Taming the inflamed heart

Inflammation has long been implicated in cardiovascular disease, but only recently has it become a target that can be identified — and potentially treated — in individual patients. Cardiovascular disease remains the leading cause of mortality worldwide, leading to 900,000 deaths each year in the USA alone, and it is typically linked to high levels of ‘bad’ (low-density lipoprotein, LDL) cholesterol. Yet even people taking lipid-lowering drugs, such as statins, can still have severe plaque, heart attacks and strokes. Recent advances in coronary imaging now allow clinicians to detect inflammation in and around coronary arteries, providing direct evidence that immunological processes, rather than lipids alone, drive heart disease and heart attacks.

Researchers from the University of Oxford developed an artificial intelligence-enhanced form of coronary computed tomography angiography (CCTA), a procedure that doctors commonly use to investigate chest pain. “It’s really zooming in on inflammation,” says Eric Topol, a cardiologist and executive vice president of Scripps Research. Other imaging methods either are invasive or do not measure inflammation.

The Oxford researchers used the artificial intelligence-enhanced CCTA to show that people with inflamed arteries had a very high risk of subsequent heart attacks and other events. One inflamed artery increased mortality risk by 13-fold, and three inflamed arteries increased the risk by 30-fold.

For Topol, that study was the wake-up call that finally confirmed the importance of inflammation in cardiovascular disease. Armed with such compelling evidence, cardiologists are hopeful they can translate it into clinical practice to improve patients’ outcomes. “We need to make a dent in the need for bypass surgery and stenting, and heart attacks and heart failure,” says Topol. “And we have a path forward with [controlling] inflammation that’s very compelling.”

The missing marker

Cardiologists have known for 25 years that low-grade inflammation, measured by blood biomarkers, is a culprit in cardiovascular disease. “It’s not only about lipids. It’s a tight interaction with inflammation,” says Natalie Arnold, a preventative cardiologist at the University Medical Center Hamburg–Eppendorf in Germany. Despite this knowledge, “we treat lipids but leave the second part of this axis completely unaddressed,” she says.

Part of the problem is that clinicians treat what they can measure. First they measured cholesterol, specifically LDLs, so they treated lipids with statins. These lipid-lowering drugs do reduce heart attacks and strokes, but up to 50% of residual cardiovascular risk in patients being treated with statins may be due to inflammation. Ziad Mallat, a cardiologist at the University of Cambridge in the UK, agrees. “Many cardiovascular diseases have a very important inflammatory component that is currently not being treated,” he says. Now inflammation can be measured at the level needed to understand inflammatory pathways and their effect on cardiovascular disease.

Whereas clinicians have several drugs to control patients’ LDL cholesterol, the only drug that has been approved by the US Food and Drug Administration to reduce cardiovascular inflammation is colchicine (Lodoco), authorized in 2023. The drug has multiple anti-inflammatory mechanisms and has long been used to treat gout. But not all clinical trials have shown that colchicine reduces the risk of major adverse cardiovascular events (MACE), plus it can cause diarrhea, nausea, cramping and muscle pain, and the cardiology community has not embraced its use.

Now, other therapies that take aim at inflammation are on the horizon (Table 1). The most advanced of these is Novo Nordisk’s ziltivekimab, a monoclonal antibody directed against the inflammatory cytokine IL-6. The company expects phase 3 trial results later this year showing whether the drug reduces MACE in people at high risk of cardiovascular events and inflammation, defined as elevated levels of an inflammatory biomarker in the blood.

Dampening down cytokines

Cardiologists already know that cytokine blockers can reduce cardiac events. In 2017, the pivotal CANTOS trial showed that the IL-1β-targeting antibody canakinumab reduced the risk of MACE. Nevertheless, the reduction in MACE was modest, people treated with canakinumab had more fatal infections than did those who received placebo, and the drug ultimately was not approved for this indication.

Cytokines such as IL-6, IL-1β and IL-18 are all part of the inflammatory response to modified LDL cholesterol. When LDL cholesterol levels are high, cholesterol becomes trapped in the wall of the coronary arteries, where it is modified by oxidation and aggregation. Modified LDL triggers an immunological cascade in atherosclerosis: it recruits white blood cells called monocytes, which mature into macrophages that ingest cholesterol and accumulate in the artery wall, leading to coronary artery disease. This ongoing inflammation weakens the stability of a lipid plaque. If the plaque ruptures, clot‑forming material is suddenly released into the bloodstream, where it can rapidly block the artery and trigger a heart attack.

“This is a really active process in terms of the way the immune system is driving atherosclerotic cardiovascular disease,” says Brittany Weber, a cardio-immunologist at the University of Texas Southwestern Medical Center.

Current trials are testing anti-inflammatory therapies in two settings: chronic use in patients at high risk, to prevent recurrent cardiovascular events; and emergency use in patients being treated for hearts attacks — an approach used by Novo Nordisk in another phase 3 trial for ziltivekimab. Other companies going after IL-6 are Novartis and CSL Behring (Table 1). A drug that targets the IL-1β receptor, anakinra, is in a phase 2 trial in which anakinra is given to patients as soon as possible after an acute heart attack. The drug “blunts that acute inflammatory response; patients seem to do better, have less progression to heart failure,” says Antonio Abbate, a physician–researcher in cardio-immunology at the University of Virginia School of Medicine who is involved in the trial.

Evidence is mounting that IL-1β and IL-6 drive heart failure as well. Inflammation is a particularly strong driver in many patients with heart failure with preserved ejection fraction (HFpEF), causing scarring of the heart muscle and stiffness of the blood vessels that prevent the heart from filling properly. Trials of cytokine blockers such as ziltivekimab in HFpEF are “one of the most bold and very exciting [areas],” says Weber. Existing treatments for HFpEF provide modest benefits, and once-monthly injections of cytokine blockers could offer new hope.

In clinical practice, some cardiologists are already familiar with an IL-1 blocker used to treat recurrent pericarditis (inflammation of the heart’s lining). And as more clinicians become dual specialists in cardio-immunology or cardio-rheumatology, they can transfer their learning from other inflammatory disorders such as rheumatoid arthritis, for which drugs such as IL-6 inhibitors are prescribed for long-term treatment.

Abbate expects cytokine blockers to be largely safe from an infection-fighting standpoint, because they do not fully shut down the response to infection. But they can mask the inflammation that acts as a warning sign of infection. The current crop of cytokine blockers, such as ziltivekimab, will need to strike a balance between suppressing harmful inflammation and maintaining crucial immune system function.

Maintaining immune balance

Drug developers are also going after another inflammation target, the NLRP3 inflammasome, with at least five early-stage trials underway. Inhibiting activity of the NLRP3 inflammasome could have broad effects on inflammation, owing to its position “at the crossroad of different stimuli,” says Abbate.

The NLRP3 inflammasome is a multi-protein sensor that triggers production of IL-1β, IL-18 and IL-6 in response to danger signals, such as modified cholesterol, and it also promotes a form of cell death that further amplifies inflammation.