May 28, 2010 (Rochester, New York) - A new study has suggested that a raised HDL-cholesterol level, if present in conjunction with a raised C-reactive-protein (CRP) level, may confer increased cardiovascular risk . And that in these patients, reduced cholesteryl-ester-transfer-protein (CETP) activity is associated with even higher risk, giving a potential explanation to the negative findings of thetorcetrapib (Pfizer) studies.
The study, published online May 20, 2010 in Arteriosclerosis, Thrombosis, and Vascular Biology, was conducted by a group led by Dr James Corsetti (University of Rochester School of Medicine and Dentistry, NY).
Corsetti commented: "We found that having a raised HDL together with a raised CRP signifies higher risk of cardiac events. This is not a good combination. This has been hinted at in previous studies, so we specifically looked to see whether we could identify this interaction in a large population group. Our findings are consistent with the thinking that HDL can be proatherogenic in an inflammatory environment."
These comments and findings bring to light that inflammation associated with a plaque would be the most sensitive in selection of picking a lesion to be stented or not. "Authors View"
Corsetti explained that functional assays have previously shown that when inflammation is present, such as in patients with chronic autoimmune conditions, HDL does not appear to be working as competently as normal. This led to a hypothesis that in an inflammatory environment, HDL may be transformed in some way from an antiatherogenic molecule to a proatherogenic molecule. His team wanted to see whether they could validate this hypothesis in a population of patients who had had a previous MI. They used data from 767 nondiabetic patients participating in the THROMBO postinfarction study who were enrolled after the index MI and followed up for recurrent coronary events (cardiac death, MI, or unstable angina) for a mean of 26 months.
They used a graphical technique known as outcome-event mapping to find out whether patients with both raised levels of HDL and CRP had an increased risk of subsequent events. Corsetti explained that outcome-event mapping deals with risk-factor levels as a continuous process rather than using specific cut-off values, which he says is a better way of studying relationships between risk factors and events. "In general, nature does not like sharp corners. Our approach maps out the relationships and so gives us a better idea about what is going on."
Results showed a definite relationship between increased levels of both HDL and CRP and a higher risk of subsequent cardiovascular events. Speculating on the mechanism behind this observation, Corsetti suggested that an inflammatory environment appears to alter the functionality of the HDL molecule, with inflammation and oxidative stress impairing the antiatherogenic features of HDL.
Implications for CETP Inhibitors?
In an additional analysis, the researchers screened for presence of a genetic marker for reduced CETP activity and found that patients who had raised HDL and raised CRP and who also had this genetic marker did particularly badly.
"Patients with increased levels of both HDL and CRP are already at high risk. But those who have this polymorphism are at even higher risk. However, the polymorphism alone does not appear to have any diagnostic relevance unless both HDL and CRP are raised."
He says this observation may have implications for drug development and may possibly explain the negative results seen with the CETP inhibitor torcetrapib.
Corsetti explained that HDL and CETP are both involved in reverse cholesterol transport, which is part of the process of removing cholesterol from the body. "CETP plays a major role in helping HDL offload its cholesterol. Our results suggest that it might not always be a good idea to reduce CETP activity." But he cautioned that it was difficult to generalize, and this observation needs to be anchored to the findings in patients with raised HDL and CRP.
In the paper, the researchers elaborate on the mechanism. They suggest that compromise in CETP action could be expected to result in the accumulation of cholesterol-rich HDL particles, which, particularly in an inflammatory setting, might more readily undergo proatherogenic transformation.
Corsetti speculated: "It may be that CETP inhibition is an appropriate strategy for some patients, but that for others-the ones with raised HDL and CRP-it could be harmful. These patients with raised HDL and CRP made up about 20% of our database. It may be that if these patients are screened out, a CETP inhibitor would be beneficial." He added that it would be very interesting to look at the data from the torcetrapib trials to see whether this was the case in those populations.
He added that there has been a "raging controversy" over the idea of CETP inhibition as a therapeutic strategy, with experts evenly divided on whether it is a good or bad idea. "Our research adds fuel to the fire," he said.
Corsetti said the next step in their research will be to collect HDL specimens from patients and compare the molecule in patients who have raised levels of HDL and CRP with a control group with normal levels. "If our hypothesis is correct, we would expect to see the HDL molecule changed in some way that would reduce its functionality when it is present in an inflammatory environment," he explained.
Corsetti believes this research is another example of the potential benefits of personalized medicine. "People are different. We are starting to grasp some of what is going on in different people that may lead to customized drug therapy targeting HDL cholesterol," he commented.
Nissen: "Provocative But Highly Speculative"
Reviewing the study for heartwire , Dr Steven Nissen (Cleveland Clinic, OH), who was involved in the trials with torcetrapib, said he didnt find this latest study "particularly compelling."
"The authors used unusual statistical methods to suggest an association between CETP polymorphisms and post-MI risk. This post hoc analysis is provocative but also highly speculative. The issue of the benefits and risks of CETP inhibition can be tested only in prospective randomized trials. We should reserve judgment until ongoing trials of CETP inhibition are completed during the next few years," he added.
Corsetti JP, Ryan D, Rainwater L, et al. Cholesteryl ester transfer protein polymorphism (TaqIB) associates with risk in postinfarction patients with high C-reactive protein and high-density lipoprotein cholesterol levels.Arterioscler Thromb Vasc Biol 2010; DOI:10.1161/ATVBAHA.110.207977.