Predictors of Clinical Evolution in Prehypertrophic Fabry Disease

Abstract

Background: In prehypertrophic Fabry disease, low myocardial T1 values, reflecting sphingolipid storage, are associated with early structural and ECG changes. The correlations between T1 values and functional parameters have not been explored. Furthermore, the potential prognostic role of T1 in predicting disease worsening is still unknown. Methods: ECG, 2D echocardiography, cardiopulmonary test, and cardiac magnetic resonance were performed in 44 Fabry patients without left ventricular hypertrophy (35.7±14.5 years, 68.2% females). After a 12-month follow-up, clinical stability was evaluated using Fabry Stabilization Index. Results: At baseline, T1 values showed a negative correlation with left ventricular mass ( r =−0.79; P <0.0001), maximum wall thickness ( r =−0.79; P <0.0001), Sokolow-Lyon Index ( r =−0.54; P <0.0001), left atrial volume ( r =−0.49; P <0.0002), and Mainz Severity Score Index ( r =−0.61; P <0.0001). No significant differences in systo-diastolic function and exercise capacity were observed comparing normal and low T1 Fabry patients. Arrhythmias were reported in 2 females with low T1 and late gadolinium enhancement. Five patients (40.0±12.4 years, 2 females) showed clinical worsening (Fabry Stabilization Index >20%) at follow-up. Higher left ventricular wall thickness (odds ratio, 2.61; CI, 1.04–6.57; P =0.04), left atrial volume (odds ratio, 1.24; CI, 1.02–1.51; P =0.03), and lower T1 values (odds ratio, 0.98; CI, 0.96–0.99; P =0.03) at baseline were independently associated with clinical worsening at follow-up. Conclusions: In prehypertrophic Fabry disease, low T1 values correlate with early electrocardiographic, morphological cardiac changes, and worsening of global disease severity but are not associated with functional abnormalities. The presence of low T1 values is a risk factor for disease worsening, thus representing a potential new tool in prognostic stratification and therapeutic approach.

An expert consensus document on the management of cardiovascular manifestations of Fabry disease

“…Of note, T1 reduction is detectable in more than 90% of FD patients with LVH but also in 40% patients without LVH 155,157,161 . In pre‐hypertrophic FD, the presence of low T1 values correlates with early ECG, morphological cardiac changes, and predicts worsening of global disease severity 162 . In contrast, T1 values may become ‘pseudo‐normal’ or even increased within the posterolateral wall affected by fibrosis.…”

Biomarkers in Fabry Disease. Implications for Clinical Diagnosis and Follow-up

“…Evidence of Gb3 accumulation by renal biopsy is also considered in cases where diagnosis can be challenging and/or if there is uncertainty about whether to start treatment. The most established markers in the evaluation of cardiac function are blood pressure measurement, cardiac rhythm abnormalities, evidence of cardiac hypertrophy in echocardiography, evidence of late gadolinium enhancement (LGE), low T1 mapping and cardiac hypertrophy as assessed by cardiac magnetic resonance imaging (cMRI) [68], as well as circulating levels of troponins (Tn) and natriuretic peptides. With respect to cerebrovascular events, a cerebral MRI is the most established procedure for the diagnosis of a stroke, and may also show a pattern of white matter lesions due to small vessel alteration.…”

Cardiovascular magnetic resonance (CMR) in restrictive cardiomyopathies

“…In a study performed on 123 patients, nT1 distinguished AFD from hypertrophic cardiomyopathy (HCM) and healthy controls (sensitivity 88% and 88%, specificity 92% and 86%, respectively) using a cutoff value of 940 ms on a 1.5 T scanner and modified lock-locker inversion (MOLLI) recovery sequence, whereas a better diagnostic performance is obtained with 3.0T scanner (sensitivity 97%, specificity 93%, threshold of 1220 ms) [35]. Myocardial nT1 lowering has also been observed in 41-59% of AFD patients with no LV hypertrophy [32,36], thus appearing an early marker of disease progression and predictor of clinical worsening at a 12-month follow-up [36]. Myocardial ECV is generally preserved in AFD patients (with lower values in males compared to females [33]).…”