March 15th, 2012

Strongest Evidence to Date for Causative Role of Inflammation in Heart Disease

Two large new meta-analyses published in the Lancet provide the first strong evidence demonstrating a cause-effect relationship between a specific inflammatory protein and the development of coronary heart disease (CHD). Both studies illuminate the role of interleukin-6 receptor (IL6R) by focusing on the common Asp358Ala variant of the IL6R gene. The variant is known to dampen the inflammatory effect of IL6R.

In one study, members of the IL6R Genetics Consortium Emerging Risk Factors Collaboration found that Asp358Ala was present in 39% of the population and was not significantly related to other risk factors. 358Ala increased concentrations of IL6R and decreased concentrations of CRP and fibrinogen. Notably, each copy of 358Ala was associated with a 3.4% reduction in the risk for CHD.

In the other study, members of the Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium performed a Mendelian randomization to analyze the impact on CHD of tocilizumab, an anti-inflammatory monoclonal antibody that blocks IL6R, in patients with rheumatoid arthritis (RA). They found that the effect of the 358Ala variant was similar to the effect of tocilizumab in RA trials and resulted in increased levels of interleukin-6 and decreased levels of CRP and fibrinogen. The investigators also observed a significant reduction in the risk for CHD in a second analysis of more than 25,000 people with CHD and 100,000 controls. They conclude that IL6R signaling appears to “have a causal role in development” of CHD and that “IL6R blockade could provide a novel therapeutic approach to prevention” of CHD.

In an accompanying comment, S Matthijs Boekholdt and Erik SG Stroes write that the presence of inflammation in atherogenesis has long been recognized, but it has been difficult to establish a causative role. Although CRP has been shown to predict risk, an earlier Mendelian randomization analysis failed to establish a causative role. Further, they note, “there is currently no evidence to show that selective targeting of inflammatory pathways modulates cardiovascular risk.” The consistent results of the two Lancet papers, they write, “lend strong support to the concept that inhibition of inflammatory pathways is an attractive strategy to reduce cardiovascular risk.”

Paul Ridker offered CardioExchange the following perspective on the studies:

The new studies are both very important for the inflammatory hypothesis of atherothrombosis, as they provide clear linkage between IL-6, its receptor, and clinical events. Moreover, the new data provide confirmatory evidence to consider agents that alter the IL-6 pathway as potential therapeutic agents. As one example, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) that my group coordinates is evaluating a novel monoclonal antibody that targets IL-1-beta and results in lower levels of fibrinogen, CRP, and IL-6. CANTOS is underway in 25 countries and is a hard outcomes trial in secondary prevention. So this field is becoming very exciting and the new data support the concept of lowering inflammation to potentially lower vascular risk.

CardioExchange editor Rick Lange generously offered his own summary and analysis of the papers:

Despite strong evidence associating inflammation with atherosclerosis, a causal role for C-reactive protein or fibrinogen in atherogenesis has remained highly controversial, especially since inflammation is linked with other conditions (i.e., obesity, hypertension, dyslipidemia, diabetes, smoking, etc.) that are known to increase cardiovascular risk.  In addition, Mendelian randomization analyses showed that variants in the gene for C-reactive protein associated with high concentrations of the protein were not associated with risk of coronary heart disease, making a causal role for C-reactive protein itself in atherogenesis less likely. Lastly, there is currently no evidence to show that selective targeting of inflammatory pathways modulates cardiovascular risk.

The 2 Lancet studies report data from individuals with genetic abnormalities in the inteleukin-6 receptor gene (ILR6) that lead to reduced concentrations of the membrane-bound form of interleukin 6 (i.e., hence reduced activation of the inflammatory pathways in hepatocytes, monocytes and macrophages that are upstream of C-reactive protein).  This genetic difference lead to (a) an anti-inflammatory effect (lower serum levels of C-reactive protein and fibrinogen) and (b) a reduction of coronary heart disease (3.4% to 5% per-allele reduction) and (c) no change in BP, lipids, obesity, hyperglycemia or smoking). So this is the strongest evidence to date that inflammation has a causative role in cardiovascular disease. Whether or not inhibition of inflammatory pathways is an attractive strategy to reduce cardiovascular risk is a separate issue, since anti-inflammatory strategies may increase the risk of infection or malignancy.

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