Author + information
- Received January 7, 2013
- Revision received March 6, 2013
- Accepted March 14, 2013
- Published online July 1, 2013.
- Takumi Inami, MD∗,
- Masaharu Kataoka, MD∗,†∗ (, )
- Nobuhiko Shimura, MD∗,
- Haruhisa Ishiguro, MD∗,
- Ryoji Yanagisawa, MD∗,
- Hiroki Taguchi, MD∗,
- Keiichi Fukuda, MD†,
- Hideaki Yoshino, MD∗ and
- Toru Satoh, MD∗∗ ()
- ∗Division of Cardiology, Second Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan
- †Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
- ↵∗Reprint requests and correspondence:
Dr. Toru Satoh or Dr. Masaharu Kataoka, Division of Cardiology, Second Department of Internal Medicine, Kyorin University School of Medicine, 6-20-2, Shinkawa, Mitaka, Tokyo 181-8611, Japan.
Objectives This study sought to identify useful predictors for hemodynamic improvement and risk of reperfusion pulmonary edema (RPE), a major complication of this procedure.
Background Percutaneous transluminal pulmonary angioplasty (PTPA) has been reported to be effective for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). PTPA has not been widespread because RPE has not been well predicted.
Methods We included 140 consecutive procedures in 54 patients with CTEPH. The flow appearance of the target vessels was graded into 4 groups (Pulmonary Flow Grade), and we proposed PEPSI (Pulmonary Edema Predictive Scoring Index) = (sum total change of Pulmonary Flow Grade scores) × (baseline pulmonary vascular resistance). Correlations between occurrence of RPE and 11 variables, including hemodynamic parameters, number of target vessels, and PEPSI, were analyzed.
Results Hemodynamic parameters significantly improved after median observation period of 6.4 months, and the sum total changes in Pulmonary Flow Grade scores were significantly correlated with the improvement in hemodynamics. Multivariate analysis revealed that PEPSI was the strongest factor correlated with the occurrence of RPE (p < 0.0001). Receiver-operating characteristic curve analysis demonstrated PEPSI to be a useful marker of the risk of RPE (cutoff value 35.4, negative predictive value 92.3%).
Conclusions Pulmonary Flow Grade score is useful in determining therapeutic efficacy, and PEPSI is highly supportive to reduce the risk of RPE after PTPA. Using these 2 indexes, PTPA could become a safe and common therapeutic strategy for CTEPH.
- chronic thromboembolic pulmonary hypertension
- flow appearance
- percutaneous transluminal pulmonary angioplasty
- reperfusion pulmonary edema
Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease in which chronic thromboembolism in the pulmonary arteries leads to pulmonary hypertension (1–9). Medical therapies using anticoagulation and pulmonary vasodilators are somewhat effective for the treatment of CTEPH (1,10,11), and the most powerful conventional therapeutic strategy is invasive surgical pulmonary endarterectomy (12–16). However, our group and others recently reported that percutaneous transluminal pulmonary angioplasty (PTPA) markedly improved subjective symptoms and pulmonary hemodynamics in patients with CTEPH and may be a promising new therapeutic strategy (17–19).
Reperfusion pulmonary edema (RPE) is a major complication of PTPA. In addition, pulmonary endarterectomy, but not PTPA, can remove the majority of lesions in 1 procedure. Each lesion dilated by PTPA is still exposed to high pulmonary arterial pressure (PAP), and this could explain why the incidence of reperfusion lung injury following PTPA is higher than that after pulmonary endarterectomy. In 2001, Feinstein et al. (20)showed that pulmonary hemodynamics were markedly improved by pulmonary angioplasty in 18 patients, and that 11 (61%) of the 18 patients developed RPE. In our previous report, 27 (53%) of 51 cases of overall procedures and 19 (68%) of 28 cases of the first procedures developed RPE, and patients with more severe clinical signs and/or hemodynamic dysfunction at baseline had a higher risk of RPE after PTPA (17).
This study, therefore, sought to identify useful predictors for the risk of RPE as well as hemodynamic improvement after PTPA.
One hundred and forty consecutive PTPA procedures (54 first, 46 second, 20 third, 17 fourth, and 3 fifth procedures) in 54 patients with CTEPH who attended Keio University Hospital or Kyorin University Hospital, Japan, from January 2009 to May 2012 were enrolled. These 54 patients were diagnosed with CTEPH by demonstration of organized pulmonary thromboembolism using contrast-enhanced lung computed tomography, perfusion lung scintigraphy, and pulmonary angiography, and ruling out collagen vascular disease, pulmonary disease, left heart abnormality, and other systemic diseases by blood tests, pulmonary function tests, and echocardiography. Among the 54 enrolled patients, 8 patients had 1 procedure, 26 had 2, 3 had 3, 14 had 4, and 3 had 5 procedures. All the patients provided informed consent, and the PTPA treatment and study protocol was approved by the institutional review boards of the hospitals.
Patients underwent right-sided heart catheterization just before PTPA, just after PTPA, and at the follow-up examinations. The timing of the follow-up right-sided heart catheterization after the last procedure was essentially 1 to 3 months, 6 months, 12 months, and every 1 year thereafter. The right atrial pressure (RAP), PAP, and pulmonary artery wedge pressure (PAWP) were measured at right-sided heart catheterization. The cardiac output (CO) was determined by the Fick technique using assumed oxygen consumption. Cardiac index was calculated by dividing CO by body surface area. The pulmonary vascular resistance (PVR) was calculated by subtracting PAWP from mean PAP and dividing by CO.
Six-min-walk distance and plasma B-type natriuretic peptide (BNP) level were measured both before PTPA and at follow-up with right-sided heart catheterization.
Indications for PTPA
The patients were selected as potential candidates for PTPA based on the following criteria: 1) more than 30 mm Hg of mean PAP or more than 3.75 Wood units (300 dynes/s/cm−5) of PVR; 2) greater than New York Heart Association functional class II; 3) patient’s own wish to undergo PTPA; and 4) did not fulfill after-mentioned exclusion criteria.
Adult patients with CTEPH who could understand the procedure of PTPA and possible complications and could give informed consent of their own free will were selected. Both the pulmonary endarterectomy and PTPA procedures were explained to them, including the possible complications of PTPA (based on the previous report by Feinstein et al. ) and the benefits and risks of pulmonary endarterectomy, the latter given by an experienced surgeon in some cases. Pulmonary endarterectomy was then recommended based on the evidence in patients whose main lesions were centrally located and whose operative risks were typical of the procedure. Our study basically selected patients with almost all the pulmonary thromboembolic lesions existing in the lobar, segmental, and subsegmental pulmonary arteries. PTPA targets basically the same lesions (lobar, segmental, and subsegmental lesions) as pulmonary endarterectomy, except for cases whose lesions exist in the main trunks of the pulmonary arteries. Thus, our study selected patients who rejected pulmonary endarterectomy or for whom we suggested PTPA was more appropriate than pulmonary endarterectomy because of their advanced age or poor physical condition. Additionally, our study included patients who had already undergone pulmonary endarterectomy but had residual pulmonary hypertension due to lesions that could not be removed with pulmonary endarterectomy.
Meanwhile, our exclusion criteria were patients who were unable to lie on the treatment table during the procedure because of mental disorders, those with active infectious disease, and those who had serious complications such as hepatic disease, kidney disease, hemorrhagic tendency, or poorly controlled diabetes mellitus or hypertension.
During our study (from January 2009 to May 2012), 1 patient had pulmonary endarterectomy because the main lesions were centrally located, and another potential candidate of PTPA, other than the 54 enrolled patients in this study, selected pulmonary endarterectomy after explanation of both pulmonary endarterectomy and PTPA, including their possible complications and benefits.
Procedure of PTPA
Warfarin was stopped for 3 days before the procedure and replaced by heparin. The goal of activated clotting time during the procedure was 250 to 300 s. Warfarin was restarted after the procedure, and heparin infusion was continued until the efficacy of warfarin reached the optimal range. All patients were treated with warfarin long term. A catheter was inserted via the femoral vein or right jugular vein, with the latter selected if the patient had a filter in the inferior vena cava. A balloon wedge pressure catheter was inserted into the main pulmonary artery tract and replaced by a long spring guidewire before a 7- to 9-F long sheath was inserted into the main pulmonary artery tract. A 6- to 8-F guide catheter was then inserted through the long sheath, and a 0.014-inch guidewire was inserted through the target lesion. The target lesions were dilated by a 1.5- to 9.0-mm monorail or over-the-wire balloon catheter. The balloons were inflated by hand through inflation device for 15 to 30 s until they were fully expanded.
Angiography of the targeted side of the lung was performed before each procedure to select and determine the target lesions, but was not performed after the procedure. To determine the flow appearance and flow grade after angioplasty, selective angiography of the treated vessels was performed through catheters engaged in the treated vessels. The balloon size was determined by measurement of vessel diameter by intravascular ultrasound or the ruler to measure the vessel diameter on cine freeze-frame. The procedural success for each target lesion was defined by dilation of the lesion diameter to the same size as the reference vessel’s diameter or by the perfusion flow level of Pulmonary Flow Grade 3 (shown in Table 1) after balloon dilation.
The enrolled patients had been treated with an appropriate combination of oral vasodilators such as bosentan, ambrisentan, sildenafil, tadalafil, or beraprost before the procedure. Epoprostenol, treprostinil, and iloprost were not used in any of the patients.
Selection of target vessels
The selection criteria of target vessels are as follows: 1) the lobe with the poorest perfusion is identified by lung perfusion scintigraphy; 2) if any of the lobes in both lungs have the same degree of poor pulmonary blood flow in lung perfusion scintigraphy, the lobes in the right lung are selected because the manipulation technique in the right lung is relatively easier than that in the left lung, and the total blood flow distribution of the right lung is physiologically larger than that of the left lung; 3) if any of the lobes, including the inferior lobe in either the right or the left lung, have the same degree of poor distribution of pulmonary blood flow in lung perfusion scintigraphy, the inferior lobe is selected because it has physiologically more distribution of blood flow compared with the superior lobe and middle lobe; and 4) the targeted segmental branches are selected based on pulmonary angiography, which means, essentially, the lesions with less anatomical information about peripheral branches, such as chronic total occlusion and pouch defects, should be put off, and the lesions with more information about peripheral branches, such as webs and bands and abrupt narrowing, are selected, because information about peripheral branches distal to the target lesions are important in order to safely perform the procedure.
These criteria are particularly important in the first-time procedure. The purposes of these criteria are: 1) to perform a safe procedure without exacerbation of hemodynamics, in particular, in cases with poorer pulmonary hemodynamics; 2) to improve pulmonary hemodynamics as effectively as possible; and 3) to achieve successful revascularization without complications. But, to achieve final obliteration of pulmonary hypertension, almost all of the remaining lesions need to be treated. Thus, the remaining lesions are selected in series in accordance with the aforementioned criteria at the second session of PTPA.
Analysis of hemodynamic improvement at follow-up
The hemodynamic parameters at baseline, just before the first procedure, and at the time of follow-up after the last procedure were compared. Although the number of enrolled patients was 54, follow-up analysis was performed in 44 patients, in whom the follow-up examinations had been performed for a total observation period of more than 50 days.
Classification of pulmonary flow appearance
Table 1shows the classification of pulmonary flow appearances seen with selective segmental pulmonary angiography. We named the classification “Pulmonary Flow Grade.” The definitions of perfusion in Pulmonary Flow Grade were described by reference to the previous report regarding Thrombolysis in Myocardial Infarction classification in myocardial infarction (21). The flow appearance of the target vessels just before and after angioplasty was graded. The correlations between the change in flow grade and hemodynamic changes were investigated.
The change of Pulmonary Flow Grade score at the time of the procedure was calculated based on the levels of segmental branches of target pulmonary arteries. To cite a case in which a segmental branch (for example, A8) had 2 subsegmental branches (for example, A8a and A8b) and only 1 subsegmental branch (A8a or A8b) with baseline Pulmonary Flow Grade 1 was treated to grade 2, the change in score of Pulmonary Flow Grade was calculated as 0.5 (because the difference of grade 1 to grade 2 is divided by 2, the number of subsegmental branches). To cite another case in which a segmental branch (for example, A10) with baseline Pulmonary Flow Grade 1 was treated to grade 3, the change in score of Pulmonary Flow Grade was calculated as 2.
Measurement of the ratio of pressures across the lesions
The pressure difference across the stenosis in the target vessel was measured by a pressure wire (PrimeWire PRESTIGE, Volcano, San Diego, California), as the ratio of distal to proximal pressures across the target lesion. The correlation between Pulmonary Flow Grade score and the ratio of proximal to distal pressures of the target lesions was analyzed.
Definition of Pulmonary Edema Predictive Scoring Index
We proposed a new index, the Pulmonary Edema Predictive Scoring Index (PEPSI), to reflect both the change in angiographic flow and the baseline severity of pulmonary hypertension due to CTEPH. Thus, PEPSI is defined as follows:
Predictive variables for RPE
Eleven variables were chosen to analyze the relation to RPE. The predictive variables comprised hemoglobin, estimated glomerular filtration rate, BNP, whether the procedure was the first session or not, mean RAP, mean PAP, cardiac index, PVR, number of target vessels, and PEPSI.
All data are presented as median (25th to 75th percentiles). Significant differences were determined using the Mann-Whitney test or Wilcoxon matched pairs signed rank test, as appropriate. Correlation between the sum total change of Pulmonary Flow Grade scores and changes in the hemodynamic parameters from baseline to follow-up were analyzed using the Spearman rank correlation coefficient. Correlation between pulmonary flow grade and the ratio of pressure difference was analyzed using the Spearman rank correlation coefficient. Univariate analysis based on the logistic regression analysis was used to examine the relationship between the occurrence of RPE and the predictive variables. The results were expressed as odds ratios with 95% confidence intervals (CI). Multivariate analysis based on logistic regression analysis was used to examine the independent effect of each variable on the occurrence of RPE. The best predictive threshold for RPE was sought by means of receiver-operating characteristic (ROC) curves. The Youden index was utilized to define the best cutoff value on the ROC curve. Adjustments for the nonindependence of multiple procedures within patients were not made. A value of p < 0.05 was considered statistically significant.
Clinical improvement by PTPA
A representative pulmonary angiogram during the PTPA is shown in Figure 1. The baseline characteristics of the 54 enrolled patients are detailed in Table 2. Among the 44 patients enrolled for follow-up analysis, the median observation period from the first procedure to the last follow-up conducted on each patient was 6.4 (4.5 to 8.6) months. A comparison of the examinations at baseline with those at follow-up is presented in Figure 2. Right-sided heart catheterization demonstrated a significant improvement in hemodynamic parameters (mean RAP, 5.5 [3 to 7] vs. 3.0 [2 to 5.8] mm Hg; mean PAP, 43 [38 to 53] vs. 25 [21 to 29] mm Hg; PVR, 9.4 [7.2 to 14.8] vs. 3.8 [2.9 to 5.5] Wood units; and cardiac index, 2.5 [1.9 to 2.9] vs. 2.8 [2.3 to 3.7] l/min/m2; baseline vs. follow-up, respectively; p < 0.01). The right ventricular systolic pressure was also significantly improved from 84 (74 to 99) mm Hg to 48 (42 to 56) mm Hg (p < 0.01). Plasma BNP was significantly decreased after PTPA (126 [61 to 390] vs. 33 [20 to 54] pg/ml; p < 0.01). Although some of the data for the 6-min-walk distance were missing due to refusal of examination by some patients because of gait disorders or dyspnea, the 6-min-walk distance was significantly lengthened at follow-up from 342 (243 to 396) m to 405 (348 to 495) m (p < 0.01, n = 33).
Correlations between total change in Pulmonary Flow Grade scores and hemodynamic changes
Among the 140 procedures in the 54 enrolled patients, the total number of target vessels was 525, the average number of target vessels per procedure was 4.0 (2.3 to 5.0), the average number of procedures per patient was 2 (2 to 4), and the average number of target vessels per patient was 9.5 (6.3 to 13.0). The duration of each procedure was determined by the extent of x-ray exposure, fluoroscopy times, and amount of contrast material in regard to the patients’ renal function and cardiac function. Thus, the reason why most patients underwent multiple procedures is because if all target lesions were treated at 1 procedure, those parameters would be over the limit. The average x-ray exposure, fluoroscopy times, and amount of contrast material per procedure were 1,531 (765 to 2,621) mGy, 74.1 (57.9 to 89.9) min, and 325 (250 to 370) ml, respectively.
The changes in Pulmonary Flow Grade scores from baseline to just after the procedure are shown in Table 3; approximately 88% of target vessels belonged to Pulmonary Flow Grade score 0 or 1 before the procedures, but approximately 89% of the target vessels changed to Pulmonary Flow Grade score 2 or 3 after angioplasty.
Correlations between the sum total changes in Pulmonary Flow Grade scores and the change in hemodynamic parameters such as PVR and mean PAP at follow-up were analyzed (Fig. 3). The sum total change of Pulmonary Flow Grade scores at the time of the procedure was significantly correlated with the change in PVR and mean PAP at follow-up (p < 0.05). However, the total number of target vessels at the time of the procedure was not correlated with the change of PVR nor mean PAP (data not shown).
Correlations between Pulmonary Flow Grade scores and the ratio of pressures across the lesions
For all the lesions with Pulmonary Flow Grade 0, it was not possible to measure pressure differences by a pressure wire. Thirty-one measurements of the ratio of the proximal to the distal pressures of the target lesions were performed in a total of 15 target vessels with Pulmonary Flow Grade 1 to 3 in 6 patients. Figure 4shows the correlation between the Pulmonary Flow Grade score and the pressure ratios, demonstrating a strong correlation (p < 0.0001).
Complications other than RPE
Among the 54 enrolled patients, 1 patient with baseline severe right heart failure developed pulmonary hemorrhage as a complication because of perforation by the wire. The perforation was completely sealed, but right heart failure was exacerbated, and the patient died 2 days after the procedure. Therefore, the mortality associated with PTPA was 1.9% in this study. Among the total of 140 procedures, a dissection occurred in 1 of the targeted pulmonary arteries just after balloon dilation in 2 procedures. The dissections did not expand, and the hemodynamics did not change. Thus, the dissections were left untouched. Extravascular leaks occurred just after balloon dilation in another 4 procedures in which the extravascular leak was stopped by prolonged low-pressure dilation of the balloon in 1 procedure and by insertion of a covered stent in the other cases. Consequently, there were 5 perforations, consisting of 1 case in the deceased patient and 4 cases of extravascular leaks, and 2 dissections in this study, which means that the rate of angiographic complications was 5% (7 of 140 procedures).
Classification and frequency of RPE
Table 4lists the definitions of the classification into 5 groups according to the severity of RPE. Figure 5shows representative chest x-ray and chest computed tomographic images of RPE classified into 5 groups based on the definitions in Table 4. Eighty-seven procedures (62%) belonged to grade 1, defined as no significant findings of pulmonary edema on chest x-ray, and the other 53 procedures (38%) belonged to grade 2 to 5, which indicated the occurrence of RPE. Nine procedures (6.4%) were grade 4 or higher, which indicates the occurrence of severe RPE, and these cases needed noninvasive positive pressure ventilation or artificial respiration. In 1 of the 2 procedures of grade 5, artificial ventilation with a percutaneous cardiopulmonary support (in other words, cardiopulmonary assist device or venoarterial extracorporeal membrane oxygenation) was needed for 5 days.
Comparison between procedures with and without RPE
Table 5shows a detailed comparison between the procedures with and without RPE of grade 2 or higher. Among the 53 procedures with RPE of grade 2 or higher, 31 procedures (58.5%) were the first-session procedures of each patient. This demonstrates that RPE occurred readily at first-time procedures. Furthermore, mean PAP, PVR, cardiac index, and BNP were more markedly abnormal in the procedures with RPE than in those without.
Significant predictive variables for RPE
We analyzed factors associated with the occurrence of RPE of grade 2 or higher (Table 6). Among the 11 variables, 8 variables (except for the number of target vessels, hemoglobin level, and mean RAP) at baseline were significantly related to the occurrence of RPE according to univariate analysis. Multivariate analysis using variables with a significant correlation of p < 0.001 in univariate analysis demonstrated that PEPSI was most strongly related to the occurrence of RPE (p < 0.0001).
ROC curve analysis for prediction of RPE
According to the results of the multivariate analysis shown in Table 6, we then analyzed the correlation between PEPSI and the occurrence of RPE of grade 2 or higher. Figure 6A shows the distribution of PEPSI with and without RPE of grade 2 or higher. Figure 6B shows ROC curve analysis, which demonstrated an observed area under the curve of 0.87, cutoff value of 35.4, sensitivity of 88.7% (95% CI: 77 to 96), specificity of 82.8% (95% CI: 73 to 90), positive predictive value of 75.8% (95% CI: 63 to 86), negative predictive value of 92.3% (95% CI: 84 to 97), odds ratio of 37.6 (95% CI: 13.6 to 103.8), likelihood ratio of a positive test of 5.1 (95% CI: 2.9 to 9.6), and likelihood ratio of a negative test of 0.14 (95% CI: 0.04 to 0.32).
We proposed Pulmonary Flow Grade scores for the classification of the angiographic flow appearances of target vessels in PTPA, and PEPSI as a marker connecting the Pulmonary Flow Grade scores with the baseline hemodynamic severity of CTEPH. This study demonstrates that the sum total change in Pulmonary Flow Grade scores is a good marker for predicting hemodynamic improvement at follow-up, and that PEPSI is useful to predict the risk of RPE in PTPA.
The present study found significant improvement in hemodynamic parameters, exercise capacity as indicated by 6-min-walk distance, and plasma BNP level after PTPA. In combination with some previous studies (17–20), these findings demonstrate that PTPA is clinically effective for the treatment of CTEPH. Some previous reports have demonstrated that about 45% to 55% of mean PAP and 65% to 70% of PVR decrease by pulmonary endarterectomy (22–24). Furthermore, the outcomes of patients treated medically have been reported sporadically (25–35), suggesting that the clinical efficacy of medical treatment tends to be lower than that of invasive surgical treatment. Meanwhile, in the results of our study, 42% of the mean PAP and 60% of the PVR decreased at about 6 months after PTPA. These findings suggest that the hemodynamic outcomes by PTPA are improved, but are not superior to, the outcomes by pulmonary endarterectomy. A large multicenter collaborative study is required in the future to compare the therapeutic efficacy, mortality, and complications of PTPA with those of pulmonary endarterectomy performed in experienced centers.
We proposed Pulmonary Flow Grade scores, which classify selective pulmonary angiography flow grade based on the flow appearance of the pulmonary veins perfused by the targeted pulmonary arteries. In the present study, the sum total change in Pulmonary Flow Grade scores was significantly correlated with hemodynamic changes of PVR and mean PAP at follow-up. In particular, our previous report demonstrated that the benefits of PTPA cannot be estimated by any immediate hemodynamic changes at the time of the procedure (17), suggesting that the performance guided by Pulmonary Flow Grade could more easily predict the therapeutic efficacy at follow-up. Furthermore, in our results, Pulmonary Flow Grade score was strongly correlated with the ratio of the proximal to the distal pressures of the target lesions obtained by a pressure wire, suggesting that the practical utility of Pulmonary Flow Grade scores is substantiated by these pressure ratios, which is an objective method of measurement of stenosis.
RPE remains the most important complication of PTPA. Indeed, Feinstein et al. (20)experienced RPE in 11 of 18 enrolled patients (61%). In this study, RPE was graded into 5 groups according to severity. As shown in Figure 5, the RPE was recognized even in the opposite lung without angioplasty, in particular in grade 3 or higher. These findings raise the possibility that the occurrence of RPE is mediated, not only by the direct injury or direct exposure of high pressure in pulmonary arteries, but also by the indirect spreading effect of inflammation via cytokines. A more detailed exploration of mechanisms of RPE is desirable. Among the 140 total procedures in this study, 53 procedures (38%) were classified as grade 2 to 5, which indicates clear occurrence of RPE, and all 9 cases with RPE of grade 4 or higher, which indicates severe RPE, needed noninvasive positive-pressure ventilation or artificial respiration. Therefore, it would be highly risky to increase the sum total change of Pulmonary Flow Grade scores blindly without concern for the occurrence of RPE.
Comparison between the procedures with and without RPE of grade 2 or higher demonstrated that the sum total change in Pulmonary Flow Grade scores in cases with RPE was significantly higher than that in those without, and that procedures in cases with greater clinical severity at baseline had a higher risk of RPE. These findings confirm that PTPA should be performed based on the index reflecting both angiographic flow change and baseline severity of pulmonary hypertension so as to obtain maximum therapeutic efficacy and minimal risk of RPE at the same time. The PEPSI, which is calculated by multiplying the sum total change in Pulmonary Flow Grade scores by baseline PVR, could therefore provide a new and useful index in clinical settings. In this study, PEPSI was the strongest factor related to the occurrence of RPE by multivariate analysis, and ROC curve analysis demonstrated that the negative predictive value of the PEPSI for the occurrence of RPE was 92.3% when the cutoff value was 35.4, suggesting the possibility that PEPSI is a useful predictor of RPE.
These findings presuppose the usefulness of PTPA performed based on PEPSI. To cite a case with baseline PVR of 12 Wood units, the targeted value of sum total change in Pulmonary Flow Grade scores is 2.95, because the optimal cutoff value of PEPSI, 35.4, divided by a PVR of 12 Wood units equals 2.95. Thus, in such a case, if the Pulmonary Flow Grade score is changed from 0 to 2 after angioplasty of the first target vessel, the procedure should be stopped without angioplasty of the second target vessel because it would be difficult to maintain the change in Pulmonary Flow Grade score within 0.95 (i.e., 2.95 − 2). Alternatively, the procedure should be carefully continued so as to control the change in Pulmonary Flow Grade score of the second target vessel within 1 (for example, change in Pulmonary Flow Grade score from 0 to 1, 1 to 2, or 2 to 3). To cite another case with a baseline PVR of 5.0 Wood units, the targeted value of the sum total change in Pulmonary Flow Grade scores is 7.1 (i.e., 35.4/5.0). In such a case, if the Pulmonary Flow Grade score is changed from 0 to 3 after angioplasty of the first target vessel and is changed from 0 to 2 after angioplasty of the second target vessel, the change in Pulmonary Flow Grade score of the third target vessel should be controlled within 2 (for example, change in Pulmonary Flow Grade score from 0 to 2 or 1 to 3). Additionally, because PEPSI is calculated using the baseline PVR, in the patients with lower PVR at baseline, it appears that it is possible to treat more target lesions or reach more changes of Pulmonary Flow Grade scores within 1 procedure, leading to more benefits in reduction in PVR and mean PAP.
The average observation period was not very long, and the number of patients was relatively small. Therefore, a study based on a longer observation period following a greater number of patients is needed to confirm our results. Furthermore, a prospective study should be performed to further demonstrate the predictive value of the PEPSI. This is also a nonrandomized study with no control arm, and these data are subject to selection bias.
PTPA is effective for the treatment of CTEPH, and the sum total change in Pulmonary Flow Grade scores is very useful for predicting the therapeutic efficacy at follow-up. With RPE recognized as the most important complication of PTPA, PEPSI, which reflects both angiographic flow change and the baseline severity of pulmonary hypertension due to CTEPH, could be a useful predictor of RPE. Our findings lead to the following hypothesis: if PTPA is performed guided by PEPSI, the risk of RPE will be minimized and therapeutic efficacy maximized, making PTPA a safe and common therapeutic strategy for CTEPH. However, the usefulness of PEPSI in this study is just a retrospective finding and would need to be tested prospectively to see whether clinical outcome is improved by using the PEPSI as a guide for PTPA.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Inami and Kataoka contributed equally to this work.
- Abbreviations and Acronyms
- B-type natriuretic peptide
- confidence interval
- cardiac output
- chronic thromboembolic pulmonary hypertension
- pulmonary arterial pressure
- pulmonary artery wedge pressure
- Pulmonary Edema Predictive Scoring Index
- percutaneous transluminal pulmonary angioplasty
- pulmonary vascular resistance
- right atrial pressure
- receiver-operating characteristic
- reperfusion pulmonary edema
- Received January 7, 2013.
- Revision received March 6, 2013.
- Accepted March 14, 2013.
- American College of Cardiology Foundation
- Humbert M.
- Bonderman D.,
- Skoro-Sajer N.,
- Jakowitsch J.,
- et al.
- McNeil K.,
- Dunning J.
- Hoeper M.M.,
- Mayer E.,
- Simonneau G.,
- Rubin L.J.
- Dartevelle P.,
- Fadel E.,
- Mussot S.,
- et al.
- Hoeper M.M.,
- Barberà J.A.,
- Channick R.N.,
- et al.
- Pepke-Zaba J.,
- Delcroix M.,
- Lang I.,
- et al.
- Jensen K.W.,
- Kerr K.M.,
- Fedullo P.F.,
- et al.
- Keogh A.M.,
- Mayer E.,
- Benza R.L.,
- et al.
- Kataoka M.,
- Inami T.,
- Hayashida K.,
- et al.
- Mizoguchi H.,
- Ogawa A.,
- Munemasa M.,
- Mikouchi H.,
- Ito H.,
- Matsubara H.
- Feinstein J.A.,
- Goldhaber S.Z.,
- Lock J.E.,
- Ferndandes S.M.,
- Landzberg M.J.
- Sheehan F.H.,
- Braunwald E.,
- Canner P.,
- et al.
- Jais X.,
- D’Armini A.M.,
- Jansa P.,
- et al.
- Reichenberger F.,
- Voswinckel R.,
- Enke B.,
- et al.
- Voswinckel R.,
- Enke B.,
- Reichenberger F.,
- et al.
- Oudiz R.J.,
- Galie N.,
- Olschewski H.,
- et al.
- Galie N.,
- Brundage B.H.,
- Ghofrani H.A.,
- et al.
- Barst R.J.,
- Langleben D.,
- Badesch D.,
- et al.
- Kim N.H.