Triple negative breast cancer cell undergoing retraction and apoptosis
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Cardiac toxicity during anthracycline-based cancer treatment is linked to levels of the protein hemopexin, according to work led by researchers at Beth Israel Deaconess Medical Center (BIDMC). In two studies conducted in women undergoing treatment for breast cancer, blood hemopexin levels were associated with cardiac toxicity. Follow up studies in mice revealed the protein has heart-protective properties.

These findings, were published in Science Advances. They suggest clinicians might one day use a simple blood test to detect risk of heart damage by measuring hemopexin levels. There is great interest in finding biomarkers of toxicity in cancer treatment. Researchers at Michigan Medicine recently reported on new biomarkers for myocarditis related to checkpoint inhibitor therapy.

“Given the increasing burden of both heart failure and cancer in the aging population, the development of new biomarkers and heart-protective strategies is essential to minimizing the impact of cancer therapy-associated cardiac toxicity,” said senior and corresponding author Aarto Asnani, MD, a cardiologist and director of the Cardio-Oncology Program at BIDMC. “This study identifies the induction of circulating hemopexin as a heart-protective mechanism relevant to patients treated with anthracyclines.”

Anthracyclines are a class of chemotherapies used in treating many forms of cancer, including leukemias, lymphomas, and breast cancer. They include doxorubicin, frequently used against breast cancer, and kill cancer cells by damaging their DNA. However, they also cause toxic effects in the heart in about ten percent of patients, which can eventually lead to heart failure, particularly in older patients.

Currently, there are no effective ways to predict which patients are at risk for anthracycline-associated cardiac toxicity.

Asnani and colleagues studied 30 women diagnosed with breast cancer and scheduled to undergo treatment with anthracyclines. Questionnaires, blood samples and echocardiograms were obtained every three months during the study period.

At three months after initiating cancer treatment, the scientists saw an overall decline in heart function across the cohort of participants, with six patients developing symptoms of heart failure within a year. During this time, the researchers monitored 1,317 proteins circulating in participants’ blood plasma. The team observed changes in a total of 39 proteins, with increases in hemopexin being most strongly associated with early heart toxicity. A second study with a cohort of 31 women yielded nearly identical results.

“Based on these human findings, we used a mouse model that closely mirrored the heart issues observed in patients treated with doxorubicin,” said first author Jing Liu, MD, PhD, a post-doctoral researcher in the Division of Cardiovascular Medicine at BIDMC. “As we saw in patients, plasma hemopexin was elevated in mice within 24 hours after completion of chemotherapy and was strongly associated with subsequent cardiac function.”

Having established a clear link between anthracycline-induced cardiac toxicity and increased hemopexin levels, the scientists sought to determine hemopexin’s functional role.

When the researchers treated wild type lab mice with doxorubicin, administering hemopexin prevented the development of cardiac dysfunction. However, when the researchers performed a similar experiment in genetically altered mice that lack the naturally occurring hemopexin protein, those mice demonstrated increased doxorubicin cardiac toxicity compared to wild type mice, suggesting the body may produce hemopexin as a protective response to anthracycline-induced cardiac damage.

“These findings serve as the basis for future investigations to develop hemopexin as both a biomarker and a protective therapy for patients at risk of chemotherapy-related heart toxicity,” said Asnani. “We are now working to investigate whether our findings apply to a larger group of patients of different genders and other types of cancer, such as lymphoma.”

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