Inflammation, C-Reactive Protein, and Atherothrombosis
Paul M Ridker* and Josh D Silvertown
(People with untreated periodontal disease are at a 14 –59% greater risk to develop cardiovascular disease.)
*Department of Medicine, Harvard Medical School, Boston, MA.†Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Boston, MA.
‡Axon Medical Communications Group, Toronto, ON.
Correspondence: Dr. Paul Ridker, Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, 900 Commonwealth Ave. E., Boston, MA 02215.
Atherothrombosis of the coronary and cerebral vessels is understood to be a disorder of inflammation and innate immunity, as well as a disorder of lipid accumulation. From a vascular biology perspective, the processes of cellular adhesion, monocyte and macrophage attachment, and transmigration of immune cells across the endothelium are crucial steps in early atherogenesis and in the later stages of mature plaque rupture , particularly the transition of unstable plaque at the time of acute thrombosis. There is abundant clinical evidence demonstrating that many biomarkers of inflammation are elevated years in advance of first ever myocardial infarction (MI) or thrombotic stroke and that these same biomarkers are highly predictive of recurrent MI, recurrent stroke, diabetes, and cardiovascular death. In daily practice, the inflammatory biomarker in widest use is high-sensitivity C-reactive protein (hsCRP); when interpreted within the context of usual risk factors, levels of hsCRP <1, 1 to 3, and >3 mg/l denote lower, average, and higher relative risk for future vascular events. Risk-prediction models that incorporate hsCRP, such as the Reynolds Risk Score, have been developed that improve risk classification and the accuracy for global risk prediction, particularly for those deemed at “intermediate risk” by usual algorithms, such as the Framingham Risk Score. With regard to cerebral vessels, increased biomarkers of inflammation, including hsCRP, have been associated with increased stroke risk as well as an increased rate of atherosclerosis progression in the carotid vessels. Although the proportion of variation in hsCRP explained by genetic factors may be as large as 20% to 40%, diet, exercise, and smoking cessation remain critical tools for risk reduction and CRP reduction. Statin therapy reduces hsCRP in a largely low-density lipoprotein (LDL)-independent manner, and the “anti-inflammatory” properties of these agents have been suggested as a pote ntial mechanism beyond LDL reduction for the efficacy of these agents. The ongoing multinational Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial of 17,802 initially healthy men and women with low levels of LDL cholesterol but increased levels of hsCRP will help to define whether vascular protection can be achieved with statin therapy, even in the absence of hyperlipidemia. Targeted anti-inflammatory therapies are being developed that may provide a direct method of translating the biology of inflammation into new clinical treatments across multiple vascular beds. This article summarizes data supporting a role for inflammation in cardiovascular disease and offers the possibility that other disorders characterized by inflammation, such as periodontal disease, may have an indirect role by influencing the risk, manifestation, and progression of vascular events.
Evidence supporting a link between periodontal disease (PD) and cardiovascular disease (CVD) is accumulating in the literature. Data derived from a meta-analysis of five prospective cohort studies, five case-control studies, and five cross-sectional studies suggested a positive correlation between PD and coronary heart disease (CHD). After adjusting for risk factors, such as sm oking, diabetes, alcohol intake, obesity, and blood pressure, subjects with PD had a 1.14- to 1.59-fold greater risk for developing CHD compared to those without PD. Although the mechanism underlying this association is not clearly understood, it was reported that specific bacteria (Aggregatibacter actinomycetemcomitans [previously Actinobacillus actinomycetemcomitans] and Porphyromonas gingivalis) that colonize periodontal pockets are also present in human atherosclerotic plaques and can gain access to the circulation through oral tissue. These pathogens produce lipopolysaccharide, which, in turn, induces macrophages to secrete cytokines (interleukin [IL]-1α and -1β and tumor necrosis factor [TNF]) that play important roles in atherothrombogenesis.
Studies reported that elevated cell- and cytokine-mediated markers of inflammation, including C-reactive protein (CRP), fibrinogen, and various cytokines, are associated with PD. The same elevated proinflammatory factors in PD have also been linked with atherothrombogenesis. The connection between vascular events and PD is further supported by evidence showing that oral bacteria can cause platelet aggregation and thromboembolic events by upregulating the expression of platelet aggregation–associated protein.
Given that PD and CVD are correlated and potentially share similar hallmarks of inflammation, it is relevant to review available data supporting a role for inflammation in CVD. This article focuses on epidemiological data linking inflammation to atherothrombosis, highlighting recent advances in establishing new biomarkers and understanding the role of genetics in the inflammatory process, and suggests new pathways for treatment.
Journal of Periodontology
2008, Vol. 79, No. 8s, Pages 1544-1551
(doi:10.1902/jop.2008.080249)