Catheter based inhibition of arterial calcification by bisphosphonates in an experimental atherosclerotic rabbit animal model Andreas Synetos a,1 , Konstantinos Toutouzas a, ⁎ ,1 , Georgios Benetos a , Maria Drakopoulou a , Georgios Trantalis a , Rafail Kotronias a , George Agrogiannis d , Eleftherios Tsiamis a , Spyridon Deftereos b,c , Periklis Davlouros d , Eustratios Patsouris e , Christodoulos Stefanadis a a First Department of Cardiology, Hippokration Hospital, Athens Medical School, Athens, Greece b Department of Cardiology, Athens General Hospital “G. Gennimatas”, Athens, Greece c Section of Cardiovascular Medicine, Greece d Cardiology Department, Patras University Hospital, Patras, Greece e Department of Pathology, Athens Medical School, Athens, Greece abstract article info Article history: Received 26 February 2014 Received in revised form 13 May 2014 Accepted 5 July 2014 Available online 11 July 2014 Keywords: Bisphosphonates Vascular calcification Balloon-catheter Von Kossa Background: Vascular calcification is an active process, sharing common molecular mechanisms with bone formation. Bisphosphonates are components, which inhibit calcification. The aim of the present study was to evaluate the safety and effectiveness of local delivery of the bisphosphonate zoledronate on inhibition of calcium formation in the arterial wall in an experimental animal model. Methods: Sixteen New Zealand rabbits were placed on vitamin D enriched atherogenic diet for 3 weeks. Subsequently, all animals underwent angiography of abdominal aorta and common iliac arteries. A mixture containing 500 μg/l zoledronate was delivered on the vascular wall of the target iliac artery, using a dedicated bal- loon catheter. A placebo mixture was administered on the contralateral iliac artery of each animal, which was used as control. At 28 days all animals were sacrificed. Histologic sections of each common iliac artery were stained with hematoxylin–eosin and von Kossa. Computer-assisted histomorphometry was performed for the calcium content quantification of each section from the target and the control iliac artery. Results: In all animals the local delivery of zoledronate and placebo mixtures was successful and uncomplicated. The mean percentage of the calcium content of the media was higher in the control artery segments compared to the target (2.66 ± 0.73 versus 1.08 ± 0.62 % of the area of the media, p b 0.01). Conclusions: Inhibition of vascular calcification by local catheter-based delivery of bisphosphonate zolendronic acid is effective without evident short-term complications. These finding and its potential clinical implication remain to be confirmed in human studies. © 2014 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Vascular calcification, an independent predictor of cardiovascular mortality [1], is an actively regulated process, rather than a passive event [2]. A variety of bone matrix proteins and regulating factors, such as bone morphogenetic protein (BMP-2), matrix GLA protein, osteopontin, osteocalcin and osteonectin have been isolated in human calcified plaques. Vascular cells have the potential of undergoing osteoblast differentiation, while inflammatory stimuli and lipids that promote the progression of atherosclerotic lesions, also regulate vascular calcification [3,4]. The common molecular mechanisms between active bone formation and vascular calcification could implicate new therapeutic approaches. Bisphosphonates have two main biological actions, the inhibition of calcification and the inhibition of bone resorption. Their use is currently indicated in osteoporosis, Paget's disease, malignant hypercalcemia and osteolytic bone metastases. The first effect is based mainly on a physicochemical mechanism, by blocking the formation and aggrega- tion of calcium phosphate crystals and their transformation into hydroxyapatite [5]. As more potent bisphosphonates were available their biological actions could not be explained only by the physicochem- ical effects and cellular actions should be involved. Indeed, the more potent nitrogen-containing bisphosphonates (including pamidronate, alendronate, risedronate, ibandronate and zoledronate) inhibit key enzymes of mevalonate/cholesterol biosynthetic pathway and hence prevent posttranslational modifications, potentially leading this way to macrophage apoptosis [3,6]. International Journal of Cardiology 176 (2014) 177–181 ⁎ Corresponding author at: 26 Karaoli and Dimitriou str., Holargos, 15562 Athens, Greece. Tel.: +30 210 6510860; fax: +30 2132088676. E-mail address: ktoutouz@gmail.com (K. Toutouzas). 1 These authors contributed equally to the manuscript. http://dx.doi.org/10.1016/j.ijcard.2014.07.008 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved. Contents lists available at ScienceDirect International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard