The concept that inflammation participates pivotally in the pathogenesis of atherosclerosis and its complications has gained considerable attention, but has not yet entered clinical practice. Experimental work has elucidated molecular and cellular pathways of inflammation that promote atherosclerosis. The recognition of atherogenesis as an active process rather than a cholesterol storage disease or a repository of calcium has highlighted some key inflammatory mechanisms. For example, mononuclear phagocytes contribute to all stages of this disease, illustrating the link between inflammation and atherosclerosis. From a clinical perspective, harnessing inflammation may now help target therapeutics, change guidelines, and enter daily practice. Multiple lines of incontrovertible evidence have proven a causal role for low-density lipoprotein (LDL) cholesterol in atherosclerosis, and we have highly effective tools for lowering LDL, consequently reducing events. Yet, even with intense LDL reduction, events still occur. Inflammation can explain some of this residual risk. An anti-inflammatory intervention has now proven capable of improving outcomes in individuals well treated with LDL-lowering agents. A suite of trials are now pursuing anti-inflammatory therapies in this context. Assessment and treatment of residual inflammatory risk are poised to provide new inroads into preventive cardiology. This brief review aims to explore the potential mechanisms underlying the association of inflammation and atherogenesis, and their clinical consequences.
The soluble form of CD40L (CD40 ligand), a pro-atherogenic mediator, has emerged as a diagnostic and prognostic marker for cardiovascular events. However, as platelets can shed CD40L upon activation, accurate measurement has proved challenging. The present study addresses the controversy regarding the appropriate specimen and preparation for laboratory evaluation of blood sCD40L (soluble CD40L). Serum and plasma (collected in EDTA, citrate or heparin) were collected from healthy volunteers ( n =20), and sCD40L was analysed by ELISA immediately or after one to three freeze–thaw cycles and at different centrifugation speeds. Urine sCD40L levels were measured in subjects with low- and high-plasma sCD40L levels. Serum sCD40L levels (5.45±4.55 ng/ml; P <0.001) were higher than in citrate, EDTA or heparin plasma (1.03±1.07, 1.43±1.03 or 1.80±1.25 ng/ml respectively), with no significant differences between plasma preparations. Increasing g values (200–13000 g ), which gradually deplete plasma of platelets, yielded lower sCD40L levels. Repeated freeze–thaw cycles significantly ( P <0.05) increased sCD40L concentrations in platelet-rich, but not platelet-depleted, plasma (up to 2.4-fold). Bilirubin and haemoglobin interfered positively, and triacylglycerols (triglycerides) and cholesterol quenched CD40L signalling. No sCD40L was detected in urine samples. In conclusion, serum yields higher sCD40L concentrations than plasma; accurate measurements of sCD40L require exclusion of platelets and avoiding their post-hoc activation. Samples with high concentrations of bilirubin, haemoglobin and/or triacylglycerols should be excluded, as these substances interfere with the assay.
The metabolic syndrome, a cluster of metabolic disorders often associated with visceral obesity, increases cardiovascular mortality and morbidity. As the body's largest endocrine organ, adipose tissue not only stores excess body energy, but also secretes a variety of bioactive adipocytokines. Obese patients, particularly those with visceral fat accumulation, have reduced plasma levels of adiponectin, the most abundant and adipose-specific adipocytokine. Although the association of adiponectin with several diseases remains controversial, many clinical studies have demonstrated that low plasma concentrations of adiponectin (hypoadiponectinaemia) associate closely with obesity-related diseases, including atherosclerotic cardiovascular diseases, Type II diabetes mellitus, hypertension and dyslipidaemia. Accumulating experimental evidence indicates that adiponectin possesses anti-atherogenic, anti-inflammatory and anti-diabetic properties and may also participate importantly in the mechanism of metabolic syndrome and other diseases. Despite these associations, further clinical and experimental investigations will be needed to illuminate the in vivo pathophysiological significance of this protein. Although evaluation of adiponectin as a novel therapy will ultimately require clinical intervention studies, this mediator may represent a novel target for the prevention and treatment of visceral obesity metabolic syndrome.