Study of 60,000 U.S. adults links inflammatory protein to fatal heart attacks, other negative outcomes

BUFFALO, N.Y. — Despite advances in the management of hypertension, high cholesterol and diabetes — all risk factors for cardiovascular issues — heart disease remains a leading cause of morbidity worldwide.

Michael LaMonte, PhD, research professor in the University at Buffalo School of Public Health and Health Professions, recently contributed to a national study looking at one inflammatory protein in the blood of almost 60,000 adults, with the hope that the findings will contribute to a solution.

The study revealed that Interleukin 6 (IL-6), a protein the body produces when the immune system is activated, was associated with nine negative cardiovascular outcomes: heart attack, stroke, atrial fibrillation (irregular heartbeat), heart failure, coronary heart disease, cardiovascular disease overall, death from any cause, death from cardiovascular disease, and death specifically from coronary heart disease.

One of the most striking findings: Individuals with the highest levels of IL-6 in their blood had twice the chance of coronary-related death versus the ones with lower levels.

“IL-6 gets released into the bloodstream when tissue is injured,” says LaMonte, who teaches in the Department of Epidemiology and Environmental Health and specializes in healthy aging. “It attempts to fix what is broken by activating the immune system, but in the case of chronic disease, there is no fix.”

LaMonte, who conducted groundbreaking research in 2017 with UB’s Women’s Health Initiative, was asked in 2020 to be part of the cross cohort collaboration (CCC) led by a medical researcher at Johns Hopkins University Ciccarone Center for the Prevention of Cardiovascular Disease. Some of the participants included in the study were associated with the Women’s Health Initiative.

Several researchers in the medical and public health fields contributed to the CCC, and a paper detailing their research was published in the Journal of the America College of Cardiology in July.

“Our study posed this question: Does the level of IL-6 relate to a person’s risk for having a variety of clinical cardiovascular consequences?” LaMonte says. “And the answer was yes.”

Indeed, it showed that people with the higher IL-6 levels had a greater risk for all nine of the cardiovascular outcomes, and this association remained even after the researchers accounted for other cardiovascular risks such as hypertension, diabetes, kidney disease, age and weight.

“Finding that inflammation is related to heart disease is nothing new. We started seeing evidence of this in the mid-1990s,” LaMonte says. “What makes this probably the most authoritative epidemiological study to date is because you can reference IL-6 in relationship to not just one but several cardiovascular diseases. Nothing has been this big and comprehensive.”

Participants from 14 large studies with a mean age of 63 were followed over several years for occurrence of at least one of nine cardiovascular risks. They lived in all 50 states, 67.6% were women and more than 25% identified as a racial minority. The average body mass index was 28.1, half of the participants were current or former smokers, and almost half had hypertension.

The researchers divided people into four groups based on their IL-6 levels and studied how their health progressed across the nine cardiovascular outcomes.

“Subgroups, such as those with diabetes and severe obesity, have been particularly understudied in the past, despite these populations representing a growing segment of the adult population that also experiences a disproportionate amount of inflammation-related heart disease,” LaMonte adds.

When evaluating subgroups who presented with other diseases, the researchers noticed that people with kidney disease were particularly affected by the protein.

“Even for people whose disease had not progressed to the point where they needed dialysis, the connection between elevated IL-6 and heart failure and cardiovascular mortality was especially strong,” he notes. “This is a group of people who clinically might benefit from IL-6 blocking drugs.”

The CCC study comes at an auspicious time. Currently, three large-scale clinical trials are ongoing in the U.S. looking at drugs that would work as an IL-6 blocking agent.

“Our findings supports IL-6 as a key upstream inflammatory biomarker of cardiovascular risk and provide epidemiologic context for ongoing trials targeting IL-6 signaling for cardiovascular disease prevention,” LaMonte says.

With its high number of female subjects, this study ties in with LaMonte’s research on the cardiovascular health and longevity of older women.

“Most heart attacks in women occur after age 65 and certain types of heart failure (with preserved ejection fraction) occur more frequently in women than men,” LaMonte says. “Interestingly, IL-6 seems to be a strong predictor of heart failure with preserved ejection fraction. And a drug that blocks IL-6 might be especially relevant in preventing this form of heart failure in aging women.”

LaMonte predicts that effective treatments for IL-6 inflammation are not far off.

“We have to wait for the clinical trials to tell us whether targeting the IL-6 inflammatory pathway works or not,” he says. “But we already have previous randomized trials showing if you block a different inflammatory pathway, you do see a reduction in clinical event rates. We are eager to see if these potential treatments would be a eureka for the heart failure epidemic in this country.”

Other participating institutions in the CCC study include Baylor University; the Texas Heart Institute; the University of Texas School of Public Health, San Antonio; the University of Pennsylvania, Philadelphia; Brown University, Southwestern Medical Center, Dallas; the University of Illinois, Chicago; the University of Alabama, Birmingham; California Pacific Medical Center Research Institute, the University of Washington, Seattle; Welch Center for Prevention, Epidemiology and Clinical Research; the National Institute on Aging; California Pacific Medical Center Research Institute, San Francisco; and the University of Vermont.