In-Stent Neoatherosclerosis Tied to Plaque Progression in Untreated Arteries

In-stent neoatherosclerosis is associated with plaque progression in native coronary arteries after DES implantation, according to a small OCT study published online June 3, 2015, ahead of print in the European Heart Journal. The findings suggest the mechanisms of the 2 pathologies are similar.

Implications:  In-Stent Neoatherosclerosis Tied to Plaque Progression in Untreated ArteriesMoreover, the results may have “important clinical implications for the development… of strategies to prevent [neoatherosclerosis] among patients undergoing PCI,” note Lorenz Räber, MD, PhD, of Bern University Hospital (Bern, Switzerland), and colleagues. This may include high-dose statins, which are known to attenuate atherosclerosis, they add.

The investigators looked at 88 patients with 88 lesions from the SIRTAX-LATE OCT study who had been randomized to PCI with a sirolimus-eluting stent (SES) or a paclitaxel-eluting stent (PES). Atherosclerosis progression was evaluated in untreated major epicardial vessels by QCA at baseline and 5 years. In addition, neoatherosclerosis—defined as fibroatheroma or fibrocalcific plaque at least 1 mm long within the neointima of a stented segment—was assessed by OCT at follow-up.

Neoatherosclerosis was seen in 14 lesions (15.9%); 9 were identified as fibroatheromas, 4 as fibrocalcific plaques, and 1 as containing both types of disease. In 4 cases, there were multiple neoatherosclerotic lesions in the same stent. The most common OCT findings potentially related to neoatherosclerosis—seen in 31.8% of stents—were signal-rich bands, which the authors say are suggestive of macrophage accumulation.

Baseline clinical, angiographic, and procedural characteristics were similar between patients with and without neoatherosclerosis, as was medication use over 5 years. In addition, there were no differences in lipid levels at baseline or 5 years, or in LDL reduction or HDL change over follow-up. However, neoatherosclerosis was over 5 times more common in PES-treated than SES-treated lesions (25.5% vs 4.9%; P = .009).

OCT also showed thicker neointima (P = .001), a larger neointimal area (P = .003) and percent volume obstruction (P = .001), and fewer protruding stent struts (P = .023) in lesions with vs without neoatherosclerosis.

Plaque Progression Greater With Neoatherosclerosis

Plaque progression over 5 years was assessed in 704 native coronary artery segments. Minimal lumen diameter (MLD) was reduced regardless of the presence of neoatherosclerosis, but the change was more pronounced in patients with vs without such lesions (-0.25 mm vs -0.13 mm; P = .002). Similarly, the increase in percent diameter stenosis was higher in those with neoatherosclerosis (6.0% vs 4.3%; P = .048).

At 5 years, non-TLR (primary clinical endpoint) was more common in patients with neoatherosclerosis, while non-TVR showed a trend in that direction (table 1).

Table 1. Clinical Events at 5 Years by Presence of Neoatherosclorosis

Clinical follow-up 4 years after OCT showed no differences in events between the groups.

According to the authors, the mechanism underlying neoatherosclerosis is likely multifactorial. It may occur “in the context of incompetently regenerated endothelium, which results in excessive uptake of circulating lipids and [leukocytes],” they say.

Previous observations that neoatherosclerosis is less frequent and occurs later after BMS vs DES implantation may indicate that the antiproliferative agents released by DES contribute to the problem, Dr. Räber and colleagues suggest. Moreover, because neoatherosclerosis is more likely to develop in patients with a progressive atherosclerosis phenotype over the long term, similar factors appear to contribute to both conditions.

Neoatherosclerosis Linked to Stent Thrombosis

Although the clinical impact of neoatherosclerosis has not been prospectively studied, observational data suggest a link between affected lesions and stent failure, the investigators note. In imaging studies and case reports, neoatherosclerosis has been identified as the culprit behind delayed in-stent restenosis and stent thrombosis, the authors report. “Accordingly, [it] may represent an accelerated and possibly more unstable manifestation of atherosclerosis,” they add.

In an accompanying editorial, Michael Joner, MD, and colleagues from the CVPath Institute (Gaithersburg, MD) say the study provides “valuable insights into the prospective evaluation of neoatherosclerosis,” which until now has mainly been investigated retrospectively at autopsy.

The study “suggests the implementation of more intense risk modification in patients diagnosed with neoatherosclerosis by OCT,” the editorialists write. However,  patients undergoing invasive imaging may be at much higher risk than asymptomatic patients not in clinical trials. “Therefore, it remains unclear… if the observed frequency of neoatherosclerosis is representative of contemporary clinical practice or rather reflects an incidental finding of a selected group of patients undergoing invasive surveillance imaging,” they say.

Don’t Expect Newer DES to Solve the Problem

A recent study showed about a 4-fold higher prevalence of neoatherosclerosis in first-generation compared with second-generation DES, Dr. Joner and colleagues note. However, they point out, stent type did not independently predict neoatherosclerosis and the difference was likely due to the fact that first-generation DES had been implanted for a longer time.

The prevalence of atherosclerosis can be affected by several factors, the editorialists observe. For example, the current analysis used a more stringent definition than previous studies that requires the presence of more advanced disease, they explain. Moreover, neoatherosclerosis may have been underdiagnosed by examining only patients who survived event-free for 5 years, they say, while those prone to more rapid progression of atherosclerosis in native or stented arteries were likely excluded.

Agreeing that native atherosclerosis progression and in-stent neoatherosclerosis seem to have a similar etiology and pathophysiology, the editorialists also point to a potentially important distinguishing feature between the 2 diseases: foamy macrophage infiltration early in neoatherosclerosis formation.

And in an email with TCTMD, Seung-Jung Park, MD, PhD, of Asan Medical Center (Seoul, South Korea), questioned whether “the mechanism of native coronary atherosclerosis can explain the entire process of in-stent neotherosclerosis as a mechanism of stent failure.” Rather, he said, the process of neoatherosclerosis is heterogeneous and time-dependent, being affected not only by individual atherosclerosis risk factors but also by local conditions, including biological reactions with various stents and fluid hemodynamics.

Although using statins to promote regression of neoatherosclerosis “theoretically makes sense, it should be proven in prospective trials,” he added.

Overall, the study “not only highlights the importance of dedicated studies to advance our understanding of this novel disease manifestation but also raises concern that effective implementation of secondary prevention measures has not yet been achieved,” Dr. Joner and colleagues conclude.


1. Taniwaki M, Windecker S, Zaugg S, et al. The association between in-stent neoatherosclerosis and native coronary artery disease progression: a long-term angiographic and optical coherence tomography cohort study. Eur Heart J. 2015;Epub ahead of print.
2. Yahagi K, Otsuka F, Virmani R, Joner M. Neoatherosclerosis: mirage of an ancient illness or genuine disease condition [editorial]? Eur Heart J. 2015;Epub ahead of print.

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  • The study was supported by research grants from Bern University Hospital and the Swiss National Science Foundation.
  • Dr. Räber reports receiving speaker fees and an unrestricted research grant from St. Jude Medical.
  • Dr. Joner reports serving as a consultant to Biotronik and Cardionovum and receiving speaking honoraria from Abbott Vascular, Biotronik, Medtronic, and St. Jude Medical.
  • Dr. Park reports no relevant conflicts of interest.

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