Heart Disease

Edited by: Eugene Russo P.M. Ridker, M. Cushman, M.J. Stampfer, R.P. Tracy, C.H. Hennekens, "Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men," New England Journal of Medicine, 336:973-9, April 3, 1997. (Cited in more than 250 papers since publication) Comments by Paul M. Ridker, associate professor of medicine, Brigham and Women's Hospital, Boston Physicians typically check patients for signs of cardiovascular disease, or atherosclerosis, by measuring cholesterol levels and taking blood pressure. But research of the last couple of years suggests that doctors might also do well to deduce susceptibility based on a patient's degree of vascular inflammation. This paper was the first major study to demonstrate the potential importance of assessing heart disease risk by measuring a patient's levels of high sensitivity C-reactive protein (hs-CRP), a marker of vascular inflammation. Although prior basic research had indicated that inflammation contributes to atherosclerosis onset--monocytes and macrophages, both inflammatory mediators, had been associated with atherosclerotic plaques--this study was the first clinical demonstration that inflammation played a major role. As such, it introduced a whole new approach to both the treatment and prevention of cardiovascular disease. As part of a large-scale prospective epidemiological study of 22,000 healthy middle-aged men, investigators measured hs-CRP levels in baseline blood samples. Subjects were then tracked into the future for their first-ever heart attacks and strokes. The results suggested that inflammation levels as predicted by hs-CRP could actually predict future cardiovascular events several years prior to the first incidence of heart attack. "That's important because it suggests ... an entirely new pathway for heart disease prediction and prevention," explains lead author Paul M. Ridker. Ridker's group also showed that inflammation was completely independent of the usual cardiovascular risk factors, things like high cholesterol, hypertension, and older age. In a subsequent 1998 study, researchers observed similar effects in women.1 "The general hypothesis that we favor is that atherosclerosis itself is in fact an inflammatory disease the same way that rheumatoid arthritis is an inflammatory disease," says Ridker. The 1997 project had additional implications. Because the research was done as part of the Physician's Health Study, a double-blind randomized trial of low-dose aspirin, Ridker and his colleagues were also able to ask whether aspirin might somehow modify the effect of inflammation on heart disease risk. When taken daily, aspirin is known to reduce heart attack incidence by about 44 percent--an ability typically attributed to its platelet inhibition properties. The study suggested that those individuals with the highest levels of hs-CRP benefited the most from taking aspirin. "Our data raised the possibility that aspirin protects against cardiovascular events due in part to this anti-inflammatory process," says Ridker. Follow-up work has focused on a number of issues including tracking the biochemical source of the heart disease-inducing inflammation. Researchers have hypothesized that it may be due in part to cytokines triggered by inflammatory mediators associated with the atherosclerotic plaque itself. They've shown that ICAM-1 (intercellular adhesion molecule 1) may be a critical mediator of inflammation in the pathogenesis of atherosclerosis.2 But, says Ridker, it's also possible that the inflammation is due to a nonvascular source--a chronic, exogenous, inflammatory stimulus such as an infectious agent. Since the 1997 study, however, Ridker's group has done a series of studies suggesting that, at least in the case of the men who took part in the original study, infectious agents, such as chlamydia or Helicobacter pylori, were not a factor in disease onset.3 "My own feeling is that the infectious part of this may be less likely," says Ridker. Ridker's team has also attempted to better understand the impact of lipid-lowering drugs on inflammation--specifically a family called the statins. They've recently shown that pravastatin actually drops hs-CRP levels, suggesting that lipid lowering drugs may, like aspirin, actually work through anti-inflammatory pathways.4,5 "[The 1997 paper] basically says we have a better way to predict heart disease risk ... that's the clinical message," comments Ridker. "The research message is that inflammation is fundamental to atherosclerotic progression. And the pharmacological message is [that] common preventive therapies may attenuate this process." P.M. Ridker et al., "Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women," Circulation, 98:731-33, 1998. P.M. Ridker et al., "Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men," Lancet, 351:88-92, 1998. P.M. Ridker et al., "Prospective study of Chlamydia pneumoniae IgG seropositivity and risks of future myocardial infarction," Circulation, 99:1161-64, March 9, 1999. P.M. Ridker et al., "Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels," Circulation, 98:839-44, 1998. P.M. Ridker et al., "Long-term effects of pravastatin on plasma concentration of C-reactive protein," Circulation, 100:230-5, July 20, 1999.

Heart Disease

The Scientist Staff

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