Implementing Novel Therapeutics to Restore Cardiomyocyte Physiology and Circumvent Sudden Death in Arrhythmogenic Heart Disease
Abstract
Heart abnormalities are the top causes of sudden death in military recruits, with the majority of cases caused by strenuous exercise. Our goal is to test a new therapy to prevent cardiac abnormalities and sudden cardiac death in young people by studying a congenital-based heart disease that causes sudden death, which is a Fiscal Year 2017 Peer Reviewed Medical Research Program Topic Area. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a devastating inherited heart muscle disease that is one of the top causes of sudden cardiac death in young people. Young populations are extremely vulnerable at early stages of ARVC, even when full clinical symptoms have not yet presented (heart appears structurally normal), as lethal arrhythmias associated with sudden death can still be triggered, especially with strenuous exercise. The clinical onset of sudden death in ARVC patients harbors close parallels with the onset of sudden death observed in military recruits, which also manifests with strenuous exercise and in a structurally normal heart when examined upon autopsy. To date, there are no known effective therapies or cures for ARVC. However, evidence suggests that this heart disease is caused by mistakes in the DNA that codes for proteins that hold heart muscle cells together known as desmosomes (cell junctions), which ultimately results in the breakdown of these cell junction structures. Desmosomal abnormalities are also found in other cardiac diseases and injury models leading to sudden death, suggesting broad relevance of this molecular target to sudden death pathways. Thus, identifying the early molecular events that are triggered following desmosomal protein loss may provide us a clue on what molecules are important and require restoration in order to circumvent the cascade of events leading to ARVC and sudden death in young people. By performing a combination of molecular, cellular, and physiological studies in hearts of a novel genetically engineered mouse model where desmosomes are deficient as well as cardiac cells generated from ARVC patient stem cells, we have uncovered a molecule that may not only be an early disease hallmark of ARVC, but may also have therapeutic value in ARVC. We specifically show that restoration of this molecule in cardiac cells generated from various ARVC patient stem cells, that have severe heart rhythm and/or functional abnormalities, can effectively reverse these abnormalities so that they function as healthy cells. We further show using gene therapy strategies that restoring this molecule in hearts from our novel genetically engineered mouse model where desmosomes are deficient, which has significant cardiac abnormalities and prone to sudden death, can improve cardiac function and prolong survival in these mice. Our aim is to comprehensively analyze the effects of restoring this molecule in cardiac muscle at early and late stages of sudden death syndromes by employing state-of-the-art molecular, genetic, cellular, and electrophysiological approaches, which leverage our novel mouse model and human stem cell models of ARVC that our laboratory has generated. Our studies will provide new insights on strategies for therapies for ARVC and lethal arrhythmias leading to sudden death in young people. These studies have potential to lead to a paradigm shift in our understanding of the mechanisms underlying ARVC and provide novel insights on how to target therapies for ARVC and sudden death in military populations and their children (that are also at risk). Our studies will help instate new policies and directions for treatment avenues for ARVC, which will improve the long-term clinical outcome and care of suddenly fatigued Soldiers or combat-exposed retirees experiencing sudden loss of consciousness. Our unique expertise in molecular and cardiac cell junction biology, physiology, and genetic models of ARVC are poised to accelerate completion of our aims.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810380
Entities
People
- Farah Sheikh
Organizations
- United States Army
- University of California, San Diego