The Role of Elevated Wall Shear Stress in Progression of Pulmonary Vein Stenosis: Evidence from Two Case Studies.

Pulmonary vein stenosis is a serious condition characterized by restriction or blockage due to fibrotic tissue ingrowth that develops in the pulmonary veins of infants or children. It is often progressive and can lead to severe pulmonary hypertension and death. Efforts to halt or reverse disease progression include surgery and catheter-based balloon dilation and stent implantation. Its cause and mechanism of progression are unknown. In this pilot study, we propose and explore the hypothesis that elevated wall shear stress at discrete pulmonary venous sites triggers stenosis. To assess this theory, we retrospectively analyzed cardiac catheterization, lung scan, and X-ray computed tomography data to estimate wall shear stress in the pulmonary veins at multiple time points during disease progression in two patients. Results are consistent with the existence of a level of elevated wall shear stress above which the disease is progressive and below which progression is halted. The analysis also suggests the possibility of predicting the target lumen size necessary in a given vein to reduce wall shear stress to normal levels and remove the trigger for stenosis progression.

Long-Term Outcomes of the Coarctation of the Aorta Stent Trials.

BACKGROUND: Long-term outcome data of stent-implantation for coarctation of the aorta are limited. We report up to 5 years of postimplant follow-up in patients enrolled into the COAST (Coarctation of the Aorta Stent Trial) and the COAST II trial (Covered Cheatham-Platinum Stents for Prevention or Treatment of Aortic Wall Injury Associated With Coarctation of the Aorta), evaluating the bare and Covered Cheatham-Platinum Stents for the treatment of coarctation of the aorta and associated aortic wall injury. METHODS: Data was prospectively collected during the 2 multi-center studies, enrolling 248 patients (COAST: n=121, COAST II: n=127). Late follow-up data (48­60 month) was compared with immediate (1 month) and early (12 months) follow-up. RESULTS: There was a notable decrease in the use of antihypertensive medication, from 53% at immediate, to 42% at early, and 29% at late follow-up. The cumulative incidence of stent fractures was 0% immediately, 2.9% at early, and 24.4% at late follow-up. Independent predictors for stent fractures at late follow-up were age <18 years, male sex, minimum stent diameter ≥12 mm, and use of bare metal stent. The cumulative incidence of reintervention was 1.6% at immediate, 5.1% at early, and 21.3% at late follow-up. Independent predictors for reinterventions at late follow-up were age <18 years, post implantation systolic arm-leg blood pressure gradient ≥10 mm Hg, minimum stent diameter at implantation <12 mm, and initial coarctation minimum diameter <6 mm. There were 13 patients with aortic aneurysms, with a cumulative incidence of 6.3% at late follow-up. CONCLUSIONS: Coarctation stenting is effective at maintaining obstruction relief up to 60 months postimplant with reduction in the number of patients requiring antihypertensive medication. However, an increase in-stent fractures and reinterventions were observed between medium and long-term follow-up. Covered stents appear to confer some protection from the development of stent fractures but do not provide complete protection from late aneurysm formation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00552812 and NCT01278303.

Outcomes in Establishing Individual Vessel Patency for Pediatric Pulmonary Vein Stenosis.

The purpose of this study was to determine what patient and pulmonary vein characteristics at the diagnosis of intraluminal pulmonary vein stenosis (PVS) are predictive of individual vein outcomes. A retrospective, single-center, cohort sub-analysis of individual pulmonary veins of patients enrolled in the clinical trial NCT00891527 using imatinib mesylate +/- bevacizumab as adjunct therapy for the treatment of multi-vessel pediatric PVS between March 2009 and December 2014 was performed. The 72-week outcomes of the individual veins are reported. Among the 48 enrolled patients, 46 patients and 182 pulmonary veins were included in the study. Multivariable analysis demonstrated that patients with veins without distal disease at baseline (odds ratio, OR 3.69, 95% confidence interval, CI [1.52, 8.94], p = 0.004), location other than left upper vein (OR 2.58, 95% CI [1.07, 6.19], p = 0.034), or veins in patients ≥ 1 y/o (OR 5.59, 95% CI [1.81, 17.3], p = 0.003) were at higher odds of having minimal disease at the end of the study. Veins in patients who received a higher percentage of eligible drug doses required fewer reinterventions (IRR 0.76, 95% CI [0.68, 0.85], p < 0.001). The success of a multi-modal treatment approach to aggressive PVS depends on the vein location, disease severity, and drug dose intensity.

Clinical Syndromic Phenotypes and the Potential Role of Genetics in Pulmonary Vein Stenosis.

Pulmonary vein stenosis (PVS) is a rare, frequently lethal disease with heterogeneous phenotypes and an unclear etiology. Limited studies have reported associations between PVS and congenital heart disease (CHD), chronic lung disease (CLD), and/or prematurity; however, to date, there have been no studies that report detailed clinical syndromic phenotypes and the potential role of genetics in PVS. An existing registry of multivessel PVS patients seen at Boston Children's Hospital (BCH) was queried between August 2006 and January 2017 for all existing genetic testing data on these patients. PVS was defined as an intraluminal pulmonary venous obstruction in ≥2 vessels with mean pressure gradients > 4 mmHg. One-hundred-and-fifty-seven patients (46% female, with a median age at PVS diagnosis of 3 months) formed the cohort. Seventy-one (45%) patients had available genetic testing information. Of the 71 patients, a likely genetic diagnosis was found in 23 (32%) patients: 13 (57%) were diagnosed with Trisomy 21 (T21), five (22%) with Smith-Lemli-Opitz Syndrome, five (22%) had other pathologic genetic disease, and 24 (33%) had variants of unknown significance. The majority of 13 patients with T21 and PVS had common atrioventricular canal (CAVC) (10, 77%) and all had severe pulmonary hypertension (PHTN), which led to their PVS diagnosis. In our study, PVS was associated with T21, the majority of whom also had CAVC and PHTN. Therefore, complete assessment of the pulmonary veins should be considered for all T21 patients, especially those with CAVC presenting with PHTN. Furthermore, prospective standardized genetic testing with detailed clinical phenotyping may prove informative about potential genetic etiologies of PVS.

Corrigendum: Clinical Protocol for a Longitudinal Cohort Study Employing Systems Biology to Identify Markers of Vaccine Immunogenicity in Newborn Infants in The Gambia and Papua New Guinea.

[This corrects the article DOI: 10.3389/fped.2020.00197.].

Clinical Protocol for a Longitudinal Cohort Study Employing Systems Biology to Identify Markers of Vaccine Immunogenicity in Newborn Infants in The Gambia and Papua New Guinea.

Background: Infection contributes to significant morbidity and mortality particularly in the very young and in low- and middle-income countries. While vaccines are a highly cost-effective tool against infectious disease little is known regarding the cellular and molecular pathways by which vaccines induce protection at an early age. Immunity is distinct in early life and greater precision is required in our understanding of mechanisms of early life protection to inform development of new pediatric vaccines. Methods and Analysis: We will apply transcriptomic, proteomic, metabolomic, multiplex cytokine/chemokine, adenosine deaminase, and flow cytometry immune cell phenotyping to delineate early cellular and molecular signatures that correspond to vaccine immunogenicity. This approach will be applied to a neonatal cohort in The Gambia (N ~ 720) receiving at birth: (1) Hepatitis B (HepB) vaccine alone, (2) Bacille Calmette Guerin (BCG) vaccine alone, or (3) HepB and BCG vaccines, (4) HepB and BCG vaccines delayed till day 10 at the latest. Each study participant will have a baseline peripheral blood sample drawn at DOL0 and a second blood sample at DOL1,-3, or-7 as well as late timepoints to assess HepB vaccine immunogenicity. Blood will be fractionated via a "small sample big data" standard operating procedure that enables multiple downstream systems biology assays. We will apply both univariate and multivariate frameworks and multi-OMIC data integration to identify features associated with anti-Hepatitis B (anti-HB) titer, an established correlate of protection. Cord blood sample collection from a subset of participants will enable human in vitro modeling to test mechanistic hypotheses identified in silico regarding vaccine action. Maternal anti-HB titer and the infant microbiome will also be correlated with our findings which will be validated in a smaller cohort in Papua New Guinea (N ~ 80). Ethics and Dissemination: The study has been approved by The Gambia Government/MRCG Joint Ethics Committee and The Boston Children's Hospital Institutional Review Board. Ethics review is ongoing with the Papua New Guinea Medical Research Advisory Committee. All de-identified data will be uploaded to public repositories following submission of study output for publication. Feedback meetings will be organized to disseminate output to the study communities. Clinical Trial Registration: Clinicaltrials.gov Registration Number: NCT03246230.

A cloud-based bioinformatic analytic infrastructure and Data Management Core for the Expanded Program on Immunization Consortium.

The Expanded Program for Immunization Consortium - Human Immunology Project Consortium study aims to employ systems biology to identify and characterize vaccine-induced biomarkers that predict immunogenicity in newborns. Key to this effort is the establishment of the Data Management Core (DMC) to provide reliable data and bioinformatic infrastructure for centralized curation, storage, and analysis of multiple de-identified "omic" datasets. The DMC established a cloud-based architecture using Amazon Web Services to track, store, and share data according to National Institutes of Health standards. The DMC tracks biological samples during collection, shipping, and processing while capturing sample metadata and associated clinical data. Multi-omic datasets are stored in access-controlled Amazon Simple Storage Service (S3) for data security and file version control. All data undergo quality control processes at the generating site followed by DMC validation for quality assurance. The DMC maintains a controlled computing environment for data analysis and integration. Upon publication, the DMC deposits finalized datasets to public repositories. The DMC architecture provides resources and scientific expertise to accelerate translational discovery. Robust operations allow rapid sharing of results across the project team. Maintenance of data quality standards and public data deposition will further benefit the scientific community.

Covered CP Stent for Treatment of Right Ventricular Conduit Injury During Melody Transcatheter Pulmonary Valve Replacement.

BACKGROUND: High-pressure balloon and stent angioplasty are frequently necessary to prepare the dysfunctional right ventricular outflow tract conduit before transcatheter pulmonary valve replacement (TPVR). Conduit injury can result, which may be catastrophic to the patient or prevent successful TPVR. METHODS AND RESULTS: The PARCS trial (Pulmonary Artery Repair With Covered Stent) was a pivotal, prospective multicenter trial to evaluate the safety and efficacy of the NuMED Covered CP Stent (CCPS) for treatment of conduit injury occurring during TPVR. The study also evaluated immediate and short-term TPVR function in patients receiving covered stents. A total of 616 patients were consented; 120 (19.5%) had a wall injury identified and were treated with CCPS. Severe conduit injuries were uncommon (5%), but predictors for severe injury were not identified. Stenotic homografts had the highest incidence of injury (29%), compared with other conduit substrates. Among patients receiving CCPS implant, 96% required no further therapy for conduit injury, and 94% underwent TPVR at that procedure. Only 2 patients (1.6%) required urgent surgery for conduit injury, despite CCPS implant. There were few CCPS-related complications. TPVR function was similar between CCPS and non-CCPS groups at follow-up. CONCLUSIONS: Conduit injury during TPVR is common, although severe injury is rare. The CCPS was a safe and effective treatment for right ventricular outflow tract conduit injury during preparation for TPVR, allowing nearly all patients to complete the procedure without identifiable impact on valve performance. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01824160.

Intermediate Outcomes in the Prospective, Multicenter Coarctation of the Aorta Stent Trial (COAST).

BACKGROUND: The Coarctation of the Aorta Stent Trial (COAST) was designed to assess the safety and efficacy of the Cheatham Platinum stent when used in children and adults with native or recurrent coarctation. Acute outcomes have been reported. We report here follow-up to 2 years. METHODS AND RESULTS: A total of 105 patients underwent attempted implantation, with 104 successes. There were no procedural deaths, serious adverse events, or surgical intervention. All patients experienced immediate reduction in upper- to lower-extremity blood pressure difference with sustained improvement to 2 years. Rates of hypertension and medication use decreased from baseline to 12 months and remained largely unchanged at 2 years. Six aortic aneurysms have been identified: 5 were successfully treated with covered stent placement, and 1 resolved without intervention. Stent fractures were noted in 2 patients at 1 year and 11 patients at 2 years, with evidence of fracture progression. To date, only larger stent diameter was associated with stent fracture. Twelve additional fractures have occurred after 2 years. No fracture has resulted in loss of stent integrity, stent embolization, aortic wall injury, or reobstruction. Nine reinterventions occurred in the first 2 years for stent redilation and address of aneurysms, and 10 additional reinterventions occurred after 2 years. CONCLUSIONS: The Cheatham Platinum stent is safe and associated with persistent relief of aortic obstruction. Stent fracture and progression of fracture occur but have not resulted in clinically important sequelae. Reintervention is common and related to early and late aortic wall injury and need for re-expansion of small-diameter stents. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00552812.