Interleukin-6 may be best marker for heart disease, stroke in elderly

American Heart Association
Tuesday, 21 October 2003

The inflammatory marker interleukin-6 (IL-6) is a stronger predictor of heart attack or stroke in elderly people than C-reactive protein (CRP), according to research in today's rapid access issue of Circulation: Journal of the American Heart Association.

Elevated CRP, which is also an inflammatory marker, was recently recognized as a marker for cardiovascular events in healthy people. "But, most previous studies have examined CRP in a younger population and very few are comparisons between these markers," said lead author Matteo Cesari, M.D., from the Sticht Center on Aging of Wake Forest University School of Medicine in Winston Salem, N.C. "The link between CRP and heart disease may be weaker in older people."

A third inflammatory marker, tumor necrosis factor-á (TNF-á), is also a reliable predictor of cardiovascular events in the elderly, according to the new study.

The findings are especially important since previous research has indicated traditional cardiovascular risk factors (such as high total cholesterol and high blood pressure) carry less weight in an overall heart disease risk score as people age, Cesari said. In this study, compared to some traditional risk factors, IL-6 and TNF-á were more significant predictors of acute events.

IL-6 and TNF-á could serve as early warning signs since they increase early in the inflammatory process, whereas CRP increases fairly late in the inflammatory cascade, Cesari said.

While IL-6 and TNF-á are promising candidates for further research, they are 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 on Aging and senior investigator of the study. "But for sure," Pahor added, "they will have a more important application in the future."

"The American Heart Association recognizes the increasing evidence supporting the role of inflammation in the atherosclerotic disease process and considers inflammatory markers as potentially useful predictors of acute cardiovascular events," said Association spokesperson Sidney C. Smith, Jr., M.D., a professor of medicine at the University of North Carolina. "It is important to understand the additive role that these markers might play in conjunction with a global risk score derived from epidemiologic factors such as age, smoking history, blood pressure and lipid abnormalities rather than to view any new marker as being the only test necessary."

Cesari and his colleagues studied 2,225 people (1,233 women) aged 70 to 79 years without cardiovascular disease when enrolled in the Health, Aging and Body Composition (Health ABC) study. The study participants, recruited from April 1997 to June 1998, were followed for an average of three and a half years. Measures of IL-6, TNF- á and CRP were obtained from blood samples taken at baseline. All cardiovascular events and any hospitalization or death for cardiovascular disease were tracked during follow-up. In that time, there were 188 coronary heart disease events, 60 stroke events, and 92 congestive heart failure events.

Participants with high levels (highest tertile) of IL-6 had a 2 to 5-fold increase in acute coronary, stroke and congestive heart failure events compared to those with low IL-6 levels (lowest tertile).

High blood levels of TNF-á increased the risk for coronary disease by 79 percent and heart failure by 121 percent compared to the reference group.

High levels of CRP did not increase significantly the risk of first stroke or coronary events compared to low CRP concentrations, but high CRP levels were associated with a 160 percent increase in risk of developing congestive heart failure.

The incidence of cardiovascular events was significantly higher for participants who smoked, had diabetes, hypertension, chronic pulmonary obstruction, high body-mass indexes, 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, elevated levels of all three inflammatory markers – IL-6, TNF-á and CRP – proved the best predictors for coronary heart disease and congestive heart failure. A similar, but not statistically significant, result was found for predicting future stroke events.

"In addition, elevated IL-6 predicted events even in people who had no known cardiovascular disease risk factors. Perhaps with these measures we could increase the precision of patient evaluation, go deeper in the evaluation of cardiovascular health of the subject and detect disease that has not yet been diagnosed," Cesari said.

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 University under Pahor's direction. Cesari is a junior investigator supported by the Wake Forest University Claude D. Pepper Older Americans Independence Center.

Other co-authors are Brenda W.J.H. Penninx, Ph.D.; Anne B. Newman, M.D., MPH; Stephen B. Kritchevsky, Ph.D.; Barbara J. Nicklas, Ph.D.; Kim Sutton-Tyrrell, R.N., Dr.PH; Susan M. Rubin, MPH; Jingzhong Ding, Ph.D.; Eleanor M. Simonsick, Ph.D. and Tamara B. Harris, M.D., M.S.

For more information, or to contact American Heart Association, see their website at: www.americanheart.org