Immune function, inflammation, and cardiovascular disease

Inflammation can exacerbate risks for cardiovascular disease — and is informing new approaches for treatment

Like a fire alarm sending signals to evacuate a smoky building, the immune system has internal guards to help the body sense and respond to danger. However, for people with risks for heart disease, these warning signals can have a negative consequence: they can increase the size of plaque in arteries, making them narrow, and trigger inflammatory events that can cause plaque to rupture. This can set the stage for a heart attack or stroke.

Researchers have long known about the connection between inflammation and the buildup of plaque in arteries, called atherosclerosis. However, what they’re learning now is driving research about ways to more precisely offset risks for cardiovascular disease.

Here is what investigators know and what they are studying:

Lower levels of chronic inflammation are better for preventing cardiovascular disease

Inflammation has a synergistic role in interacting with lipids, or fat in the bloodstream, to exacerbate cardiovascular disease risks, explained Peter Libby, M.D., a cardiovascular medicine specialist at Brigham and Women’s Hospital and the Mallinckrodt Professor of Medicine at Harvard Medical School. “The inflammatory process is orchestrating everything from the very beginning of atherosclerosis up to its progression and complications,” he said. This can trigger severe blood clots and cause plaque to rupture. This helps explain why lower levels of inflammation and low-density lipoprotein (LDL) cholesterol, a common lipid, are often better.

Through ongoing research, Libby and other investigators are studying the mechanisms that can lead to these complications in addition to how to detect elevated levels of inflammation and lipids at earlier stages. By measuring these levels, physicians can help patients take steps to lower them if they become elevated, he explained.

Statins are often a go-to therapy for reducing LDL cholesterol as well as inflammation. They have been shown to curb cardiovascular disease risks in some people by about 20-30%.

If a person still has elevated levels of inflammation after taking a daily statin, a physician may prescribe a different lipid-lowering therapy or provide a separate anti-inflammatory medication.

Colchicine, used to treat gout, is one option. It was approved by the Food and Drug Administration in 2023 to reduce inflammation in people with atherosclerosis or who have underlying risks. It has also been shown to have a similar effect as statins (when taken with a lipid-lowering therapy) in offsetting risks for cardiovascular events.

Today, researchers are studying how colchicine could be used alone or with other therapies to help people recover from a heart attack or stroke. They are also testing new therapeutic approaches by targeting different pathways of inflammation.

When it comes to testing anti-inflammatory therapies, finding the right balance is essential

Through ongoing studies to develop safe and effective therapies, investigators have also discovered that it’s critical to find the right inflammatory target and balance.

“The immune system is complex,” said Ahmed A.K. Hasan, M.D., Ph.D., a medical officer and program director at NHLBI. “Manipulating one part of it could have unknown and/or unintended consequences.” Lowering inflammation too much could alter the body’s immune response and leave some patients vulnerable to increased risks for infection, such as sepsis or pneumonia. “We need to develop targeted anti-inflammatory drugs and have multiple therapeutic approaches to impact different pathways,” Hasan explained.

The ability to study molecular features of immune cells and the expression of genes is helping researchers fine-tune this process. Researchers can now study patterns of immune cells and inflammatory signatures in certain conditions, which can help identify new targets for treatment. The insight researchers are gaining is also helping them understand why some patients respond better than others to certain therapies.

Research about how to inhibit or reduce inflammation in people with clonal hematopoiesis of indeterminate potential (CHIP) is one example.

CHIP is a result of leukemia-like mutations in blood-forming cells that can occur later in life and affects about 1 in 10 adults ages 70 and older. CHIP is linked to increased risks for blood cancer, but certain mutations, including TET2, are also linked to increased risks for atherosclerosis and heart failure. Researchers are studying if targeting different inflammatory pathways among people with TET2 mutations could offset these risks.

At the New York University Grossman School of Medicine, Chiara Giannarelli, M.D., Ph.D., is also looking at inflammatory pathways, but with a different focus. Giannarelli, the principal investigator at the Giannarelli Lab and an associate professor of cardiology and pathology, has found that targeting genetic signatures of inflammation in immune cells, as opposed to single immune targets, could reduce plaque size.

As part of this research, Giannarelli found that an experimental therapy previously studied for cancer and Alzheimer’s disease reduced the size of atherosclerotic plaques in animal models and reduced inflammation in human plaque tissue in a dish. These findings may inform future drug targets and studies for atherosclerosis, she said.

Anti-inflammatory targets may have broad applications

“Cardiovascular disease and inflammation don’t exist in a vacuum,” said Giannarelli. “Patients often have comorbidities and having cardiovascular disease can influence the onset of other conditions and vice versa.”

She noted the immune system is involved in nearly every facet of disease. Through studying intersections with cardiovascular disease, researchers have advanced insight about potential ways to prevent or treat other conditions, such as joint pain, among people with systemic chronic inflammatory conditions.

Cardiology researchers are also borrowing lessons from other fields, including cancer research. The same concepts for using therapeutic targets to shrink cancer tumors and prevent cancerous cells from metastasizing may inform strategies for reducing inflammation in atherosclerotic plaque and in preventing stable plaque from rupturing.

“We see the same basic mechanisms that are rather monotonous play out in many diseases,” said Libby. “Inflammation is the common theme from the beginning to the end of atherosclerosis and across many conditions.”

The researchers agreed that ongoing advancements in technology and science, and increased shared knowledge across fields, will only help improve risk predictions for and identify new ways to prevent and manage cardiovascular disease.