The myocardial phenotype of Fabry disease pre-hypertrophy and pre-detectable storage

Abstract

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 < 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 < 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.

Electrocardiographic Characteristics and Their Correlation with Echocardiographic Alterations in Fabry Disease

“…GLS identifies subclinical cardiac involvement in a variety of conditions [31]; and in FD, GLS can be impaired even with normal LV wall thickness [15]. Augosto et al have recently described several phases of FD including a silent 'accumulation stage' where LV wall thickness is normal, with evidence of detectable infiltration on CMR with corresponding impairment in GLS on TTE [32]. A previous study that used a binary definition to classify patients into 2 groups-normal versus abnormal ECG (defined as any of the following: prolonged or shortened PQ interval; prolonged QRS duration; the presence of LVH criteria; or t wave inversion), also demonstrated correlation with impaired GLS [33].…”

Cardiac Imaging in Anderson-Fabry Disease: Past, Present and Future

“…Mathur et al demonstrated that base-to-apex CS gradient discriminates between AFD patients without hypertrophy or LGE and healthy controls independent of native T1, suggesting that loss of base-to-apex CS gradient may be an early marker of cardiac involvement in AFD [ 85 ]. More recently, Augusto et al described a slightly reduced GLS as a primary cardiac phenomenon, because of the altered myocardial coupling to the systemic vasculature due to systemic endothelial and smooth muscle changes [ 87 ]. However, additional studies will be necessary to validate the utility of CMR speckle tracking in AFD patients.…”

Recognition of pre-hypertrophic cardiac involvement in Fabry Disease based on automated electrocardiographic measures

“…Of note, early stages are characterized by endocardial shortening and a lesser degree of QT-dispersion, in contrast to later stages with manifest signs of a cardiomyopathy [7]. Further, in a recently published analysis of ECG parameters in prehypertrophic FD as compared to a normal cohort revealed measures similarly suggestive of these mechanisms [22]. However, since in contrast to the present study, manually analyzed advanced ECG parameters were included, it remains speculative whether an automated ECG analysis with the present statistical approach would have identified the same or other parameters to be significant.…”