C-reactive protein and atherothrombosis: Cause or effect?

The complex relationship between the inflammatory response and vascular injury and repair is of major importance to the pathogenesis of cardiovascular disease. CRP is not only a strong marker for cardiovascular morbidity but a modulator that suppresses local and systemic thromboregulatory pathways. In the present review we address the question of whether CRP is involved in atherogenesis, in thrombosis, or in both components of the atherothrombotic process. While CRP is present in the atherosclerotic lesion, it is probably not pro-atherogenic and correlates only minimally with atherogenesis. Alas, CRP promotes thrombus formation and vascular occlusion. Thus, CRP is most likely not affecting atheroma build-up but rather the deleterious process of plaque vulnerability and thrombus formation. Dwelling into CRP mechanism of action may lead to the design of new diagnostic modalities that will add to the predictive value of CRP in identifying those patients at high cardiovascular risk. Furthermore, defining the mechanistic domain is the foundation to the cause–effect detection of possible therapeutic interventions to counter CRP morbid effects.     

C-reactive protein: risk marker or mediator in atherothrombosis?

Inflammation appears to be pivotal in all phases of atherosclerosis from the fatty streak lesion to acute coronary syndromes. An important downstream marker of inflammation is C-reactive protein (CRP). Numerous studies have shown that CRP levels predict cardiovascular disease in apparently healthy individuals. This has resulted in a position statement recommending cutoff levels of CRP <1.0, 1.0 to 3.0, and >3.0 mg/L equating to low, average, and high risk for subsequent cardiovascular disease. More interestingly, much in vitro data have now emerged in support of a role for CRP in atherogenesis. To date, studies largely in endothelial cells, but also in monocyte-macrophages and vascular smooth muscle cells, support a role for CRP in atherogenesis. The proinflammatory, proatherogenic effects of CRP that have been documented in endothelial cells include the following: decreased nitric oxide and prostacyclin and increased endothelin-1, cell adhesion molecules, monocyte chemoattractant protein-1 and interleukin-8, and increased plasminogen activator inhibitor-1. In monocyte-macrophages, CRP induces tissue factor secretion, increases reactive oxygen species and proinflammatory cytokine release, promotes monocyte chemotaxis and adhesion, and increases oxidized low-density lipoprotein uptake. Also, CRP has been shown in vascular smooth muscle cells to increase inducible nitric oxide production, increase NFkappa(b) and mitogen-activated protein kinase activities, and, most importantly, upregulate angiotensin type-1 receptor resulting in increased reactive oxygen species and vascular smooth muscle cell proliferation. Future studies should be directed at delineating the molecular mechanisms for these important in vitro observations. Also, studies should be directed at confirming these findings in animal models and other systems as proof of concept. In conclusion, CRP is a risk marker for cardiovascular disease and, based on future studies, could emerge as a mediator in atherogenesis.     

Visceral fat in relation to health: is it a major culprit or simply an innocent bystander?

The aim of this review is to look critically at the widely accepted notion that visceral fat accumulation is the main determinant of obesity related diseases. Most of the epidemiological evidence is based on anthropometric indicators of fatness and fat distribution and their implications for visceral fat accumulation may not be unequivocal. In most cross-sectional studies in which visceral fat is associated with the level of risk factors or presence of disease, no adjustment is made for potential confounders. There are potential confounders at different levels of the causal chains linking visceral fat to health. Firstly, there are aspects of body composition or fat depots associated with visceral fat accumulation such as total body fat or total subcutaneous fat. Total and subcutaneous fat are, by themselves, potentially strong determinants for metabolic disturbances and disease. Secondly, there are behavioural factors (for example smoking, alcohol consumption, physical activity, dietary habits) which have been found to be associated with both the amount of visceral fat and health outcomes. Thirdly, there are hormonal mechanisms (adrenal and gonadal steroids as well as growth hormone) which may affect both the accumulation of visceral fat as well as the development of diseases. Finally, even if associations between visceral fat and risk factors or presence of diseases would be firmly established, the causality of the observed associations may not always be easy to interpret. Prospective studies are needed with appropriate control of potential confounding variables. It is concluded that, based on the current evidence, it is difficult to quantify the independent contribution of visceral fat to the development of a variety of chronic diseases.     

Coronary myocardial bridge: an innocent bystander?

Myocardial bridge (MB) or tunneled coronary artery is an inborn abnormality, which implicates a systolic vessel compression with a persistent mid-late diastolic diameter reduction. Myocardial bridges are often observed during coronary angiography with an incidence of 0.5%-5.5%. The most involved coronary artery is the left anterior descending artery followed by the diagonal branches, the right coronary artery, and the left circumflex. The overall long-term prognosis is generally benign. However, several risk or precipitating factors (e.g., high heart rate, left ventricular hypertrophy, decreased peripheral vascular resistance) may trigger symptoms (most frequently angina). Herein, we describe two cases of symptomatic myocardial bridge, where medical treatment (i.e., inotropic negative drug) and coronary stenting were successfully utilized to treat this pathology. We also focus on the clinical presentation, and the diagnostic and therapeutic modalities to correctly manage this frequently observed congenital coronary abnormality, underlining the fact that in cases of typical angina symptoms without any significant coronary artery disease, MB should be considered as a possible differential diagnosis.     

Lipids,atherosclerosis and CVD risk: Is CRP an innocent bystander?

AimTo evaluate recent human studies with respect to the interpretation of whether elevated plasma levels of C-reactive protein (CRP) cause cardiovascular disease (CVD), or whether elevated CRP levels more likely is an innocent bystander.Data synthesisElevated CRP concentrations are consistently associated with CVD risk. A recent study showed that aggressive statin treatment caused reductions of 50% in LDL cholesterol, 37% in CRP, 44% in CVD events, and 20% in total mortality, and that the highest treatment benefits were obtained in those with the lowest achieved levels of both LDL cholesterol and CRP. However, a reduction in CRP levels after statin treatment could be secondary to the reduced LDL cholesterol levels, and thereby less inflammation in atherosclerotic plaques. We recently performed 4 large Mendelian randomization studies, studies that demonstrated that elevated CRP associate with increased risk of CVD, that genetic variation in the CRP gene associate with increased CRP levels, but that this genetic variation in the CRP gene do not associate with increased risk of CVD. In contrast to previous studies, these new studies had enough statistical power to effectively exclude that genetically elevated CRP cause CVD.ConclusionThese data suggest that elevated CRP per se does not cause CVD; however, inflammation per se possibly contributes to CVD. Elevated CRP levels more likely is a marker for the extent of atherosclerosis or for the inflammatory activity and vulnerability of atherosclerotic plaques, and thus simply an innocent bystander in CVD.     

Resistin - a mediator of obesity-associated insulin resistance or an innocent bystander?

The objective of this review is to summarize the current evidence of a novel adipocytokine, resistin. Resistin is a novel peptide hormone that belongs to a family of tIssue-specific resistin-like molecules originally named for its resistance to insulin. Although a seminal proposal by Steppan et al. suggested resistin to be a hormone that links obesity to diabetes, several studies have subsequently been published supporting the concept that insulin resistance and obesity are actually associated with a decreased resistin expression. Resistin expression is regulated by a variety of agents and hormones, including thiazolidinediones, insulin, tumor necrosis factor alpha and growth hormone. Studies about their role in the regulation of resistin expression are, however, inconsistent in many cases. Experiments in humans have shown no differences in resistin expression between normal, insulin-resistant or type 2 diabetic samples. However, some recent genetic studies have demonstrated an association between resistin and insulin resistance and obesity. In addition, regional variation in the expression of resistin mRNA and protein levels in humans is an interesting finding with the highest levels found in the abdominal depot. In conclusion, resistin is a fascinating new hormone for which a definite role in metabolism will be revealed in the near future.     

Is C-reactive protein an independent risk factor for essential hypertension?

CONTEXT: C-reactive protein (CRP), predicts coronary heart disease incidence in healthy subjects and has been associated with decreased endothelium-dependent relaxation, a potential risk factor for hypertension. However, the relationship between CRP and hypertension has not been studied. OBJECTIVE: To assess whether circulating levels of CRP are independently related to essential hypertension. DESIGN: Cross-sectional population survey. We measured circulating levels of CRP, blood pressure and cardiovascular risk factors among participants. Binomial regression was used to calculate the adjusted effect of CRP on the prevalence of hypertension. SETTING: General community of Bucaramanga, Colombia. PARTICIPANTS: A random sample of 300 subjects > or = 30 years old. MAIN OUTCOME MEASURE: Arterial blood pressure. RESULTS: Overall hypertension prevalence was 46.0%. The unadjusted prevalence of hypertension was 58.7% in the highest quartile of CRP, but only 34.7% in the lowest quartile. After adjustment for age, sex, body mass index, family history of hypertension, fasting glycemia, sedentary behaviour, and alcohol consumption, the prevalence of hypertension was 1.14 [95% confidence interval (CI), 0.82, 1.58; P= 0.442], 1.36 (95% CI, 0.99, 1.87; P= 0.057) and 1.56 (95% CI, 1.14, 2.13; P = 0.005) times higher in subjects in the second, third and fourth quartiles of CRP, as compared to subjects in the first quartile. CONCLUSIONS: Our results suggest, for the first time, that CRP level may be an independent risk factor for the development of hypertension. However, because of the cross-sectional nature of our study, this finding should be confirmed in prospective cohort studies, aimed at elucidating the role of CRP in the prediction, diagnosis and management of hypertension.     

Cytomegalovirus and immune senescence: Culprit or innocent bystander?

Immune senescence may be defined as the age-related reduction and dysregulation of immune function, and has been associated with increased incidence and severity of infectious diseases and with poor efficacy of prophylactic vaccines in the elderly. Several studies have demonstrated that persistent infections with Herpes viruses in general and Cytomegalovirus (CMV) in particular have a profound influence on subset distribution, phenotype and potentially also on the function of T cells in ageing individuals. The association of CMV-seropositivity and accumulation of CMV-specific CD8⁺ T cells with decreased survival in longitudinal studies of very elderly has fostered the hypothesis that CMV-infection may be an important causative factor for the development of immune senescence. Here, we have critically summarized the current body of evidence supporting this hypothesis, highlight some controversial issues about its relevance and mechanisms and propose areas of future research to demonstrate unequivocally whether and how persistent infections might compromise the ageing immune system.     

Iron in hepatitis C: villain or innocent bystander?

Elevations in serum transferrin-iron saturation and ferritin are common in patients with chronic hepatitis C infection, especially if they have concomitant elevations in serum aminotransferases. However, serum markers of iron stores do not accurately reflect hepatic iron content, or predict clinically important endpoints such as response to interferon and disease progression. In contrast, hepatic iron concentration, which is usually normal or only mildly elevated in chronic hepatitis C infection in the absence of cirrhosis, is one of the strongest predictors of response to interferon monotherapy. Iron depletion by phlebotomy consistently reduces serum aminotransferases and in combination with interferon may have improved antiviral efficacy compared to interferon alone. Unfortunately, no data are available on the role, if any, of iron depletion therapy, as an adjunct to interferon and ribavirin combination treatment. Future studies should focus on the efficacy of combining iron depletion with pegylated interferon and ribavirin and on the effect of long-term iron depletion on histologic progression of chronic hepatitis C infection.     

Is high-sensitivity C-reactive protein an effective screening test for cardiovascular risk?

We evaluate the suggestion that high-sensitivity C-reactive protein testing be used for risk assessment in the primary prevention of cardiovascular disease, using the criteria proposed by the Guide to Clinical Preventive Services developed by the US Preventive Services Task Force. We conclude that at present, none of the 3 major criteria--accuracy, reliability, and likelihood of beneficial intervention--are satisfied.     

Elevated serum uric acid levels in metabolic syndrome: an active component or an innocent bystander?

Elevated serum uric acid (SUA) levels are commonly seen in patients with the metabolic syndrome (MetS). Several mechanisms, both direct and indirect, connect the increased SUA levels with the established diagnostic criteria of MetS. It is possible that the increased cardiovascular disease risk associated with the MetS is partially attributed to elevated circulating SUA concentration. Several drugs used in the treatment of MetS may alter SUA levels. Thus, lifestyle measures together with the judicious selection of drugs for the treatment of hypertension, dyslipidemia, and insulin resistance associated with MetS may result in a reduction of SUA levels and possibly cardiovascular disease risk. This review summarizes the pathophysiologic association between SUA and MetS and focuses on the prevention of hyperuricemia and its cardiovascular consequences.