2019 HLH Research Update

Hypoplastic left heart (HLH) Research Update

12 August 2019

The overarching aim of this study is to understand the cellular, molecular and genetic causes of hypoplastic left heart (HLH), a condition that is among the most severe of heart defects occurring in babies at birth. HLH babies are born with a small cardiac left ventricle, the main pumping chamber of the heart. While HLH fetuses are viable, after birth, without treatment, HLH is inevitably lethal. Therapy involves three surgeries, during which the heart is radically reconstructed. Even though HLH is relatively infrequent (4-8% of all heart defects) and advances in surgery have brought survival to 76% at 25 years, there are many possible complications, sometimes necessitating heart transplantation. There is also a massive cost to the health care system, and a life-long economic and emotional burden on families.

Researchers can now create a type of super stem cell (induced pluripotent stem cells) from any tissue such as skin, from any individual. Stem cells of this sort can be grown in a dish and directed with chemicals to form virtually any mature cell type in the body, including heart muscle cells. This has brought the exciting possibility of studying human disease using (previously inaccessible) patient-specific human tissue. Developments in stem cell culture now allow the formation of cardiac mini-organs (called 3D organoids) containing muscle, vessels and other heart cells, enabling analysis of disease at a whole organ level.

Our team of researchers and clinicians are studying the causation of HLH using super stem cells. We have made stem cells from 10 HLH patients and their parents, who serve as genetically well-matched healthy controls. Researchers previously thought that HLH arose from altered blood flow and pressure secondary to the valve and vessel defects seen in HLH hearts.

However, our preliminary studies show that HLH cardiac muscle has underlying growth and functional defects, and reduced expression of genes associated with both heart and brain development, potentially connecting heart structural defects with the poor learning outcomes seen in HLH babies after birth. Our aims here are to delve more deeply into the molecular causes of HLH using 3D beating cardiac stem cell organoids, and to identify and test individual causative genes for this disease.

We will also use the organoid model to screen for drugs that overcome muscle growth and functional defects seen in HLH, which could be further developed into therapies that support the post-surgical HLH heart throughout life.

*This project was supported by the NSW Government's Cardiovascular Research Capacity Building Program.

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