A New View of Heart Health: Accumulation of Mutations - Boston Children's Answers

A New View of Heart Health: Accumulation of Mutations – Boston Children’s Answers

An unprecedented study opens a new window on the aging heart. (Image: Adobe Stock. Illustration: Patrick Bibbins, Children’s Hospital Boston)

Why do so many people get heart disease as they age? We know that factors like high blood pressure or high cholesterol contribute to the risk of heart disease, but they don’t explain all cases. A groundbreaking study from Boston Children’s Hospital offers a new perspective on heart health. It shows that our heart muscle cells accumulate new genetic mutations from childhood and lose the ability to repair them. Combined with other risk factors, they could potentially contribute to disease over time.

“As you get older and get more mutations, you add deleterious effects that could push the heart past a tipping point toward disease,” says Dr. Ming Hui Chen, a cardiologist at the Division of Genetics and Genomics and Boston Children’s Cardiology Department, which oversaw the research. “It can get to a point where so much DNA is damaged that the heart can’t beat well.”

Cataloging new mutations in the heart

The research team, led by Dr. Sangita Choudhury and Dr. August Yue Huang, from the Division of Genetics and Genomics, delved into heart muscle genetics. They studied the cells of 12 children and adults of all ages – from infancy to 82 – who died of causes unrelated to heart disease.

In total, they sequenced the complete genomes of 56 individual heart muscle cells, called cardiomyocytes. They then compared the number of new, non-inherited mutations, called somatic mutations, in cells of different ages.

As you age and gain more mutations, you add deleterious effects that could push the heart beyond a tipping point into disease.

The older the individual, the more single nucleotide DNA variants their heart cells have (changes in building blocks A, T, C and G). The pattern of these mutations suggested that many of them were caused by oxidative damage.

“Because the heart is still beating, it uses a lot of energy,” says Dr. Chen. “This energy production creates chemical by-products known as reactive oxygen species or ROS. When ROS levels get too high, they can damage DNA.

Collaborators pose together in the laboratory
From left to right: Drs. Chen, Huang, Choudhury, Walsh and Lee. (Photo: Michael Goderre, Children’s Hospital Boston)

Add insult to injury

Some of the newly acquired mutations interfered with genes involved in basic cellular functions. For example, some have affected the cytoskeleton, the scaffolding that gives cells their structure.

But making matters worse, other mutations interfered with the pathways cells normally use to repair DNA damage.

“Aging appears to impact DNA repair mechanisms,” says Dr. Choudhury. “These mechanisms can be overridden if there is enough oxidative damage. This is the first time that new mutations have been examined in the human heart at the single-cell level.

In fact, the researchers were struck by how quickly heart cells acquired mutations. Because heart cells don’t continue to divide — a time in a cell’s life cycle when DNA is more exposed — many people thought they were less susceptible to mutations. But the team’s analysis suggests that mutations accumulate in heart cells as fast or faster than in other cell types, including some dividing cells. The team estimates that, on average, starting in early childhood, each heart cell acquires more than 100 new mutations each year.

This is the first time that new mutations have been studied in the human heart at the level of a single cell.

The technically challenging study relied on single-cell whole genome sequencing and bioinformatics techniques developed in the laboratory of Dr. Christopher Walsh at Boston Children’s, including Drs. Choudhury and Huang are members. The Walsh lab focuses on neuroscience and recently used the new methods to document a parallel phenomenon in the brain: the accumulation of mutations in neurons in people with Alzheimer’s disease.

Future goal: Explore mutations in cardiovascular disease

The researchers note that their study was not designed to investigate other types of mutations beyond single-nucleotide variants, such as DNA insertions or deletions. Also, because they looked at healthy heart cells, the study doesn’t prove that the mutations are involved in heart disease – it just shows that they accumulate over time.

In the future, the researchers plan to examine mutations in the tissues of patients with different cardiovascular diseases. As a first step in this direction, Dr. Chen plans to collect data from cancer patients who have heart disease. His research focuses on how chest radiation therapy and chemotherapy for cancer affect heart health.

“We also want to look at different cell types in the heart,” says Dr Choudhury. “We have only touched the tip of the iceberg.”

The study was published on August 11 in the journal natural aging. Chen, Walsh and Dr. Eunjung Alice Lee were co-principal investigators.

Explore clinical studies at the Heart Center.

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