Single Heart Research Articles

Contemporary Outcomes of Tracheostomy in Patients With Single Ventricle Heart Lesions.

Approximately 0.2% to 2.7% of children with congenital heart disease require a tracheostomy after cardiac surgery with the majority having single ventricle (SV) type heart lesions. Tracheostomy in SV patients is reported to be associated with high mortality. We hypothesized that short- and long-term survival of patients with SV heart disease would vary according to tracheostomy indication. This is a single center, 20-year, retrospective review of all patients with SV heart disease who underwent tracheostomy. Demographic, cardiac anatomy, surgical, intensive care unit, and hospital course data were collected. The primary outcome was survival following tracheostomy. Secondary outcome was the completion of staged palliation to Fontan. In total, 25 patients with SV heart disease who underwent tracheostomy were included. Indications for tracheostomy included one or more of the following: tracheobronchomalacia (n = 8), vocal cord paralysis (n = 7), tracheal/subglottic stenosis (n = 6), primary respiratory insufficiency (n = 4), diaphragm paralysis (n = 3), suboptimal hemodynamics (n = 2), and other upper airway issues (n = 1). Survival at six months, one year, five years, and ten years was 76%, 68%, 63%, and 49%, respectively. Most patients completed Fontan palliation (64%). Patients who underwent tracheostomy for suboptimal hemodynamics and/or respiratory insufficiency had a higher mortality risk compared to those with indications of upper airway obstruction or diaphragm paralysis (hazard ratio 4.1, 95% confidence interval 1.2-13.7; P = .02). Mortality risk varies according to tracheostomy indication in patients with SV heart disease. Tracheostomy may allow staged surgical palliation to proceed with acceptable risk if it was indicated for anatomic or functional airway dysfunction.

Phenomenological analysis of simple ion channel block in large populations of uncoupled cardiomyocytes.

Current understanding of arrhythmia mechanisms and design of anti-arrhythmic drug therapies hinges on the assumption that myocytes from the same region of a single heart have similar, if not identical, action potential waveforms and drug responses. On the contrary, recent experiments reveal significant heterogeneity in uncoupled healthy myocytes both from different hearts as well as from identical regions within a single heart. In this work, a methodology is developed for quantifying the individual electrophysiological properties of large numbers of uncoupled cardiomyocytes under ion channel block in terms of the parameters values of a conceptual fast-slow model of electrical excitability. The approach is applied to a population of nearly 500 rabbit ventricular myocytes for which action potential duration (APD) before and after the application of the drug nifedipine was experimentally measured (Lachaud et al., 2022, Cardiovasc. Res.). To this end, drug action is represented by a multiplicative factor to an effective ion conductance, a closed form asymptotic expression for APD is derived and inverted to determine model parameters as functions of APD and $\varDelta $APD (drug-induced change in APD) for each myocyte. Two free protocol-related quantities are calibrated to experiment using an adaptive-domain procedure based on an original assumption of optimal excitability. The explicit APD expression and the resulting set of model parameter values allow (a) direct evaluation of conditions necessary to maintain fixed APD or $\varDelta $APD, (b) predictions of the proportion of cells remaining excitable after drug application, (c) predictions of stimulus period dependency and (d) predictions of dose-response curves, the latter being in agreement with additional experimental data.

Morbidity and mortality following heart failure rehabilitation: The effect of programme completion and 6-min walk test distance

Objective To compare real-world data from a single centre heart failure rehabilitation programme, evaluating the effect of programme completion and improved functional capacity on morbidity and mortality in patients with heart failure. Design A retrospective longitudinal analysis of service outcomes. Setting A single-centre London based NHS trust. Participants Patients attending heart failure rehabilitation between 2016 and 2020. Intervention Patients participated in a 12-week heart failure rehabilitation programme with those completing ≥6 rehabilitation sessions classified as ‘completers’. Main Measures Pre and post 6-min walk tests measured improvement in physical ability, depicted by a meaningful increase in distance (≥30 m). Kaplan–Meier survival analysis was used to predict risk of event (myocardial infarction, cerebrovascular accident, heart failure readmission and death) between ‘completers’ and ‘non-completers’. Kaplan–Meier Log rank was employed for ‘completers’, examining time to event between ‘improvers’ (6-min walk test ≥30 m) and ‘non-improvers’ (6-min walk test <30 m). Results 137 patients (male 61%) attended heart failure rehabilitation over the 4-year period. 86% (n = 117) of patients completed the programme. During the follow-up period, there were 25 events, including three deaths. There was no statistically significant difference in time to event between completers and non-completers, (P = 0.563). Improvement in 6-min walk test results demonstrate some short-term benefit, however no long-term benefits in morbidity and mortality were seen (P = 0.888). Conclusions Completion of heart failure rehabilitation is not associated with a lower risk of combined event in this study. Improved 6-min walk test appears to be associated with short-term advantage in event-free survival time.

Long term survival of antenatally diagnosed functionally single ventricle congenital heart disease

Abstract Funding Acknowledgements Type of funding sources: None. Background Antenatal diagnosis of single ventricle congenital heart disease (CHD) allows prenatal counselling, better parental preparation and support as well as improved perinatal management. Expectant parents frequently ask about likely outcomes and expected longer term survival. Our aim is to review the survival of antenatally diagnosed single ventricle CHD presenting at our institutions between January 2000 and July 2022. Methods Retrospective data was collected from the fetal cardiac and paediatric cardiology databases. Maternal data, fetal cardiac diagnosis, postnatal cardiac diagnosis and management were collected for each patient. The outcomes were separated into 2 groups – Cohort 1 (CO1) [2000 to 2007] and Cohort 2 (CO2) [2008 to 2022]. Results A total of 495 fetuses were diagnosed with single ventricle CHD in the 21 years and 7 months period, with outcomes illustrated in Table 1. For the small LV group with intention to treat at birth, there was 46% survival at over 10 years for the CO1 group and 69% survival at over 10 years for CO2 group. There was however no significant difference in the survival between the CO1 and CO2 groups (log rank test p=0.12). For the small RV group with intention to treat at birth, there was 71% survival at over 10 years for the CO1 group and 91% survival at over 10 years for CO2 group. There was significant difference in the survival between the CO1 and CO2 groups (log rank test p=0.03). No analysis was made for the unspecified hypoplasia as the numbers were too small. Conclusions For both the antenatal small LV and small RV groups, the termination rate and compassionate care option remained unchanged between both cohorts. Overall, there has been improvement in the survival for the antenatal small LV and RV groups with intention to treat. This is likely due to improved perinatal management with detailed management plan and designated delivery at tertiary neonatal hospital close to the cardiac surgical centre, improved surgical expertise and experience, improved cardiac intensive care management as well as availability of ECMO for the sicker patients. In the antenatal small LV groups, although there has been improvement in survival, this is not yet statistically significant due to more complex patients with more co-morbidity being accepted for surgery. Whereas for the antenatal small RV groups, we see statistically significant improvement with survival reaching 90% at 10 years, due to increased use of non-surgical intervention like ductal stenting over conventional BT shunts which carry higher morbidity and mortality risk. Our survival outcomes are comparable with other published data across the world.

Ultra-high pressure balloon angioplasty for pulmonary artery stenosis in children with congenital heart defects: Short- to mid-term follow-up results from a retrospective cohort in a single tertiary center.

Balloon angioplasty (BA) has been the treatment of choice for pulmonary artery stenosis (PAS) in children. There remains, however, a significant proportion of resistant lesions. The ultra-high pressure (UHP) balloons might be effective in a subset of these lesions. In this study, we analyzed the safety and efficacy with short- to mid-term follow-up results of UHP BA for PAS in children with congenital heart defects (CHD) in our center. This is a retrospective cohort study in a single tertiary heart center. Children diagnosed with PAS associated with CHD were referred for UHP BA. All data with these children were collected for analysis with updated follow-up. A total of 37 UHP BAs were performed consecutively in 28 children. The success rate was 78.4%. A significantly (P = 0.005) larger ratio of the balloon to the minimal luminal diameter at the stenotic waist (balloon/waist ratio) was present in the success group (median 3.00, 1.64-8.33) compared to that in the failure group (median 1.94, 1.41 ± 4.00). Stepwise logistic regression analysis further identified that the balloon/waist ratio and the presence of therapeutic tears were two independent predictors of procedural success. The receiver operating characteristic curve revealed a cut-off value of 2.57 for the balloon/waist ratio to best differentiate success from failure cases. Signs of therapeutic tears were present in eight cases, all of whom were in the success group. Perioperative acute adverse events were recorded in 16 patients, including 11 pulmonary artery injuries, three pulmonary hemorrhages, and two pulmonary artery aneurysms. During a median follow-up period of 10.4 (0.1-21.0) months, nine cases experienced restenosis at a median time of 40 (4-325) days after angioplasty. The UHP BA is safe and effective for the primary treatment of PAS in infants and children with CHD. The success rate is high with a low incidence of severe complications. The predictors of success are a larger balloon/waist ratio and the presence of therapeutic tears. The occurrence of restenosis during follow-up, however, remains a problem. A larger number of cases and longer periods of follow-up are needed for further study.

Use of Rivaroxaban in Children with Congenital Heart Disease: A Single-Center Case Series.

Rivaroxaban is a direct oral anticoagulant approved for therapeutic and prophylactic anticoagulation in both adults and children. Studies on rivaroxaban use in pediatric patients with congenital heart disease (CHD) are limited. Currently, warfarin (oral) and enoxaparin (injection) are the primary options for pediatric outpatient anticoagulation. Rivaroxaban may be a less burdensome alternative, but its use has not been well described in the pediatric CHD population. We describe our single-center experience. From May 2020-July 2022, we identified all pediatric CHD patients started on rivaroxaban. Dosing was based on recommendations reported in the EINSTEIN-Jr (Male et al. in Lancet Haematol 7:e18-e27, 2020) and UNIVERSE study (McCrindle et al. in J Am Heart Assoc 10:e021765, 2021) protocols. Qualitative outcomes on safety and efficacy are reported. There were 27 patients studied with an age range of 4months-15years at time of medication initiation. Single ventricle heart disease was present in 70% (19/27) of patients. Of the 27 patients initiated on rivaroxaban, 15 (56%) were started for VTE prophylaxis and 12 (44%) were started for VTE treatment. No patients started on rivaroxaban for prophylaxis developed a VTE. There was resolution or lack of propagation in 10 of the 12 patients started for treatment. There were two clinically relevant bleeding episodes. Our single-center case series describes the experience with rivaroxaban for VTE prophylaxis and treatment in pediatric congenital heart disease. Larger studies are required to further investigate safety, efficacy, and use indications.

A New Approach to Detecting Atrial Fibrillation Using Count Statistics of Relative Changes between Consecutive RR Intervals.

The ratio of the difference between neighboring RR intervals to the length of the preceding RR interval (x%) represents the relative change in the duration between two cardiac cycles. We investigated the diagnostic properties of the percentage of relative RR interval differences equal to or greater than x% (pRRx%) with x% in a range between 0.25% and 25% for the distinction of atrial fibrillation (AF) from sinus rhythm (SR). We used 1-min ECG segments with RR intervals with either AF (32,141 segments) or SR (32,769 segments) from the publicly available Physionet Long-Term Atrial Fibrillation Database (LTAFDB). The properties of pRRx% for different x% were analyzed using the statistical procedures and metrics commonly used to characterize diagnostic methods. The distributions of pRRx% for AF and SR differ significantly over the whole studied range of x% from 0.25% to 25%, with particularly outstanding diagnostic properties for the x% range of 1.5% to 6%. However, pRR3.25% outperformed other pRRx%. Firstly, it had one of the highest and closest to perfect areas under the curve (0.971). For pRR3.25%, the optimal threshold for distinction AF from SR was set at 75.32%. Then, the accuracy was 95.44%, sensitivity was 97.16%, specificity was 93.76%, the positive predictive value was 93.85%, the negative predictive value was 97.11%, and the diagnostic odds ratio was 514. The excellent diagnostic properties of pRR3.25% were confirmed in the publicly available MIT-BIH Atrial Fibrillation Database. In a direct comparison, pRR3.25% outperformed the diagnostic properties of pRR31 (the percentage of successive RR intervals differing by at least 31 ms), i.e., so far, the best single parameter differentiating AF from SR. A family of pRRx% parameters has excellent diagnostic properties for AF detection in a range of x% between 1.5% and 6%. However, pRR3.25% outperforms other pRRx% parameters and pRR31 (until now, probably the most robust single heart rate variability parameter for AF diagnosis). The exquisite pRRx% diagnostic properties for AF and its simple computation make it well-suited for AF detection in modern ECG technologies (mobile/wearable devices, biopatches) in long-term monitoring. The diagnostic properties of pRRx% deserve further exploration in other databases with AF.

Prevalence and associated factors of post-traumatic stress disorder in parents whose infants have single ventricle heart disease.

Post-traumatic stress disorder occurs in parents of infants with CHD, contributing to psychological distress with detrimental effects on family functioning and well-being. We sought to determine the prevalence and factors associated with post-traumatic stress disorder symptoms in parents whose infants underwent staged palliation for single ventricle heart disease. A large longitudinal multi-centre cohort study evaluated 215 mothers and fathers for symptoms of post-traumatic stress disorder at three timepoints, including post-Norwood, post-Stage II, and a final study timepoint when the child reached approximately 16 months of age, using the self-report questionnaire Impact of Event Scale - Revised. The prevalence of probable post-traumatic stress disorder post-Norwood surgery was 50% of mothers and 39% of fathers, decreasing to 27% of mothers and 24% of fathers by final follow-up. Intrusive symptoms such as flashbacks and nightmares and hyperarousal symptoms such as poor concentration, irritability, and sudden physical symptoms of racing heart and difficulty breathing were particularly elevated in parents. Higher levels of anxiety, reduced coping, and decreased satisfaction with parenting were significantly associated with symptoms of post-traumatic stress disorder in parents. Demographic and clinical variables such as parent education, pre-natal diagnosis, medical complications, and length of hospital stay(s) were not significantly associated with symptoms of post-traumatic stress disorder. Parents whose infants underwent staged palliation for single ventricle heart disease often reported symptoms of post-traumatic stress disorder. Symptoms persisted over time and routine screening might help identify parents at-risk and prompt referral to appropriate supports.

Interstage Single Ventricle Heart Disease Infants Show Dysregulation in Multiple Metabolic Pathways: Targeted Metabolomics Analysis

BackgroundInfants with SVHD experience morbidity related to pulmonary vascular inadequacy. Metabolomic analysis involves a systems biology approach to identifying novel biomarkers and pathways in complex diseases. The metabolome of infants with SVHD is not well understood and no prior study has evaluated the relationship between serum metabolite patterns and pulmonary vascular readiness for staged SVHD palliation. ObjectivesThe purpose of this study was to evaluate the circulating metabolome of interstage infants with single ventricle heart disease (SVHD) and determine whether metabolite levels were associated with pulmonary vascular inadequacy. MethodsThis was a prospective cohort study of 52 infants with SVHD undergoing Stage 2 palliation and 48 healthy infants. Targeted metabolomic phenotyping (175 metabolites) was performed by tandem mass spectrometry on SVHD pre-Stage 2, post-Stage 2, and control serum samples. Clinical variables were extracted from the medical record. ResultsRandom forest analysis readily distinguished between cases and controls and preoperative and postoperative samples. Seventy-four of 175 metabolites differed between SVHD and controls. Twenty-seven of 39 metabolic pathways were altered including pentose phosphate and arginine metabolism. Seventy-one metabolites differed in SVHD patients between timepoints. Thirty-three of 39 pathways were altered postoperatively including arginine and tryptophan metabolism. We found trends toward increased preoperative methionine metabolites in patients with higher pulmonary vascular resistance and higher postoperative tryptophan metabolites in patients with greater postoperative hypoxemia. ConclusionsThe circulating metabolome of interstage SVHD infants differs significantly from controls and is further disrupted after Stage 2. Several metabolites showed trends toward association with adverse outcomes. Metabolic dysregulation may be an important factor in early SVHD pathobiology.

ЭМПАГЛИФЛОЗИН В ЛЕЧЕНИИ ПАЦИЕНТОВ С ХРОНИЧЕСКОЙ СЕРДЕЧНОЙ НЕДОСТАТОЧНОСТЬЮ, ЕГО ВЛИЯНИЕ НА ЖЕЛУДОЧКОВЫЕ НАРУШЕНИЯ РИТМА

The study aims to assess empagliflozin affecting ventricular dysrhythmia and late potential of ventricles in patients with chronic heart failure with low etiology ejection fraction. The study included 35 male patients (61.7 ± 11.2 years old) who received standard therapy, followed by 10 mg empagliflozin in 6 months. The examination included echocardioscopy, 12-leads electrocardiography, signal-averaged electrocardiography, and daily electrocardiography monitoring. 10 mg empagliflozin added to the standard therapy provided for a statistically significant decrease in the number of single premature heart beats by 67.7 % (p = 0.001), in the episodes of unstable ventricular tachycardia by 74.5 % (p = 0.001), in the frequency of late ventricular potential by 31 % (Chisquare = 5.51; р = 0.019), and for a statistically insignificant trend to ejection fraction increase (p &gt; 0.05).

Abortion restriction impact on burden of neonatal single ventricle congenital heart disease: a decision-analytic model

Abortion restriction impact on burden of neonatal single ventricle congenital heart disease: a decision-analytic model

Effectiveness of Simulation- Versus Didactic Video-Based Learning to Teach Advanced Lung Isolation Techniques

Mastery of lung isolation is crucial for optimal cardiothoracic anesthesia education. The authors tested the hypothesis that simulation- is more effective than didactic video-based learning (cognitive, affective, and psychomotor) to teach anesthesiology fellows advanced lung isolation techniques. A prospective randomized study. At a single academic heart center, simulation laboratory. Thirty anesthesiology fellows with equivalent prior experience in basic lung isolation techniques. Randomized participants received 1 of 2 structured educational interventions of equivalent duration designed to teach advanced lung isolation skills, a simulation workshop, or a video-based didactic session. To assess Bloom's taxonomy domains, performance measurements included pre- and postintervention cognitive tests and affective surveys and a postintervention psychomotor task (time to complete lung isolation). Changes in test and survey scores and time to completion were compared using the Mann-Whitney U test; p values < 0.05 were considered significant. Improvements in lung isolation learning assessments were greater in the simulation group, but significant differences only existed in the affective domain. Specifically, affective survey score increases were greater in the simulation group (simulation- versus video-based didactic: +19.0 v +4.0; p ≤ 0.001), whereas there was no significant difference in cognitive pre- to posttest scores (simulation- versus video-based: +28.6 v +19.1, p=0.23), and time to achieve lung isolation (simulation- versus video-based: 32 v 36 seconds, p=0.46). Although greater affective learning of advanced lung isolation skills occurred with simulation-based compared to didactic video-based education, the authors found no differences between the teaching approaches in cognitive and psychomotor learning among anesthesiology fellows.

Abstract 12509: Characterization and Risk Factors for Death or Transplant After Stage Ii/glenn Palliation in Infants With Single Ventricle Heart Disease

Background: Infants with single ventricle heart disease have a 20% mortality rate during the first year of life with most deaths occurring prior to Stage II/Glenn. Although the time after the Stage II procedure is believed to be a lower risk period, significant morbidity and mortality may occur during this time. Methods: Retrospective cohort analysis of infants enrolled in the National Pediatric Cardiology Improvement Collaborative who underwent staged single ventricle palliation from 2016-2021 and survived to Stage II operation. Multivariable logistic regression and classification and regression tree analysis were performed to identify risk factors for the composite of mortality or transplantation between Stage II surgery and the first birthday. Candidate variables (n=75) included sociodemographic, prenatal, birth, anatomic, stage I intra- and post-operative, interstage course, and Stage II operative characteristics. Results: Of the 1455 patients in the cohort who survived to Stage II, the overall event rate was 7% (76 (5%) died and 34 (2%) were referred for transplant). Overall event rates at 30 and 100 days after Stage 2 were 2% and 5%, respectively ( Figure 1A ). Independent risk factors for mortality and transplantation included shunt type and AV valve repair at Stage I, ECMO and reintubation after Stage I, pre-operative weight and ≥ moderate AV valve regurgitation prior to Stage II, Stage II cross-clamp time, and comprehensive Stage II surgery ( Figure 1B). Patient race/ethnicity and socioeconomic status were not associated with worse outcome. Conclusions: Mortality rates after Stage II surgery to 1 year of age remain high ~5%. Some of the risk factors identified have been shown to also predict interstage mortality, whereas others (reintubation, pre-operative weight, and Stage II characteristics) may be unique to the period after Stage II. Further research is needed to understand whether risk factor modification results in improved transplant-free survival.

Abstract 11038: Clinical Characteristics and Outcomes of High-Cost Pediatric Heart Transplant Hospitalizations in the United States

Introduction: Pediatric heart transplantation (HT) is resource-intensive, with the HT hospitalization being a major driver of costs. We sought to determine the characteristics and outcomes of patients whose HT hospital admissions incur high costs. Methods: The Pediatric Health Information System database was queried for pediatric (&lt;18 y) hospital admissions between 1/1/2008 and 12/31/2021 in which HT was performed. High-cost HT admission was defined as ≥95 th percentile of cost for all HT admissions during the study period. Costs were standardized across centers using a cost-to-charge ratio; all cost values (in US dollars) were indexed to the 2020 US Consumer Price Index. The primary outcome was mortality during the index HT admission. Clinical characteristics and outcomes were compared between high-cost HT admissions and lower-cost HT admissions (&lt;95 th cost percentile) using logistic regression. Results: A total of 4352 pediatric HTs were identified; for the entire cohort, median HT admission cost was $501,535 (IQR $270,291 - $902,302). Within the high-cost group (N = 217), HT admission costs ranged from $1,971,069 - $44,500,000; the majority (N = 195) had costs between $2 million and $5 million. High-cost admissions accounted for 23% of costs within the entire cohort. Median length of stay in the high-cost group was 247d (IQR 160d-342d) and 59d (IQR 24d-115d) in the lower-cost group (P&lt;0.001). High-cost HT admissions increased over time (2.9% of admissions in 2008; 5.5% in 2021, P&lt;0.001). Patients with high-cost HT admissions were younger (1y vs 6y, P&lt;0.001), more likely to have single ventricle congenital heart disease (42.4% vs 28.9%, P&lt;0.001), undergo ECMO (55.3% vs 19.3%) and/or VAD (37.3% vs 16.2%, P&lt;0.001 for both), and receive dialysis (13.8% vs 3.6%, P&lt;0.001). Hospital mortality was higher in high-cost HT patients (22.6% vs 4.2%, P&lt;0.001); this relationship persisted after adjusting for clinical and center characteristics (OR 7.2, 95% CI 4.97 - 10.57, P&lt;0.001). Conclusions: High-cost admissions for pediatric HT contribute disproportionately to overall hospital mortality and cost after HT, and are associated with high resource utilization. These findings highlight opportunities to improve outcomes in this growing and high-risk population.

Abstract 15324: The Fontan Circulation Shows Decreased Cell Survival and Oxidative Damage

Introduction: Single ventricle congenital heart disease such as hypoplastic left heart syndrome (HLHS) with a Fontan circulation accounts for the largest group of children hospitalized with circulation failure, with an in-hospital mortality of 20-50%. We sought to (i) evaluate the mechanisms underlying circulation failure and (ii) identify novel therapeutic targets. Methods: Blood was collected from patients with HLHS s/p Fontan and from controls with normal cardiac anatomy and function (N=5/group). Plasma microvesicles (MV) were isolated and proteomics assessed using data independent acquisition mass spectroscopy. Dysregulated proteins with a fold change &gt;1.5 or &lt; -1.5, p&lt;0.05 were evaluated using Ingenuity pathway analysis. Results: Age of Fontan patients vs. controls was 17.04±2 vs. 15.7±2.5, p=0.4; 20% were male in both groups. 60% of Fontan patients were in NYHA class II/III, 40% in NYHA class IV; 80% had Fontan-associated liver disease. Circulating MVs were released from cardiomyocytes, endothelial cells, and hepatocytes based on cell surface markers. Upregulated proteins (N=27) implicated cell death pathways (Solute carrier family 2, Angiotensinogen, CD14); while downregulated proteins (N=88) implicated impaired cell survival (tyrosine-protein kinase Yes, endothelial growth factors). MVs contained mitochondria and endoplasmic reticulum proteins implicating upregulation in reactive oxygen species signaling (catalase A, S100A8) and downregulation in antioxidant enzymes (GPX1, PRDX 5). Conclusion: Circulating MVs from patients with HLHS s/p Fontan are released from the heart, blood vessels, and liver providing a noninvasive signature of organ remodeling. The MV protein cargo implicates heightened cell death, oxidative damage and impaired cell survival, thereby providing insight into the mechanisms of Fontan associated circulation failure. Figure: Decreased Cell Survival and Oxidative Damage in the Fontan Circulation

Abstract 12182: Cardiac Transcriptome Remodeling and Impaired Bioenergetics in Single Ventricle Congenital Heart Disease

Introduction: Single Ventricle congenital heart disease (SV) encompasses a group of cardiac abnormalities where improper development of the heart results in only one functional pumping chamber. From a molecular standpoint, how the myocardium adapts to the chronic altered hemodynamic conditions of SV physiology, and the mechanisms implicated in the transition to heart failure (HF) which is common in the SV population, are poorly understood. Here, we test the hypothesis that metabolic remodeling represents a pathophysiologic mechanism of heart failure progression in SV. Methods: We performed comprehensive multi-omics analysis (transcriptomics, metabolomics, and lipidomics) of the SV myocardium from both failing (SVHF, N=15) and non-failing (SVNF, N=9) SV subjects, compared with biventricular non-failing controls (BVNF, N=4). Furthermore, we assessed functional components of mitochondrial bioenergetics in each of these populations. Results: Integrated multi-omics analysis demonstrated dysregulation of multiple metabolic pathways in the failing SV heart (A). Functional cardiac bioenergetics analysis revealed decreased mitochondrial carnitine palmitoyl transferase activity (B) and mitochondrial dysfunction (C), with corresponding decreases in tricarboxylic acid cycle metabolites, high energy phosphates, and lipid intermediates in the failing SV heart. Moreover, some of these bioenergetic perturbations precede the onset of overt failure, and are seen in the non-failing SV heart (B-C). Conclusions: Our findings indicate that SV physiology induces myocardial metabolic alterations that limit mitochondrial fatty acid β-oxidation and decrease cardiac energy generation. Together, these data suggest SV patients may be uniquely vulnerable to changes in energetic demand and may benefit from therapeutic strategies aimed at preserving cardiac bioenergetics and preventing cardiometabolic remodeling for the treatment or prevention of HF.

Abstract 10776: A Supervised Classification Model Detects Fontan Patients Based on Clinical Notes With Higher Accuracy Than ICD Codes

Introduction: The Fontan operation palliates single ventricle heart defects. As native anatomy varies, Fontan cases cannot always be identified by ICD9 or 10CM codes. Hypothesis: We sought to train and evaluate a supervised machine learning (ML) system to identify Fontan cases based on unstructured clinical notes in a large database. Methods: 160 adult Fontan patients from validated clinical data at a single tertiary referral center with available text notes were studied. The imbalanced data set had more non-Fontan cases than Fontan patients; thus we created multiple datasets with different positive : negative case ratios ranging from 1:2 to 1:10. We used stratified 80-20 training-testing splits of data. Vectorized representations of text notes were used as features. We trained a Support Vector Machine (SVM) model, mostly used for text classification, to identify Fontan cases from notes. For each dataset, we performed random 80-20 data splitting 10 times and reported average F 1 score (harmonic mean of recall/sensitivity &amp; precision/positive predictive value) over the positive class. Results: The model achieved a mean F 1 score of 0.95 for the positive class on the data split with 1:2 positive-negative ratio. Increasing data imbalance from 1:2 to 1:10 did not substantially impact performance. The mean F 1 score over all data splits was 0.94, and SD 0.01. We also computed precision, recall, and F 1 score of ICD codes to identify Fontan patients. Performance comparisons between ICD codes only and Natural Language Processing (NLP)/ML are in Table 1. Conclusions: A supervised classification model more effectively detects Fontan patients based on clinical notes with higher accuracy than ICD codes. The model is robust and insensitive to data imbalance. Findings suggest our model may work effectively in real-world data. Since the sensitivity of ICD codes is high but PPV is low, it may be beneficial to apply ICD codes as a filter prior to applying NLP/ML to improve performance.

Abstract 13196: Inter-Stage Infants With Single Ventricle Heart Disease Show Prominent Dysregulation in Multiple Metabolic Pathways: A Targeted Metabolomics Analysis

Objectives: To evaluate the circulating metabolome of interstage infants with single ventricle heart disease (SVHD) and determine whether metabolite levels were associated with pulmonary vascular inadequacy. Background: Infants with SVHD experience morbidity related to pulmonary vascular inadequacy. Metabolomic analysis involves a systems biology approach to identifying novel biomarkers and pathways in complex diseases. The metabolome of infants with SVHD is not well understood and no prior study has evaluated the relationship between metabolite levels and pulmonary vascular readiness for staged SVHD palliation. Methods: Prospective cohort study of 52 infants with SVHD undergoing Stage 2 palliation and 48 healthy infants. Targeted metabolomic phenotyping (n=175 metabolites) performed by tandem mass spectrometry on SVHD pre-Stage 2, post-Stage 2, and control serum samples. Clinical variables were extracted from the medical record. Results: Random Forest analysis readily distinguished between cases and controls (Figure), and pre-op and post-op samples. Seventy-four of 175 metabolites differed between SVHD and controls. Twenty-seven of 39 metabolic pathways were altered including pentose phosphate and arginine metabolism. Seventy-one metabolites differed in SVHD patients between timepoints. Thirty-three of 39 pathways were altered post-operatively including arginine and tryptophan metabolism. We found trends towards increased pre-operative methionine metabolites in patients with higher pulmonary vascular resistance and higher post-operative tryptophan metabolites in patients with greater post-operative hypoxemia. Conclusions: The circulating metabolome of interstage SVHD infants differs significantly from controls and is further disrupted after Stage 2. Several metabolites showed promising trends towards association with adverse outcomes. Metabolic dysregulation may be an important factor in early SVHD pathobiology.

Abstract 13643: Examining the Association Between Social Determinants of Health and Health-Related Quality of Life Among Children With Cardiac Conditions

Introduction: Patient-reported outcomes like health-related quality of life (HRQOL) measure the health and well-being of patients, providing insights not communicated by traditional outcomes. The degree to which social determinants of health (SDOH) influence HRQOL is under-studied. Methods: A cross-sectional analysis of subjects aged 8-18 years referred for cardiac catheterization from 1/1/18-12/31/21 was performed, evaluating the association between HRQOL (measured through child and caregiver-proxy reports of cardiac-specific HRQOL (Pediatric Cardiac Quality of Life Inventory (PCQLI)) and general HRQOL (Pediatric Quality of Life Inventory (PedsQL))) and a panel of potential SDOH. Potential SDOH measures were calculated at subject’s neighborhood level by linking their addresses to block group/census tract data. SDOH measures included Childhood Opportunity Index, which measures neighborhood resources supporting child development, and Social Deprivation Index, which measures neighborhoods’ levels of disadvantage. Linear regression was used to evaluate the association between SDOH and HRQOL (PCQLI and PedsQL total scores), adjusting for presence of cardiac symptoms (New York Heart Association Class). Results: In total, 111 subjects (age 12.8±2.9 years, of which 89% identified as White, 5% Black, and 8% Hispanic, and 27% Medicaid-insured) were studied. Primary cardiac diagnoses included single ventricle heart disease (19%), complex biventricular repairs (20%), and orthotopic heart transplantation (12%). The majority (69%) denied having symptoms. Out of a potential 100, subject-reported scores were 67±18 on the PCQLI and 74±19 on the PedsQL. Caregiver-proxy reported scores were 70±17 on the PCQLI and 71±19 on the PedsQL. Worse SDOH was consistently associated with lower HRQOL adjusted for presence of symptoms (Table 1). Conclusions: Worse SDOH was associated with worse HRQOL in pediatric cardiac patients independent of symptoms severity

Abstract 14039: The Cardioprotective and Anti-Inflammatory Effect of Inhaled Nitric Oxide During Fontan Surgery: A Prospective Randomized Study

Introduction: Open heart surgery that requires cardiopulmonary by-pass (CPB) evokes tremendous stress and inflammatory responses, affecting postoperative organ function, morbidity, and mortality. Although part of this reaction triggers protective and anti-inflammatory phenomena, it is harmful, particularly in patients with single ventricle congenital heart defects during Fontan surgery. Unfortunately, there is no perfect anti-inflammatory and stress defence strategy despite decades of research. Hypothesis: This study aimed to investigate the influence of nitric oxide (NO) inhaled directly into the oxygenator during CPB on a proteome profile of inflammatory cytokines, metabolic response markers, heart and lung protection indicators, and the early clinical outcomes. Methods: The study involved 115 patients randomized to the Fontan-NO group, receiving NO inhalation (n=48) and the Fontan group, not receiving NO (n=49). Eighteen patients were excluded from the study. The clinical data were prospectively analyzed. Proteome profiler essays were used for repeated measurements of investigated analytes. Results: Fontan-NO patients had significantly lower levels of lactate (p=0.04) and glucose (p=0.02), lower pulmonary artery pressure (p=0.03) and catecholamine index (p=0.042), shorter ventilatory support time (p=0.03) and ICU stay (p=0.04). Plasma factors analysis has shown a significantly higher concentration of interleukin-10, tissue inhibitor of metalloproteinase, prolactin, and angiopoietin and a lower concentration of interleukin-6, interleukin-8, interleukin-1β, granulocyte-macrophage colony-stimulating factor, pentraxin, matrix metalloproteinase-8, troponin-I, CK-MB, and insulin in Fontan-NO group. Multiple regression analysis revealed the influence of Il-6 and Il-8 on respiratory support time and ICU stay and the relationship between catecholamine index, duration of effusions, and indicators of myocardial damage. Conclusions: NO inhaled into the oxygenator during CPB can alleviate the inflammatory response, improve myocardial and lung protection, and reduce metabolic stress in patients with a single ventricle undergoing Fontan surgery. The observed effects can influence short-term clinical outcomes.