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Evaluation of Novel Balloon Pulmonary Angioplasty Using Intravascular Ultrasound for Total Occlusion Lesions and Blood Flow in the Postprocedural Phase After Initially Unsuccessful Procedures
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Any views and opinions expressed are those of the author(s) and/or participants and do not necessarily reflect the views, policy, or position of the Journal of Invasive Cardiology or HMP Global, their employees, and affiliates.
J INVASIVE CARDIOL 2024. doi:10.25270/jic/24.00204. Epub August 15, 2024.
Abstract
Objectives. Outcomes of balloon pulmonary angioplasty (BPA) using intravascular ultrasound (IVUS) with a rounded tip to cross a total occlusion lesion in chronic thromboembolic pulmonary hypertension without passing a conventional guidewire remain unclear. Even in initially unsuccessful cases of total occlusion lesions, improved blood flow may be observed in the postprocedural phase as a result of breaking the thrombosis cap surface. The aim of the study was to verify the initial success of BPA with a new technique using IVUS for total occlusion lesions and to evaluate peripheral blood flow in the postprocedural phase in initially unsuccessful cases.
Methods. Initial success rate and associated factors were evaluated in 50 total occlusion lesions by attempted IVUS passage using a new technique without a preceding guidewire from August 2016 to February 2024. Peripheral blood flow improvement in the postprocedural phase among initially unsuccessful cases was investigated via subsequent angiographic examination or during follow-up.
Results. The success rate was 54%, and the sole determinant of success was the angle of the lesion. Peripheral perfusion improved in 15 of 23 initially unsuccessful cases in the postprocedural phase. Even in the unsuccessful cases, significant improvement in peripheral perfusion occurred in the postprocedural phase in the patients undergoing dilatation with the balloon advanced partway into the total occlusion lesion to confirm intravascular location of the balloon (P = .0257).
Conclusions. BPA treatment of total occlusion lesions may improve perfusion in the postprocedural phase even following an initially unsuccessful treatment. Maximizing use of IVUS may provide an adjunctive role in BPA of total occlusion lesions.
Introduction
Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease in which pulmonary artery stenosis or occlusion due to organized thrombus results in pulmonary hypertension and impaired quality of life and life prognosis.1 The hemodynamic and prognostic benefits of balloon pulmonary angioplasty (BPA) treatment of patients with CTEPH have been reported in many countries.2-4 Procedural complications and success rates of BPA treatment vary depending on the lesion types.5 The lesions of CTEPH are categorized by their characteristic appearance on pulmonary angiography as ring-like stenoses, web lesions, subtotal occlusion lesions, total occlusion lesions, or tortuous lesions. BPA treatment of CTEPH involves a series of procedures whereby the lesions are crossed with a guidewire and dilated with a balloon catheter. Therefore, the success of the procedure depends on the ability to cross a lesion blocked by organized thrombus using a guidewire. Total occlusion lesions include those that can be passed easily, as well as those with a thick thrombus layer that makes passage difficult.
Yang et al reported that total occlusion lesions have hard intimal layers and that the BPA success rate depends on the thickness of the layer and the site of occlusion.6 A 0.014-inch guidewire may enter the thrombo-intimal or subintimal space without passing into the peripheral vessel, which can result in the formation of a blind end or intimal dissection distal to the lesion, thus preventing the wire from passing through.
Although we usually use intravascular ultrasound (IVUS) or optical frequency domain imaging to evaluate vessel diameter and lumen properties,7 we believe that IVUS can also be used as a tool to cross CTEPH lesions filled with organized thrombus. We thought it useful to use IVUS to bluntly pass larger tracts of the lumen, and have previously reported a method to pass organized thrombosed lesions of CTEPH by taking advantage of the shape and characteristics of IVUS;8 we named this technique the “precedent IVUS technique”. We used the Eagle Eye Platinum ST IVUS (Philips Volcano) in this study because the IVUS catheter tip is more rounded compared with that of other IVUS systems, and this was thought to reduce the likelihood of pulmonary artery injury. Further, images can be obtained at a close distance of 2.5 mm from the tip. The ability to visualize near the tip allows for immediate recognition of IVUS perforation outside the vessel.
However, although the BPA procedure for total occlusion lesions may be terminated without complete improvement in perfusion, it may improve in the postprocedural phase, which is defined as the period during which pulmonary arteriography was performed on the same vessel at follow-up or during additional treatment. There are case reports of improved blood flow in the postprocedural phase caused by partially breaking the surface of the total occlusion lesion in the first attempt at passage, even if no flow was observed in the vessels distal to the lesion.9
Although there have been reports in the postprocedural phase of successful BPA for total occlusion lesions, no studies have evaluated the improvement of blood flow in the postprocedural phase in cases of initially unsuccessful BPA. Therefore, the purpose of this study was to evaluate the success rate of lesion passage using the precedent IVUS technique for total occlusion lesions of pulmonary arteries and to evaluate the improvement in remote blood flow in cases of initially unsuccessful BPA.
Methods
This was a single-center retrospective study conducted at the Saitama Cardiovascular and Respiratory Center (SCRC) between August 2016 to February 2024. We performed BPA on patients who presented to our hospital with shortness of breath and chest pain, and who were diagnosed as having CTEPH by echocardiography, chest computed tomography (CT) scan, lung perfusion scintigraphy, and right heart catheterization. In total, 352 BPA sessions were performed in 94 patients at the SCRC. The precedent IVUS technique was performed on the total occlusion lesions. This study was approved by the Ethics Committee of the SCRC (approval no. 2019012), and informed consent was obtained from the patients for the study and interventions described and to the publication thereof.
Precedent IVUS technique
After removing ring-down artifacts, which are luminous rings of false images surrounding the IVUS catheter, the overall size of the IVUS image was adjusted to fit the screen according to the observed vessel diameter. While performing this procedure, the IVUS image was on live mode. The technique entails slightly advancing the guidewire to the organized thrombus, pushing it into the thrombus, and guiding the IVUS along the guidewire. After we confirm the position of the IVUS in the organized thrombus, the IVUS and guidewire are grasped together and advanced such that the IVUS is slightly ahead of the guidewire. Thus, instead of manipulating the guidewire through the lesion, it is crossed by pushing the IVUS forward (Figure 1, Videos 1-6). Using the ultrasound image, we confirm the presence of the IVUS in the true lumen of the vessel and continue to advance the IVUS through the lesion into the true lumen distal to the lesion. Based on their morphology, total occlusion lesions have extremely hard intimal layers,6 and advancement of the IVUS catheter alone is often prevented by the lesion. Therefore, we need to use a hard-tip guidewire from the beginning of the procedure because it is necessary to first penetrate the entrance of the obstruction with this guidewire before the IVUS can penetrate the lesion.
Each patient received at least 3 months of anticoagulation with a direct oral anticoagulant or warfarin, which was also administered on the day of BPA treatment. Unfractionated heparin 2000 IU was administered before starting BPA, with an additional 1000 IU administered hourly. All patients underwent BPA via the femoral vein approach with a 6-French (Fr) or 7-Fr guiding catheter.10 Selection of guidewires was left to the physician’s discretion. A guidewire that can handle a heavy tip load (Astato XS40; ASAHI INTECC or Chevalier 14 Tapered 30; Cordis Cordis/Johnson & Johnson) was used to penetrate the proximal cap of the hard lesion.
Study design
Among the patients with CTEPH who underwent BPA, we selected cases and total occlusion lesions that were treated with the precedent IVUS technique. We evaluated lesion passage in the selected cases, and we evaluated improvement of blood flow in the unsuccessful cases, including that during the postprocedural phase.
The primary outcome was initial success in opening the total occlusion lesions. Initial success was defined as a case in which the lesion was passed using the precedent IVUS technique, dilated with a balloon catheter, and pulmonary blood flow of Grade 2 or 3 was achieved. Cases that ended with blood flow of Grade 0 or 1 were considered unsuccessful.11 The secondary outcome was the presence or absence of peripheral blood flow in the postprocedural phase. Considering that there are cases in which blood flow improves in the postprocedural phase simply by breaking the cap of the thrombus layer, the presence of such blood flow was evaluated based on whether balloon dilatation was performed in cases in which the precedent IVUS technique was unsuccessful.
Other influences on procedural success were also evaluated: hemodynamic data, number of sessions, pulmonary hypertension medications, lesion type, vessel diameter, oxygen saturation, vessel angle, and distribution of lesion localization were compared between the successful and unsuccessful cases at baseline and on the day the precedent IVUS technique was performed.
Lesion morphology and vessel diameter
The target vessel lesion types were classified with reference to a previous report, and total occlusion lesions were selected.5 The vessel diameter of the lesion was defined as the value obtained by IVUS immediately proximal to the occlusion.
Target vessel angle and diameter
To determine whether the support force of the guiding catheter plays a role in the success of the precedent IVUS technique, the angle of the lesion was evaluated. Two directional views were obtained: 0º anteroposterior and 60º left anterior oblique views. We scored the angles of the lesion in these 2 views acquired at angiography to account for the effect of the degree of flexion of the target vessel, with straight lines scored as 0 points, less than 45 degrees as 1 point, between 45 and 90 degrees as 2 points, and greater than 90 degrees as 3 points. Scoring was set as the sum of the scores for the 2 angiographic views (Figure 2).
Safety assessment
Safety was assessed using the following categories: a decrease in SpO2 greater than 3%, use of gelatin sponges for hemostasis, appearance of bloody sputum, vascular perforation, use of mechanical ventilation, and appearance of ground-glass opacity or consolidation on CT scans in sessions in which the precedent IVUS technique was performed. To determine the incidence of complications, categories were counted based on the presence of complications. If more than 1 category was present, all categories were counted as positive.
Statistical analysis
Continuous variables in the results are expressed as the median and 25th to 75th percentiles, and numbers (frequency, %) were used for categorical parameters. Comparisons between 2 groups were made using the Mann-Whitney U test for ratio scales and Fisher’s exact probability test with the Bonferroni method for normal scales. The normal distribution of each data subset was checked using graphical methods and a Shapiro-Wilk test. Logistic regression analysis was used to assess the factors of success or failure. Statistical significance was defined as a P-value of less than 0.05. EZR (Saitama Medical Center, Jichi Medical University), a graphical user interface for R (The R Foundation for Statistical Computing), was used for the analyses.
Results
Baseline characteristics and hemodynamics
In 35 patients, 50 total occlusion lesions were treated with the precedent IVUS technique. Baseline characteristics, oxygenation parameters, and hemodynamic data of the patients are summarized in Table 1. The median age of the patients was 66.3 years and 83% were women. Mean pulmonary artery pressures (mPAP) measured by right heart catheterization during the initial BPA and the precedent IVUS technique were 42.7 mm Hg and 27.8 mm Hg, respectively. The precedent IVUS technique generally required a median of 2 sessions, whereas only 1 session was required in 7 cases. This procedure was often performed after hemodynamic improvement was obtained because we believed that vascular injury would increase complications under conditions of high mPAP and high pulmonary vascular resistance.
Initial success and postprocedural phase improvement in blood flow
Of the 50 lesions identified as total occlusions, 27 (54%) could be passed using only the precedent IVUS technique followed by balloon dilatation to obtain Grade 2 or 3 peripheral blood flow. In 16 of the 23 unsuccessful cases, balloon dilatation was performed at the site where IVUS confirmed the vessel lumen. Of these 16 patients who underwent balloon dilatation, 13 achieved improvement in peripheral perfusion during the postprocedural phase. In the remaining 7 unsuccessful cases, balloon dilatation was not performed, at the discretion of the operator, because of the patients’ persistent cough and increased pulmonary artery pressure during the procedure. Two of these 7 patients had Grade 3 flow at the next pulmonary angiogram. As a result, 15 of the 23 unsuccessful cases showed peripheral perfusion on pulmonary angiography performed in the postprocedural phase. The balloon dilatation patients showed significantly more peripheral perfusion in the postprocedural phase than did the non-balloon dilatation patients (P = .0257) (Figure 3).
Factors determining treatment success of precedent IVUS technique
An analysis of the factors that determined a successful or unsuccessful treatment with the precedent IVUS technique, such as number of sessions, hemodynamics, lesion localization, pulse rate, target vessel angle, guiding catheter size, presence of pulmonary vasodilator, and guidewire tip loading, are shown in Table 2. Logistic regression analysis showed that the total angle of the target vessel was the only independent factor influencing the successful or unsuccessful use of the precedent IVUS technique, with significantly smaller angles between the lesion and catheter observed in the successful cases (P = .0114). Distribution of the lesions was not significantly different between the successful and unsuccessful cases of precedent IVUS technique use (42 right, 9 left, 6 lobar, 19 segmental, and 26 subsegmental arteries). Furthermore, pulmonary vasodilator use, mPAP, and pulmonary vascular resistance did not correlate with a successful or unsuccessful procedure. No significant difference in hemodynamics occurred in the postprocedural phase as a result of a successful or unsuccessful procedure.
Complications of treatment of total occlusion lesions
Table 3 shows the complications that occurred related to use of the precedent IVUS technique. Complications were seen only in unsuccessful cases. There were 10 cases of perforation only with the precedent IVUS technique. In these cases, the total occlusion lesion could be crossed only partway using the precedent IVUS technique, and the perforations were caused by the IVUS diverting midway into a side branch vessel. There were 7 other cases of vascular perforation as a result of manipulating advancement of the parallel 0.014-inch guidewire because the lesion could be passed only partway using the precedent IVUS technique. Of the 17 patients with perforation, 8 required hemostasis with gelatin sponge injection, with 6 of the perforations caused by the precedent IVUS technique and 2 by guidewire manipulation. Oxygen saturation decreased by more than 3% in only 1 patient, and bloody sputum was observed in 2 patients. No patients required mechanical ventilation.
Discussion
To our knowledge, this is the first study to evaluate passage of total occlusion lesions of the pulmonary artery with the precedent IVUS technique approach and to assess improvement in peripheral perfusion during the postprocedural phase in cases in which the initial procedure was unsuccessful. The initial success rate for total occlusion lesions using the precedent IVUS technique was 54%. Although it was difficult to compare success rates due to the different definitions of success among several previous studies, there was no clear increase in the success rate.5,6,12 However, even in the initially unsuccessful cases, blood flow in some cases improved in the postprocedural phase simply as a result of breaking the cap of the thrombus layer with balloon dilatation. The phenomenon of improved peripheral blood flow in the postprocedural phase was also observed in the patients requiring injection of gelatin sponges due to perforation. The performance of balloon dilatation within an organizing thrombus, even if vascular perforation occurs, may be acceptable. The present study showed the possibility of obtaining peripheral blood flow during the postprocedural phase by breaking the cap of the total occlusion in the approach to total occlusion lesions, even without achieving complete initial success. The precedent IVUS technique may be suggested as a viable adjunctive technique.
Benefits of using IVUS to prevent complications
The advantage of the precedent IVUS technique is real-time visualization, which confirms that the true lumen of the occluded vessel has been entered. If we can confirm entry into the true lumen, we can safely dilate with the balloon catheter.
We thought that blunt advancement by the precedent IVUS technique would contribute to the prevention of pulmonary artery injury, but there were more cases of perforation than expected. However, no serious complications requiring the use of a ventilator were observed. The perforations that occurred with the precedent IVUS technique were different than those caused by 0.014-inch guidewire perforation. Manipulation of the 0.014-inch guidewire can cause penetration of the vessel wall in the proximal portion of the vessel because the guidewire can pass under the intima. The perforation pattern with the IVUS technique often showed perforation by the tip at a bifurcation or narrow branch due only to blunt advancement of the IVUS catheter.
Perforation of a total occlusion lesion during BPA is often asymptomatic. Therefore, if a vascular perforation goes undetected and contrast is administered at high pressure or balloon dilatation is performed extravascularly, the fistula may enlarge and hemostasis may be difficult to achieve. Thus, early recognition of extravascular perforation is essential. Because we can confirm whether the IVUS location is intravascular or extravascular, a gelatin sponge can be prepared before withdrawal of the IVUS.13 If the location is extravascular, we can also achieve hemostasis by dilating the balloon just proximal of the perforation site to prevent hemodynamic disturbance.
Success factors and issues
Smaller vessel diameters also result in smaller targets, and larger angles of the guiding catheter and target vessel limit the force that can be transmitted when advancing the IVUS. Therefore, a higher success rate was expected for larger vessel diameters and smaller angles. The only factor that influenced the success of the precedent IVUS technique was the vessel bifurcation angle; vessel diameter, hemodynamics, and pulmonary vasodilators played no apparent role in procedural success. There was also concern that the success rate would be lower when treating vessels in the upper lobe because guiding catheter backup is often inadequate, but no significant difference was found.
There are 2 possible reasons why lesion angle was a factor in the success of the precedent IVUS technique. First, the closer the vessel is to a straight line, the more force can be applied to the IVUS. If the angle of the vessel is large, the force required to advance the IVUS is greater than normal because the force transmitted to the tip is weakened when the IVUS is advanced by the operator’s hand. As a result, the IVUS can be pushed out of the lesion because of the distribution of the thrusting force. Second, the fact that the perforations in this study occurred distal to a subsegmental artery, even though the occluded lesion site was a segmental artery, suggests that the strength of the accumulated force was immediately transmitted to the peripheral artery after passing through the occluded site.
Pulmonary arteries are often not straight. In particular, distal vessels beyond the subsegmental arteries are tortuous and bifurcated, making branch selection difficult for IVUS, which generally needs to proceed in a straight line. Therefore, in some cases, the precedent IVUS technique was switched to conventional operation of the guidewire in the middle of the IVUS procedure even when IVUS could be advanced, but this was unsuccessful; vascular perforation occurred during this process, and thus caution should be exercised when changing to conventional manipulation of a guidewire with a strong tip for lesions that are difficult to pass.
The reason that vessel diameter did not affect the success rate was attributed to the fact that the measurement of the vessel diameter was based on the diameter of the vessel at the entry point of the occlusion. Even if the diameter of the vessel at the occlusion site is large, vessels beyond the segmental artery often branch and have smaller diameters.
Potential new approaches for total occlusion lesions
This study suggests that the initial success of the precedent IVUS technique alone is effective in conditions in which the pulmonary artery is straight. However, its effectiveness in diverse pulmonary arteries is limited, and the force applied to obtain initial success can lead to branch perforation. When passage using this technique is difficult, switching to conventional guidewire manipulation is also likely to be unsuccessful. However, peripheral blood flow was confirmed in the postprocedural phase in 80% of the cases, even when the first attempt was unsuccessful. It is possible that operators may not need to focus on achieving initial success in opening total occlusion lesions in a single session because blood flow may improve in the postprocedural phase simply by breaking the cap in the thrombus layer. This suggests the need for a detailed study of the lesion structure of total occlusion lesions.
Thrombotic pulmonary artery occlusions in CTEPH are the result of sequential events of freshly organized thrombus formation and occur as a result of activation of endothelial cells and myofibroblasts.14 Regulation of angiogenesis is thought to involve hemodynamic stimulation of endothelial cells in addition to chemical stimulation by angiogenic factors. It has been reported that severed blood vessels elongate downstream, rather than upstream, from blood flow during wound angiogenesis.15 The same might be true for human pulmonary arteries. In the present study, the fact that peripheral vessels were not visible immediately after the initial treatment in the unsuccessful uses of the precedent IVUS technique, but that peripheral blood flow was observed during the postprocedural phase, suggests that damage caused by balloon dilatation of the occluded lesion induced and stimulated angiogenesis in the endothelial cells, resulting in vascular elongation from the vessels peripheral to the lesion. From the perspective of angiogenesis, balloon dilatation to an area in which the vessel lumen was identified by IVUS, even if peripheral vessels were not visualized, may affect blood flow in the postprocedural phase.
Limitations
This study is a single-center, retrospective, observational study and is limited by the small number of patients. Among total occlusion lesions, there may be heterogeneity in lesion hardness, flexion, and thickness, which may affect the success rate of lesion passage. There may also be a bias toward patency in the postprocedural phase depending on lesion thickness; as the force with which IVUS is advanced is left to individual judgment, initial success may vary among individuals.
Conclusions
In patients with CTEPH, the precedent IVUS technique has the potential to improve peripheral perfusion in the postprocedural phase by breaking the cap of the thrombus layer of a totally occluded lesion in a pulmonary artery, even without initial success in treating the total occlusion lesion. The precedent IVUS technique may be useful as a viable adjunct technique in the approach to treating a total occlusion lesion.
Affiliations and Disclosures
Shinya Nagayoshi, MD; Shinya Fujii, MD, PhD; Takashi Miyamoto, MD, PhD;
Makoto Muto, MD, PhD
From the Division of Cardiology, Saitama Cardiovascular and Respiratory Center, Saitama, Japan.
Disclosures: The authors report no financial relationships or conflicts of interest regarding the content herein.
Address for correspondence: Shinya Nagayoshi, MD, Division of Cardiology, Saitama Cardiovascular and Respiratory Center, 1696 Itai, Kumagaya City, Saitama 360-0197, Japan. Email: shinyabistro@gmail.com
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