Why do so many people get heart disease as they get older? We know that factors such as high blood pressure or high cholesterol contribute to heart disease risk, but they don’t explain all conditions. A first-of-its-kind study from Boston Children’s provides a new lens for heart health. It shows that heart muscle cells accumulate new genetic mutations that start in childhood – and lose the ability to repair them. Along with other risk factors, they can contribute to disease over time.
“As you age and have more mutations, you add harmful effects that may push the heart beyond the tipping point to disease,” Dr. Ming Hui Chenpediatric cardiologist in Boston Department of Genetics and Genomics And the Cardiology Departmentwho supervised the research. “You might get to a point where so much DNA is damaged that the heart can’t beat well.”
Cataloging new mutations in the heart
Research team led by Dr. Sangeeta Chowdhury And the Dr. August Yu Huang, in the Department of Genetics and Genomics, takes a deep dive into the genetics of heart muscle. They studied cells from 12 children and adults across the age spectrum — from infancy to 82 years — who died of causes unrelated to heart disease.
In all, they sequenced the complete genomes of 56 heart muscle cells, known as cardiomyocytes. They then compared the number of new, non-inherited mutations, known as somatic mutations, in cells of different ages.
As you age and have more mutations, you add harmful effects that may push the heart beyond the tipping point to disease.
The older the individual, the more DNA single-nucleotide variants (changes in building blocks A, T, C, and G) the heart cells had. The pattern of these mutations indicates that many of them resulted from oxidative damage.
“Because the heart is always pumping blood, it uses a lot of energy,” Dr. Chen explains. “This energy production produces chemical byproducts known as reactive oxygen species, or ROS. When levels of reactive oxygen species are too high, they can damage DNA.”
Which made matters worse
Some of the newly acquired mutations interfered with genes involved in basic cell functions. For example, some affected the cytoskeleton, the scaffolding that gives cells their structure.
But to make matters worse, other mutations interfered with pathways cells normally use to repair DNA damage.
“It appears that aging affects the mechanisms of DNA repair,” says Dr. Choudary. These mechanisms may be stressful if there is sufficient oxidative damage. This is the first time that novel mutations have been seen in the human heart at the single-cell level.”
In fact, the researchers were amazed at how quickly heart cells acquired the mutations. Because heart cells don’t keep dividing – a period in the cell’s life cycle when DNA is most exposed – many people think they are less susceptible to mutations. But the team’s analysis suggests that the mutations accumulate in heart cells as quickly or faster than other cell types — including some that divide. The team estimates that, on average, starting in childhood, each heart cell acquires more than 100 new mutations each year.
This is the first time that new mutations have been seen in the human heart at the single-cell level.
The technically challenging study relied on whole-cell genome sequencing and pioneering bioinformatics techniques in the lab Dr. Christopher Walsh In Boston Children’s, including d. Chaudhry and Huang are two members. Walsh’s lab focuses on neuroscience and has recently used new methods to document a parallel phenomenon in the brain: Mutations accumulate in neurons in people with Alzheimer’s disease.
Future goal: Exploring mutations in cardiovascular disease
The researchers note that their study was not designed to investigate types of mutations other than single-nucleotide variants, such as DNA insertions or deletions. Also, because they looked at healthy heart cells, the study didn’t prove that the mutations are linked to heart disease — it just shows that they accumulate over time.
In the future, the researchers plan to look at mutations in tissues from patients with various cardiovascular diseases. As a first step in this direction, Dr. Chen plans to collect data from cancer patients with heart disease. Her research focuses on how chest radiation and cancer chemotherapy affect heart health.
“We also want to look at different types of cells in the heart,” Dr. Choudary says. “We just touched the tip of the iceberg.”
study was Published on August 11 in the magazine aging nature. Chen Walsh and Dr. Eunjung Alice Lee They were co-investigators.
explore Clinical Studies at the Heart Center.