Early Vascular Healing After Endothelial Progenitor Cell Capturing Stent Implantation

Abstract: Objectives. To assess early vascular healing with endothelial progenitor cell (EPC)-capturing stents. Background. Endothelialization of stent struts is crucial after stenting, since delayed vascular healing predisposes to stent thrombosis. The antibody-coated Genous stent promotes rapid endothelialization by capturing circulating EPCs. Methods. We enrolled 20 patients who had EPC-capturing stent implanted in the left anterior descending (LAD) coronary artery. Patients underwent optical coherence tomography 30 days following the index procedure. Coronary flow reserve (CFR) was assessed in the LAD by transthoracic echocardiography at 30 days. Results. After follow-up of 31.8 ± 5.3 days, the binary stent strut coverage was 95% and the percentage of malapposed struts was 2.4%. No thrombi were detected. The mean neointimal hyperplasia (NIH) thickness was 108 ± 96 µm and the percent NIH area was 8.9 ± 7.4%. The mean CFR was 2.4 ± 0.7. Conclusions. The EPC-capturing stent showed rapid endothelialization, low NIH area, and few malapposed struts at 30 days.

J INVASIVE CARDIOL 2012;24(12):631-635

Key words: endothelialization, EPC capturing, neointimal hyperplasia

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Prolonged dual antiplatelet therapy (DAPT) poses a problem in situations where bleeding risk is elevated or elective surgery is needed shortly after percutaneous coronary intervention (PCI). The endothelial progenitor cell (EPC)-capturing Genous stent (OrbusNeich) is coated with antibodies that attract circulating EPCs on the surface of the stent, thus promoting rapid stent endothelialization and enabling shorter DAPT.^1-3 

Optical coherence tomography (OCT) has become the preferred imaging modality for the evaluation of stent endothelialization and vascular healing after PCI.⁴ OCT data on vascular healing and endothelialization with the EPC-capturing stent are scarce. 

Endothelial dysfunction has been reported in stented vessels with signs of delayed healing.⁵ In the absence of epicardial coronary stenosis, impaired coronary flow reserve (CFR) reflects microcirculatory and endothelial dysfunction. CFR can be non-invasively measured by transthoracic echocardiography (TTE). The left anterior descending (LAD) coronary artery is most suitable for this measurement for anatomical reasons.^6-8

Our primary objective was to evaluate the extent of endothelialization of the EPC-capturing stent 30 days after deployment. We also sought to assess the vasodilatory response in the stented vessel with CFR and to analyze possible association of the OCT and CFR findings.

Methods

Study population and design. We enrolled 20 consecutive patients who underwent successful coronary stenting with EPC-capturing stent in a single native lesion in the proximal or mid-segment LAD at Satakunta Central Hospital in Pori, Finland. Multiple stenting in the same lesion was allowed only as bailout. Patients with acute coronary syndrome (ACS) as well as stable angina pectoris were included.

We excluded patients with unprotected left main disease, aorto-ostial lesions, a contraindication to aspirin, clopidogrel or heparin, and those with life expectancy of less than 12 months. Stenting of possible lesions in vessels other than the LAD was performed during separate procedures based on clinical judgment. Informed written consent was obtained from each patient and a control visit including OCT and CFR studies was scheduled at 30 days after the index procedure.

The primary endpoint was binary stent strut coverage at 30 days. Secondary endpoints included percentage of malapposed stent struts, neointimal hyperplasia (NIH) thickness, and CFR at 30 days. Major adverse cardiovascular events (MACEs), including myocardial infarction, target vessel revascularization, and death, were also recorded during follow-up. The study protocol was approved by the Ethics Committee of Satakunta Central Hospital and it conforms to the ethical guidelines of the Declaration of Helsinki.

OCT image acquisition. OCT images were obtained at follow-up using the C7-XR frequency-domain system (LightLab Imaging Inc), with the non-occlusive technique, using the radial or femoral approach. A motorized pullback system was used at 20 mm/s and OCT images were acquired at 100 frames/second. OCT images were analyzed offline independently by two experienced investigators blinded to patient baseline, angiographic, and procedural data, employing the proprietary software (LightLab Imaging Inc). Stent strut coverage, strut malapposition, NIH, and possible thrombosis were evaluated at 1 mm intervals (every fifth frame) in cross-sectional images.

OCT image analysis and definitions. OCT measurements were performed as described by Bezerra et al.⁴ Definitions and terminology comply with the recently published consensus guidelines.⁹ All analyzable stent struts except those overlaying a side branch were classified as either covered or uncovered. Binary stent strut coverage was defined as the number of covered struts divided by the number of analyzed struts per stent. A covered stent strut was defined as a strut with a measurable layer of neointimal tissue covering it. The thickness of the neointimal layer over each covered strut was also measured.

The incomplete stent apposition (ISA) distance was measured for protruding struts as the perpendicular distance from the endoluminal surface of the strut reflection to the border of the vessel lumen. A stent strut was classified as malapposed if the ISA distance exceeded 100 µm. The strut thickness of the Genous CoCr stent is 81 µm and a margin of 18 µm was added as a correction for half of the blooming effect as described previously.⁴ The sum of 99 µm was rounded up to 100 µm considering the 10-20 µm axial resolution of the frequency-domain OCT.

All analyzed stent struts were also divided into five categories depending on stent strut neointimal coverage and apposition status: (a) apposed to the vessel wall and covered with neointima; (b) apposed to the vessel wall and uncovered; (c) malapposed and covered; (d) malapposed and uncovered; and (e) stent struts over a side branch.

The existence of a side branch in a cross-section was recognized by evaluating previous and subsequent cross-sections as needed. If the image quality of a cross-section was inadequate to allow reliable measurements, a subsequent cross-section with adequate quality was used for measurements. Stent cross-sectional area (stent CSA) and lumen cross-sectional area (lumen CSA) were traced manually or semi-automatically. NIH area was calculated by subtracting lumen CSA from stent CSA and percent NIH area was calculated by dividing the NIH area by the stent CSA multiplied by 100. If the lumen or stent CSA were not measurable, they were omitted. A percentage of uncovered struts more than 5% was considered abnormal.

Coronary flow reserve. Assessment by TTE was carried out with an Acuson Sequoia C 512 mainframe (Acuson Inc) employing a 4.0 MHz transducer. Subjects were instructed to avoid caffeine, alcohol, large meals, and tobacco for 12 hours before the study. B-mode and color Doppler mapping were used to identify the distal LAD as previously described.⁶ Baseline coronary flow velocities were measured with pulsed-wave Doppler; an average of at least three cardiac cycles was obtained. Hyperemia was induced by intravenous infusion of adenosine, which was continued until the maximal increase in flow velocity was seen. In offline analysis, the mean diastolic velocity (MDV) was measured at baseline and during the maximal response to adenosine infusion. CFR was calculated as the hyperemic-to-baseline ratio. Heart rate (HR) and blood pressure (BP) were monitored at baseline and during adenosine infusion to detect possible hemodynamic changes that could affect the measurements. All coronary flow velocity measurements were carried out at 30-day follow-up visit before coronary angiography, and analyzed by an experienced investigator blinded to clinical data. Intra- and interobserver variabilities for CFR measurements (coefficient of variation) in our laboratory were 2.6 ± 4.0% and 8.6 ± 9.8%, respectively.⁷

Statistical analysis. Continuous variables are presented as mean ± standard deviation, while categorical variables are described with absolute and relative (percentage) frequencies. In offline analysis, patients were divided into two groups according to the CFR response: normal (CFR >2.5) and abnormal (CFR ≤2.5). The independent samples t-test was used to compare continuous variables when appropriate. Chi-square test or Fisher’s exact test was used to compare categorical variables. The population was also classified according to the percentage of malapposed and uncovered stent struts (cut-off 5%) according to the classification previously used in the assessment of the determinants of uncovered stent struts.¹⁰ Spearman correlation was used to test the association between percentage of uncovered and malapposed stent struts and CFR class. All tests were two-sided and a P<.05 was considered statistically significant. All data were analyzed with SPSS version 17.0 (SPSS).

Results

Baseline patient characteristics are shown in Table 1 and procedural and lesion characteristics in Table 2. Most treated lesions had complex features, and 60% of patients presented with ACS. The mean follow-up was 32 days (range, 25-47 days). No MACEs or angiographic restenosis occurred during follow-up. OCT measurements are presented in Table 3. The binary stent strut coverage was 95%, and no thrombi were detected. The thickness of NIH and percentage of NIH area were low. The distribution of uncovered and/or malapposed struts is presented in Figure 1. The NIH thickness and total percentages of uncovered and malapposed struts per stent are presented in Figure 2. The percentage of malapposed stent struts was 2.4%. There were 7 patients (35%) with more than 5% of uncovered struts. 

The average CFR was 2.4 ± 0.7 and 13 patients (65%) had abnormal (≤2.5) CFR, but none of them had hemodynamically significant stenosis. Systolic BP values were 127 ± 19 and 124 ± 18 (P=.32) and diastolic BP values were 66 ± 10 and 60 ± 10 (P=0.001) at baseline and during adenosine, respectively. HR values were 61 and 64 (P=0.33), respectively. OCT findings according to the CFR response are presented in Table 4. The number of patients who had more than 5% of uncovered struts was 2 (28.5%) in the group with normal CFR and 5 (38.5%) in the group with abnormal CFR (P=1.00). There was no difference in the number of patients with more than 5% of malapposed struts (0 [0%] vs 2 [15.4%], respectively; P=.52).

CFR ≤2.5 tended to be associated with the percentage of stent struts which were uncovered and malapposed (R=-0.43; P=.066), but there was no statistically significant difference in the distribution of stent strut categories between the two groups (Table 4) or in the total percentage of malapposed or uncovered struts. There was also no statistically significant difference in the mean NIH thickness between these two groups (99 ± 28 µm vs 109 ± 64 µm; P=.69).

Discussion

This is the first OCT study to assess early vascular healing after an EPC-capturing stent implantation. At 30 days, EPC-capturing stents were endothelialized with a binary stent strut coverage of 95%, and no signs of thrombi were detected. Functional healing of the stented coronary artery as assessed by CFR was, however, abnormal in two-thirds of patients. No MACE occurred during the short follow-up.

Most of the previous OCT studies on stent endothelialization have been performed later after stent deployment. The binary stent strut coverage of various drug-eluting stents (DESs) has varied between 84%-99% after a follow-up of 3-13 months^11-17 and from 98%-99% for bare-metal stents (BMSs) after a follow-up of 6-13 months.^16,17 There are currently only a few small OCT studies evaluating early stent healing after PCI. Prati et al studied very early stent healing at 3-7 days after stent implantation¹⁸ in 15 patients with a total of 28 stents implanted. In this small series, binary stent strut coverage was 89% for BMS and 87% for DES.¹⁸ There are histological data supporting rapid endothelialization of the EPC-capturing stent, with 96% coverage 5 days post implantation on swine coronary arteries.¹⁹ Based on previous long-term follow-up data and animal models, the endothelialization of the EPC-capturing stent seems to be more rapid when compared to DES. Considering the descriptive nature of the present study, comparisons between healing of different stent types would obviously require a randomized comparative study design. However, results of the present study support the hypothesis of relatively rapid endothelialization of the EPC-capturing stent and are in agreement with histological data from an animal study.¹⁹

Measuring CFR with TTE allowed us to analyze the recovery of coronary microcirculation and endothelial function. Vasodilation response was abnormal (CFR <2.5) in 65% of patients. In the absence of stenosis, CFR depicts the vasodilator capacity of the coronary circulation.⁶ The potential explanations for this finding include other diseases or states that cause microcirculatory dysfunction (diabetes, smoking), transmural myocardial infarction, or endothelial dysfunction. Only two patients had diabetes, and there were no transmural infarctions in either group. Therefore, factors other than endothelial dysfunction are unlikely to have a major contribution to the abnormal CFR response. Seven patients with abnormal CFR had malapposed and uncovered stent struts. This may reflect that epicardial vessel wall was not healed appropriately in terms of OCT findings in these patients and contribute to the impaired vasoreactivity. Supporting this hypothesis, one previous report demonstrated that incomplete stent endothelialization detected by OCT is associated with abnormal vasomotor response.¹⁰ Taken together, these CFR findings indicate that functional healing of the stented segment after EPC-capturing stent implantation is not complete at 1 month. We have assessed serial CFR response post PCI (data not shown). It appears that the rate of patient with normal (CFR >2.5) functional healing increases from 1- to 6-month follow-up. The clinical implications of this finding need to be clarified. It is possible that poor vasodilation is associated with increased platetet activity and/or increased neoatherosclerosis of the stented segment. One possible explanation is that although struts are covered with tissue, they are not covered with functional endothelium but fibrin or thrombus, and thus, vasodilation is abnormal. 

Advantages of TTE methodology in the assessment of CFR include avoiding the need for arterial access, fluoroscopy, or iodinated contrast agents. Pitfalls of this methodology include all the inherent pitfalls of CFR measurement using any method. Baseline flow can be affected by hemodynamic status, BP, and HR. Achieving maximal hyperemia is of particular importance. It is also important to carry out the assessment exactly in the same segment of the coronary tree in the same patient. These issues were carefully taken into account when performing the assessment. No major hemodynamic changes were detected despite the expected decrease in diastolic BP. Flow velocity tracings were continuously measured to be able to detect the highest response during adenosine infusion. TTE has been used in CFR investigations by several independent laboratories,^20-24 and TTE measurements have been found to correlate closely with measurements carried out with an intracoronary flow wire,^20,22 magnetic resonance imaging,²³ and positron emission tomography.²⁴ Previously, the feasibility of transthoracic Doppler echocardiography in the detection of coronary flow in the LAD has been 95%-100%.^22,25 In this study, the feasibility was 100%.

The HEALING-II study showed promising results in patients treated with an EPC-capturing stent for de novo coronary lesions despite only 1 month of DAPT.²⁶ Several single-center prospective studies have shown EPC-capturing stents to be safe and effective in unselected populations indicating low risk for stent thrombosis at long-term follow-up (up to 2 years).^27-32 The multicenter e-Healing Registry showed low rates of stent thrombosis and repeat revascularization with the EPC-capturing stent at 12-month follow-up.³³ However, the mortality of diabetic patients was higher than in non-diabetics, and the incidence of TLR was higher in insulin-treated diabetics.³⁴ EPC-capturing stents have also been successfully used in STEMI patients.^35-37 Short (2 weeks to 1 month) DAPT following EPC stent implantation has also successfully been used on patients requiring undeferrable non-cardiac surgery or long-term oral anticoagulant therapy.^30,32

Previous data support the regimen of short DAPT with the EPC-capturing stent. Stent strut coverage has been proposed as a surrogate for risk of stent thrombosis.³⁸ Based on strut coverage, the risk of stent thrombosis after 30 days appears low. However, there are several other factors affecting the risk of stent thrombosis, such as the coverage of side branch struts, which was not analyzed in the present study. The role of endothelial dysfunction reported after PCI remains unclear and warrants further larger studies. Our results support the hypothesis of rapid endothelialization of the EPC-capturing stent, which can be beneficial in clinical situations where prolonged DAPT is undesirable.

Study limitations. The findings of the current study should be interpreted cautiously. This was a single-center, descriptive study with a small sample size, and therefore, selection bias is possible. Larger studies are needed to evaluate the behavior of the EPC-capturing stent in an unselected population. The study was not designed to assess the safety of short DAPT on patients treated with EPC-capturing stent and all patients were on DAPT during the 1-month follow-up. Thus, conclusions on the safety of short DAPT on these patients cannot be made. The percentage of diabetics in the present study was small, only 10%. The outcome of diabetic patients treated with the EPC-capturing stent has been worse than non-diabetics.³⁴ Our main goal was to evaluate early stent healing and naturally further larger studies are needed to assess the long-term healing of the EPC-capturing stent.

Conclusions

Our findings support the theory of relatively rapid endothelialization following the EPC-capturing stent implantation. Functional healing of the stented coronary artery as assessed by vasodilation response of the coronary microcirculation, however, was normal in only one-third of patients at 30-day follow-up.

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____________________________________________________

From the ¹Department of Medicine, Turku University Hospital, Turku, Finland and the ²Heart Center, Satakunta Central Hospital, Pori, Finland.

Funding: This study was supported by grants (TL) from the Aarne Koskelo Foundation, Helsinki, Finland and Paavo Nurmi Foundation, Helsinki, Finland. 

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted April 13, 2012, provisional acceptance given May 16, 2012, final version accepted June 25, 2012

Address for correspondence: Pasi P. Karjalainen, Heart Center, Satakunta Central Hospital, Sairaalantie 3, Pori, Finland. Email: pasi.karjalainen@satshp.fi