—  SPECIALTY CONFERENCE  —

Cardiovascular Pathology

Case 4 - Hypersensitivity in Cypher Sirolimus-eluting Stent / Accelerated Neoatherosclerosis in Taxus Paclitaxel-eluting Stent

Renu Virmani, CV Path, Gaithersburg, MD





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Clinical History
Case #4a: 67 year old woman with a history of acute MI and left circumflex (LCA) balloon angioplasty in 1999, BMS placement in LCA in 2000, DES (Cypher sirolimus-eluting stents) placement in LAD and LD1 in 2006, BMS placement in LD1 in 2007, and DES (Taxus Liberte Paclitaxel-eluting stents and Endeavor Resolute Zotarolimus-eluting stents) in RCA in 2007; presented with AMI and cardiogenic shock in April 2010.

Case #4b: 61 year old black male, with history of ischemic cardiomyopathy, ventricular and supraventricular arrhythmias, hypertension, hyperlipidemia, diabetes, acute and chronic renal failure, coronary artery stents in LAD and RCA 10 years ago (BMS), in LCX 9 years ago (BMS), and in RI 4 years ago (DES). The subject received AICD placement 8 years ago and replacement 2 years ago, and recent ablation; found deceased on floor at home.


Case 4a - Figure 1
low-power image of Cypher stent with vessel positive remodeling (Movat, 12.5x).
Case 4a - Figure 2
extensive fibrin accumulation behind and around struts (Movat, 40x).
Case 4a - Figure 3
fibrin accumulation and intense inflammation (Movat, 100x).
Case 4a - Figure 4
inflammation and uncovered struts (H&E, 100x).

Case 4a - Figure 5
extensive inflammation with eosinophil infiltration (Luna, 1000x).
Case 4b - Figure 1
low-power image of BMS implanted in RCA (Movat, 20x).
Case 4b - Figure 2
newly formed necrotic core within the in- stent area. A number of cholesterol crystals (needle- shaped) were identified in the core. (Movat, 100x)
Case 4b - Figure 3
low-power image of Taxus stent implanted in RI (Movat, 20x).

Case 4a - Figure 4
newly formed necrotic core around struts (Movat, 200x).
Case 4b - Figure 5
fibrous cap was infiltrated by inflammatory cells (H&E, 400x).

Introduction:
The advent of Drug-eluting stent (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. On the other hand, there is increasing concern over the risk of late stent thrombosis particularly following cessation of antiplatelet therapy. The clinical implications of LST are dire with a reported mortality of up to 45%.

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Case #4a: In the Cypher sirolimus-eluting stent implanted for 3.5 years in left anterior descending artery (LAD), there is extensive peri-strut chronic inflammation with lymphocytes, macrophages, eosinophils and focal granulomatous inflammation with multinucleated giant cells; multiple foci of malapposition of stent struts with extensive fibrin-rich thrombus interposed between stents and vessel wall. In the area of bare metal stent (BMS) implanted for 2.5 years in diagonal branch, there is up to 40% luminal narrowing by fibrous neointimal thickening with minimal inflammation.

Case #4b: BMS implanted for 10 years in proximal right coronary artery (RCA) showed peri-strut angiogenesis and newly formed necrotic core within the in-stent area. Taxus paclitaxel-eluting stent placed for 4 years in proximal and distal ramus intermedius (RI) demonstrated necrotic core formation around struts. The fibrous cap was thinned and infiltrated by macrophages and lymphocytes. There was adherent fibrin and platelet rich thrombus in the lumen area.

Differential Diagnoses:
Late DES thrombosis due to ;

i) Delayed arterial healing (Poor endothelialization, residual necrotic core prolapse, fibrin accumulation)

ii) Hypersensitivity

iii) Neoatherosclerosis

Final Diagnosis:
Case #4a - Hypersensitivity in Cypher sirolimus-eluting stent

Case #4b - Accelerated neoatherosclerosis in Taxus paclitaxel-eluting stent

Review of the Literature/Treatment Options:
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, which is a major risk factor for LST [1]. In addition, local arterial hypersensitivity with extensive eosinophilic infiltrate of the intima and media has been observed in cases of LST [2, 3]. 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, incomplete apposition, stent fracture, in-stent restenosis with superimposed thrombosis, and struts penetrating the necrotic core [4, 5, 6, 7]. Furthermore, emerging evidences suggest in-stent neoatherosclerosis as an important substrate for late stent failure for both BMS and DES especially in the extended phase. A recent histopathological study revealed that neoatherosclerosis in DES is more frequent and occurs earlier than in BMS likely from poor endothelialization or dysfunction [8].

Conclusion(s):
New stent technologies should aim both to inhibit neointimal proliferation and to promote endothelialization without compromising healing. Further modifications of stent design may overcome the problem of LST associated with current devices, which should improve early clinical outcomes of patients treated by interventional means.

References:
  1. Joner M, Finn AV, Farb A, Mont EK, Kolodgie FD, Ladich E, Kutys R, Skorija K, Gold HK, Virmani R. Pathology of drug-eluting stents in humans: Delayed healing and late thrombotic risk. J Am Coll Cardiol. 2006;48:193-202

  2. Virmani R, Guagliumi G, Farb A, Musumeci G, Grieco N, Motta T, Mihalcsik L, Tespili M, Valsecchi O, Kolodgie FD. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: Should we be cautious? Circulation. 2004;109:701-705

  3. Nebeker JR, Virmani R, Bennett CL, Hoffman JM, Samore MH, Alvarez J, Davidson CJ, McKoy JM, Raisch DW, Whisenant BK, Yarnold PR, Belknap SM, West DP, Gage JE, Morse RE, Gligoric G, Davidson L, Feldman MD. Hypersensitivity cases associated with drug-eluting coronary stents: A review of available cases from the research on adverse drug events and reports (radar) project. J Am Coll Cardiol. 2006;47:175-181

  4. Nakazawa G, Finn AV, Vorpahl M, Ladich RE, Kolodgie FD, Virmani R. Coronary responses and differential mechanisms of late stent thrombosis attributed to first generation sirolimus- and paclitaxel- eluting stents. J Am Coll Cardiol. 2011;In Press

  5. Nakazawa G, Yazdani SK, Finn AV, Vorpahl M, Kolodgie FD, Virmani R. Pathological findings at bifurcation lesions: The impact of flow distribution on atherosclerosis and arterial healing after stent implantation. J Am Coll Cardiol. 2010;55:1679-1687

  6. Nakazawa G, Finn AV, Vorpahl M, Ladich E, Kutys R, Balazs I, Kolodgie FD, Virmani R. Incidence and predictors of drug-eluting stent fracture in human coronary artery a pathologic analysis. J Am Coll Cardiol. 2009;54:1924-1931

  7. Nakazawa G, Finn AV, Joner M, Ladich E, Kutys R, Mont EK, Gold HK, Burke AP, Kolodgie FD, Virmani R. Delayed arterial healing and increased late stent thrombosis at culprit sites after drug-eluting stent placement for acute myocardial infarction patients: An autopsy study. Circulation. 2008;118:1138-1145

  8. Nakazawa G, Otsuka F, Nakano M, Vorpahl M, Yazdani SK, Ladich E, Kolodgie FD, Finn AV, Virmani R. The pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents. J Am Coll Cardiol. 2011;57:1314-1322