Fabry Disease Cardiomyopathy: A State-of-the-Art Review

Authors, Journal, Affiliations, Type, DOI

• Authors: Shivangi Pande, Fahimeh Varzideh, Jessica Gambardella, Stanislovas S. Jankauskas, Federica Andrea Cerasuolo, Letizia Spinelli, Urna Kansakar, Antonio De Luca, Irwin J. Kurland, Simone Sidoli, Guido Iaccarino, Junichi Sadoshima, Gaetano Santulli
• Journal: Progress in Cardiovascular Diseases (2025), 92:43–65
• Affiliations: Albert Einstein College of Medicine (New York); Federico II University (Naples); Rutgers New Jersey Medical School; University of Campania "Luigi Vanvitelli"
• Type: Systematic Review (PROSPERO CRD420251118911); no competing interests declared
• DOI: https://doi.org/10.1016/j.pcad.2025.08.003

Overview

This PROSPERO-registered systematic review comprehensively covers the mechanisms, diagnosis, treatment, and prognosis of Fabry cardiomyopathy. The paper adds important depth in molecular pathophysiology (TLR4/Notch1/NF-κB, TGF-β/CTGF pro-fibrotic signalling, mitochondrial dysfunction and impaired autophagy from the Santulli group), detailed histopathological features, biomarker landscape, and emerging therapies. A particularly important finding is that a meta-analysis of 11 cardiac MRI studies showed ERT augmented LGE (increased fibrosis), challenging the assumption of reliable cardiac protection. The paper also highlights the inadequacy of existing animal models and reframes female AFD as an X-linked dominant condition with its own high mortality burden.

Keywords

Anderson-Fabry disease, Diastolic Dysfunction, Lysosomes, Mitochondria, Gb3, Lyso-Gb3, Fibrosis, Enzyme Replacement Therapy, Gene Therapy, CRISPR

Key Takeaways

Epidemiology

• Global incidence 1:40,000–1:117,000 (classical estimates); likely underestimated; could be 1:10,000 with comprehensive screening.
• Newborn screening reveals higher prevalence: 1:3,100 (Italy), 1:1,250 (Taiwan) — mostly late-onset variants.
• LVH prevalence in Fabry disease: ~50% in males, ~33% in females.
• Cryptogenic stroke cohorts: notable percentage have undiagnosed AFD.
• Fabry disease in dialysis: ~1:7,000 in Japan.
• Diagnostic delay: ~15 years from first symptoms to diagnosis — individual clinician awareness remains the bottleneck.

Pathophysiology — Molecular Mechanisms

Gb3 Accumulation and Cellular Damage

• Under physiological conditions, Gb3 is hydrolysed by GLA in lysosomal degradation. Without GLA, Gb3 disrupts lipid raft microdomains and triggers inflammation, oxidative stress, and apoptosis.
• Classic Fabry: <1% enzymatic function; atypical: >1% with delayed single-organ onset.
• Lyso-Gb3 (deacylated form) is a biomarker of diastolic dysfunction and cardiac involvement. (sources/fabry-pcvd-2025, rating: medium)

Oxidative Stress and Inflammatory Signalling

• Gb3 increases ROS production → oxidative damage to cardiomyocytes and cardiac fibroblasts.
• Specific pathway: Gb3 binds TLR4 in peripheral blood mononuclear cells → triggers Notch1 signalling → activates NF-κB pathway → sustained pro-inflammatory cytokine production.
• Inflammation correlates with elevated cytokines and oxidative stress in cardiac tissue.
• (sources/fabry-pcvd-2025, rating: medium)

Pro-Fibrotic Signalling

• TGF-β and CTGF (connective tissue growth factor) are upregulated by Gb3 accumulation → activate cardiac fibroblasts → interstitial fibrosis → adverse myocardial remodelling → diastolic dysfunction.
• Elevated Lyso-Gb3 also implicated in fibrotic pathway activation.
• Crosstalk between endothelial cells and cardiomyocytes fosters pro-fibrotic environment.
• (sources/fabry-pcvd-2025, rating: medium)

Mitochondrial Dysfunction and Impaired Autophagy

• Impaired autophagy is a key process in Fabry disease — reduces clearance of damaged organelles and proteins (critical in energy-demanding cardiac tissue). Demonstrated by the Santulli group.
• Autophagic dysfunction → accumulation of toxic substrates → further oxidative stress (vicious cycle).
• Impaired autophagy → cardiac hypertrophy; also linked to necroptosis in cardiomyocytes → cell death and cardiac injury.
• Gb3 engages apoptotic pathways independently.
• (sources/fabry-pcvd-2025, rating: medium)

Microvascular Dysfunction

• Gb3 deposition in vascular smooth muscle and endothelial cells → impaired vasodilation → altered perfusion → myocardial ischaemia in absence of significant epicardial disease.
• Contributes to angina and HF even without obstructive CAD.
• (sources/fabry-pcvd-2025, rating: medium)

Histological Features of Fabry Cardiomyopathy

Myocyte Vacuolisation — "Zebra Bodies"

• Hallmark histopathological finding: Gb3 deposits in myocytes and endothelial cells form "lamellated zebra bodies" — concentric lamellar inclusions visible on electron microscopy.
• These intracellular vacuoles reduce effective contractile mass.
• Similar deposits identified in other tissues, but cardiac implications are most critical.
• Gb3 deposits, despite being visible in cardiac lysosomes, represent only a minimal percentage of total cardiac mass in Fabry patients.
• (sources/fabry-pcvd-2025, rating: medium)

Interstitial Fibrosis

• Results from imbalance between matrix degradation and synthesis, driven by TGF-β and CTGF upregulation.
• Extent of fibrosis correlates with severity of clinical symptoms and diastolic dysfunction.
• Extensive fibrosis predisposes to arrhythmogenic events.
• Established fibrosis may not be fully reversible — early intervention is critical.
• Fibrosis is an important prognostic marker: increased fibrosis → poorer outcomes, greater adverse cardiovascular event risk.
• (sources/fabry-pcvd-2025, rating: medium)

Biomarkers in Fabry Cardiomyopathy

Lyso-Gb3 (Primary Biomarker)

• Most sensitive and specific biomarker for Fabry disease.
• Directly correlates with disease severity and organ burden (cardiac and renal).
• Remains elevated even in late-onset phenotypes — useful for early diagnosis and ongoing monitoring.
• Measured by mass spectrometry.
• Utility is Fabry-specific — not a screening tool in general LVH (which may be hypertensive or aortic).
• (sources/fabry-pcvd-2025, rating: medium)

Established Cardiac Biomarkers

• NT-proBNP: Elevated in AFD associated with LVH; indicates HF risk; useful for early detection of evolving cardiac dysfunction.
• High-sensitivity cardiac troponin (hs-cTn): Elevated levels indicate myocardial injury; correlate with severity of cardiac impairment; guides treatment decisions.
• (sources/fabry-pcvd-2025, rating: medium)

Emerging Biomarkers

• microRNAs: Gaining interest as non-invasive markers of cardiovascular pathology in AFD; involved in disease mechanisms.
• miR-17: Demonstrated by the Santulli group to be a major regulator of the Warburg effect in skeletal muscle of Fabry patients — links to fatigue mechanism (see below).
• Additional lipid metabolites under investigation as markers of disease variability.
• (sources/fabry-pcvd-2025, rating: medium)

Clinical Presentation

Cardiac and Systemic Features

• Classic AFD: cardiac involvement begins 3rd–4th decade; exertional dyspnoea (HF from LVH); atypical chest pain (microvascular ischaemia); palpitations/syncope (arrhythmias — more prevalent in males); VT and rhythm disturbances require vigilant monitoring.
• Structural changes and functional decline begin well before overt symptoms.

Quality of Life and Fatigue

• Chronic fatigue is one of the most prevalent and debilitating symptoms — affects paediatric and adult patients regardless of disease severity or treatment status.
• Key finding (Santulli group): Fatigue in AFD results primarily from alterations in skeletal muscle energy metabolism (miR-17/Warburg effect), not from cardiac failure — a counterintuitive finding with management implications.
• Other QoL burdens: neuropathic pain, GI disturbances, depression, thermoregulatory abnormalities; QoL scores lower than general population across multiple domains.
• QoL deficits persist even on ERT or chaperone therapy → need for psychosocial support and comprehensive symptom management.
• (sources/fabry-pcvd-2025, rating: medium)

Female Fabry Disease — Reframing as X-Linked Dominant

• Two X-linked lysosomal enzyme deficiency diseases: Fabry and Hunter syndrome. Unlike Hunter, females with Fabry disease are patients, not carriers.
• Some experts argue AFD should be classified as X-linked dominant (not X-linked recessive) given the frequency and severity of disease in females.
• Females can require cardiac transplantation in severe cases.
• Mean age of death in female Fabry patients: 55.4 years — a major mortality burden largely underappreciated.
• Female patients often face delayed access to treatment due to underdiagnosis from phenotypic spectrum breadth.
• (sources/fabry-pcvd-2025, rating: medium)

Diagnosis

Enzyme + Genetic Testing

• Males: GLA activity in plasma or leucocytes (reduced/absent); confirm with genetic testing.
• Females: enzyme activity may be normal due to X-inactivation → GLA molecular genetic testing mandatory.
• Over 1,000 GLA mutations catalogued.

Echocardiography

• Standard: E/A ratio and IVRT assess diastolic function (impaired relaxation precedes LVH); LVH measurement (M-mode/2D); left atrial enlargement (consequence of diastolic dysfunction, risk of AF and thromboembolism).
• Advanced (Speckle-Tracking Echocardiography/STE): GLS quantifies systolic function non-invasively; identifies subclinical dysfunction before wall thickness changes. Myocardial stiffness assessment.
• AI/ML: Applied to measure LV wall thickness, myocardial texture, and EF; interest in distinguishing Fabry from HCM and amyloidosis.

Cardiac MRI

• LGE: midwall inferolateral fibrosis (spares subepicardial and subendocardial regions); correlates with cardiac dysfunction severity; guides ERT decisions; prognostic.
• T1 mapping: native T1 serves as early biomarker of myocardial involvement before hypertrophy is detectable.
• Asymmetric LVH predominantly affecting inferolateral wall — can be misdiagnosed as HCM.

Therapeutic Strategies

Enzyme Replacement Therapy (ERT)

• Agalsidase alfa (Replagal) and agalsidase beta (Fabrazyme): IV infusion q2w; cornerstone of treatment.
• ERT Paradox — major concern: Histological data from patients on ERT ≥18 months showed cardiomyocyte disarray, severe vacuolisation, cell death, and fibrosis. A meta-analysis of 11 cardiac MRI studies demonstrated that ERT augmented LGE (increased myocardial fibrosis). Heart disease remains the most common cause of death in Fabry disease.
• ERT limitations: high immunogenicity → anti-drug antibodies (ADAs) in many patients; cardiac cell resistance to available therapies limits HF efficacy; >$200,000/year cost.
• ERT does not completely reverse fibrotic changes or restore normal cardiac function in advanced disease.
• Elfabrio (pegunigalsidase alfa): Newer PEGylated ERT with extended half-life, elevated activity, reduced ADA inhibitory effects; approved; trials ongoing for biweekly vs. monthly dosing.
• (sources/fabry-pcvd-2025, rating: medium)

Chaperone Therapy (Migalastat)

• Oral competitive inhibitor; stabilises misfolded GLA for amenable variants.
• High bioavailability, good immunological tolerance; favourable outcomes in cardiorenal parameters even in classical Fabry disease.
• Limitation: Effective only in patients with misfolded mutant GLA forms and only in early-to-mid stage disease. (sources/fabry-pcvd-2025, rating: medium)

Substrate Reduction Therapy (SRT)

• Lucerastat, Venglustat (glucosylceramide synthase inhibitors), Eliglustat (Gaucher-approved).
• Cross blood-brain barrier — potential neurological benefit.
• Not effective in patients with very low residual enzyme activity — relies on residual clearance capacity.
• (sources/fabry-pcvd-2025, rating: medium)

Gene Therapy and CRISPR

• Lentiviral (AVR-RD-01): Autologous CD34+ HSC transduction; initial GLA restoration; differences not statistically significant at 5 years; expression persisted ≤18 months; no leukemogenic transformation; minimal side effects.
• AAV serotype trials (ST-920-201, FLT190, 4D-310, AMT191): Decreased Gb3 and elevated GLA in preliminary results; some patients developed atypical haemolytic uraemic syndrome.
• CRISPR: Silencing A4GALT (Gb3 synthase gene) → rescues nephropathic phenotype in iPSC-derived kidney organoids and vasculopathy in iPSC-derived endothelial cells. Significant therapeutic potential.
• (sources/fabry-pcvd-2025, rating: medium)

Adjunctive Cardiac Therapies

• ACE inhibitors, ARBs, beta-blockers, diuretics used to optimise cardiac function and QoL alongside ERT.
• ICD warranted for severe arrhythmias or significant cardiac events.
• (sources/fabry-pcvd-2025, rating: medium)

Animal Models — A Critical Limitation

• GLA-KO rodents have no cardiac phenotype — compensatory upregulation of α-galactosidase B (NAGA/GALB) and galactosidase Beta 1 (GLB1), which can metabolise Gb3, prevents accumulation.
• Other transgenic models (overexpressing mutated GLA or Gb3 synthase under β-actin promoter) do not reproduce human disease pathophysiology — no cardiac phenotype.
• Major research bottleneck: No animal model fully recapitulates Fabry cardiomyopathy — limits preclinical drug development and mechanistic validation.
• (sources/fabry-pcvd-2025, rating: medium)

Limitations of the Document

• Systematic review methodology, but quality of individual underlying studies for major claims (particularly the ERT/LGE meta-analysis) is not detailed in the main text.
• Some internal inconsistency in T1 mapping description (paper states "elevated T1 values correlate with Gb3" — contradicts established literature and EHJ review, which correctly states reduced native T1 = early Gb3 storage marker). This appears to be an error in the paper.
• PROSPERO registration provides some quality assurance, but most included studies are observational.
• Funded by NIH (multiple grants); no competing interests declared.

Key Concepts Mentioned

• concepts/Fabry-Cardiomyopathy — central subject; histopathology, biomarkers, ERT paradox, molecular pathways
• concepts/HFpEF — diastolic dysfunction and HFpEF as dominant cardiac manifestation
• concepts/Late-Gadolinium-Enhancement — inferolateral midwall LGE; augmented by ERT per meta-analysis
• concepts/AAV-Gene-Delivery — multiple AAV serotype trials in Fabry disease

Key Entities Mentioned

• entities/Anderson-Fabry-Disease — primary entity; female reframing, animal models, QoL data
• entities/Heart-Failure — HF as common endpoint; ERT limited efficacy in HF patients

Wiki Pages Updated

• wiki/sources/fabry-pcvd-2025.md — created (this file)
• wiki/entities/Anderson-Fabry-Disease.md — updated (female AFD, animal models, ERT paradox, QoL data; source_count → 3)
• wiki/concepts/Fabry-Cardiomyopathy.md — updated (biomarkers, histology, ERT paradox, new contradictions; source_count → 2)
• wiki/wikiindex.md — updated
• wiki/sourceindex.md — updated
• log.md — appended