Pathology of Drug-Eluting Stents in Humans
Delayed Healing and Late Thrombotic Risk
Michael Joner, MD*,1,
Aloke V. Finn, MD ,1,
Andrew Farb, MD ,
Erik K. Mont, MD ,
Frank D. Kolodgie, PhD*,
Elena Ladich, MD*,
Robert Kutys, MS*,
Kristi Skorija, BS*,
Herman K. Gold, MD and
Renu Virmani, MD*,*
* CVPath, International Registry of Pathology, Gaithersburg, Maryland
Cardiac Unit, Department of Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts
Miami Dade County Medical Examiner Department, Heart Radiology, Miami, Florida
Interventional Cardiology Devices Branch, U.S. Food and Drug Administration, Rockville, Maryland
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Figure 1 Flow diagram illustrating cause of death in drug-eluting stents (DES) patients with stents in place >30 days. These cases are divided into three major categories depending on whether stents showed evidence of late thrombosis, were patent, or were restenotic. AMI = acute myocardial infarction; SCD = sudden cardiac death.
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Figure 2 Line chart comparing the percentage of endothelialization in drug-eluting stents (DES) versus bare-metal stents (BMS) as a function of time. Note that DES (solid line) consistently show less endothelialization compared with BMS (dashed line) regardless of time point. Even beyond 40 months DES are not fully endothelialized, whereas BMS are completely covered by 6 to 7 months.
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Figure 3 Mechanisms of late stent thrombosis in ostial and bifurcation stenting. (A to D) Radiograph and histologic sections (Movat pentachrome) from a 77-year-old man who had two stents placed in the native left anterior descending coronary artery (LAD) for stable angina 450 days before sudden cardiac death. (A) Radiograph of the LAD with two stents in place, a proximal Cypher and a distal bare-metal stent (NIR). The Cypher stent struts (*) protrude into the ostium of the left circumflex artery (LCx). (B) Section taken from the proximal Cypher stent, which is totally occluded by a platelet-rich thrombus while distally it is patent (C) with minimal neointimal tissue. The NIR stent (D) in the distal LAD demonstrates 50% in-stent area stenosis consisting of neointimal tissue composed of smooth muscle cells in a proteoglycan/collagen matrix with absence of fibrin. (E to H) Radiographs and histologic sections (Movat pentachrome) from a 68-year-old black woman with a history of stenting of the LCx and left obtuse marginal (LOM) using the crush technique (Taxus to LCx and Cypher to LOM) 172 days before death. She presented 2 days before her death with acute myocardial infarction and was taken to the catheterization laboratory, where 90% occlusion of the LCx near the LOM take-off was found. The LCx artery was opened with balloon angioplasty, but the patient died of complications shortly thereafter. (E) Cypher struts within LOM and fracture of the Taxus stent after the LOM take-off. Histologic sections taken proximal to the bifurcation (F) and at the LCx/LOM bifurcation (G) show thrombus (Th) in the LCx (Taxus), whereas the Cypher stent is covered by neointimal growth. Two struts with overlying thrombus are shown at high power in H. Note the absence of neointimal coverage of the Taxus struts with overlying thrombus.
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Figure 4 Histologic sections of the stented artery from a 38-year-old woman who had undergone stenting of the proximal left anterior descending coronary artery (LAD) with a 3.0 x 12-mm Taxus stent 6 months before death. The patient had been taking clopidogrel and aspirin, but presented to a local emergency room with severe chest pain and shortly thereafter went into ventricular fibrillation and died. (A) Radiograph of the stented LAD. (B and C) Proximal and middle sections of the stented LAD stained with Movat pentachrome and hematoxylin and eosin (HE), respectively. There is total occlusion of the lumen by platelet-rich thrombus (Th) with absence of healing of the stent strut regions, which are surrounded by fibrin. The stent is placed across the orifice of the diagonal branch. High-power view of the stent struts in D (Movat) and E (HE) show peristrut fibrin with absence of smooth muscle, endothelial, and inflammatory cells.
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Figure 5 Histologic sections stained with hematoxylin and eosin (HE) from patent drug-eluting stents (DES) and bare-metal stents (BMS) from various time points. Coronary arteries with Cypher (A) and Taxus (B) stents at 68 and 57 days, respectively. High-power views showing inflammatory infiltrate around Cypher struts (C) including eosinophils (inset Luna stain), whereas around the Taxus stent struts (D) there is a predominance of fibrin. At 130 and 124 days, respectively, there is focal fibrin deposition and giant cell reaction seen around the Cypher stent (E), whereas in the Taxus stent (F) there is greater inflammation including eosinophils (inset Luna stain). A BMS at 124 days is shown in G and H.
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Figure 6 A 65-year-old man suffered traumatic injury to the head resulting in death. This patient had received two stents in the left anterior descending coronary artery (LAD), a proximal Cypher and a distal Bx Velocity 15 months before death, which were found to be patent at autopsy. A (Cypher) and D (Bx Velocity) are radiographs of the stented LAD segment. All sections shown have been stained with Movat pentachrome. (B) Histologic section of the Cypher stented artery showing minimal coverage of the struts by fibrin. (C) High-power magnification showing peristrut fibrin with rare endothelial cells but no luminal thrombus, whereas inflammation and smooth muscle cells are only rarely observed. (E) Section of the Bx Velocity stent. There is abundant neointimal tissue consisting of smooth muscle cells in a proteoglycan collagen matrix and an overlying endothelium. (F) High-power section of the boxed area in E. Lymphocytes are present around the stent strut with minimal fibrin underneath the strut. The luminal surface of the stent is covered by smooth muscle cells in a proteoglycan/collagen rich matrix.
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