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Effects of Percutaneous Transluminal Angioplasty and Endovascular Brachytherapy on Vascular Remodeling of Human Femoropopliteal Artery: 2 Years Follow-up by Noninvasive Magnetic Resonance Imaging
Corresponding author. Prof. Dr. Augusto Gallino, MD, FACC, Head of the Department of Cardiovascular Medicine, Ospedale San Giovanni (EOC) Bellinzona, Cardiology/Internal Medicine, Soleggio, CH-6500 Bellinzona, Switzerland.
We aimed to assess in vivo the long-term effects of percutaneous transluminal angioplasty (PTA) and endovascular brachytherapy (EVBT) on vessel wall by serial MRI.
Methods
Twenty patients with symptomatic stenosis of the femoropopliteal artery were randomly assigned to PTA (n=10) or PTA+EVBT (n=10, 14 Gy by γ-source). High-resolution MRI was performed prior, at 24-hours, 3-months, and 24-months after intervention. MRI data were analyzed by an independent, blinded observer.
Results
The effects of both procedures on vessel wall at 24-hours and 3-months have been reported. Despite similar percent decrease in lumen area between 3- and 24-months in both groups (−8% for PTA and −11% for PTA+EVBT), at 24-months lumen area gain compared to baseline was +30% in PTA versus +82% in PTA+EVBT (p<0.05). Total vessel area, which was increased at 24-hours and 3-months, returned to pre-treatment value in both groups.
Conclusions
We demonstrated non-invasively that restenosis and inward remodeling after PTA are delayed by EVBT. At 24-months, patients treated with brachytherapy have larger lumen than those treated with PTA alone. The decrease in luminal and total vessel area between 3- and 24-months after EVBT indicates that the restenotic and remodeling process is not abolished but delayed with this therapy.
Guidelines for peripheral percutaneous transluminal angioplasty of the abdominal aorta and lower extremity vessels. A statement for health professionals from a Special Writing Group of the Councils on Cardiovascular Radiology, Arteriosclerosis, Cardio-Thoracic and Vascular Surgery, Clinical Cardiology, and Epidemiology and Prevention, the American Heart Association.
The mechanisms of luminal enlargement after PTA have been classically explained with a displacement of atherothrombotic plaque material into the vessel wall. We recently documented in vivo that acute lumen enlargement after PTA is mainly consequence of severe disruption of atherothrombotic plaque, deep dissection into the vessel wall and positive (outward) vascular remodeling.
Effects of percutaneous transluminal angioplasty and endovascular brachytherapy on vascular remodeling of human femoropopliteal artery by noninvasive magnetic resonance imaging.
The severity of the vascular injury induced by balloon angioplasty and the following negative (inward) remodeling of the arterial wall induced by the vascular healing process could partially explain the high restenosis rate after invasive procedures. In fact, restenosis still remains the major limitation of PTA in medium and small size vessels such as femoropopliteal arteries, especially in the setting of long lesions and poor vessel run-off.
Several antiproliferative treatment strategies have been tested to reduce restenosis. Among them endovascular brachytherapy (EVBT) appears to be one of the most effective.
The mechanism responsible for the postulated anti-restenotic properties of EVBT on vessel wall remains mainly unclear. Until now, most of the human in vivo data on the assessment of the effects of EVBT on vascular wall and lumen have been obtained by intracoronary ultrasound (IVUS).
However, the invasiveness of IVUS represents a major limitation for sequential follow-up examinations in humans.
Magnetic resonance imaging (MRI) allows serial, noninvasive in vivo assessment of interventions on atherothrombosis in several vascular beds such as the aorta, the carotid and femoral arteries.
Effects of aggressive versus conventional lipid-lowering therapy by simvastatin on human atherosclerotic lesions: a prospective, randomized, double-blind trial with high-resolution magnetic resonance imaging.
Lipid lowering by simvastatin induces regression of human atherosclerotic lesions: two years' follow-up by high-resolution noninvasive magnetic resonance imaging.
In vivo high resolution MR imaging has been validated in human atherosclerotic femoral arteries with intravascular ultrasound (IVUS). MRI showed high concordance with IVUS for assessment of lumen area, vessel wall dimensions and vascular calcifications.
Effects of percutaneous transluminal angioplasty and endovascular brachytherapy on vascular remodeling of human femoropopliteal artery by noninvasive magnetic resonance imaging.
PTA induced deep dissection into the vessel wall. Interestingly enough, at 3 months plaque disruption and dissection were completely healed in patients treated with balloon dilatation only, whereas these features persisted in about 50% of the patients treated with combined approach of balloon dilatation and local endovascular brachytherapy. Luminal loss after PTA was partially due to inward vessel remodeling. Brachytherapy prevented inward remodeling and induced an increase in lumen area at 3 months, but partially prevented healing of the disrupted vessel surface.
The aim of the present study was to compare the long-term effects of PTA and PTA+EVBT on severely stenotic femoropopliteal lesions by means of serial, noninvasive high resolution MRI.
Patients and Methods
Each patient gave his or her written informed consent to participate in the study, which was approved by the local ethics committee.
Twenty consecutive symptomatic patients (71.4±6.5 years, 14 males) aged older than 55 years with claudication (≥3 to the Rutherford scale) and severe superficial femoropopliteal artery stenosis were included in the study and randomly assigned to PTA alone (n=10) or PTA+EVBT (n=10, 14 Gy by gamma-source), and imaged by high-resolution MRI before, 24-hours, 3-months and 2 years after intervention (Fig. 1). Patients were not eligible for the study if they had non-atherosclerotic occlusive disease, vascular surgery during the preceding 6 months, uncontrolled hypertension, hemorrhagic diathesis, impaired renal function (creatinine level >180 mmol/l), life expectancy of <2 years, or contraindication for MRI. All patients underwent treatment with Aspirin 100 mg daily and statins (atorvastatin 40 to 80 mg/day).
All interventional procedures were performed by a standard (Seldinger) technique by using intra-arterial digital subtraction angiography (Integris V 3000, Philips Medical Systems, Best, The Netherlands). No atherectomy device or stent implantation was allowed. Ipsilateral anterograde puncture of the common femoral artery and a 6F introducer sheath (Cordis Europe NV) were used in all procedures. Five or six millimeters balloon catheters were used to perform angioplasty of the stenotic lesions. The segment at which angioplasty was performed was marked with a radio opaque ruler, and movement of the table and angiographic unit was avoided in order to prevent parallax error. One to one randomization was performed by using sealed envelopes to assign patients to PTA alone or PTA+EVBT at the end of the standard PTA procedure.
Endovascular brachytherapy
Endovascular brachytherapy was performed by a single radiotherapist (with 10 years of experience in radiation therapy) at a high dose rate by using gamma-irradiation by a 192Ir-source. A 5F closed-tip non-centered applicator catheter (Nucletron) was advanced through the 6F sheath and placed in the balloon-treated lesion, so that the tip of catheter reached 1.5 cm distal to the distal end of the interventional length (IL). The active source length corresponded to the IL plus 1 cm on the distal and proximal end. The dose distribution was calculated by means of a computer assisted planning system (Plato-BPS, version 13.2, Nucletron) with a 2.5 mm stopping point. The reference dose of 14 Gy was applied in a depth of 5 mm from the source (reference vessel radius 3 mm plus reference depth of 2 mm in the center of the IL). Marks on a dummy wire measured the IL and the length of the angioplasty segment. After its definition the dummy wire was removed. The application catheter was connected to the after-loader and the source was advanced into the applicator. No sham procedure was performed in patients treated with PTA only; therefore the patients and the interventional radiologist were not blinded to the procedure. In contrast, an investigator blinded to patient identity, DSA findings and treatment group performed the off center analysis of the MRI images.
Magnetic resonance imaging and analysis
Magnetic Resonance Imaging (MRI) consisted in serial high resolution studies performed in all patients before PTA, 24-hours, 3 months and 24-months after PTA±EVBT using a 1.5-Tesla unit, (Gyroscan Intera, Release 8.1; Philips Medical Systems, Best, The Netherlands) with a gradient strength of 30 mT/m and a slew rate of 150 mT/m/ms.
The current MRI protocol which has been previously described in detail [3] consisted of the following 3 steps: (1) Gradient echo scout series to localize anatomical structures, (2) time-of-flight MR angiography to localize the stenotic lesion and provide anatomic landmarks in order to define precise location of the stenosis of interest, and (3) plaque imaging sequences. T1-weighted (T1W), proton density-weighted (PDW) and T2-weighted (T2W) three dimensional, double inversion recovery (black blood) fast spin echo sequences (2IR-FSE) with ECG-triggering were used to obtain images in the axial plane. The 3D volume of cross-sectional images was acquired perpendicular to the long axis of the vessel of interest. Predefined anatomical landmarks, for example the distance between common femoral artery bifurcation to maximum stenosis were used to obtain reproducible image positions in the different studies (Fig. 2). All subsequent plaque imaging sequences were then performed by using this superficial receive-only coil centered at the level of the stenosis of interest.
Fig. 2MRI method for serial plaque imaging: after localization of the stenosis of interest, a 3D volume (yellow box), containing 10 contiguous cross-sectional images perpendicular to the lumen axis was acquired and matched over time using measurements from anatomical landmarks (such as common femoral artery bifurcation). Manual tracing of vessel border (lumen and outer border) was performed to quantify vessel dimensions (lower panel). Outer vessel border defined the total vessel area (TVA). V: Femoral vein.
High resolution MR images were acquired by using the following parameters: repetition time (TR) 2 to 3 RR intervals for T2W/ PDW and 1 RR for T1W; echo time (TE): T2W 42 msec, PDW and T1W 9.4 msec; field of view, 9×9 cm; slice thickness, 2,5 mm; acquisition matrix, 256×218 (zero-filled interpolated to 512×436, in order to reduce the partial-volume effects in imaging pixels); in plain resolution, 0.35×0.41 mm; number of slices, 10 for each for each sequence; 2 signal averages; scan mode, 3D; echo train-length 24; bandwidth 310 Hz per pixel; echo spacing 9.4 msec. The signal from fat was reduced by a chemical shift suppression pulse. The total MRI examination time was approximately 35 to 45 minutes.
Computer-assisted quantitative analysis of the MR cross-sectional images (Image Pro-Plus, Media Cybernetics) was performed by a blinded operator (RC) using manual tracing of the vessel borders. Lumen area was defined as the area encompassed by the inner boundary of the intimal surface. Total vascular area was defined by the outer vessel boundary, and vessel wall area was calculated by subtracting lumen area from the total vessel area (Fig. 2). Area measurements were performed on PDW images. In cases with suboptimal image quality T1W images were used for analysis. Quantitative changes in cross sectional MR images were compared to pre-PTA values. The mean value of 10 contiguous MR images centered in the lesion was computed for statistical analysis. Matching of the MR images was performed using vascular landmarks. The presence of vessel wall disruption was evaluated visually in all lesions. Dissection after PTA was defined as the presence of a tear in the intimal surface separating the lesion from the underlying arterial wall.
Statistics
Data are presented as mean±1SE. Percent changes are reported as 100×(mean at time T2 mean at time T1)/(mean at time T1). Statistical analysis was performed using ANOVA for repeated measures (Stat View 4.1, ABACUS Inc) and student t test. A value of P<0.05 was considered significant.
Results
Baseline clinical data, angiographic and procedural characteristics from patients are shown in Table 1, Table 2. The two groups (i.e., PTA and PTA+EVBT), consisting of 10 patients each, had comparable baseline characteristics, including risk factors for occlusive vascular disease and lesion characteristics. All patients had immediate angiographic success, which had been defined as less than 50% residual stenosis in the treated segment, and there were no complications related to PTA. There were no procedural or radiation-related complications, such as thromboembolic occlusion of a peripheral vessel or acute occlusion within the irradiated region on control angiography performed immediately after EVBT. There was no case of late thrombotic occlusion in the EVBT group or formation of aneurysms.
Table 1Baseline clinical characteristics of patients according to assigned treatment
Two-years follow-up was not available in one case in the EVBT group because the patient refused to undergo the MRI follow-up examination. Two patients of the PTA only group were lost to 2-years follow-up examination due to the need of reintervention because of restenosis or death unrelated to cardiovascular disease (Fig. 1).
Acute and mid-term effects
Cross-sectional MRI before intervention revealed an average percent area stenosis of 80% (ranging 69 to 92%), which did not differ between the treatment groups. Short and mid term results of PTA and EVBT have been previously reported 3. In summary, cross-sectional MR imaging performed at 24-hours after percutaneous intervention revealed deep disruption of the atherosclerotic plaques and no difference in lumen area, total vessel area and vessel wall area between the groups. At 3 months luminal loss after PTA was partially due to inward vessel remodeling. Brachytherapy prevented inward remodeling and induced an increase in lumen area, but partially preventing healing of disrupted vessel surface (Fig. 3). Quantitative data are included in Table 3.
Fig. 3Representative MR cross-sectional images in patients treated with PTA alone (upper panel) and with PTA+EVBT (lower panel) before, at 24 hours, 3 and 24 months after intervention. Zoomed cross-sectional images at the level of the artery are included in the panel in the left corner (4 time enlargement for PTA and 3 time enlargement for PTA+EVBT images). Acutely, similar enlargement of lumen area and expansion of vessel wall (outward remodeling) was seen in both groups. Patients treated with PTA alone showed features of inward remodeling already at 3 months, which was delayed in those treated with PTA+EVBT.
At 24 months, patients treated with PTA+EVBT maintained a significantly larger lumen area compared to those treated with PTA alone (p=0.047, between groups over time comparison, Table 3. Compared to baseline, cross-sectional lumen area increased at 24-months follow-up by 30% in the PTA and by 82% in the PTA+EVBT group, despite similar results immediately after the intervention. Interestingly, a trend towards restenosis was observed at 24 months in the PTA+EVBT group with a non-significant lumen loss of 11% compared to the 3-months follow-up (p=0.056). The quantitative analysis reported in Fig. 4 demonstrates that EVBT delayed the restenotic and remodeling process as indicated by the shifting of the curves to the right.
Fig. 4Line graphs showing the effect of PTA (white) and PTA+EVBT (black) on lumen area (P=0.047 between groups over time) and total vessel area (P=0.08 between groups over time). BL: Baseline; 24 hrs: at twenty-four hours; mo: months. Square: lumen area. Circle: total vessel area (TVA).
Between 3 and 24 months follow-up MRI revealed a significant reduction in TVA in both groups, which at 24 months did not differ anymore between the groups (p=0.08, between groups over time comparison) indicating that inward remodeling occurred also in the PTA+EVBT group.
Deep dissection and disruption of the atherosclerotic plaque were seen acutely after intervention but were no longer visible in the PTA group at 3-months follow-up, indicating healing of the vessel wall. On the contrary, dissection or splitting of the atherosclerotic lesion persisted in 50% and in 10% of the patients treated with PTA+EVBT after 3 and 24 months, respectively.
Discussion
We demonstrated non-invasively using serial MRI that restenosis and inward remodeling after PTA are delayed by EVBT. Percutaneous balloon intervention led to a significant enlargement of the lumen area that was maintained up to 2 years. The combination of balloon angioplasty and brachytherapy led to an even more pronounced enlargement of the lumen area. Patients treated with PTA alone showed no further decrease in lumen area between 3 and 24-months follow-up, whereas luminal loss was observed in those treated with brachytherapy. Therefore, EVBT does not abolish but appears to delay significantly the process of restenosis. Similarly, the negative (inward) remodeling of the vessel wall, as shown by the decrease of the total vessel area, was also retarded in the brachytherapy group compared to the PTA group.
We conclude that EVBT initially prevents restenosis and even enhances the outward (positive) remodeling of the vessel wall within the first three months after PTA but the process of restenosis appears to begin before 24 months. These findings are in agreement with a recently published study from Wolfram and colleagues who demonstrated that the applied dose of 12 Gy gamma irradiation inhibited recurrence of disease at 6 months follow-up when compared with PTA alone. Between 36 and 60 months they observed a late catch-up phenomenon and comparable stenosis recurrence rate at 5 years follow-up.
Another recent publication confirms the lack of a sustained angiographic, hemodynamic and clinical benefit of EVBT after a mean follow-up of 32 months.
In addition to these two studies that used digital subtraction angiography for follow-up after vascular intervention, our MRI data also allowed not only measurement of lumen area but also assessment of vascular remodeling after endovascular therapy which is known to play a major role in restenosis after PTA.
The current study demonstrates the potential of MRI for serial assessment of vascular remodeling which is a major factor in restenosis after angioplasty.
At present, IVUS is considered the gold standard for quantitative evaluation of arterial remodeling in humans. However, in contrast to MRI serial application of IVUS in humans is limited because of its invasiveness.
Our study shows that even though lumen area is significantly increased by EVBT at three and 24 months this happens at the expense of the delayed healing of the balloon-induced deep disruptions of the vessel wall. This should draw the attention to the community of interventionalists to limit this treatment modality to selected patients. In fact, the persistence of dissections and delayed healing with the associated changes in the biological properties of the intima and in particular of the endothelium may eventually even lead to increased thrombogenic features in these vessels such as observed in patients treated with EVBT and stent implantation after discontinuing double antiaggregant therapy (Aspirin and Clopidogrel).
Vascular brachytherapy with 192Ir after femoropopliteal stent implantation in high-risk patients: twelve-month follow-up results from the Vienna-5 trial.
A potential limitation of the present study is the small number of patients included. However, high resolution MRI has been validated in several experimental studies with histology and IVUS for assessment of atherosclerosis of the vessel wall.
High resolution MRI measures cross-sectional lumen area, which is known to correlate better with hemodynamic effect of stenosis than does a reduction in diametric measurements as provided by catheter-based angiography.
In addition, the study design with serial imaging allowed each patient to act as his own control and therefore limits the number of needed observations.
In conclusion, high-resolution MR imaging after PTA shows deep disruption of the atherosclerotic plaques followed by extensive remodeling process of the arterial wall. Luminal loss after PTA is partially due to inward vessel remodeling. Brachytherapy initially prevents inward remodeling and induces an increase in lumen area, at a cost of persistent plaque disruption in some patients. The remodeling and healing process appear to be delayed by endovascular brachytherapy compared to PTA alone but begins before 24 months. Our results support the hypothesis that restenosis may be delayed in patients treated with EVBT at the price of persistent dissection with the potential risk of late thrombosis.
The current study also confirms that MRI can be used to assess in vivo the long term effects of interventions (such as PTA and EVBT) on femoral artery as has been the case for studies investigating the effect of lipid-altering drugs on carotid artery and aorta.
Acknowledgments
We are grateful for the technical assistance of Markus Scheidegger, PhD and Michael Wyss, Application Engineer from Philips Medical Systems, Switzerland. We also thank Paolo Santini and the team of MR technicians for their collaboration and support. The study was supported by an academic grant of the Swiss Heart Foundation (RW, AG) and the Swiss National Science Foundation (RC: SNF320000-109905).
References
Pentecost M.J.
Criqui M.H.
Dorros G.
Goldstone J.
Johnston K.W.
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et al.
Guidelines for peripheral percutaneous transluminal angioplasty of the abdominal aorta and lower extremity vessels. A statement for health professionals from a Special Writing Group of the Councils on Cardiovascular Radiology, Arteriosclerosis, Cardio-Thoracic and Vascular Surgery, Clinical Cardiology, and Epidemiology and Prevention, the American Heart Association.
Effects of percutaneous transluminal angioplasty and endovascular brachytherapy on vascular remodeling of human femoropopliteal artery by noninvasive magnetic resonance imaging.
Effects of aggressive versus conventional lipid-lowering therapy by simvastatin on human atherosclerotic lesions: a prospective, randomized, double-blind trial with high-resolution magnetic resonance imaging.
Lipid lowering by simvastatin induces regression of human atherosclerotic lesions: two years' follow-up by high-resolution noninvasive magnetic resonance imaging.
Vascular brachytherapy with 192Ir after femoropopliteal stent implantation in high-risk patients: twelve-month follow-up results from the Vienna-5 trial.
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