Serum Biomarkers of Endothelial Dysfunction in Fabry Associated Cardiomyopathy

Abstract

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.

Biomarkers in Fabry Disease. Implications for Clinical Diagnosis and Follow-up

“…Increases in plasma levels of some markers related to ECM turnover, such as MMP-9, were also found in patients with FD [78,125] in addition to increases in BNP, MR-proANP, MMP-2, TNF, TNFR1, TNFR2, IL-6, galectin-1, Lyso-Gb3 and its analogues, some of them being associated with the severity of heart disease assessed by the MSSI scores [78]. However, the association between MMP-9 and cardiomyopathy could not be proven subsequently [126]. On the other hand, in a study in which 66% of patients had cardiac fibrosis at the onset of the disease, baseline serum levels of PIIINP, procollagen type I carboxy-terminal propeptide (PIPP) and collagen type I carboxy-terminal telopeptide (CICT) were increased [127].…”

The Cardiovascular Phenotype in Fabry Disease: New Findings in the Research Field

“…In Fabry patients, an increased intima-media thickness and an impaired artery flow-mediated dilatation are associated with plasma lyso-Gb3 level independently from age and sex, suggesting an early onset of atherosclerosis [ 29 ]. Such a clinical picture correlates with elevated serum levels of MMP-9 and angiostatin, which indicate an increased extracellular matrix turnover in Fabry patients [ 30 ]. Furthermore, the increase of VEGF-A serum levels, a specific endothelial cell mitogen, suggests vascular damage [ 31 ].…”

Anderson–Fabry Disease: From Endothelial Dysfunction to Emerging Therapies

“…Increased levels of 3NT were not only found in mice but also in biobanked plasma samples from patients with classical Anderson-Fabry disease, suggesting its potential use as a biomarker for vascular impairment in the disease [35]. According to preliminary evidence in humans, other molecules with the potential of serum biomarkers of the disease include matrix metalloproteinase 9 (MMP-9), angiostatin, symmetric dimethylarginine (SDMA), and the L-homoarginine (hArg)/SDMA ratio [36]. In particular, SDMA was found to be associated with diagnosed cardiomyopathy, indexed left-ventricular mass, and high sensitive troponin T in these patients [36].…”