Keywords
INTRODUCTION
Stent use has been one of the major breakthroughs in the treatment of patients with coronary artery disease.1 Together with its many advantages some associated pitfalls are restenosis and stent thrombosis.2-9 Regarding the vascular responses after stenting (ie, restenosis and remodeling), a response-to-injury pattern of wound healing occurs, mainly characterized by an increase in smooth muscle cells and extracellular matrix.10
In the Taxus II study a significant reduction in lumen size was observed at the proximal edge in both paclitaxel eluting stent and bare metal stent groups, while at the distal edge the reduction was only present in the bare metal stent group. This was mainly due to an augment in plaque size not fully compensated by vessel wall remodeling.11
Nowadays spectral analysis of the intravascular ultrasound (IVUS) radiofrequency data (RFD) analysis12,13 is emerging as a tool to assess tissue composition in the coronary arteries. Thus, not only serial geometrical changes can be analyzed, but also its composition.
However, in stented vessels this can only be performed at the edges of the stent, because the actual stent area and its surroundings cannot be analyzed with IVUSRFD, due to: a) misclassification of the stent struts as "dense calcium"; b) lack of proper validation of IVUSRFD in this context; and c) potential interference of the superficial stent struts on the backscattering of the tissue behind them.
We hypothesized that the tissue involved in the increase of plaque at the stent edges, as assessed by IVUS-RFD, is mainly fibro-fatty tissue, which has been described as loosely packed bundles of collagen fibers with regions of lipid deposit and extracellular matrix without necrotic areas.14
We thus sought in vivo the temporal geometrical and tissue composition changes at the edge of paclitaxeleluting stent as assessed by IVUS-RFD analysis.
METHODS
Patient Selection
The BEside TAXus® (BETAX) study was a longitudinal and prospective cohort of non-consecutive patients who had a clinical indication for coronary intervention and were treated with Taxus® stent (Taxus® Express2TM; Boston Corporation, Natick, MA, USA) in at least one of their coronary arteries. Only patients who gave informed written consent were included in the study. Patients with stable angina and acute coronary syndromes were included. Acute coronary syndromes comprise unstable angina, non-ST segment elevation myocardial infarction and ST-segment elevation myocardial infarction. IVUSRFD imaging was performed at post-stenting and at 6 months. Our local Ethics Committee approved the protocol.
IVUS-RFD Acquisition and Analysis
Details regarding the validation of the technique, on explanted human coronary segments and in vivo post-atherectomy, have been previously reported.12-14
Briefly, IVUS-RFD uses spectral analysis of IVUS radiofrequency data to construct tissue maps that are correlated with a specific spectrum of the radiofrequency signal and assigned color codes (fibrous [labeled green], fibrofatty [labeled greenish-yellow], necrotic core [labeled red], and dense calcium [labeled white]).12,13
IVUS-RFD was acquired using a continuous pullback (Eagle-EyeTM 20 MHz Volcano Therapeutics, Rancho Cordova, CA, USA) by a dedicated IVUS-RFD console (Volcano Therapeutics, Rancho Cordova, CA, USA). The IVUS-RFD recordings were stored on a DVD and sent to Corelab (Erasmus Medical Center/Cardialysis, Rotterdam, The Netherlands) for offline analysis.
The 5-mm proximal (p) and 5-mm distal (d) segments adjacent to the stent were subsequently divided into 1-mm 5 subsegments (ss) (Figure).
Figure. A: area changes in geometrical measurements at the proximal and distal 5-mm of the Taxus stent. B and C: absolute and relative temporal changes in plaque composition. CSA indicates cross-sectional area.
The IVUS-RFD sampling rate during pullback is gated to peak R-wave and is therefore dependent on heart rate. For instance, during constant heart rate of 60 bpm, data will be collected every 0.5 mm.
Compositional and geometrical data were obtained for every cross-sectional area (CSA) and expressed as mean areas and percent for each IVUS-RFD component.
Statistical Analysis
Discrete variables are presented as counts and percentages. Continuous variables are presented as means (SD). A P value (2-sided) less than .05 was considered significant. Assumptions for normality were checked after transformation based on a P value >.20 at Kolmogorov-Smirnov test and by visual assessment of Q-Q plots of residuals. Accordingly, log transformation was performed on the variables with skewed distribution.
The comparison between baseline and follow-up was performed using paired Student t test.
Statistical analyses were performed with use of SPSS software version 11.5.
RESULTS
Overall, 30 patients were included in this study, but only 24 (26 stented segments) patients were ultimately analyzed. Two patients refused angiographic follow-up and in other 4 patients the IVUS image quality was poor (non-continuous pullback and presence of IVUS artifacts). The baseline characteristics of the patient population are depicted in Table 1. The mean age was 57.6 (11.2) years, most being male patients (75%) and 66% of the patients presented with stable angina. The studied vessel was the left anterior descending artery in 46.2 %, the left circumflex in 26.9 %, and the right coronary artery in 26.9 % of the cases. The mean number of stent per patient was 1.5 (0.7). No stent thrombosis has been observed so far.
IVUS-RFD Findings. Changes From Baseline to Follow-up in Geometrical and Compositional Parameters Within and Between the Proximal and Distal Segments.
At baseline, the mean vessel CSA (16.5 [4.9] vs 11.5 [4.0] mm2; P<.001), plaque CSA (7.7 [3.6] vs 5.3 [2.7] mm2; P<.001), and lumen CSA (8.8 [2.6] vs 6.2 [1.7] mm2; P<.001) of the entire 5-mm edge segment in the proximal edge were larger than their counterparts in the distal segment. The same holds at follow-up for the measurements of the mean vessel CSA (17.5 [5.9] vs 12.8 [4.0] mm2; P<.001), plaque CSA (8.2 [4.4] vs 5.1 [2.6] mm2; P<.001), and lumen CSA (9.3 [3.0] vs 7.7 [4.0] mm2; P<.001) (Table 2).
At the proximal and distal edges, a serial expansive vascular remodeling was observed at follow-up, with a significant increase in mean vessel CSA of the entire proximal (P=.031) and trend towards an increase in the distal segment (P=.06).
Since plaque CSA hardly increases, this remodeling resulted in a significant increase in mean lumen CSA was observed (Table 2).
In terms of tissue composition, at baseline, in the proximal segment as compared to the distal, the percentage of calcified tissue was not different (10.7% [11.5%] vs 11.0% [14.2%]; P=.80), the same was true for the necrotic core (17.0% [13.5%] vs 18.5% [16.5%]; P=.23); on the contrary significantly larger percentage of fibrous (57.9% [19.3%] vs 47.8% [29.2%]; P<.001), and fibrofatty tissue (11.7% [11.9%] vs 7.0% [9.3%]; P<.001) were observed.
At follow-up, all tissue types were larger in the proximal segment than in the distal, calcified (5.8% [8.2%] vs 3.3% [6.3%]; P<.001), necrotic core (14.2% [13.8%] vs 10.8% [12.6%]; P<.001), fibrous (56.9% [18.4] vs 53.0% [28.7%]; P<.001), and fibrofatty tissue (18.7% [13.4%] vs 13.7% [13.1%]; P<.001) (Table 2).
Overall, in the proximal and distal segments a significant increase of fibrofatty tissue was observed, whereas a decrease of calcified and necrotic core over the time was present. Fibrous tissue did not show significant temporal changes (Table 2).
Subsegmental Analysis of Longitudinal Changes at 5-mm Edge Segment of Proximal and Distal Edges
The mean absolute difference vessel CSA (follow-up - baseline) was positive throughout the proximal and distal segments; this was accompanied by a positive mean absolute difference in lumen CSA; the most prominent increase in plaque CSA (although not significant) was documented in first three proximal subsegments. (Figure). In particular, at the proximal edge, in the first 2 millimeters the vessel wall grew to compensate for the plaque growth (1-mm pss, D+0.52 and D+0.54 mm2; 2-mm pss, D+0.65 and D+0.58 mm2; vessel area change and plaque area change respectively) without affecting the lumen size (1-mm pss, D-0.02 mm2; 2-mm pss, D+0.07 mm2 in lumen area change), while in the following 3 subsegments overcompensation was observed, that is the vessel wall grew more than the plaque (3-mm pss, D+1.98 and D+1.18 mm2;
4-mm pss, D+1.32 and D+0.12 mm2; 5-mm pss, D+0.54 and D+0.14 in vessel area change and plaque area change respectively), resulting in an increase in lumen size (3-mm pss, D+0.81 mm2; 4-mm pss, D+1.21 mm2; and 5-mm pss, D+0.69 mm2). At the distal edge, overcompensation was observed in all 5 subsegments, resulting in an increase in lumen size (1-mm dss, D+0.88; D+0.23 and D+1.35 mm2; 2-mm dss, D+0.67; D+0.04 and D+1.24 mm2; 3-mm dss, D+0.17; D-0.63 and D+1.72 mm2; 4-mm dss, D+0.51; D-0.36 and D+1.42 mm2; 5-mm dss, D+0.63; D-0.10 and D+1.61mm2 in vessel, plaque and lumen area change respectively).
At 6-month follow-up, the percentage of fibrofatty tissue increased in all subsegments, while fibrous tissue showed a more heterogeneous behavior, with calcified tissue and necrotic core being decreased throughout the ten subsegments analyzed. (Figure).
DISCUSSION
The main findings of this study were the following: a) at the proximal and distal edge, a serial expansive vascular remodeling was observed, with an increase in mean vessel area and mean lumen area of the entire edge from baseline to follow-up; b) in the first 3 subsegments adjacent to the proximal part of the stent the most prominent increase in mean plaque area was observed. This is in line with the results of the Taxus II and IV studies11,15; and c) overall, in the proximal and distal segment a significant increase of fibrofatty tissue was observed, while a decrease of calcified tissue and necrotic core over time was present.
The serial changes in tissue composition at the edges of the stent could vary depending on the location (proximal vs distal edge), shear stress conditions,16 morphological baseline characteristics (degree of obstruction) of the segment as well as baseline tissue composition. Last but not least, the degree of vessel wall injury after dilatation plays a role.17 In animal and human pathological studies the response-to-injury process after stenting has been extensively described.10 Restenosis occurs secondary to accumulation of smooth muscle cells and extracellular matrix, which consists of proteoglycans, hyaluronan and collagen (Type I and III). This extracellular matrix modulates neointimal growth and remodeling.10 The IVUS-RFD tissue type that correlates with extracellular matrix is the fibro-fatty tissue, which happened to be the one that mostly increased in this study and, positive remodeling was also observed at both stent edges at 6 months. Serial remodeling has been proposed as the best approach to evaluate the geometrical vessel wall changes18. In this regard other previous Taxus® stent studies have described this phenomenon at the edges. In particular, in TAXUS II11 a positive remodeling was only observed at the distal edge in both slow and moderate release Taxus group due to an increase in plaque size and hardly not change in lumen size; while in TAXUS IV15 almost no change was observed in vessel size at the proximal edge and a trend towards negative remodeling was observed at the distal edge. It is difficult to put into perspective these three studies, since they all have different sample size, in TAXUS IV authors acknowledged potential selection bias. So, although this study has a small sample size; a more complete characterization of the serial changes has been achieved.
In the present study, necrotic core rich areas were left unstented (proximal edge 17% [13.5%] and distal edge 18.5% [16.5%]), however no stent thrombosis has been observed in this small cohort of patients. Proposed pathological mechanisms of stent thrombosis are stenting of necrotic core-rich plaques with extensive tissue prolapse and plaque disruption in the proximity of the stented arterial segment.19,20 IVUS-RFD is not only able to characterize necrotic core with high sensitivity and specificity,14 it also provides geometrical analysis of each frame, allowing us to have the combined assessment of necrotic core and plaque size. Thus, pre-stenting imaging using IVUS-RFD can give us an insight into the extent of plaque and necrotic core within and beyond the intended stenting segment. This latter assessment is important since stenting has been lately performed from "normal to normal" arterial segments in angiography; however, disruption of adjacent necrotic core-rich areas that are angiographically disease-free should be avoided. Indeed, it has been reported that incomplete coverage of coronary atherosclerotic plaques with drug-eluting stents may impact on long-term clinical events, especially in necrotic-core rich plaques.19 Nevertheless, in this study, a decrease in necrotic core was showed at both edges at follow-up. Whether this is related to the presence of a stent or even more to the drug type eluted on the stent remains to be elucidated.
The limitations of this study are various. Firstly, only a small cohort of patients has been included, since the study was considered mainly exploratory and without formal statistical hypothesis. Secondly, it would have been ideal to study completely the stent segment plus the edge effects, however as mentioned earlier, there is no validation of the tissue characterization behind the stent struts which may themselves interfere with the process of ultrasound backscattering of the tissue located behind the struts. Six-month follow-up may be a relatively short period of time to fully evaluate the tissue changes at the edges of the stent considering the fact that longer angiographic follow-up has been suggested to better evaluate the vascular responses at these locations.
CONCLUSIONS
Serial expansive vascular remodeling was observed at the proximal and distal stent edges, to accommodate a tissue growth mainly due to an increase in fibrofatty tissue.
ABREVIATIONS
CSA: cross-sectional area
IVUS: intravascular ultrasound
RFD: radiofrequency data
SEE EDITORIAL ON PAGES 1001-6
Correspondence: Dr. P.W. Serruys,
Thoraxcenter, Bd583a,
Dr. Molewaterplein 40, 3015-GD, Rotterdam, The Netherlands
E-mail:p.w.j.c.serruys@erasmusmc.nl
Received November 30, 2007.
Accepted for publication March 13, 2008.