Long-term, high-level hepatic secretion of acid α-glucosidase for Pompe disease achieved in non-human primates using helper-dependent adenovirus.

Pompe disease (glycogen storage disease type II (GSD-II)) is a myopathy caused by a genetic deficiency of acid α-glucosidase (GAA) leading to lysosomal glycogen accumulation causing muscle weakness, respiratory insufficiency and death. We previously demonstrated in GSD-II mice that a single injection of a helper-dependent adenovirus (HD-Ad) expressing GAA resulted in at least 300 days of liver secretion of GAA, correction of the glycogen storage in cardiac and skeletal muscles and improved muscle strength. Recent reports suggest that gene therapy modeling for lysososomal storage diseases in mice fails to predict outcomes in larger animal models. We therefore evaluated an HD-Ad expressing GAA in non-human primates. The baboons not only tolerated the procedure well, but the results also confirmed that a single dose of the HD-Ad allowed the livers of the treated animals to express and secrete large amounts of GAA for at least 6 months, at levels similar to those achieved in mice. Moreover, we detected liver-derived GAA in the heart, diaphragm and skeletal muscles of the treated animals for the duration of the study at levels that corrected glycogen accumulation in mice. This work validates our proof-of-concept studies in mice, and justifies future efforts using Ad-based vectors in Pompe disease patients.

Long-term follow-up of the STARFlex device for closure of secundum atrial septal defect.

BACKGROUND: There is limited published outcome data on the STARFlex device for transcatheter closure of atrial septal defects (ASD). AIM: To contribute to the long term outcomes of ASD device closure with the STARFlex device. METHODS: Results of a prospective FDA approved clinical trial (1999-2001) from a single institution of the STARFlex device for simple ASD was reviewed. The inclusion criteria included age >or=2 years, isolated secundum ASD, evidence of right ventricular volume overload, and maximum stretched diameter <22 mm. A retrospective review of the original study data with most recent follow-up was performed. Clinical success in the trial was defined as complete closure or residual leak

Patent ductus arteriosus in preterm infants: is early transcatheter closure a paradigm shift?

The optimal management approach of the patent ductus arteriosus (PDA) in premature infants remains uncertain owing the lack of evidence for long-term benefits and the limited analyses of the complications of medical and surgical interventions to date. In recent years, devices suitable to plug the PDA of premature infants (including extremely low birthweight, <1000 g) have become available and several trials have demonstrated successful and safe transcatheter PDA closure (TCPC) in this population. Whether TCPC represents a paradigm shift in PDA management that will result in improved short- and long-term outcomes, less bronchopulmonary dysplasia, improved neurodevelopment, or better long term renal function remains to be seen. Careful rigorous study of the potential benefits of TCPC in this highly vulnerable population in the context of well-designed adequately powered trials is needed prior to widespread adoption of this approach.

Dynamic mechanical properties of intact human cervical spine ligaments.

BACKGROUND CONTEXT: Most previous studies have investigated ligament mechanical properties at slow elongation rates of less than 25 mm/s. PURPOSE: To determine the tensile mechanical properties, at a fast elongation rate, of intact human cervical anterior and posterior longitudinal, capsular, and interspinous and supraspinous ligaments, middle-third disc, and ligamentum flavum. STUDY DESIGN/SETTING: In vitro biomechanical study. METHODS: A total of 97 intact bone-ligament-bone specimens (C2-C3 to C7-T1) were prepared from six cervical spines (average age: 80.6 years, range, 71 to 92 years) and were elongated to complete rupture at an average (SD) peak rate of 723 (106) mm/s using a custom-built apparatus. Nonlinear force versus elongation curves were plotted and peak force, peak elongation, peak energy, and stiffness were statistically compared (p<.05) among ligaments. A mathematical model was developed to determine the quasi-static physiological ligament elongation. RESULTS: Highest average peak force, up to 244.4 and 220.0 N in the ligamentum flavum and capsular ligament, respectively, were significantly greater than in the anterior longitudinal ligament and middle-third disc. Highest peak elongation reached 5.9 mm in the intraspinous and supraspinous ligaments, significantly greater than in the middle-third disc. Highest peak energy of 0.57 J was attained in the capsular ligament, significantly greater than in the anterior longitudinal ligament and middle-third disc. Average stiffness was generally greatest in the ligamentum flavum and least in the intraspinous and supraspinous ligaments. For all ligaments, peak elongation was greater than average physiological elongation computed using the mathematical model. CONCLUSIONS: Comparison of the present results with previously reported data indicated that high-speed elongation may cause cervical ligaments to fail at a higher peak force and smaller peak elongation and they may be stiffer and absorb less energy, as compared with a slow elongation rate. These comparisons may be useful to clinicians for diagnosing cervical ligament injuries based upon the specific trauma.

The snare-assisted technique for transcatheter coil occlusion of moderate to large patent ductus arteriosus: immediate and intermediate results.

OBJECTIVES: The purpose of this study was to evaluate the feasibility, safety and efficacy of using a snare-assisted technique to coil occlude the moderate to large size patent ductus arteriosus (PDA). BACKGROUND: Transcatheter occlusion of small PDAs using Gianturco coils is safe and effective. However, in larger size PDAs and/or those with short PDA length, the procedure still carries risks of coil embolization, incomplete occlusion and failure to implant the coil. METHODS: From January 1994 to June 1997, the records of 104 consecutive snare-assisted coil occlusions of moderate to large PDAs (minimum diameter >2.0 mm) were reviewed. Immediate and intermediate outcomes including complete and partial occlusion, failure to implant and complications were analyzed with respect to ductal type and size. RESULTS: Patient age ranged from 0.1 to 70.1 years (median 3.3 years). Minimum PDA diameter ranged from 2.1 to 6.8 mm (mean 3.0 +/- 0.9 mm). Angiographic types were A-62, B-13, C-6, D-14 and E-9. Using the snare-assisted technique, coil placement was successful in 104/104 patients (100%), irrespective of size or angiographic type. Immediate complete closure was observed in 73/104 (70.2%) and was related to smaller PDA size, but not to angiographic type. Complete closure was documented in 102/104 (98.1%) at 2- to 16-month follow-up. Successful closure was unrelated to PDA size or type. Coil embolization to the pulmonary artery occurred in 3/104 (2.9%) patients and was not related to PDA size or type. The need for multiple coils was found in 28/104 patients (26.9%), and was related to larger PDA size, but not to angiographic type. CONCLUSIONS: The snare-assisted delivery technique allows successful occlusion of moderate to large PDAs up to 6.8 mm, irrespective of angiographic type. This technique permits improved control and accuracy of coil placement, and facilitates delivery of multiple coils.

Reconstruction of stenotic or occluded iliofemoral veins and inferior vena cava using intravascular stents: re-establishing access for future cardiac catheterization and cardiac surgery.

OBJECTIVES: The study evaluated the safety and efficacy of stent reconstruction of stenotic/occluded iliofemoral veins (IFV) and inferior vena cava (IVC). BACKGROUND: Patients with congenital heart defects and stenotic or occluded IFV/IVC may encounter femoral venous access problems during future cardiac surgeries or catheterizations. METHODS: Twenty-four patients (median age 4.9 years) underwent implantation of 85 stents in 22 IFV and 6 IVC. Fifteen vessels were severely stenotic and 13 were completely occluded. Although guide wires were easily passed across the stenotic vessels, occluded vessels required puncture through the thrombosed sites using a stiff wire or transseptal needle. Once traversed, the occluded site was dilated serially prior to stent implantation. RESULTS: Following stent placement, the mean vessel diameter increased from 0.9 +/- 1.6 to 7.4 +/- 2.6 mm (p < 0.05). Twenty-one of 28 vessels had long segment stenosis/occlusion requiring two to seven overlapping stents. Repeat catheterizations were performed in seven patients (9 stented vessels) at mean follow-up of 1.6 years. Seven vessels remained patent with mean diameter of 6.4 +/- 2.0 mm. Two vessels were occluded, but they were easily recanalized and redilated. Echocardiographic follow-up in two patients with IVC stents demonstrated wide patency. In four additional patients, a stented vessel was utilized for vascular access during subsequent cardiac surgery (n = 3) and endomyocardial biopsy (n = 1). Therefore, 13 of 15 stented vessels (87%) remained patent at follow-up thus far. CONCLUSIONS: Stenotic/obstructed IFV and IVC may be reconstructed using stents to re-establish venous access to the heart for future cardiac catheterization and/or surgeries.

Intravascular stents in congenital heart disease: short- and long-term results from a large single-center experience.

OBJECTIVES: This report describes the results of the Food and Drug Administration's phase 1 and 2 clinical trials of intravascular stents at Texas Children's Hospital. BACKGROUND: Since the late 1980s, intravascular stent implantation for the treatment of arterial and venous stenoses in congenital heart disease has been highly successful. METHODS: Stents were placed in postoperative pulmonary artery (PA) stenoses, congenital PA stenoses or stenoses of systemic veins/venous anastomoses. Prospective collection of data according to protocol was done before intervention, after stent implantation and at follow-up catheterization. RESULTS: At stent implantation, pressure gradients decreased significantly in all three groups (mean +/- SD): from 46 +/- 25 to 10 +/- 13 mm Hg in postoperative PA stenoses (p < 0.001); from 71 +/- 45 to 15 +/- 21 mm Hg in congenital PA stenoses (p < 0.001); and from 7 +/- 6 to 1 +/- 2 mm Hg in stenoses of systemic veins/venous anastomoses stenoses (p < 0.001). Vessel diameters markedly increased: from 6 +/- 3 to 12 +/- 3 mm in postoperative PA stenoses (p < 0.001); from 3 + 1 to 9 + 1 mm in congenital PA stenoses (p < 0.001); and from 3 +/- 4 to 12 +/- 4 mm in stenoses of systemic veins/venous anastomoses (p < 0.001). In the postoperative and congenital PA stenoses groups, right ventricular pressure decreased (right ventricular pressure indexed to femoral artery pressure ratio): from 0.63 +/- 0.2 to 0.41 +/- 0.02 (p < 0.001) and from 0.71 +/- 0.3 to 0.55 +/- 0.35 (p = 0.04), respectively. Perfusion to a single affected lung increased from 31 +/- 17% to 46 +/- 14% (p < 0.001). On recatheterization (mean 14 months), results varied minimally. Repeat angioplasty of residual stent stenoses was safe and effective. Complications included four early patients with stent migration, three with stent thrombosis and two deaths. There were no late complications. Significant restenosis occurred in only three patients. CONCLUSIONS: Intravascular stents for the treatment of vascular stenoses in congenital heart disease provide excellent immediate and long-term results.

Early diagnosis of coarctation of the aorta in children: a continuing dilemma.

UNLABELLED: Because late repair of coarctation of the aorta (COA) is associated with premature cardiovascular disease in adult life, early detection and treatment is important. OBJECTIVES: To determine the timing of referral to see whether early detection of COA has improved in the past decade, to evaluate the pattern of and reasons for medical center referral, and to assess the clinical signs relating to the diagnosis of COA. METHODS: The records of 50 consecutive patients older than 1 year who had surgical repair of COA from 1980 to 1990 were reviewed. The age of referral, pattern of referral, and presence of standard clinical signs of COA were analyzed, and data were compared with those from the previous decade. RESULTS: The mean and median ages at referral were 8.4 and 5.8 years, respectively. Pediatricians accounted for 64% of the referrals. A specific diagnosis of COA was made in 2 (4%) of 50 patients before referral to a pediatric cardiologist. The most consistent clinical findings were a cardiac murmur and a systolic blood pressure gradient between the arms and legs of greater than 10 mm Hg, which were both present in all patients. Lower-extremity pulses were decreased in 37 (74%) and absent in 9 (18%). Forty-seven children (94%) had upper-extremity hypertension (> 95th percentile for age); 25 (50%) had systolic blood pressure higher than 140 mm Hg. COA would have been missed in 82% of children if absent lower-extremity pulses were required as a diagnostic feature. These findings were similar to those reported by our institution in the previous decade, suggesting that early detection has not improved. CONCLUSIONS: The timing of, reasons for, and sources of referral for COA in this study, compared with data from the previous decade, indicate no improvement in early detection of COA by pediatricians. Screening all children for COA by routinely measuring upper- and lower-extremity blood pressures during at least one physical examination after the newborn period is mandatory.

Does ductal occlusion with the gianturco coil cause left pulmonary artery and/or descending aorta obstruction?

Thirty-two patients (median age 4.5 years) underwent transcatheter Gianturco coil occlusion of a patent ductus arteriosus. Transthoracic echocardiography was performed the day after coil placement and at intermediate follow-up (median 8.6 months). Echocardiographic results were compared with angiographic and hemodynamic data obtained during catheterization. Two-dimensional (2D) echocardiography performed the day after ductal occlusion displayed evidence of coil protrusion into the left pulmonary artery in 28 of 31 patients (90%) and into the descending aorta in 17 of 29 (59%). However, pulsed Doppler analysis demonstrated normal left pulmonary arterial flow velocities in 28 of 29 patients (97%) and normal descending aortic flow velocities in 26 of 27 (96%). Pulse Doppler results were corroborated by angiographic and hemodynamic catheterization data, which showed no evidence of adjacent vessel obstruction. Peak Doppler velocities among patients with and without 2D echocardiographic left pulmonary artery or descending aorta coil impingement did not differ significantly. The discrepancy between 2D and pulse Doppler findings did not change significantly at intermediate follow-up. Thus, transcatheter occlusion of the patent ductus arteriosus with properly implanted Gianturco coils does not cause significant obstruction to flow in the left pulmonary artery or descending aorta despite frequently misleading 2D echocardiographic images of coil impingement on these vessels.

A method providing bidirectional control of coil delivery in occlusions of patent ductus arteriosus with shallow ampulla and Pott's shunts.

A novel method using a snare and bioptome to provide bidirectional control of a Gianturco coil for occlusion of a patent ductus arteriosus with a shallow ampulla and Pott's shunts is presented. This method greatly reduces the risk of coil embolization and optimizes coil position in difficult cases.

Single therapeutic catheterization to treat coexisting coarctation of the aorta and patent ductus arteriosus.

A case of a pediatric patient found to have coexisting coarctation of the aorta and patent ductus arteriosus who underwent balloon dilation of the coarctation and coil occlusion of the ductus in a single cardiac catheterization is presented. Review of the English literature revealed no previous reports of this combination of transcatheter interventions during a single catheterization procedure.

Transcatheter patent ductus arteriosus closure in an infant using the Gianturco-Grifka Vascular Occlusion Device.

A 2-month-old child with Down syndrome and a large patent ductus arteriosus underwent transcatheter closure using a new Food and Drug Administration-approved occlusion device. This device is described, along with its usefulness for other vascular defects.

Transcatheter closure of surgical shunts in patients with congenital heart disease.

The aim of this study was to review contemporary techniques, devices, and results of transcatheter occlusion of surgical shunts in 2 pediatric cardiac programs. Closure of superfluous surgical shunts may reduce cardiac work and risk of endocarditis. Previous studies have shown that transcatheter closure of shunts is feasible, but have not demonstrated acceptable efficacy or safety. In addition, the performance of new techniques and devices has not been reviewed. Between 1993 and 1998, 18 patients with congenital heart disease underwent transcatheter closure of 19 Blalock-Taussig shunts. Detachable and standard Gianturco coils and Gianturco-Grifka vascular occlusion devices were employed. All 19 shunts had complete closure. Eight shunts had initial placement of detachable coils. Five shunts had stents placed that bridged the pulmonary end of the shunts. These 5 and 4 additional shunts had closure by standard coils. Two shunts were closed with Gianturco-Grifka devices. There were no complications, no embolizations, and no requirement for surgery precipitated by the procedures. This review of contemporary techniques, devices, and results suggests that transcatheter occlusion of surgical shunts is effective and safe.

Transcatheter closure of the patient ductus arteriosus in adults using the Gianturco coil.

BACKGROUND AND HYPOTHESIS: Although results of surgical ligation of the patent ductus arteriosus (PDA) in the pediatric age group are excellent, surgical management of the adult with a PDA may be more problematic. The PDA that presents in adulthood may be calcified and friable, rendering simple ligation via a thoracotomy difficult, inadequate, and hazardous. Patch closure of the ductus arteriosus from either the aortic or pulmonary artery orifice using cardiopulmonary bypass or transient aortic cross-clamping is necessary but increases surgical risk. Furthermore, older patients with diseases unrelated to their PDA and patients with Down's syndrome may have higher risks with intubation, general anesthesia, and surgery. Early results of percutaneous transcatheter occlusion of the PDA with Gianturco coils performed under sedation and local anesthesia are promising. METHODS: Six adults with mean age of 39.1 years (range 23.1-62.0 years) were found to have an isolated PDA with mean minimum diameter of 2.7 mm (range 1.0-5.0 mm) at cardiac catheterization. All underwent percutaneous transcatheter occlusion of the PDA using Gianturco coils. RESULTS: Coil implantation was successful in all patients. There were no complications and all were discharged home within 24 hours. Complete ductal occlusion was seen immediately in 4 of 6 patients (67%) while 2 of 6 (33%) had small residual leaks. However, complete occlusion was achieved in all patients by 6 months following the procedure. CONCLUSION: Transcatheter occlusion of the PDA using coils is safe and efficacious in adults.

Delivery of stents to target lesions: techniques of intraoperative stent implantation and intraoperative angiograms.

Mullins et al. [6] reported the first use of stent implantation to treat stenotic branch pulmonary arteries in 1988. In the early to mid-1990s, numerous reports confirmed its safety and efficacy, but there were limited stent and balloon designs and stent implantations were performed using relatively large delivery systems (10- to 12-Fr sheaths) [7, 8]. The general accepted patient size was limited to those weighing 12 kg or greater. Intraoperative stent implantation for branch pulmonary artery stenosis was reported in the early to mid-1990s [1-3, 5, 9]. Indications in these early reports included small patient size or difficult anatomy or patients who had additional cardiac lesions and needed surgery independent of the branch stenosis. The idea was to take advantage of the open-heart exposure provided in the operating room to permit direct access to the stenotic segment. Hence, all intraoperative stent implants were performed under direct visualization on bypass. There were no discussions on advantages over the routine percutaneous approach. Currently, with advances in stent and balloon technology as well as increased operator experience, many of those reported cases probably would have undergone cardiac catheterization for a percutaneous stent implant rather than open-heart surgery. The purpose of this report is to review the current indications, advantages, and disadvantages of intraoperative stent implantation as well as to discuss the techniques that are helpful to optimize intraoperative stent positioning. The role and advantages of intraoperative angiography will also be presented.

Percutaneous transcatheter coil occlusion of the patent ductus arteriosus aided by the nitinol snare: further observations.

PURPOSE: To assess the safety and efficacy of the nitinol snare to aid in the delivery of a Gianturco coil in percutaneous occlusion of a patent ductus arteriosus (PDA). METHODS: Seventeen patients (mean age 8.2 years) underwent catheterization and coil occlusion of a PDA (mean minimum diameter 1.9 mm). A nitinol snare was used to deliver and position the coil in the ductus. RESULTS: A single Gianturco coil was placed successfully in all patients, resulting in complete ductal occlusion documented by aortic angiography. Color echocardiography documented a trivial residual shunt in one patient who had no audible cardiac murmurs following the procedure. There was no hemodynamic or echocardiographic evidence of left pulmonary artery obstruction. There were no complications and all patients were discharged within 24 hr following the procedure. CONCLUSIONS: Percutaneous coil occlusion of the PDA is safe and effective. Snare-controlled coil delivery eliminates the risk of coil dislodgement and optimizes coil position.

Additional aortopulmonary collaterals in patients referred for coil occlusion of a patent ductus arteriosus.

Coexisting aortopulmonary collaterals in patients diagnosed with a patent ductus arteriosus (PDA) are rare findings. Percutaneous transcatheter closure of PDA and requisite aortography offer an unique opportunity to identify and treat these systemic arterial anomailes, which would be missed by echocardiographic evaluation alone. The significance of these collaterals is unclear, but it may contribute to left heart dilation from additional left to right shunting in patients with an otherwise isolated small PDA. Of 18 patients undergoing transcatheter occlusion of a PDA with Gianturco coils, 2 were found to an additional significant aortopulmonary collaterals, which were also occluded.

Repeat dilation of intravascular stents in congenital heart defects.

BACKGROUND: Intravascular (Palmaz) stents have been successfully implanted in patients with congenital and acquired branch pulmonary stenosis. Early results are excellent; however, there is no information on restenosis and repeat dilation in patients with congenital heart disease. The purpose of this study is to review the incidence of restenosis and demonstrate the safety and efficacy of repeat dilation of stents in this group of patients. METHODS AND RESULTS: Of 94 patients with 163 implanted stents in this single-center study, 43 patients with 73 implanted stents underwent recatheterization. Only 2 of 73 restudied stents (3%) developed significant restenosis. In 20 patients, 30 stents were redilated. At stent implantation, the mean age of this subgroup was 14.2 years, the mean intraluminal diameter increased from 4.9 to 10.7 mm (P = .0001), and the systolic gradient (mean) across the stent decreased from 52 to 11 mm Hg (P = .0001). At recatheterization (mean, 13 months), all stents were patent. The mean diameter decreased by 1.2 mm (P = .0001), but the increase in the gradient (mean, 3 mm Hg) was not significant (P = .11). After repeat dilation, the diameter increased from 9.5 to 12.2 mm (P = .0001), and the gradient decreased from 14 to 8 mm Hg (P = .0003). The 2 stents with restenosis were redilated successfully. Two patients underwent a successful second redilation of 3 stents at 18 and 26 months. There were no complications. CONCLUSIONS: All stents remained patent. The occurrence of significant restenosis is low (3%), and these restenoses can be redilated and/or restented. Repeat dilation of the Palmaz stent implanted in branch pulmonary artery stenosis can be performed with safety and efficacy (94% success rate) up to 3 years after stent implantation.

Arterial stents in the management of neurofibromatosis and renovascular hypertension in a pediatric patient: case report of a new treatment modality.

A 17-year-old male with neurofibromatosis presented with severe hypertension secondary to an abdominal aortic coarctation and bilateral renal artery stenoses. Despite previous surgical bypass grafts and aggressive medical management, including treatment with diuretics, beta-blocker, calcium channel blocker, angiotensin converting enzyme (ACE) inhibitors, and direct vasodilator agents, severe hypertension persisted. Following intravascular stent placement in the aorta and both renal arteries, blood pressures normalized.

Relief of factitious coarctation following occlusion of large patent ductus arteriosus with Gianturco-Grifka vascular occluder.

We report an infant with a large patent ductus arteriosus (PDA) and a hypoplastic aortic isthmus presenting with factitious coarctation due to high ductal flow. Following transcatheter occlusion of the PDA with a Gianturco-Grifka vascular occluder, the aortic gradient resolved, thereby eliminating the need for surgery on the isthmus.