Columbus, OH - August 2016
The only effective therapy available for calcific aortic valve disease (CAVD) is native valve replacement. With up to 33 percent of the general population affected by the disease, this costly surgical option is far from ideal.
“Biological replacement tissue valves will likely calcify, and mechanical valves fail to grow with pediatric patients,” says Joy Lincoln, PhD, principal investigator in the Center for Cardiovascular Research at The Research Institute at Nationwide Children’s Hospital. “Additional surgeries are common, and anti-coagulant therapy is required for the rest of patients’ lives.”
Ongoing research at Nationwide Children’s into the causes of CAVD – supported by a recent four-year, $2.5 million grant from the National Heart, Lung, and Blood Institute at the National Institutes of Health – may ultimately result in medical therapies to prevent calcification, or to stop the process already underway.
Awarded to Dr. Lincoln, Vidu Garg, MD and Brenda Lilly, PhD, the grant continues an investigation into CAVD which began in 2005, when Dr. Garg found mutations in the human genetic regulator NOTCH1 that prevent the buildup of calcium deposits on the aortic valve. In 2013, Drs. Garg, Lincoln, Lilly and their collaborators found that NOTCH1 function is turned on and off by nitric oxide.
“We know what causes calcification – lack of nitric oxide in the system. What we don’t know is what causes the valve interstitial cells to change and calcify, and that definitely hinders new treatment development,” explains Dr. Lilly, principal investigator in the Center for Cardiovascular Research and The Heart Center at Nationwide Children’s. “This grant will allow us to determine how nitric oxide regulates Notch1 activity to prevent valve interstitial cells from changing and causing calcification, and whether we can use nitric oxide 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 may 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 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 nitric oxide and endothelial cells occurs and can lead to novel therapies for this disease.”
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 nitric oxide in the cardiovascular system, the researchers say.
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.