Cardiovascular disease comprises markedly different types of pathology: atherosclerosis, the lifelong process caused by LDL cholesterol; atherothrombosis or another catastrophic acute event that causes arterial occlusion; and ischemic infarction of the tissue supplied by an occluded artery. The levels of tissue damage and inflammation, and the concentrations of CRP associated with these different pathologies, differ by orders of magnitude and should not be confused or conflated with each other.
CRP as a predictor of cardiovascular events. The prognostic association of CRP with future cardiovascular events, that is seen both in general population cohorts and in patients with stable or unstable angina, is shared with similar significance by all other systemic markers of inflammation that have been studied. There is evidently a relationship between underlying inflammation, or at least signs of metabolic or cellular ?distress?, and progression of atherosclerosis to atherothrombotic events. Baseline CRP values in general populations are strongly correlated with most of the known causal risk factors for coronary heart disease: obesity, smoking, metabolic syndrome, diabetes, hypertension, exercise, age, socio-economic position, accounting for about 70% of the variation in CRP. CRP is therefore not an independent risk marker. The low grade increase in CRP values associated with increased risk in general population cohorts is most likely a response to life time inflammatory and/or metabolic stresses, many of which are causes of cardiovascular disease.
In the different setting of acute coronary syndrome, systemic evidence of higher grade inflammation is associated with poor prognosis to which the systemic markers, including CRP, might make a pathogenetic contribution.
After arterial occlusion has caused ischemic tissue damage, there is invariably a substantial CRP response which also predicts poor outcome and may actually contribute directly to it.
Biology of CRP as pathogenic molecule. It has been recognised for decades that human CRP could potentially be pro-inflammatory, in particular via its capacity to bind to extrinsic or endogenous macromolecular ligands and then activate complement. In addition we first showed in 1982 that human CRP could selectively bind LDL and might thereby be involved in atherogenesis. The more recent observations that CRP binds avidly to modified LDL and oxidised phospholipids and that it is present in atherosclerotic plaques together with activated complement components, heightened such speculation. However the presence of CRP in the lesions is not specific, as most plasma proteins can be detected within plaques, and it is not proof that CRP is either pro-atherogenic or atheroprotective. Currently there is no robust evidence either way. Study of atherogenesis in apoE-/- mice with and without transgenic human CRP, provides no suggestion that human CRP is either pro-atherogenic, pro-atherothrombotic or atheroprotective. Although this is the best available in vivo model, it is limited by the fact that the human CRP is operating in a xenogeneic milieu and may not be able to exert the same effects that it does in humans.
A wide range of pro-inflammatory and potentially pro-atherogenic and pro-atherothrombotic effects of human CRP on cells in vitro have been reported lately but these are all controversial. Many are not reproducible with genuinely pure authentic human CRP as opposed to commercial recombinant bacterial human CRP, and all are inconsistent with the dynamic behaviour and concentration range of human CRP in health and disease. Furthermore, neither administration of pure authentic human CRP to mice or rats, nor transgenic expression of human CRP in either wild type or apoE-/- mice, have any adverse or pro-inflammatory effects.
In contrast there are compelling clinical and pathological observations linking the major acute phase response of CRP after acute myocardial infarction to subsequent adverse effects. In addition to the association between CRP production and outcome, CRP and activated complement are co-deposited in all acute myocardial infarction lesions, and we have shown that administration of human CRP to rats after coronary artery ligation markedly increases infarct size in a CRP specific and complement dependent fashion. We have also reported the same effect on cerebral infarct size in rats after middle cerebral artery occlusion. Rat CRP, although very abundant and also deposited in the infarcts, does not activate rat complement and has no such adverse effect. It is likely that binding of human CRP to dead and damaged cells and consequent complement activation contribute to eventual lesion severity in human acute myocardial infarction and possibly also stroke.
CRP as a therapeutic target. We have lately reported the rational design, novel synthesis, mode of action and in vivo efficacy of the first specific CRP inhibitor drug, bis(phosphocholine)-hexane, which completely inhibits ligand binding and complement activation by CRP in vitro and in vivo. Administration of this drug to rats undergoing coronary artery ligation had no effect, but when given to rats also receiving human CRP it completely abrogated the increased morbidity, mortality and infarct size experienced after coronary ligation by rats receiving human CRP alone. It will now be interesting to see whether inhibition of CRP function is beneficial in patients with acute coronary syndromes and after acute myocardial infarction. If so the way will be open to investigation of CRP blockade in a wide range of other diseases in which there are both tissue damage and sustained high CRP concentrations.
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