Inflammation and autoimmune-like dysfunction may play a role in heart failure

HERSHEY, Pa. — When the heart’s muscle is weakened or injured due to a heart attack, it can make it hard for the heart to pump enough blood to meet the body’s needs. Over time, it can lead to heart failure, where the heart’s function drops below 40%. The condition affects an estimated 6.7 million people over the age of 20 in the United State, according the Centers for Disease Control and Prevention. Approximately 50% of patients with heart failure die within five years of developing the condition, and there’s no cure to stop this disease from progressing.

“For the last 25 to 35 years, we’ve used the same medications for heart failure, but none of the current medicines alter disease progression. The reason for that is we really don’t understand the underlying mechanisms that leads to this progressive cardiac dysfunction,” said Shyam Bansal, associate professor of medicine at Penn State College of Medicine and vice chair for basic science research at Penn State Heart and Vascular Institute.

Now, Bansal and a team of researchers from Penn State College of Medicine have revealed that the culprit may be the body’s own defense system doing more harm than good. Specifically, they found that a type of immune cell, called helper T cells, usually involved in healing wounds and fighting infections becomes overly activated in failing human hearts, causing damage. The researchers explained that this activation of T cells — the first time it’s been seen in human hearts — highlights the impact of inflammation and immune dysfunction in heart failure and reveals potential therapeutic targets that could be used to design new drugs to treat heart failure. The team published their work in the Journal of Molecular and Cellular Cardiology.

“We’ve never appreciated the role of helper T cells when it comes to heart failure,” said Bansal, senior author on the paper. “This research points to helper T cells as being a key player in mediating disease pathology and opens new avenues for blunting progressive cardiac dysfunction during heart failure by targeting inflammation and dysfunctional T-cells.”

Typically, T cells are found circulating in the blood, in the lymph nodes or in the spleen. When there’s an infection or injury, they mobilize alongside other immune cells to start the healing process. Bansal said he wanted to know, if T cells can help repair a cut on the skin, why can’t they fix injured heart tissue that eventually leads to heart failure?

That question became the basis of Bansal’s research. In previous studies in a mouse model of heart failure, he and his colleagues found that while helper T cells are protective immediately following a heart attack, something happens to these cells during the chronic heart failure stage, leading them to damage the heart instead of healing it, Bansal explained.

With this study, they wanted to see if helper T cells activated and acted similarly in humans. The researchers investigated the molecular and cellular activity of individual cells in tissue samples from healthy and failing human hearts, as well as from publicly available datasets.

The researchers found that T cells activated and proliferated more in human failing hearts compared to healthy human hearts, specifically in CD4+ helper T cells, which are typically involved in coordinating the body’s immune response to fight infections and heal wounds.

In particular, the CD4+ helper T cells exhibited higher levels of a specific type of cell signaling activity related to estrogen. When this signaling pathway is amplified, especially in helper T cells, it’s been shown to promote heart tissue scarring and inflammation that’s linked to decreased heart function, the researchers explained. In previous studies, Bansal and his colleagues found increased estrogen signaling activity of CD4+ helper T cells is involved in progressive cardiac dysfunction during heart failure.

While the researchers explained that they don’t yet know the specific role that CD4+ T cells play in heart failure, the findings provide a new direction and perspective on how to look at the condition. Their studies point to a new angle on heart failure, suggesting it might have an autoimmune component — something that has not been considered before, they said.

Bansal said they will continue to examine the role of inflammation as an underlying cause of heart failure. In future studies, they plan to investigate whether the identified pathways could be targeted by designing new therapeutic treatments to stop the activated autoimmune-like T cells and disease progression.

Other Penn State College of Medicine authors on the paper include first author Austin Angelotti, postdoctoral scholar with the Penn State Heart and Vascular Institute; Thiruvelselvan Ponnusamy, postdoctoral scholar with the Penn State Heart and Vascular Institute; Vinay Kumar, researcher; Gianna Passarelli, doctoral candidate; Jozef Malysz, associate professor of pathology and laboratory medicine; Balakrishnan Mahesh, associate professor of surgery; Behzad Soleimani, professor and John Anton and Marian Trescher Waldhausen chair of surgery and director of the Penn State Heart and Vascular Institute; and Elisa Bradley, associate professor of medicine.

Funding from the National Institutes of Health and the American Heart Association supported this work.

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