Cardiomyocyte Autonomous Contractility Defects in Hypoplastic Left Heart Syndrome (HLHS)
Abstract
Infants can be born with a severe heart malformation (congenital heart disease) called hypoplastic left heart syndrome (HLHS), where the left half of the heart is underdeveloped and non-functional. Without any intervention, HLHS is fatal. Significant medical and surgical advances over the past several decades have allowed many infants with HLHS to now survive into childhood or even adulthood. The most common treatment for infants with HLHS is a series of open-heart surgeries, which modify the patterns of blood flow so that patients can survive with just one pumping chamber instead of two: the right ventricle becomes the main pump, supplying blood to the body. However, sometimes early during childhood and other times during the second or third decade of life, the right ventricle can become weak, with a decreased ability to squeeze, resulting in heart failure. It is challenging to predict which HLHS patients will develop heart failure, and when. In the majority of HLHS patients, we do not understand the factors that cause the heart muscle to fail. Traditional heart failure medications are used in HLHS patients with heart failure; however, these medications do not improve outcomes nor reverse heart failure. Specifically, many medications that improve outcomes in adults with heart failure are not effective in children with HLHS, likely because the underlying cause of heart failure is different between these two populations and the body’s response to heart failure may change with age. Unfortunately, the only option for long-term survival for HLHS patients with end-stage heart failure is heart transplantation. While heart transplantation can be life-sustaining, we do not consider heart transplantation a cure, since complications such as rejection, coronary artery disease, infection, and cancer can arise following heart transplantation. Additionally, subsequent heart transplants may be needed, as transplanted hearts last 15 years on average. Identifying the mechanisms underlying heart failure in HLHS is needed to develop novel medical therapies specifically for HLHS patients, which may delay or even decrease the need for heart transplantation. As such, this proposal is well-aligned with the Fiscal Year 2022 (FY22) Peer Reviewed Medical Research Program (PRMRP) Strategic Goal to develop less-invasive treatment technologies for associated cardiovascular conditions within the FY22 PRMRP Topic Area of Congenital Heart Disease. The overall goal of the proposed research project is to better understand the changes in HLHS heart muscle cells that predispose them to fail. In addition to HLHS being a disease where the heart is structurally abnormal, there is suggestion that the heart muscle cells themselves have intrinsic defects that may contribute to the development of heart failure. This proposal will generate heart muscle cells from circulating white blood cells from HLHS patients, known as human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM). This hiPSC-CM model will be used to study the proteins and contractile function of HLHS heart cells, without having to directly take a heart tissue biopsy from a HLHS patient. Additionally, we will utilize these patient- derived HLHS hiPSC-CM to perform an unbiased screen of thousands of potential compounds to see if any have efficacy in improving heart muscle cell contraction. By increasing our understanding of the causes of heart failure in HLHS hearts, we hope to identify targets for novel and effective medical therapies specifically for this vulnerable population. Ultimately, information gained from this proposal will help improve outcomes for children and adults with HLHS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310165
Entities
People
- Stephanie Nakano
Organizations
- United States Army
- University of Colorado Denver