Oxidative stress biomarkers in Fabry disease: is there a room for them?

Simoncini, Costanza; Torri, S; Montano, Vincenzo; Chico, Lucia; Gruosso, F.; Tuttolomondo, Antonino; Pinto, Antonio; Simonetta, Irene; Cianci, Vittoria; Salviati, Alessandro; Vicenzi, Virginia; Marchi, Giacomo; Girelli, Domenico; Concolino, Daniela; Sestito, Simona; Zedde, Marialuisa; Siciliano, Gabriele; Mancuso, Michelangelo

doi:10.1007/s00415-020-10044-w

Cited by 16 publications

(19 citation statements)

References 31 publications

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“…Autopsy studies of FD patients show plaques that are more concentric with a white discolouration [ 35 ]. It is theorised that the microvascular endothelial dysfunction and arterial wall stress from sphingolipid infiltration results in the formation of reactive oxygen species (ROS) [ 36 ]. ROS may increase the risk of vascular dysfunction including superimposed atherosclerosis [ 37 ].…”

Section: Calcification Computed Tomography and Invasive Angiographymentioning

confidence: 99%

Atherosclerosis in Fabry Disease—A Contemporary Review

Roy

Umar

Ochoa-Ferraro

et al. 2021

JCM

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Fabry disease (FD) is a lysosomal storage disorder characterised by a deficiency in the enzyme α-galactosidase A resulting in sphingolipid deposition which causes progressive cardiac, renal, and cerebral manifestations. The case illustrates a patient with FD who died suddenly, and medical examination demonstrated myocardial scarring and prior infarction. Angina is a frequent symptom in FD. Our own data are consistent with registry data indicating a high prevalence of risk factors for coronary artery disease (CAD) in FD that may accelerate conventional atherosclerosis. Patients with FD also have a higher high-density lipoprotein (HDL)/total cholesterol (T-Chol) ratio which may further accelerate atherosclerosis through expression of early atherosclerotic markers. Patients with FD may develop CAD both via classical atherosclerosis and through formation of thickened fibrocellular intima containing fibroblasts with storage of sphingolipids. Both mechanisms occurring together may accelerate coronary stenosis, as well as alter myocardial blood flow. Our data supports limited data that, although coronary flow may be reduced, the prevalence of epicardial coronary stenosis is low in FD. Microvascular dysfunction and arterial wall stress from sphingolipid deposition may form reactive oxygen species (ROS) and myeloperoxidase (MPO), key atherosclerotic mediators. Reduced myocardial blood flow in FD has also been demonstrated using numerous imaging modalities suggesting perfusion mismatch. This review describes the above mechanisms in detail, highlighting the importance of modifying cardiovascular risk factors in FD patients who likely develop accelerated atherosclerosis compared to the general population.

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Section: Calcification Computed Tomography and Invasive Angiographymentioning

confidence: 99%

Atherosclerosis in Fabry Disease—A Contemporary Review

Roy

Umar

Ochoa-Ferraro

et al. 2021

JCM

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“…Excessive ROS production drives oxidative stress and exacerbates inflammation 3,15 in FD cell models 17–19 . Using cells from ERT‐treated FD patients, we demonstrate neutrophil‐mediated ROS activity and associated aberrant gene expression with LPS or IFN‐γ stimulation (Figure 7, S4A).…”

Section: Discussionmentioning

confidence: 89%

Inhibition of epigenetic reader proteins by apabetalone counters inflammation in activated innate immune cells from Fabry disease patients receiving enzyme replacement therapy

Wasiak

Tsujikawa

et al. 2022

Pharmacology Res & Perspec

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Fabry disease (FD) is a rare X‐linked disorder of lipid metabolism, characterized by the accumulation of globotriaosylceramide (Gb3) due to defective the lysosomal enzyme, α‐galactosidase. Gb3 deposits activate immune‐mediated systemic inflammation, ultimately leading to life‐threatening consequences in multiple organs such as the heart and kidneys. Enzyme replacement therapy (ERT), the standard of care, is less effective with advanced tissue injury and inflammation in patients with FD. Here, we showed that MCP‐1 and TNF‐α cytokine levels were almost doubled in plasma from ERT‐treated FD patients. Chemokine receptor CCR2 surface expression was increased by twofold on monocytes from patients with low eGFR. We also observed an increase in IL12B transcripts in unstimulated peripheral blood mononuclear cells (PBMCs) over a 2‐year period of continuous ERT. Apabetalone is a clinical‐stage oral bromodomain and extra terminal protein inhibitor (BETi), which has beneficial effects on cardiovascular and kidney disease related pathways including inflammation. Here, we demonstrate that apabetalone, a BD2‐selective BETi, dose dependently reduced the production of MCP‐1 and IL‐12 in stimulated PBMCs through transcriptional regulation of their encoding genes. Reactive oxygen species production was diminished by up to 80% in stimulated neutrophils following apabetalone treatment, corresponding with inhibition of NOX2 transcription. This study elucidates that inhibition of BET proteins by BD2‐selective apabetalone alleviates inflammatory processes and oxidative stress in innate immune cells in general and in FD. These results suggest potential benefit of BD2‐selective apabetalone in controlling inflammation and oxidative stress in FD, which will be further investigated in clinical trials.

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“…The patient-reported hypoventilation symptom questionnaire (HYSQ) was developed to standardize the assessment of hypoventilation symptoms. Recent literature has provided evidence that patient-reported outcome measures are feasible and of added value in routine ALS care [ 16 ]. A preliminary questionnaire of 19 items was created based on literature, expert opinion and guidelines for management of MND [ 5 , 6 ].…”

Section: Methodsmentioning

confidence: 99%

Using patient-reported symptoms of dyspnea for screening reduced respiratory function in patients with motor neuron diseases

et al. 2020

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Background Poor monitoring of respiratory function may lead to late initiation of non-invasive ventilation (NIV) in patients with motor neuron diseases (MND). Monitoring could be improved by remotely assessing hypoventilation symptoms between clinic visits. We aimed to determine which patient-reported hypoventilation symptoms are best for screening reduced respiratory function in patients with MND, and compared them to the respiratory domain of the amyotrophic lateral sclerosis functional rating scale (ALSFRS-R). Methods This prospective multi-center study included 100 patients with MND, who were able to perform a supine vital capacity test. Reduced respiratory function was defined as a predicted supine vital capacity ≤ 80%. We developed a 14-item hypoventilation symptom questionnaire (HYSQ) based on guidelines, expert opinion and think-aloud interviews with patients. Symptoms of the HYSQ were related to dyspnea, sleep quality, sleepiness/fatigue and pneumonia. The diagnostic performances of these symptoms and the ALSFRS-R respiratory domain were determined from the receiver operating characteristic (ROC) curves, area under the curve (AUC), sensitivity, specificity, predictive values and accuracy. Results Dyspnea-related symptoms (dyspnea while eating/talking, while lying flat and during light activity) were combined into the MND Dyspnea Scale (MND-DS). ROC curves showed that the MND-DS had the best diagnostic performance, with the highest AUC = 0.72, sensitivity = 75% and accuracy = 71%. Sleep-quality symptoms, sleepiness/fatigue-related symptoms and the ALSFRS-R respiratory domain showed weak diagnostic performance. Conclusion The diagnostic performance of the MND-DS was better than the respiratory domain of the ALSFRS-R for screening reduced respiratory function in patients with MND, and is, therefore, the preferred method for (remotely) monitoring respiratory function.

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Oxidative stress biomarkers in Fabry disease: is there a room for them?

Cited by 16 publications

References 31 publications

Atherosclerosis in Fabry Disease—A Contemporary Review

Atherosclerosis in Fabry Disease—A Contemporary Review

Inhibition of epigenetic reader proteins by apabetalone counters inflammation in activated innate immune cells from Fabry disease patients receiving enzyme replacement therapy

Using patient-reported symptoms of dyspnea for screening reduced respiratory function in patients with motor neuron diseases

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