Hypoplastic Left Heart Syndrome Patient Cells Share Insights

By Amanda Chase, PhD
December 4, 2020

Hypoplastic left heart syndrome (HLHS) is a severe birth defeat of the heart that disrupts normal blood flow. During development, the left side of the heart does not develop correctly, disrupting the ability of the heart to pump oxygenated blood to the body. Left untreated, this disease is fatal. Treatment includes a series of surgeries to redirect blood flood so the right ventricle pumps blood to the body to compensate for the underdeveloped left side. Many patients still require a heart transplant, some early in life, due to unexplained right ventricular (RV) failure. Understanding why there is early RV failure for some patients, and how to prevent or treat that failure, is an important step to improving care for HLHS patients.

Disease modeling is heavily reliant upon a good platform for modeling the disease. The advancement of induced pluripotent stem cells (iPSCs) and their derivation into cardiomyocytes (iPSC-CMs) is an increasingly utilized platform for understanding diseases and finding therapies, and could be a platform for studying HLHS. Stanford Cardiovascular Institute affiliated researchers Sharon Paige, MD, PhD, and senior author Sean Wu, MD, PhD, used HLHS patient-derived iPSC-CMs as a platform for better understanding HLHS in their recent Circulation paper.

Figure. Induced pluripotent stem cells (iPSCs) were derived from patients with hypoplastic left heart syndrome (HLHS), and healthy controls. iPSCs were made into cardiomyocytes and were studied to determine if the patients cells mirrored what is observed in patients.

The benefit of using iPSC-CMs is that the researchers were able to study lines derived from 3 patients known to have developed early RV failure and 5 healthy controls, including 2 unrelated individuals and 1 unaffected parent from each patient. Using these tools, they showed that contraction force and acceleration were reduced in HLHS iPSC-CMs, mirroring what was seen in the patients.

They were also able to show that genes that were expressed differently in an HLHS patient compared to a healthy individual were mostly defined as heart failure coordinators, showing that these iPSC-CMs can be a good platform for studying the disease. Importantly, the authors were able to show that mitochondrial dysfunction contributes to the reduced contractility (i.e., ability to pump). This dysfunction may underlie early RV failure seen in some HLHS patients, and provide a novel therapeutic target for intervention.

Other Stanford authors include Francisco Galdos, Soah Lee, Elizabeth Chin, Sara Ranjbarvaziri, Dries Feyen, Adrija Darsha, Sidra Xu, Julia Ryan, Aimee Beck, Yifei Miao, Mingxia Gu, Daniel Bernstein, Mark Mercola, Marlene Rabinovitch, Euan Ashley, and Victoria Parikh.

Dr. Sharon Paige

Dr. Sean Wu