The Inflammatory Hypothesis: Any Progress in Risk Stratification and Therapeutic Targets?

About a decade ago, the prevailing wisdom was that conventional risk factors explained only about half of the risk for a myocardial infarction or stroke. However, most studies did not assess some of the newer lipid markers (such as the apolipoproteins) or measures of abdominal obesity, diet, or psychosocial factors and moreover did not try to quantify the population-attributable risk. Consequently, efforts to identify novel risk factors were undertaken to improve cardiovascular risk prediction. Article p 1591 The hypothesis that inflammation is a central contributor to atherothrombosis has stimulated sustained efforts to characterize the specific molecules and pathways that may be involved and to identify biomarkers in humans that enable detection of underlying inflammatory activation to improve cardiovascular risk prediction. Ridker and coworkers1 reported that systemic low-grade inflammation assessed by measurements of the acute-phase reactant C-reactive protein (CRP) is associated with future cardiovascular events in apparently healthy individuals. This intriguing concept stimulated intense interest in further investigating the ability of inflammatory markers to add information for cardiovascular risk stratification beyond that obtained from traditional risk factors. The value of CRP for cardiovascular risk prediction has been assessed in 3 different clinical settings: apparently healthy individuals, stable patients at risk for cardiovascular events or with documented coronary heart disease, and patients presenting with acute coronary syndromes. The utility of CRP for risk stratification has been proposed mainly in healthy individuals. Several large, prospective cohort studies have consistently reported that higher levels of CRP are associated with an increased risk for cardiovascular disease (CVD). Whereas earlier work reported a relative risk of 2.3 in the upper quintile of CRP versus the lowest, using a multivariable model including age, smoking status, diabetes, hypertension, and LDL cholesterol,1,2 recent observational studies typically report much more modest relative risks of 1.3 to 1.7.3–7 …