Patient-derived Heart Cells Offer New Insights into Severe Congenital Heart Disease

Hypoplastic left heart syndrome (HLHS) is one of the most severe forms of congenital heart disease. In this condition, the left side of the heart does not develop properly, leaving the heart unable to pump oxygen-rich blood to the body without surgical intervention. Although genetic factors are known to contribute to HLHS, they do not fully explain why the condition develops or why its severity differs between patients.

A research group led by Associate Professors Emmi Helle from the Centre of Excellence of Metabolic Integration and Stem Cells and Metabolism Research Program, University of Helsinki and Virpi Talman from the University of Turku has now shown that heart muscle cells derived from patients with HLHS carry intrinsic molecular vulnerabilities that may reduce their ability to cope with developmental stress. The findings suggest that the disease may arise not only from genetic predisposition, but also from how genetically susceptible heart cells respond to environmental stressors during development.

In the study, led by doctoral researcher Margarida Varela, the researchers used human induced pluripotent stem cells to generate cardiomyocytes, or heart muscle cells, from both healthy individuals and patients with HLHS. This allowed them to study patient-specific heart cells in the laboratory and investigate how these cells differ at baseline, as well as how they respond when exposed to stress. “We wanted to understand whether HLHS cardiomyocytes are already different before any external challenge, whether they react differently when stimulated, and whether these differences could make them more vulnerable during heart development,” Varela explains.

The team found that HLHS cardiomyocytes showed broad changes in gene activity. Importantly, many of the affected genes are known to be involved in cardiac development, contraction, rhythm regulation, metabolism and cellular stress responses. The researchers also observed reduced activity in processes that normally help coordinate heart muscle development and function. “These cells appeared broadly similar to healthy cardiomyocytes, but when we examined them in greater detail, we saw that key regulatory and stress-response programmes were weakened,” says Varela.

To determine whether these molecular changes had functional consequences, Varela exposed the cells to different types of stress. HLHS cardiomyocytes showed a stronger response to endothelin-1, a molecule associated with cardiac stress and growth. In particular, they produced higher levels of proBNP, a well-known marker of cardiac stress, compared with healthy control cells. By contrast, mechanical stretch, used to mimic the physical forces experienced by heart cells, did not reveal major differences between healthy and HLHS cardiomyocytes. “In a developing foetal heart, this reduced resilience could become important,” says Varela.

Taken together, the findings support a model in which HLHS is influenced by both inherited cellular susceptibility and environmental or developmental stress. Maternal metabolic disease, hypertension, oxidative stress and altered foetal blood flow have all been suggested as possible stressors during heart development. “Our results suggest that HLHS arises from multifactorial causes” Helle summarises. “They support the idea that genetically vulnerable cardiomyocytes may have a reduced capacity to adapt when exposed to stress during development.”

The researchers now hope that studying larger cohorts of patient-derived cells will help reveal whether there are shared molecular features that connect different HLHS patients. Such work could make it possible to distinguish patient-specific variation from common disease mechanisms, bringing researchers closer to understanding why some developing hearts fail to form normally and how this vulnerability might one day be prevented or reduced.