Science Advances: Proteins that may protect the heart in certain cancer treatment options

Anthracyclines are a class of chemotherapy drugs that are effective in treating a variety of cancers, including leukemia, lymphoma, and breast cancer
.
Anthracyclines — such as doxorubicin, commonly used to treat breast cancer — kill cancer cells
by damaging their DNA.
However, these effective chemotherapy treatments can also have toxic effects on the heart in about 10% of patients, eventually leading to heart failure, especially in older patients
with pre-existing cardiovascular disease.
Currently, doctors lack reliable strategies to predict which patients are at risk for this anthracycline-related heart damage — known as cardiotoxicity, where decreased heart function can lead to heart failure — or detect it
in its early stages.

Now, a team led by researchers at Beth Israel Deaconess Medical Center (BIDMC) has identified a protein
associated with anthracycline-associated cardiotoxic onset.
In two studies conducted on women undergoing breast cancer treatment, levels of a protein called hemagglutinin circulating in the blood were associated with
increased cardiotoxicity.
Follow-up studies in mice revealed that the protein has heart-protecting properties
.
The findings, published in Science Advances, suggest that the body's production of this protein is a protective measure against treatment-induced cardiotoxicity
.
If that's the case, clinicians may one day use the protein to monitor patients undergoing anthracycline cancer treatment, with a simple blood test to detect signs of
abnormal heart function.

"Given the increased burden of heart failure and cancer in the elderly population, the development of new biomarkers and cardioprotective strategies is critical to minimize the impact of cardiotoxicity associated with cancer treatment," said
Aarti Asnani, MD, Cardiologist and Senior Corresponding Author of the BIDMC Cardiac Oncology Program.
"This study establishes that induction of circulating hemagglutinin is a cardioprotective mechanism
associated with anthracycline therapy in patients.
"

Asnani and colleagues studied 30 women
who had been diagnosed with breast cancer and planned to receive anthracycline chemotherapy.
Before receiving the doxorubicin regimen, participants had blood tests and other data
collected at baseline.
During the study, questionnaires, blood samples, and echocardiography
were performed every three months.

Three months after starting cancer treatment, the scientists found an overall decline in heart function among participants across the cohort, and 6 patients developed heart failure symptoms
within a year.
During this time, the researchers monitored 1,317 proteins
circulating in the participants' plasma.
The team observed changes in a total of 39 proteins, of which an increase in hemagglutinin was most strongly associated
with early cardiotoxicity.
Another study involving 31 women came up with almost identical results
.

"Based on these human findings, we used a mouse model that closely mirrors the heart problems observed in patients treated with doxorubicin," said
first author Jing Liu, Ph.
D.
, a postdoctoral researcher in the Division of Cardiovascular Medicine at BIDMC.
"As we saw in patients, plasma hemagglutinin was elevated in mice within 24 hours of the end of chemotherapy and was strongly associated
with subsequent cardiac function.
"

After establishing a clear link between anthracycline-induced cardiotoxicity and elevated levels of hemagglutinins, scientists sought to determine the functional role
of hemagtinins.
When the researchers treated wild-type (normal) laboratory mice with doxorubicin, they found that giving hemagglutinin prevented the development of
heart dysfunction.
However, when they conducted similar experiments in transgenic mice lacking native hemagglutinin, hemagglutinin-deficient mice showed higher doxorubicin cardiotoxicity
compared to wild-type mice.
The findings suggest that the body may produce hemagglutinins as a protective response
to anthracycline-induced heart damage.

Asnani, who is also an associate member of the BIDMC Cancer Institute, said: "These findings provide the basis for future research to develop hemagglutinin as a biomarker and also a protective treatment
for patients at risk of chemotherapy-related cardiotoxicity.
" "We are now investigating whether our findings apply to a wider range of patients of different sexes and other types of cancer, such as lymphoma
.
"

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