2.1.3. Cardiovascular Manifestations

The common cardiovascular complications of PXE are due to the presence of abnormal calcified elastic fibers in the internal elastic lamina of medium-sized arteries. The broad spectrum of phenotypes includes peripheral arterial disease (PAD), resulting from restrictive vascular calcification in the lower limbs, increased susceptibility to atherosclerosis [34–36], intermittent claudication, and possibly myocardial infarction and hypertension. The fibrous thickening of the endocardium and atrioventricular valves can also result in restrictive cardiomyopathy and/or mitral valve prolapse and atrial septal aneurysm [37]. A cardiac evaluation of French PXE patients revealed sporadic cases of left ventricular hypertrophy, aortic stenosis, and valvulopathies. Overall in this cohort, PXE does not appear to be associated with frequent cardiac complications. However, the development of cardiac hypertrophy in old *Abcc6*−/<sup>−</sup> mice suggests that aging PXE patients might be susceptible to late cardiopathy [38].

Extra cardiac downstream effects of arterial mineralization include renovascular hypertension, gastrointestinal bleeding and central nervous system complications (such as stroke and dementia) [30,39].

A comprehensive analysis of the arterial consequences (macro- and micro-arterial beds were investigated) of ABCC6 ablation in mice was published in 2014 [40]. This report revealed scattered arterial calcium depositions as a result of osteochondrogenic transdifferentiation of vascular cells as mice age (as seen via increase *Runx2* expression). Lower elasticity and increased myogenic tone without major changes in agonist-dependent contraction was found in older *Abcc6*−/<sup>−</sup> mice suggesting reduced control of peripheral blood flow, which in turn may alter vascular homeostasis which is not unlike the PAD observed in PXE patients.
