Plasma Desmosine and Abdominal Aortic Aneurysm Disease

Mordi, Ify; Forsythe, Rachael; Gellatly, Corry; Iskandar, Zaid; McBride, Olivia; Saratzis, Athanasios; Chalmers, R. T. A.; Chin, Calvin; Bown, Matthew J.; Newby, David E.; Lang, Chim C.; Huang, Jeffrey T.‐J.; Choy, Anna Maria

doi:10.1161/jaha.119.013743

Cited by 29 publications

(23 citation statements)

References 42 publications

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“…The high-performance liquid chromatography-capillary electrophoresis (HPLC-CE) method used by Annovazzi et al (2004) [ 14 ] is less specific for plasma desmosines than the LC-MS/MS method we used, since it lacks the specificity to differentiate desmosines from other elastin-derived peptides [ 29 ]. Indeed, our plasma levels are more in line with other studies reported in the literature [ 7 , 8 , 10 , 20 ].…”

Section: Discussionsupporting

confidence: 93%

“…This might contribute to the pathogenesis of peripheral arterial disease in PXE. Elastin degradation is a prominent feature in lung diseases, including chronic obstructive pulmonary disease (COPD) [ 6 ], cystic fibrosis [ 7 ], and idiopathic pulmonary fibrosis [ 8 ], but it has also been shown to be associated with increased carotid femoral pulse wave velocity [ 9 ] and abdominal aortic aneurysms [ 10 ]. Elastin degradation and calcification have been shown to interact, and the different processes might amplify each other [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Increased Elastin Degradation in Pseudoxanthoma Elasticum Is Associated with Peripheral Arterial Disease Independent of Calcification

Bartstra

Spiering

Ouweland

et al. 2020

JCM

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Pseudoxanthoma elasticum (PXE) results in extensive fragmentation and calcification of elastin fibers in the peripheral arteries, which results in peripheral arterial disease (PAD). Current research focuses on the role of calcifications in the pathogenesis of PXE. Elastin degradation and calcification are shown to interact and may amplify each other. This study aims to compare plasma desmosines, a measure of elastin degradation, between PXE patients and controls and to investigate the association between desmosines and (1) arterial calcification, (2) PAD, and (3) PAD independent of arterial calcification in PXE. Plasma desmosines were quantified with liquid chromatography-tandem mass spectrometry in 93 PXE patients and 72 controls. In PXE patients, arterial calcification mass was quantified on CT scans. The ankle brachial index (ABI) after treadmill test was used to analyze PAD, defined as ABI < 0.9, and the Fontaine classification was used to distinguish symptomatic and asymptomatic PAD. Regression models were built to test the association between desmosines and arterial calcification and arterial functioning in PXE. PXE patients had higher desmosines than controls (350 (290–410) ng/L vs. 320 (280–360) ng/L, p = 0.02). After adjustment for age, sex, body mass index, smoking, type 2 diabetes mellitus, and pulmonary abnormalities, desmosines were associated with worse ABI (β (95%CI): −68 (−132; −3) ng/L), more PAD (β (95%CI): 40 (7; 73) ng/L), and higher Fontaine classification (β (95%CI): 30 (6; 53) ng/L), but not with arterial calcification mass. Lower ABI was associated with higher desmosines, independent from arterial calcification mass (β (95%CI): −0.71(−1.39; −0.01)). Elastin degradation is accelerated in PXE patients compared to controls. The association between desmosines and ABI emphasizes the role of elastin degradation in PAD in PXE. Our results suggest that both elastin degradation and arterial calcification independently contribute to PAD in PXE.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Increased Elastin Degradation in Pseudoxanthoma Elasticum Is Associated with Peripheral Arterial Disease Independent of Calcification

Bartstra

Spiering

Ouweland

et al. 2020

JCM

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“…In thoracic aneurysm patients, increased brillin-1 fragments in the circulation are associated with aortic dissection (30). Along those lines, elastin fragments (desmosin) may be used as biomarker, since plasma desmosin showed a strong correlation with aortic diameter and aortic events in abdominal aortic aneurysm patients (31). Elastin fragments could also discriminate thoracic aorta dissection patients (including MFS) from other cardiovascular patients and controls (32).…”

Section: Measuring the Effect Of Resveratrolmentioning

confidence: 99%

The Effect of Resveratrol on Aortic Function in Patients with Marfan Syndrome – Rationale and Design of the Resvcue Marfan Trial.

Andĕl

Ooij

Scholte

et al. 2021

Preprint

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Background Marfan syndrome (MFS) is a connective tissue disorder characterized by mutations in the fibrillin-1 (FBN1) gene. The most important manifestation is progressive enlargement of the aorta, ultimately leading to aortic dissection or rupture. Present day pharmacological treatment is based on drugs that decrease repetitive stress on the aorta and improve elastic properties and transport function of the aorta. Unfortunately, this is not sufficient for most patients and surgical resection and reconstruction of the enlarged part of the aorta is still necessary. We have shown earlier that the food supplement Resveratrol inhibits aortic growth and promotes aortic repair in a murine MFS model. Resveratrol is a natural polyphenol commonly found in the skin of berries and in nuts. Here, we hypothesize that Resveratrol treatment will also be protective against aortic dilatation and functional deterioration in humans with MFS. Methods/Design The RESVcue Marfan study is an investigator-initiated, prospective, pre-post observational, multicenter trial. Four specialized academic centers in the Netherlands will recruit 100 patients with genetically confirmed MFS. Patients will use Resveratrol for one year, on top of their ongoing medicinal regime. The primary endpoints consist of the following two main parameters; 1) aortic aneurysm expansion rate and 2) improvement of aortic functional indices. All indices will be measured before and after treatment by echocardiography and (4D flow) MRI. The 4D flow MRI allows for analysis of blood flow patterns and quantification of stresses on the aortic wall, distensibility and pulse wave velocity. Blood and skin samples will be taken to assess the effect of Resveratrol on potential biomarkers associated with Resveratrol metabolism and changes in the primary endpoints. Three psychological tests (The Well-being questionnaire (SF-12), the Hospital Depression and Anxiety Scales (HADS) questionnaire and the Checklist Individual Strength (CIS)) will be taken by the MFS patients to assess the effect of Resveratrol on their well-being. Discussion The RESVcue Marfan trial may provide sufficient data on beneficial effects of Resveratrol on aortic aneurysm expansion rate, aortic functional properties, and biomarkers in patients with MFS to justify a future randomized trial in a larger cohort for a longer study period.Trial registration NL66127.018.18, approved on 24 September 2018. https://www.toetsingonline.nl/ Resveratrol as potential aortic growth inhibitor in patients with Marfan syndrome.

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“…Association of increased blood levels of elastin fragments (desmosine), transforming growth factor beta (TGF-β), microfibrillar associated protein 4 (MFAP4), or homocysteine with enhanced aorta pathology is described in MFS [ 10 – 13 ].…”

Section: Introductionmentioning

confidence: 99%

Genome-wide methylation patterns in Marfan syndrome

et al. 2021

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Background Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene (FBN1). Here, we undertook the first epigenome-wide association study (EWAS) in patients with MFS aiming at identifying DNA methylation loci associated with MFS phenotypes that may shed light on the disease process. Methods The Illumina 450 k DNA-methylation array was used on stored peripheral whole-blood samples of 190 patients with MFS originally included in the COMPARE trial. An unbiased genome-wide approach was used, and methylation of CpG-sites across the entire genome was evaluated. Additionally, we investigated CpG-sites across the FBN1-locus (15q21.1) more closely, since this is the gene defective in MFS. Differentially Methylated Positions (DMPs) and Differentially Methylated Regions (DMRs) were identified through regression analysis. Associations between methylation levels and aortic diameters and presence or absence of 21 clinical features of MFS at baseline were analyzed. Moreover, associations between aortic diameter change, and the occurrence of clinical events (death any cause, type-A or -B dissection/rupture, or aortic surgery) and methylation levels were analyzed. Results We identified 28 DMPs that are significantly associated with aortic diameters in patients with MFS. Seven of these DMPs (25%) could be allocated to a gene that was previously associated with cardiovascular diseases (HDAC4, IGF2BP3, CASZ1, SDK1, PCDHGA1, DIO3, PTPRN2). Moreover, we identified seven DMPs that were significantly associated with aortic diameter change and five DMP’s that associated with clinical events. No significant associations at p < 10–8 or p < 10–6 were found with any of the non-cardiovascular phenotypic MFS features. Investigating DMRs, clusters were seen mostly on X- and Y, and chromosome 18–22. The remaining DMRs indicated involvement of a large family of protocadherins on chromosome 5, which were not reported in MFS before. Conclusion This EWAS in patients with MFS has identified a number of methylation loci significantly associated with aortic diameters, aortic dilatation rate and aortic events. Our findings add to the slowly growing literature on the regulation of gene expression in MFS patients.

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Plasma Desmosine and Abdominal Aortic Aneurysm Disease

Cited by 29 publications

References 42 publications

Increased Elastin Degradation in Pseudoxanthoma Elasticum Is Associated with Peripheral Arterial Disease Independent of Calcification

Increased Elastin Degradation in Pseudoxanthoma Elasticum Is Associated with Peripheral Arterial Disease Independent of Calcification

The Effect of Resveratrol on Aortic Function in Patients with Marfan Syndrome – Rationale and Design of the Resvcue Marfan Trial.

Genome-wide methylation patterns in Marfan syndrome

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