I. Patrick Kay

Late Coronary Occlusion After Intracoronary Brachytherapy

BACKGROUND Intracoronary brachytherapy appears to be a promising technology to prevent restenosis. Presently, limited data are available regarding the late safety of this therapeutic modality. The aim of the study was to determine the incidence of late (>1 month) thrombosis after PTCA and radiotherapy. METHODS AND RESULTS From April 1997 to March 1999, we successfully treated 108 patients with PTCA followed by intracoronary beta-radiation. Ninety-one patients have completed at least 2 months of clinical follow-up. Of these patients, 6.6% (6 patients) presented with sudden thrombotic events confirmed by angiography 2 to 15 months after intervention (2 balloon angioplasty and 4 stent). Some factors (overlapping stents, unhealed dissection) may have triggered the thrombosis process, but the timing of the event is extremely unusual. Therefore, the effect of radiation on delaying the healing process and maintaining a thrombogenic coronary surface is proposed as the most plausible mechanism to explain such late events. CONCLUSIONS Late and sudden thrombosis after PTCA followed by intracoronary radiotherapy is a new phenomenon in interventional cardiology.

Geometric Vascular Remodeling After Balloon Angioplasty and β-Radiation Therapy: A Three-Dimensional Intravascular Ultrasound Study

BACKGROUND Endovascular radiation appears to inhibit intimal thickening after overstretching balloon injury in animal models. The effect of brachytherapy on vascular remodeling is unknown. The aim of the study was to determine the evolution of coronary vessel dimensions after intracoronary irradiation after successful balloon angioplasty in humans. METHODS AND RESULTS Twenty-one consecutive patients treated with balloon angioplasty and beta-radiation according to the Beta Energy Restenosis Trial-1.5 were included in the study. Volumetric assessment of the irradiated segment and both edges was performed after brachytherapy and at 6-month follow-up. Intravascular ultrasound images were acquired by means of ECG-triggered pullback, and 3-D reconstruction was performed by automated edge detection, allowing the calculation of lumen, plaque, and external elastic membrane (EEM) volumes. In the irradiated segments, mean EEM and plaque volumes increased significantly (451+/-128 to 490.9+/-159 mm(3) and 201.2+/-59 to 241.7+/-74 mm(3); P=0.01 and P=0.001, respectively), whereas luminal volume remained unchanged (250.8+/-91 to 249.2+/-102 mm(3); P=NS). The edges demonstrated an increase in mean plaque volume (26.8+/-12 to 32. 6+/-10 mm(3), P=0.0001) and no net change in mean EEM volume (71. 4+/-24 to 70.9+/-24 mm(3), P=NS), resulting in a decrease in mean luminal volume (44.6+/-16 to 38.3+/-16 mm(3), P=0.01). CONCLUSIONS A different pattern of remodeling is observed in coronary segments treated with beta-radiation after successful balloon angioplasty. In the irradiated segments, the adaptive increase of EEM volume appears to be the major contributor to the luminal volume at follow-up. Conversely, both edges showed an increase in plaque volume without a net change in EEM volume.

I like the candy, I hate the wrapper: the (32)P radioactive stent

United States patent 5059166, issued October 22, 1991, to Robert and Tim Fischell, described an “intraarterial stent with the capability to inhibit intimal hyperplasia.”1 The proponents of this patent went on to say in their proposal: “Since radiation from a radioisotope source is capable of selectively inhibiting the growth of hyperproliferating cells as compared with normal cells, a radioisotope material which forms part of the stent can be used to decrease the rate of arterial reclosure. The radioisotope could be placed inside the stent, alloyed into the metal from which the stent is made, or preferably, it can be coated onto the stent’s exterior surface.” So began the story of the radioactive stent. Eight years and several animal species later, we are becoming aware of the bright and dark sides of this treatment modality in the human model. The safety and efficacy study by Albiero and colleagues2 describes the dose-related decrease noted at 6-month follow-up of intrastent neointimal hyperplasia after implantation of 32P radioactive stents at activities of 0.75 to 12 μCi. Whereas in-stent restenosis was all but obliterated at higher doses of radiation, intralesion restenosis was high because of late lumen loss at the stent edges. Aptly, the authors coined the term “candy wrapper” to describe this new restenotic pattern. It is possible that the animal workers who implanted the first radioactive stents observed this phenomenon. Unfortunately, the significance of this finding may not have been immediately apparent. The study by Albiero and colleagues reflects the courage of the investigators who, despite indifferent and at times contradictory results from animal work, persisted in their endeavor to discover whether radioactive stent implantation would be effective in humans. Previously, Hehrlein et al,3 4 using the rabbit iliac model, polyisotopic 55Co (elements 55Co, 56Co, 57 …

Radioactive Stents Delay but Do Not Prevent In-Stent Neointimal Hyperplasia

Background—Restenosis after conventional stenting is almost exclusively caused by neointimal hyperplasia. &bgr;-Particle–emitting radioactive stents decrease in-stent neointimal hyperplasia at 6-month follow-up. The purpose of this study was to evaluate the 1-year outcome of 32P radioactive stents with an initial activity of 6 to 12 &mgr;Ci using serial quantitative coronary angiography and volumetric ECG-gated 3D intravascular ultrasound (IVUS). Methods and Results—Of 40 patients undergoing initial stent implantation, 26 were event-free after the 6-month follow-up period and 22 underwent repeat catheterization and IVUS at 1 year; they comprised half of the study population. Significant luminal deterioration was observed within the stents between 6 months and 1 year, as evidenced by a decrease in the angiographic minimum lumen diameter (−0.43±0.56 mm;P =0.028) and in the mean lumen diameter in the stent (−0.55±0.63 mm;P =0.001); a significant increase in in-stent neointimal hyperplasia by IVUS (18.16±12.59 mm3 at 6 months to 27.75±11.99 mm3 at 1 year;P =0.001) was also observed. Target vessel revascularization was performed in 5 patients (23%). No patient experienced late occlusion, myocardial infarction, or death. By 1 year, 21 of the initial 40 patients (65%) remained event-free. Conclusions—Neointimal proliferation is delayed rather than prevented by radioactive stent implantation. Clinical outcome 1 year after the implantation of stents with an initial activity of 6 to 12 &mgr;Ci is not favorable when compared with conventional stenting.

Remodeling of Atherosclerotic Coronary Arteries Varies in Relation to Location and Composition of Plaque

The aim of this study was to determine the contribution of morphologic characteristics and location of plaque in remodeling of atherosclerotic coronary arteries. Consecutive intravascular ultrasound studies performed in native coronary arteries before an intervention were included in the study. Total vessel, lumen and plaque + media areas were measured at target lesion, and distal and proximal references. Remodeling index was calculated as target total vessel area/proximal reference total vessel area, and categorized into 3 groups based on relative total vessel-area ratio: (1) > 1.1 (group A, adequate remodeling); (2) 0.9 to 1.1 (group B, failure of compensatory enlargement); and (3) <0.9 (group C, coronary shrinkage). Eighty-nine narrowings were assessed in 80 intravascular ultrasound studies. Thirty-eight lesions (43%) were defined as soft and 51 (57%) as hard. Soft plaques were more prevalent in group A than in groups B and C (p = 0.001). Conversely, the arc of calcium was larger in group C lesions (p = 0.005). At distal segments, group A lesions were more prevalent than those in groups B and C, whereas at proximal segments group C lesions were more prevalent (p = 0.007). Multivariate analysis identified the arc of calcium and the location of plaque at distal segments as independent predictors of compensatory enlargement (odds ratio 0.94, 95% confidence interval 0.90 to 0.99; odds ratio 4.6; 95% confidence interval 1.4 to 15.7, respectively), whereas hard plaques were an independent predictor of coronary shrinkage (odds ratio 4.6; 95% confidence interval 1.7 to 12.5). In conclusion, composition and location of plaque appeared to be major determinants of vessel remodeling during the process of atherosclerosis.

Geographical miss during catheter-based intracoronary beta-radiation: Incidence and implications in the BRIE study

OBJECTIVES We sought to determine the incidence and causes of geographical miss (GM) and to evaluate its impact on edge restenosis after intracoronary beta-radiation therapy. BACKGROUND Edge restenosis is a limitation of intracoronary beta-radiation therapy. Geographical miss is the situation in which the radiation source does not fully cover the injured segment and may lead to edge restenosis. METHODS We analyzed 175 vessels treated according to the Beta-Radiation In Europe (BRIE) study protocol. The effective irradiated segment (EIRS) and both edges were studied with quantitative coronary angiography. The edges of the EIRS that were injured constituted the GM edges. Restenosis was defined as diameter stenosis >50% at follow-up. Geographical miss was determined by simultaneous electrocardiographic-matched, side-by-side projection of the source and balloons deflated at the injury site, in identical angiographic projections surrounded by contrast. RESULTS Geographical miss affected 41.2% of the edges and increased edge restenosis significantly compared with non-GM edges (16.3% vs. 4.3%, respectively, p = 0.004). Restenosis was increased both in the proximal (p = 0.05) and distal (p = 0.02) GM edges compared with noninjured edges. Geographical miss associated with stent injury significantly increased edge restenosis (p = 0.006), whereas GM related to balloon injury did not significantly increase edge restenosis (p = 0.35). The restenosis in the EIRS was similar between vessels with and without GM (24.3% and 21.6%, respectively, p = 0.8). CONCLUSIONS Geographical miss is strongly associated with restenosis at the edges of the EIRS. This effect is more prominent when caused by stenting. Geographical miss does not increase restenosis in the EIRS.

Positive Geometric Vascular Remodeling Is Seen After Catheter-Based Radiation Followed by Conventional Stent Implantation but Not After Radioactive Stent Implantation

BackgroundRecent reports demonstrate that intracoronary radiation affects not only neointimal formation but also vascular remodeling. Radioactive stents and catheter-based techniques deliver radiation in different ways, suggesting that different patterns of remodeling after each technique may be expected. Methods and ResultsWe analyzed remodeling in 18 patients after conventional stent implantation, 16 patients after low-activity radioactive stent implantation, 16 patients after higher activity radioactive stent implantation, and, finally, 17 patients who underwent catheter-based radiation followed by conventional stent implantation. Intravascular ultrasound with 3D reconstruction was used after stent implantation and at the 6-month follow-up to assess remodeling within the stent margins and at its edges. Preprocedural characteristics were similar between groups. In-stent neointimal hyperplasia (NIH) was inhibited by high-activity radioactive stent implantation (NIH 9.0 mm3) and by catheter-based radiation followed by conventional stent implantation (NIH 6.9 mm3) compared with low-activity radioactive stent implantation (NIH 21.2 mm3) and conventional stent implantation (NIH 20.8 mm3) (P =0.008). No difference in plaque or total vessel volume was seen behind the stent in the conventional, low-activity, or high-activity stent implantation groups. However, significant increases in plaque behind the stent (15%) and in total vessel volume (8%) were seen in the group that underwent catheter-based radiation followed by conventional stent implantation. All 4 groups demonstrated significant late lumen loss at the stent edges; however, edge restenosis was seen only in the group subjected to high-activity stent implantation and appeared to be due to an increase in plaque and, to a lesser degree, to negative remodeling. ConclusionsDistinct differences in the patterns of remodeling exist between conventional, radioactive, and catheter-based radiotherapy with stenting.

Residual Plaque Burden, Delivered Dose, and Tissue Composition Predict 6-Month Outcome After Balloon Angioplasty and β-Radiation Therapy

BACKGROUND Inhomogeneity of dose distribution and anatomic aspects of the atherosclerotic plaque may influence the outcome of irradiated lesions after balloon angioplasty (BA). We evaluated the influence of delivered dose and morphological characteristics of coronary stenoses treated with beta-radiation after BA. METHODS AND RESULTS Eighteen consecutive patients treated according to the Beta Energy Restenosis Trial 1.5 were included in the study. The site of angioplasty was irradiated with the use of a beta-emitting (90)Sr/(90)Y source. With the side branches used as anatomic landmarks, the irradiated area was identified and volumetric assessment was performed by 3D intracoronary ultrasound imaging after treatment and at 6 months. The type of tissue, the presence of dissection, and the vessel volumes were assessed every 2 mm within the irradiated area. The minimal dose absorbed by 90% of the adventitial volume (D(v90)Adv) was calculated in each 2-mm segment. Diffuse calcified subsegments and those containing side branches were excluded. Two hundred six coronary subsegments were studied. Of those, 55 were defined as soft, 129 as hard, and 22 as normal/intimal thickening. Plaque volume showed less increase in hard segments as compared with soft and normal/intimal thickening segments (P<0.0001). D(v90)Adv was associated with plaque volume at follow-up after a polynomial equation with linear and nonlinear components (r = 0.71; P = 0.0001). The multivariate regression analysis identified the independent predictors of the plaque volume at follow-up: plaque volume after treatment, D(v90)Adv, and type of plaque. CONCLUSIONS Residual plaque burden, delivered dose, and tiss composition play a fundamental role in the volumetric outcome at 6-month follow-up after beta-radiation therapy and BA.

Three-dimensional intravascular ultrasonic volumetric quantification of stent recoil and neointimal formation of two new generation tubular stents

Currently, several different designs of coronary stents are available. However, only a few of the new generation stents have been investigated in large randomized trials. Mechanical behavior of first-generation stents (Palmaz-Schatz, Gianturco-Roubin) may not be applied to the new designs. We investigated the chronic mechanical behavior (recoil) of 2 stents recently approved by the Food and Drug Administration (MULTILINK and NIR). Forty-eight patients with single-stent implantation (23 MULTILINK and 25 NIR) were assessed by means of volumetric 3-dimensional intravascular ultrasound analysis after the procedure and at 6-month follow-up. In addition, volumetric assessment of neointimal formation was performed. No significant chronic stent recoil was detected in both groups (delta MULTILINK stent volume: +5.6+/-41 mm3 [p = NS] and delta NIR stent volume + 2.1+/-26 mm3 [p = NS]). A similar degree of neointimal formation at 6 months was observed between the 2 stents (MULTILINK 46+/-31.9 mm3 vs NIR 39.9+/-27.6 mm3, p = NS). In conclusion, these 2 second-generation tubular stents did not show chronic recoil and appeared to promote similar proliferative response after implantation in human coronary arteries.

Elevated Plasma Active Matrix Metalloproteinase-9 Level Is Associated With Coronary Artery In-Stent Restenosis

Objective—This study aimed to determine whether the plasma levels of matrix metalloproteinase-9 (MMP-9) or tissue inhibitor of metalloproteinases-1 (TIMP-1) were altered in patients with a history of symptomatic in-stent restenosis (ISR). Methods and Results—A group of 158 patients with a history of ISR were compared with 128 symptom-free patients. Plasma samples and a detailed risk factor history were collected. Plasma samples were analyzed for pro–MMP-9 and latent MMP-9 and active MMP-9, latent MMP-3, and TIMP-1. Several variables were associated with ISR, including index coronary disease extent and severity (number of diseased vessels and American College of Cardiology/American Heart Association lesion classification), number, diameter, and total length of stent(s) inserted, and plasma high-density lipoprotein cholesterol. Plasma active MMP-9 (odds ratio, 1.96; 95% CI, 1.43 to 2.69) showed independent risk association with ISR. Patients with multiple sites of ISR had significantly higher levels of active MMP-9 compared with patients with only a single ISR lesion or no ISR. Conclusion—Plasma active MMP-9 levels may be a useful independent predictor of bare metal stent ISR.