Vascular Changes and Black Hole Phenomenon after Coronary Brachytherapy: A Pathologically Distinct Entity

ABSTRACT: Restenosis remains an important issue even after coronary brachytherapy despite its efficacy in the treatment for in-stent restenosis. The acute and chronic changes in vascular wall are unique following brachytherapy. The restenotic tissue post coronary brachytherapy is relatively acellular and appears echolucent in intravascular ultrasound examination. This is dubbed the “black hole” phenomenon. Despite the similarity in the mode of action of brachytherapy and drug eluting stent implantation, the black hole phenomenon seems to be uncommon after drug-eluting stent implantation except in those patients who have had prior brachytherapy, bare-metal placement and after treatment of saphenous venous graft stenosis. It is possible that not all neointima in stents are created equal. We should propose that neointima be considered primary neointima if it forms after bare metal stenting, secondary neointima if it forms after CBT or DES, and perhaps tertiary if after combined CBT and DES. This type of classification may prove useful for research or clinical purposes. Almost certainly black hole phenomenon results from a modified neointima. However, we do not know whether this is the same restenotic tissue that was present before CBT but just depleted of its cellular element secondary to autolysis or a newly formed tertiary neointima? It is also not clear whether the changes in vascular wall and restenosis are similar after CBT or drug-eluting stent placement. However, there are some unique vascular changes that seem to be common after both of these procedures.

J INVASIVE CARDIOL 2008;20;560–562


Intracoronary radiation therapy reduces recurrence of in-stent restenosis and is an effective treatment for in-stent restenosis (ISR).1–3 However, late restenosis4 and late thrombosis5 after coronary brachytherapy (CBT) remain persistent problems. Recurrent in-stent restenosis (ISR) after CBT is still a major issue. It is not clearly known whether sirolimus or taxol-derivative drug-eluting stenting (DES) is effective against restenosis after brachytherapy, despite reports of its efficacy.6 Even in the era of DES, brachytherapy will likely remain an important niche tool for the treatment of ISR within DES. These patients, as well as those with recurrent ISR after brachytherapy for ISR in bare-metal stents (BMS) are a common and challenging subset presenting for treatment. Intravascular ultrasound (IVUS) has been shown to be a useful adjunctive imaging tool in these procedures to ensure optimal stent deployment and to evaluate ISR.

Restenosis after brachytherapy has unique cellular and morphological differences as compared to restenosis after bare-metal stent implantation, with implications for understanding the pathophysiologic process, research protocols and clinical practice.7–9 This article focuses on the acute and chronic cellular and morphological changes in the vascular wall after intracoronary brachytherapy and their implications for the understanding and treatment of recurrent ISR following brachytherapy or possibly DES implantation.

Acute vascular changes after coronary brachytherapy. In the acute phase after coronary brachytherapy, aseptic inflammation of the periadventitial connective tissue including vasa vasorum is seen.10 However, necrosis is not common at the therapeutic dosage. Vasculitis of the vasa vasorum is observed even at 28 days after radiation11 and an inflammatory reaction of the peri-adventitial tissue up to 8 months after brachytherapy is possible. This smoldering inflammatory response ultimately results in periadventitial scarring and occlusion of the vasa vasori, and leads to chronic vessel wall remodeling in non-stented vessels.12 There is an effective reduction of cellular proliferation in both the media and adventitia at 3 days after balloon injury by intravascular irradiation done at the time of angioplasty in a porcine model. Radiation did not affect cell proliferation in the intima or media 7 days after angioplasty. There was no increase in apoptosis in the media or adventitial layers 3 and 7 days after irradiation. There was also inhibition of adventitial fibrosis by the radiation treatment at the third, seventh and fourteenth day after radiation.13

The cellular components of stent neointima 18 hours after radiation were similar to stent neointima of specimens not treated with radiation, and there was no evidence of acute inflammation of the neointima. Also, the presence of factor VIII-positive endothelial cells in the vascular lumen indicated that the endothelial lining was not completely destroyed.10 Reendothelization is delayed after CBT. Following BMS implantation, despite a 60% loss in the endothelial cell monolayer within 1 hour after direct stent implantation, there is complete regeneration of the damaged endothelial cell layer within 14 days.14 However, in irradiated arteries, only 35–40% of the luminal surface was covered by endothelial cells at 1 month, indicating that reendothelialization is delayed by CBT.15

In summary, the acute inflammatory changes were seen predominantly in the periadventitial tissue and vasa vasorum and might result in fibrosis and vascular remodeling in the long term. Short-term inhibition of cellular proliferation and apoptosis in the media and adventitia were seen, and there was also a delay in reendothelialization of the stented segment.

Chronic vascular changes after coronary brachytherapy. In chronic stages, there are differences in the cellular components in the restenotic tissue in cases of restenosis following CBT compared with pathologic findings after BMS implantation. The first feature is the abundance of extracellular matrix. This was observed in coronary artery lesions at the edge of a stent in a patient 6 months after excimer laser angioplasty and brachytherapy — the so-called “candy-wrapper” lesion,16 and also within ISR tissue.17

The second feature is the paucity of cellular proliferation. Radiation may either stimulate or inhibit cellular proliferation, depending on dose. It is possible that CBT results in inhibition of cellular proliferation in some areas and of focal areas of proliferation in others. In restenosis after brachytherapy, the restenotic tissue was found to be hypocellular with a relative abundance of proteoglycan.16–18 In certain cases, these relatively acellular areas of restenotic tissue on IVUS are echolucent, appearing black without ultrasound back-scatter despite angiographic evidence of restenosis. This has been dubbed “black hole” because of its characteristic appearance in IVUS imaging7 (Figure 1). The black hole phenomenon was first described after intracoronary radiation7–9 and is seen in 50% of patients with restenosis after brachytherapy.8,9 This is an important clinical and research limitation of IVUS imaging in these cases. First, the absence of neointimal tissue in the stent on IVUS imaging does not exclude its presence. A correlation with the angiographic appearance is critical to alert the operator that contrast injection or Doppler-flow imaging during the IVUS interrogation is necessary to define the residual lumen within the stent versus the volume of neointima. An adequate IVUS result after treating recurrent ISR previously treated with brachytherapy is difficult to judge. The IVUS results should be correlated with visual and/or quantitative angiographic evaluation for research protocols as well as for optimal clinical practice. Increasing the gain during IVUS interrogation does not improve the visualization of this echolucent tissue compared to the vessel lumen.

There is also evidence of positive vascular remodeling after CBT.15 This might be partly due to the difference in the collagen content and type in the extracellular matrix. The changes in the collagen content, type of collagen (relative proportion of type 1 and type 3 collagen) and the proportion of collagen cross-linking seen in other vascular beds, as well as in myocardium,19 can be seen in coronary arteries. Following BMS implantation, the neointima up to 18 months was found to be hypercellular and rich in type III collagen, versican and hyaluronan, with relatively less type I collagen and decorin. This was in contrast to stents 18 or more months old that showed a smaller amount ofversican, hyaluronan and type III collagen, and more type I collagen and decorin. The neointimal cell density and the smooth muscle cells were lower in the neointima of stents older than 18 months.20 However, this being an observational postmortem study, we should be aware of the inherent sampling bias. There are no longitudinal studies looking in detail at the extracellular matrix in recurrent ISR after brachytherapy.

Is restenotic tissue post brachytherapy different from that after drug-eluting stent implantation?
The black hole phenomenon has not been reported in the larger IVUS trials following DES implantation (DES),21–25 although the inhibition of cellular proliferation is seen as in brachytherapy. There seems to be a high incidence of black hole phenomenon in patients after DES implantation to treat recurrent ISR after previous brachytherapy has failed. Whether this finding is related to a combination of radiation and antiproliferative properties of the DES remains to be elucidated. The clinical implication of this phenomenon also needs to be looked into. This observation may be secondary to the effect of past intracoronary brachytherapy in the same segments where black holes were noted. The mechanism of black hole formation may be secondary to the modification of cellular growth in the area of previous radiation, since such hypocellular regions have not been described after DES implantation. Such tissue modification may be a result of prior radiation and/or the effects of DES implantation. Studies with larger patient cohorts are required to elucidate the exact mechanism of this phenomenon.

Black holes are also occasionally seen in DES restenosis without prior brachytherapy. Though it is uncommon, the incidence of an IVUS presence of black holes in sirolimus-eluting stent (SES) restenosis is observed more often when SES are implanted for treatment of saphenous vein graft stenosis or for BMS restenosis.26 The SES restenosis presents earlier and is more severe in patients with IVUS evidence of black holes in the restenotic tissue.26 There are no data on the incidence of this phenomenon with DES other than the SES data. More importantly, the risk of thrombosis and the rate of target lesion revascularizaton due to the presence of black holes in DES restenosis are also not known. Careful analysis of large DES trials with follow-up IVUS examination might help us understand how black holes may affect the subsequent risk of thrombosis or rate and severity of restenosis.

This highlights the importance of recognizing this phenomenon when analyzing the IVUS images after brachytherapy and DES implantation. To date, a large number of patients have been treated with coronary brachytherapy. Hence, restenosis after this procedure is a major clinical issue and many of these patients are and will be treated with DES in the near future. Therefore, attention by the interventionalist is warranted to recognize this phenomenon when analyzing IVUS images of these patients, since this hypocellular tissue may be easily overlooked.

Analysis of the temporal relationship between the appearance of black holes and the intracoronary brachytherapy and DES implantation may be important to determine whether this is due to a synergistic effect of both treatments. We also do not know whether this phenomenon is restricted to certain classes of drugs coated on the stent, as many are being tested for their efficacy in preventing restenosis. Finally, whether this phenomenon is a generic effect of intracoronary brachytherapy, or is restricted to the use of either beta or gamma sources needs to be determined.

Conclusion

In addition to stent underdeployment, ISR is due to the formation of neointimal tissue within the stent. Based on animal studies, the secondary neointima that is found within stents after ISR treated with brachytherapy is histologically different than the primary neointima that forms after BMS implantation. This secondary neointima is relatively acellular compared to primary neointima. Whether the secondary neointima is the primary neointima with depletion of its cellular elements or de novo tissue formation is unknown. This observation that post-brachytherapy ISR tissue is histologically different in animal models likely explains the observation in humans of echolucent black hole neointima observed by IVUS in humans. The frequency of the black hole finding in patients with prior brachytherapy failure treated with DES suggests additional or potentiation of the physiologic process leading to acellular secondary neointima. Additional studies on the histological and functional characteristics of secondary neointima seem prudent. Perhaps the neointima that forms after DES treatment of brachytherapy failures should be further modified and should be referred to as tertiary neointimal tissue.