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Relationship between ankle brachial index and arterial remodeling in pseudoxanthoma elasticum.

ABSTRACT: Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease characterized by elastic fiber fragmentation and calcification in the cutaneous, ophthalmologic, and vascular tissues. Cardiovascular manifestations such as peripheral arterial disease (PAD) are frequent in PXE. Because of the changes in the elastic properties and medial calcification of the arterial wall in PXE, the impact of the arterial remodeling on the ankle brachial index (ABI), a well-established diagnostic method for the detection and follow-up of PAD, remains to be determined in this disease.This was a cross-sectional, comparative, open study, which took place at the PXE Consultation Center, University Hospital of Angers. The subjects were 53 patients (mean age, 49 ± 14 years; 35 females) with PXE clinically proven on the basis of established criteria (skin changes, angioid streaks, and skin biopsy). The ABI at rest, symptoms of intermittent claudication (IC), carotid intima-media thickness (IMT), carotid-femoral pulse wave velocity (c-f PWV), compliance (CC), and ? stiffness index were measured in a single-center cohort.Forty-five percent of the PXE patients had an ABI ?0.90, but only one patient had an ABI >1.40. IC was found in 23% of the patients with an ABI ?0.90. There were no significant differences between the patients with a low and normal ABI in terms of IMT (P = .566) or ? stiffness index (P = .194), but differences were significant for c-f PWV (P = .010) and CC (P = .011). Adjusted multivariate linear regression for the Framingham-Laurier score showed that patients with a low ABI had less compliant carotid arteries (B = 0.318, P = .039).PAD detected by a low ABI is very frequent in PXE, although with limited prevalence of symptomatic claudication. Unexpectedly, ABI was low in such calcifying PAD and associated with lower CC, independently of atherosclerosis risk factors. These findings demonstrate that PXE represents a unique monogenic model of PAD in which the specific arterial wall remodeling could change the diagnostic value of the ABI to detect PAD.

SUBMITTER: Leftheriotis G

PROVIDER: S-EPMC5529101 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Relationship between ankle brachial index and arterial remodeling in pseudoxanthoma elasticum.

Lefthériotis Georges G Abraham Pierre P Le Corre Yannick Y Le Saux Olivier O Henrion Daniel D Ducluzeau Pierre Henri PH Prunier Fabrice F Martin Ludovic L

Journal of vascular surgery 20110701 5

<h4>Objectives</h4>Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease characterized by elastic fiber fragmentation and calcification in the cutaneous, ophthalmologic, and vascular tissues. Cardiovascular manifestations such as peripheral arterial disease (PAD) are frequent in PXE. Because of the changes in the elastic properties and medial calcification of the arterial wall in PXE, the impact of the arterial remodeling on the ankle brachial index (ABI), a well-established diagnosti ...[more]

PMID: 21723076

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Project description:Pseudoxanthoma elasticum (PXE) is a genetic metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. The lack of functional ABCC6 protein leads to ectopic mineralization that is most apparent in the elastic tissues of the skin, eyes and blood vessels. The clinical prevalence of PXE has been estimated at between 1 per 100,000 and 1 per 25,000, with slight female predominance. The first clinical sign of PXE is almost always small yellow papules on the nape and sides of the neck and in flexural areas. The papules coalesce, and the skin becomes loose and wrinkled. The mid-dermal elastic fibers are short, fragmented, clumped and calcified. Dystrophic calcification of Bruch's membrane, revealed by angioid streaks, may trigger choroidal neovascularization and, ultimately, loss of central vision and blindness in late-stage disease. Lesions in small and medium-sized artery walls may result in intermittent claudication and peripheral artery disease. Cardiac complications (myocardial infarction, angina pectoris) are thought to be relatively rare but merit thorough investigation. Ischemic strokes have been reported. PXE is a metabolic disease in which circulating levels of an anti-mineralization factor are low. There is good evidence to suggest that the factor is inorganic pyrophosphate (PPi), and that the circulating low levels of PPi and decreased PPi/Pi ratio result from the lack of ATP release by hepatocytes harboring the mutant ABCC6 protein. However, the substrate(s) bound, transported or modulated by the ABCC6 protein remain unknown. More than 300 sequence variants of the ABCC6 gene have been identified. There is no cure for PXE; the main symptomatic treatments are vascular endothelial growth factor inhibitor therapy (for ophthalmic manifestations), lifestyle, lipid-lowering and dietary measures (for reducing vascular risk factors), and vascular surgery (for severe cardiovascular manifestations). Future treatment options may include gene therapy/editing and pharmacologic chaperone therapy.

Project description:Pseudoxanthoma elasticum (PXE) is a genetic disease considered as a paradigm of ectopic mineralization disorders, being characterized by multisystem clinical manifestations due to progressive calcification of skin, eyes, and the cardiovascular system, resembling an age-related phenotype. Although fibroblasts do not express the pathogenic ABCC6 gene, nevertheless these cells are still under investigation because they regulate connective tissue homeostasis, generating the "arena" where cells and extracellular matrix components can promote pathologic calcification and where activation of pro-osteogenic factors can be associated to pathways involving mitochondrial metabolism. The aim of the present study was to integrate structural and bioenergenetic features to deeply investigate mitochondria from control and from PXE fibroblasts cultured in standard conditions and to explore the role of mitochondria in the development of the PXE fibroblasts' pathologic phenotype. Proteomic, biochemical, and morphological data provide new evidence that in basal culture conditions (1) the protein profile of PXE mitochondria reveals a number of differentially expressed proteins, suggesting changes in redox balance, oxidative phosphorylation, and calcium homeostasis in addition to modified structure and organization, (2) measure of oxygen consumption indicates that the PXE mitochondria have a low ability to cope with a sudden increased need for ATP via oxidative phosphorylation, (3) mitochondrial membranes are highly polarized in PXE fibroblasts, and this condition contributes to increased reactive oxygen species levels, (4) ultrastructural alterations in PXE mitochondria are associated with functional changes, and (5) PXE fibroblasts exhibit a more abundant, branched, and interconnected mitochondrial network compared to control cells, indicating that fusion prevail over fission events. In summary, the present study demonstrates that mitochondria are modified in PXE fibroblasts. Since mitochondria are key players in the development of the aging process, fibroblasts cultured from aged individuals or aged in vitro are more prone to calcify, and in PXE, calcified tissues remind features of premature aging syndromes; it can be hypothesized that mitochondria represent a common link contributing to the development of ectopic calcification in aging and in diseases. Therefore, ameliorating mitochondrial functions and cell metabolism could open new strategies to positively regulate a number of signaling pathways associated to pathologic calcification.

Project description:BackgroundNon-invasive clinic-based tools for assessing PAD are not without limitations. Therefore, costly tests like Doppler study, CT angiography and MR angiography are often required to make a diagnosis. Ankle brachial index (ABI), commonly used for assessment of PAD, has high false positivity rates in sclerosed, calcified arteries which render them non-compressible. Toe brachial index (TBI) can be an alternative, as digital arteries are relatively unaffected by these changes.AimTo compare the reliability of ABI and TBI in diagnosing PAD in type 2 diabetes using CT angiography (CTA) as the reference.Methods175 adults with T2D were selected. ABI &TBI were measured with an automated vascular Doppler XT 6 ports bilaterally for all subjects. For any subject, the limb with lower ABI and TBI was included for analysis. ABI < 0.9 & TBI < 0.6 were taken as evidence of PAD. CTA showing > 50% narrowing was taken as evidence of PAD.Results24% of our study subjects had CTA confirmed PAD. ABI has low sensitivity of 35.29% (95% CI 0.21-0.52) compared to TBI being 82.35% (95% CI 0.66-0.92). The specificity however was similar. ABI < 0.9 was able to detect CTA confirmed PAD, but ABI > 0.9, including the so-called normal ABI (0.9-1.3) was unable to detect PAD. ROC showed ABI at 1.005 has sensitivity 64.71% (95% CI 0.48- 0.79) and specificity 61.7% (95% CI 0.53-0.69) and TBI at 0.6 has sensitivity 82.35% (95% CI 0.66-0.92) & specificity 92% (95% CI 0.87-0.96). Utilizing Cohen's Kappa, the reliability of ABI with respect to CTA showed fair agreement (K = 0.225, p = 0.001), whereas the reliability of TBI with respect to CTA showed substantial agreement (K = 0.759, p < 0.0001).ConclusionABI < 0.9 detects PAD reliably, but presence of PAD in patients with ABI > 9.0 including the normal of ABI (0.9-1.3) can be confirmed with TBI, which correlated strongly with CTA. TBI is also non-inferior for PAD detection, when ABI < 0.9. TBI and not ABI can be utilized for initial assessment of PAD in subjects with T2D.

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Relationship between ankle brachial index and arterial remodeling in pseudoxanthoma elasticum.

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Relationship between ankle brachial index and arterial remodeling in pseudoxanthoma elasticum.

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