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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).