Researchers team experimented on the early cascade of events that may eventually cause stenosis, a severe narrowing of the aortic valve that reduces blood flow to body tissues and weakens the heart. The current treatment for stenosis is valve replacement, which typically requires risky and expensive open-heart surgery. This study has published in Proceedings of the National Academy of Sciences.

Masters said, "Our study sheds new light on the differences between atherosclerosis and CAVD, especially in terms of bottleneck events that we can target with drugs." "With a better understanding of how the disease progresses from early to later stages, we may eventually be able to stop CAVD in its tracks and avoid valve replacement surgery."

Since the hearts of mice and other small animals are vastly different from the human organ, CAVD research has long been hampered by a lack of good animal models. That's why the pigs — specifically those bred to have an overdose of fatty molecules in their arteries — were an important starting point for the current study.

Their valves provided a snapshot of early CAVD that is challenging to capture in humans, showing that it typically begins with the accumulation of certain sugar molecules called glycosaminoglycans (GAGs) in valve tissue. But to examine exactly how this tissue responds to increasing levels of GAGs, the researchers needed a greater amount of valve tissue than living pigs could provide.

This multi-stage process may explain why 25 percent of adults over the age of 65 have CAVD with partially blocked aortic valves, but only one percent goes on to develop stenosis due to a valve that can no longer open and close properly. The fact that native valve cells cannot oxidize LDL themselves, while smooth muscle cells in blood vessels can, also highlights a key distinction between CAVD and atherosclerosis.

The study, which included first author Ana Porras, a postdoctoral in Masters' lab, has important implications for the development of new drugs that may prevent early CAVD from progressing to stenosis by making GAGs less likely to bind LDL.

"The ability to examine multiple steps in this novel in vitro model for early CAVD opens up several promising avenues for developing drugs that are distinct from those for atherosclerosis."