1-s2.0-s0735109714002927-mmc1.docx

APPENDIX

Methods Patients. Between January 2009 and July 2010, 465 children aged 3 to 12 years with pmVSD from three major medical centers in northwest China (Xijing Hospital, Xi’an; Xi’an Children’s Hospital, Xi’an; Hanzhong Central Hospital, Hanzhong) were enrolled in the study. According to the study design (Figure 1), patients with small defects without hemodynamic changes or symptoms, and patients whose anatomy was not suitable for transcatheter closure were excluded. After clinical and transthoracic echocardiographic (TTE) assessment for eligibility, 236 patients were excluded from the study (196 due to ineligible anatomy or possibility of spontaneous closure, 33 declined to participate the study, and 7 due to other reasons), and the other 229 were randomly allocated to either the surgical or the transcatheter group. Random treatment allocations were generated in advance of patient enrollment; the investigators were blinded to the allocations. All patients were routinely screened by clinical and transthoracic two-dimensional and Doppler color echocardiography and enrolled. Clinical manifestations include symptoms, hemodynamic changes, heart murmur with significant noninvasive or noninvasive measurements, and history of infective endocarditis, et al. Inclusion criteria were 1) diagnosis of pmVSD; 2) age > 3 and < 12 years; 3) body weight >10 kg; 4) pmVSD size > 3 mm; 5) pmVSD shunt > 2 ml by color-flow Doppler mapping; 6) a distance of >1 mm from the pmVSD to the aortic valve; 7) a calculated pulmonary vascular resistance of < 8 Wood units by cardiac catheterization; and 8) left-to-right shunt with hemodynamic changes (elevated pulmonary arterial pressure, blood flow and vascular resistance). Patients were excluded if they exhibited any of the following: 1) muscular or postoperative residual pmVSD; 2) age < 3 or > 12 years; 3) body weight < 10 kg; 4) pmVSD size < 3 mm; 5) pmVSD shunt < 2 ml; 6) severe aortic regurgitation; 7)

pmVSD with unfavorable anatomy, i.e. no adequate rim to aortic valve (< 1mm), or large defects (> 20 mm), or aortic valve prolapse, or presence of thick interfering tricuspid tendons chordae; 8) irreversible pulmonary vascular disease with a calculated pulmonary vascular resistance > 8 Wood units; 9) a right-to-left shunt. The ethics committee of each participating hospital approved the study, and the parents of the patients provided written informed consent for the patients. This study was registered with ClinicalTrials.gov (NCT00890799) and was carried out in accordance with the Declaration of Helsinki (1996) and all relevant Chinese regulations. Echocardiography. A comprehensive transthoracic echocardiographic (TTE) study, which included M-mode, two-dimensional, continuous-wave, pulsed-wave, and color-flow Doppler echocardiography, was performed prior to operation or intervention and at each follow-up visit (Fig. 2). The jets of pmVSD were routinely measured in at least two orthogonal planes, such as from parasternal (long and short axis) and apical views. The maximum sizes of the left atrium and the left and right ventricles in diastole were measured in the apical four-chamber view to derive values for left ventricular end diastolic volume, end systolic volume, and ejection fraction. Pulmonary artery pressure was estimated from the regurgitant velocity of the tricuspid valve. Catheterization. Each patient underwent catheterization before surgery or transcatheter intervention. Catheterization was done in the catheterization laboratory with the patients under conscious sedation and local anesthesia. Hemodynamic parameters, including pulmonary arterial, aortic, atrial, and ventricular pressures, were recorded, and oximetric values were measured in the cardiac chambers and vessels, based on which Qp/Qs was calculated.

Occluding device. Shanghai pmVSD occluder (Lepu Medical Technology Co, Ltd, Beijing, China, Fig. 3) was used in this study. This device differs from the Amplatzer membranous VSD occluder (St. Jude Medical, Inc. St. Paul, MN, USA) in 2 areas. The Shanghai pmVSD occluder is symmetrical with concentric disks of equal sizes; this design simplifies the releasing technique and reduces procedural time . In contrast to the Amplatzer membranous VSD occluder, the Shanghai pmVSD occluder was redesigned at the waist of the occluder to introduce a smooth transition curve; the thickness of the waist was increased from 2 mm to 3 mm and above to possibly reduce the risk of complete heart block. The Shanghai pmVSD occluder was approved in 2003 by the State Food and Drug Administration of the People’s Republic of China. It has been used in more than 10,000 patients with pmVSD in China since then. Transcatheter device implantation. Transcatheter intervention was performed with the patient under conscious sedation and local anesthesia after measurement and collection of oximetric and pressure data. Heparin (100 IU/kg) and antibiotics were administered intravenously during the procedure. The femoral vein and artery were accessed, and a left ventriculogram was obtained in the left anterior oblique projection to profile the pmVSD. The pmVSD was measured at its largest dimension. A right Judkins catheter was passed from the arterial access with a 260-mm slippery guidewire across the pmVSD. The guidewire was snared from the pulmonary artery or vena cava through the venous access to establish an arteriovenous circuit. A long sheath (6-9 Fr) was advanced through the arteriovenous circuit to the left ventricle. An occluder was selected on the basis of measurements ascertained from a left ventriculogram and TTE, as described in previous reports . The pmVSD occluder was deployed through the long sheath under fluoroscopic and echocardiographic guidance; the size, position, and effectiveness of the device closure were determined.

All patients were transferred to general wards immediately following the intervention.

ECG signals were monitored continuously during the first 24 h after the procedure. Patients who did not experience any complications were routinely kept in the hospital for 2 days following the procedure. Patients who had arrhythmic abnormalities, such as prolonged PR interval or atrioventricular block, were kept in the hospital for 7 days. All patients were given aspirin daily (5 mg/kg) for 6 months following the procedure. Surgical procedure. The surgical closure was performed with the patient under general anesthesia the second day after catheterization. The chest was opened through a standard median sternotomy. The ascending aorta, superior vena cava, and inferior vena cava were exposed and cannulated. Cardiopulmonary bypass was initiated, and body temperature was lowered to 28°C. Cardioplegia and cardiac arrest were initiated, and the pmVSD was examined via a right atriotomy. Depending on the size of the pmVSD, direct-suture, Dacron or pericardium patch was used to repair the defect. After the heart was de-aired, the patient was gradually weaned from the cardiopulmonary bypass. All patients were transferred to the ICU for further treatment. Patients with no complications routinely stayed in the ICU for 1 day and were then transferred to the general ward for 3 days before discharge. Follow-up protocol. All patients were followed up for 2 years. Each patient underwent serial follow-up at 3 days, 3 months, 6 months, 1 year, and 2 years following intervention or surgery. The primary end point was the incidence of overall mortality. Secondary end points included a major adverse cardiovascular and cerebrovascular event, complete atrioventricular block requiring pacemaker implantation, and new-onset valvular regurgitation requiring surgical repair. Follow-up included a clinical examination, electrocardiogram, and TTE. PR intervals were measured by 12-lead electrocardiography. Adverse events were determined at each assessment and divided into major and minor categories. Major adverse events

included death, complete atrioventricular block requiring pacemaker implantation, thromboembolism, residual shunt more than 2 ml, and new-onset valvular regurgitation requiring surgical repair. Minor adverse events included vascular complications at the puncture site, new or increased valvular regurgitation less than two grades, blood loss requiring transfusion, and first- or second-degree heart block without any long-term complications. Time of return to normal activity was assessed using a 56-question questionnaire to quantitatively evaluate physical and psychosocial status. Total hospitalization cost was calculated from information compiled after the patients were discharged. Laboratory tests. Blood was analyzed routinely for red and white blood cell counts, platelet counts, and quantity of free hemoglobin before surgery or intervention and 1 day and 3 days after surgery or intervention. For each patient, 2-mL blood samples were collected at 7 time points: at the induction of anesthesia and 1, 3, 6, 12, 24, and 72 h after pmVSD occluder deployment/aorta cross-clamp removal. The plasma, which was separated by centrifugation, was placed in a -70°C freezer for later analysis. The biochemical assays included measurement of levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and creatinine by an automatic biochemistry analyzer (Abbott Laboratories, Abbott Park, IL, USA) at 0, 1, 24, and 72 h. Investigators blinded to the study measured concentrations of plasma cardiac troponin I (cTnI) and creatine kinase-MB (CK-MB) using an Access AccuTnI assay system (Beckman-Coulter, Fullerton, CA, USA). The total amounts of cTnI and CK-MB released by the surgical and transcatheter patients were represented as 0 to 72-h area under the curve after pmVSD repair. A urine test was performed 1 day after surgery or intervention to check hemoglobinuria for hemolysis. Statistical analysis. Data were presented as mean ± standard deviation, median with range, or frequencies

and/or percentages. SPSS 16.0 for Windows (SPSS, Inc., Chicago, IL, USA) was used for the statistical analysis. The t test, Chi-square test, Fisher’s exact test, and non-parametric test were used for comparison between the two groups, where appropriate. The analyses were based on the intention-to-treat principle. All of the tests of significance were 2-sided, and a p < 0.05 was considered statistically significant.

Movie Legends

1.

TTE movie showing pmVSD before intervention (four-chamber view).

2.

TTE movie showing pmVSD before intervention (short-axis view).

3.

TTE movie showing pmVSD after transcatheter intervention (four-chamber view).

4.

TTE movie showing pmVSD after transcatheter intervention (short-axis view).

5.

Movie of left ventriculography to profile the shape of pmVSD (tubular type).

6.

Movie of left ventriculography after deployment of pmVSD occluder (tubular type).

7.

Movie of left ventriculography to profile the shape of pmVSD (window-like type).

8.

Movie of left ventriculography after deployment of pmVSD occluder (window-like type).

9.

Movie of left ventriculography to profile the shape of pmVSD (aneurysmal type).

10. Movie of left ventriculography after deployment of pmVSD occluder (aneurysmal type). 11. Movie of left ventriculography to profile the shape of pmVSD (infundibular type). 12. Movie of left ventriculography after deployment of pmVSD occluder (infundibular type).