ATLANTA-Now it’s cardiologists invoking Koch’s postulates.
Fourteen years after gastroenterologists began to suspect Helicobacter pylori as the cause of ulcers and other GI ailments, the cardiovascular world is seeking an infectious link in the atherosclerosis chain. There are already two suspects: Chlamydia pneumoniae and herpesviruses, especially cytomegalovirus. But many other germs are also under scrutiny, even H. pylori itself.
Dr. Barry Marshall of the University of Virginia, then an obscure researcher in Australia, fulfilled Koch’s postulates in 1984 when he caused his own gastritis by swallowing a vial of H. pylori and curing the infection with antibiotics. Yet an MI is a different kettle of fish.
“I’ve yet to meet someone willing to be infected with C. pneumoniae and see whether a heart attack follows,” Dr. J. Brent Muhlestein of LDS Hospital in Salt Lake City told the American College of Cardiology meeting here. But he and others are piling up seroepidemiological data, developing animal models, and even staging intervention trials to try to sort out clues that could help explain why so many people with none of the usual risk factors still die.
The infection quest began with a series of studies linking high antibody titers to both organisms and increased risk of atherosclerosis and restenosis after coronary intervention. CMV has also been linked to accelerated arteriosclerosis after heart grafts.
Just this summer Johns Hopkins’ Dr. Michael Davidson reported that C. pneumoniae infection preceded arterial plaques in 56 Alaska natives who died of accidents but had left stored blood samples. His group identified the bacteria in coronary artery lesions of 22 of the Alaskans, and found those who had severe infection were nearly 10 times more likely to have C. pneumoniae in the lesions than those with little or no evidence of earlier infection.
Last year, pilot trials of macrolide antibiotics among coronary-disease patients with high C. pneumoniae antibody titers in England and Argentina showed a reduction in recurrent coronary events.
And at the University of Utah, Dr. Jeffrey Anderson is shepherding 300 patients with known coronary disease through the first U.S. clinical trial of a macrolide, a study prompted by increasing recognition that both local and systemic inflammation, perhaps from infection, has a role in the pathophysiology of atherosclerosis.
At Brigham and Women’s Hospital in Boston, Dr. Paul Ridker says high-normal levels of C-reactive protein predicted coronary events in angina patients and even in healthy men and women. Men with the highest initial CRP levels in the Physicians’ Health Study, says Dr. Ridker, had a threefold higher risk for a first MI eight to 10 years after entry. This summer he cited a fivefold rise in the risk of any cardiovascular disease and a sevenfold rise in the risk of an MI or stroke among those with high CRP levels in the Women’s Health Study. For peripheral vascular disease, he saw almost a dose-response effect.
The physicians’ study also showed that low-dose aspirin reduced the MI risk by about 44% from controls’. But the risk was 55% lower than that of placebo-treated men among those with higher CRP levels, suggesting an anti-inflammatory effect.
Lipid-lowering statins may have the same effect, the group showed in another study.
Dr. Peter Libby’s group, also at Brigham and Women’s, has found that IV endotoxin given to rabbits produces a big local jump in cytokines in atheromas, suggesting spurts of arterial plaque growth. Such infectious nudges may mean the difference between an insignificant mural thrombus and an occlusive one, he speculates.
Dr. Stephen Epstein’s group at NIH found greater neointimal response to balloon injury among rats injected with CMV and greater migration of smooth muscle cells from the adventitia to the neointima. He also found when circulating monocytes harboring latent CMV enter the subintimal space, vessel wall constituents activate the virus bringing upregulation of scavenger receptors and an increased internalization of oxidized LDL. This may lead to foam cells.
Others have found a procoagulant effect, increased leukocyte adhesion, and decreased fibrinolytic activity associated with HSV infection, and inflammatory changes probably modulated by immune response. In patients with suspected coronary disease, says Dr. Epstein, a humoral immune response to CMV seems to convey susceptibility to coronary artery disease, but a cellular response conveys resistance.
Dr. Davidson’s group also found C. pneumoniae associated with foam cells in more than three-fourths of the Alaskan plaque specimens. Dr. Muhlestein’s team set the stage for clinical trials with studies of cholesterol-fed infected rabbits. After seven weeks, there was significantly more intimal hyperplasia in animals not given macrolide antibiotics than in those that were.
But early results with 300 coronary-disease patients randomized to macrolides or placebo in Dr. Anderson’s two-year study were disappointing. At three months, levels of four markers of inflammation didn’t differ between the groups, he reported here. And in the early analysis, treated and untreated groups shared 16 cardiovascular events evenly.
By six months, though, there were significant changes in CRP and IL-6 levels among treated patients, a trend in IL-1 levels, and no difference in TNF levels. -Judy Ismach
ATLANTA-Now it’s cardiologists invoking Koch’s postulates.
Fourteen years after gastroenterologists began to suspect Helicobacter pylori as the cause of ulcers and other GI ailments, the cardiovascular world is seeking an infectious link in the atherosclerosis chain. There are already two suspects: Chlamydia pneumoniae and herpesviruses, especially cytomegalovirus. But many other germs are also under scrutiny, even H. pylori itself.
