Highlight
- A novel 3-year prognostic score has been developed for Fabry Disease (FD) cardiomyopathy, incorporating age, left ventricular mass index (LVMI), late gadolinium enhancement (LGE) extent, and septal T1 values.
- Normal septal T1 values demonstrated a 100% negative predictive value for adverse cardiovascular events during a median follow-up of 40 months.
- The study validates the prognostic utility of T1 mapping across different acquisition sequences (MOLLI and ShMOLLI), providing a more reproducible tool for clinical risk stratification.
Disease Burden and Clinical Context
Fabry Disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency of the enzyme alpha-galactosidase A. This deficiency leads to the progressive systemic accumulation of globotriaosylceramide (Gb3) in various tissues, including the heart. Fabry cardiomyopathy is characterized by a transition from early myocardial storage to hypertrophy, and eventually to inflammation and replacement fibrosis. While early diagnosis and management with enzyme replacement therapy (ERT) or chaperone therapy can improve outcomes, cardiomyopathy remains the leading cause of morbidity and mortality in these patients. Identifying which patients are at high risk for major adverse cardiovascular events (MACE) is critical for optimizing therapeutic interventions.
Cardiac magnetic resonance (CMR) imaging has emerged as the gold standard for phenotyping FD cardiomyopathy. Key features such as left ventricular hypertrophy (LVH) and late gadolinium enhancement (LGE)—the latter representing focal fibrosis—are well-established markers of disease severity. However, the prognostic weight of early storage, often detected as low native T1 values on CMR mapping, has been debated. Furthermore, the clinical adoption of T1 mapping has been hindered by reproducibility issues across different sequences (e.g., MOLLI vs. ShMOLLI) and vendors. There is a clear unmet medical need for a standardized, multi-parametric score that integrates these various pathological processes to predict clinical outcomes.
Study Design and Population
In a prospective, observational study recently published in the European Heart Journal – Quality of Care and Clinical Outcomes, researchers led by Camporeale et al. aimed to bridge this gap. The study enrolled 167 patients with a confirmed diagnosis of FD. All participants underwent a baseline CMR including T1 mapping (using both ShMOLLI and MOLLI sequences) and LGE assessment.
The primary endpoint was a composite of all-cause death, heart failure hospitalization, new-onset atrial fibrillation or flutter, non-sustained or sustained ventricular tachycardia, major bradyarrhythmias, and myocardial infarction with non-obstructive coronary arteries (MINOCA). Patients were followed for a median duration of 40 months to assess the predictive accuracy of various CMR parameters.
Key Findings: The Interplay of Storage and Fibrosis
Over the follow-up period, 27 patients (16%) reached the primary composite endpoint. The study identified several key independent predictors of these adverse events. Left ventricular mass index (LVMI) was significantly associated with risk (HR 1.02, p<0.001), confirming that hypertrophy is a persistent marker of disease progression. However, the presence and extent of fibrosis were even more potent indicators. The presence of LGE carried a hazard ratio of 20.12 (p<0.001), and the risk increased by 51% for every additional myocardial segment showing LGE (HR 1.51, p<0.001).
Perhaps the most significant contribution of this research is the role of septal T1 values. Native T1 mapping reflects myocardial storage of Gb3 (which lowers T1) and, in some contexts, interstitial expansion or inflammation (which raises T1). The researchers found that septal T1 was significantly associated with the composite endpoint (HR 0.98, p<0.001). Remarkably, this association held true regardless of whether the ShMOLLI or MOLLI sequence was used, addressing the long-standing concern regarding sequence-dependent variability.
The Negative Predictive Value of Normal T1
A standout finding from the cohort was that none of the patients with normal T1 values experienced an adverse cardiovascular event during the study period. This suggests that a normal T1 value serves as a powerful safety marker, indicating a low-risk status for at least three years, regardless of other baseline characteristics. This “negative predictive value” could be a game-changer in clinical practice, allowing for less aggressive monitoring in patients who have not yet developed significant myocardial storage or structural changes.
The Proposed 3-Year Prognostic Score
Based on their multivariable analysis, the authors proposed a weighted prognostic score that integrates four key variables:
- Age
- Left Ventricular Mass Index (LVMI)
- Number of LGE-positive segments
- Septal T1 value
This score demonstrated high performance in predicting 3-year cardiovascular outcomes. By moving beyond a single-parameter assessment, the score captures the multi-stage nature of FD cardiomyopathy—from the early biochemical storage phase (T1) to the structural adaptation phase (LVMI) and finally the irreversible damage phase (LGE).
Expert Commentary and Clinical Implications
The inclusion of T1 mapping in a clinical score is a significant step forward. Traditionally, T1 mapping was viewed as a research tool due to the lack of standardization. However, by demonstrating that the prognostic value is consistent across sequences, this study validates its use in routine clinical care. Clinicians can now use native T1 as a quantitative marker to refine risk stratification.
From a mechanistic perspective, the data supports the theory that myocardial storage is not merely a bystander but a precursor to the inflammatory and fibrotic cascades that drive arrhythmias and heart failure. The fact that normal T1 correlates with an event-free course reinforces the importance of early intervention before Gb3 accumulation becomes detectable by CMR. However, some limitations must be acknowledged. As an observational study, it cannot definitively prove that early treatment based on T1 values will prevent future events, although it provides a strong rationale for such a strategy. Additionally, the relatively small number of events (27) suggests that larger, multicenter cohorts will be needed to further refine the score’s calibration.
Conclusion
The study by Camporeale et al. provides a robust framework for predicting cardiovascular risk in Fabry Disease. By integrating age, LVMI, LGE extent, and septal T1 values into a unified score, clinicians can more accurately identify high-risk patients who may benefit from closer monitoring or intensified therapy. Furthermore, the high negative predictive value of normal T1 mapping offers a reliable method for identifying low-risk individuals, potentially reducing the burden of frequent clinical interventions for these patients. This score represents a significant advancement in the personalized management of Fabry cardiomyopathy.
References
Camporeale A, Guida G, Pieroni M, Pieruzzi F, Lusardi P, Ferraresi M, Econimo L, Burlina A, Mignani R, Graziani F, Milani V, Ambrogi F, Tondi L, Disabato G, Attanasio A, De Angeli G, Chow K, Spagnolo P, Carrafiello G, Lombardi M. Prognostic role of myocardial storage, hypertrophy and inflammation/fibrosis in Fabry Cardiomyopathy: a new predictive score including T1 values. Eur Heart J Qual Care Clin Outcomes. 2025 Dec 15:qcaf154. doi: 10.1093/ehjqcco/qcaf154. PMID: 41392709.
