Case 1 -

Interventional Cardiovascular Pathology Elena R. Ladich CVPath Institute, Inc. Gaithersburg, MD

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Cypher Stent In Left Circumflex Artery With Late Stent Thrombosis (LST) Introduction Since their commercial introduction in 2003, drug eluting stents (DES) have rapidly altered the management of coronary artery disease. Prior to their development, the percutaneous management of coronary artery disease was performed predominantly by implantation of bare metal stents (BMS). Although BMS technology dramatically lowered the rate of restenosis compared with balloon angioplasty, in-stent restenosis secondary to neointimal proliferation remained an important clinical problem. The advent of DES has substantially reduced the incidence of restenosis after stent implantation. The stents act as a vector for local drug delivery altering in-stent pathophysiology by delivering high concentrations of antiproliferative compounds directly to the site of arterial injury. Two FDA approved DES are currently in use-- Cypher (sirolimus-eluting) and Taxus (paclitaxel-eluting). Drug delivery from the stent platform is controlled through polymer-based drug release. Clinical trials have shown that DES have reduced the rate of angiographic restenosis by as much as 70% to 90% compared with BMS, however, there is increasing concern over the risk of late stent thrombosis (> 30 days post implantation) particularly following cessation of antiplatelet therapy. Although the rate of late thrombosis appears to be similar in BMS and DES in clinical trials up to 12 months, in "real world" clinical practice there is an increase in LST for patients with DES. The clinical implications of LST are dire with a reported mortality of up to 45%. Case 1 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 1 - Figure 1 - Platelet-rich thrombus around stent strut with persistent peri-strut fibrin (Movat x 10) Case 1 - Figure 2 - Lumen with occlusive platelet-rich thrombus (Movat x 2) Case 1 - Figure 3 - Giant cells around stent struts (Movat x 20) Case 1 - Figure 4 - X-ray showing Cypher stent in left circumflex artery Pathology of Coronary Artery Stenting Neointimal Proliferation With the introduction of coronary artery stenting, a variety of pathologic responses related to device implantation have been observed. Examination of postmortem human coronary arteries demonstrate that after stenting, arteries follow a response to injury pattern of wound healing. Thrombus deposition and acute inflammation are followed by a granulation tissue response with neovascularization, smooth muscle proliferation and migration, and the replacement of acute by chronic inflammatory cells. Restenosis after stenting occurs secondary to the accumulation of smooth muscle cells and extracellular matrix (ECM). The ECM contains varying concentrations of proteoglycans, hyaluronan, and collagen (types I and III). The ECM modulates important events within the developing neointima including cell proliferation, migration, growth factor expression and remodeling. Proteoglycans and hyaluronan are synthesized by smooth muscle cells and participate in regulation of vascular permeability, lipid metabolism, and thrombosis. The neointima remodels over time with changes in proteoglycans and replacement of type III collagen with type I collagen. In summary, neointimal hyperplasia is a proliferative maladaptive healing response to stent implantation and injury. Late Stent Thrombosis (LST) The major pathologic finding distinguishing DES from BMS is demonstration of significant delay in arterial healing characterized by persistent peristrut fibrin deposition, a decrease in smooth muscle cells, and poor endothelialization. Delayed healing has been demonstrated in both Cypher and Taxus DES at autopsy and is a major risk factor for LST. In addition, local arterial hypersensitivity with extensive eosinophilic infiltrate of the intima and media has been observed in cases of LST. It has been postulated that a combination of factors including delayed endothelialization due to antiproliferative drugs and/or persistence of the nonerodable polymer contribute to the hypersensitivity reactions. Other factors associated with LST include stent malapposition (arterial wall expansion), stenting over major branch points, stent length, incomplete apposition caused by suboptimal stent deployment, in-stent restenosis with superimposed thrombosis and struts penetrating the necrotic core. Breaching a necrotic core may lead to the exposure of thrombogenic lipid content to flowing blood. New stent technologies should aim to inhibit neointimal proliferation and promote endothelialization without compromising healing in order to avoid late thrombotic complications. Selected References: Farb A, Burke AP, Kolodgie FD, Virmani R. Pathological mechanisms of fatal late coronary stent thrombosis in humans. Circulation, 2003; 108: 1701-1706 Virmani R. Guagliumi G, Farb A, Musumeci G, Grieco N, Motta T, Mihalcsik L, Tespili M, Valsecchi O, Kolodgie F. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious? Circulation 2004; 109: 701-705 Joner M, Finn A, Farb A, Mont E, Kolodgie F, Ladich E, Kutys R, Skorija K, Gold HK, Virmani R. Pathology of drug-eluting stents in humans. J Am Coll Cardiology, 2006; 48: 193-202. Farb A, Weber D, Koldogie F, Burke A, Virmani R. Morphological predictors of restenosis after coronary stenting in humans. Circulation 2002; 105: 2974-2980 Moses, JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. NEJM 2003; 349: 1315-1323.