Cardiac Phenotype of Prehypertrophic Fabry Disease

Abstract

Background: Fabry disease (FD) is a rare and treatable X-linked lysosomal storage disorder. Cardiac involvement determines outcomes; therefore, detecting early changes is important. Native T1 by cardiovascular magnetic resonance is low, reflecting sphingolipid storage. Early phenotype development is familiar in hypertrophic cardiomyopathy but unexplored in FD. We explored the prehypertrophic cardiac phenotype of FD and the role of storage.

Methods and results: A prospective, international multicenter observational study of 100 left ventricular hypertrophy-negative FD patients (mean age: 39±15 years; 19% male) and 35 age- and sex-matched healthy volunteers (mean age: 40±14 years; 25% male) who underwent cardiovascular magnetic resonance, including native T1 and late gadolinium enhancement, and 12-lead ECG. In FD, 41% had a low native T1 using a single septal region of interest, but this increased to 59% using a second slice because early native T1 lowering was patchy. ECG abnormalities were present in 41% and twice as common with low native T1 (53% versus 24%; P=0.005). When native T1 was low, left ventricular maximum wall thickness, indexed mass, and ejection fraction were higher (maximum wall thickness 9±1.5 versus 8±1.4 mm, P<0.005; indexed left ventricular mass 63±10 versus 58±9 g/m², P<0.05; and left ventricular ejection fraction 73±8% versus 69±7%, P<0.01). Late gadolinium enhancement was more likely when native T1 was low (27% versus 6%; P=0.01). FD had higher maximal apical fractal dimensions compared with healthy volunteers (1.27±0.06 versus 1.24±0.04; P<0.005) and longer anterior mitral valve leaflets (23±2 mm versus 21±3 mm; P<0.005).

Conclusions: There is a detectable prehypertrophic phenotype in FD consisting of storage (low native T1), structural, functional, and ECG changes.

Keywords: Fabry disease; hypertrophy, left ventricular; magnetic resonance imaging; phenotype.

Figure 1.

A patient with obvious but missed low native T1. Top: The usual approach is to draw one region of interest (ROI) in a single short-axis (SA) slice. This generated a normal native T1 (932 ms). Note, however, there is blue myocardium in the second, unmeasured slice. By drawing other ROIs on both slices (bottom), the low native T1 is captured.

Figure 2.

Spectrum of native T1 in left ventricular hypertrophy–negative Fabry disease with corresponding late gadolinium enhancement (LGE) images. Patient 1: Normal native T1 in both basal and mid short axis (SA). Patient 2: Patchy low native T1 in the lateral walls. Patient 3: Patchy low native T1 mainly in both SA slices. Patient 4: Patchy low native T1 in the mid SA septum but normal native T1 in basal SA. Patient 5: low native T1 all across both SA.

Figure 3.

Comparison of ECG abnormalities between low native T1 and normal native T1 Fabry disease subgroups. AF indicates atrial fibrillation; BBB, bundle branch block; and VE, ventricular ectopics.

Figure 4.

Normal versus abnormal ECG and late gadolinium enhancement (LGE)–positive vs LGE-negative in the low native T1 and normal native T1 Fabry disease (FD) subgroups showing ECG abnormalities are found in 76% vs 24% (P=0.005) and LGE in 87% versus 13% (P=0.01).

Figure 5.

Example of a Fabry disease (FD) patient with low native T1 and no late gadolinium enhancement (LGE) with abnormal ECG (T-wave inversion in leads III, aVF, V₄ through V₆). Anterior mitral valve leaflet (AMVL) elongation (24 mm) and hypertrabeculation (fractal dimensions_maxapical 1.32) were also present; these latter 2 features, however, are native T1-independent.