Inflammation and anti-inflammatory therapy in CVD
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- A historical overview on inflammation in atherosclerosis 0:28
- Why do coronary arteries occlude? The role of inflammation 2:59
- Anti-inflammatory therapies in CVD 7:09
- Anti-inflammatory therapy in rheumatoid arthritis 12:00
- Summary 13:05
Hello, I'm Thom Lüscher and I'm delighted to speak about inflammation and the anti-inflammatory therapy in cardiovascular disease and I will be complementary to the lecture of Filippo Crea that already put the stage for my lecture as well.
So, inflammation started with a pioneer. Celsus was a Roman physician that wrote books and he coined the term rubor, calor, dolor and tumor, but obviously he looked at skin lesions that were reddish, that hurt, that were warm and presented as a tumor on the skin.
So we can translate this of course to cardiovascular disease and the first one who did so was Rudolf Virchow in the 19th century when he said atherosclerosis is a chronic inflammation induced by cholesterol. Quite the visionary statement at that time, again, published in books rather than in papers.
And if we translate it to the vascular wall as shown here, we can say that rubor is neovascularization, calor is increased metabolism, dolor are cytokines and autocoids. We don't feel it in the vascular wall, but it's the same mechanism. And of course the tumor is related to white blood cells, to cholesterol crystals, to collagen and necrotic tissue that accumulates in the plaque.
When we look at the molecular mechanism, we know that actually monocytes and T-cells enter the vascular wall in the atherosclerotic process. They produce a lot of cytokines when they take up modified cholesterol and other lipids that are a major antigen for the induction of the inflammatory response.
Now, with Paul Ridker, we published this paper some years ago in the European Heart Journal where we show that the activation of NLRP3 by cholesterol crystals but also other agonists leads to the production of cytokines of the interleukin family that in the liver then induces the production of C-reactive protein that we use in clinical practice.
When we look at this in patients with coronary artery disease we can see here on the left those with stable coronary artery disease: very, very little increase in CRP. When they present with an acute coronary syndrome or ACS: huge increase in CRP. And on the right you can see the same thing for serum amyloid A another acute phase protein.
When we look at what happens over decades and a plaque will develop, it becomes vulnerable because it contains oxidized lipids and this is exposed to shear stress and pulsatility and eventually we end up with a plaque rupture that leads to thrombus formation and occlusion in a STEMI as shown here.
We actually pursued this further in the cath lab and you can see on the left where we have a percu search catheter with a balloon at the end. And with the black point, you can see the export catheter sucking up blood and eventually the thrombus. And on the right, you see the situation after successful opening of the LAD.
Now, this is the schematic what we did. You can see as an example, the right coronary artery with the guide catheter in the ostium, the percu search catheter below the actual occluding lesion and then the export catheter that removes the blood at the site of coronary occlusion. And in the panels we see that in fact, interleukin-6 and serum amyloid A are markedly increased. So, there is massive local inflammation compared to the aorta. That is the comparison sample. And the inflow markers such as lipoproteins are unchanged. As is CRP, because it's produced in the liver and not in the coronary arteries.
We looked at a number of cytokines. You can see on the right, there is a whole family, a storm of cytokines, that are increased at the site of coronary occlusion.
And of course, we can remove the thrombus as well and look at this under the microscope. And if we do so, we see neutrophils, also other white blood cells, but in this case it's neutrophils and macrophages stained with CD68. And you can see on the right panel that they also produce interleukins as shown by the the staining that that has been visualized here.
So it's clearly the macrophages at the site of coronary occlusion that produce a lot of cytokines contributing to a plaque rupture and coronary occlusion. Now, what is the activation of these macrophages? Of course, the Toll-like receptors are very important in innate immunity and you can see in red, these are markedly increased in macrophages obtained from the thrombus compared to those circulating in the peripheral blood. And of course, this is activated by a number of agonists that you all know and leading eventually to cytokines, such as interleukins, TNF and others.
Now, in addition, at the site of coronary occlusion, we measured enzymes that digest collagenase, such as fibrin peptide A or metalloproteases and you can see they're hugely expressed at the side of coronary occlusion demonstrating what has been shown in mice by Peter Libby, in patients, in the cath lab at the time of an acute coronary occlusion.
And eventually, of course, this will digest the cap and lead to the catastrophe that clinically presents as a STEMI.
In addition, the inflammation also activates tissue factor in endothelial cells that normally don't express it as well as, in smooth muscle cells. So, we can say that all these cytokines, actually induce inflammation. Inflammation begets coagulation, very important in this context.
And of course, this activates further the neutrophils to express extracellular traps that then eventually lead to a very solid clot that is typical for ST-segment elevation myocardial infarction.
In mice, we have a model of acute intervascular carotid thrombotic occlusion that has been established by Giovanni Camici in our laboratory. And we looked at a canakinumab analog for mice that we have received. And on the top you see that if we inhibit interleukin-1β by canakinumab analog. The occlusion time is prolonged in the carotid artery induced by laser injury and therefore there is a protective effect also in terms of coagulation by anti-inflammatory therapies. And this also affects neutrophil extracellular traps as we could show by MPO attached to DNA or as well as tissue factor that is reduced in the context of interleukin-1β inhibition.
And of course, this leads me to the question how far did we get so far and what could anti-inflammatory therapy do? Since Eisenhower's heart attack the event rate in hospital reached ten percent down from fifty, but has been stable so far. So there is an unmet medical need in patients with acute coronary syndromes.
And this of course has been addressed by Paul Ridker and he will dwell on that in the CANTOS trial where he was able to reduce CRP as well as the events by inhibiting interleukin-1β by canakinumab. But interestingly, the most of the effect in the CANTOS trial was in those that could supress their interleukin-6 rather than interleukin-1β only production.
And here you see that polymorphism of interleukin-6 receptors has been looked at in a meta-analysis. If patients have less activation of this pathway, CRP as well as fibrinogen has been markedly reduced and therefore interleukin-6 seems to be in this mendelian randomization evidence causally involved in acute coronary syndromes and the inflammation associated with it.
When you use an interleukin 6 antibody as Ridker did published in the Lancet recently, you can indeed suppress CRP in patients with coronary artery disease, as expected.
But canakinumab will not make it to the market and so we have to deal with other drugs and an old drug that may be used in a new disease and that's colchicine. Typically used for gout and you can see the formula and the plant that it is derived from.
And indeed colchicine not only interferes with tubule information and therefore cellular function but also interferes with NLRP3 that is activated by urate crystals as much as by cholesterol crystals. And therefore has a profound anti-inflammatory effect.
And in fact, this has been tested in two trials, the COLCOT trial and the LoDoCo trial, on the left and right respectively and you see there was a significant reduction in MACE. However, it was mainly the reduction in revascularization in COLCOT and infarction in Lodoco trials and not of mortality as such.
And here you see a meta-analysis of these trials. And you see, overall MACE are significantly reduced with a hazard ratio of 0.65. And when we look in detail, you can see mortality on top, not affected however, revascularization, myocardial infarction, and amazingly stroke was significantly affected. So, overall, a modest effect size so far. But the limitation of these trials is that patients were not selected as to whether they had marked inflammation or not as assessed by CRP levels.
There has been further studies on the effects of colchicine in myocardial injury in acute, myocardial infarction. So, in the first days of it, and this is the outline of the trial. It's a relatively small trial, randomizing a limited number of patients with acute coronary syndromes into placebo or colchicine, on top of standard therapy. And what they found is, that infarct size was unchanged under these conditions so the anti-inflammatory effects of colchicine in the acute setting are not demonstrable.
So I would like to end with rheumatoid arthritis, which is known to be associated with a two to three fold increased risk of myocardial infarction, low cholesterol levels, but high inflammation. So it's a good paradigmatic model to look at this in detail.
Now, when we look at the trial with methotrexate, that Paul Ridker did recently, there was no effect whatsoever of this very pathway. So maybe in rheumatoid arthritis, other pathways are important.
Indeed, we showed with David Hürlimann some years ago, when we looked at flow mediated dilation in patients with rheumatoid arthritis and no coronary disease, that their flow mediated dilation was markedly reduced, as you can see in the left panel. And TNF antagonists with infliximab significantly improved flow mediated dilation or endothelial function, so maybe TNF is more important in this context.
So with this I would like to summarize that inflammation is closely associated with CAD and ACS. It involves innate and adaptive immunity. It is driven by modified lipids and other antigens in the plaque. Anti-inflammatory therapy reduces plaque and thrombus formation, but recent trials were not convincing. So I think except for canakinumab, we need more data on other anti-inflammatory therapies in the future. And I'm sure that Paul Ridker will dwell on that. So with this, I would like to thank you for your attention.
This presentation by Thomas Lüscher is part of a series titled "Inflammation: The next therapeutic frontier in targeting cardiovascular risk". This series consists of an introduction, three lectures and a discussion in which four experts in this field will bring you up to date on the role of inflammation in atherosclerosis and how to translate findings from science and clinical trials into practice.
Professor Thomas Lüscher is affiliated with the Royal Brompton and Harefield Hospitals and Imperial College, London, UK and Center for Molecular Cardiology at the Universität Zürich, Switzerland.
This recording was independently developed under auspices of PACE-cme. The views expressed in this recording are those of the individual presenter and do not necessarily reflect the views of PACE-cme.
Funding for this educational program was provided by an unrestricted educational grant received from Novo Nordisk.
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