Circulating levels of several inflammatory biomarkers have been studied to assess their value in predicting CVD. The best characterized and well standardized biomarker of inflammation is C-reactive protein (CRP). Numerous studies [12
] have now confirmed that CRP levels are elevated in patients with the MetS. Furthermore, it has been proposed that high sensitivity CRP (hsCRP) be added as a clinical criterion for MetS and for creation of an hsCRP-modified CHD risk score [12
Evidence supporting the hypothesis that elevated CRP levels contributes to increased cardiovascular risk is now available from at least six major prospective studies, these include the Physicians’ Health Study (PHS), Women’s Health Study (WHS), Atherosclerosis Risk in Communities (ARIC), Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) in the United States and Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) and Reykjavik studies from Europe [13
]. Additionally, with regards to MetS, Yudkin et al.
] in 107 nondiabetic patients conducted Z
-score analyses and found a very significant correlation between inflammatory markers and several features of the MetS. CRP levels were shown to be strongly associated with insulin resistance calculated from the homeostatic model assessment (HOMA) model, BP, low HDL, triglycerides, and to levels of the proinflammatory cytokines, IL-6 and tumor necrosis factor (TNF). BMI and insulin resistance were the strongest determinants of the inflammatory state. There is a linear relationship between the number of metabolic features and increasing levels of hsCRP. Furthermore, Festa et al.
] in the Insulin Resistance and Atherosclerosis Study (IRAS) showed that hsCRP was positively correlated with BMI, waist circumference, BP, triglycerides, cholesterol, LDL cholesterol, plasma glucose, and fasting insulin, and inversely correlated with HDL cholesterol and insulin sensitivity index. The strongest associations are observed between CRP levels, central adiposity, and insulin resistance. The largest study to date that examined the association between inflammation and the MetS was the NHANES III study [21
]. In a representative sample of the US population (8570 participants >20 years of age), patients with the MetS, defined using ATPIII criteria, were more likely than those without the syndrome to have elevated levels of markers of inflammation such as CRP, fibrinogen as well as leukocyte count. Thus, there appears to be a clear relationship between the numbers of metabolic features and increasing hsCRP levels. In addition, we have shown that CRP levels were equivalent to the ratio of high-molecular weight (HMW) adiponectin:CRP in predicting MetS using receiver operating characteristic (ROC) analyses [22•
]. Furthermore, Sugiura et al.
] have also reported that leptin (positively) and adiponectin (negatively) were independently associated with CRP. It is also worthwhile noting that adiponectin decreased CRP synthesis and secretion, whereas leptin increases CRP secretion. Thus, MetS is a proinflammatory state characterized by increased CRP levels.
Ridker et al.
] evaluated in a large-scale population cohort of the WHS, the potential interrelationships between CRP, the MetS, and incident cardiovascular events (CVEs). In the 8-year prospective follow-up of 14 719 women in the WHS, an hsCRP of more than 3 mg/l in patients with MetS predicted a greater age-adjusted relative risk (RR) for future CVE. Furthermore, they reported that at all levels of severity of the MetS, CRP added prognostic information with regard to subsequent risk of incident CVE and was additive to the Framingham risk score. Thus, it has been proposed that hsCRP be added as a clinical criterion for MetS and for creation of an hsCRP-modified CHD risk score [25
In the WOSCOPS, in which 6447 men were followed for 4.9 years, an hsCRP level of more than 3 mg/l predicted greater cardiovascular risk in patients with the MetS in a multivariate model [26
]. In the Framingham Offspring Study [13
], both CRP and MetS were independent predictors of new CVEs but were not additive. In an Italian study, patients with MetS and CRP of more than 3 mg/l had higher incidence of both carotid and CAD. Pischon et al.
] showed in the Nurses’ Health Study and Health Professionals Follow-up Study that although MetS was a strong predictor of CHD in both men and women, however, CRP was additive in men only. It should be emphasized that in this study, a modified definition of MetS was used, as waist circumference, BP, and glucose were not available at baseline. In a smaller Japanese Study [28
] of 461 patients with acute myocardial infarction (AMI), CRP levels were additive to MetS in predicting future major adverse cardiac events (MACEs). Furthermore, recent investigation relating increased CRP levels and MetS in 1044 older (≥65 years of age) individuals has also led to the conclusion that MetS is associated with low-grade systemic inflammation, and the association is mainly supported by a strong independent correlation between waist circumference and high hsCRP levels. Collectively, all these studies support the hypothesis that an increased CRP in the setting of MetS confers an increased risk of future CVEs.
Additionally, a genome-wide association study [24
] has been performed recently among 6345 apparently healthy women in which 336 108 single-nucleotide polymorphisms (SNPs) were evaluated as potential determinants of plasma CRP concentration. Overall, seven loci that associate with plasma CRP at levels achieving genome-wide statistical significance were found. Two of these loci [glucokinase hexokinase 4 regulator (GCKR) and hepatic nuclear factor 1 homeobox A (HNF1A)] are suspected or known to be associated with maturity-onset diabetes of the young, one is a gene-desert region on 12q23.2, and the remaining four loci are in or near the leptin receptor protein gene, the apolipoprotein E gene, the IL-6 receptor protein gene, or the CRP
gene itself. The protein products of six of these seven loci are directly involved in MetS, insulin resistance, β cell function, weight homeostasis, and/or premature atherothrombosis. Thus, it is concluded that a common variation in several genes involved in metabolic and inflammatory regulation have significant effects on CRP levels, consistent with CRP’s identification as a useful biomarker of risk for incident vascular disease and diabetes. All these findings have sparked increased discussion about the formal addition of hsCRP to the criteria of MetS. In addition to the prognostic information that hsCRP evaluation might add to the current definition of MetS, there are several other practical appeals of hsCRP measurement. First, hsCRP is strongly associated with components of MetS that are difficult to measure in routine clinical practice, such as impaired fibrinolysis and insulin resistance [19
]. Also, the widespread availability of commercial assays now for hsCRP has made its measurement simple and inexpensive. In addition, hsCRP does not display diurnal variation and demonstrates long-term stability comparable with cholesterol, and it can be reliably evaluated with a single nonfasting measurement [29
]. The addition of hsCRP measurement to our present diagnosis of the MetS may significantly improve the early detection of risk for future diabetes and CVE in individuals. Overall, it appears that in patients with MetS, an elevated CRP confers a greater risk for CVE by its action on vascular cells such as activation of monocytes and induction of endothelial cell dysfunction.