Progression of Fabry Cardiomyopathy Despite Enzyme Replacement Therapy

Pieroni, Maurizio; Camporeale, Antonia; Bona, Roberta Della; Sabini, Alessandra; Cosmi, Deborah; Magnolfi, Annalisa; Bolognese, Leonardo

doi:10.1161/circulationaha.113.002799

Cited by 14 publications

(11 citation statements)

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“…Effects of agalsidase alfa on proteinuria were very variable across five different CRs: two CRs showed improved proteinuria [56,62], two described worsening [65,125], and one noted no change during treatment [64]. In two CRs, the change in proteinuria was dependent on agalsidase alfa dose: patients experienced an increase in proteinuria with agalsidase alfa 0.2 mg/kg EOW dose but a decrease in proteinuria when the dose was subsequently increased to 0.4 mg/kg EOW [63,67].…”

Section: Resultsmentioning

confidence: 99%

“…There were four CRs which reported an increase in LVH/LVMi with agalsidase alfa after 12 months [61], 6 years [64], 9 years [57], and 12 years [60]. Another CR described stabilization of LVMi, indicated by absence of progression to LVH, in one patient treated with agalsidase alfa [59] and in another who switched regimens (from agalsidase alfa to agalsidase beta and back to agalsidase alfa) [84].…”

Section: Resultsmentioning

confidence: 99%

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The effect of enzyme replacement therapy on clinical outcomes in male patients with Fabry disease: A systematic literature review by a European panel of experts

Germain

Elliott

Falissard

et al. 2019

Molecular Genetics and Metabolism Reports

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152

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BackgroundEnzyme replacement therapy (ERT) with recombinant human α-galactosidase has been available for the treatment of Fabry disease since 2001 in Europe and 2003 in the USA. Treatment outcomes with ERT are dependent on baseline patient characteristics, and published data are derived from heterogeneous study populations.MethodsWe conducted a comprehensive systematic literature review of all original articles on ERT in the treatment of Fabry disease published up until January 2017. This article presents the findings in adult male patients.ResultsClinical evidence for the efficacy of ERT in adult male patients was available from 166 publications including 36 clinical trial publications. ERT significantly decreases globotriaosylceramide levels in plasma, urine, and in different kidney, heart, and skin cell types, slows the decline in estimated glomerular filtration rate, and reduces/stabilizes left ventricular mass and cardiac wall thickness. ERT also improves nervous system, gastrointestinal, pain, and quality of life outcomes.ConclusionsERT is a disease-specific treatment for patients with Fabry disease that may provide clinical benefits on several outcomes and organ systems. Better outcomes may be observed when treatment is started at an early age prior to the development of organ damage such as chronic kidney disease or cardiac fibrosis. Consolidated evidence suggests a dose effect. Data described in male patients, together with female and paediatric data, informs clinical practice and therapeutic goals for individualized treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The effect of enzyme replacement therapy on clinical outcomes in male patients with Fabry disease: A systematic literature review by a European panel of experts

Germain

Elliott

Falissard

et al. 2019

Molecular Genetics and Metabolism Reports

Self Cite

152

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“…Myocardial fibrosis in FC is a progressive process that cannot be reversed by ERT and is a crucial outcome determinant [ 33 , 34 , 35 ]. In addition, previous studies have proposed a role of Alox12/15 and its metabolites in the development of cardiac fibrosis and systolic dysfunction [ 36 , 37 ].…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Arachidonate 12/15-Lipoxygenase Improves α-Galactosidase Efficacy in iPSC-Derived Cardiomyocytes from Fabry Patients

Chien

Chou²,

Chang

et al. 2018

IJMS

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(1) Background: A high incidence of intervening sequence (IVS)4+919 G>A mutation with later-onset cardiac phenotype have been reported in a majority of Taiwan Fabry cohorts. Some evidence indicated that conventional biomarkers failed to predict the long-term progression and therapeutic outcome; (2) Methods: In this study, we constructed an induced pluripotent stem cell (iPSC)-based platform from Fabry cardiomyopathy (FC) patients carrying IVS4+919 G>A mutation to screen for potential targets that may help the conventional treatment; (3) Results: The FC-patient-derived iPSC-differentiated cardiomyocytes (FC-iPSC-CMs) carried an expected IVS4+919 G>A genetic mutation and recapitulated several FC characteristics, including low α-galactosidase A enzyme activity and cellular hypertrophy. The proteomic analysis revealed that arachidonate 12/15-lipoxygenase (Alox12/15) was the most highly upregulated marker in FC-iPSC-CMs, and the metabolites of Alox12/15, 12(S)- and 15(S)-hydroxyeicosatetraenoic acid (HETE), were also elevated in the culture media. Late administration of Alox12/15 pharmacological inhibitor LOXBlock-1 combined with α-galactosidase, but not α-galactosidase alone, effectively reduced cardiomyocyte hypertrophy, the secretion of 12(S)- and 15(S)-HETE and the upregulation of fibrotic markers at the late phase of FC; (4) Conclusions: Our study demonstrates that cardiac Alox12/15 and circulating 12(S)-HETE/15(S)-HETE are involved in the pathogenesis of FC with IVS4+919 G>A mutation.

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“…Enzyme Replacement Therapy (ERT) has proven to significantly reduce accumulation of Gb3, especially intracellular deposits in the coronary endothelium ( 9 , 10 ) and to halt or even partially reverse FC. However, in advanced stages of FD with a severe cardiac phenotype the effectiveness of ERT is profoundly diminished and the disease can even progress ( 11 – 13 ). Therefore, a better understanding of the underlying mechanisms contributing to the development of FC is urgently needed to improve treatment and outcome of FD patients.…”

Section: Introductionmentioning

confidence: 99%

Serum Biomarkers of Endothelial Dysfunction in Fabry Associated Cardiomyopathy

Loso¹,

Lund²,

Avanesov

et al. 2018

Front. Cardiovasc. Med.

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Background: Fabry disease (FD) is characterized by early development of vasculopathy and endothelial dysfunction. However, it is unclear whether these findings also play a pivotal role in cardiac manifestation. As Fabry cardiomyopathy (FC) is the leading cause of death in FD, we aimed to gather a better insight in pathological mechanisms of the disease.Methods: Serum samples were obtained from 17 healthy controls, 15 FD patients with and 7 without FC. FC was defined by LV wall thickening of >12 mm in cardiac magnetic resonance imaging and serum level of proBNP, high sensitive Troponin T (hsT), and globotriaosylsphingosine (lyso-GB3) were obtained. A multiplex ELISA-Assay for 23 different angiogenesis markers was performed in pooled samples. Markers showing significant differences among groups were further analyzed in single samples using specific Elisa antibody assays. L-homoarginine (hArg), L-arginine, asymmetric (ADMA), and symmetric Dimethylarginine (SDMA) were quantified by liquid chromatography—mass spectrometry.Results: Angiostatin and matrix metalloproteinase 9 (MMP-9) were elevated in FD patients compared to controls independently of the presence of FC (angiostatin: 98 ± 25 vs. 75 ± 15 ng/mL; p = 0.001; MMP-9: 8.0 ± 3.4 vs. 5.0 ± 2.4 μg/mL; p = 0.002). SDMA concentrations were highest in patients with FC (0.90 ± 0.64 μmol/l) compared to patients without (0.57 ± 0.10 μmol/l; p = 0.027) and vs. controls (0.58 ± 0.12 μmol/l; p = 0.006) and was positively correlated with indexed LV-mass (r = 0.61; p = 0.003), hsT (r = 0.56, p = 0.008), and lyso-Gb3 (r = 0.53, p = 0.013). Accordingly, the ratio of L-homoarginine to SDMA (hArg/SDMA) was lowest in patients with FC (2.63 ± 1.78) compared to controls (4.16 ± 1.44; p = 0.005). For L-arginine, hArg and ADMA no significant differences among groups could be detected, although a trend toward higher ADMA and lower hArg levels could be observed in the FC group. Furthermore, a significant relationship between kidney and cardiac function could be revealed (p = 0.045).Conclusion: Elevated MMP-9 and angiostatin levels suggest an increased extracellular matrix turnover in FD patients. Furthermore, endothelial dysfunction may also be involved in FC, as SDMA and hArg/SDMA are altered in these patients.

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Progression of Fabry Cardiomyopathy Despite Enzyme Replacement Therapy

Cited by 14 publications

References 5 publications

The effect of enzyme replacement therapy on clinical outcomes in male patients with Fabry disease: A systematic literature review by a European panel of experts

The effect of enzyme replacement therapy on clinical outcomes in male patients with Fabry disease: A systematic literature review by a European panel of experts

Inhibition of Arachidonate 12/15-Lipoxygenase Improves α-Galactosidase Efficacy in iPSC-Derived Cardiomyocytes from Fabry Patients

Serum Biomarkers of Endothelial Dysfunction in Fabry Associated Cardiomyopathy

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