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Dallas, TX - A post-mortem study of patients who died suddenly with coronary artery disease (CAD) shows these patients had increased levels of C-reactive protein (CRP) - an inflammatory marker previously linked to CAD - not only in the serum, but within atherosclerotic plaques. The rise in CRP was also associated with higher numbers of plaques with thin or eroded fibrous caps, signaling their higher risk of rupture. The new report appears as a rapid access publication in Circulation online.1
"This is the first autopsy study to corroborate the association between mild elevations of serum hs-CRP and coronary atherosclerosis," the researchers, led by Dr Renu Virmani (Armed Forces Institute of Pathology, Washington, DC) write, and support the concept that inflammation is an important component of plaque instability.
"What is interesting is that CRP correlates with plaque burden and also with vulnerable plaques," Virmani told heartwirein an interview. "This is the first time it's been linked with sudden cardiac death, so that's interesting, I think."
Their findings add to the body of evidence that in Virmani's mind, justifies CRP testing as a routine preventive measure despite continued debate about its utility in the cardiovascular community. "These people were all dying suddenly, and we haven't made a dent in sudden cardiac death in 50 years," she says. As long as other inflammatory conditions can be ruled out, she feels a CRP above 3 g/mL should flag someone requiring more aggressive prevention measures, including statins and aspirin. "I feel that's it's worth doing it," she says of the CRP testing. "In fact, I get it done myself."
Direct measure of CRP in plaques
CRP is an acute-phase reactant, increasing about 1000-fold in response to infection, ischemia, trauma, burns, and inflammatory conditions. A large number of studies have suggested CRP is an independent risk factor for atherosclerotic vascular disease. Plasma CRP in the highest quartile is associated with up to a 7-fold increased risk of symptomatic disease, depending on the subject group, they note. Baseline CRP levels predict future MI and stroke risk, and high levels have been linked to poor prognosis in unstable angina.
In this study, Virmani et al compared serum CRP levels in patients with sudden death versus control patients, and correlated the serum CRP findings to immunohistochemical localization of CRP within plaques, and the number of plaques with thin caps considered vulnerable to rupture.
The researchers obtained post-mortem sera and hearts from 302 men and women who had died suddenly, but without a known inflammatory condition. Of these, 73 deaths were attributed to atherothrombi, 71 were sudden coronary deaths with stable plaque, and 158 were control cases, including those with unnatural sudden deaths, and natural noncardiac deaths without conditions known to elevate CRP. The deaths from atherothrombi were further classified into 55 with plaque rupture and 18 with plaque erosion. They reported that mean CRP levels were significantly elevated compared to controls in those with acute plaque rupture, plaque erosion, and even those with stable plaques.
CRP levels by plaque classification|
Classification |
Median CRP levels (g/mL) |
% of patients with CRP >3 g/mL |
p value (versus controls) |
|
Acute plaque rupture | 3.2 | 52.8% | 0.0001 |
|
Plaque erosion | 2.9 | 38.9% | 0.005 |
|
Stable plaque | 2.5 | 35.2% | 0.0003 |
|
Controls | 1.4 | 20.5% | - |
Multivariate analysis showed that atherthrombi, stable plaque, and plaque burden were all significantly associated with hs-CRP independent of age, sex, smoking status, or BMI, they write. They also found that mean staining intensity for CRP of macrophages and lipid core in plaques was significantly greater in cases with high CRP levels than those with low CRP (p=0.0001).
Further, those high-CRP patients also had greater mean numbers of "thin-cap" atheromas - 0.95 in the low-CRP group, compared to 3.0 in the high-CRP group of coronary deaths (p<0.0001).
Virmani et al note that although elevated levels of CRP "were greatest in hearts harboring acute rupture and erosion," they were "unable to demonstrate any significant increase or spike in serum hs-CRP with lethal acute coronary thrombosis compared to patients dying with stable plaque." Although this lack of association may be due to their relatively small sample size, they write, it may also be that this inflammatory mechanism is only part of the risk for developing fatal thrombosis, interacting with other traditional risk factors such as smoking or hypercholesterolemia.
"Although hs-CRP is strongly related to the presence of thin-cap atheromas, as the present study demonstrates, additional factors that may not be directly related to inflammation clearly play an important role in the subsequent development of occlusive fibrin platelet thrombi," the researchers write.
