Quantitative Myocardial Perfusion in Fabry Disease

Abstract

Background: Fabry disease (FD) is an X-linked lysosomal storage disease resulting in tissue accumulation of sphingolipids. Key myocardial processes that lead to adverse outcomes in FD include storage, hypertrophy, inflammation, and fibrosis. These are quantifiable by multiparametric cardiovascular magnetic resonance. Recent developments in cardiovascular magnetic resonance perfusion mapping allow rapid in-line perfusion quantification permitting broader clinical application, including the assessment of microvascular dysfunction. We hypothesized that microvascular dysfunction in FD would be associated with storage, fibrosis, and edema.

Methods: A prospective, observational study of 44 FD patients (49 years, 43% male, 24 [55%] with left ventricular hypertrophy [LVH]) and 27 healthy controls with multiparametric cardiovascular magnetic resonance including vasodilator stress perfusion mapping. Myocardial blood flow (MBF) was measured and its associations with other processes investigated.

Results: Compared with LVH- FD, LVH+ FD had higher left ventricular ejection fraction (73% versus 68%), more late gadolinium enhancement (85% versus 15%), and a lower stress MBF (1.76 versus 2.36 mL/g per minute). The reduction in stress MBF was more pronounced in the subendocardium than subepicardium. LVH- FD had lower stress MBF than controls (2.36 versus 3.00 mL/g per minute; P=0.002). Across all FD, late gadolinium enhancement and low native T1 were independently associated with reduced stress MBF. On a per-segment basis, stress MBF was independently associated with wall thickness, T2, extracellular volume fraction, and late gadolinium enhancement.

Conclusions: FD patients have reduced perfusion, particularly in the subendocardium with greater reductions with LVH, storage, edema, and scar. Perfusion is reduced even without LVH suggesting it is an early disease marker.

Keywords: cardiomyopathies; edema; fibrosis; lysosomal storage diseases.

Figure 1.. Multiparametric cardiovascular magnetic resonance assessment in patients with Fabry disease (FD) and controls.

Left to right—steady-state free precession cines, native T1 maps, T2 maps, stress myocardial blood flow (MBF) maps, late gadolinium enhancement (LGE). A, Healthy control—no left ventricular hypertrophy (LVH), normal T1, normal T2, normal stress MBF, no LGE. B, FD, no LVH, low T1 (sphingolipid storage), normal T2, no LGE. C, FD patient with severe LVH, storage (some pseudonormalization of T1 in LGE areas), high T2 in LGE areas, and extensive LGE. MBF falls with increasing disease severity, particularly in the endocardium.

Figure 2.. Box and whisker plots demonstrating stress myocardial blood flow (MBF) in Fabry disease (FD) and controls.

Each box displays the median and interquartile ranges (IQR) for MBF. The whiskers represent 1.5× the IQR. Outliers (>1.5× the IQR) are indicated by the circles. Controls have higher MBF than FD patients, even without left ventricular hypertrophy (LVH; P=0.002), and FD patients with LVH have lower stress MBF than FD LVH− (P=0.005) and controls (P<0.001).

Figure 3.. Endocardial (orange) and epicardial (blue) stress myocardial blood flow (MBF) in Fabry disease (FD) and controls.

Each box displays the median and interquartile ranges (IQR) for MBF. The whiskers represent 1.5× the IQR. Outliers (>1.5× the IQR) are indicated by the circles. There is an epicardial to endocardial perfusion gradient in FD patients with left ventricular hypertrophy (LVH+; P=0.013). There is no significant gradient in healthy controls (P=0.271) or FD patients without LVH (LVH−; P=0.208).

Figure 4.. Box and whisker plots demonstrating stress myocardial blood flow (MBF) in each myocardial segment compared with wall thickness.

Each box displays the median and interquartile ranges (IQR) for MBF. The whiskers represent 1.5× the IQR. Outliers 1.5× to 3× the IQR are indicated by the circles and >3× IQR by the star. As wall thickness increases, the stress MBF falls (P<0.001).