New Hope For Stopping an Understudied Heart Disease in Its Tracks
Source: University of Wisconsin-Madison
Summary: For many decades researchers have focused less on damaged valves than on atherosclerosis but they are now catching up on understanding the roots of calcific aortic valve disease (CAVD).
The aortic valve (AV) is one of the main valves found in the human heart between the left ventricle and aorta (body’s largest vessel). AV plays an essential role in pushing oxygen-rich blood from the heart into the aorta, and from there to all other organs. For many decades researchers have focused less on damaged valves than on atherosclerosis (clogging or hardening of blood vessels caused by plaques), but they are now catching up on understanding the roots of calcific aortic valve disease (CAVD). Researchers from the University of Wisconsin-Madison teased apart, for the first time, 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 study findings were published in the journal Proceedings of the National Academy of Sciences.
The only available current treatment for stenosis is valve replacement, which typically requires risky and expensive open-heart surgery. Pigs were considered as good animal models to study the valves which provided a snapshot of early CAVD, showing that it typically begins with the accumulation of certain sugar molecules called glycosaminoglycans (GAGs) in valve tissue. The research team created a first-of-its-kind platform mimicking hallmarks of early porcine CAVD in a lab dish. Key for this model was the ability to grow valve cells in their native healthy form. When the native valve cells were exposed to changing amount of GAGs and keeping all other conditions the same, the researchers noticed two distinct effects: GAGs directly increased a chemical needed to grow new blood vessels, and also trapped low-density lipoprotein (LDL) molecules.
The trapping made it more likely for oxygen to react with LDL molecules, and the accumulation of oxidized LDL appeared to be a bottleneck event for a multi-stage process toward valve cell damage. This multi-stage process may explain why 25% of adults over the age of 65 have CAVD with partially blocked aortic valves, but only 1% goes on to develop stenosis due to a valve that can no longer open and close properly. The study 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.
Prof. Kristyn 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.”
More Information: Ana M. Porras et al, “Creation of disease-inspired biomaterial environments to mimic pathological events in early calcific aortic valve disease,” PNAS (2017). www.pnas.org/cgi/doi/10.1073/pnas.1704637115