Finding a Therapy for Ischemic Cardiomyopathy

by Amanda Chase, PhD
April 29, 2022

Coronary heart disease, a major cause of morbidity and mortality, occurs when the arteries cannot deliver enough oxygen-rich blood to the heart. This is often the result of plaque build-up and/or heart attack. The lack of blood supply to the heart, in turn, results in ischemic cardiomyopathy, when the ability of the heart to pump blood is decreased due to a weakened left ventricle (LV; the heart’s main pumping chamber). The LV has a plasticity that allows remodeling, the changing of shape or structure. Following a heart attack, for example, LV remodeling can occur, likely due to the stress. While this may be of benefit initially to compensate for damage, the continued remodeling leads to exaggerated remodeling and cardiac function deteriorates, ultimately leading to heart failure. Heart failure has a 50% survival rate 5 years after survival, making a critical need for more effective therapies to prevent remodeling.

Remodeling of the heart is largely due to altered function of cardiomyocytes (heart muscle cells). Cardiomyocyte function is regulated by an intricate network of signaling pathways that control aspects of remodeling. Recent work published in Gene Therapy with senior author Michael Kapiloff, Reinhard Family Professor of Ophthalmology, sought to use knowledge of these signaling pathways to prevent remodeling. They had previously shown that a complex made up of multiple proteins, organized by a protein called mAKAPb, regulates cardiac remodeling by influencing gene expression of various factors. Therefore, mAKAPb was an intriguing target for preventing remodeling.

Adeno-associated virus (AAV) gene therapy uses vectors that can effectively and accurately deliver specific information. This research team created an AAV vector that could deliver information to decrease expression of mAKAPb (via shRNA) specifically in cardiomyocytes. Intriguingly, they showed that this specific vector (AAV9sc.shmAKAP) downregulated mAKAPb expression in both the mouse heart and in human induced cardiomyocytes. This prevented cardiac remodeling, retained cardiac structure and function, and prevented heart failure in mouse models of ischemic cardiomyopathy. These findings show a proof-of-concept for a new potential gene therapy for ischemic cardiomyopathy and supports the development of a translational pipeline for treatment of heart failure.

Other Stanford Cardiovascular Institute affiliated authors include Jinliang Li, Jennifer Ataam, Hrishikesh Thakur, and Ioannis Karakikes. First author Eliana Martinez is affiliated with the University of Miami. Additional authors Kristin Tokarski and Kimberly Dodge-Kafka are affiliated with University of Connecticut Health Center.