Cardiac involvement in Fabry disease: Implications of retinal vessel analysis in detecting early microvascular alterations despite ERT
Authors: Kuchler Timon , Regenbogen Claudia , Günthner Roman , Reiberio Andrea , Carbajo Javier , Hannane Nora , Wunderle Michael , Assaf Abdalrahman , Lech Maciej , Hannsen Henner , Streese Lukas , Hughes Derralynn , Haller Bernhard , Kotliar Konstantin , Heemann Uwe , Schmaderer Christoph 
Published: January 2025

Background

Cardiac complications driven by microvascular changes are one of the primary reasons for mortality in patients with Fabry disease (FD). While enzyme replacement therapy (ERT) can effectively clear globotriaosylceramide (Gb3) deposits in the endothelium, it remains controversial whether ERT fully resolves microvascular dysfunction, particularly in advanced cases.

Methods

We conducted a cross-sectional observational study of 63 FD patients, of whom 60 had quality retinal vessel analysis (RVA) data and were age- and gender-matched to a healthy control group (HC, n=60, matched out of 204). Associations with disease severity, echocardiographic and laboratory parameters, and ERT were explored.

Results

FD patients exhibited significantly reduced venular flicker-induced dilation (vFID, 3.5% ± 1.6% vs. 4.6% ± 2.4%; p = 0.006), narrower central retinal arteriolar equivalents (CRAE, 165.2 µm [153.5 - 183.2] vs. 183.2 µm [174.7 - 191.4], p < 0.001), and lower arteriolar-venular ratio (AVR, 0.82 [0.74 - 0.87] vs. 0.86 [0.82 - 0.91]; p < 0.001) compared to HC, independent of cardiovascular risk factors. Despite ERT, retinal microvascular health remains incompletely recovered in severely affected FD patients. Narrower retinal arterioles are closely associated with echocardiographic parameters and laboratory markers of cardiac involvement. Additionally, CRAE demonstrated accuracy comparable to LysoGb3 levels in identifying GLA variants with a potential cardiac phenotype. FD patients exhibited elevated chronic inflammation and endothelial dysfunction markers, including Rantes, MCP1, CXCL10, ICAM-1, VCAM-1, and VEGF. In FD patients with cardiac variants, higher levels of inflammatory parameters were associated with impaired retinal microcirculation.

Conclusion

Our findings demonstrate that RVA can detect microvascular alterations in FD, offering a potential non-invasive approach for assessing disease severity and monitoring cardiovascular health. The persistence of retinal microvascular changes despite ERT may reflect the need for earlier interventions. Longitudinal studies are warranted to further explore the predictive value of RVA for Fabry-related cardiovascular outcomes.

Registration

https://clinicaltrials.gov/study/NCT06758648; Unique identifier:NCT06758648.

Novelty and Significance

What Is Known?

Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by the accumulation of globotriaosylceramide (Gb3), leading to microvascular dysfunction and cardiac complications.

Enzyme replacement therapy (ERT) and pharmacological chaperone therapy (PCT) are available treatments, but their ability to fully reverse microvascular changes remains uncertain.

Retinal vessel analysis (RVA) is a non-invasive tool previously used to monitor systemic microvascular health in cardiovascular diseases.

What New Information Does This Article Contribute?

Retinal microvascular abnormalities, including arteriolar narrowing and reduced venular dilation, are detectable in FD, even in patients receiving ERT.

Retinal vessel parameters are strongly associated with systemic markers of cardiac involvement.

RVA offers a non-invasive, cost-effective method to assess microvascular health and could serve as a valuable tool for disease monitoring and stratification in FD.

FD is a rare genetic disorder associated with significant microvascular and cardiac complications due to the progressive accumulation of Gb3. Although ERT is a cornerstone of FD management, we demonstrate that retinal microvascular abnormalities persist despite treatment, particularly in patients with advanced disease. By employing RVA, the study highlights the close association between retinal arteriolar narrowing, systemic markers of cardiac involvement and disease severity. These findings underscore the potential of RVA as a non-invasive, cost-effective method for assessing endothelial health, monitoring disease severity and cardiac involvment in FD. Additionally, the results suggest that earlier interventions and adjunctive therapies targeting endothelial dysfunction and inflammation may be necessary to improve outcomes in advanced cases. RVA could play a pivotal role in routine care by providing insights into systemic vascular health and optimizing Fabry-specific therapies.