Calcification-induced vascular disease: insights from pseudoxanthoma elasticum

Vascular disease has a large worldwide medical burden. Even if all modifiable vascular risk factors are at recommended targets a large residual vascular risk remains, exposing an area of unmet medical need. Arterial calcification, in particular medial arterial calcification (MAC), may open up a promising target for preventive (pharmaceutical) treatment on top of other preventative strategies. However, since MAC and atherosclerosis (intimal wall disease) often occur simultaneously, little is known about the precise clinical consequences of MAC. In the rare calcification disorder pseudoxanthoma elasticum MAC occurs with little interference of atherosclerosis. PXE is caused by biallelic mutations in the ABCC6 genes causing low levels of inorganic pyrophosphate and progressive ectopic mineralization. PXE is characterized by mineralization of elastic fibers with skin involvement (e.g. yellowish papules or plaques), eye involvement (e.g. angioid streaks) and vascular involvement (arterial calcification).

In the first part of this thesis vascular manifestations of PXE are described in order to enhance knowledge on the clinical consequences of MAC. We found that the peripheral arteries in the legs and arms and the intracranial carotid arteries are the predominant arteries that are calcified in PXE patients. In PXE, vascular involvement is of non-atherosclerotic nature with alterations in the medial layer (and around the internal elastic lamina) of arterial walls and in the heart. PXE patients have thicker arterial walls than the general population and pronounced arterial stiffening. Cerebrovascular disease (15%) and peripheral artery disease (46%) are highly prevalent among PXE patients, which cannot be explained by traditional risk factors. Arterial angioplasties or stenting should not be recommended as a primary surgical approach in PXE patients with femoral artery lesions.

The second part of this thesis focused on the relation between risk factors and vascular disease. Among type 2 diabetes mellitus patients HbA1c is modestly related to vascular events. Inter-arm systolic blood pressure differences relate to vascular events in patients without clinical manifest vascular disease, whereas this relation is not apparent in patients with manifest vascular disease.

The last part of this thesis investigates the potential of bisphosphonates, well-established drugs for the treatment of osteoporosis, as treatment for calcification-induced vascular disease. PXE mice studies suggested that bisphosphonates, in particular etidronate, may reduce arterial calcification and inhibit disease progression in PXE.

In a systematic review and meta-analysis of randomized controlled bisphosphonate trials we showed that bisphosphonates reduce all-cause mortality and seem to reduce vascular mortality in various populations. Also, we report the results of the Treatment of Ectopic Mineralization in Pseudoxanthoma elasticum (TEMP) study, a randomized placebo-controlled trial in which we investigated the effectiveness and safety of one year treatment with etidronate (cyclical 20 mg/kg for two weeks every 12 weeks) on ectopic mineralization among patients with PXE. We showed that in PXE patients, etidronate reduced arterial calcification and subretinal neovascularization events, while not lowering femoral 18F-NaF PET activity, compared to placebo without important safety issues. On the basis of these results all PXE patients should be considered for etidronate treatment.