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Does the risk factor profile have predictive value for the site of atherosclerosis?
  1. H Sinzinger
  1. Correspondence to:
 Professor H Sinzinger
 Institute for Diagnosis and Treatment of Atherosclerosis and Lipid Disorders (ATHOS), Nadlergasse 1, A-1090 Vienna, Austria; helmut.sinzingermeduniwien.ac.at

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Inflammatory markers are significantly higher in patients with carotid atherosclerosis than in those with middle cerebral artery (MCA) infarcts

Atherosclerosis is increasingly linked with inflammation, a claim already made by Rudolf Virchow in 1856. Vascular biology has demonstrated that inflammation also plays a key role in stroke development. The best examined inflammatory marker is C-reactive protein (CRP). High sensitivity (hs)-CRP predicts the risk not reflected by traditional risk factors1 for stroke and coronary heart disease (CHD). Interleukin-6 is an even better predictor than CRP and correlates with stroke severity, infarct volume, and long term outcome and is an independent predictor of stroke2; hs-CRP is a more valuable predictor than low density lipoprotein cholesterol (LDL). As hs-CRP and LDL are additive predictors, they identify different risk factors.

The CRP gene markedly accelerates atherosclerosis, indicating an active role. CRP is locally generated within the arterial wall. Intraplaque inflammation may attenuate invasion of endothelial progenitor cells and has been postulated to play a crucial role in thinning of the lesion cap and eventual rupture. Ultimate local differences in CRP have not yet been studied.

In this issue, Bang et al3 (see pp 1128–34) demonstrate that inflammatory markers are significantly higher in patients with carotid atherosclerosis than in those with middle cerebral artery (MCA) infarcts. They observed an inverse correlation between MCA atherosclerosis and CRP after adjusting for age/sex and stroke severity and concluded that MCA lesions may be more stable and require differential therapeutic approaches. MCA atherosclerosis patients may therefore be unlikely to benefit from statins.

However, comparing risk factor prevalence does not exclude all potential pitfalls. Lipids and lipoproteins can be reliably assessed only within 48 h after the acute event.4 Inflammatory response varies in the acute phase. As blood was drawn over a range of 1 week, correlation of lipid with non-lipid parameters may be misleading.

In addition, other factors may have influenced the data, such as obesity, known to increase CRP and oxidation injury; in fact, the strongest correlation is with waist circumference. Periodontal disease, chlamydia pneumonia, Helicobacter pylori or cytomegalovirus, physical activity, NYHA class, positive family history, nutrition, etc could also be responsible for increased CRP. Was there a difference between the groups examined by Bang et al? What was the reason for extreme CRP elevation in three patients?

Normal CRP is zero. As even minor elevation of CRP increases vascular risk, it needs to be treated and all potential causative factors should be examined. However, the prognostic value of elevated CRP, even if estimated at different time intervals,5 is definite, although data based on CRP measured during the acute phase are contradictory.6

In the western world, life style risk factors could result in elevation of CRP. However, as most people do not make recommended life style changes, what is left? Drugs?

Many questions remain. Is the greatest reduction in stroke risk achieved in patients with higher pre-therapeutic CRP7 or is a lower CRP achieved by statins an indicator of better outcome? Different statins may have different effects on inflammatory response. A greatly varying individual LDL response on statins has been documented, but not yet examined for inflammatory response. What is the role of pleiotropic statin effects in stroke? Should patients with higher CRP receive more potent statins or higher doses known to lower CRP more severely? Should patients with extracranial atherosclerosis despite normal lipid values receive statins for primary prevention? Treating to new targets (for LDL and CRP) enhances the benefit in CHD. Does the same apply for stroke? Is there a difference for intra- and extracranial or large and small vessels or race?

Different risk factor profiles and pathogenetic mechanisms may favour atherogenesis at different vascular sites (as shown for lipoproteins, smoking, and diabetes). To search for different treatments should be a future priority. The claim that MCA atherosclerosis patients are unlikely to benefit from statins is not yet substantiated sufficiently for clinical consequence.

Inflammatory markers are significantly higher in patients with carotid atherosclerosis than in those with middle cerebral artery (MCA) infarcts

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