Single Heart Research Articles

Abstract 13241: Long-Term Clinical Outcome After Transcoronary Cardiosphere-Derived Cell Infusion in Patients With Single Ventricle Congenital Heart Disease

Introduction: Although transcoronary infusion of cardiosphere-derived cells (CDCs) in patients with single ventricles provides short-term improvement in cardiac function, the long-term efficacy is still unknown. Hypothesis: We tested the hypothesis that CDC infusion is associated with improved long-term clinical outcome in patients with single ventricles and heart failure. Methods: Patients were enrolled in the TICAP phase 1 (Transcoronary Infusion of Cardiac Progenitor Cells in Patients With Single Ventricle Physiology) and PERSEUS phase 2 (Cardiac Progenitor Cell Infusion to Treat Univentricular Heart Disease) trials between January 5, 2011, and January 30, 2015. The inclusion criteria were that patients were aged <6 years who were diagnosed with single ventricle lesions undergoing stage 2 (bidirectional Glenn) or stage 3 (total cavopulmonary connection) palliation. Medical records of patients with single ventricles were obtained and analyzed as a control group who were eligible but were treated by staged palliation alone. We evaluated the effectiveness of CDCs using an integrated cohort study in 93 patients with single ventricles, including 40 patients who received CDC infusion and 53 controls. Results: At the time of this study, 35 patients with CDC infusion and 43 controls were alive without cardiac transplantation, with mean follow-up of 10.0±1.2 years. The absolute changes in brain natriuretic peptide ( P = 0.015), atrioventricular regurgitation grade ( P = 0.018), and weight for age ( P < 0.001) from baseline to last follow-up showed significant improvements in CDC-treated patients compared with controls. Survival rate did not differ between the 2 groups (log-rank P = 0.351), whereas overall patients treated by CDCs had lower incidents of late failure ( P = 0.043) and adverse events ( P = 0.036) compared with controls. Multivariate proportional hazard regression analyses showed that CDC infusion was associated with lower risks of late failure ( P = 0.003) and adverse events ( P = 0.013). Conclusions: Intracoronary delivery of CDCs in patients with single ventricles did not improve all-cause mortality rate but significantly reduced the incidence of late failure and adverse events at 8 years of follow-up.

Abstract 18567: Acute Inhibition of Phosphodiesterase 1 (PDE1) Decreases Tension Generation in Pediatric Heart Failure

Introduction: Children with heart failure (HF) due to dilated cardiomyopathy (DCM) or single ventricle congenital heart disease (SV) ultimately require heart transplantation due to the lack of effective medical therapies. Inhibition of PDE1 (PDE1i) is currently being investigated in adult HF, however it is unclear if PDE1i use should be extrapolated to pediatric HF. Objective: To evaluate the acute effect of PDE1i on loaded myocardial contractility in pediatric DCM and SV trabeculae. Methods: Hearts were obtained from DCM (N=25) and SV (N=27) children who underwent transplant between 2010-2020. Right ventricular trabeculae are freshly isolated and mounted in a multi-chamber muscle bath. Ex vivo contractile response of isolated trabeculae was measured in response to 10uM PDE1i, the non-selective β-agonist isoproterenol (Iso), and untreated. To assess contractile response with increased cyclic adenosine monophosphate (cAMP) from β-adrenergic stimulation, a subset of baths received Iso and PDE1i. Percent change in max tension was determined by the difference between max tension and baseline tension, divided by baseline tension. Results: In pediatric DCM and SV trabeculae, acute PDE1i resulted in lower max tension generation when compared to untreated trabeculae (DCM p=0.003 and SV p=0.01). In DCM trabeculae, % change in tension was also lower with PDE1i when compared to Iso (p=0.0053) however there was only a trend toward significance in SV (p=0.06). There was no difference between % change in tension between Iso and PDE1i+Iso in either DCM or SV. Conclusions: Although PDE1 has high expression and activity in human cardiomyocytes, acute PDE1i treatment of explanted trabeculae results in decreased max tension generation. Even in the setting of elevated cAMP, PDE1i does not alter max tension generation. Thus, while there may be beneficial effects of PDE1i in pediatric HF, the consequences are unlikely related to a direct increase in cardiomyocyte contractility.

Abstract 15192: The Impact of Fontan Circulatory Failure on Heart Transplant Survival: A 20 Center Study

Introduction: Fontan circulatory failure (FCF) is a chronic state in palliated single ventricle heart disease with high morbidity and mortality including heart failure, multisystem end-organ disease, and need for heart transplant (HT). Specific FCF morbidities have not been rigorously defined limiting study of how FCF morbidities impact pre- and post-HT outcomes. Hypothesis: FCF-specific morbidities affect survival from HT waitlisting (WL) through 1-year post-HT. Methods: This 20-center, retrospective cohort study collected demographic, medical/surgical history, WL data, and peri- and post-HT data in Fontan patients WL since 2008. Using Delphi methodology, investigators defined FCF-specific morbidities and collected data. Appropriate univariate 2-group statistics compared surviving individuals with those who 1) died anytime from WL to 1-year post-HT, 2) died on the WL, 3) died within 1-year post-HT. Multivariable logistic regression determined independent risk factors for mortality between WL and 1-year post-HT. Results: Of 409 WL patients, 24 (5.9%) died on the WL. Of the 316 (77%) who underwent HT, 27 (8.5%) did not survive to 1-year. Univariate risk factors for WL death included higher aortopulmonary collateral burden, > 1 hospitalizations in prior year, younger age, sleep apnea, higher NYHA class, non-enrollment in school or work, and single-parent home. Risk factors for 1-year post-HT mortality included HLHS diagnosis, patent fenestration, anatomic Fontan obstruction, clinical cyanosis (pulse oximetry < 90%), polycythemia, portal variceal disease, psychiatric disease requiring treatment, and higher HLA class II PRA. For the 15% of patients not surviving from WL to 1-year post-HT, independent risk factors for mortality included >1 hospitalization in the year prior to WL (aOR 2.0, p=0.05) and clinical cyanosis (aOR 5.0, p=0.002). Notably, some FCF morbidities did not impact post-WL survival including protein-losing enteropathy, plastic bronchitis, and kidney disease. Conclusions: Fontan-palliated patients continue to have high mortality from WL through HT. Among FCF specific morbidities, cyanosis is associated with worsened survival and needs further study. Continued study of FCF phenotype is possible via this dataset.

Abstract 17103: The Proteomic Fingerprint in Patients With Single Ventricle Disease in the Interstage Period: Evidence of Chronic Inflammation and Widespread Activation of Biological Networks

Introduction: Children with single ventricle heart disease (SVHD) experience significant morbidity across systems and time: (AKI 70%, neurodevelopmental impairment 33%, growth failure 14%, NEC 5.5%). Proteomics is a novel method to identify new biomarkers and mechanisms of injury in complex physiologic states. Hypothesis: Does the proteome of patients with SVHD differ from healthy children, and which biological systems are activated or repressed? Methods: Infants with SVHD in the interstage period were compared to similar-age healthy controls. Serum samples were collected, stored at -80C, and run on a panel of 1500 proteins in single batch analysis (Somalogic Inc., CO). Partial Least Squares-Discriminant Analysis (PLS-DA) was used to compare the proteomic profile of cases and controls and t-tests to detect differences in individual proteins (FDR < 0.05). Protein network analysis with functional enrichment was performed in STRING and Cytoscape. Results: PLS-DA readily discriminated between cases (n=33) and controls (n=24) based on their proteomic pattern alone (Accuracy=0.96, R2=0.97, Q2=0.80) (Fig 1a). 568 proteins differed between groups (FDR < 0.05). The 15 proteins with the greatest effect on the proteomic phenotype between the groups are shown (Fig 1b). We identified 25 up-regulated functional clusters and 13 down-regulated (5 clusters highlighted in Fig 1c). Active biological systems fell into six key groups: angiogenesis and cell proliferation/turnover, immune system activation and inflammation, altered metabolism, neuronal development, gastrointestinal system, and cardiac development. Conclusions: We report a clear differentiation in the circulating proteome of patients with SVHD and healthy controls with >500 circulating proteins distinguishing the groups. This proteomic data identifies various dysregulated protein networks across multiple organ systems with promising biological plausibility as drivers of SVHD morbidity.

Hybrid stage 1 palliation with simultaneous off-pump ventricular assist device placement in neonates with high-risk single ventricle anatomy: Initial experience

BackgroundInfants with single ventricle heart disease and severe atrioventricular valve regurgitation have poor outcomes following conventional staged palliation. As such, ventricular assist device (VAD) placement along with hybrid stage 1 palliation has been proposed as a bridge to heart transplant. We present a novel surgical technique for VAD implantation concurrent with hybrid stage 1 that avoids cardiopulmonary bypass. MethodsWe performed a retrospective review of our institutional experience with this novel surgical technique. ResultsThree patients (weight, 2.7-3.5 kg; age, 3 to 5 days) underwent hybrid stage 1 with VAD placement, consisting of bilateral 3.5-mm expandable polytetrafluoroethylene (PTFE) pulmonary artery bands, a ductal stent, a 6-mm Berlin Heart outflow cannula onto the main pulmonary trunk with a 10-mm graft, a 6-mm Berlin Heart outflow cannula onto the right atrium, and a 10-mL Berlin Heart pump. In patients with severe aortic arch hypoplasia or coarctation, a 4-mm PTFE graft was sewn from the VAD outflow graft to the innominate artery to protect coronary and cerebral perfusion. Procedures were performed off bypass with minimal blood product use. Patients were extubated on postoperative days 2, 2, and 5. There were no procedural complications. All patients were transferred out of the intensive care unit and demonstrated appropriate weight gain. Anticoagulation strategy was bivalirudin and antiplatelet therapy. The patients underwent transplantation after 149 days, 157 days, and 288 days of support. ConclusionsOff-pump single ventricle VAD placement is technically feasible and can be done at the time of hybrid stage 1 palliation with minimal operative morbidity as a bridge to transplant.

The Effect of Udenafil on Heart Rate and Blood Pressure in Adolescents With the Fontan Circulation

The Fontan Udenafil Exercise Longitudinal (FUEL) trial showed that treatment with udenafil was associated with improved exercise performance at the ventilatory anaerobic threshold in children with Fontan physiology. However, it is not known how the initiation of phosphodiesterase 5 inhibitor therapy affects heart rate and blood pressure in this population. These data may help inform patient selection and monitoring after the initiation of udenafil therapy. The purpose of this study is to evaluate the effects of udenafil on vital signs in the cohort of patients enrolled in the FUEL trial. This international, multicenter, randomized, double-blind, placebo-controlled trial of udenafil included adolescents with single ventricle congenital heart disease who had undergone Fontan palliation. Changes in vital signs (heart rate [HR], systolic [SBP] and diastolic blood pressure [DBP]) were compared both to subject baseline and between the treatment and the placebo groups. Additional exploratory analyses were performed to evaluate changes in vital signs for prespecified subpopulations believed to be most sensitive to udenafil initiation. Baseline characteristics were similar between the treatment and placebo cohorts (n=200 for each). The groups demonstrated a decrease in HR, SBP, and DBP 2 hours after drug/placebo administration, except SBP in the placebo group. There was an increase in SBP from baseline to after 6-min walk test in the treatment and placebo groups, and the treatment group showed an increase in HR (87.4 ± 15.0 to 93.1 ± 19.4 beats/min, p <0.01) after exercise. When comparing changes from baseline to the 26-week study visit, small decreases in both SBP (-1.9 ± 12.3 mm Hg, p=0.03) and DBP (-3.0 ± 9.6 mm Hg, p <0.01) were seen in the treatment group. There were no clinically significant differences between treatment and placebo group in change in HR or blood pressure in the youngest age quartile, lightest weight quartile, or those on afterload-reducing agents. In conclusion, initiation of treatment with udenafil in patients with Fontan circulation was not associated with clinically significant changes in vital signs, implying that for patients similar to those enrolled in the FUEL trial, udenafil can be started without the requirement for additional monitoring after initial administration.

Predictors of Survival After Heart Transplant in the New Allocation System: A UNOS Database Analysis.

Clinical predictors of posttransplant graft loss since the United Network for Organ Sharing (UNOS) heart allocation system change have not been well characterized. Single organ adult heart transplants from the UNOS database were identified (n = 10,252) and divided into a test cohort (n = 6,869, 67%) and validation cohort (n = 3,383, 33%). A Cox regression analysis was performed on the test cohort to identify recipient and donor risk factors for posttransplant graft loss. Based on the risk factors, a score (max 16) was developed to classify patients in the validation cohort into risk groups of low (≤1), mid (2-3), high (≥4) risk. Recipient factors of advanced age, Black race, recipient blood group O, diabetes, etiology of heart failure, renal dysfunction, elevated bilirubin, redo-transplantation, elevated pulmonary artery pressure, transplant with a durable ventricular assist device, or transplant on extracorporeal membrane oxygenation (ECMO) or ventilator were associated with more posttransplant graft loss. Donor factors of ischemic time and donor age were also associated with outcomes. One year graft survival for the low-, mid-, high-risk groups was 94%, 91%, and 85%, respectively. In conclusion, easily obtainable clinical characteristics at time of heart transplant can predict posttransplant outcomes in the current era.

A novel method to extend viability and functionality of living heart slices.

Living heart slices have recently emerged as a powerful experimental model for fundamental cardiac research. By retaining the structure and function of the native myocardium while maintaining the simplicity of cell culture models, heart slices can be easily employed in electrophysiological, pharmacological, biochemical, and structural investigations. One single heart yields many slices (>20 slices for rodents, >100 slices for porcine or human hearts), however due to the low throughput of most assays and rapid slice degeneration within 24 h of preparation, many slices remain unused and are discarded at the end of the preparation day. Here we present a novel method to extend viability and functionality of living heart slices, enabling their use in experiments over several consecutive days following preparation. By combining hypothermic conditions with inhibition of myosin II ATPase using 2,3-butanedione monoxime (BDM), slices prepared from the left ventricle of porcine hearts remain viable and exhibit preserved contractile function and morphology for up to 6 days. Electrophysiological function was also confirmed over the 6 days by extracellular field potentials recordings. This simple method not only maximizes the use of slices prepared from one single heart, thus reducing the number of animals required, but also increases data reproducibility by allowing multiple electrophysiological, pharmacological, biochemical, and structural studies to be performed from the same heart.

Three decades of collaboration through the Pediatric Heart Transplant Society Registry: A journey through registry data with a highlight on children with single ventricle anatomy.

The Pediatric Heart Transplant Society (PHTS) Registry was founded 30 years ago as a collaborative effort among like-minded providers of this novel life-saving technique for children with end-stage heart failure. In the intervening decades, the data from the Registry have provided invaluable knowledge to the field of pediatric heart transplantation. This report of the PHTS Registry provides a comprehensive look at the data, highlighting both the longevity of the registry and one unique aspect of the PHTS registry, allowing for exploration into children with single ventricle anatomy. The PHTS database was queried from January 1, 1993 to December 31, 2019 to include pediatric (age < 18 years) patients listed for HT. For our analysis, we primarily analyzed patients by era. The early era was defined as children listed for HT from January 1, 1993 to December 31, 2004; middle era January 1, 2005 to December 31, 2009; and recent era January 1, 2010 to December 31, 2019. Outcomes after listing and transplant, including mortality and morbidities, are presented as unadjusted for risk, but compared across eras. Since 1993, 11 995 children were listed for heart transplant and entered into the PHTS Registry with 9755 listed during the study period. The majority of listings occurred within the most recent era. Waitlist survival improved over the decades as did posttransplant survival. Other notable changes over time include fewer patients experiencing allograft rejection or infection after transplant. Waitlist and posttransplant survival have changed dramatically in patients with single ventricle physiology and significantly differ by stage of single ventricle palliation. Key points from this PHTS Registry summary and focus on patients with single ventricle congenital heart disease in particular, include the changing landscape of candidates and recipients awaiting heart transplant. There is clear improvement in waitlist and transplant outcomes for children with both cardiomyopathy and congenital heart disease alike.

Hereditary haemorrhagic telangiectasia and SMAD4 mutation in a patient with complex single ventricle heart disease.

We report a case of hypoplastic left heart syndrome and with subsequent aortopathy and then found to have hereditary haemorrhagic telangiectasia/juvenile polyposis syndrome due to a germline SMAD4 pathologic variant. The patient's staged palliation was complicated by the development of neoaortic aneurysms, arteriovenous malformations, and gastrointestinal bleeding thought to be secondary to Fontan circulation, but workup revealed a SMAD4 variant consistent with hereditary haemorrhagic telangiectasia/juvenile polyposis syndrome. This case underscores the importance of genetic modifiers in CHD, especially those with Fontan physiology.

Does the induction immunotherapy (basiliximab) influence the early acute cellular rejection index after orthotopic heart transplantation?- Preliminary assessment report

The study aimed to determine the influence of induction therapy on the acute cellular rejection (ACR) index in adult heart transplant recipients during the one-year observation. The study population consisted of 256 consecutive adult patients (pts), aged 51.5 (±11.9) years, 199 (77%) men treated with orthotopic heart transplantation (OHT) in the period between 2015 and 2020 in a single high-volume heart transplant center. The endomyocardial biopsies (EMBs) were performed according to the protocol consisting of 7 protocolary EMBs for up to 3 months and 10 EMBs for up to one year after OHT. The rejection index (ACRI) was calculated as the number of scheduled EMBs with the ACR ≥ 2 divided by the total number of protocolary EMBs.The study population was divided into two groups according to the application of basiliximab. The total number of pts. who received basiliximab was 10 (3.9%). The main indications for the usage of the induction therapy were heart retransplantation, mechanical circulatory support (MCS), severe renal insufficiency (eGFR <30 mL/min/1.73 m2), and a panel of reactive antibody (PRA) > 10%. In the group with induction, the mean age was 49 (±14) years; 3 (30%) patients had the MCS prior to OHT, and 3 (30%) patients had heart retransplantation. Four (40%) patients had diabetes mellitus, and 4 (40%) patients had severe renal insufficiency. As maintenance therapy during the observation period, tacrolimus was given to 10 (100%) patients, everolimus to 2 (20%) patients, and MPA to 9 (90%) patients.In the group with no induction, the mean age was 51.8 (±12) years, MCS was used in 56 (23%) patients, 2 (0.8%) patients were retransplanted; 10 (4%) patients had eGFR <30 mL/min/1.73 m2 and 58 (24%) patients had diabetes. Tacrolimus was administered to 243 (99%) patients, cyclosporine to 3 (1%), everolimus to 40 (16%), and mycophenolate to 245 (99.6%) heart recipients.The median one-year ACRI was 0.0, IQR:0.0–0.08 in the group with induction vs. 0.077, IQR: 0.0–0.154 with no induction; p = 0.11. ACRI up to three months was significantly higher in the entire cohort in comparison to up to one year (P < 0.01).The multivariate analysis showed that only everolimus implementation and younger age at the time of transplant influenced patients' mortality rate (P < 0.01).Significant graft rejections (≥ 2R ISHLT) are most common in the first three months after OHT. Patients who are initially at high risk of significant cellular rejection may benefit from induction therapy.

TFAM Modulates Cardiomyocytes Pyroptosis Induced by Ionizing Radiation through mtDNA/TLR9/NF-kB Pathway

Mitochondrial transcription factor A (TFAM) is a pivotal factor for regulating mitochondrial DNA (mtDNA) replication, transcription and biogenesis. Previous studies have reported that cytosolic mtDNA stress can lead to cardiomyocytes pyroptosis, which is characterized by inflammasome formation. In this study, we attempted to investigate the mechanism of TFAM regulate cardiomyocytes pyroptosis induced by ionizing radiation. The peripheral blood serum of patients with esophageal cancer before and after definitive chemoradiotherapy was collected for Luminex multiplex cytokine assays. C57BL/6 mice were irradiated with the whole heart using small animal radiation research platform (SARRP) to construct a radiation-induced myocardial damage (RIMD) mouse model, and the ventricular function was evaluated using 9.4T Bruker magnetic resonance (MR) scanner. The function changes of cardiomyocytes exposed to radiation were observed in vitro and in vivo after knocking out GSDMD. Furthermore, the changes of mitochondrial function, the levels of cytosolic mtDNA, and the protein levels of NF-kB and pyroptosis pathway in irradiated cardiomyocytes were analyzed by knockdown and overexpression of TFAM in vitro and in vivo. By multifactor cytokine assays we found that pyroptosis related IL-1β and IL-18 were significantly increased in patients with high mean heart dose (MHD) after radiotherapy, while those with low MHD were not significantly increased after radiotherapy. Next, we successfully constructed the RIMD mouse model using a single heart irradiation of 20 Gy. We found that the gene expression of pyroptosis pathway was significantly up-regulated after cardiac irradiation by myocardial tissue transcriptomic sequencing. Compared with wild-type (WT) mice, cardiac systolic function of Gsdmd-/- mice was significantly improved at 1, 2, 6, 12, and 24 weeks after heart irradiation. In vitro, we also demonstrated increased viability of irradiated cardiomyocytes by knocking out GSDMD. In vitro and in vivo experiments confirmed the expression of TFAM decreased after radiation. By overexpression of TFAM, we found that irradiated cardiomyocytes showed improved mitochondrial function, decreased release of mtDNA into cytoplasm through mitochondrial permeability transition pores (mPTPs), decreased binding of cytosolic mtDNA to TLR9, and decreased expression of NF-kB and pyroptosis pathway proteins. Dual luciferase gene reporter assays and Chromatin immunoprecipitation (CHIP) assay confirmed that p65 could bind the NLRP3 promoter region. In addition, we found that ventricular function deteriorated and improved in mice with knockdown and overexpression of TFAM through adeno-associated virus serotype 9 (AAV9), respectively. Our study indicated that TFAM regulate irradiated cardiomyocytes pyroptosis through mtDNA/TLR9/NF-kB pathway. We provide a novel mechanism of RIMD, revealing an underappreciated intervention target for RIMD.

Circulating biomarkers of extracellular matrix dysregulation are associated with adverse post-stage 2 outcomes in infants with single ventricle heart disease

Children with single ventricle heart disease (SVHD) experience morbidity due to inadequate pulmonary blood flow. Using proteomic screening, our group previously identified members of the matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinase (TIMP), and fibroblast growth factor (FGF) families as potentially dysregulated in SVHD. No prior study has taken a targeted approach to mapping circulating levels of these protein families or their relationship to pulmonary vascular outcomes in SVHD. We performed a prospective cohort study of 70 SVHD infants pre-Stage 2 palliation and 24 healthy controls. We report targeted serum quantification of 39 proteins in the MMP, TIMP, and FGF families using the SomaScan platform. Clinical variables were extracted from the medical record. Twenty of 39 tested proteins (7/14 MMPs, 2/4 TIMPs, and 11/21 FGFs) differed between cases and controls. On single variable testing, 6 proteins and no clinical covariates were associated with both post-Stage 2 hypoxemia and length of stay. Multiple-protein modeling identified increased circulating MMP 7 and MMP 17, and decreased circulating MMP 8 and FGFR2 as most associated with post-Stage 2 hypoxemia; increased MMP 7 and TIMP 4 and decreased circulating MMP 1 and MMP 8 were most associated with post-operation length of stay. The MMP, TIMP, and FGF families are altered in SVHD. Pre-Stage 2 imbalance of extracellular matrix (ECM) proteins—increased MMP 7 and decreased MMP 8—was associated with multiple adverse post-operation outcomes. Maintenance of the ECM may be an important pathophysiologic driver of Stage 2 readiness in SVHD.

Genetic and clinical variables act synergistically to impact neurodevelopmental outcomes in children with single ventricle heart disease

BackgroundRecent large-scale sequencing efforts have shed light on the genetic contribution to the etiology of congenital heart defects (CHD); however, the relative impact of genetics on clinical outcomes remains less understood. Outcomes analyses using genetics are complicated by the intrinsic severity of the CHD lesion and interactions with conditionally dependent clinical variables.MethodsBayesian Networks were applied to describe the intertwined relationships between clinical variables, demography, and genetics in a cohort of children with single ventricle CHD.ResultsAs isolated variables, a damaging genetic variant in a gene related to abnormal heart morphology and prolonged ventilator support following stage I palliative surgery increase the probability of having a low Mental Developmental Index (MDI) score at 14 months of age by 1.9- and 5.8-fold, respectively. However, in combination, these variables act synergistically to further increase the probability of a low MDI score by 10-fold. The absence of a damaging variant in a known syndromic CHD gene and a shorter post-operative ventilator support increase the probability of a normal MDI score 1.7- and 2.4-fold, respectively, but in combination increase the probability of a good outcome by 59-fold.ConclusionsOur analyses suggest a modest genetic contribution to neurodevelopmental outcomes as isolated variables, similar to known clinical predictors. By contrast, genetic, demographic, and clinical variables interact synergistically to markedly impact clinical outcomes. These findings underscore the importance of capturing and quantifying the impact of damaging genomic variants in the context of multiple, conditionally dependent variables, such as pre- and post-operative factors, and demography.

Applying the Hybrid Concept as a Bridge to Transplantation in Infants Without Hypoplastic Left Heart Syndrome

Therapies to support small infants in decompensated heart failure that are failing medical management are limited. We have used the hybrid approach, classically reserved for high-risk infants with single ventricle physiology, in patients with biventricular physiology with left ventricular failure. This approach secures systemic circulation, relieves left atrial hypertension, protects the pulmonary vasculature, and allows the right ventricle to support cardiac output. This approach can be used as a bridge to transplantation in select individuals. Infants without single ventricle congenital heart disease who were treated with the hybrid approach between 2008 and 2021 were included in analysis. Eight patients were identified. At the time of hybrid procedure, the median weight was 3.2 kg (range 2.4–3.6 kg) and the median age was 18 days (range 1–153 days). Seventy five percent were mechanically ventilated and 88% were on inotropic support. The median duration from hybrid procedure to transplant was 63 days (range 4–116 days). All patients experienced a good outcome (delisted for improvement or transplanted). The hybrid procedure is an appropriate therapeutic bridge to transplantation in a carefully selected subset of critically ill infants without single ventricle congenital heart disease in whom alternate therapies may confer increased risk for morbidity and mortality.

Human Milk Feeding and Direct Breastfeeding Improve Outcomes for Infants With Single Ventricle Congenital Heart Disease: Propensity Score-Matched Analysis of the NPC-QIC Registry.

Background Infants with single ventricle congenital heart disease undergo 3 staged surgeries/interventions, with risk for morbidity and mortality. We estimated the effect of human milk (HM) and direct breastfeeding on outcomes including necrotizing enterocolitis, infection-related complications, length of stay, and mortality. Methods and Results We analyzed the National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC) registry (2016-2021), examining HM/breastfeeding groups during stage 1 and stage 2 palliations. We calculated propensity scores for feeding exposures, then fitted Poisson and logistic regression models to compare outcomes between propensity-matched cohorts. Participants included 2491 infants (68 sites). Estimates for all outcomes were better in HM/breastfeeding groups. Infants fed exclusive HM before stage 1 palliation (S1P)had lower odds of preoperative necrotizing enterocolitis (odds ratio [OR], 0.37 [95% CI, 0.17-0.84]; P=0.017) and shorter S1P length of stay (rate ratio [RR], 0.87 [95% CI, 0.78-0.98]; P=0.027). During the S1P hospitalization, infants with high HM had lower odds of postoperative necrotizing enterocolitis (OR, 0.28 [95% CI, 0.15-0.50]; P<0.001) and sepsis (OR, 0.29 [95% CI, 0.13-0.65]; P=0.003), and shorter S1P length of stay (RR, 0.75 [95% CI, 0.66-0.86]; P<0.001). At stage 2 palliation, infants with any HM (RR, 0.82 [95% CI, 0.69-0.97]; P=0.018) and any breastfeeding (RR, 0.71 [95% CI, 0.57-0.89]; P=0.003) experienced shorter length of stay. Conclusions Infants with single ventricle congenital heart disease in high-HM and breastfeeding groups experienced multiple significantly better outcomes. Given our findings of improved health, strategies to increase the rates of HM/breastfeeding in these patients should be implemented. Future research should replicate these findings with granular feeding data and in broader congenital heart disease populations, and should examine mechanisms (eg, HM components, microbiome) by which HM/breastfeeding benefits these infants.

Parental perceptions of the effect of the COVID-19 pandemic on outpatient services for patients with single ventricle congenital heart disease

BackgroundPatients with congenital heart disease (CHD), particularly single ventricle CHD, may experience neurodevelopmental delays. The COVID-19 pandemic created numerous challenges surrounding access to care. This study evaluates the effect of the pandemic on delivery of outpatient therapies to this high-risk group and satisfaction with services. ObjectivesTo determine the effect of the pandemic on the delivery of outpatient therapies to patients with SV-CHD at our center, as well as parental satisfaction, at various time points. MethodsA survey was administered to parents of patients with single ventricle CHD regarding services at various stages of the pandemic. Patients were eligible if they had a bidirectional Glenn operation between 1/1/2010–3/1/2020. The survey assessed the services received and parental satisfaction pre-pandemic, mid-pandemic, and at the time of survey administration (7/2022–2/2023). ResultsOf 228 eligible patients, 133 were contacted, and 36 (27 %) completed the survey. Nineteen (52.8 %) had a child with developmental delay. During the pandemic, 84 % (n = 16/19) of patients who qualified for services were receiving them. Services were largely virtual or hybrid (n = 12/16, 75 %), compared to 100 % in-person pre-pandemic and at the time of survey completion. Satisfaction with services during the pandemic was low, with 12.5 % (n = 2/16) stating they were “extremely satisfied,” compared with 93.3 % (n = 14/15) pre-pandemic and 46.7 % (n = 7/15) at the time of survey completion. ConclusionIn our study, patients with single ventricle CHD continued to receive outpatient services during the pandemic; however, these services were largely virtual, and satisfaction was low. By the time of survey completion, services had returned in person with improvement in satisfaction. More studies are needed to elucidate if changes in the delivery of services during the pandemic may have affected neurodevelopmental status in this high-risk group.

The Effects of Cardiac Implantable Electronic Device Personal Protective Equipment Use in Patients with Pediatric and Adult Congenital Heart Disease.

Pediatric and adult congenital heart disease (ACHD) patients encounter physical and emotional barriers. Cardiac implantable electronic devices (CIEDs), including pacemakers and implantable cardiac defibrillators (ICD) often compound these issues. Patient fear associated with damaging the CIED system can lead to avoidance of physical activity and reduced quality of life (QOL). CIED personal protective equipment (PPE) is a potential treatment for decreasing this fear. We sought to determine the effects of CIED PPE use in the pediatric and ACHD population. Patients 5 years or older with a CIED at a single pediatric and ACHD heart rhythm center received a CIED protector and customized athletic shirt. QOL was assessed using the PedsQL TM 4.0 SF15 prior to and after 6-12months. Of the 77 patients enrolled, 26 completed repeat assessment. The mean age at enrollment was 15.6years (range 5-36) with a mean device age of 2.2years (< 1-10years). Pacemakers were present in 77% and 23% had ICDs. The PPE was used in 92% with no PPE malfunction. Fear associated with physical activity was reduced, z = -4, p < 0.001, with a large effect size (r = 0.55). There was a trend toward increased physical activity. Total QOL scores improved, z = -2.771, P < 0.05, with a medium effect size (r = 0.4). This first study of CIED PPE in children shows that providing CIED PPE to pediatric and ACHD patients may decrease their fear of damaging their device system, increasing physical activity levels, and improving quality of life.

Atrial Arrhythmias in Adults with Fontan Palliation.

Single ventricle physiology is a rare form of congenital heart disease and was, historically, a uniformly lethal condition. However, the atriopulmonary Fontan operation, and its successive iterations, the lateral tunnel and extracardiac conduit Fontan, became the fundamental approach to treating single ventricle heart disease. Over time, dysrhythmias are some of the most common complications with Fontan physiology, compounding morbidity and mortality. Atrial arrhythmias are prevalent in the Fontan population and occur in about 15-60% of patients with Fontan palliation, increasingly with age. Diagnosing atrial arrhythmias in patients with Fontan palliation may be challenging because of low voltage amplitudes arising from myopathic atrial tissue making it difficult to clearly assess atrial depolarization on surface electrocardiograms (ECG), vague symptoms not suggestive of tachyarrhythmia, or atrial arrhythmia with ventricular rates below 100beats per minute. Intra-atrial reentrant tachycardia (IART) is the most common type of supraventricular tachycardia in adults with Fontan palliation. Acute management of atrial arrhythmias in patients with Fontan palliation involves prompt assessment of a patient's hemodynamic stability, anticoagulation and thrombosis risk, systemic ventricular function, and risk of sedation or anesthesia if needed. Long-term management of atrial arrhythmias is often multifactorial and may include long-term anti-arrhythmic therapy, permanent pacing, and ablation. The best approach for the management of atrial arrhythmias in adults with Fontan palliation is patient-specific and involves collaboration between congenital electrophysiologists, adult congenital cardiologists, and the patient.

A Wireless Wearable Patch for Remote Monitoring of Respiratory and Cardiac Rhythm in Children.

Remote patient monitoring (RPM) is an innovative strategy to promote health and improve patient management and care. Recent advances in healthcare technologies have seen the emergence of wearable sensors allowing longitudinal physiological measurements in any environment. This paper introduces a wireless wearable patch 'Leo' for continuous remote monitoring of physiological data at home and healthcare settings. This includes single lead ECG, chest impedance, heart rate (HR), respiration rate (RR) and body posture. To test Leo's ability to capture longitudinal physiological data at home, 15 children experiencing acute severe asthma exacerbations were recruited during their emergency department (ED) visits. Participants wore the Leo device for 7 (+/-2) days post-hospital discharge. Nocturnal RR and HR and variability were higher during the first half of the night on Day1 compared to Day7 (p<0.005). Participants also completed a usability questionnaire and reported the patch wear to be comfortable (average score of 3.3 out of 5) and easy to wear during the night (average score of 3.5 out of 5) with 5/15 (33%) reported very slight barely perceptible skin irritation/redness and 2 (13%) reported well defined skin irritation and redness.Clinical Relevance- These results highlight the potential use of the Leo device in clinical practice for continuous un-obstructive monitoring of diseased populations, such as asthma.