High-sensitivity C-reactive protein (hsCRP) was first discovered in 1930, but its link to CHD was reported more than 60 years later. hsCRP is an acute-phase reactant mainly produced in hepatocytes in response to several cytokines, including IL-6 released from activated leukocytes in response to infection or trauma and from vascular SMCs during atherosclerosis lesion evolution. The role of CRP in atherosclerotic plaque formation is complex, acting in many cells involved in the process (Fig. 1.2) [27]. Although previous reports suggested a role of CRP as a surrogate of the underlying inflammatory process of atherothrombosis, accumulating evidence from in vitro and in vivo studies in clinical and experimental models robustly indicate a role of CRP as a proatherogenic factor [27–30].

In brief, CRP induces endothelial cell activation and dysfunction by several distinct activities, including directly binding with highly atherogenic oxidized LDL-C (oxLDL); increasing adhesion molecules (VCAM-1, ICAM-1, E-selectin, MCP-1); decreasing eNOS, prostacyclin, and tPA; impairing endothelial progenitor cell (EPC) number and function; and increasing pro-inflammatory cytokines and other important mediators of endothelial lesion (such as PAI-1, IL-8, CD40/CD40L, MMP-1, and ET-1) underlying atherosclerosis; in addition, it facilitates monocyte adhesion and transmigration into the vessel wall, a critical early step in the atherosclerotic process, and promotes other important modifications on monocytes (increasing tissue factor, superoxide, and myeloperoxidase contents, decreasing IL-10 amounts, promoting oxLDL uptake, decreasing cholesterol efflux, and enhancing macrophage colony-stimulating factor [M-CSF] levels and proliferation); CRP also catalyzes macrophage polarization, which is a pro-inflammatory trigger in plaque deposition, leading to macrophage infiltration of both adipose tissue and atherosclerotic lesions [27–30].

Several lines of evidence have indicated that inflammation plays a central role in all stages of the atherothrombotic process. In clinical terms, translation of the atherosclerosis inflammatory hypothesis to practice has been based on observational evidence linking inflammatory biomarkers to the risk of future vascular events, namely, using hsCRP [31–33]. In fact, large-scale prospective studies demonstrate that CRP strongly and independently predicts adverse CV events, including MI, ischemic stroke, and sudden cardiac death [14, 33, 34]. The inclusion of CRP to classical cholesterol screening improves CV risk prediction independently of LDL-C, suggesting that increased CRP may identify asymptomatic individuals at high risk for future events, despite average cholesterol concentrations [33]. Furthermore, CRP concentration monitoring adds relevant prognostic information on CV risk at all LDL-C concentrations, but also at all levels of the FRS [33, 34]. As shown in the meta-analysis of Kaptoge et al., the magnitude of CV risk associated with a one-standard-deviation increase in hsCRP levels is at least as large as that associated with a one-standard-deviation increase in either total cholesterol or blood pressure [35]. Additionally, increased plasma CRP concentrations correlate with the components of MetS, such as central obesity, increased plasma triglyceride concentrations, low plasma concentrations of HDL-C, hypertension, and increased concentrations of blood glucose [33], and CRP contributes to risk prediction of MetS patients [36]. This evidence led to the development of the Reynolds Risk Score, which adds CRP to the FRS and improves global CV risk prediction in women by reclassifying >50 % of women considered at intermediate risk into higher- or lower-risk categories [37].

CRP was classified as an independent marker of CV risk by an expert panel assembled by the CDC and the AHA, as a way to improve risk stratification in populations’ primary prevention [38]. The panel recommended that global risk prediction in asymptomatic individuals deemed at intermediate risk for CVD by classical risk factors should include CRP measurement and the cutoff points of <1 mg/L for low-risk and >3 mg/L for high-risk individuals.

Further than being used as an adjunctive tool in risk prediction and reclassification, there is interest in using hsCRP levels to select patients for statin initiation and to tailor intensity of therapy. Statins reduce hsCRP in an LDL-independent manner, and the benefits are superior in patients with inflammation [39]; the lower the hsCRP levels, the lower the risk [40, 41]. These evidences raised the question of whether patients that do not meet criteria for statin prescription (given the low/average LDL-C concentrations) would benefit from that medication if they had hsCRP > 2 mg/L, indicative of an enhanced inflammatory response, thus suggesting that statins could have a dual influence: reduction of LDL-C levels and direct anti-inflammatory effects. These questions/hypotheses were the basis for the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) [42], which enrolled 17,802 men and women with no evidence of CV disease and average or low LDL-C contents, for testing the putative benefit of rosuvastatin (20 mg po daily) treatment. JUPITER trial showed a major reduction in CV events (54 % in MI and 51 % in ischemic stroke) and in all-cause mortality (20 %), as well as in need for bypass surgery or angioplasty (46 %), with an overall 44 % relative risk reduction for the primary endpoint of major arterial vascular events. Results were identical between several subpopulations in all ethnic groups, including women vs. men, elderly, as well as with and without arterial hypertension, obesity, or MetS [42–44]. As recently commended [45], JUPITER trial also showed that there was a significant reduction in venous thromboembolism (43 %), and the maximum levels of risk reduction were found in those who achieved low hsCRP levels. Magnitude of hsCRP reduction could not be predicted on the basis of the magnitude of LDL-C reduction, and the reduction of absolute risk of events for both the rosuvastatin-treated and placebo-treated (control) groups was greater among those with higher levels of CRP at study entry, an effect not observed for LDL-C. Genetic determinants of rosuvastatin-induced LDL-C reduction were found to differ from the genetic determinants of rosuvastatin-induced CRP reduction, altogether suggesting that at least part of the benefits of statin therapy were due to anti-inflammatory effects independent of LDL-C reduction. All those strong evidences coming from JUPITER trial, including the smaller number needed to treat (NNT) found for subjects with low LDL-C levels and elevated hsCRP concentrations (when compared with primary prevention patients under treatment of dyslipidemia or arterial hypertension) [46], had impacted the spectrum of patients candidate for statin therapy according to the FDA, as well as to other several national authorities, now including patients with elevated hsCRP levels and at least one additional risk factor, independently of high or average LDL-C levels.

Despite several strong indications coming from that trial, highlighting a statin benefit that goes beyond the effect on LDL-C reduction, additional studies were recommended to clearly test the hypothesis that directly targeting inflammation will improve vascular outcomes. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) and the Cardiovascular Inflammation Reduction Trial (CIRT) have recently started and will evaluate, respectively, a human monoclonal antibody that targets human interleukin-1β (IL-1β) and low-dose methotrexate, in order to reduce cardiovascular event rates, due to direct anti-inflammatory effects [47, 48]. The results of these trials are expected with great curiosity, as they could be essential to define new algorithms to improve CV risk prediction and to gather information that could serve as basis to define new drugs targeting the machinery of inflammation.