Professor Gillian Cockerill, Head of the Vascular Biology Research Centre at St George’s Hospital University of London, UK, speaks with Cardio Debate & Radcliffe Cardiology about HDL and Cardiovascular Risk during the “Advances in the Pathogenesis and Management of Cardiovascular Disease” 2015 meeting, organised by the Cardiovascular Sciences Research Centre of St George’s University and held at the Royal College of Surgeons of England in London, UK.
HDLs have anti-inflammatory properties; which inflammation pathways are affected by HDL?
Well that’s quite a good question. Just to paraphrase it, what I would like to tell you about are the inflammatory pathways that have currently been investigated at molecular level with regards to how efficient high density lipoproteins can be at ablating or reducing inflammation in diseases.
Currently there’s an awful lot of data on raising HDL as being protective in sepsis. So the pathways of inflammation that are elicited in sepsis are very well characterised, and there’s a lot of molecular analysis information that we have on the way HDL interferes with the binding of LPS to CD14 on monocytes and endothelium.
And another pathway that has been looked at with regards to HDL, which is a common pathway of many diseases, is the ability of high density lipoprotein to inhibit cytokine-induced adhesion molecules on endothelial cells. And so prevent monocyte-adhesion and inflammation through those pathways.
And there are common cellular inflammatory pathways that are found in the etiology of a number of diseases.
Why has CTP inhibition so far failed to show a beneficial effect in patients with coronary disease?
The cholesterol ester transfer protein inhibitor class of drugs have thus far given unimpressive results. They are supposedly able to raise high density lipoprotein and some have the ability to also lower low density lipoproteins.
Now so far the drugs tested which have significant high density lipoprotein raising abilities have given very negative results in clinical trials, where they have been used to look at the improvement in acute coronary syndrome patients. And it may be that the ability of this drug to raise the production of high density lipoproteins is not overcoming the ability of that high density lipoprotein to become affected by the factors that are involved in the inflammatory scenario of a chronic condition.
We know that chronic disease alters the status of high density lipoproteins, and has been shown to be able to modify high density lipoprotein from protective to almost protagonistic.
So in an acute coronary syndrome patient, the high density lipoprotein is no longer anti-inflammatory. Its complexity is adjusted in interacting with other lipoproteins in cell membranes, and results in a particle that is pro-inflammatory – or at least no anti-inflammatory. So perhaps the actual hypothesis is somewhat naïve in that raising HDL alone is the way to go.
What we need to do is to find out what is the mechanism of raising HDL that is protective, rather than just simply raise HDL globally with these treatments.
Currently there remain two products in market under trial – evacetrapib and anacetrapib – and they are due to report either this year or next year. But both those drugs not only have HDL raising ability, but they have further LDL-lowering abilities in addition. So benefits may come from further lowering of low density lipoprotein. But nevertheless it will be interesting to see what happens to the heterogeneity and complexity of HDLs in those patients treated with the drugs.