Transcript – Stent Choice When Treating Patients with COVID-19-Induced Cardiac Injury

Aloke Finn:

Hi, I’m Aloke Finn. I’m going to talk about stent choice when treating patients with COVID-19-Induced cardiac injury. We’re going to discuss the thromboresistance of different stents compared under simulated cytokine storm conditions. Here are my disclosures.

So, some background, 20% to 30% of patients with COVID-19 have evidence of cardiac injury, including troponin I elevation. And those with evidence of cardiac injury have increased mortality compared to those without. PCI may be indicated in some cases with COVID-19, yet it remains unknown what type of device is safest. COVID-19 can induce a cytokine storm, which is associated with hypercoagulation with excess risk of thrombosis, perhaps including stent thrombosis, and the potential effects with PCI and COVID-19 have not been studied systematically. As you can see here, there’s been some case reports suggesting increased risk of stent thrombosis.

At least in these four cases that had COVID-19. This was featured in TCTMD. A more recent study by Choudry et al. basically studied a consecutive series of patients with STEMI with and without COVID-19 and divided them up by stent thrombosis, multivessel thrombosis, modified thrombus grade, blush grade, and D-dimer. And you can see cases with COVID had greater evidence or greater risk of stent thrombosis, greater risk of multivessel thrombosis, greater modified grade thrombus, grade four or five. So larger amounts of thrombus in the coronary worst myocardial blush grade, significantly worse and greater D-dimer levels.

COVID 19 can induce a cytokine storm, and in this paper published in JCI Insight recently they compared patients with severe COVID infection versus non-severe COVID infection patients. As you can see here, patients with severe COVID disease, had greater requirements for oxygen than non-severe patients. They also had greater levels of inflammatory cytokines as indicated in the red circle. You can see cytokines such as IL-eight, IL-one beta, TNF-alpha, RANTES and MCP-one. IL-six were all greater in patients with severe COVID versus non-severe COVID. And the results basically suggested an overexuberant response of pro-inflammatory cytokines is involved with COVID 19 and severely sick patients. And basically serum IL-six and IL-eight were closely associated with disease progression.

The purpose of the following study was to compare the thromboresistance of different stents under cytokine storm conditions. We wanted to specifically examine the effects of a fluorinated polymer coated stent. That is the COBRA PzF stent versus an uncoated scent, verses an abluminally coated drug eluting stent, synergy in this case. So in this study, we drafty compared a thin Strut COBRA chromium stent. That is the COBRA BMS and identical COBRA chromium stent covered with a modified polythene AF fluorinated polymer called the COBRA PzF nanocoated stent. When we compare this to the synergy stent, which as you all know is a thin strut, platinum chromium drug-eluting stent with an abluminal PLGA bioabsorbable polymer coating, which alludes everolimus, the luminal surface of synergy. Notably it’s bare metal.

As you all know the relationship between medical device and thrombogenesis is extremely important, when a stent is placed in the body in the coronary artery, immediately we get platelets and fibrinogen prothrombotic aspects that adhere to the stent surface. The idea behind fluorinated polymers is that they absorb proteins less than just albumin highly, and that protein surface protects the stents from the prothrombotic effects of platelets and fibrinogen essentially preventing them from binding.

This is shown here in this experiment where they looked at the effects of the PVDF-HPF coordinate polymer versus stainless steel on binding albumin. You can see albumin absorption was much higher in the fluorinated polymer surface versus the stainless steel surface, including after elution with a detergent where the albumin stuck more highly to the fluorinated polymer surface, that also translated into less monocyte adherence to the surface for the PVDF-HPF fluorinated polymer versus stainless steel.

So the experimental setup, we used human whole blood, which was treated with 100 picograms per milliliter of TNF alpha. One of the pro-inflammatory cytokines associated with cytokine storm and 400 picograms per milliliter of IL-six and other cytokines associated with the cytokine storm. These concentrations were chosen in accordance with the highest blood levels and seen in patients with severe COVID-19. We use both nanocoated and uncoated COBRA-PzF stents, as I discussed, and a synergy stent, they were deployed in a flow loop system and circulated with cytokine-treated versus control blood for 60 minutes. We processed the stents for immunofluorescent staining for platelets, followed by scanning electron microscopy. When we compared platelet adhesion to the stents under cytokine storm and control conditions. As you can see here, the In vitro cytokine flow loop, simulating stent implantation in cytokine storm conditions, you can see each stent was placed in a separate flow loop condition with human blood flowing through simulating coronary shear rates. We use silicon tubing for this and the blood was circulated for 60 minutes. So what did this experiment show?

Well, you can see here when we compared non-cytokine storm conditions. And we looked at platelet adherence, which is shown here in red on this handbook from my class to be shown above it’s quite obvious. The coated COBRA PzF had much less platelet binding than the uncoated and synergy control stents.

Overall synergy had the most platelet binding versus the COBRA PzF uncoated stent. That’s shown here in the bar graphs, where we look at two separate aspects of platelet binding, both the platelet covered area under controlled conditions, as well as the staining intensity. And we basically multiplied these to get a platelet adhesion value. You can see synergy had by far the most platelet binding followed by the uncoated COBRA PzF and the coated COBRA PzF. And that’s shown here in the scanning electron microscopy, you can see that this is the coated COBRA PzF blood control. You can see there’s hardly any platelet binding shown on the struts, which correlates quite nicely between the SCM and the confocal microscopy was just a few platelets. The uncoated COBRA PzF under control conditions had more platelet binding than the coated stent that’s shown here on the example shown with the confocal and the matching scan electron microscopy as well as the high power views.

The synergy by far had the most platelet binding. You can see here shown on the confocal microscopy as well as the SCM. It was far more as I showed you in the synergy stent.

So how about under cytokine storm conditions? What happened well, you can see overall, there was more platelet binding under storm conditions. You can see here, the coated stent sorry, the COBRA PzF coated stent still had an advantage when it came to platelet binding shown in red as compared to the uncoated COBRA PzF stent, and the synergy stent. In addition, overall platelet binding was greater, but still the COBRA PzF stent performed the best in terms of platelet binding, as shown on the bar graph on the right with much less platelet binding, almost the same under cytokine storm and non-cytokine storm conditions versus the uncoated COBRA and the synergy stent, which both had far more platelet binding.

This is an example here of the high power SCMs. This is the coated COBRA PzF stent showing you very few platelets adhering, even under cytokine storm conditions.

Here is the uncoated COBRA PzF showing far more platelet binding, and that’s shown on the nice match SCM and confocal microscopy, and yet even more platelet binding on the synergy stent as shown here on the matching confocal and SCM.

So here… Now I’m going to compare the appearance of the platelet binding under coated COBRA PzF under control conditions versus cytokine storm conditions. And you can see in terms of the amount of platelet binding, they’re almost identical. There was really no difference in terms of platelet binding between the COBRA PzF still under control conditions and cytokine storm conditions. This was not the same for the uncoated COBRA PzF stent where there was significantly more platelet binding under cytokine storm conditions, and not under a control condition, suggesting again, that the cytokine storm does induce a hypercoagulability, which really is seen best in stents with a metallic bare metallic surface.

This was also seen in the synergy stent where really there was so much binding under control conditions, that there was really not a lot of difference seen between control and cytokine storm conditions, perhaps a little bit greater platelet adherence, but not a lot, perhaps because there was already so much platelet binding.

In conclusion. This is the first experimental examination of the performance of different stents under simulated cytokine storm conditions. The COBRA PzF stent should have the most favorable anti-thrombotic properties. This was seen under control conditions, although it was more pronounced under cytokine storm conditions, especially compared to uncoated control stent, and as well as the synergy stent.

Metallic surfaces, that is those seen in the uncoated COBRA and the synergy performed poorly compared to fluorinated polymer surfaces in terms of platelet adhesion and platelet adherence overall was highest in synergy regardless of conditions. Platelet adhesion was significantly increased under cytokine storm conditions in the uncoated, but not in the coated COBRA. The anti-thrombogenic properties can be attributed to unique nanocoating of the COBRA PzF and the use of COBRA PzF might be a promising treatment for COVID-19 patients given its thromboresistant profile. Thank you for your attention.