Unique cell, immune system ‘signatures’ may reveal causes of congenital heart disease
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Researchers using RNA sequencing have identified unique cell and immune system signatures in tissue samples of children with congenital heart disease, offering a rare opportunity to better understand the origins of a complex disease.
Due to improved supportive medical therapies, the number of children with congenital heart disease who survive into adulthood has increased to more than 90%. However, these patients have increased risk for severe sequelae including HF and noncardiac death, such as cancer and infection. The underlying cause of declining heart function in congenital disease remains poorly understood and there is an unmet need for targeted therapeutics.
A team of researchers from the Texas Heart Institute, Baylor College of Medicine and Texas Children’s Hospital recently profiled heart and blood samples from children with congenital heart disease, including hypoplastic left heart syndrome, tetralogy of Fallot and dilated and hypertrophic cardiomyopathies undergoing heart surgery. Using single-cell RNA sequencing and other technologies, researchers were able to interrogate samples at the single-cell level from patients with congenital heart disease.
Among other findings, the researchers observed congenital heart disease-specific cell states in cardiomyocytes, which had evidence of insulin resistance and increased expression in select genes. Additionally, peripheral immune cell profiling suggested deficient monocytic immunity in congenital heart disease, possibly driving the increased risk for infection and cancer.
The novel findings, described as an “atlas” for understanding congenital heart disease, could open the door to better defining congenital heart disease outcomes and developing new therapies.
Healio spoke with James F. Martin, MD, PhD, director of the cardiomyocyte renewal laboratory at Texas Heart Institute and the Vivian L. Smith Chair in Regenerative Medicine at Baylor College of Medicine, about the promise of single-cell genomics, creating a “map” of the diseased heart, and the potential for lifesaving therapies for children with congenital heart disease. Martin and colleagues’ work was recently published in Nature.
Healio: Why is the underlying cause of congenital heart disease in children still so poorly understood?
Martin: Heart development itself is complex. There are many different developmental events that can go wrong, and very commonly these things when they go wrong can give rise to a similar type of defect. The second is it is difficult to get access to hearts to study; pediatric tissue samples are rare and difficult to obtain. Much of the work has been done with rodent models to try and understand congenital heart disease. That gets you to a certain place, but rodents are not humans.
Healio: How did this work come about?
Martin: Over the years, pediatric cardiologists and surgeons have done a great job helping these children born with congenital heart disease live longer. There has been a lot of amazing work over the years. Even with all that, after a repair for a congenital heart disease defect, some patients do well and others do not do so well. It remains unclear why that is. We wanted to address that and understand what the differences are that are not obvious with typical phenotyping, and apply newer, single-cell genomics methodologies to figure out what is underlying the different trajectories of these different congenital heart diseases. We wanted to do something good for these children.
Healio: Can you briefly describe what you and your colleagues found?
Martin: We performed single-cell nuclear RNA sequencing and analyzed more than 157,000 nuclei from donors and patients with congenital heart disease. This allowed us to look at the individual cell types in the heart, muscle cells, fibroblasts, cardiomyocytes and inflammatory cells. We found there were specific signatures in some types of congenital heart disease that were enriched in specific defects. Certain genetic pathways, for example, were changed in the fibroblasts of the hypoplastic left heart, as well as in the tetralogies, we also found some metabolic changes in the cardiomyocytes that were enriched in those diagnoses.
The other thing we found was that many of the cell types in the heart — even though they had different diagnoses — there was commonality in their cell state. Even though they had different diagnoses, there was overlap in the different cell types. It may be that it is a stress response, and that stress response looks the same in each type of diagnosis.
We also found evidence that there was an immunosuppressed signature surrounding vessels in many of these hearts. This is a profiling paper, so these are first observations, really a first look. Now, there is a lot of work to do.
Healio: What might these findings mean going forward?
Martin: That is a central question. One of the other reasons we are interested in doing this work is we would like to figure out if there are pathways that are more amenable to manipulation, like gene therapy. We are trying to figure that out right now. As you can imagine, that is something that we must be careful about. We are in the planning stages now.
Since this was a profiling study, we want to get more information about functional consequences of these changes in the gene expression. That is several years’ worth of work. Once we get there, that is when we start to think more carefully about therapies.
The big picture is we are really at the beginning. It is a frontier, using these incredible methods to understand an organ. There is a big effort to “map” these human organs — so-called human organ atlases. Putting that together with our approach, doing the same thing, but in diseased tissue, we are going to learn quite a bit during the coming decade. This will allow us to hopefully make great strides not only in diagnosis, but treatment. The opportunities for helping these children are improving every day.
For more information:
James F. Martin, MD, PhD, can be reached at jfmartin@bcm.edu.
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