In-Stent Neoatherosclerosis as a Cause for High-Risk Non ST-Elevation Myocardial Infarction

The long-term success of drug-eluting stenting is limited by stent thrombosis and stent restenosis. In the case of drug-eluting stents, two of the potential mechanisms of late restenosis include inflammation-driven intimal hyperplasia and atherosclerosis with subsequent plaque rupture.^1,2 We present a case of a patient diagnosed with very late stent ‘thrombosis’ (VLST) that may have been caused by hyperplastic tissue versus progressive atherosclerosis and late plaque rupture, despite chronic immunosuppressant use.

Case Description

A 52-year-old male presented with rapidly progressive dyspnea on exertion, orthopnea, and paroxysmal nocturnal dyspnea over the past 3 days in the context of withholding clopidogrel for 7 days for a hydrocele repair. He denied anginal pain, but did note mild lower extremity swelling. His past medical history included diabetes, living donor kidney transplant requiring chronic mycophenolate and prednisone use, and coronary artery disease. Two years prior, he underwent percutaneous coronary intervention with one everolimus-eluting 2.25 x 12 mm stent placed in the left circumflex artery (LCX) and one 2.5 x 12 mm everolimus drug-eluting stent (DES) placed in the distal right coronary artery (RCA). Though hemodynamically stable, his exam was notable for respiratory distress and volume overload suggesting congestive heart failure. He was found to have ST-segment depressions in V3-V6, and a peak troponin I elevation of 84.58 ng/mL (normal 0-0.03 ng/mL). An echocardiogram demonstrated diastolic dysfunction and new left ventricular inferolateral hypokinesis. His coronary angiogram showed a thrombotically completely occluded mid-LCX stent and a chronic total occlusion of the RCA. During coronary angioplasty, manual aspiration thrombectomy was performed. A macroscopic tissue sample resembling neointimal tissue rather than friable thrombus was retrieved from the LCX (Figures 1-4). Given the small caliber of the prior stent and the satisfactory angiographic result post plaque removal, no further stenting was indicated. The patient was ultimately discharged uneventfully and was recovering well at follow-up.

Discussion

The rate of ‘very late stent thrombosis’ varies by study, ranging from as low as 0.5% at 3 years for zotarolimus- and everolimus-eluting stents in one study, to as high as 14.7% at 20 months for everolimus-eluting stents in another.^3,4

In-stent restenosis refers to the gradual development of lumen loss within a previously stented coronary artery segment. When the process leads to at least 50% restenosis and culminates in revascularization of the target vessel due to ischemic symptoms, electrocardiogram changes, or functional testing, this is known as ‘clinical restenosis.’⁵ Abstracting definitions of time course from the Academic Research Consortium definitions for stent thrombosis, clinical restenosis occurring greater than one year after stent implantation would be classified as ‘very late.’^6,7 In the case of drug-eluting stents, ‘very late’ stent restenosis is thought to arise from delayed healing and impaired endothelialization, and the resulting neointimal hyperplasia.^2,8 By contrast, abrupt stent thrombosis is most commonly associated with ST-elevation myocardial infarction and neointimal atherosclerotic plaque rupture.¹ And although inflammation is thought to play a role in the process of atherosclerosis in general, as well as neointimal hyperplasia and late stent restenosis in particular,^2,8-10 our patient nevertheless experienced late stent occlusion with a predominantly macroscopic tissue-based lesion rather than grossly thrombic material. The extracted tissue was elastic and non-friable, and did not fragment in heparin solution, which could suggest hyperplastic tissue as the predominant etiology. Alternatively, the extracted tissue may have been composed of platelet-rich thrombus from neointimal plaque rupture, which is the more common etiology of stent occlusion as demonstrated on imaging and pathology studies.^11-13 While histologic sections would be needed for definitive characterization, the development of VLST due to either hyperplasia or plaque rupture — particularly in a patient receiving a second-generation drug-eluting stent and already taking multiple systemic immunosuppressants — highlights the limitations of inflammation-centric theories of the mechanism of in-stent restenosis in the drug-eluting stent era.

References

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¹Cardiovascular Disease Fellow, PGY-5, University of South Dakota Sanford School of Medicine; ²Internal Medicine Resident, PGY-3, University of South Dakota Sanford School of Medicine; ³Professor of Medicine, University of South Dakota Sanford School of Medicine, Sanford Cardiovascular Institute, Sioux Falls, South Dakota

Disclosures: The authors report no conflicts of interest regarding the content herein.

The authors can be contacted via Dr. Chirag Kirit Desai at chirag.desai@sanfordhealth.org.