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04-01-2010 | Cardiology | Article

CRP link to vascular disease clear, but causality remains doubtful


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MedWire News: C-reactive protein (CRP) level is continuously associated with coronary heart disease, ischemic stroke, and vascular mortality, as well as other chronic diseases, but the associations with ischemic vascular risk are largely explained by known risk factors, researchers report in The Lancet.

“Although our results support the idea that some process related to persistent inflammation is associated with vascular disease and other chronic disorders, most of the association with ischemic vascular disease depends on conventional risk factors and fibrinogen concentration,” say John Danesh and colleagues in the Emerging Risk Factors Collaboration, based at the University of Cambridge in the UK.

They add that, taken with available genetic data, their findings “reduce the likelihood for causality for CRP in coronary heart disease.”

For the most powerful and comprehensive study of the link between CRP and chronic diseases to date, the researchers meta-analyzed individual medical records of over 160,000 people without a history of vascular disease from 54 long-term studies of cardiovascular risk factors.

During 1.31 million person-years at risk (median 5.8 years to first outcome), there were 7381 nonfatal myocardial infarctions and 3070 deaths from coronary heart disease, 2846 ischemic strokes, 469 hemorrhagic strokes, 1180 unclassified strokes, and 1659 deaths from other vascular diseases. A further 10,236 deaths from non-vascular diseases and 860 from unknown causes occurred.

Danesh and colleagues report that loge CRP concentration was almost log-linearly associated with risk for coronary heart disease risk and ischemic stroke, with curvilinear associations seen for all vascular and non-vascular mortality.

After adjustment for age and gender only, each 1-standard deviation increase in loge CRP (three-fold higher CRP) concentration was associated with relative risk (RRs) for coronary heart disease, ischemic stroke, vascular mortality, and non-vascular mortality of 1.63, 1.44, 1.71, and 1.55, respectively.

The corresponding RRs for coronary heart disease, ischemic stroke, and vascular mortality were attenuated after additional adjustment for conventional cardiovascular disease risk factors to 1.37, 1.27, and 1.55, respectively.

Further adjustment for fibrinogen level among participants with available data revealed that the RR for coronary heart disease fell from 1.36 to 1.23, and that for vascular mortality from 1.52 to 1.34, whereas the RR for ischemic stroke was unchanged, at 1.32.

The researchers comment that large studies are needed to concurrently assess several proximal and distal inflammatory markers, such as interleukin-6 and CRP, respectively, and markers of rupture-prone plaque, eg, lipoprotein-associated phospholipase A2, as well as their genetic and lifestyle determinants.

“Further work is also needed to assess whether evidence of low-grade inflammation mainly indicates external triggers (eg, socioeconomic position or infection), insulin resistance, hereditary predisposition, or some combination of such factors,” they write.

Matthijs Boekholdt and John Kastelein, from the Academic Medical Center in Amsterdam, The Netherlands, wrote in an accompanying editorial: “Although these findings add weight to the evidence against causality, it should be noted that neither classical epidemiological nor Mendelian randomization studies can provide a definitive answer in this debate.”

Only randomized trials of agents specifically targeting CRP will provide the answer, they say.

In the meantime, they note that in JUPITER (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin), the CRP reductions achieved on statin therapy predicted the efficacy of treatment.

“So, even if CRP turns out not to be causal in cardiovascular disease, it might be useful to identify individuals at cardiovascular risk and to quantify the efficacy of our interventions,” they conclude.

MedWire ( is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

By Caroline Price

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