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Heart Dysfunction Insights Drawn From Age-Related Cardiomyocyte Mutations

NEW YORK – Aging hearts are marked by cardiomyocyte heart cell mutations that can be traced back to specific DNA damage and base repair defects, according to a new single-cell genomic analysis that included individuals from across the human lifespan.

"The accumulation of somatic DNA mutations over time is a hallmark of aging in many dividing and nondividing cells, but has not been studied in postmitotic human cardiomyocytes," co-senior and co-corresponding author Christopher Walsh, a genetics and genomics researcher affiliated with Boston Children's Hospital, Harvard Medical School, and the Broad Institute, and his colleagues explained in their new paper, noting that "[u]nderstanding mutational signatures and their mechanism of formation might lead us to unveil the mechanism of DNA damage and disease progression of the aging heart."

As they reported in Nature Aging on Thursday, the researchers turned to single-cell whole-genome sequencing to characterize single-base somatic mutations in 56 individual cardiomyocyte cells isolated from fresh-frozen, post-mortem heart samples taken from the heart's left ventricle in a dozen individuals. These samples included ones from three people over 75 years old, six individuals between 30 and 66 years old, and three infants or toddlers under 4 years of age.

Using computational methods for finding mutations, the team detected a distinct age-related rise in somatic single-nucleotide changes, suggesting that heart cells accumulate such variants at a rate that is on par with hepatocyte cells in the liver — far faster than some other cell types in the body, including neurons or lymphocytes.

"[T]he number of [somatic single-nucleotide variants] and the likelihood of disrupting essential gene function in human cardiomyocytes increases significantly with age, suggesting that the age-related cellular dysfunction in aged cardiomyocytes could be due partially to somatic mutations," the authors suggested, "although more studies will be needed to draw a causal relationship between mutational burden and age-associated decrease in cardiac function."

Within aging cardiomyocytes, the researchers uncovered four main mutational signatures that could be traced back to processes such as defective mismatch DNA repair, diminished oxidative DNA damage repair by base excision, and botched nucleotide excision repair. At the same time, the investigators folded in RNA sequence data from 168 healthy hearts that were profiled for the Genotype-Tissue Expression project to flag mutations expected to impair cardiomyocyte function and to predict mutation-related expression changes.

With additional enzyme-linked immunosorbent assay profiling, the team saw further signs that oxidative damage was more pronounced in cardiomyocyte samples from five older individuals, as compared to those from five infants.

As cardiomyocytes are known to undergo polyploidization, these results suggested to the researchers that those extra genome copies could buffer against such oxidative stress-related DNA mutations, even in cardiomyocytes found in young individuals.

"Our prediction models show that tetraploid cardiomyocytes have a significantly lower probability of complete gene [knockout] compared with diploid cardiomyocytes, indicating that cardiomyocyte polyploidization potentially offers a mechanism to ameliorate the deleterious effects of this rapid mutation accumulation," the authors noted.