Characterization of Cardiovascular Involvement in Pseudoxanthoma Elasticum Families

Abstract

Objective-Pseudoxanthoma elasticum (PXE) is an autosomal recessive connective tissue disorder with involvement of the skin, the retina, and the cardiovascular system. Cardiovascular involvement is mainly characterized by mineralization and fragmentation of elastic fibers of blood vessels and premature atherosclerosis. We conducted an ultrasound study to investigate the cardiovascular phenotype and to propose recommendations for the management of patients with PXE and heterozygous ABCC6 mutation carriers. Approach and Results-Thirty-two patients, 23 carriers, and 28 healthy volunteers underwent cardiac and vascular ultrasound studies. Cardiac imaging revealed left ventricular diastolic dysfunction in patients with PXE with a significantly prolonged deceleration time and lower septal early diastolic velocities of the mitral annulus compared with controls. Carriers also demonstrated significantly prolonged deceleration time. Carotid-to-femoral pulse wave velocity was significantly increased in patients with PXE when compared with carriers and controls. Vascular imaging revealed a high prevalence of peripheral artery disease in both patients and carriers and a significantly higher carotid intima-media thickness compared with controls. Conclusions-The results of this study clearly demonstrate impaired left ventricular diastolic function, impairment of the elastic properties of the aorta, and a high prevalence of peripheral artery disease in patients with PXE. Carriers also seem to exhibit a cardiovascular phenotype with mainly mild diastolic dysfunction and accelerated atherosclerosis. Increased awareness for cardiovascular events in both patients and heterozygous carriers is warranted. The ABCC6 gene (chrom. 16p13.1) codes for an ATPdependent transmembrane transporter, which is most abundant in the liver and kidney. Remarkably, the expression of the ABCC6 transporter in tissues clinically affected by PXE is very low. 19 This observation led to the hypothesis that PXE is primarily a metabolic disorder in which circulating serum factor(s) plays a role. 17 Another, and probably complimentary, pathogenetic mechanism is the so-called cellular hypothesis in which fibroblast perturbation may evoke local mineralization and elastic fiber alterations. This hypothesis is based on the observation that elastic fiber alterations are not present homogeneously throughout the skin and blood vessels of patients with PXE, but only in peculiar regions. Moreover, PXE skin fibroblasts exhibit a distinct behavior with altered biosynthetic expression profile and cell-cell and cell-matrix interactions compared with fibroblasts from normal subjects. [20][21][22] This study focuses on the cardiovascular phenotype of patients with PXE and carriers. Cardiovascular changes in patients with PXE are characterized by (1) mineralization and fragmentation of elastic fibers of the internal elastic lamina, medial and adventitial layers of medium-sized arteries and aorta, as well as of the endocardium, pericardium, connective tissue around vessels in t...

Increased vascular occlusion in patients with pseudoxanthoma elasticum

“…Some publications describe cardiovascular manifestations of PXE. This inherited multisystem disorder seems to increase the cardiovascular risk and is associated with an increased occurrence of atherosclerotic changes [7][8][9]. However, untill today there is little knowledge about the distribution and the pathomechanism of atherosclerosis in patients with PXE.…”

Pseudoxanthoma elasticum: diagnostic features, classification and treatment options

“…Overall, increased risk of cardiovascular complications has been observed not only in patients with PXE but also in heterozygous ABCC6 mutation carriers. In particular, heterozygous carriers of the loss-of-function mutation p.R1141X, the most common mutation in the Caucasion populations, is associated with a strong increase in the prevalence of coronary artery disease [17–19]…”

Carotid strain measurement in patients with pseudoxanthoma elasticum – Hint for a different pathomechanism?

“…To our knowledge, the latest study regarding the vascular stiffness of PXE patients, was performed by Campens et al in 2013 and showed that PXE had a higher PWV compared to controls. They concluded, that PXE patients' aorta was stiffer (1).…”

“…Characteristic clinical symptoms of PXE include typical skin signs including yellowish papules and inelastic skinfolds especially on the lateral neck, the axillae and the popliteal fossae (1,2). Other characteristic signs are ophthalmologic alterations like angoid streaks or retinal pigment epithelium atrophy and cardiovascular manifestations such as a high prevalence of peripheral artery disease (PAD), intermittent claudication or chronic vascular occlusions which are mostly localized in the lower limb specially the femoral arteries (13)(14)(15).…”

“…Results vary a lot between different authors and cohorts. The findings are contradictory as they spread between a more elastic artery, no changes or stiffer arteries at different sites of the arterial tree (1,9).…”