Fontan circulation linked to accelerated biological aging in youth

Our birthdays tell us how long we have lived, but not necessarily how our bodies are aging. Biological age reflects the condition and function of our cells and tissues, shaped by genetics, lifestyle, environment, and disease. In people with chronic conditions such as cancer, kidney disease, and heart disease, researchers have observed signs of aging that appear earlier than expected for a person's age. This is known as accelerated biological aging.

In cardiovascular disease, this difference may have important consequences. While accelerated biological aging has been linked to worse outcomes in adults with heart failure, people born with heart defects may also face an increased risk of age-related health problems. These observations raise an important question: could measuring biological aging help researchers better understand the long-term health of people living with complex heart conditions.

One group for whom this question is particularly relevant is people living with a Fontan circulation. Some children are born with severe heart defects that leave only one functioning pumping chamber, or ventricle, rather than two. A series of surgeries in early childhood creates a new route for blood flow: blood returning from the body travels directly to the lungs, without a separate ventricle pumping it there. The single working ventricle then pumps oxygen-rich blood to the body. This arrangement, called Fontan circulation, leaves patients living with a fundamentally different system for moving blood through the heart, lungs, and body.

To explore biological aging in this population, a Stanford Cardiovascular Institute team led by senior author Sushma Reddy compared 90 children and adults with a Fontan circulation with 59 people with normal heart structure and function. Most participants were adolescents. Published in the Journal of the American Heart Association, the study includes co-first authors Jennifer Woo and Annabelle Grace Binti Vincent.

The researchers examined telomeres, protective caps at the ends of chromosomes (structures that carry our DNA). Telomeres help protect genetic material and generally shorten as cells divide and as we age. Their length provides one marker scientists can use to study biological aging. By measuring telomeres in white blood cells, the team found that people with Fontan circulation had shorter telomeres than the comparison group, with differences apparent even at young ages. The findings point to signs of accelerated biological aging in a population largely made up of young people.

The pattern was more pronounced in patients whose right ventricle, rather than the left, served as the main pump sending blood to the body. Shorter telomeres were also associated with less favorable circulation measurements, including less blood pumped relative to body size, greater resistance to blood flow through the body's vessels, and lower oxygen levels in blood returning from the upper body. These connections suggest that a marker of cellular aging is associated with specific features of how the Fontan circulation functions.

Follow-up measurements added another important observation. At follow-up, typically about a year later, nearly half of the patients with telomere loss had an increase in the number of associated health conditions. That compared with about one in five among those whose telomeres remained stable or lengthened. This link between telomere loss and a growing burden of health problems suggests that tracking biological aging could offer another way to understand patients' health over time.

The findings are a starting point, not a test for predicting an individual patient's future. The study could not determine whether telomere shortening contributes to health problems or results from them. It also remains unclear whether patients had shorter telomeres from birth or developed them as a consequence of their altered circulation. Importantly, the study did not establish that telomere length predicts survival or the need for a heart transplant.

The next step is to follow changes in telomere length over longer periods to determine whether they can provide earlier clues to future health problems. If confirmed, biological aging could offer an additional tool for monitoring patients and understanding their long-term outlook. The work also provides a foundation for investigating whether interventions that influence biological aging could help slow its effects. For people living with Fontan circulation, the goal is to look beyond age in years to better understand the changes occurring within the body and, ultimately, use that knowledge to improve long-term health.