- Email: [email protected]
Frequency and Risk of In-Stent Stenosis Following Pulmonary Artery Stenting
Frequency and Risk of In-Stent Stenosis Following Pulmonary Artery Stenting Anna Hallbergson, MD, PhDa,b,c, James E. Lock, MDa,b, and Audrey C. Marshall, MDa,b,* Peripheral and central pulmonary artery (PA) stenoses can result in right ventricular hypertension, dysfunction, and death. Percutaneous PA angioplasty and stent placement relieve obstruction acutely, but patients frequently require reintervention. Within a heterogeneous patient population with PA stents referred for catheterization because of noninvasive signs of PA obstruction, we have observed that in-stent stenosis (ISS) occurs commonly in some groups, challenging previous reports that this phenomenon occurs infrequently. We set out to evaluate the incidence and demographics of patients with previous PA stent placement who develop ISS. Consecutive patients with previously placed stents presenting for catheterization and undergoing PA angiography were reviewed (104 patients, 124 cases). We defined ISS angiographically, as a 25% narrowing of the contrastfilled lumen relative to the fluoroscopically apparent stent diameter at any site along the length of the stent. For inclusion, we required that the stenotic segment be narrower or equal in size to the distal vessel. ISS was diagnosed in 24% of patients, with the highest incidence among patients with tetralogy of Fallot and multiple aortopulmonary collaterals, Williams syndrome, or Alagille syndrome. In conclusion, ISS after PA stent placement is a more frequent problem than previously reported, and patients with inherently abnormal PAs are disproportionately affected. Increased clinical surveillance after stent placement and investigation of innovative preventive strategies may be indicated. Ó 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;113:541e545)
Peripheral pulmonary stenosis (PPS) occurs in the context of diffuse arteriopathies (e.g., Williams syndrome) and cardiac developmental defects (e.g., tetralogy of Fallot [TOF]). In either case, multiple lobar and/or sublobar obstructions can lead to proximal pulmonary artery (PA) hypertension. Although right ventricular (RV) function is typically preserved, this can result in severe RV hypertension. Unmitigated, this RV hypertension results in arrhythmia, ventricular failure, and death.1,2 PPS is managed surgically3 when lesions are located proximally, but more peripheral disease usually calls for endovascular management, with transcatheter balloon angioplasty or stent placement.4,5 Stents are known to be effective in lesions refractory to balloon angioplasty and have greatly enhanced the therapeutic armamentarium of the interventionalists.4e6 Rates of in-stent stenosis (ISS) have previously been reported to be very low.6e8 However, among patients with PPS referred for catheterization, we have observed a significant rate of angiographic ISS. Currently, no published information is available on rates of ISS among patients with PPS. We thus set out to describe the incidence of ISS in this patient cohort.
a Department of Cardiology, Boston Children’s Hospital, Boston, Massachusetts; bDepartment of Pediatrics, Harvard Medical School, Boston, Massachusetts; and cDivision of Cardiology, The Children’s Hospital of Philadelphia, Philadelphia. Manuscript received August 9, 2013; revised manuscript received and accepted October 9, 2013. This work was supported by The Keane Family Foundation (Boston, Massachusetts). See page 544 for disclosure information. *Corresponding author: Tel: (617) 355-6529; fax: (617) 713-3808. E-mail address: [email protected] (A.C. Marshall).
0002-9149/13/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.10.016
Methods The aim of this study was to determine the incidence of ISS in (1) patients with PPS referred for catheterization and (2) patients with Williams or Alagille syndrome. To address the first objective, we searched an institutional database for consecutive patients having catheterization during the year 2012 who had undergone PA stent placement within the previous 10 years. This list was supplemented with any patient who had a PA stent redilated at our institution during the year 2012; this allowed us to identify some additional patients whose stents were not initially placed at our institution or placed >10 years ago. Cases were excluded from consideration if there were no angiographic data available for review or if the stent had fractured in a manner precluding meaningful measurement of stent or luminal diameter. A total of 124 cases (104 patients) were included in our review. Indication for catheterization in this patient population at our institution has remained consistent for many years, including preoperative examination, noninvasive imaging suggestive of significantly elevated RV pressure (2/3 of systemic), pulmonary blood flow maldistribution (<1/3 of flow to 1 lung), worsening RV function, cyanosis due to PA stenosis, or worsening in symptoms.9 To address the second objective, we searched the institutional database to identify all patients with either Williams or Alagille syndrome who had been catheterized at our center at any time after PA stent placement. This identified 14 patients with Williams syndrome and 12 patients with Alagille syndrome who had undergone angiographic evaluation subsequent to PA stent placement at our center from 2003 to 2012. The diagnosis of either syndrome was based on documentation of meeting genetic and/or clinical criteria. www.ajconline.org
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The American Journal of Cardiology (www.ajconline.org) Table 1 Demographics Variable Male Age at catheterization (yrs) Body surface area at catheterization (m2) Weight at catheterization (kg) Stent redilation performed (% of cases) Total catheterizations per patient (n) PA stents per patient Time since stent placement (yrs) Time since the most recent stent dilation (yrs) Diagnosis TOF with MAPCAs TOF without MAPCAs MAPCAs (not TOF) Alagille syndrome* Williams syndrome Nonsyndromic PPS Truncus arteriosus D-TGA Other biventricular HLHS Other univentricular Stent type Genesis premounted Genesis XD Coronary Other Unavailable
Figure 1. (A) Severe right PA ISS in a 3-year-old with Williams syndrome. (B) No significant ISS in the right PA of a 7-year-old with truncus arteriosus. Percent ISS is calculated as follows (see arrows): (stent diameter luminal diameter)/stent diameter 100.
We defined ISS angiographically, as a 25% narrowing of the contrast-filled lumen relative to the fluoroscopically apparent stent diameter at any site along the length of the stent or stent complex (Figure 1). In addition, the segment was only deemed stenotic if it was equal to or narrower than the distal vessel to avoid inclusion of ISS due to significant stent overexpansion at the time of placement. Twenty-five percent ISS was empirically chosen based on our observation that this degree of angiographic narrowing is often hemodynamically significant and responsive to redilation. Determination of ISS was expressed as percentage of current stent diameter, as opposed to absolute measurement of luminal compartments. This allowed us to accommodate for the large range in patient and stent sizes in the pediatric population. Furthermore, defining ISS by percentage of stent lumen (rather than by a certain number of mm) removed much of the risk of calibration error, which otherwise could be significant, particularly in small vessels. Data collection was performed by evaluation of 2012 angiographic records for assessment of ISS and review of medical records and a cardiology department clinical database for demographic information. In general, images were acquired in 2 planes, and the best longitudinal image of each stent was evaluated. Among patients with multiple PA stents, the identification of ISS in any of the stents resulted in the patient being considered as affected. In these cases, measurements were performed on only one of the stents,
All Cases (n ¼ 124) 56% 5.5 (0.10e64) 0.88 0.47 26.6 22 80 6 (2e19) 1 (1e7) 2.8 (0.04e19) 1.5 (0.03e13) 48 (39) 16 (13) 6 (4.8) 7 (5.6) 4 (3.2) 5 (4.0) 5 (4.0) 6 (4.8) 13 (11) 15 (12) 5 (4.0) n ¼ 133 stents 76 (57) 21 (16) 6 (5) 15 (11) 15 (11)
Data are presented as median (range) or mean SD, as appropriate. Diagnoses and stent types are presented as % of total cases or stents, respectively. * Of 7 cases with Alagille syndrome, 6 had TOF (also accounted for in their respective TOF group).
typically the one that was most severely narrowed for purposes of data analysis. Computerized 2-dimensional measurements were performed using Vericis 8.30 (Merge Healthcare, Chicago, Illinois) by measuring the narrowest contrast-filled lumen diameter inside the stent and the fluoroscopically apparent stent diameter at that site. Values are expressed as median with a range or means with SD where applicable. ISS rates in different diagnostic groups were compared using Fisher’s exact test. Two-tailed paired t tests were used to compare means of continuous variables. Statistical significance was set at p < 0.05. Results Age at the time of catheterization in 2012 was 5.5 years (range, 0.1 to 64). As expected based on our practice, approximately 40% of cases were performed on patients with TOF, pulmonary atresia, and multiple aortopulmonary collaterals (TOF/pulmonary atresia/MAPCAs). Other forms of biventricular conditions, including D-loop transposition of the great arteries (D-TGA) and truncus arteriosus, made up 19% of cases. Single ventricle conditions, primarily hypoplastic left heart syndrome (HLHS) (at any stage of palliation), made up 15% of cases. Patients with PPS from an identified arteriopathy made up 8% of total cases. Total lifetime catheterizations through 2012 ranged from 2 to 19
Congenital Heart Disease/Pulmonary Artery In-Stent Stenosis
Figure 2. Distribution of patients with PPS with previously placed stents catheterized in 2012 by underlying diagnosis and portion of patients by diagnosis with ISS. The percentage of patients in each group affected by ISS is listed above each column. Bi-V ¼ biventricular.
(median 6). Time since stent placement was 2.8 years (range 0.04 to 19) and time since most recent stent dilation was 1.5 years (range 0.03 to 13). Approximately 3/4 of stents were Genesis (Cordis, Miami Lakes, Florida) stents (premounted or XD). Demographics of patients evaluated to address the first objective are listed in Table 1. There were 26 patients (Williams syndrome n ¼ 14, Alagille syndrome n ¼ 12) in the group addressing the second objective. Age at the time of catheterization in this group was 4.4 years (range 0.5 to 20). In this patient cohort, the incidence of angiographic PA ISS was 24% (25 of 104 patients), representing 124 total cases. In affected patients (i.e., by our definition 25% ISS and at most equal luminal size to distal vessel), the average degree of ISS was 43% (SD 12%, range 27% to 72%) stenosis, that is, on average, the in-stent lumen was narrowed by nearly half. Subgroup analysis of ISS severity was not performed because of limited sample size of affected patients. Mean time since stent placement was similar for patients with and without ISS (4.1 4.1 and 4.2 4.1 years, respectively). Time since last intervention was less in patients with ISS (1.5 1.6 years) compared with those without significant ISS (2.7 2.9 years, p <0.05). The distribution of stent types was also similar between the 2 groups (p >0.05). Stent redilation was performed in 80% of total cases (100% of cases with ISS). Presumably, redilations without underlying ISS were performed to accommodate somatic growth. Some patient groups had a high tendency to be affected by ISS, whereas others were rarely affected (Figure 2). Patients with MAPCAs had a 38% incidence of ISS, specifically 13 (36%) of 36 patients with TOF/pulmonary atresia/MAPCAs and 2 of 3 patients with other conditions associated with MAPCAs. Underlying diagnoses of the latter 2 patients were complex biventricular heterotaxy with pulmonary atresia and single RV with pulmonary atresia, respectively. The average severity of ISS among affected patients in the TOF/pulmonary atresia/MAPCA group was 44%, that is, similar to the average for the entire cohort affected by ISS. In patients with TOF without MAPCAs, the
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Figure 3. Comparison of the incidence of PA ISS in patients with arteriopathy (Williams or Alagille syndrome), TOF and/or MAPCAs, and other congenital heart disease (including the remaining diagnoses listed in Table 1). The former 2 groups have a significantly higher rate of ISS than the latter (p <0.01).
incidence was 27% (4 of 15 patients). There were 7 patients with 22q11 deletion in the cohort, all of whom had TOF/ pulmonary atresia/MAPCAs but interestingly had a low incidence (14%) of ISS (1 of 7 patients), which was not significantly different from the rate seen in TOF/pulmonary atresia/MAPCA patients without the 22q11 deletion based on the present small sample size. ISS was nearly absent in other structural congenital heart disease, including HLHS at any stage of repair (0 of 13 patients), D-TGA (0 of 6 patients), truncus arteriosus (1 of 5 patients), and other biventricular conditions (0 of 12). This latter group of patients with other structural congenital heart disease was significantly less affected by ISS compared with the patients with TOF and/or MAPCAs or arteriopathy (p <0.01; Figure 3). The more extensive review of patients with genetic arteriopathic conditions supported their high incidence of ISS, including 36% of patients (5 of 14) with Williams syndrome and 50% of patients (6 of 12) with Alagille syndrome (9 of whom also had TOF). Discussion ISS is a source of recurrent obstruction in previously stented PAs and is more common among patients with PPS referred for catheterization than previously recognized.6e8 Our results suggest that patients with arteriopathies and TOF should receive vigilant surveillance for ISS. The incidence of ISS after PA stent placement in our cohort of patients was 24% (31% of cases). In the sole previous report that systematically assessed for degree of stenosis (including a definition and grading system), the severity of ISS was defined by the thickness (in mm) of tissue between lumen and stent. In designing our study, we found a static definition of ISS problematic, given the range in PA sizes in children with congenital heart disease (e.g., a 1-mm cell layer in a 5-mm stent will contribute to more stenosis than a 1-mm cell layer in a 10-mm stent). Although the previous study had a broader cohort of patients, most had repaired TOF and pulmonary atresia, suggesting significant overlap of our patient populations. Median time from stent placement to reassessment was comparable with our study (2 vs 2.8 years),
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The American Journal of Cardiology (www.ajconline.org)
although approximately 1/2 of our patients had undergone stent redilation since placement. The time interval from last redilation was approximately 1.5 years (range, 0.03 to 13) in our cohort. Not surprisingly, the group affected by ISS had undergone more recent stent redilation. In the previous study, significant neointimal proliferation (>1 mm) was reported in only 4 (1.8%) of 220 patients, and restenosis based on both angiographic and hemodynamic criteria had an incidence of 5%. In contrast, using percentage of luminal loss as a marker for ISS, we found a 24% incidence. Underlying PA pathology clearly plays a role in the development of ISS. To our knowledge, this is the first report suggesting that patients with certain underlying diagnoses (TOF, MAPCAs, or primary arteriopathy) are at unique risk for ISS after PA stent placement. Patients with other congenital heart disease in this cohort, most of whom have stents placed because of postoperative PA obstructions, were typically spared from ISS (39 of 41 patients unaffected). From these findings, one can infer that stents placed in normal vasculature subject to surgical anastomoses, kinking, compression, or stretching are at lower risk of ISS. Similarly, there is little risk of ISS after redilation of an unaffected stent because of the somatic growth of a patient in these seemingly low-risk groups. In contrast, in patients in whom primary inherent abnormalities of the vascular wall are central to the disease (i.e., TOF, MAPCAs, congenital arteriopathy), there is a significant risk of ISS. Close monitoring for increasing RV hypertension or pulmonary blood flow maldistribution with low threshold for invasive reassessment is warranted after stent placement in high-risk patients. Obviously, “underlying PA pathology” is an indistinct term. On a microscopic level, the inherent PA abnormalities in patient populations vulnerable to PPS manifest as specific cellular changes, some of which have been described in detail. In the elastin-deficiency Williams syndrome, the obstructive lesions are due to increased smooth muscle cell proliferation and abnormal elastic lamellae, which result in medial hypertrophy. Lumen loss is then exacerbated by primary underdevelopment of vessels.10,11 In Alagille syndrome (aka arteriohepatic dysplasia), mutations in JAG-1 and disruption in notch signaling result in abnormal vasculogenesis, affecting multiple vascular beds, including the PAs.12 In these pathologic vessels, the endothelial response to injury imposed by stent placement may be unique. However, if there are similarities to the mechanism of ISS studied in coronary artery disease, then effective therapies (such as mammalian target of rapamycin inhibitors) may offer benefit to our patients with PA stenosis. Many stress factors may modulate the degree to which vessels exhibit and/or develop ISS. These include stent implantation techniques, preexisting endothelial vessel wall injury, and stent location and type. At our center, predilation with either low- or high-pressure balloons is typical before stent placement, which conceivably could be an instigating factor to neointimal proliferation. At the time of stent placement and redilation, balloon angioplasty can be performed using high or low inflation pressure, which could potentially also confer different risk of ISS. Although these factors may play a role in PA ISS, we use relatively similar implantation techniques such as predilation, inflation pressure, stent type despite underlying diagnosis. Of note, among our patients
with arteriopathy, we have observed a higher rate of vascular injury in response to angioplasty, which could potentially contribute to their higher rates of ISS at the time of subsequent stent placement. Previous reports of ISS in PA have suggested that stent placement at an unfavorable angle or leaving a gap between 2 tandem stents increases risk of ISS.7,8 In the present study cohort, stent types were evenly distributed among patients with and without ISS, suggesting little contribution of stent type to subsequent development of ISS. Our findings suggest that purely anatomic management in the catheterization laboratory may be insufficient to combat PA ISS and that reducing ISS may be a focus of future outpatient management. In fact, necessary redilations in the catheterization laboratory may in some patients act as a stimulus for further ISS. Our observations of patients affected by ISS suggest that it occurs early and rapidly after the procedure indicating that the proliferative response after injury sets in motion the process of luminal loss in a fashion similar to that observed in coronary arteries. Drug-eluting stents are now well established for coronary artery stenting and have been associated with lower rates of cardiac death, myocardial infarction, and stent thrombosis than bare-metal stents.13 Use of drug-eluting stents in PAs would be preferable for our patient population as well but appropriate stent sizes are currently unavailable making investigation of other proliferative inhibition for patients with PPS warranted. Future innovative therapies to address ISS may include antiproliferative therapy such as rapamycin (sirolimus) as suggested from animal models.14 The data presented herein indicate that the patients most likely to benefit from such therapy are those with TOF, MAPCAs, and/or arteriopathies. Our center is currently investigating the potential for future clinical use of rapamycin in this patient population. Our study was a retrospective review of patients referred for catheterization, which imposes several study limitations. A selection bias may be introduced as patients are typically referred because of clinical and/or noninvasive imaging indications, which may bias toward higher rates of ISS (as opposed to scheduled prospective reassessment of potential ISS at a set time after stent placement). Furthermore, there is a lack of a standardized definition of ISS in the PA literature making comparisons to previous studies difficult and necessitated an arbitrary definition based on our clinical experience of what constitutes significant ISS. We limited this definition to angiographic appearance, whereas it may be preferably to also include hemodynamic data, for example, stent pressure gradients, which are not universally recorded or available for review at our institution. Disclosures The authors have no conflicts of interest to disclose. 1. Bird LM, Billman GF, Lacro RV, Spicer RL, Jariwala LK, Hoyme HE, Zamora-Salinas R, Morris C, Viskochil D, Frikke MJ, Jones MC. Sudden death in Williams syndrome: report of ten cases. J Pediatr 1996;129:926e931. 2. Geggel RL, Gauvreau K, Lock JE. Balloon dilation angioplasty of peripheral pulmonary stenosis associated with Williams syndrome. Circulation 2001;103:2165e2170.
Congenital Heart Disease/Pulmonary Artery In-Stent Stenosis 3. Monge MC, Mainwaring RD, Sheikh AY, Punn R, Reddy VM, Hanley FL. Surgical reconstruction of peripheral pulmonary artery stenosis in Williams and Alagille syndromes. J Thorac Cardiovasc Surg 2013;145: 476e481. 4. Maglione J, Bergersen L, Lock JE, McElhinney DB. Ultra-highpressure balloon angioplasty for treatment of resistant stenoses within or adjacent to previously implanted pulmonary arterial stents. Circ Cardiovasc Interv 2009;2:52e58. 5. Law MA, Shamszad P, Nugent AW, Justino H, Breinholt JP, Mullins CE, Ing FF. Pulmonary artery stents: long-term follow-up. Catheter Cardiovasc Interv 2010;75:757e764. 6. Fogelman R, Nykanen D, Smallhorn JF, McCrindle BW, Freedom RM, Benson LN. Endovascular stents in the pulmonary circulation. Clinical impact on management and medium-term follow-up. Circulation 1995;92:881e885. 7. Ing FF, Grifka RG, Nihill MR, Mullins CE. Repeat dilation of intravascular stents in congenital heart defects. Circulation 1995;92: 893e897. 8. McMahon CJ, El-Said HG, Grifka RG, Fraley JK, Nihill MR, Mullins CE. Redilation of endovascular stents in congenital heart disease: factors implicated in the development of restenosis and neointimal proliferation. J Am Coll Cardiol 2001;38:521e526.
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9. Baker CM, McGowan FX, Keane JF, Lock JE. Pulmonary artery trauma due to balloon dilation: recognition, avoidance and management. J Am Coll Cardiol 2000;36:1684e1690. 10. Urbán Z, Riazi S, Seidl TL, Katahira J, Smoot LB, Chitayat D, Boyd CD, Hinek A. Connection between elastin haploinsufficiency and increased cell proliferation in patients with supravalvular aortic stenosis and Williams-Beuren syndrome. Am J Hum Genet 2002;71:30e44. 11. Williams JCP, Barratt-Boyes BG, Lowe JB. Supravalvular aortic stenosis. Circulation 1961;24:1311e1318. 12. Kamath BM, Spinner NB, Emerick KM, Chudley AE, Booth C, Piccoli D, Krantz ID. Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality. Circulation 2004;109:1354e1358. 13. Palmerini T, Biondi-Zoccai G, Della Riva D, Mariani A, Sabaté M, Valgimigli M, Frati G, Kedhi E, Smits PC, Kaiser C, Genereux P, Galatius S, Kirtane AJ, Stone GW. Clinical outcomes with drug-eluting and bare metal stents in patients with ST-segment elevation myocardial infarction: evidence from a comprehensive network meta-analysis. J Am Coll Cardiol 2013;62:496e504. 14. Li W, Li Q, Qin L, Ali R, Qyang Y, Tassabehji M, Pober BR, Sessa WC, Giordano FJ, Tellides G. Rapamycin inhibits smooth muscle cell proliferation and obstructive arteriopathy attributable to elastin deficiency. Arterioscler Thromb Vasc Biol 2013;33:1e8.
Peripheral pulmonary stenosis (PPS) occurs in the context of diffuse arteriopathies (e.g., Williams syndrome) and cardiac developmental defects (e.g., tetralogy of Fallot [TOF]). In either case, multiple lobar and/or sublobar obstructions can lead to proximal pulmonary artery (PA) hypertension. Although right ventricular (RV) function is typically preserved, this can result in severe RV hypertension. Unmitigated, this RV hypertension results in arrhythmia, ventricular failure, and death.1,2 PPS is managed surgically3 when lesions are located proximally, but more peripheral disease usually calls for endovascular management, with transcatheter balloon angioplasty or stent placement.4,5 Stents are known to be effective in lesions refractory to balloon angioplasty and have greatly enhanced the therapeutic armamentarium of the interventionalists.4e6 Rates of in-stent stenosis (ISS) have previously been reported to be very low.6e8 However, among patients with PPS referred for catheterization, we have observed a significant rate of angiographic ISS. Currently, no published information is available on rates of ISS among patients with PPS. We thus set out to describe the incidence of ISS in this patient cohort.
a Department of Cardiology, Boston Children’s Hospital, Boston, Massachusetts; bDepartment of Pediatrics, Harvard Medical School, Boston, Massachusetts; and cDivision of Cardiology, The Children’s Hospital of Philadelphia, Philadelphia. Manuscript received August 9, 2013; revised manuscript received and accepted October 9, 2013. This work was supported by The Keane Family Foundation (Boston, Massachusetts). See page 544 for disclosure information. *Corresponding author: Tel: (617) 355-6529; fax: (617) 713-3808. E-mail address: [email protected] (A.C. Marshall).
0002-9149/13/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.10.016
Methods The aim of this study was to determine the incidence of ISS in (1) patients with PPS referred for catheterization and (2) patients with Williams or Alagille syndrome. To address the first objective, we searched an institutional database for consecutive patients having catheterization during the year 2012 who had undergone PA stent placement within the previous 10 years. This list was supplemented with any patient who had a PA stent redilated at our institution during the year 2012; this allowed us to identify some additional patients whose stents were not initially placed at our institution or placed >10 years ago. Cases were excluded from consideration if there were no angiographic data available for review or if the stent had fractured in a manner precluding meaningful measurement of stent or luminal diameter. A total of 124 cases (104 patients) were included in our review. Indication for catheterization in this patient population at our institution has remained consistent for many years, including preoperative examination, noninvasive imaging suggestive of significantly elevated RV pressure (2/3 of systemic), pulmonary blood flow maldistribution (<1/3 of flow to 1 lung), worsening RV function, cyanosis due to PA stenosis, or worsening in symptoms.9 To address the second objective, we searched the institutional database to identify all patients with either Williams or Alagille syndrome who had been catheterized at our center at any time after PA stent placement. This identified 14 patients with Williams syndrome and 12 patients with Alagille syndrome who had undergone angiographic evaluation subsequent to PA stent placement at our center from 2003 to 2012. The diagnosis of either syndrome was based on documentation of meeting genetic and/or clinical criteria. www.ajconline.org
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The American Journal of Cardiology (www.ajconline.org) Table 1 Demographics Variable Male Age at catheterization (yrs) Body surface area at catheterization (m2) Weight at catheterization (kg) Stent redilation performed (% of cases) Total catheterizations per patient (n) PA stents per patient Time since stent placement (yrs) Time since the most recent stent dilation (yrs) Diagnosis TOF with MAPCAs TOF without MAPCAs MAPCAs (not TOF) Alagille syndrome* Williams syndrome Nonsyndromic PPS Truncus arteriosus D-TGA Other biventricular HLHS Other univentricular Stent type Genesis premounted Genesis XD Coronary Other Unavailable
Figure 1. (A) Severe right PA ISS in a 3-year-old with Williams syndrome. (B) No significant ISS in the right PA of a 7-year-old with truncus arteriosus. Percent ISS is calculated as follows (see arrows): (stent diameter luminal diameter)/stent diameter 100.
We defined ISS angiographically, as a 25% narrowing of the contrast-filled lumen relative to the fluoroscopically apparent stent diameter at any site along the length of the stent or stent complex (Figure 1). In addition, the segment was only deemed stenotic if it was equal to or narrower than the distal vessel to avoid inclusion of ISS due to significant stent overexpansion at the time of placement. Twenty-five percent ISS was empirically chosen based on our observation that this degree of angiographic narrowing is often hemodynamically significant and responsive to redilation. Determination of ISS was expressed as percentage of current stent diameter, as opposed to absolute measurement of luminal compartments. This allowed us to accommodate for the large range in patient and stent sizes in the pediatric population. Furthermore, defining ISS by percentage of stent lumen (rather than by a certain number of mm) removed much of the risk of calibration error, which otherwise could be significant, particularly in small vessels. Data collection was performed by evaluation of 2012 angiographic records for assessment of ISS and review of medical records and a cardiology department clinical database for demographic information. In general, images were acquired in 2 planes, and the best longitudinal image of each stent was evaluated. Among patients with multiple PA stents, the identification of ISS in any of the stents resulted in the patient being considered as affected. In these cases, measurements were performed on only one of the stents,
All Cases (n ¼ 124) 56% 5.5 (0.10e64) 0.88 0.47 26.6 22 80 6 (2e19) 1 (1e7) 2.8 (0.04e19) 1.5 (0.03e13) 48 (39) 16 (13) 6 (4.8) 7 (5.6) 4 (3.2) 5 (4.0) 5 (4.0) 6 (4.8) 13 (11) 15 (12) 5 (4.0) n ¼ 133 stents 76 (57) 21 (16) 6 (5) 15 (11) 15 (11)
Data are presented as median (range) or mean SD, as appropriate. Diagnoses and stent types are presented as % of total cases or stents, respectively. * Of 7 cases with Alagille syndrome, 6 had TOF (also accounted for in their respective TOF group).
typically the one that was most severely narrowed for purposes of data analysis. Computerized 2-dimensional measurements were performed using Vericis 8.30 (Merge Healthcare, Chicago, Illinois) by measuring the narrowest contrast-filled lumen diameter inside the stent and the fluoroscopically apparent stent diameter at that site. Values are expressed as median with a range or means with SD where applicable. ISS rates in different diagnostic groups were compared using Fisher’s exact test. Two-tailed paired t tests were used to compare means of continuous variables. Statistical significance was set at p < 0.05. Results Age at the time of catheterization in 2012 was 5.5 years (range, 0.1 to 64). As expected based on our practice, approximately 40% of cases were performed on patients with TOF, pulmonary atresia, and multiple aortopulmonary collaterals (TOF/pulmonary atresia/MAPCAs). Other forms of biventricular conditions, including D-loop transposition of the great arteries (D-TGA) and truncus arteriosus, made up 19% of cases. Single ventricle conditions, primarily hypoplastic left heart syndrome (HLHS) (at any stage of palliation), made up 15% of cases. Patients with PPS from an identified arteriopathy made up 8% of total cases. Total lifetime catheterizations through 2012 ranged from 2 to 19
Congenital Heart Disease/Pulmonary Artery In-Stent Stenosis
Figure 2. Distribution of patients with PPS with previously placed stents catheterized in 2012 by underlying diagnosis and portion of patients by diagnosis with ISS. The percentage of patients in each group affected by ISS is listed above each column. Bi-V ¼ biventricular.
(median 6). Time since stent placement was 2.8 years (range 0.04 to 19) and time since most recent stent dilation was 1.5 years (range 0.03 to 13). Approximately 3/4 of stents were Genesis (Cordis, Miami Lakes, Florida) stents (premounted or XD). Demographics of patients evaluated to address the first objective are listed in Table 1. There were 26 patients (Williams syndrome n ¼ 14, Alagille syndrome n ¼ 12) in the group addressing the second objective. Age at the time of catheterization in this group was 4.4 years (range 0.5 to 20). In this patient cohort, the incidence of angiographic PA ISS was 24% (25 of 104 patients), representing 124 total cases. In affected patients (i.e., by our definition 25% ISS and at most equal luminal size to distal vessel), the average degree of ISS was 43% (SD 12%, range 27% to 72%) stenosis, that is, on average, the in-stent lumen was narrowed by nearly half. Subgroup analysis of ISS severity was not performed because of limited sample size of affected patients. Mean time since stent placement was similar for patients with and without ISS (4.1 4.1 and 4.2 4.1 years, respectively). Time since last intervention was less in patients with ISS (1.5 1.6 years) compared with those without significant ISS (2.7 2.9 years, p <0.05). The distribution of stent types was also similar between the 2 groups (p >0.05). Stent redilation was performed in 80% of total cases (100% of cases with ISS). Presumably, redilations without underlying ISS were performed to accommodate somatic growth. Some patient groups had a high tendency to be affected by ISS, whereas others were rarely affected (Figure 2). Patients with MAPCAs had a 38% incidence of ISS, specifically 13 (36%) of 36 patients with TOF/pulmonary atresia/MAPCAs and 2 of 3 patients with other conditions associated with MAPCAs. Underlying diagnoses of the latter 2 patients were complex biventricular heterotaxy with pulmonary atresia and single RV with pulmonary atresia, respectively. The average severity of ISS among affected patients in the TOF/pulmonary atresia/MAPCA group was 44%, that is, similar to the average for the entire cohort affected by ISS. In patients with TOF without MAPCAs, the
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Figure 3. Comparison of the incidence of PA ISS in patients with arteriopathy (Williams or Alagille syndrome), TOF and/or MAPCAs, and other congenital heart disease (including the remaining diagnoses listed in Table 1). The former 2 groups have a significantly higher rate of ISS than the latter (p <0.01).
incidence was 27% (4 of 15 patients). There were 7 patients with 22q11 deletion in the cohort, all of whom had TOF/ pulmonary atresia/MAPCAs but interestingly had a low incidence (14%) of ISS (1 of 7 patients), which was not significantly different from the rate seen in TOF/pulmonary atresia/MAPCA patients without the 22q11 deletion based on the present small sample size. ISS was nearly absent in other structural congenital heart disease, including HLHS at any stage of repair (0 of 13 patients), D-TGA (0 of 6 patients), truncus arteriosus (1 of 5 patients), and other biventricular conditions (0 of 12). This latter group of patients with other structural congenital heart disease was significantly less affected by ISS compared with the patients with TOF and/or MAPCAs or arteriopathy (p <0.01; Figure 3). The more extensive review of patients with genetic arteriopathic conditions supported their high incidence of ISS, including 36% of patients (5 of 14) with Williams syndrome and 50% of patients (6 of 12) with Alagille syndrome (9 of whom also had TOF). Discussion ISS is a source of recurrent obstruction in previously stented PAs and is more common among patients with PPS referred for catheterization than previously recognized.6e8 Our results suggest that patients with arteriopathies and TOF should receive vigilant surveillance for ISS. The incidence of ISS after PA stent placement in our cohort of patients was 24% (31% of cases). In the sole previous report that systematically assessed for degree of stenosis (including a definition and grading system), the severity of ISS was defined by the thickness (in mm) of tissue between lumen and stent. In designing our study, we found a static definition of ISS problematic, given the range in PA sizes in children with congenital heart disease (e.g., a 1-mm cell layer in a 5-mm stent will contribute to more stenosis than a 1-mm cell layer in a 10-mm stent). Although the previous study had a broader cohort of patients, most had repaired TOF and pulmonary atresia, suggesting significant overlap of our patient populations. Median time from stent placement to reassessment was comparable with our study (2 vs 2.8 years),
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although approximately 1/2 of our patients had undergone stent redilation since placement. The time interval from last redilation was approximately 1.5 years (range, 0.03 to 13) in our cohort. Not surprisingly, the group affected by ISS had undergone more recent stent redilation. In the previous study, significant neointimal proliferation (>1 mm) was reported in only 4 (1.8%) of 220 patients, and restenosis based on both angiographic and hemodynamic criteria had an incidence of 5%. In contrast, using percentage of luminal loss as a marker for ISS, we found a 24% incidence. Underlying PA pathology clearly plays a role in the development of ISS. To our knowledge, this is the first report suggesting that patients with certain underlying diagnoses (TOF, MAPCAs, or primary arteriopathy) are at unique risk for ISS after PA stent placement. Patients with other congenital heart disease in this cohort, most of whom have stents placed because of postoperative PA obstructions, were typically spared from ISS (39 of 41 patients unaffected). From these findings, one can infer that stents placed in normal vasculature subject to surgical anastomoses, kinking, compression, or stretching are at lower risk of ISS. Similarly, there is little risk of ISS after redilation of an unaffected stent because of the somatic growth of a patient in these seemingly low-risk groups. In contrast, in patients in whom primary inherent abnormalities of the vascular wall are central to the disease (i.e., TOF, MAPCAs, congenital arteriopathy), there is a significant risk of ISS. Close monitoring for increasing RV hypertension or pulmonary blood flow maldistribution with low threshold for invasive reassessment is warranted after stent placement in high-risk patients. Obviously, “underlying PA pathology” is an indistinct term. On a microscopic level, the inherent PA abnormalities in patient populations vulnerable to PPS manifest as specific cellular changes, some of which have been described in detail. In the elastin-deficiency Williams syndrome, the obstructive lesions are due to increased smooth muscle cell proliferation and abnormal elastic lamellae, which result in medial hypertrophy. Lumen loss is then exacerbated by primary underdevelopment of vessels.10,11 In Alagille syndrome (aka arteriohepatic dysplasia), mutations in JAG-1 and disruption in notch signaling result in abnormal vasculogenesis, affecting multiple vascular beds, including the PAs.12 In these pathologic vessels, the endothelial response to injury imposed by stent placement may be unique. However, if there are similarities to the mechanism of ISS studied in coronary artery disease, then effective therapies (such as mammalian target of rapamycin inhibitors) may offer benefit to our patients with PA stenosis. Many stress factors may modulate the degree to which vessels exhibit and/or develop ISS. These include stent implantation techniques, preexisting endothelial vessel wall injury, and stent location and type. At our center, predilation with either low- or high-pressure balloons is typical before stent placement, which conceivably could be an instigating factor to neointimal proliferation. At the time of stent placement and redilation, balloon angioplasty can be performed using high or low inflation pressure, which could potentially also confer different risk of ISS. Although these factors may play a role in PA ISS, we use relatively similar implantation techniques such as predilation, inflation pressure, stent type despite underlying diagnosis. Of note, among our patients
with arteriopathy, we have observed a higher rate of vascular injury in response to angioplasty, which could potentially contribute to their higher rates of ISS at the time of subsequent stent placement. Previous reports of ISS in PA have suggested that stent placement at an unfavorable angle or leaving a gap between 2 tandem stents increases risk of ISS.7,8 In the present study cohort, stent types were evenly distributed among patients with and without ISS, suggesting little contribution of stent type to subsequent development of ISS. Our findings suggest that purely anatomic management in the catheterization laboratory may be insufficient to combat PA ISS and that reducing ISS may be a focus of future outpatient management. In fact, necessary redilations in the catheterization laboratory may in some patients act as a stimulus for further ISS. Our observations of patients affected by ISS suggest that it occurs early and rapidly after the procedure indicating that the proliferative response after injury sets in motion the process of luminal loss in a fashion similar to that observed in coronary arteries. Drug-eluting stents are now well established for coronary artery stenting and have been associated with lower rates of cardiac death, myocardial infarction, and stent thrombosis than bare-metal stents.13 Use of drug-eluting stents in PAs would be preferable for our patient population as well but appropriate stent sizes are currently unavailable making investigation of other proliferative inhibition for patients with PPS warranted. Future innovative therapies to address ISS may include antiproliferative therapy such as rapamycin (sirolimus) as suggested from animal models.14 The data presented herein indicate that the patients most likely to benefit from such therapy are those with TOF, MAPCAs, and/or arteriopathies. Our center is currently investigating the potential for future clinical use of rapamycin in this patient population. Our study was a retrospective review of patients referred for catheterization, which imposes several study limitations. A selection bias may be introduced as patients are typically referred because of clinical and/or noninvasive imaging indications, which may bias toward higher rates of ISS (as opposed to scheduled prospective reassessment of potential ISS at a set time after stent placement). Furthermore, there is a lack of a standardized definition of ISS in the PA literature making comparisons to previous studies difficult and necessitated an arbitrary definition based on our clinical experience of what constitutes significant ISS. We limited this definition to angiographic appearance, whereas it may be preferably to also include hemodynamic data, for example, stent pressure gradients, which are not universally recorded or available for review at our institution. Disclosures The authors have no conflicts of interest to disclose. 1. Bird LM, Billman GF, Lacro RV, Spicer RL, Jariwala LK, Hoyme HE, Zamora-Salinas R, Morris C, Viskochil D, Frikke MJ, Jones MC. Sudden death in Williams syndrome: report of ten cases. J Pediatr 1996;129:926e931. 2. Geggel RL, Gauvreau K, Lock JE. Balloon dilation angioplasty of peripheral pulmonary stenosis associated with Williams syndrome. Circulation 2001;103:2165e2170.
Congenital Heart Disease/Pulmonary Artery In-Stent Stenosis 3. Monge MC, Mainwaring RD, Sheikh AY, Punn R, Reddy VM, Hanley FL. Surgical reconstruction of peripheral pulmonary artery stenosis in Williams and Alagille syndromes. J Thorac Cardiovasc Surg 2013;145: 476e481. 4. Maglione J, Bergersen L, Lock JE, McElhinney DB. Ultra-highpressure balloon angioplasty for treatment of resistant stenoses within or adjacent to previously implanted pulmonary arterial stents. Circ Cardiovasc Interv 2009;2:52e58. 5. Law MA, Shamszad P, Nugent AW, Justino H, Breinholt JP, Mullins CE, Ing FF. Pulmonary artery stents: long-term follow-up. Catheter Cardiovasc Interv 2010;75:757e764. 6. Fogelman R, Nykanen D, Smallhorn JF, McCrindle BW, Freedom RM, Benson LN. Endovascular stents in the pulmonary circulation. Clinical impact on management and medium-term follow-up. Circulation 1995;92:881e885. 7. Ing FF, Grifka RG, Nihill MR, Mullins CE. Repeat dilation of intravascular stents in congenital heart defects. Circulation 1995;92: 893e897. 8. McMahon CJ, El-Said HG, Grifka RG, Fraley JK, Nihill MR, Mullins CE. Redilation of endovascular stents in congenital heart disease: factors implicated in the development of restenosis and neointimal proliferation. J Am Coll Cardiol 2001;38:521e526.
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9. Baker CM, McGowan FX, Keane JF, Lock JE. Pulmonary artery trauma due to balloon dilation: recognition, avoidance and management. J Am Coll Cardiol 2000;36:1684e1690. 10. Urbán Z, Riazi S, Seidl TL, Katahira J, Smoot LB, Chitayat D, Boyd CD, Hinek A. Connection between elastin haploinsufficiency and increased cell proliferation in patients with supravalvular aortic stenosis and Williams-Beuren syndrome. Am J Hum Genet 2002;71:30e44. 11. Williams JCP, Barratt-Boyes BG, Lowe JB. Supravalvular aortic stenosis. Circulation 1961;24:1311e1318. 12. Kamath BM, Spinner NB, Emerick KM, Chudley AE, Booth C, Piccoli D, Krantz ID. Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality. Circulation 2004;109:1354e1358. 13. Palmerini T, Biondi-Zoccai G, Della Riva D, Mariani A, Sabaté M, Valgimigli M, Frati G, Kedhi E, Smits PC, Kaiser C, Genereux P, Galatius S, Kirtane AJ, Stone GW. Clinical outcomes with drug-eluting and bare metal stents in patients with ST-segment elevation myocardial infarction: evidence from a comprehensive network meta-analysis. J Am Coll Cardiol 2013;62:496e504. 14. Li W, Li Q, Qin L, Ali R, Qyang Y, Tassabehji M, Pober BR, Sessa WC, Giordano FJ, Tellides G. Rapamycin inhibits smooth muscle cell proliferation and obstructive arteriopathy attributable to elastin deficiency. Arterioscler Thromb Vasc Biol 2013;33:1e8.