Study suggests inflammatory protein is strongly associated with heart disease

Exercise-induced cardiac ischemia, or reduced blood flow to the heart, is associated with high levels of C-reactive protein (CRP)-a marker of inflammation-in people with coronary heart disease, according to a new study by researchers at the San Francisco VA Medical Center (SFVAMC). The finding adds to the evidence that inflammation is associated with cardiovascular disease.

“Patients with the highest levels of CRP were about four times more likely to be ischemic during our treadmill tests,” said Mary A. Whooley, MD, senior author of the study, physician in General Internal Medicine at the SFVAMC and assistant professor of medicine and epidemiology and biostatistics at UCSF.

Whooley and her colleagues discovered that the association between CRP levels and inducible ischemia was weakened in patients taking medications to treat their heart disease. The drugs appear to be protecting people with high CRP levels from inducible ischemia, the researchers said. “People on beta blockers and statins appeared to have less inflammation associated with their ischemia,” Whooley said.

The study will be published on the Internet December 16, 2002 by the journal Circulation (Circulation) in advance of its January 23, 2003 issue.

The study’s findings suggest an important relationship between inflammation and heart disease, said Mary S. Beattie, MD, first author of the study and UCSF assistant clinical professor of medicine. “Previously, no one had looked at how people go from having an elevated CRP to having a heart attack. Our study supports the idea that heart disease is more of a systemic disease rather than just a plumbing problem,” Beattie said, referring to the clogging of arteries characteristic of advanced heart disease.

Recent studies have indicated that, on a population level, high levels of CRP predict future heart attacks. Some researchers have suggested that levels of CRP are better than cholesterol levels at predicting future cardiac events.

But, until now, scientists did not know that inflammation on a given day was associated with ischemia, a precursor to heart disease.
According to the American Heart Association, up to 4 million Americans may have undetected ischemia and be at high risk of having a heart attack without warning. Myocardial ischemia is a condition in which heart tissue is starved for oxygen because of partial blockages in the arteries that feed the heart. As these blockages increase in size, or become more inflamed, the heart tissue becomes more and more starved for oxygen. Ischemia can lead to a heart attack when blood flow to a section of the heart becomes completely blocked, and the affected heart muscle dies.

The current study included 229 participants of the Heart and Soul Study, an ongoing prospective cohort study designed to determine how psychosocial factors influence disease progression in patients with coronary disease. The Heart and Soul Study began in September of 2000, and 425 participants were recruited from the San Francisco VA Medical Center, the VA Palo Alto Health Care System and the UCSF Medical Center, by October 2001.

Researchers measured CRP in frozen serum samples from 118 participants who had exercise-induced ischemia and 111 who did not. The remaining 196 participants had possible ischemia and were excluded from the analysis.

Seventy-five percent of those in the highest of five CRP categories had inducible ischemia, compared to 45 percent in the lower four categories combined. Excluding those taking beta blockers or statins increased the number who experienced exercise-induced ischemia to 93 percent of those with highest CRP levels.

The current study does not reveal whether inflammation causes heart disease or whether heart disease causes inflammation. Researchers conducting the Heart and Soul Study are collecting data they hope will resolve that question, Whooley said. “It’s hard to know whether ischemia or inflammation comes first. It may be that inflammation causes ischemia by increasing the degree of blockage in people’s coronary arteries, or it may be that ischemia causes inflammation by damaging the heart tissue. We will try to sort this out by following patients over time to determine whether CRP predicts future events independent of baseline ischemia,” Whooley said. Depending on future results, treating inflammation may take on a more prominent role in treating and preventing heart disease.

Additional authors included SFVAMC physician in General Internal Medicine and UCSF professor of medicine and epidemiology and biostatistics Michael G. Shlipak, MD, MPH; professor of medicine and epidemiology and biostatistics Warren S. Browner, MD, MPH; UCSF professor of medicine and Division of Cardiology Nelson B. Schiller, MD; SFVAMC physician in General Internal Medicine Haiying Liu, MD, MPH.

This research was funded by grants from the Department of Veterans Affairs, the American Federation for Aging Research, the Robert Wood Johnson Foundation and the Ischemia Research and Education Foundation. Whooley and Shlipak are supported by Research Career Development Awards from the Department of Veterans Affairs Health Services Research and Development Service.