Deciphering pseudoxanthoma elasticum : Causes, consequences and treatment of arterial calcification

Abstract

Despite improvements in treatment, patients with vascular disease are still at high risk for new cardiovascular events, even when all modifiable risk factors are at guideline recommended targets. Therefore, new targets to further reduce this residual risk are needed. Arterial calcification of the medial arterial wall might be such a target. In contrast to atherosclerotic calcification, medial arterial calcification (MAC) contributes to arterial stiffness and can be seen as the disease causing type of arterial calcification. Causal investigations of the role of MAC in cardiovascular disease are difficult since it co-occurs with atherosclerotic calcification. Pseudoxanthoma elasticum (PXE) is a rare calcification disorder. Due to pathogenic variants in the ABCC6 gene, PXE patients develop extensive ectopic calcification in the elastic fibers of the skin, the Bruch’s membrane in the eye and the medial layer of the peripheral arteries, which leads to pseudoxanthoma’s on the skin, reduced visual acuity and peripheral arterial disease (PAD). In PXE, MAC already develops at a young age with little interference of atherosclerosis. Studying PXE might provide insights into the causes and clinical consequences of MAC and provide opportunities to study potential treatments of calcification-induced vascular disease. The first part of this thesis investigates causes of ectopic calcification in PXE. We found that patients with a more severe genotype have more severe arterial calcification and calcification of Bruch’s membrane, but not more severe peripheral arterial disease or worse visual acuity. Low levels of the calcification inhibitor inorganic pyrophosphate (PPi) cause ectopic calcification in PXE. We show that PPi levels are 60% reduced compared to a control population, but is not associated with the severity of calcification, nor with clinical consequences. The second part of this thesis describes clinical consequences of MAC in PXE. We show that PXE patients have higher intracranial arterial pulsatility and more cerebral small vessel disease compared to controls. Calcification of the carotid siphon is associated with increased pulsatility and small vessel disease. Increased arterial pulsatility cannot be explained by reduced pulsatility attenuation along the carotid siphon. Bruch’s membrane calcification rather than arterial pulsatility probably explains the reduced choroidal thickness that is seen in PXE. Systemic elastin degradation is increased in PXE patients and higher plasma levels are associated with the more severe PAD. In the third part of this thesis investigates possible treatments of arterial calcification. In a post-hoc analysis of a double blind, randomized, placebo controlled clinical trial we show that etidronate inhibits systemic calcification in the carotid siphon, common carotid artery, aorta, iliac and leg arteries in PXE. Another possible treatment of arterial calcification is vitamin K supplementation. In a double blind, randomized, placebo controlled clinical trial we show that six months vitamin K supplementation does not reduce systemic arterial calcification progression in patients with type 2 diabetes mellitus. In conclusion, this thesis provides insights into the causes and consequences of ectopic calcification in PXE and into the role of MAC in cardiovascular disease. MAC might be a novel, treatable target for cardiovascular risk reduction in more general populations as well.