Targeting Inflammation to Reduce Conduction Complications After TAVI

What is the current evidence linking perioperative inflammation to the development of conduction disturbances following transcatheter aortic valve implantation?

The current evidence mainly stems from three main areas: from a mechanistic point of view and from an observational point of view, and even from a randomized trial evidence point of view. The mechanistic point of view, which is the direct evidence that we have, comes from the local and systematic inflammatory markers previously observed to increase within the first few days after the procedure.² Those markers kind of peaked during the same time when we observed the conduction disturbances to also peak after the operation. This was the first mechanistic evidence that there might be some inflammatory component to the development of post-TAVR conduction disturbances, and not just only the traditional mechanical reasons that we always thought to be responsible. The observational evidence came afterwards from studies like our previous study in JAHA that observed that giving colchicine to patients before TAVR could reduce the risk of post-procedural low-grade conduction disturbances.³ While the current analysis we are presenting here at EHRA extended tis line by exploring the use of steroids before the procedure and the risk of inflammatory conduction disturbances after the procedure, which showed even stronger findings that steroids reduced the risk of permanent pacemaker use. And finally, the randomized evidence came from the pivotal Co-STAR trial (NCT04870424) that was just concluded a few months ago and published in Nature Communications, which also showed that among 120 patients, there was a reduction in the permanent pacemaker use.⁴ Fortunately, the GLUCO-TAVR trial (NCT06076824) is currently ongoing to provide further randomized evidence on the principle.⁵

How significant is the contribution of inflammatory pathways compared with mechanical factors in driving post-TAVI conduction abnormalities?

I think so far, it’s not quantified how much of the contribution is from inflammation versus mechanical factors. Our guess is that mechanical contribution is still the main factor, but inflammation kind of aggregates that contribution or can be a risk modifier. So patients might have mechanical triggers that are then aggravated or exacerbated by the presence of inflammation resulting in more prolonged or more serious conduction disturbances. However, a very interesting part here is that we do believe there is an independent association between inflammation and those conduction disturbances, because many of those conduction disturbances are temporary in nature. And frequently when we wait for days, those resolve on their own; if this is by only mechanical nature, it shouldn’t resolve that fast. So, we believe this could be a temporary effect from an inflammatory independent nature, regardless of the presence of a mechanical factor.

What strategies to mitigate perioperative inflammation show the most promise in reducing the risk of conduction disturbances?

So far, we can’t say that there is a certain strategy that is proven effective in reducing this. However, the evidence that we currently have from the current studies that were published are about two main agents, which are colchicine in the trial and in our previous study, as well as the use of systemic steroids in our current analysis and in the ongoing trial. Those two agents are strong potent, especially for steroids, anti-inflammatory agents, and the strongest factor or the strongest agent to actually reduce the risk with a reasonable effect size was steroids. It’s important to notice that those two agents were only studied in observational studies, and even in the Co-STAR trial, it was prematurely halted due to safety concerns. So we can’t say that this is strict evidence to be implemented in practice currently, but it opens the door for us to explore this more.

Now, this is one strategy to mitigate this. The second strategy that’s more promising and that we vouched for during the EHRA is to coat the valve with an anti-inflammatory or immunomodulatory agent that could redefine how inflammation is dealt with after the procedure. And if this is proven promising, this can give the patients the benefit of reducing post-operative conduction disturbances and the need for permanent pacemaker while yet sparing them the systemic side effects of strong medications like steroids. And finally, other potential agents that might be further explored include other anti-inflammatory agents like monoclonal antibodies that could be targeted against other inflammatory markers like interleukins. But this is still in theory, and there is currently no evidence to support any of this.

Could valve coating technologies realistically modulate the local inflammatory response? And what are the key considerations in their development?

Yeah, a very important point. And I think, yes, it could modulate the local inflammatory response because if the main mechanism of having those inflammatory responses is due to localized nature, coming from the injury of the endothelium by the valve or from the expansion of the valve itself or ischemia-reperfusion injury. All of this can be mitigated if the valve could release a localized targeted anti-inflammatory agent that would prevent all of this from happening in the early time after the procedure. And the main considerations, in my opinion, that should be considered when developing a technique like this is to make it prevent inflammation as early as possible after the procedure while yet not affecting the reendothelization and healing process itself, which would prevent complications like valve dislodgement or the risk of thrombosis from happening.

Based on your findings, do you see a role for routine anti-inflammatory approaches or device innovation in reducing the need for permanent pacing after TAVI?

Definitely. In our current analysis, we found that there is a third reduction in risk of needing permanent pacemakers in patients exposed to steroids. This is a promising finding so far. In the Co-STAR trial, the authors also found that colchicine reduced the need for permanent pacemaker, although with a smaller effect. This could suggest some form of a dose response relationship where the higher and more potent the anti-inflammatory agent is, the stronger the effect that we can expect. And so, yes, so far, the current evidence is promising and justifies the effort and need to further explore this pathway for how much impact it can have for those patients if they can be spared a permanent device inserted in their hearts for the rest of their life. We do not want to treat aortic stenosis but then getting our patients discharged with a permanent device, with its whole wide scope of complications and side effects.