Male mice fare worse after heart radiation, revealing sex differences in cardiac injury

Radiation therapy saves lives. For millions of people treated for breast cancer, lung cancer, lymphoma and other malignancies that sit close to the chest wall, targeted beams of ionizing radiation destroy tumor cells that would otherwise spread and kill. Yet the heart often lies within or beside the treatment field, and the price of a cure can be a slow, silent injury to the myocardium that surfaces months or even years later as radiation-induced heart disease, or RIHD. Clinicians have long recognized that some patients develop heart failure, arrhythmias, valve disease or accelerated coronary artery blockages after thoracic radiotherapy, but predicting who will deteriorate remains frustratingly imprecise. A new study from researchers at the Mayo Clinic, published in the journal Biology of Sex Differences, adds a striking and previously missing variable to that equation: biological sex.

Leading the effort, cardiovascular researcher Emily R. Whelan and her colleagues, with radiation oncologist Bradford S. Hoppe and immunologist DeLisa Fairweather as co-senior authors, set out to answer a deceptively simple question that has never been systematically addressed in the laboratory. Mouse models of RIHD exist and are widely used to probe the molecular cascade that connects a dose of radiation to eventual cardiac dysfunction, yet, to the authors’ knowledge, no prior study had examined whether male and female mice respond differently to the same cardiac radiation exposure. Given that sex differences pervade cardiovascular medicine, from the prevalence of autoimmune myocarditis to the presentation of ischemic heart disease, the omission was conspicuous. The new work, the team reports, is the first translational study to demonstrate sex differences in RIHD in mice.

The experimental design was deliberately rigorous. Female and male BALB/cJ mice, an inbred strain frequently used in immunology and cardiology research, received a single 22 Gray dose of radiation delivered precisely to the whole heart through a C5 collimator in an X-ray machine. Twenty-two Gray is a substantial dose, calibrated to model the cardiac exposures accumulated during modern thoracic radiotherapy. Sham-treated control animals underwent identical anesthesia and were placed in the X-ray machine for the same duration but received zero radiation, ensuring that any differences observed could be attributed to the radiation itself rather than to the stress of the procedure. The investigators then tracked the animals across three carefully chosen time points: 24 hours after irradiation, capturing the innate response; day 10, representing the acute phase; and day 35, marking the transition into chronic disease.

At the cellular level, the earliest signature of injury was unmistakable in both sexes. By day 10, cardiomyocytes in the irradiated hearts carried double-stranded DNA breaks, the canonical lesion produced by ionizing radiation as it shreds the double helix. But the damage was not distributed equally. Female mice accumulated significantly more DNA damage than their male counterparts, a difference that reached high statistical significance. On its face, the finding seems paradoxical: the sex that ultimately fared worse clinically was not the one bearing more broken DNA. That dissonance became one of the study’s central puzzles, and its resolution appears to lie in what happened next inside the cells’ power plants.

To understand how the genome responded to the insult, the team performed bulk RNA sequencing of heart tissue at day 10, an approach that captures the activity of thousands of genes simultaneously. The transcriptomic landscape told a story of broad convergence. Both sexes mounted similar pathway-level responses, upregulating cellular repair programs in an attempt to patch the radiation damage, and both exhibited signatures of mitochondrial dysfunction, the progressive impairment of the organelles that generate the energy a beating heart demands. Radiation, in other words, pushed male and female hearts down many of the same molecular roads. But at a critical intersection, the paths diverged: female hearts significantly upregulated Pgc1α, the master transcriptional regulator of mitochondrial biogenesis and function, a change the males did not achieve to the same degree. Pgc1α acts something like a foreman for the cell’s energy infrastructure, coordinating the construction and maintenance of mitochondria, and its induction in females suggests a superior capacity to repair the mitochondrial damage that radiation inflicted on both sexes.

The structural consequences of radiation were visible in the vasculature as well. Radiation increased both vessel area and vessel wall thickness at day 10 and again at day 35, reflecting the vascular remodeling that is a hallmark of RIHD in patients. Here, however, the sexes traded places. By day 35, irradiated males displayed greater vessel area than irradiated females, indicating that the chronic vascular expansion was more pronounced in males. Vascular injury is thought to be a key upstream driver of radiation heart disease, since damaged endothelium promotes inflammation, thrombosis and the fibrotic scarring that stiffens heart tissue, so the male-predominant vascular remodeling foreshadowed the divergent clinical outcomes that followed.

By day 35, the two sexes had arrived at distinctly different destinations. Female mice developed mild cardiomyopathy, measurable but modest, without the hallmarks of aggressive disease. The males told a darker story: their hearts developed myocardial and perivascular fibrosis, the deposition of collagen scar tissue within the muscle itself and around the coronary vessels, along with the features of inflammatory dilated cardiomyopathy, abbreviated iDCM. In iDCM, immune-driven inflammation weakens and enlarges the heart chambers, impairing the pump’s ability to fill and eject blood. Consistent with this inflammatory phenotype, the male hearts showed elevated levels of interleukin-1β, a potent pro-inflammatory cytokine, together with adverse cardiac remodeling. The authors highlight this contrast as one of the study’s key findings: males developed worse cardiomyopathy than females, with elevated IL-1β, cardiac remodeling and inflammatory dilated cardiomyopathy, while females upregulated Pgc1α, which may have improved their heart function.

The implications for human medicine are potentially significant, though the authors are careful to frame them as a starting point rather than a conclusion. Radiation-induced heart disease is a leading cause of non-cancer mortality among long-term survivors of breast cancer and Hodgkin lymphoma, and cardiologists currently manage these patients with the same toolkit used for other forms of heart failure. If the biological mechanisms underlying RIHD differ between men and women, as this mouse study strongly suggests, then prevention strategies, monitoring protocols and even drug choices might eventually need to be tailored by sex. A therapy that bolsters mitochondrial repair, for instance, might conceptually benefit patients whose hearts fail to mount a Pgc1α response, a pattern the data associate with the more severe male phenotype. The elevated IL-1β in males likewise points toward inflammation as a sex-biased therapeutic target, an avenue already being explored in other inflammatory cardiovascular conditions.

The study also carries a methodological message for the research community. Preclinical cardiovascular research has historically leaned heavily on male animals, a practice that regulatory agencies and scientific funders have spent the past decade working to reverse. Had the Mayo Clinic team studied only one sex, they would have produced an incomplete and potentially misleading picture of radiation heart disease: a male-only study would have overstated the severity of RIHD, while a female-only study would have understated it. By running both sexes in parallel with sham controls, identical dosimetry and multi-omics readouts spanning histology, cytokine measurement, echocardiography and transcriptomics, the investigators captured the full divergence of the two phenotypes.

Much remains to be learned. The authors themselves emphasize that further research is needed to better understand the mechanisms driving sex differences in RIHD using translational animal models, and the 35-day window, while sufficient to reveal chronic fibrosis and iDCM in this sensitive strain, is brief compared with the years over which human RIHD unfolds. Hormonal influences, immune cell composition, X-chromosome-linked gene dosage and differences in DNA damage repair capacity are all plausible contributors that the current study raises but does not resolve. What the work delivers, convincingly, is proof of principle: the heart’s response to radiation is not sex-neutral. For the growing population of cancer survivors living with irradiated hearts, that recognition may prove to be the first step toward care that accounts for the biology of the patient as fully as it accounts for the physics of the beam.

Subject of Research: Sex differences in the cardiac response to radiation in a mouse model of radiation-induced heart disease

Article Title: Sex differences in a mouse model of radiation-induced cardiomyopathy

Article References: Whelan, E. R., Perona, E. E., Fliess, J. J., Kocsis, S. C., Weigel, G. J., McCabe, E. J., Hamilton, C., Di Florio, D. N., Balamurugan, V., Beetler, D. J., Macomb, L. P., Strandes, M. W., Wilson, F. C., Murphy, E. F., Darakjian, A. A., Watkins, M. M., Puls, A. M., Hartmoyer, C. J., Bonvie-Hill, N., … Fairweather, D. (2026). Sex differences in a mouse model of radiation-induced cardiomyopathy. Biology of Sex Differences. https://doi.org/10.1186/s13293-026-00998-3

Image Credits: AI Generated

DOI: 10.1186/s13293-026-00998-3

Keywords: radiation-induced heart disease, sex differences, cardiomyopathy, mitochondrial dysfunction, Pgc1α, fibrosis, inflammation, DNA damage, vascular remodeling, interleukin-1β, BALB/c mice, radiotherapy