Abstract

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.

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.

Summary 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.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

Partially funded by an investigator initiated trial by Takeda/Shire

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee/IRB of the Technical University of Munich Medical Faculty gave ethical approval for this work

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

Data are not available due to german data protections laws

Non-standard Abbreviations and AcronymsADS3Average Fabry Disease Severity Scoring SystemaFIDArteriolar Flicker-Induced DilationAVRArteriolar-Venular RatioCKCreatine KinaseCKDChronic Kidney DiseaseCNVDCentral Nervous Vascular DiseaseCRAECentral Retinal Arteriolar EquivalentCRVECentral Retinal Venular EquivalentCVCardiovascularCVDCardiovascular DiseaseCXCL10C-X-C motif chemokine 10DVADynamic Retinal Vessel AnalysisECEndothelial CellEDEndothelial DysfunctionERDSEnd-Stage Renal DiseaseERTEnzyme Replacement TherapyFDFabry DiseaseFMDFlow-Mediated DilationGb3GlobotriaosylceramideHCHealthy ControlHVDHeart Valve DiseaseICAM-1Intercellular Adhesion Molecule-1IVSInterventricular SeptumLDHLactate DehydrogenaseLVEDDLeft Ventricular End-Diastolic DiameterLVHLeft Ventricular HypertrophyLysoGb3GlobotriaosylsphingosinMCP1Monocyte Chemoattractant Protein-1NLRP3NOD-, LRR-, and Pyrin Domain-Containing Protein 3NT-proBNPN-terminal prohormone of Brain Natriuretic PeptidePCTPharmacological Chaperone TherapyPWVPulse-Wave VelocityRANTESChemokine (C-C Motif) Ligand 5RVARetinal Vessel AnalysisSMCSmooth Muscle CellSVAStatic Retinal Vessel AnalysisVCAM-1Vascular Cell Adhesion Molecule-1VEGFVascular Endothelial Growth FactorVUSVariant of Uncertain SignificancevFIDVenular Flicker-Induced Dilation