Key Link Between Heart Enzyme and Sudden Cardiac Death Uncovered in Study by Michael S. Kapiloff
A Miller School researcher has identified a key linkage between a little-known enzyme and hypertrophic cardiomyopathy, an inherited heart defect that can be deadly in children and cause sudden cardiac death in seemingly healthy young athletes.
“Our laboratory study points the way to potential new therapeutic strategies for improving cardiac function and reducing the toll of heart failures,” said Michael S. Kapiloff, M.D., Ph.D., professor of pediatrics and Director of the Cardiac Signal Transduction and Cellular Biology Laboratory at the Interdisciplinary Stem Cell Institute. His research was supported by a grant from the National Heart, Lung, and Blood Institute.
Published this month in the American Journal of Physiology – Heart and Circulatory Physiology, the study was featured in an October AJP podcast led by associate editor Meredith Bond, who discussed its importance with Kapiloff and Nikolaos Frangogiannis, M.D., of Albert Einstein College of Medicine.
In the study, Kapiloff and his team examined the role of the enzyme Type 3 p90 ribosomal S6 kinase (RSK3) in the development of myocardial interstitial fibrosis — abnormal scarring of the heart muscle of the left ventricle and a feature of hypertrophic cardiomyopathy (HCM) that is associated with sudden death.
“Our prior studies on genetically modified mice showed that RSK3 binds to the protein mAKAP, which orchestrates the regulation of heart muscle cell growth and scarring,” Kapiloff explained. “This new study found that RSK3 could be eliminated, halting the abnormal heart muscle scarring without ill effects to the mice.”
Nearly 5 million Americans – both children and adults – develop heart failure annually. The most commonly inherited heart defect, affecting one in 500 people, HCM is a leading cause of sudden death in children, and accounts for about one-third of sudden deaths in young athletes, according to Kapiloff.
“While HCM is caused by mutations in certain proteins found in the heart, the clinical progression of this condition varies greatly among individuals,” Kapiloff said. Despite the name of the disorder, abnormal heart muscle growth is not always present in patients, who may have heart rhythm abnormalities or other problems due to the development of scar tissue from interstitial fibrosis.
“Our key finding was that even in mice with normal-sized hearts, the presence of RSK3 enzyme was linked to heart failure,” Kapiloff said. “By understanding that underlying mechanism, we may be able to intervene to stop the development of HCM or even restore the heart to normal functioning. We have a wonderful therapeutic opportunity here.”
Kapiloff, who received UM’s 2013 Micah Batchelor Award for Excellence in Children’s Health Research to advance his work on RSK3, believes therapies to inhibit RSK3 may also help clinicians treat other cardiovascular diseases. “Our laboratory experiments are part of a translational pathway that could lead to clinical trials in human patients within this decade,” he said.
Lead authors of the study, “p90 ribosomal S6 kinase 3 contributes to cardiac insufficiency in α-tropomyosin Glu180Gly transgenic mice,” were postdoctoral fellow Catherine L. Passariello, Ph.D., and Marjorie Gayniol, M.D., a recent pediatric cardiology fellow.