Identification of Risk Factors for Arrhythmia Post Transcatheter Closure of Perimembranous Ventricular Septal Defect

Abstract: Objective. Arrhythmias are frequently observed after transcatheter closure of perimembranous ventricular septal defect (pmVSD), especially in the early postprocedure period. Independent risk factors associated with postclosure arrhythmias are still elusive. The current study aimed to identify such risk factors via regression analysis with a long-term follow-up. Methods. A group of 553 patients from June 2003 to December 2010 who received symmetric Amplatzer-type pmVSD occluders for pmVSD in our center were followed for 2-8 years. The complications during the follow-up period were classified as early (within 1 year), continuous (persisted >1 year), or late (recurrent or onset after 1 year). We first evaluated the potential risk factors (age, procedure time, size of the defect, size of the occluder, diameter of the defect, distance of lesion to aortic rim, distance of lesion to tricuspid rim, presence of aneurysm, orifice size on aneurysm, arrhythmia before procedure, procedure time) by comparing complicated and uncomplicated cases using univariate analysis, then logistic analysis for independent risk factors. Results. We identified 90 cases of early, 59 cases of continuous, and 13 cases of late complications. The size of the occluder was identified as an independent risk factor for early, continuous, and late arrhythmias. Preexisting arrhythmias were found to be risk factors for early and late arrhythmias, while the distance between the defect and the tricuspid rim was identified as a risk factor for continuous arrhythmias. Conclusion. The size of the occluder, preexisting arrhythmias, and the distance between the defect and the tricuspid rim were found to be risk factors for arrhythmias after transcatheter closure of pmVSD. Selection of properly sized occluders might be crucial to reduce postclosure complications. 

J INVASIVE CARDIOL 2015;27(8):E158-E166

Key words: ventricular septal defect, transcatheter closure, complication, risk factor

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Congenital heart disease (CHD) is the most common type of birth defect, with an incidence of 6%-8% in live births.¹ Ventricular septal defects (VSDs) account for almost one-fifth of these defects. Perimembranous ventricular septal defect (pmVSD) is located in the upper portion of the ventricular septum and is the most common VSD subtype. The abnormal interventricular hemodynamics profoundly impact the quality of life of these patents.² For a long time, surgical closure was the routine treatment choice in most countries.^3-6 In the last decade, with the rapid developments in technology, transcatheter closure was found to carry fewer complications and better prognosis compared with traditional surgical procedure.⁷ In addition, transcatheter closure has been used for the treatment of patent ductus arteriosus and atrial septal defects. It has been well documented that this approach is now a routinely recommended procedure in clinical practice.^8-10

Recent studies have shown that atrioventricular block (AVB) and other arrhythmias are frequently observed at early-term and middle-term follow-up after transcatheter occlusion of pmVSDs.^11-15 Severe AVB attack among these patients remains a low incidence and could be treated with large doses of dexamethasone and pacemaker implantation. However, many patients developed recurrent arrhythmias, raising concerns over the safety of transcatheter occlusion. While most postclosure arrhythmias are mild and transient, recurrent and late-onset arrhythmias are important factors for patients, family, and doctors. 

Currently, the independent risk factors for the development of arrhythmia complications after transcatheter closure are not clearly defined. Although some factors have been associated with early complications, the factors contributing to continuous and late-onset/recurrent arrhythmias remain to be determined. A long-term follow-up study with a large sample size was needed to identify the independent risk factors for early, continuous, and late complications after closure, respectively.^11,15 Here, we reported our long-term follow-up results from a large group of subjects (553 successfully followed cases from a total of 645 candidates) who received transcatheter closure of pmVSD. In the current study, we analyzed the risk factors for early, continuous, and late complications and obtained important insights regarding factors contributing to the complications at the different periods after closure.

Methods

Patient population. From June 2003 to December 2010, a total of 645 patients received transcatheter closure of pmVSD at our center. All patients were diagnosed with pmVSD by transthoracic echocardiography (TTE) and/or clinical evidence of left-to-right interventricular shunt. Prior to the closure procedure, patients were evaluated by transthoracic echocardiography. The distance from the lesion to the aortic valve rim was measured in the long-axis parasternal and apical five-chamber views. The distance to tricuspid valve rim was measured in the parasternal short-axis view. In addition, chest radiography and electrocardiography (ECG) were performed to identify pulmonary and cardiovascular concerns. A left ventricular angiography was used to confirm the shape, size, and location of the defect, as well as its distance to valves. 

To identify the candidates for transcatheter closure, we used the following inclusion criteria: (1) age >2.5 years; (2) pmVSD diagnosed by TTE with a diameter between 2-16 mm; (3) left-to-right shunt; (4) distance from upper pmVSD ring to aortic valves ≥2 mm. Exclusion criteria included: (1) aortic valve prolapse; (2) severe aortic or tricuspid regurgitation; (3) mean pulmonary artery pressure ≥70 mm Hg; (4) right-to-left shunting through the defect; (5) New York Heart Association (NYHA) functional class IV; and (6) the presence of other types of congenital heart disease or previous surgery. Moreover, patients with postoperative residual pmVSD or previous infarction were also excluded during the analyses of follow-up results. These criteria are consistent with the guidelines of transcatheter closure for congenital heart disease.^16,17 All patients received symmetric Amplatzer-type pmVSD occluders manufactured by AGA Medical, Lifetech Scientific, Starway Medical, or SHAMA. As these occluders all have the same symmetric double-disk structure and similar functional features, they were considered to be the same type of device.^18-20 Informed consent was obtained from all of patients or their guardians.

Procedure. The pmVSD closures were performed under general anesthesia in children <10 years old and local anesthesia in older children. Dynamic ECG monitoring was applied during and after the procedure for 3 days. Right and left cardiac catheterization was performed via percutaneous transfemoral route. Hemodynamics of the pulmonary vessels were measured and pulmonary vessel resistance was evaluated before the final occlusion. Real-time TTE imaging was performed during the procedure to assess the profile VSD in the left ventricular long-axis oblique view. The size of the VSD and the distances to the aortic and tricuspid valves were further confirmed by angiography. Wherever a cusp of the aortic valve and defect were superimposed, it was considered a contraindication of transcatheter closure. The size of the device was usually selected to be 1-2 mm larger than the defect measured by angiocardiography. Larger devices (about 3-4 mm larger than the diameter of the defects) were chosen in patients with an aneurysm or when complete closure could not be achieved using a device with regular diameter. Heparin (100 U/kg) was administered to all patients after successful femoral artery access. Antibiotics were infused intravenously for 3 days, including the procedure day and 2 postoperative days. Transcatheter closure of the pmVSD was performed following the standard procedure as previously described.^21-23 ECG was performed on day 1, day 3, and day 7 after the procedure. Aspirin was given for 6 months after the procedure. 

Follow-up and classification of complications. All patients received several follow-up examinations at 1, 3, 6, and 12 months post procedure and then annually. The patients and their guardians were informed in advance and reminded for each scheduled visit. Except for a few cases that were followed at the different centers (wherein results were collected through fax), almost all follow-up data was collected at our center. During follow-up, clinical characteristics were measured, and echocardiography and ECG were performed. Arrhythmias were examined by 12-lead ECG and Holter monitor. In cases of unexpected late complications, patients underwent chest x-ray to understand the position and shape of the occluder. Of note, arrhythmias detected within 24 hours of the procedure were not considered to be complications in the current study. Early arrhythmia complications were defined as arrhythmias detected at a follow-up visit during the first year. If a complication detected during the first year persisted after 1 year, it was classified as a continuous complication. Late complications were those with an onset or relapse after the first year, specifically during years 2-8. Given the fact that not all patients could attend the scheduled hospital follow-up visits, only patients who completed at least 3 follow-up visits within the first year and at least 1 visit in later years were included in the retrospective review and subsequent analyses.

Evaluation of risk factors. During the follow-up, we reviewed each patient’s basic clinical data before closure, such as formation of aneurysm, change of orifice size on the aneurysm, size of the occluder, diameter of the defect, procedure time, and preexisting arrhythmias, which were detected at least once before the procedure among multiple previous ECGs. The early complications included heart block (AVBs at different degrees) and impulse formation disorders. During the analysis, the early complications were divided into three groups: AVBs; impulse formation disorders; and uncomplicated cases. The arrhythmias that persisted after the first year were defined as continuous arrhythmia and were analyzed by comparison with the matched uncomplicated subjects. Those who had a new-onset and relapse after the first year were included in the late complication group, and analyzed in the same manner as the continuous complications. After comparing differences among the individual groups, we identified the potential risk factors by univariate analysis, and further identified independent risk factors using logistic analysis.

Statistical analysis. Continuous variables were expressed as mean ± standard deviation. Differences between two groups were analyzed by independent t-tests. Non-continuous variables were expressed as proportions, and differences between groups were analyzed by c² test or Fisher’s exact test. Independent risk factors for complications and corresponding 95% confidence intervals (CIs) were determined by logistic regression model. According to the results of univariate analysis, each variable with a P-value <.10 was entered into the mode. For logistic regression tests, a P-value <.05 was considered a significant difference. Analyses were performed with SPSS software version 20.0 (SPSS, Inc).

Results

Among 645 candidate patients, a total of 22 patients were excluded according to the predefined criteria and 70 were lost during follow-up. The successful follow-up rate was 88.7%. Data were collected from 553 patients with a follow-up duration of 2.6-8.2 years. The follow-up procedure is diagrammatically demonstrated in Figure 1. Data regarding age, weight, gender, Qp/Qs, Pp/Ps, size of the defect, size of the occluder, distance of the lesion to the aortic rim, and preexisting arrhythmias were collected from the medical records before the procedure (Table 1).  The enrolled patients consisted of 342 females and 211 males with an age range of 2.7-16.2 years and body weight range of 11.9-51.0 kg. No difference in gender, age, or body weight was detected between complicated and uncomplicated cases. The defect diameter ranged between 2.3-12.8 mm as measured by TTE, and 2.6 to 12.4 mm as measured by left ventricular angiography. The diameter of the symmetric Amplatzer-type pmVSD occluder ranged from 4-16 mm. The Qp/Qs ranged from 1.6-6.8, and Pp/Ps ranged from 0.2-0.6. A total of 553 patients were successfully followed for 1 year, 457 patients for 1-5 years, and 96 patients for >5 years. The complications are summarized in Table 1. Of note, any type of arrhythmia other than the ones listed was not observed in the studied patients.

Early complications. Heart blocks (branch blocks and AVBs) and impulse formation disorders were the two major early complications, which are summarized in Tables 1 and 2. Comparisons were first conducted between complicated and uncomplicated cases. Univariate analysis revealed that the size of the occluder (8.2 ± 3.0 mm vs 6.9 ± 2.6 mm), the diameter of the defect (5.5 ± 2.6 mm vs 4.6 ± 2.5 mm), the orifice size on the aneurysm (2.7 ± 1.1 mm vs 2.5 ± 0.9 mm), the presence of an aneurysm (150/190 vs 233/345) and preexisting arrhythmias (31/190 vs 23/345) correlated with early AVB. Logistic analysis (Table 3) was further performed for the aforementioned parameters and demonstrated that the size of the occluder (odds ratio [OR], 1141; 95% CI, 1.030-1.264) and preexisting arrhythmias (OR, 2.000; 95% CI, 1.103-3.627) were independent risk factors for heart block in the early term after closure.

Early impulse formation disorders were also compared between complicated and uncomplicated cases using univariate analysis at first, and demonstrated that the size of the occluder (8.6 ± 3.2 mm vs 6.9 ± 2.6 mm), diameter of the defect (5.6 ± 2.5 mm vs 4.6 ± 2.5 mm), preexisting arrhythmias (7/44 vs 23/345), and the orifice size on the aneurysm (2.9 ± 1.1 mm vs 2.5 ± 0.9 mm) were correlated with impulse formation disorders (Table 2). Logistic analysis revealed that the size of the occluder was an independent risk factor for early impulse formation disorders (OR, 1.200; 95% CI, 1.024-1.406) (Table 4).

Continuous complications. Most of the early AVBs and impulse formation disorders were transient and would disappear within 1 month of the procedure. Our results demonstrated that 54 cases of arrhythmia and 5 cases of impulse formation disorder detected over the first year of follow-up persisted afterward. Univariate analysis revealed that the size of the occluder (8.9 ± 2.9 mm vs 6.8 ± 2.6 mm), the diameter of the defect (6.1 ± 2.4 mm vs 4.6 ± 2.7 mm), the distance from the lesion to the tricuspid rim (2.7 ± 1.9 mm vs 3.3 ± 1.1 mm), and the presence of an aneurysm (47/54 vs 228/334) correlated with continuous AVBs (Table 5). Logistic analysis revealed that the size of the occluder and the distance from the lesion to the tricuspid rim were two independent risk factors for continuous complications (OR, 1.213; 95% CI, 1.053-1.397 and OR, 0.770; 95% CI, 0.614-0.965, respectively) (Table 6). Of note, 2 cases progressed to more severe types of arrhythmia. One case of incomplete right bundle-branch block (IRBBB) observed immediately after procedure progressed to complete right bundle-branch block (CRBBB) in the fourth year of follow-up. One case of left anterior hemiblock (LAH) progressed to complete left bundle-branch block (CLBBB) + IRBBB in the second year after closure and changed to LAH + IRBBB in the third year. As premature beats may occur in the healthy population and the incidence of continuous premature beats was low in our patients (Table 1), the correlation between premature beats and device implantation was clinically insignificant and risk factor analysis was not conducted.

Late complications. Over long-term follow-up, impulse formation disorders were not considered to be complications. Heart block was detected in 13 cases (Table 1). Univariate analysis for the difference between complicated and uncomplicated cases revealed that the size of the occluder (9.5 ± 2.9 mm vs 6.8 ± 2.6 mm, respectively), the diameter of the defect (6.9 ± 3.2 mm vs 4.6 ± 2.7 mm), preexisting arrhythmias (7/13 vs 16/334), and the distance from the lesion to the tricuspid rim (2.8 ± 0.6 mm vs 3.3 ± 1.1 mm) were correlated with heart blocks (Table 7). Logistic analysis revealed that preexisting arrhythmias before the procedure and occluder size were independent risk factors for late-onset or recurrent heart block (OR, 11.365; 95% CI, 3.329-38.802 and OR, 1.279; 95% CI, 1.007-1.625, respectively) (Table 8). Of note, 2 patients suffered recurrent heart blocks. One case of complete AVB was corrected with dexamethasone and recurred as CRBBB + LAH after 2 years. One case of CRBBB recovered after a short treatment course and recurred as IRBBB 3 years later. Two cases of late-onset arrhythmia were caused by the alteration of the device shape, as shown by echocardiography and x-ray (Figures 2 and 3). Because neither severe arrhythmia nor residual shunt were recorded, no further intervention was performed. The relationship between shape alteration of the devices and late-onset arrhythmia needs further investigation.

Discussion 

Complications after closure of pmVSD include AVB, branch block, impulse formation disorders, hemolysis, aortic valve regurgitation, tricuspid regurgitation, and device embolism.^21,24 When the defect is adjacent to the cardiac conduction system, heart block is the most common complication, and complete AVB is considered the most serious complication in clinical practice.^6,25,26 Regarding early complications following pmVSD closure, recent follow-up studies have demonstrated that patients who received transcatheter closure using Amplatzer-type occluder had a higher success rate and fewer complications than those who received traditional cardiac surgery.¹² However, late complications and long-term outcomes after closure, especially >5 years, have not been well studied; only a few reports with small sample sizes were found in the literature review. In the current study, we present our long-term follow-up results from a total of 553 patients for up to 8 years. A comprehensive evaluation of the early, continuous, and late complications was conducted, attempting to identify the independent risk factors for the complications in different terms. To the best of our knowledge, this is the largest study among the published investigations evaluating and identifying the risk factors for complications after transcatheter closure of pmVSD. We found that the complications observed in the early term that disappeared within 1 month of treatment did not increase risk for high-degree AVB in the long term. In addition, dexamethasone treatment was effective for high-degree AVB and was capable of reducing the severity. Continuous complications were found in 59 patients, but none developed high-degree AVB. Over long-term follow-up, we found that the incidence for late complications was very low (2.3%). 

Heart block. Although 190 cases (34.36%) experienced a variety of heart blocks in the early term after closure, most of them were mild and not life threatening, such as IRBBB, CRBBB and LAH. Only 6 subjects (1.63%) experienced severe AVBs, including 2 cases of second-degree AVB and 4 cases of third-degree AVB. All were successfully treated with temporary pacemakers and dexamethasone, and nobody needed permanent pacemaker implantation. According to the previous studies, complete AVB was the most serious complication after closure, with a low incidence. The incidence of second-degree AVB or complete AVB was approximately 1% in patients who underwent traditional surgical closure and 1%-5% in patients who received transcatheter closure.^26,28,29 While our results indicate that the overall incidence of all types of heart block was 34.36%, the incidence of second-degree AVB and complete AVB was 1.63%, which was similar to previously reported results.

Early AVB occurred in many patients after the procedure; however, most of them were transient, and disappeared within 1 month, even as early as before hospital discharge. Complete AVB was converted to milder AVB types with proper treatment, and was not found at long-term follow-up. In a study conducted by Yip et al,²⁶ complete AVB disappeared in the 2 relevant cases after high-dose steroid and aspirin treatment. Zhou et al³⁰ reported that atrioventricular conduction recovered after 21 days in 1 patient who refused a permanent pacemaker. The occluder size and preexisting arrhythmias before the procedure were the independent risk factors for early arrhythmias. Because part of the pmVSD margin is in the area where the atrioventricular conduction bundle emerges from the central fibrous body and become subendocardial, the conduction bundle is prone to damage from the compression of the catheter and/or pmVSD occlusion device.³¹ The oversizing of the occluder is thought to cause mechanical injury and induce local inflammation, which directly or indirectly influences the cardiac conduction system. Importantly, our analyses revealed that preexisting arrhythmias before closure was an independent risk factor for both early and late arrhythmia. We speculate that the preexisting arrhythmias may be caused by a congenital abnormality of conductive fibers, which are more susceptible to direct injury and/or subsequent inflammation.

Continuous arrhythmias were found in one-tenth of our patients. The large size of the occluder and the short distance of the lesion to the tricuspid rim were identified as risk factors for this type of complication. It has been previously reported that the distance from the pmVSD to the tricuspid rim was also associated with rhythm disorder and blocks.^32,33 It is postulated that the distance between the lesion and the tricuspid rim reflects the distance of the occluder to the conduction bundle. Therefore, the shorter this distance, the higher chance of the conduction system being affected by mechanical injury and local inflammation. While oversized occluders cause mechanical injury and local inflammation, which subsequently influence the conduction of the heart in the early term, most of these early complications disappeared with the resolution of local inflammation and edema. As 2 cases of mild arrhythmia progressed into more severe types of arrhythmia, it is suggested that long-term follow-up is necessary for continuous arrhythmias.

Our analyses showed that the size of the occluder and arrhythmias existing before the procedure were also independent risk factors for late complications. It appears that the size of the occluder was a risk factor contributing to arrhythmia after closure, including early, continuous, and late complications. 

As preexisting abnormal heart conductive system disorders may persist for a long time, such children had increased risk for late-onset arrhythmia. It is strongly suggested that once an abnormal ECG is detected before the procedure, follow-up should be performed more carefully and frequently. As 2 cases of late-onset arrhythmias were identified due to alteration of the device shape, we recommend x-ray examination for such patients. Although most patients with early heart block recovered, some suffered relapse or developed another type of heart block later. Despite temporary recovery, early heart block may recur later and should be closely followed. 

Although the size of the occluder, the diameter of the defect, the distance from the lesion to the tricuspid rim, and the presence of an aneurysm were correlated with continuous AVBs, only the size of the occluder and the distance from the lesion to the tricuspid rim were identified as risk factors for continuous complications. Therefore, unusually larger devices (about 3-4 mm larger than the diameter of the defect) should be carefully considered before placement. In cases that such large devices are necessary to achieve complete closure, especially for those who had complex structure of the aneurysm, the increased risk for arrhythmia should be considered.

Age and body weight at the time of the procedure have been identified as potential risk factors in previous studies. For example, Wei et al³⁴ and Wang et al³⁵ reported that complications occurred more frequently in younger children (<5 years and <3 years, respectively). Zuo et al³⁶ reported that age and body weight were risk factors for atrioventricular blocks. In our study, no differences in age and body weight were detected between our complicated and uncomplicated cases, suggesting that age and body weight might be marginal risk factors that need more investigation. In the aforementioned studies, it was argued that patients with a younger age and/or lower weight were more susceptible to injury from the procedure, which induced early or late complications. In the current study, we found no correlation between the degree of injury and age/body weight, but our analyses did show that the injury caused by surgical procedure and/or occluder might be implicated in the relapsed and long-term arrhythmias.

Impulse formation disorders. Premature beats have also been reported by Li et al,¹⁵ while Szkutnil et al³⁷ reported that 1 case of ventricular tachycardia occurred immediately after release of both implant discs, which was corrected with high-energy shock after the vascular sheath was removed. Impulse formation disorders occurred in a small proportion of patients. In the current study, impulse formation disorders were found in 44 subjects (7.96%) in the early term. The most common types of impulse formation were non-paroxysmal junctional tachycardia and junctional escape rhythm. Because most impulse formation disorders are relatively mild complications, most previous studies focused on complete AVB, and the risk factors for impulse formation disorders have not been well studied. We found that the size of the occluder, the diameter of the defects, preexisting arrhythmias, and the orifice size on the aneurysm were related to impulse formation disorders, but the size of the occluder was the only independent risk factor for impulse formation disorders. We believe that the mechanical injury and local inflammation caused by the occluder may contribute to impulse formation disorders. In our patients, most impulse formation disorders ceased soon after the procedure or in the early follow-up period and only a few cases persisted up to 1 year. Because premature beats are present in a healthy population, premature beats detected after 1 year are perhaps clinically insignificant. 

Study limitations. Despite important follow-up data and identification of risk factors for implications after transcatheter closure of pmVSD, we are also aware of some study limitations. A total of 14.3% of cases were excluded or lost during follow-up. Some of the risk factors for late complications with a large 95% CI were obtained from a small sample size. We believe the learning curve may also be an important factor influencing patient prognosis, but this could not be well assessed in the current study.

Conclusion

The analyses of our long-term follow-up study showed that the transcatheter closure of pmVSD is safe, carrying only some mild complications. Although some severe arrhythmias occurred immediately after the procedure, they all resolved and converted to milder type with proper treatment. The oversizing of the occluder device was a risk factor for heart blocks and impulse formation disorders after closure. Therefore, the selection of the right occluder size is crucial to reduce postclosure complications. In addition, preexisting arrhythmias before the procedure imply an increased risk for both early and late arrhythmias. A short distance between the lesion and the tricuspid rim implies an increased risk for continuous arrhythmias. Such increased arrhythmia risks should be considered in these patients, and a closer and longer follow-up is recommended.

Acknowledgments. We would like to thank Dr Derek A. Wainwright at Northwestern University for the careful editing of this manuscript. 

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^*Joint first authors.

From ¹the Department of Pediatric Cardiovascular Disease; ²Ministry of Education Key Laboratory of Women and Children’s Diseases and Birth Defects; ³Program for Yangtze River Scholars and Innovative Research Team in University, West China Second University Hospital, Sichuan University; and ⁴West China Medical School; and ⁵West China Stomatology School, Sichuan University, Chengdu, Sichuan, China.

Funding: This work was supported by grants from the National Natural Science Foundation of China (No. 81070136 and No. 81270226), the Program for Yangtze River Scholars and Innovative Research Team in University (No. IRT0935) and Key Technology R&D Program of Science and Technology of Sichuan Province (No. 2014SZ0009).

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

Manuscript submitted November 25, 2013, provisional acceptance given March 13, 2014, final version accepted October 17, 2014.

Address for correspondence: Prof Kaiyu Zhou, MD, Dept. of Pediatric Cardiology, West China Second University Hospital, Sichuan University, No. 20, 3rd section, South Renmin Road, Chengdu, 610041, China. Email: kaiyuzhou313@163.com