inversion recovery LGE imaging demonstrating persistent mid-wall, non-ischemic enhancement in the basal inferolateral segment (arrow), consistent with the characteristic pattern of Fabry cardiomyopathy. |
Conclusion
This case illustrates the regional heterogeneity of myocardial tissue characterization in Fabry cardiomyopathy under long-term enzyme replacement therapy. In the early phase of Fabry disease, intracellular glycosphingolipid (Gb3) accumulation within cardiomyocytes shortens native myocardial T1 below the normal range, the classical CMR hallmark used to distinguish Fabry cardiomyopathy from other causes of LV hypertrophy.[1]
However, as the disease advances and myocardial fibrosis develops, typically first in the basal inferolateral wall, replacement of viable myocardium by fibrous tissue progressively lengthens T1, first returning it toward the normal range (pseudo-normalization) and ultimately elevating it above normal.[2] The elevated inferolateral native T1 (1189 ms) in this patient therefore does not represent normalization: it reflects an advanced fibrotic stage in which fibrosis has become the dominant tissue component, overriding the storage-related T1 shortening.
The concomitant elevation of native T2 (62 ms) at the same inferolateral location is equally important. Elevated T2 reflects active myocardial inflammation accompanying the established fibrosis, a pattern recognized as prognostically unfavorable and associated with increased risk of ventricular arrhythmia and heart failure progression.[3] The coexistence of elevated T1, elevated T2, markedly elevated ECV (55%), and persistent LGE at the basal inferolateral wall thus defines a convergent multiparametric signature of advanced irreversible fibrosis with ongoing inflammatory activity, not a treatment effect.[4]
In contrast, the preserved septal T1 (950 ms) combined with a normal septal ECV (24%), confirming the absence of interstitial fibrosis at this location, is most consistent with a partial treatment response to enzyme replacement therapy: enzyme replacement has likely limited glycosphingolipid accumulation in the septal myocardium, allowing partial substrate clearance and T1 normalization without established fibrosis. Published data confirm that 83% of Fabry patients on enzyme replacement therapy show an increase in native T1 toward normal values without significant ECV change, reflecting partial reduction of intracellular storage rather than fibrotic remodeling.[5]
This case demonstrates that clinical stability, normal ECG, and preserved LVEF are insufficient surrogates for myocardial disease control in Fabry cardiomyopathy. Multiparametric CMR, combining native T1 mapping, T2 mapping, ECV quantification, and LGE, is essential for longitudinal monitoring of regional disease activity, for distinguishing active inflammatory fibrotic progression from partial treatment response, and for guiding individualized therapeutic decisions.
Perspective
In Fabry disease, native T1 is characteristically low in the early storage phase due to intracellular Gb3 accumulation.[1] In advanced disease, myocardial fibrosis progressively elevates T1 above the normal range (pseudo-normalization and elevation).[2] An elevated inferolateral T1 with coexisting elevated ECV and LGE reflects irreversible advanced fibrosis not treatment response.[4]
Elevated native T2 in the basal inferolateral wall signals active myocardial inflammation accompanying established fibrosis.[3] This combined pattern of elevated T1, T2, and ECV at the same location is prognostically unfavorable and may persist despite long-term ERT, indicating incomplete suppression of inflammatory disease activity. A preserved septal T1 with normal ECV in a patient on long-term ERT is most consistent with partial treatment efficacy, partial substrate clearance without established fibrosis, and contrasts with the irreversible inflammatory-fibrotic evolution in the inferolateral segment of the same patient.[5]
Clinical stability, normal ECG, and preserved systolic function are insufficient surrogates for myocardial disease control in Fabry cardiomyopathy. Multiparametric CMR follow-up integrating T1 mapping, T2 mapping, ECV, and LGE is essential for monitoring treatment adequacy and detecting regional disease progression.
Click here to see the entire case on CloudCMR.
References
- Sado DM, White SK, Piechnik SK, et al. Identification and assessment of Anderson-Fabry disease by cardiovascular magnetic resonance noncontrast myocardial T1 mapping. Circ Cardiovasc Imaging. 2013;6(3):392–398.
- Nordin S, Kozor R, Banypersad SM, et al. Proposed staging of Fabry cardiomyopathy based on multiparametric cardiovascular magnetic resonance. JACC Cardiovasc Imaging. 2019;12(8 Pt 1):1537–1548.
- Augusto JB, Nordin S, Vijapurapu R, et al. Myocardial edema, myocyte injury, and disease severity in Fabry disease. Circ Cardiovasc Imaging. 2020;13(4):e010171.
- Moon JC, Sachdev B, Elkington AG, et al. Gadolinium enhanced cardiovascular magnetic resonance in Anderson-Fabry disease. Eur Heart J. 2003;24(23):2151–2155.
- Figliozzi F, Kollia E, Simistiras A, et al. Effects of enzyme replacement therapy on cardiac MRI findings in Fabry disease: a systematic review and meta-analysis. Radiol Cardiothorac Imaging. 2024;6(3):e230154.
Case prepared by:
Erin K Romberg, MD
Editorial Board Member, Cases of SCMR
Seattle Children’s Hospital, Seattle Washington USA