A first-in-human phase I/IIa gene transfer clinical trial for Duchenne muscular dystrophy using rAAVrh74.MCK.GALGT2.

In a phase 1/2, open-label dose escalation trial, we delivered rAAVrh74.MCK.GALGT2 (also B4GALNT2) bilaterally to the legs of two boys with Duchenne muscular dystrophy using intravascular limb infusion. Subject 1 (age 8.9 years at dosing) received 2.5 × 1013 vector genome (vg)/kg per leg (5 × 1013 vg/kg total) and subject 2 (age 6.9 years at dosing) received 5 × 1013 vg/kg per leg (1 × 1014 vg/kg total). No serious adverse events were observed. Muscle biopsy evaluated 3 or 4 months post treatment versus baseline showed evidence of GALGT2 gene expression and GALGT2-induced muscle cell glycosylation. Functionally, subject 1 showed a decline in 6-min walk test (6MWT) distance; an increase in time to run 100 m, and a decline in North Star Ambulatory Assessment (NSAA) score until ambulation was lost at 24 months. Subject 2, treated at a younger age and at a higher dose, demonstrated an improvement over 24 months in NSAA score (from 20 to 23 points), an increase in 6MWT distance (from 405 to 478 m), and only a minimal increase in 100 m time (45.6-48.4 s). These data suggest preliminary safety at a dose of 1 × 1014 vg/kg and functional stabilization in one patient.

Reintervention and Survival After Transcatheter Pulmonary Valve Replacement.

BACKGROUND: Transcatheter pulmonary valve (TPV) replacement (TPVR) has become the standard therapy for postoperative pulmonary outflow tract dysfunction in patients with a prosthetic conduit/valve, but there is limited information about risk factors for death or reintervention after this procedure. OBJECTIVES: This study sought to evaluate mid- and long-term outcomes after TPVR in a large multicenter cohort. METHODS: International registry focused on time-related outcomes after TPVR. RESULTS: Investigators submitted data for 2,476 patients who underwent TPVR and were followed up for 8,475 patient-years. A total of 95 patients died after TPVR, most commonly from heart failure (n = 24). The cumulative incidence of death was 8.9% (95% CI: 6.9%-11.5%) 8 years after TPVR. On multivariable analysis, age at TPVR (HR: 1.04 per year; 95% CI: 1.03-1.06 per year; P < 0.001), a prosthetic valve in other positions (HR: 2.1; 95% CI: 1.2-3.7; P = 0.014), and an existing transvenous pacemaker/implantable cardioverter-defibrillator (HR: 2.1; 95% CI: 1.3-3.4; P = 0.004) were associated with death. A total of 258 patients underwent TPV reintervention. At 8 years, the cumulative incidence of any TPV reintervention was 25.1% (95% CI: 21.8%-28.5%) and of surgical TPV reintervention was 14.4% (95% CI: 11.9%-17.2%). Risk factors for surgical reintervention included age (0.95 per year [95% CI: 0.93-0.97 per year]; P < 0.001), prior endocarditis (2.5 [95% CI: 1.4-4.3]; P = 0.001), TPVR into a stented bioprosthetic valve (1.7 [95% CI: 1.2-2.5]; P = 0.007), and postimplant gradient (1.4 per 10 mm Hg [95% CI: 1.2-1.7 per 10 mm Hg]: P < 0.001). CONCLUSIONS: These findings support the conclusion that survival and freedom from reintervention or surgery after TPVR are generally comparable to outcomes of surgical conduit/valve replacement across a wide age range.

Long-Term Outcomes After Melody Transcatheter Pulmonary Valve Replacement in the US Investigational Device Exemption Trial.

BACKGROUND: The Melody valve was developed to extend the useful life of previously implanted right ventricular outflow tract (RVOT) conduits or bioprosthetic pulmonary valves, while preserving RV function and reducing the lifetime burden of surgery for patients with complex congenital heart disease. METHODS: Enrollment for the US Investigational Device Exemption study of the Melody valve began in 2007. Extended follow-up was completed in 2020. The primary outcome was freedom from transcatheter pulmonary valve (TPV) dysfunction (freedom from reoperation, reintervention, moderate or severe pulmonary regurgitation, and/or mean RVOT gradient >40 mm Hg). Secondary end points included stent fracture, catheter reintervention, surgical conduit replacement, and death. RESULTS: One hundred seventy-one subjects with RVOT conduit or bioprosthetic pulmonary valve dysfunction were enrolled. One hundred fifty underwent Melody TPV replacement. Median age was 19 years (Q1-Q3: 15-26). Median discharge mean RVOT Doppler gradient was 17 mm Hg (Q1-Q3: 12-22). The 149 patients implanted >24 hours were followed for a median of 8.4 years (Q1-Q3: 5.4-10.1). At 10 years, estimated freedom from mortality was 90%, from reoperation 79%, and from any reintervention 60%. Ten-year freedom from TPV dysfunction was 53% and was significantly shorter in children than in adults. Estimated freedom from TPV-related endocarditis was 81% at 10 years (95% CI, 69%-89%), with an annualized rate of 2.0% per patient-year. CONCLUSIONS: Ten-year outcomes from the Melody Investigational Device Exemption trial affirm the benefits of Melody TPV replacement in the lifetime management of patients with RVOT conduits and bioprosthetic pulmonary valves by providing sustained symptomatic and hemodynamic improvement in the majority of patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00740870.

Multicenter Study of Endocarditis After Transcatheter Pulmonary Valve Replacement.

BACKGROUND: Endocarditis has emerged as one of the most impactful adverse events after transcatheter pulmonary valve replacement (TPVR), but there is limited information about risk factors for and outcomes of this complication. OBJECTIVES: The purpose of this study was to evaluate risk factors for and outcomes of endocarditis in a large multicenter cohort. METHODS: The authors established an international registry focused on characterizing endocarditis after TPVR, including the incidence, risk factors, characteristics, and outcomes. RESULTS: Investigators submitted data for 2,476 patients who underwent TPVR between July 2005 and March 2020 and were followed for 8,475 patient-years. In total, 182 patients were diagnosed with endocarditis a median of 2.7 years after TPVR, for a cumulative incidence of 9.5% (95% CI: 7.9%-11.1%) at 5 years and 16.9% (95% CI: 14.2%-19.8%) at 8 years (accounting for competing risks: death, heart transplant, and explant) and an annualized incidence of 2.2 per 100 patient-years. Staphylococcus aureus and Viridans group Streptococcus species together accounted for 56% of cases. Multivariable analysis confirmed that younger age, a previous history of endocarditis, and a higher residual gradient were risk factors for endocarditis, but transcatheter pulmonary valve type was not. Overall, right ventricular outflow tract (RVOT) reintervention was less often to treat endocarditis than for other reasons, but valve explant was more often caused by endocarditis. Endocarditis was severe in 44% of patients, and 12 patients (6.6%) died, nearly all of whom were infected with Staphylococcus aureus. CONCLUSIONS: The incidence of endocarditis in this multicenter registry was constant over time and consistent with prior smaller studies. The findings of this study, along with ongoing efforts to understand and mitigate risk, will be critical to improve the lifetime management of patients with heart disease involving the RVOT. Although endocarditis can be a serious adverse outcome, TPVR remains an important tool in the management of RVOT dysfunction.

Utility of CT Angiography for the Prediction of Coronary Artery Compression in Patients Undergoing Transcatheter Pulmonary Valve Replacement.

OBJECTIVES: We aimed to evaluate the utility of computed tomography angiography (CTA) for coronary compression (CC) prediction in patients with congenital heart disease undergoing balloon-expandable transcatheter pulmonary valve replacement (TPVR). BACKGROUND: Coronary compression is a serious complication of TPVR, but the value of preprocedural CTAs to assess CC risk is largely unexplored. METHODS: In all, 586 patients underwent TPVR between January 2009 and July 2018. Adults with a pre-TPVR CTA and children with a CTA performed less than one year prior to TPVR were included. Patients with poor CTA image quality or with aborted cases due to reasons other than CC were excluded. Sixty-six patients were finally included. Cardiac anatomy was assessed via multiplanar reconstruction of CTAs. RESULTS: Coronary compression occurred in 9 (14%) of the 66 patients who underwent TPVR. Most CC cases (seven of nine) occurred in patients with conduits. Proximity of the right ventricular outflow tract (RVOT) landing zone to the coronary arteries and to the chest wall was a significant risk factor for compression (P < .001 and P = .019, respectively). Compression risk increased significantly if patients had an RVOT to coronary artery distance of ≤3 mm (P < .001) and an RVOT to chest wall distance of ≤8 mm (P = .026). Anomalous course of coronary arteries was another significant univariate risk factor (P = .003). CONCLUSIONS: Right ventricular outflow tract landing zone distance of ≤3 mm to a coronary artery, landing zone distance of ≤8 mm to the chest wall, and anomalous coronary arteries are associated with increased CC risk. Electrocardiogram gating may not be necessary if coronary arteries are opacified on CTAs. Larger studies are needed to explore and confirm these coronary artery compression risk factors.

Association between patient age at implant and outcomes after transcatheter pulmonary valve replacement in the multicenter Melody valve trials.

OBJECTIVES: To investigate whether age and valve size at implant contribute to outcomes after Melody transcatheter pulmonary valve replacement (TPVR). BACKGROUND: Patient age and valve size at implant contribute to longevity of surgical pulmonary valves. METHODS: All patients discharged with a Melody valve in the pulmonary position, as part of three prospective Melody valve multicenter studies, comprised the study cohort. Acute and time-related outcomes were analyzed according to age: children (≤12 years), adolescents (13-18 years), young adults (19-29 years), and older adults (≥30 years). RESULTS: Successful Melody valve implantation occurred in 49 children, 107 adolescents, 96 young adults, and 57 older adults. Pediatric patients (≤18 years) were more likely to have TPVR for conduit stenosis than adults (62% vs. 44%); children had the smallest conduits. After TPVR, pediatric and adult patients had similar decreases in right ventricular (RV) size by MRI, but adults had improved percentage predicted peak VO2 (58% preimplant to 64% postimplant, p = .02) and FEV1 (69% pre to 71% post, p = .005). Younger age was associated with shorter freedom from RVOT dysfunction, reintervention, and explant. Children had the shortest freedom from endocarditis (p = .041), but all other groups had 5-year freedom from endocarditis of ≥90%. CONCLUSIONS: Younger age was associated with shorter time to RVOT dysfunction, reintervention, and explant after Melody TPVR. Patients ≥13 years of age were at low risk for endocarditis and explant to 5 years. A better understanding of time-related outcomes by age will aid in the comparison of therapeutic options for TPVR candidates. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT00740870 (NCT00740870), https://clinicaltrials.gov/ct2/show/NCT01186692 (NCT01186692), and https://clinicaltrials.gov/ct2/show/NCT00688571 (NCT00688571).

Gene Delivery for Limb-Girdle Muscular Dystrophy Type 2D by Isolated Limb Infusion.

In a previous limb-girdle muscular dystrophy type 2D (LGMD2D) clinical trial, robust alpha-sarcoglycan gene expression was confirmed following intramuscular gene (SGCA) transfer. This paved the way for first-in-human isolated limb infusion (ILI) gene transfer trial to the lower limbs. Delivery of scAAVrh74.tMCK.hSGCA via an intravascular route through the femoral artery predicted improved ambulation. This method was initially chosen to avoid safety concerns required for large systemic vascular delivery viral loads. ILI methods were adopted from the extensive chemotherapy experience for treatment of malignancies confined to the extremities. Six LGMD2D subjects were enrolled in a dose-ascending open-label clinical trial. Safety of the procedure was initially assessed in the single limb of a non-ambulant affected adult at a dose of 1 × 1012 vg/kg. Subsequently, ambulatory children (aged 8-13 years) were enrolled and dosed bilaterally with either 1 × 1012 vg/kg/limb or 3 × 1012 vg/kg/limb. The six-minute walk test (6MWT) served as the primary clinical outcome; secondary outcomes included muscle strength (maximum voluntary isometric force testing) and SGCA expression at 6 months. All ambulatory participants except one had pre- and post-treatment muscle biopsies. All four subjects biopsied had confirmed SGCA gene delivery by immunofluorescence, Western blot analysis (14-25% of normal), and vector genome copies (5.4 × 103-7.7 × 104 vg/µg). Muscle strength in the knee extensors (assessed by force generation in kilograms) showed improvement in two subjects that correlated with an increase in fiber diameter post gene delivery. Six-minute walk times decreased or remained the same. Vascular delivery of AAVrh74.tMCK.hSGCA was effective at producing SGCA protein at low doses that correlated with vector copies and local functional improvement restricted to targeted muscles. Future trials will focus on systemic administration to enable targeting of proximal muscles to maximize clinical benefit.

An Isolated Limb Infusion Method Allows for Broad Distribution of rAAVrh74.MCK.GALGT2 to Leg Skeletal Muscles in the Rhesus Macaque.

Recombinant adeno-associated virus (rAAV)rh74.MCK.GALGT2 is a muscle-specific gene therapy that is being developed to treat forms of muscular dystrophy. Here we report on an isolated limb infusion technique in a non-human primate model, where hindlimb blood flow is transiently isolated using balloon catheters to concentrate vector in targeted leg muscles. A bilateral dose of 2.5 × 1013 vector genomes (vg)/kg/limb was sufficient to induce GALGT2-induced glycosylation in 10%-60% of skeletal myofibers in all leg muscles examined. There was a 19-fold ± 6-fold average limb-wide increase in vector genomes per microgram genomic DNA at a bilateral dose of 2.5 × 1013 vg/kg/limb compared with a bilateral dose of 6 × 1012 vg/kg/limb. A unilateral dose of 6 × 1013 vg/kg/limb showed a 12- ± 3-fold increase in treated limb muscles compared to contralateral untreated limb muscles, which received vector only after release into the systemic circulation from the treated limb. Variability in AAV biodistribution between different segments of the same muscle was 125% ± 18% for any given dose, while variability between the same muscle for any given treatment dose was 45% ± 7%. These experiments demonstrate that treatment of muscles throughout the leg with rAAVrh74.MCK.GALGT2 can be accomplished safely using an isolated limb infusion technique, where balloon catheters transiently isolate the limb vasculature, but that intra- and inter-muscle transduction variability is a significant issue.

Transcatheter pulmonary valve replacement using the melody valve for treatment of dysfunctional surgical bioprostheses: A multicenter study.

BACKGROUND: Stented bioprosthetic valves (BPVs) are commonly used for surgical pulmonary valve (PV) replacement in postoperative congenital heart disease, but develop structural failure in a time-related fashion. The Melody transcatheter PV (TPV) (Medtronic, Minneapolis, Minn) has been used to treat BPV dysfunction, but there have been few studies in this population. METHODS: We performed a retrospective, multicenter study to evaluate Melody valve function in patients who underwent TPV replacement (TPVR) into a dysfunctional pulmonary BPV. RESULTS: One hundred patients who underwent TPVR at 10 centers between January 2010 and June 2015 were enrolled. The median patient age was 22 years (range, 5-79 years), and 32 patients were age <18 years. The underlying diagnosis was tetralogy of Fallot in 80 patients, and moderate or severe pulmonary regurgitation (PR) was present in 84%. The TPV was implanted into various types of BPVs, with a median size of 23 mm (range, 19-33 mm). At hospital discharge, PR was mild or less in all but 1 patient, and the mean Doppler right ventricular outflow tract (RVOT) gradient was reduced from a mean of 29.3 ± 12.0 mm Hg to 16.2 ± 6.9 mm Hg (median, 29 mm Hg to 16 mm Hg; P < .001). During follow-up (median, 12.4 months), no patients underwent reintervention on the TPV. Endocarditis was diagnosed in 1 patient who was managed medically without intervention. The mean RVOT gradient at the most recent follow-up was ≤35 mm Hg in all patients, and was similar to that at early postimplantation. PR was more than mild in only 1 patient. Hemodynamic outcomes did not differ between patients with small BPVs (≤23 mm) and those with large BPVs (≥25 mm). CONCLUSIONS: TPVR restores competence and relieves the obstruction of dysfunctional surgical BPVs, with excellent early results in both small and large BPVs, highlighting the potential for TPVR to extend the life of existing BPVs in adults and children. Collaboration between surgeons and cardiologists is important to determine the optimal lifetime management, combining surgical PV replacement and TPVR in this population.

Building a comprehensive team for the longitudinal care of single ventricle heart defects: Building blocks and initial results.

INTRODUCTION: With increasing survival of children with HLHS and other single ventricle lesions, the complexity of medical care for these patients is substantial. Establishing and adhering to best practice models may improve outcome, but requires careful coordination and monitoring. METHODS: In 2013 our Heart Center began a process to build a comprehensive Single Ventricle Team designed to target these difficult issues. RESULTS: Comprehensive Single Ventricle Team in 2014 was begun, to standardize care for children with single ventricle heart defects from diagnosis to adulthood within our institution. The team is a multidisciplinary group of providers committed to improving outcomes and quality of life for children with single ventricle heart defects, all functioning within the medical home of our heart center. Standards of care were developed and implemented in five target areas to standardize medical management and patient and family support. Under the team 100 patients have been cared for. Since 2014 a decrease in interstage mortality for HLHS were seen. Using a team approach and the tools of Quality Improvement they have been successful in reaching high protocol compliance for each of these areas. CONCLUSIONS: This article describes the process of building a successful Single Ventricle team, our initial results, and lessons learned. Additional study is ongoing to demonstrate the effects of these interventions on patient outcomes.

Intravascular Ultrasound Characterization of a Tissue-Engineered Vascular Graft in an Ovine Model.

Patients who undergo implantation of a tissue-engineered vascular graft (TEVG) for congenital cardiac anomalies are monitored with echocardiography, followed by magnetic resonance imaging or angiography when indicated. While these methods provide data regarding the lumen, minimal information regarding neotissue formation is obtained. Intravascular ultrasound (IVUS) has previously been used in a variety of conditions to evaluate the vessel wall. The purpose of this study was to evaluate the utility of IVUS for evaluation of TEVGs in our ovine model. Eight sheep underwent implantation of TEVGs either unseeded or seeded with bone marrow-derived mononuclear cells. Angiography, IVUS, and histology were directly compared. Endothelium, tunica media, and graft were identifiable on IVUS and histology at multiple time points. There was strong agreement between IVUS and angiography for evaluation of luminal diameter. IVUS offers a valuable tool to evaluate the changes within TEVGs, and clinical translation of this application is warranted.

Arrhythmias After Stage I Hybrid Palliation in Single-Ventricle Patients.

The hybrid procedure is an alternative palliative strategy for patients with single-ventricle physiology. No data exist documenting the incidence of arrhythmias after the hybrid procedure. Goal of this study was to determine the incidence and type of arrhythmias in patients undergoing the hybrid procedure. A retrospective chart review was performed including all patients undergoing the hybrid procedure between January of 2010 through December of 2013. Sixty-five patients underwent the hybrid procedure during this time period (43 HLHS, 22 other). Average gestational age at admission was 37.7 weeks. Average age at time of procedure was 7.6 days. Five patients had documented arrhythmias (7.7 %). Four were supraventricular tachycardias, and 1 was a sinus bradycardia. One patient with arrhythmia died during hospitalization, and another patient with arrhythmia died during the interstage period. Hybrid palliation for patients with single-ventricle physiology has a low incidence of arrhythmias. In this cohort of patients, arrhythmias did not contribute to mortality. There was a trend toward association between arrhythmias and longer total length of hospital stay.

ECMO: Incidence and Outcomes of Patients Undergoing the Hybrid Procedure.

OBJECTIVE: To document the extracorporeal membrane oxygenation (ECMO) incidence and outcome in patients undergoing the hybrid procedure at an institution that routinely performs this procedure. DESIGN: A retrospective chart review on all patients with single ventricle physiology that underwent the hybrid procedure between 7/2002 and 12/2014. Patients were excluded if they underwent the hybrid procedure after 60 days of birth or subsequently underwent a biventricular repair. SETTING: A single center, tertiary pediatric hospital. PATIENTS: One hundred eighty-one patients with single ventricle physiology that underwent the hybrid procedure between 7/2002 and 12/2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We studied a total of 181 patients (105 males: 76 females). Gestational age was 37.8 ± 2.0 weeks and birth weight was 3.0 ± 0.7 kg. Underlying diagnosis was hypoplastic left heart syndrome in 149 patients and other in 32 patients. Age at surgery was 7.8 ± 6.8 days and weight at surgery was 3.1 ± 0.6 kg. Two patients underwent ECMO support after the hybrid procedure. One patient had aortic atresia/mitral atresia and weighed 2.3 kg and the other patient had aortic atresia/mitral stenosis and weighed 2.1 kg at time of surgery. Both patients died. Incidence of ECMO support after hybrid procedure was 1.3% (2/149) for the hypoplastic left heart syndrome patients and 1.1% (2/181) for the entire cohort. CONCLUSION: Mortality in patients who underwent ECMO after the hybrid procedure was higher than reported for the Norwood procedure, however, the incidence of ECMO after hybrid procedure was also significantly lower than reported for the Norwood procedure. Future studies are needed to determine how to improve outcomes in this complex patient population.

Changes in right ventricular function in neonates with hypoplastic left heart syndrome before and after the hybrid procedure.

AIMS: Decreased right ventricular function via deformation analysis has been noted in patients with hypoplastic left heart syndrome (HLHS) after the Norwood procedure. No data exist in HLHS patients undergoing the hybrid procedure. The goal of this study was to evaluate right ventricular functional changes in HLHS patients undergoing the hybrid procedure under steady-state conditions. METHODS AND RESULTS: Echocardiograms were prospectively obtained on patients with HLHS before and after the hybrid procedure. Fractional area change, tricuspid inflow velocities, tissue Doppler imaging (TDI), and deformation analysis were performed. Paired Wilcoxon's signed rank or Student's t-test was used for analysis. P < 0.05 was considered significant. Twenty HLHS patients were studied (10 males:10 females). Median age at the pre-hybrid echocardiogram was 3 (1-16) days, age at hybrid procedure was 5 (3-17) days, and age at post-hybrid echocardiogram was 10 (6-34). There were significant decreases in systolic function as measured by TDI and deformation analysis. There was no significant change in right ventricular fractional area change. Diastolic function was also noted to significantly decrease after the hybrid procedure. CONCLUSION: Systolic and diastolic functions decreased after the hybrid procedure despite the fact that patients avoided cardiopulmonary bypass. These results are comparable with previous reports in HLHS patients undergoing the Norwood procedure. Further studies are needed to determine if these echocardiographic changes have prognostic significance.

Arrhythmias Following Comprehensive Stage II Surgical Palliation in Single Ventricle Patients.

Post-operative arrhythmias are common in pediatric patients following cardiac surgery. Following hybrid palliation in single ventricle patients, a comprehensive stage II palliation is performed. The incidence of arrhythmias in patients following comprehensive stage II palliation is unknown. The purpose of this study is to determine the incidence of arrhythmias following comprehensive stage II palliation. A single-center retrospective chart review was performed on all single ventricle patients undergoing a comprehensive stage II palliation from January 2010 to May 2014. Pre-operative, operative, and post-operative data were collected. A clinically significant arrhythmia was defined as an arrhythmia which led to cardiopulmonary resuscitation or required treatment with either pacing or antiarrhythmic medication. Statistical analysis was performed with Wilcoxon rank-sum test and Fisher's exact test with p < 0.05 significant. Forty-eight single ventricle patients were reviewed (32 hypoplastic left heart syndrome, 16 other single ventricle variants). Age at surgery was 185 ± 56 days. Cardiopulmonary bypass time was 259 ± 45 min. Average vasoactive-inotropic score was 5.97 ± 7.58. Six patients (12.5 %) had clinically significant arrhythmias: four sinus bradycardia, one 2:1 atrioventricular block, and one slow junctional rhythm. No tachyarrhythmias were documented for this patient population. Presence of arrhythmia was associated with elevated lactate (p = 0.04) and cardiac arrest (p = 0.002). Following comprehensive stage II palliation, single ventricle patients are at low risk for development of tachyarrhythmias. The most frequent arrhythmia seen in these patients was sinus bradycardia associated with respiratory compromise.

Potential Molecular Mechanism of Retrograde Aortic Arch Stenosis in the Hybrid Approach to Hypoplastic Left Heart Syndrome.

BACKGROUND: The hybrid palliation for hypoplastic left heart syndrome has emerged as an alternative approach to the Norwood procedure. The development of patent ductus arteriosus (PDA) in-stent stenosis can cause retrograde aortic arch stenosis (RAAS), leading to significant morbidity. This study aimed to identify potential mechanisms of PDA in-stent stenosis contributing to RAAS. METHODS: Tissues from stented PDAs were collected from 17 patients undergoing comprehensive stage II repair between 2009 and 2014. Patients requiring RAAS intervention based on cardiology-surgery consensus were defined as RAAS(+) (n = 10), whereas patients without any RAAS intervention were defined as RAAS(-) (n = 7). Tissues were examined by quantitative polymerase chain reaction analysis for vascular smooth muscle cell (VSMC) differentiation and proliferation markers. RESULTS: Patient characteristics were hypoplastic left heart syndrome with aortic atresia in 6 and with aortic stenosis in 3; unbalanced atrioventricular canal in 3; double-inlet left ventricle/transposition of the great arteries in 3; and double-outlet right ventricle in 2. VSMC differentiation markers (ß-actin, SM22, and calponin) and signaling pathways for VSMC modulation (transforming growth factor-ß1, Notch, and platelet derived growth factor-BB) were significantly higher in the RAAS(+) than in RAAS(-) patients. The proliferation marker Ki67 was increased in RAAS(+) patients. Cell cycle markers were comparable in both groups. CONCLUSIONS: Increased VSMC differentiation and proliferation markers suggest a mechanism for inward neointima formation of the PDA in RAAS. The apparent lack of change in cell cycle markers is contrary to coronary artery in-stent stenosis, suggesting further targets should be examined. Combined primary in vitro PDA cell culture and proteomics can be strong tools to elucidate targets to reduce PDA in-stent stenosis for RAAS in the future.

Mustard baffle obstruction and leak - How successful are percutaneous interventions in adults?

Atrial switch operations for D-Transposition of the great arteries (D-TGA) were performed until the late 20th century. These patients have substantial rates of re-operation, particularly for baffle related complications. This study sought to analyze the efficacy of percutaneous transcatheter intervention (PTI) for baffle leak and/or stenosis in adult atrial switch patients. Adult patients with a prior atrial switch operation who underwent heart catheterization (2002-2014) at a tertiary adult congenital heart disease referral center were retrospectively analyzed. In 58 adults (30 ± 8 years, 75% men, 14% New York Heart Association (NYHA) functional class ≥2) who underwent 79 catheterizations, PTI was attempted in 50 (baffle leak (n = 10, 20%), stenosis (n = 27, 54%), or both (n = 13, 26%)). PTI was successful in 45 and 5 were referred for surgery due to complex anatomy. A total of 40 bare metal stents, 18 covered stents, 16 occlusion devices, 2 angioplasties, and 1 endovascular graft were deployed. In isolated stenosis, there was improvement in NYHA functional class after PTI (8 vs. 0 patients were NYHA FC > 2, p = 0.004), which was matched by improvement in maximal oxygen consumption on exercise testing (VO2) (25.1 ± 5.4 mL/kg/min vs. 27.9 ± 9 mL/kg/min, p = 0.03). There were no procedure-related deaths or emergent surgeries in this cohort. This single-center cohort is the largest reported series of adult atrial switch operation patients who have undergone PTI for baffle stenosis and/or leak. We demonstrate that PTI with an expert multi-disciplinary team is a safe and effective alternative to surgery in adult patients with an atrial switch operation.

Experiência Inicial com o Implante Percutâneo da Válvula Melody® no Brasil / Initial Experience with Percutaneous Implantation of the MelodyTM Valve in Brazil

Introdução: Stress is associated with cardiovascular diseases.O implante percutâneo da válvula pulmonar é uma alternativa para condutos com disfunção. Descrevemos aqui a primeira experiência com o implante da válvula Melody® no Brasil. Métodos: Foram selecionados pacientes com estenose ou insuficiência pulmonar significativa em condutos de 16 a 22 mm. Foram empregadas técnicas padronizadas. Factibilidade, segurança e eficácia desse procedimento foram avaliadas. Resultados: Desde dezembro de 2013, dez pacientes (média de idade e peso de 16,5 anos e 49 kg, respectivamente) foram submetidos ao procedimento com intervalo médio de 11,9 ± 8,6 anos desde a última cirurgia. Insuficiência pulmonar foi indicação para o tratamento em três pacientes, estenose em dois e lesão mista em cinco. A válvula Melody® foi implantada com sucesso em todos os casos. A média da pressão sistólica do ventrículo direito e a relação ventrículo direito/ventrículo esquerdo diminuíram de 49,2 ± 15,9 para 35,8 ± 5,7 mmHg e de 0,55 ± 0,18 para 0,39 ± 0,08 mmHg (p < 0,01 para ambos). Não observamos estenose e nem insuficiência pulmonar residual significativa. Um paciente teve extravasamento contido requerendo um stent coberto e um segundo implante valvular. Todos os pacientes receberam alta do hospital em 72 horas. As válvulas funcionaram adequadamente ...

Background: Transcatheter pulmonary valve implantation is an alternative for dysfunctional conduits. We report the first experience with the MelodyTM valve implantation in Brazil. Methods: Patients with significant pulmonary stenosis or significant pulmonary insufficiency in conduits measuring 16 to 22 mm were enrolled. Standardized techniques were employed. The feasibility, safety and efficacy of this procedure were assessed. Results: From December 2013, ten patients (mean age and weight of 16.5 years and 49 kg, respectively) have undergone the procedure with a mean interval of 11.9 ± 8.6 years since the last surgery. Pulmonary insufficiency was an indication for treatment in three patients, pulmonary stenosis in two, and mixed lesion in five. The MelodyTM valve was successfully implanted in all cases. Mean right ventricular systolic pressure and right ventricle/left ventricle ratio decreased from 49.2 ± 15.9 to 35.8 ± 5.7 mmHg and from 0.55 ± 0.18 to 0.39 ± 0.08 mmHg (p < 0.01 for both). Significant residual pulmonary stenosis or pulmonary insufficiency was not observed. One patient had a contained conduit tear requiring a covered stent and a second valve implantation. All patients were discharged within 72 hours. The valves were properly functioning in a mean follow-up of 4.1 ± 2.2 months with no complications. Conclusions: Transcatheter MelodyTM valve implantation was feasible, safe and effective ...

Stenting of the right ventricular outflow tract in 2 dogs for palliation of dysplastic pulmonary valve stenosis and right-to-left intracardiac shunting defects.

Two dogs with severe dysplastic pulmonary valve stenosis and right-to-left shunting defects (patent foramen ovale, perimembranous ventricular septal defect) underwent palliative stenting of the right ventricular outflow tract and pulmonary valve annulus using balloon expandable stents. One dog received 2 over-lapping bare metal stents placed 7 months apart; the other received a single covered stent. Both procedures were considered technically successful with a reduction in the transpulmonary valve pressure gradient from 202 to 90 mmHg in 1 dog and from 168 to 95 mmHg in the other. Clinical signs of exercise intolerance and syncope were temporarily resolved in both dogs. However, progressive right ventricular concentric hypertrophy, recurrent stenosis, and erythrocytosis were observed over the subsequent 6 months leading to poor long-term outcomes. Stenting of the right ventricular outflow tract is feasible in dogs with severe dysplastic pulmonary valve stenosis, though further study and optimization of the procedure is required.

Neutrophil/Lymphocyte ratio and association with arch intervention in patients with hypoplastic left heart syndrome undergoing hybrid procedure.

BACKGROUND: Hybrid procedure is an alternative initial palliation for patients with hypoplastic left heart syndrome (HLHS). One major complication with this procedure is stenosis in the aortic arch isthmus possibly due to inflammation from the patent ductus arteriosus (PDA) stent. In adult studies, neutrophil/lymphocyte (N/L) ratio has been used as a marker for increased inflammation and has been associated with increased risk for coronary artery stent stenosis. The goal of this study was to determine if there were differences in N/L ratio between patients with HLHS undergoing hybrid procedure that required an arch intervention (AI-Group) vs. those that did not require an intervention (NAI-Group). METHODS: Retrospective chart review was performed on patients with HLHS undergoing hybrid procedure between July 2002 and January 2013. Complete blood counts as well as differentials were recorded at four time periods: 1 day prehybrid palliation, one day posthybrid palliation, 1 week posthybrid palliation, and 3 weeks posthybrid palliation. RESULTS: One hundred six patients were evaluated (AI-Group = 38, NAI-Group = 68). AI-Group generally had a higher N/L ratio vs. NAI-group and this was significant immediately 1 day posthybrid palliation: AI-Group vs. NAI-Group, prehybrid (2.95 ± 2.62 vs. 2.44 ± 1.71), 1 day posthybrid (5.95 ± 4.16 vs. 4.34 ± 3.87, P < .05), 1 week posthybrid (2.72 ± 3.01 vs. 2.28 ± 2.12), and 3 weeks posthybrid (1.85 ± 1.24 vs. 1.45 ± 1.16), respectively. Lymphocyte percentage was significantly lower in the AI-Group vs. NAI-Group 3 weeks posthybrid palliation (33.00 + 11.30% vs. 40.65 + 16.82%). CONCLUSION: Patients that required an arch intervention after hybrid palliation had a higher N/L ratio immediately after the procedure. This may signify increased inflammatory reaction that places these patients at risk for stenosis. Future studies are needed to determine if N/L ratio is a robust marker to risk stratify patients undergoing the hybrid procedure for arch complications.