Soluble Mediators of Microvascular Dysfunction — Identifying the Invisible Culprits?

Percutaneous intervention of saphenous vein grafts is associated with approximately 20% risk of major adverse cardiovascular events secondary to decreased antegrade flow or “no-reflow” during the procedure.¹ The mechanism of this phenomenon is probably multifactorial and involves microvascular dysfunction and potentially platelet-mediated loss of capillary autoregulation. Since the typical vein graft lesion is friable with large plaque volume, it may be that embolization of thrombotic and atheromatous material during the intervention is the trigger that starts a cascade of events, leading to microvascular obstruction.² In addition to particulate obstruction, we have learned to recognize the importance of soluble mediators that may play a key role in this process.³ Distal embolization and no-reflow are serious complications of vein graft intervention and are associated with significant long-term morbidity and mortality.⁴ The most effective method for preventing microvascular embolization during vein graft intervention is the use of distal protection devices.^1,5,6 These devices have shown to reduce the incidence of no-reflow, and they are routinely used today in clinical practice. These include the GuardWire^®(Medtronic Vascular, Minneapolis, Minnesota) system which transiently occludes the vein graft during PCI with a balloon inflated via a 0.014 inch hypotube. Liberated particles or vasoconstrictors are removed by aspiration before balloon deflation and restoration of antegrade flow. The second prototypic embolic protection device is the FilterWire^™ EZ (Boston Scientific, Natick, Massachusetts) which captures release particles in a porous mesh, the advantage of which is to maintain antegrade perfusion during the intervention. Post-percutaneous coronary intervention (PCI), the filter is retrieved using a capture sheath. The randomized FIRE trial demonstrated that saphenous vein graft (SVG) PCI with the FilterWire EZ was not inferior to intervention performed with the GuardWire System.⁵ Interestingly, despite the fact that both devices have similar clinical efficacy at reducing distal embolization preventing no-reflow as shown in the FIRE trial,⁵ rigorous particulate analysis was not performed; therefore, it is not clear which device was more efficient at particle removal. Theoretically, it is also possible that these devices differ in their ability to trap soluble moieties responsible for the changes in the microcirculation that are observed during no-reflow.³ In this issue of the journal, Salloum and colleagues⁷ reported an interesting observational study examining several vasoactive molecules released during vein graft intervention and that may be implicated in the development of no-reflow. The investigators measured several vasoactive molecules in 28 patients (34 lesions in 31 vein grafts) referred for vein graft intervention. Distal protection was achieved in all the cases with the GuardWire. The investigators obtained blood samples from the target vessel using the Export catheter at baseline followed by two consecutive samples after stenting. Multiple assays were performed in this study including molecules involved in vasoconstriction (endothelin and serotonin), thrombotic factors (tissue factor, plasminogen activator inhibitor, thrombin/antithrombin III complex, and prothrombin fragment), as well as inflammatory mediators such as soluble CD 40 ligand. Vein graft stenting resulted in a significant elevation in most of all these factors, adding to the theory that distal embolization and no-reflow is multifactorial and mediated by vasoconstrictive, thrombotic and inflammatory factors. This is the first report to document the release of specific vasoactive substances during vein graft stenting. Several of these molecules have been implicated in acute coronary events.^8–11 These findings are particularly important today as we attempt to understand the importance and potential role of soluble factors in the pathogenesis of no-reflow. However, this study has not proven a causal link between these vasoactive substances and no-reflow. Paik and colleagues created a porcine model of reduced flow by injecting an infusate of macerated thrombus in the coronary arteries of pigs who were pretreated with a nitric oxide inhibitor L-NAME.¹² Golino also demonstrated elevated coronary sinus levels of serotonin following PTCA, which was associated with epicardial vasoconstriction. This effect was blocked by the serotonin inhibitor ketanserin.¹³ Taken together, these studies suggest a putative role for these vasoactive substances in the pathophysiology of no-reflow. In the present study, the concentration of most of the vasoactive substances was successfully reduced from the target vessel to levels that are significantly lower than post-stenting levels, suggesting that balloon occlusion distal protection devices efficiently remove these substances before they can exert their deleterious effects on the microvasculature. It is unlikely that embolic protection filters, with their inherent porosity, would achieve similar effects. Protection of microvascular function is the goal of embolic protection. This must encompass protection from “what is seen and unseen.”

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