Cytokine Markers Could Be Potent Predictors of Heart Disease, Report Researchers at Wake Forest University Baptist Medical Center

October 20, 2003

Two hormone-like proteins that are markers for inflammation could become potent new predictors of future cardiovascular events in otherwise healthy, functioning, older adults, according to a study from Wake Forest University Baptist Medial Center and colleagues reported in this week’s on-line edition of Circulation.

These markers, called cytokines, could be especially useful because the reliability of traditional risk factors – such as smoking, hypertension and total cholesterol – tends to decrease with age, explained lead author Matteo Cesari, M.D., of Wake Forest’s Sticht Center on Aging.

The two cytokines – interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha, proteins associated with the immune system – are more potent indicators than C-reactive protein (CRP), an inflammatory marker previously shown to have predictive value for cardiovascular events.

“Perhaps with these measures we could increase the precision of a patient evaluation and go deeper in the evaluation of cardiovascular health to detect disease that has not yet been diagnosed,” said Cesari.

While IL-6 and TNF-alpha are promising candidates for further research, they are far more difficult and expensive to measure than CRP, and it might be some time before they can be put into diagnostic practice, said Marco Pahor, M.D., director of the Sticht Center and senior investigator of the study. “But for sure,” Pahor added, “cytokines will have a more important application in the future.”

Researchers studied 2,225 Medicare beneficiaries aged 70 to 79 who had no life-threatening illnesses or evidence of congestive heart failure, coronary heart disease, stroke or peripheral vascular disease at the start of the study period. Participants demonstrated no difficulty walking one-quarter mile, climbing 10 steps or performing basic activities of daily living. They lived in the areas either around Pittsburgh, Pa., or Memphis, Tenn., received telephone calls every six months and had clinical visits every year.

There were 340 cardiovascular “events” during the follow-up period—188 instances of coronary heart disease, 92 of congestive heart failure, and 60 cases of stroke.

Not surprisingly, the incidence of cardiovascular problems was significantly higher for patients who smoked, had diabetes, hypertension, chronic pulmonary obstruction, high body-mass indices, high levels of triglycerides and creatinine, and low levels of high-density lipid (HDL) cholesterol and albumin.

However, even among study participants without these traditional risk factors, it was elevated levels of all three inflammatory markers that researchers compared – interleukin-6, tumor necrosis factor-alpha and C-reactive protein – that proved the best predictor of coronary heart disease and congestive heart failure. A similar, but not statistically significant, result was found for predicting future stroke events.

“This finding opens up new avenues of exploration that could lead to better methods of identifying older adults who are at increased risk of developing cardiovascular disease," said co-author Tamara Harris, M.D., of the National Institute on Agings Laboratory of Epidemiology, Demography, and Biometry.

The research is part of a growing body of evidence underscoring the role of inflammation in the development of atherosclerosis. Throughout the body, inflammation is a typical response to injury. The inflammatory process, in turn, follows predictable stages triggered at least in part by IL-6 and TNF-alpha. “The inflammatory cascade begins with IL-6 and TNF-alpha; they’re at the beginning,” Cesari said. “They activate the release from the liver of CRP.”

The research is an ancillary study from the Health Aging and Body Composition study, a seven-year National Institutes of Health initiative. The ancillary study is based at Wake Forest under Pahor’s direction. In addition to Cesari and Pahor, co-authors of the article are from Wake Forest, the University of Pittsburgh, the University of California-San Francisco and the National Institute on Aging in Bethesda, Md. Cesari is a junior investigator supported by the Wake Forest University Claude D. Pepper Older Americans Independence Center.

The research is available today in the online edition of Circulation and will be published later in the journal’s print edition.


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