Inflammatory and coagulative markers of atherosclerosis.

Many markers associated with atherosclerosis have been identified in the last 50 years. Some of them act as factors, both mathematically (factors 1⁄4 risk multipliers) and biologically (factors from the latin facient, producing), and others are mere indicators. Among the novel markers (Table 1), many are strictly connected with inflammation or coagulation. Some studies on these markers have been considered with suspect, because they were conducted on patients rather than on general population, because the number of subjects was low, or because the experimental design was inadequate. Nevertheless, the results of all studies are univocal and similar to those of population-based large-scale studies. Today there is, therefore, general agreement on the role of these novel markers. Although incertitude remains about the underlying pathophysiological mechanism, inflammation and haemostasis are considered as driving forces in the process of atherosclerosis. There is evidence of inflammation in vascular atherosclerotic disease. Activated mast cells are present in human coronary atheromas as well as in the adventitia of coronary arteries of patients with variant angina, the CD3þ/DRþ T-lymphocytes are more represented in variant than in stable angina, and inflammatory burden controlateral to a symptomatic carotid stenosis has been detected using high-resolution magnetic resonance. More generally, inflammation and neoangiogenesis play a central role in atherosclerosis and make the atherosclerotic process a continual evolving model. Sometimes (as in the case of subjects with Clamydia pneumoniae or periodontal disease), the inflammatory response to a well-determined infection turns out to be atherogenetic, probably promoting a pro-atherogenic serum lipid profile. In other cases—the great majority—the link of atherogenesis with inflammation is uncertain or even merely presumptive. Urinary albumin excretion (UAE) is an index of glomerular dysfunction and an independent predictor of atherosclerosis and its complications as well. The so-called microalbuminuria (UAE 30–300 mg/day or albumin-to-creatinine ratio 30–300 mg/dL) determined by sensitive techniques is even an earlier predictor. Carotid arteries have been commonly used to demonstrate this association simply because the supraortic district is more accessible to ultrasonographic techniques, and in this site plaques can be detected and measured with extreme precision. UAE is a continuous variable and should not be categorized. Jorgensen et al. just tackle this topic by analysing in a longitudinal perspective 4037 cases from general population after excluding those with diabetes or with known inflammatory disease. Their results, deriving from a very accurate phenotype, indicate that albumin-to-creatinine ratio, even far lower than the usual label of microalbuminuria, is associated with carotid plaque development. Nephropathy sustaining albuminuria must be, of course, a concomitant or an indicator, rather than the cause, of a general endothelial vascular dysfunction, but the mechanism of this association is uncertain, particularly in non-diabetic subjects. Early nephropathy actually correlates with atherosclerosis and its complications (in our general population, top vs. bottom serum creatinine, even in the normal range, increases by the risk of coronary death five-fold in elderly men). As a matter of fact, it may be difficult to clarify whether UAE, an expression of renal microcirculatory abnormality, acts as a marker of early nephropathy rather than of atherosclerosis per se. The link between these two conditions must be chronic low-grade inflammation. UAE correlates with fibrinogen, homocysteine, and C-reactive protein, shifting interest from kidney to inflammation/haemostasis or perhaps underlying the flogistic component of both early nephropathy and early atherosclerosis. Tzoulaki et al. in another longitudinal study among a great number of subjects also highlight inflammatory, haemostatic, and rheological biomarkers of incident vascular damage, namely, C-reactive protein, interleukin-6, fibrinogen, D-dimer, adhesion molecules, haematocrit, and blood viscosity. The increasing evidence suggests that C-reactive protein and fibrinogen are useful in assessing cardiovascular risk. C-reactive protein has numerous atherogenic effects such as generation of oxygen radicals, clotting, expression of plasminogen activator inhibitor 1, and plaque destabilization. Out of acute occasional inflammation, high levels of high-sensitive C-reactive protein are a marker of vasospasm