AUTHOR=Loso Jefferson , Lund Natalie , Avanesov Maxim , Muschol Nicole , Lezius Susanne , Cordts Kathrin , Schwedhelm Edzard , Patten Monica 

TITLE=Serum Biomarkers of Endothelial Dysfunction in Fabry Associated Cardiomyopathy

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=5

YEAR=2018

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2018.00108

DOI=10.3389/fcvm.2018.00108

ISSN=2297-055X

ABSTRACT=<p><bold>Background:</bold> 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.</p><p><bold>Methods:</bold> Serum samples were obtained from 17 healthy controls, 15 FD patients with and 7 without FC. FC was defined by LV wall thickening of &gt;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.</p><p><bold>Results:</bold> 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; <italic>p</italic> = 0.001; MMP-9: 8.0 ± 3.4 vs. 5.0 ± 2.4 μg/mL; <italic>p</italic> = 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; <italic>p</italic> = 0.027) and vs. controls (0.58 ± 0.12 μmol/l; <italic>p</italic> = 0.006) and was positively correlated with indexed LV-mass (<italic>r</italic> = 0.61; <italic>p</italic> = 0.003), hsT (<italic>r</italic> = 0.56, <italic>p</italic> = 0.008), and lyso-Gb3 (<italic>r</italic> = 0.53, <italic>p</italic> = 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; <italic>p</italic> = 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 (<italic>p</italic> = 0.045).</p><p><bold>Conclusion:</bold> 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.</p>