Utility of the NEONATE Score at an Institution that Routinely Performs the Hybrid Procedure for Hypoplastic Left Heart Syndrome.

NEONATE score > 17 has been proposed as a risk factor for interstage mortality/cardiac transplant (IM/T) for patients with single ventricle physiology. Hybrid procedure is assigned 6 points, the highest possible score for that surgical variable. Most centers reserve the hybrid procedure for high-risk patients. Goal of this study was to evaluate the NEONATE score at a center that routinely performs the hybrid procedure. Retrospective chart review of patients undergoing the hybrid procedure was performed (2008-2021). Demographics and variables used for the NEONATE score were collected. Maximization of Youden's J Statistic used to determine cohort-specific optimal threshold for patients undergoing comprehensive Stage II procedure (H-CSII) versus those with IM/T (H-IM/T). Total of 120 patients met inclusion criteria (H-CSII = 105, H-IM/T = 15). Gestational age was median 39 weeks (IQR 38, 39) and birth weight was 3.18 kg (2.91, 3.57). No patient was discharged with opiates or required post-operative extracorporeal circulatory support. Optimal threshold, as selected by maximizing Youden's J Statistic, was 22. Score > 22 had a positive predictive value of 0.33 (95% CI 0.12-0.62), negative predictive values of 0.90 (95% CI 0.83-0.95), and accuracy of 0.83 (95% CI 0.75-0.90) for IM/T. At a center that routinely performs the hybrid procedure, value of > 22 had the highest accuracy. This suggests that the hybrid procedure is not necessarily intrinsically a risk-factor for IM/T, but rather patient selection for the hybrid procedure may play a larger role at centers that do not routinely perform this procedure.

Partnering With Stakeholders to Inform the Co-Design of a Psychosocial Intervention for Prenatally Diagnosed Congenital Heart Disease.

Input from diverse stakeholders is critical to the process of designing healthcare interventions. This study applied a novel mixed-methods, stakeholder-engaged approach to co-design a psychosocial intervention for mothers expecting a baby with congenital heart disease (CHD) and their partners to promote family wellbeing. The research team included parents and clinicians from 8 health systems. Participants were 41 diverse parents of children with prenatally diagnosed CHD across the 8 health systems. Qualitative data were collected through online crowdsourcing and quantitative data were collected through electronic surveys to inform intervention co-design. Phases of intervention co-design were: (I) Engage stakeholders in selection of intervention goals/outcomes; (II) Engage stakeholders in selection of intervention elements; (III) Obtain stakeholder input to increase intervention uptake/utility; (IV) Obtain stakeholder input on aspects of intervention design; and (V) Obtain stakeholder input on selection of outcome measures. Parent participants anticipated the resulting intervention, HEARTPrep, would be acceptable, useful, and feasible for parents expecting a baby with CHD. This model of intervention co-design could be used for the development of healthcare interventions across chronic diseases.

Incidence of and Risk Factors for Aortic Arch Interventions After the Comprehensive Stage II Procedure for Hypoplastic Left Heart Syndrome.

Minimal data exist about the incidence and risk factors for arch intervention after comprehensive stage II (CSII). Goal of this study was to document incidence of arch interventions after CSII and determine if any differences existed between those who underwent an arch intervention (aiCSII) versus those did not have an intervention. Single-center retrospective chart review of all hypoplastic left heart syndrome patients who underwent a CSII between 6/1/2005 and 2/1/2020 was performed. Univariate analysis was conducted in addition to principal components analysis (PCA). One hundred patients were evaluated. Sixteen patients underwent 24 arch interventions. Age at initial arch reintervention was 1.3 ± 1.2 years (median 1.0 years, range 0.5-2.2 years). Univariate analysis showed that the aiCSII group were more likely to be female, to have had a retrograde arch intervention post-hybrid procedure, and to be younger at time of CSII. On echocardiograms, aiCSII group had significantly higher pre-CSII patent ductus arteriosus velocities, arch velocities on their 1st post-operative and discharge study post-CSII, and arch velocities pre-Fontan. Gradients were higher in the aiCSII via pre-Fontan catheterization. With PCA, echocardiographic and catheterization data remained significantly associated with aiCSII versus those who did not undergo an arch intervention (OR = 4.5 (1.9, 19.8), p = 0.008). Incidence of arch intervention post-CSII was 16%. Echocardiographic arch velocities during the CSII hospitalization were the strongest predictors for subsequent aortic arch interventions. Further studies are needed to determine any modifiable variables that may reduce the incidence of arch interventions.

Early Integration of Palliative Care in Families of Children with Single Ventricle Congenital Heart Defects: A Quality Improvement Project to Enhance Family Support.

Children with single ventricle congenital heart defects (SVCHD) experience a significant risk of early mortality throughout their lifespan, particularly during their first year of life. Due to the intense care needed for these children and families, pediatric palliative care (PPC) team consults should be routine; however, medical staff are often reluctant to broach the idea of PPC to families. The involvement of PPC for many carries with it an association to end-of-life (EOL) care. Setting the standard of PPC involvement from the time of admission for the first palliative surgery led to increased family support, decreased days to consult, improved acceptance and communication. The purpose of this article is to describe a quality improvement project of early integration of PPC with families of children with SVCHD. Lessons learned will be presented, including the resources needed and the barriers encountered in assimilating PPC into the standard of care for all patients with SVCHD. The single ventricle (SV) and PPC teams collaborated to enhance the support given to SV families. Education was initiated with cardiology and PPC providers to understand the goal of consistent PPC consults beginning after birth for patients with SVCHD. Parents were educated during fetal consultation regarding the involvement of the PPC team. The SV team ensured compliance with the PPC initiative by identifying eligible patients and requesting consult orders from the primary providers. PPC consultation increased significantly over the 40 month study period to nearly 100% compliance for children with SVCHD who are undergoing pre-Fontan surgery. In addition, mean days to consult decreased dramatically during the study to a current average of 3 days into the patient's hospitalization; the data likely suggest that more PPC consults were routinely ordered versus urgently placed for unexpected complications. Data indicate that patients are being followed by the PPC team at an earlier age and stage in their SV journey which allows for more opportunity to provide meaningful support to these patients and families. The early involvement of the PPC team for children with SV physiology was operationally feasible and was accepted by families, thus allowing PPC providers to establish a therapeutic relationship early in the disease trajectory with the family. It allowed more continuity throughout the SV journey in a proactive fashion rather than a reactive manner.

Launching a New Strategy for Multidisciplinary Management of Single-Ventricle Heart Defects.

Children born with single-ventricle heart defects, particularly hypoplastic left heart syndrome, have a lifetime high risk of mortality and comorbidities. They have complex medical challenges in addition to their cardiac needs, including growth and feeding complications and neurodevelopmental issues. These concerns require a coordinated effort among specialties to help patients maximize their potential. Additionally, because many complex heart defects are diagnosed prenatally, coordination of care between the pre- and postnatal care teams is imperative. Nursing leadership improves program coordination and efficiency. The purpose of this article is to describe the development and implementation of our hospital's synchronized, multidisciplinary team to support children with single-ventricle heart defects and their families. (Critical Care Nurse. 2018;38[1]:60-71).

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.

Design, synthesis, and evaluation of imidazo[4,5-c]pyridin-4-one derivatives with dual activity at angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-γ.

Identification of a series of imidazo[4,5-c]pyridin-4-one derivatives that act as dual angiotensin II type 1 (AT1) receptor antagonists and peroxisome proliferator-activated receptor-γ (PPARγ) partial agonists is described. Starting from a known AT1 antagonist template, conformational restriction was introduced by incorporation of an indane ring that when combined with appropriate substitution at the imidazo[4,5-c]pyridin-4-one provided novel series 5 possessing the desired dual activity. The mode of interaction of this series with PPARγ was corroborated through the X-ray crystal structure of 12b bound to the human PPARγ ligand binding domain. Modulation of activity at both receptors through substitution at the pyridone nitrogen led to the identification of potent dual AT1 antagonists/PPARγ partial agonists. Among them, 21b was identified possessing potent dual pharmacology (AT1 IC(50) = 7 nM; PPARγ EC(50) = 295 nM, 27% max) and good ADME properties.

Discovery of a series of imidazo[4,5-b]pyridines with dual activity at angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-γ.

Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-γ (PPARγ) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPARγ confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPARγ activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC(50) = 1.6 nM) with partial PPARγ agonism (EC(50) = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.

Synthesis and evaluation of novel alpha-heteroaryl-phenylpropanoic acid derivatives as PPARalpha/gamma dual agonists.

The synthesis of a new series of phenylpropanoic acid derivatives incorporating an heteroaryl group at the alpha-position and their evaluation for binding and activation of PPARalpha and PPARgamma are presented in this report. Among the new compounds, (S)-3-{4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-phenyl}-2-1,2,3-triazol-2-yl-propionic acid (17j), was identified as a potent human PPARalpha/gamma dual agonist (EC(50)=0.013 and 0.061 microM, respectively) with demonstrated oral bioavailability in rat and dog. 17j was shown to decrease insulin levels, plasma glucose, and triglycerides in the ZDF female rat model. In the human apolipoprotein A-1/CETP transgenic mouse model 17j produced increases in hApoA1 and HDL-C and decreases in plasma triglycerides. The increased potency for binding and activation of both PPAR subtypes observed with 17j when compared to previous analogs in this series was explained based on results derived from crystallographic and modeling studies.

Effects of modifications of the linker in a series of phenylpropanoic acid derivatives: Synthesis, evaluation as PPARalpha/gamma dual agonists, and X-ray crystallographic studies.

A new series of alpha-aryl or alpha-heteroarylphenyl propanoic acid derivatives was synthesized that incorporate acetylene-, ethylene-, propyl-, or nitrogen-derived linkers as a replacement of the commonly used ether moiety that joins the central phenyl ring with the lipophilic tail. The effect of these modifications in the binding and activation of PPARalpha and PPARgamma was first evaluated in vitro. Compounds possessing suitable profiles were then evaluated in the ob/ob mouse model of type 2 diabetes. The propylene derivative 40 and the propyl derivative 53 demonstrated robust plasma glucose lowering activity in this model. Compound 53 was also evaluated in male Zucker diabetic fatty rats and was found to achieve normalization of glucose, triglycerides, and insulin levels. An X-ray crystal structure of the complex of 53 with the PPARgamma-ligand-binding domain was obtained and discussed in this report.