Development of pharmacological treatment against aortic valve calcification

Abstract

Aortic valve calcific disease (CAVD) with aortic stenosis is the third leading cardiovascular disease worldwide. The burden of CAVD is expected to increase in parallel with an ageing population. Today the only therapeutic option is heart surgery with replacement of an aortic valve prosthesis or transcatheter valve implantation with inherited set of complications. Reducing CAVD will reduce morbidity, improve life quality of patients, and reduce costs for society. Our aim is to reduce the burden of the aortic valve replacement surgery with a drug that will inhibit the development of aortic valve calcification and stenosis.

We have developed an advanced in vitro model of the aortic valve calcification using human valve interstitial cells (VIC) which are known to be crucial for calcification. VIC were isolated from the valves obtained from healthy donors or the patients undergoing calcific aortic valve replacement. Drugs were screened against experimentally induced calcification in VIC.

We have identified a drug used for different indication that inhibited the calcification accumulation in our model. The drug was able to stop the development of aortic valve calcification in a dose-dependent manner. The compound is safe and known to be well tolerated in prolonged use in patients. Further we have tested other drugs in the same drug family and confirmed that those also have an ant-calcification effect. To confirm the mechanism of aortic valve calcification we have first in art identified the drug’s primary target in human valves.

A class of drugs significantly inhibited calcification in an in vitro model of aortic valve calcification. Pharmacological therapy at an early stage of CAVD might delay or stop heart valve calcification. In addition, these drugs might act against other conditions with soft tissue calcification, conditions which today have no therapy. The repurposing route will allow a short−cut road to clinical use.