A new view of heart health: Accumulating mutations


Alt Text: An x-ray of the heart with dots showing mutations.
A unique study opens a new window on the aging heart. (Image: Adobe Stock. Illustration: Patrick Bibbins, Boston Children’s Hospital)

Why do so many people develop 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 unique study from Boston Children’s Hospital offers a new perspective on heart health. It shows that the cells in our heart muscle accumulate new genetic mutations as early as childhood – and lose the ability to repair them. In conjunction 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 into disease,” says Dr. Ming Hui Chen, cardiologist at the Boston Children’s Department of Genetics and Genomics and Department of Cardiology. who oversaw the research. “It can get to the 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 in the Department of Genetics and Genomics delved deep into the genetics of heart muscle. They examined cells from 12 children and adults across the age range – from infancy to 82 years – who had died from causes unrelated to heart disease.

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

As you get older and get more mutations, you add deleterious effects that could push the heart past a tipping point into disease.

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

“Because the heart is always pumping, it uses a lot of energy,” explains 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.”

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

Adding insult to injury

Some of the newly acquired mutations disrupted genes involved in basic cell functions. For example, some involved the cytoskeleton, the scaffolding that gives cells their structure.

But what makes matters worse are other mutations that interfere with signaling pathways that cells normally use to repair DNA damage.

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“Aging seems to affect DNA repair mechanisms,” says Dr. Choudhury. “These mechanisms can be overwhelmed when there is enough oxidative damage. This is the first time that new mutations in the human heart have been studied at the single-cell level.”

In fact, the researchers were impressed by how quickly heart cells acquired mutations. Because heart cells stop dividing — a time in a cell’s life cycle when DNA is more exposed — many people thought they were less prone to mutation. However, the team’s analysis suggests that mutations in heart cells accumulate just as fast or faster than in other cell types – including some cells that are dividing. The team estimates that each heart cell, on average, acquires more than 100 new mutations each year beginning in infancy.

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

The technically difficult study relied on single-cell genome sequencing and bioinformatics techniques developed in Dr. Christopher Walsh at Boston Children’s, of which Dr. 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.

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Future goal: Research into mutations in cardiovascular diseases

The researchers note that their study was not designed to examine other types of mutations beyond single nucleotide variants, such as B. 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 want to investigate mutations in the tissue of patients with various cardiovascular diseases. As a first step in this direction, Dr. Chen to collect data from cancer patients with heart disease. Her research focuses on how breast radiation and chemotherapy for cancer affect heart health.

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

The study was published in the journal Aug. 11 aging in nature. Chen, Walsh and Dr. Eunjung Alice Lee were lead investigators.

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