(From the September 2016 issue of Research Now)
Calcific aortic valve disease, or CAVD, is the most common valvular disorder in developed countries. CAVD causes calcium buildup in the valve of the aorta in the heart, leading to stiffening of the valve, reduced blood flow to the body, and heart failure. The National Heart, Lung, and Blood Institute at the National Institutes of Health (NIH) has awarded Vidu Garg, MD, along with Joy Lincoln, PhD, and Brenda Lilly, PhD, in the Center for Cardiovascular Research in The Research Institute at Nationwide Children's Hospital a four-year, $2.5 million grant to continue working to identify what causes CAVD.
“CAVD affects up to 33 percent of the population at large, generally in adults 65 and older, as well as infants born with structural malformations of their aortic valve,” says Dr. Lincoln, a principal investigator in the Center for Cardiovascular Research. “Currently, the only way to fix this problem is to replace the native valve. But biological replacement tissue valves will likely calcify and mechanical valves fail to grow with the pediatric patient. Additional surgeries are common, and anti-coagulant therapy is required for the rest of their lives.”
The aortic valve is comprised of valve interstitial cells (VICs), and surrounding endothelial cells regulate the behavior of these VICs. When the endothelial cells stop working correctly, a gaseous signaling molecule called nitric oxide (NO) no longer reaches the VICs, transforming them into bone-like cells that create calcium, depositing it on the aortic valve in nodules and preventing it from opening and closing. The diseased valve then has to work harder to push blood out into the body and the heart can stop working effectively.
The grant continues an investigation into CAVD which began in 2005, when Dr. Garg found mutations in a human genetic regulator called NOTCH1 that prevents the buildup of calcium deposits on the valve. The team has also found that NOTCH1 function is turned on and off by NO.
“We know what causes calcification – lack of nitric oxide in the system. What we don’t know is what causes the VICs to change and calcify, and that definitely hinders new treatment development,” explains Dr. Lilly, a principal investigator in the Center for Cardiovascular Research in The Research Institute and The Heart Center at Nationwide Children’s. “This grant will allow us to determine how NO regulates Notch1 activity to prevent VICs from changing and causing calcification, and whether we can use NO donors to stop that process where it’s already occurring.”
The team of researchers also hopes to identify how the Notch1 receptor is affected in the absence of nitric oxide to prevent CAVD in otherwise healthy individuals. They plan to use their findings from this relationship for therapies that will either prevent the calcification process or halt its progress in patients who have already experienced calcium buildup. They hope to remove the need for the aortic valve replacement.
“This research addresses a serious knowledge gap in our understanding of what leads to the diseased state of CAVD, which has risk factors similar to atherosclerosis – hypertension, diabetes, and hypercholesteremia,” says Dr. Garg, director of the Center for Cardiovascular Research at The Research Institute and cardiologist in The Heart Center at Nationwide Children’s. “All of these contribute to endothelial cell dysfunction, and this grant will help us elucidate how this communication of NO and endothelial cells occurs and can lead to novel therapies for this disease.”
CAVD sends 55,000 patients to the hospital and causes 15,000 deaths annually, but the only effective therapy currently available is surgical repair and replacement, which is costly and risky. The findings from this research may ultimately lead to animal and clinical trials for nonsurgical treatment of CAVD, as well as potential treatments of other cardiac diseases and dysfunctions, which are widely affected by the presence of NO in the cardiovascular system.
Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, Grossfeld PD, Srivastava D. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005 Sep 8.
Bosse K, Hans CP, Zhao N, Koenig SN, Huang N, Guggilam A, LaHaye S, Tao G, Lucchesi PA, Lincoln J, Lilly B, Garg V. Endothelial nitric oxide signaling regulates Notch1 in aortic valve disease. Journal of Molecular and Cellular Cardiology. 2013 April 11.