Dear colleagues, let me thank the organizers for this opportunity to discuss with you a fascinating topic: the anti-inflammatory treatment of ischemic heart disease.

It all started long ago, in 1994, when we published this study in the New England Journal of Medicine, inspired by Attilio Maseri. Until that time, the emphasis had been on platelets, thrombus, lipids, but not on inflammation.

This was the first study putting inflammation on the map, simply showing that among patients with an acute inflammatory syndrome, patients with higher levels of CRP, C reactive protein, a marker of inflammation, had a much worse outcome.

And then during the following 20 years, several studies have shown convincingly, that inflammation is important in all stages of atherosclerosis, starting with fatty streaks, up to plaque disruption. And both innate and adaptive immunity are involved in this

process.

But we have to wait for 2017 to have the final convincing proof of the inflammatory hypothesis. Then this came with the CANTOS trial, published by Paul Ridker. In this study, patients with a recent MI were randomized to placebo or three increasing doses of canakinumab, an important interleukin-1β antagonist.

A pure anti-inflammatory treatment, which, as you can see, didn't affect lipids, nor hypertension. Of course this potent anti-inflammatory treatment resulted in a marked reduction of CRP levels, and, importantly, was associated to a significant reduction of ischemic events. Again, proof of the concept of the inflammatory hypothesis, for the first time.

And, in particular, patients with the lowest levels of C-reactive protein during treatment, the red line, had the best outcome. Confirming, again, the working hypothesis, proposed in 1994.

But we had problems with CANTOS. The first problem is that the benefit was there, was significant, but really, from a clinical standpoint, quite limited. There was no difference in total mortality and a higher risk of fatal infections with canakinumab, versus placebo.

And then, with interesting data, with an old molecule, much older than canakinumab, colchicine. Colchicine is a potent, anti-inflammatory drug, which inhibits the inflammasome, interferes with neutrophil function, and also interferes with neutrophil-platelet interaction.

Well, for trials, two in particular, prove the benefit of colchicine. The first trial is LoDoCo 2, in which patients with chronic coronary disease were randomized to colchicine versus placebo. And you can see a significant reduction of ischemic events. And then the COLCOT trial in patients with a recent MI, which gave the same signal; a remarkable reduction of ischemic events.

And this is a very comprehensive meta-analysis of four trials, published in the European Heart Journal, showing a 22% reduction in myocardial infarction, 46% reduction in stroke, 23% reduction in coronary revascularization, but no reduction of cardio-vascular death. And then, in this very accurate meta-analysis, focused on fatal events in these four trials with colchicine, I published with Domenico D'Amario, we found that non-cardiovascular mortality was higher in patients randomized to colchicine. Thus cardiovascular mortality was significantly reduced, but non-cardiovascular mortality was significantly increased and in these four trials total mortality didn't change. So, we have here an important signal of safety which we cannot ignore.

And these are the challenges which, in my opinion, we face. One challenge is the identification

of patients susceptibility to the beneficial effects of anti-inflammatory therapy. I think that perhaps not all patients are equally susceptible to an anti-inflammatory treatment, and in particular, as we will see, we have two very different mechanisms of coronary instability: fissure and erosion. Another challenge is that we must have evidence that the benefits of immune system inhibition outweigh the systemic immunosuppressive effects. It is a complex balance between benefit and damage. And then another window of opportunity is represented by plaque healing.

But let's come first to plaque fissure versus erosion. This is a typical example of plaque fissure, complicated by thrombus formation. Well, the mechanism of plaque fissure and erosion are different.

In this recent study, we compared plaque fissure versus erosion, assessed by OCT, and we found that this very aggressive subset of T-cells, called CD4+CD28null T-cells. This subset is very aggressive and was expanded in patients with an acute syndrome and plaque fissure, as compared to stable angina and patients with an acute syndrome, but with plaque erosion. So, this potent activation of adaptive immunity was found in fissure, but not in erosion.

And here, we come to plaque erosion. You can see a solid fibrotic plaque with no fissure, but this solid fibrotic plaque kills the patient with thrombus formation.

And long ago, in 2010, with Giampaolo Niccoli and Renu Virmani, for the first time, we found that the mechanism of erosion and fissure are different. In plaque erosion, you can see that the thrombus is characterized by the presence of cells, positive for myeloperoxidase (MPO). While in plaque fissure, MPO was not expressed in cells, contained in the thrombus at the site of plaque fissure.

And in this recent study, we found another remarkable difference between fissure and erosion. Indeed, we assessed in peripheral blood cells, the presence of hyaluronidase-2 I will tell you what it is. And Hyal-2 was more expressed in patients with erosion as compared to patients with fissure. And also another molecule involved in hyaluronan-metabolism was highly expressed in blood cells, in peripheral blood cells of patients with erosion versus fissure.

And putting together this data and also other data coming from experimental studies,

in particular published by Professor Libby and his group, we can perhaps build up a hypothesis explaining plaque erosion. And in this working hypothesis, hyaluronan metabolism is particularly important. Well, in the presence of disturbed local flow, we observe the overexpression of toll-like receptors on endothelial cells. Then monocytes, if they are very rich in Hyal-2 expression, this results in the production of low molecular weight-hyaluronan, from high molecular weight-hyaluronan. And this makes a difference because high molecular weight-hyaluronan is inactive, it is not proinflammatory, while after conversion in low molecular weight-hyaluronan, this is proinflammatory. In particular, it is a ligand of toll-like receptor 2 which leads to endothelial cell-detachment and denudation. In addition, these fragments of low molecular weight-hyaluronan are also a ligand of CD44, expressed in polymorphonuclear cells. And in addition, low molecular weight-hyaluronan also promotes platelet-monocyte binding and their interaction and this explosive situation can eventually lead to thrombus formation. Again, a working hypothesis showing that anyway mechanism of erosion and mechanism of fissure are different. And this is important when we come to anti-inflammatory treatment of ischemic heart disease, and acute coronary syndrome.

And then another challenge we are facing is that we need drugs, which have a benefit without creating damage. And, as you can imagine, the balance between immune system-inhibition and the side effects of this inhibition, is not easy to reach.

And here you have a nice review published recently by Claudia Monaco. These are the immunotherapies tested in completed and ongoing trials. In green, you can see the successful stories, in particular, canakinumab and colchicine. And in blue, ongoing trials testing new anti-inflammatory treatments. Again, here we need a drug where the balance between benefits and damage is positive.

And I close with another opening, another interesting window, which is plaque healing. Well, so far we've focused our attention on plaque disruption. It can be erosion, it can be fissure, but plaque disruption.

What we are learning, what we have summarized in this review, published in the New England with Rocco Vergallo, is that in the majority of cases, both erosion and fissure, they do not produce overt symptoms, do not result in an acute coronary syndrome, but in the majority of cases, both erosion and fissure are subclinical, because they can heal. This leads to an aggravation of the hemodynamic effects of the atherosclerotic plaque, but in the absence of an acute event. Again, plaque can cause clinical syndromes, it can cause an acute coronary syndrome, but the majority of fissure and eroded plaque eventually heal, thanks to this healing process.

And in this study, we found something which I think is interesting. We compared the prevalence of healed plaques in three populations; patients with recurrent acute coronary syndrome, on the left, patients with stable angina, and patients with a single acute event, followed by a long period of stability. And you can see that the prevalence of plaque healing is much higher in patients with stable angina, with a long history of chronic stable angina, as compared to what we have seen in patients with recurrent acute episodes. So, plaque healing really can promote stability of ischemic heart disease.

One challenge we can consider, one therapeutic opportunity we have in front of us, is to transform patients, who are poor healers leading to repeated acute events in good healers, characterized by clinical stability. And in this setting, we have, again, a long list of possible therapeutic interventions we can consider and explore in the future.

And then we come to my last slide. It is a fascinating topic anti-inflammatory treatment

of ischemic heart disease. It all started in 1994. This working hypothesis has been proved by CANTOS trial, but a lot remains to do, because we need a drug, which really is beneficial without creating substantial damage. And the balance, again, in this setting, is quite complex. And this is why I close with these important words, written by Winston Churchill: "It is not the end. It is not even the beginning of the end. But at this stage, it is just the end of the beginning." And I wish to thank you for your kind attention.

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