Comparative outcomes of cardioplegic arrest versus beating heart in pediatric undergoing extracardiac total cavopulmonary connection.

BACKGROUND: Total cavopulmonary connection (TCPC) is a definitive palliative procedure for functionally univentricular congenital heart disease. The study aims to compare the impact of on-pump cardioplegic arrest and on-pump beating heart cardiopulmonary bypass (CPB) on the prognosis of pediatric patients undergoing extracardiac TCPC. METHODS: The medical data of patients (< 18 years) who underwent extracardiac TCPC with CPB between January 2008 and December 2020 in the cardiac surgery center were retrospectively analyzed. Depending on CPB strategies, the patients were assigned to the beating-heart (BH) and cardioplegic arrest (CA) groups. Data including baseline characteristics, intra/postoperative variables, and clinical outcomes were collected for analysis with 1:1 propensity score matching and multivariable stepwise logistic regressions. RESULTS: Fifty-seven matched patient pairs were obtained. No significant difference existed between the two groups in the in-hospital mortality (3.5% vs. 1.8%, P = 1) and one-year survival rate (100% vs. 96.4%, P = 0.484). The BH group had significantly less intraoperative platelet transfusion (10 mL vs. 150 mL, P = 0.019) and blood loss (100 mL vs. 150 mL, P = 0.033) than the CA group. The CA group had significantly higher vasoactive-inotropic scores (P < 0.05) and longer postoperative ICU stays (2.0 d vs. 3.7 d, P = 0.017). No significant difference existed between the two groups in the incidence of postoperative adverse events. CONCLUSION: Although both CPB strategies are safe and feasible for extracardiac TCPC, the BH technique would cause less intraoperative platelet transfusion and blood loss, and achieve faster early-term postoperative recovery.

Predictors of spontaneous pregnancy loss in single ventricle physiology.

BACKGROUND: Pregnant patients with single ventricle (SV) physiology carry a high risk of spontaneous pregnancy loss (SPL), yet the clinical factors contributing to this risk are not well defined. METHODS: Single-centre retrospective study of pregnant patients with SV physiology seen in cardio-obstetrics clinic over the past 20 years with chart review of their obstetric history. Patients without a known pregnancy outcome were excluded. Univariable Bayesian panel-data random effects logit was used to model the risk of SPL. RESULTS: The study included 20 patients with 44 pregnancies, 20 live births, 21 SPL and 3 elective abortions. All had Fontan palliation except for two with Waterston and Glenn shunts. 10 (50%) had a single right ventricle (RV). 14 (70%) had moderate or severe atrioventricular valve regurgitation (AVVR). Atrial arrhythmias were present in 16 (80%), Fontan-associated liver disease (FALD) in 15 (75%) and FALD stage 4 in 9 (45%). 12 (60%) were on anticoagulation. Average first-trimester oxygen saturation was 93.8% for live births and 90.8% for SPL. The following factors were associated with higher odds of SPL: RV morphology (OR 1.72 (95% credible interval (CrI) 1.0008-2.70)), moderate or severe AVVR (OR 1.64 (95% CrI 1.003-2.71)) and reduced first-trimester oxygen saturation (OR 1.83 (95% CrI 1.03-2.71) for each per cent decrease in O2 saturation. CONCLUSION: Pregnant patients with SV physiology, particularly those with RV morphology, moderate or severe AVVR, and lower first-trimester oxygen saturations, have a higher risk of SPL. Identifying these clinical risk factors can guide preconception counselling by the cardio-obstetrics team.

Diastolic dysfunction: assessment and implications on the single ventricle circulation.

PURPOSE OF REVIEW: Patients with a functionally single ventricle (SV) are palliated with a series of procedures leading to a Fontan circulation. Over the life span, a substantial proportion of SV patients develop heart failure that can arise from circulatory or ventricular failure. Diastolic dysfunction (DD) is an important determinant of adverse outcomes in SV patients. However, assessment and categorization of DD in the SV remains elusive. We review recent literature and developments in assessment of DD in the SV and its relation to clinical outcomes. RECENT FINDINGS: DD is prevalent in the SV and associated with worse outcomes. Occult DD can be exposed with provocative testing by exercise or preload challenge during catheterization. Likewise, sensitivity to detect DD may be increased via assessment of atrial function and strain imaging. Recent studies revisiting previous concepts such as incoordinate diastolic wall motion show that these are associated with SV end-diastolic pressures and post-Fontan recovery, yielding accessible DD assessment. Emerging technologies such as ultrafast ultrasound (UFUS) can provide noninvasive assessment of myocardial stiffness, inefficient diastolic flow patterns and intraventricular pressure gradients, thereby yielding new tools and insights into diastolic myocardial and hemodynamic properties. SUMMARY: Characterizing DD in the SV continues to have substantial limitations, necessitating synthesis of multiple parameters into an overall assessment, accounting for their change over time, and in the context of the patient's clinical status. New and emerging techniques may help advance DD assessment and the ability to track response to treatment of new targets.

Low Ventricular Stiffness Is Associated With Suboptimal Outcomes in Patients With a Single Right Ventricle After the Fontan Operation: A Novel Phenotype.

BACKGROUND: Despite a rigorous screening process, including cardiac catheterization, a subset of patients with a single right ventricle (SRV) demonstrates suboptimal short-term outcomes after the Fontan operation. The goal of this study was to perform a comprehensive assessment of diastolic function in pre-Fontan patients with an SRV using invasive reference-standard measures and determine their associations with post-Fontan outcomes. METHODS AND RESULTS: Children aged 2 to 6 years with SRV physiology undergoing pre-Fontan heart catheterization were recruited prospectively. Patients were divided into those who had an optimal or suboptimal outcome. A suboptimal outcome was defined as length of stay ≥14 days or heart transplant/cardiac death in first year after Fontan. Patients underwent pressure-volume loop analysis using reference-standard methods. The measure of ventricular stiffness, ß, was obtained via preload reduction. Cardiac magnetic resonance imaging for extracellular volume and serum draws for matrix metalloproteinase activity were performed. Of 19 patients with an SRV, 9 (47%) had a suboptimal outcome. Mean age was 4.2±0.7 years. Patients with suboptimal outcomes had lower ventricular stiffness (0.021 [0.009-0.049] versus 0.090 [0.031-0.118] mL-1; P=0.02), lower extracellular volume (25% [28%-32%] versus 31% [28%-33%]; P=0.02), and lower matrix metalloproteinase-2 (90 [79-104] versus 108 [79-128] ng/mL; P=0.01) compared with patients with optimal outcomes. The only invasive measure that had an association with suboptimal outcome was ß (P=0.038). CONCLUSIONS: Patients with an SRV with suboptimal outcome after the Fontan operation had lower ventricular stiffness and evidence of maladaptive extracellular matrix metabolism compared with patients with optimal outcome. This appears to be a novel phenotype that may have important clinical implications and requires further study.

Retrospective Cohort Study of Additional Procedures and Transplant-Free Survival for Patients With Functionally Single Ventricle Disease Undergoing Staged Palliation in England and Wales.

BACKGROUND: Reinterventions may influence the outcomes of children with functionally single-ventricle (f-SV) congenital heart disease. METHODS AND RESULTS: We undertook a retrospective cohort study of children starting treatment for f-SV between 2000 and 2018 in England, using the national procedure registry. Patients were categorized based on whether they survived free of transplant beyond 1 year of age. Among patients who had transplant-free survival beyond 1 year of age, we explored the relationship between reinterventions in infancy and the outcomes of survival and Fontan completion, adjusting for complexity. Of 3307 patients with f-SV, 909 (27.5%), had no follow-up beyond 1 year of age, among whom 323 (35.3%) had ≥1 reinterventions in infancy. A total of 2398 (72.5%) patients with f-SV had transplant-free survival beyond 1 year of age, among whom 756 (31.5%) had ≥1 reinterventions in infancy. The 5-year transplant-free survival and cumulative incidence of Fontan, among those who survived infancy, were 93.4% (95% CI, 92.4%-94.4%) and 79.3% (95% CI, 77.4%-81.2%), respectively. Both survival and Fontan completion were similar for those with a single reintervention and those who had no reinterventions. Patients who had >1 additional surgery (adjusted hazard ratio, 3.93 [95% CI, 1.87-8.27] P<0.001) had higher adjusted risk of mortality. Patients who had >1 additional interventional catheter (adjusted subdistribution hazard ratio, 0.71 [95% CI, 0.52-0.96] P=0.03) had a lower likelihood of achieving Fontan. CONCLUSIONS: Among children with f-SV, the occurrence of >1 reintervention in the first year of life, especially surgical reinterventions, was associated with poorer prognosis later in childhood.

Transcatheter Fontan completion: Creation of an extracardiac Fontan.

Patients with functionally univentricular hearts are usually palliated surgically. There have been several reports of successful attempts to complete the Fontan procedure without surgery. The pathways created at the time of the preconditioning were largely reminiscent of the lateral tunnel Fontan. However, this approach is still confidentially limited to a small number of centers. In 2013, we designed a circuit that mimics the actual surgical technique of extracardiac total cavopulmonary connection to allow for transcatheter completion in an animal study. A polytetrafluoroethylene conduit was connected between the pulmonary artery and the inferior vena cava (IVC). The superior anastomosis was occluded to avoid flow between IVC and superior vena cava (SVC). The conduit was connected to the right atrium (RA) and a large fenestration was created to allow free flow from the IVC to the RA. Extrapolating our approach, a center reported the successful transcatheter completion of an extracardiac Fontan in a 6-year-old child. However, this technique is not directly transposable to our population of patients who require preconditioning in infancy. We report here an innovative extension of this technique that may allow preparing patients in infancy, ideally at the time of the Glenn in the future, to receive an extracardiac Fontan at 2 years/11 kg without additional surgery.

Clinical Presentation and Therapy of Tricuspid Atresia and Univentricular Heart.

Although the terms "single ventricle" and "univentricular heart" are frequently used to describe a variety of complex congenital heart defects, in fact, nearly all hearts have two ventricles, although one of the two may be too small to be functional. A better term for these hearts would therefore be "functional single ventricle."

Human Genetics of Tricuspid Atresia and Univentricular Heart.

Tricuspid atresia (TA) is a rare congenital heart condition that presents with a complete absence of the right atrioventricular valve. Because of the rarity of familial and/or isolated cases of TA, little is known about the potential genetic abnormalities contributing to this condition. Potential responsible chromosomal abnormalities were identified in exploratory studies and include deletions in 22q11, 4q31, 8p23, and 3p as well as trisomies 13 and 18. In parallel, potential culprit genes include the ZFPM2, HEY2, NFATC1, NKX2-5, MYH6, and KLF13 genes. The aim of this chapter is to expose the genetic components that are potentially involved in the pathogenesis of TA in humans. The large variability in phenotypes and genotypes among cases of TA suggests a genetic network that involves many components yet to be unraveled.

The utility of novel STE parameters in echocardiographic assessment of single ventricle after Fontan palliation.

Background and aims of the study A functionally single ventricle (FSV) refers to a group of congenital heart defects that are not amenable for biventricular correction. The Fontan operation is utilized as surgical treatment for most of FSV patients. The evaluation of FSV function is extremely difficult due to its unique pathophysiology. This study aimed to explore the efficacy of speckle tracking echocardiography (STE) parameters measured at rest and during exercise for comprehensive assessment of univentricular heart. METHODS: We enrolled 37 patients with a functionally single ventricle after the Fontan operation, hospitalized in the Department of Congenital Heart Defects between years 2019 and 2021.The echocardiographic stress tests were performed in the Echocardiography Laboratory of the Congenital Heart Defects Department. The study was conducted on a bicycle ergometer in a semi-recumbent position. The parameters obtained by speckle tracking echocardiography (STE): the longitudinal strain of the FSV free wall (Ɛ) and the longitudinal strain of myocardial layers: subendocardial, medial and subepicardial were analyzed. A transmural longitudinal strain gradient (TG) was calculated as the difference between longitudinal deformation of the subendocardial and subepicardial layers. Current results of cardiac magnetic resonance imaging (CMR) and cardio-pulmonary test (CPET) were also incorporated. Demographic data, past interventions, pharmacological treatment and comorbidities were extracted from medical records. RESULTS: Ɛ at rest and during exercise were not related to the parameters of physical capacity obtained on CPET nor to the CMR results. The transmural strain gradient was dependent on physical performance parameter- peak oxygen uptake- and related to the FSV ejection fraction calculated by magnetic resonance imaging. CONCLUSIONS: The transmural strain gradient and FSV free wall strain are readily measurable and suitable for evaluating single ventricle function. The TG is positively correlated with peak oxygen uptake during the cardiopulmonary test and with the ejection fraction derived from cardiac magnetic resonance imaging. The applicability of these findings in patients undergoing the Fontan procedure warrants further exploration.

Atrial septal interventions during and after hybrid stage I palliation of hypoplastic left heart syndrome.

BACKGROUND: Hybrid stage I palliation (HS1P) is an alternative approach for initial palliation in hypoplastic left heart syndrome (HLHS) patients. Unlike surgical stage I palliation where atrial septectomy is routinely performed, atrial septal intervention (ASI) during HS1P is variable. In this study, we described our experience with ASI in single ventricle (SV) patients who underwent HS1P and identified factors associated with need for ASI after HS1P. METHODS: Data were retrospectively collected for all HLHS patients who underwent HS1P at our center over the past 12 years. We evaluated ASIs performed during the HS1P (intra-HS1P ASI) and ASIs performed during the period from HS1P to the subsequent surgical stage, either interval Norwood stage I or comprehensive stage II (post-HS1P ASI). Patient factors and procedural data were compared to identify factors associated with undergoing post-HS1P ASI and the impact of ASI on patient outcomes was evaluated. RESULTS: Of 50 SV patients included, 23 (46%) underwent intra-HS1P ASI and 26 (52%) underwent post-HS1P ASI. Need for post-HS1P ASI was lower among patients who had an intra-HS1P ASI as compared to those who did not (30% vs. 70%; p = 0.005). There were no significant differences in short or Midterm outcomes between patients who underwent intra-HS1P ASI or post-HS1P ASI and their counterparts. CONCLUSIONS: ASI is common both during and after HS1P but is generally well tolerated and type of ASI does not significantly impact overall patient outcomes. Our findings suggest that the current approach of individualizing management of ASI in the HS1P population is effective and safe.

Heart Transplantation after Univentricular Palliation: Improved Outcomes and Increased Complexity.

AIM: Heart transplantation (HT) in patients with failing univentricular circulation is often challenging. This is compounded by the ever-increasing number of patients with prior Norwood-type reconstruction of the aorta, large aortic root, and often dense adhesions from multiple prior operations. We aimed to elucidate differences in outcomes of HT in patients with prior univentricular palliations, with and without prior Norwood-type aortic arch reconstruction (ArchRec). METHODS: All patients who underwent HT for failed univentricular palliation during the 1990-2022 period were included in the study. RESULTS: Of 45 patients, 18 had undergone ArchRec. Hospital mortality improved in the recent era (17.4% before 2006 vs 0% after 2006; p=0.11), despite a higher proportion of patients with ArchRec (17.4% before 2006 vs 60.8% after 2006, p=0.002). Patients with ArchRec had a higher number of prior cardiac surgeries (4.1±1.5 vs 3.2±1.3, p=0.04), longer cardiopulmonary bypass time (320±23 vs 242±21 min, p=0.02), more concomitant arch reconstruction (33.3% vs 0%, p=0.02), greater need for post-HT extracorporeal membrane oxygenation (33.3% vs 3.7%; p=0.01) and longer hospital stay (37.1±30.5 days vs 23.6±11.8 days, p=0.04). Freedom from death or retransplantation for all patients was 91%, 73%, 67%, and 53% at 1, 5, 10, and 15-years, respectively. Prior ArchRec, Fontan procedure, and earlier eras were not risk factors for death. CONCLUSIONS: The outcomes of HT after univentricular palliation have improved in recent times and low operative mortality can be achieved. Despite increased complexity, good similar outcomes can be achieved in patients with and without prior arch reconstruction regardless of the palliation stage.

Molecular Pathways and Animal Models of Tricuspid Atresia and Univentricular Heart.

The process of valve formation is a complex process that involves intricate interplay between various pathways at precise times. Although we have not completely elucidated the molecular pathways that lead to normal valve formation, we have identified a few major players in this process. We are now able to implicate TGF-ß, BMP, and NOTCH as suspects in tricuspid atresia (TA), as well as their downstream targets: NKX2-5, TBX5, NFATC1, GATA4, and SOX9. We know that the TGF-ß and the BMP pathways converge on the SMAD4 molecule, and we believe that this molecule plays a very important role to tie both pathways to TA. Similarly, we look at the NOTCH pathway and identify the HEY2 as a potential link between this pathway and TA. Another transcription factor that has been implicated in TA is NFATC1. While several mouse models exist that include part of the TA abnormality as their phenotype, no true mouse model can be said to represent TA. Bridging this gap will surely shed light on this complex molecular pathway and allow for better understanding of the disease process.

Bilateral pulmonary artery banding facilitates the systemic ventricular outflow tract growth for biventricular and univentricular repair candidates of complex arch anomaly.

Various surgical approaches address complex heart disease with arch anomalies. Bilateral pulmonary artery banding (bPAB) is a strategy for critically ill patients with complex arch anomalies. Some reports argued the potential effect of bPAB on the growth of the left ventricular outflow tract (LVOT) during inter-stage after bPAB. This study aimed to analyze the LVOT growth for biventricular repair candidates with arch anomaly and systemic ventricular outflow tract (SVOT) for univentricular repair candidates with arch anomaly. This retrospective study analyzed 17 patients undergoing initial bPAB followed by arch repair. The Z-scores of LVOT and SVOT were compared between pre-bPAB and pre-arch repair. Patient characteristics, transthoracic echocardiogram data, and PAB circumferences were reviewed. The diameter of the minimum LVOT for biventricular repair (BVR) candidates, the pulmonary valve (neo-aortic valve, neo-AoV) and the pulmonary trunk (the neo-ascending aorta, neo-AAo) for univentricular repair (UVR) candidates, and the degree of aortic or neo-aortic insufficiency in each candidate was statistically analyzed. 17 patients were divided into the UVR candidates (group U) with 9 patients and the BVR candidates (group B) with 8 patients. In group B, the median value of the Z-score of the minimum LVOT increased from -3.2 (range: - 4.1 ~ - 1.0) at pre-PAB to -2.8 (range: - 3.6 ~ - 0.3) at pre-arch repair with a significant difference (p = 0.012). In group U, the median value of the Z-score of the neo-AoV increased from 0.5 (range: - 1.0 ~ 1.7) at pre-bPAB to 1.2 (range: 0.2 ~ 1.9) at pre-arch repair with a significant difference (p < 0.01). The median value of the Z-score of the neo-AAo was also increased from 3.1 (range: 1.5 ~ 4.6) to 4.3 (range: 3.1 ~ 5.9) with a significant difference (p = 0.028). The growth of the LVOT for BVR candidates and SVOT for UVR candidates during the inter-stage between bPAB and arch repair was observed. These results suggest the potential advantage of bPAB in surgical strategies. Further research is needed to validate these findings and refine surgical approaches.

Maternal-fetal comorbidities and obstetrical outcomes of fetal single ventricle cardiac defects: 10 years' experience with a multidisciplinary management protocol at a single center.

OBJECTIVES: To describe and compare maternal and fetal comorbidities and obstetrical outcomes in pregnancies with hypoplastic left and right heart (HLHS and HRH) single ventricle cardiac defects (SVCD) from a single center under a multidisciplinary protocol. METHOD: A single center retrospective review of fetal SVCD from 2013 to 2022. Maternal-fetal comorbidities, delivery, and postnatal outcomes were compared between HLHS and HRH using descriptive statistics and univariate and multivariate analyses. RESULTS: Of 181 SVCD pregnancies (131 HLHS; 50 HRH), 9% underwent termination, 4% elected comfort care, 5 died in utero and 147/152 liveborns survived to the first cardiac intervention. Cesarean delivery occurred in 57 cases (37%), planned in 36 and unplanned in 21. Comorbidities, which did not differ between HLHS and HRH, included fetal growth restriction (FGR, 17%), prematurity (14%), maternal hypertension (9%), maternal obesity (50%), fetal extracardiac anomalies and chromosome anomalies (12%, 13%). In multivariate analysis, only earlier gestational age at delivery and oligohydramnios predicted decreased odds of survival at one year. CONCLUSION: Maternal-fetal comorbidities are common in both HLHS and HRH. Earlier gestational age at delivery and oligohydramnios predict lower postnatal survival. FGR, even with severe early onset, did not significantly impact short- or long-term neonatal survival in single ventricle conditions.

Managing Bilateral Discontinuous Pulmonary Arteries of Ductal Origin in Single-Ventricle Anatomy.

BACKGROUND: We describe outcomes and management strategies for single-ventricle and bilaterally discontinuous pulmonary arteries (PAs) originating from bilateral ductus arteriosus. METHODS: We reviewed 22 patients with aforementioned anatomy and PA centralization from 1995 to 2023, excluding those with biventricular repair. RESULTS: Median age at centralization was 9 days (minimum-maximum, 0 days-2 years). Centralization was performed with systemic-to-pulmonary shunt (n =20 [91%]; 2 after bilateral ductal stents) or bidirectional cavopulmonary connection (n = 2 [9%]) using pericardial roll (n = 14 [64%]), patch-augmented direct anastomosis (n = 7 [32%]), and interposition graft (n = 1 [5%]) techniques. Concurrent total anomalous pulmonary venous connection (TAPVC, n = 11 [50%]) was associated with significantly inferior survival (P = .01). Five patients (23%) died at a median of 59 days (minimum-maximum, 6-257 days) after centralization, all with noncardiac TAPVC. At the latest follow-up for 17 survivors (median, 13.5 years; minimum-maximum, 0.5-25.1 years after centralization), 12 completed Fontan, 4 completed second-stage palliation, and 1 received a transplant before second-stage palliation. PA reintervention was required in 14 patients (64%), including 3 with reoperations independent of staged palliation. Echocardiography from baseline to before the second stage demonstrated branch PA growth with significantly increased diameters (left, P = .0006; right, P = .0002); z-scores significantly increased for right (P = .004) but not left (P = .11). CONCLUSIONS: Successful single-ventricle palliation is possible, although high risk, for patients with bilateral discontinuous ductal PAs. Early postcentralization mortality remains substantial, particularly with associated noncardiac TAPVC. Many require reintervention to maintain PA growth, typically concurrently with staged palliation.

Safety and feasibility pilot study of continuous low-dose maternal supplemental oxygen in fetal single ventricle heart disease.

OBJECTIVE: Fetuses with single ventricle physiology (SVP) exhibit reductions in fetal cerebral oxygenation, with associated delays in fetal brain growth and neurodevelopmental outcomes. Maternal supplemental oxygen (MSO) has been proposed to improve fetal brain growth, but current evidence on dosing, candidacy and outcomes is limited. In this pilot study, we evaluated the safety and feasibility of continuous low-dose MSO in the setting of SVP. METHODS: This single-center, open-label, pilot phase-1 safety and feasibility clinical trial included 25 pregnant individuals with a diagnosis of fetal SVP. Participants self-administered continuous MSO using medical-grade oxygen concentrators for up to 24 h per day from the second half of gestation until delivery. The primary aim was the evaluation of the safety profile and feasibility of MSO. A secondary preliminary analysis was performed to assess the impact of MSO on the fetal circulation using echocardiography and late-gestation cardiovascular magnetic resonance imaging. Early outcomes were assessed, including perinatal growth and preoperative brain injury, and neurodevelopmental outcomes were assessed at 18 months using the Bayley Scales of Infant and Toddler Development 3rd edition, and compared with those of a contemporary fetal SVP cohort (n = 217) that received the normal standard of care (SOC). RESULTS: Among the 25 participants, the median maternal age at conception was 35 years, and fetal SVP diagnoses included 16 with right ventricle dominant, eight with left ventricle dominant and one with indeterminate ventricular morphology. Participants started the trial at approximately 29 + 2 weeks' gestation and self-administered MSO for a median of 16.1 h per day for 63 days, accumulating a median of 1029 h of oxygen intake from enrolment until delivery. The only treatment-associated adverse events were nasal complications that were resolved typically by attaching a humidifier unit to the oxygen concentrator. No premature closure of the ductus arteriosus or unexpected fetal demise was observed. In the secondary analysis, MSO was not associated with any changes in fetal growth, middle cerebral artery pulsatility index, cerebroplacental ratio or head-circumference-to-abdominal-circumference ratio Z-scores over gestation compared with SOC. Although MSO was associated with changes in umbilical artery pulsatility index Z-score over the study period compared with SOC (P = 0.02), this was probably due to initial baseline differences in placental resistance. At late-gestation cardiovascular magnetic resonance imaging, MSO was not associated with an increase in fetal cerebral oxygen delivery. Similarly, no differences were observed in neonatal outcomes, including preoperative brain weight Z-score and brain injury, mortality by 18 months of age and neurodevelopmental outcomes at 18 months of age. CONCLUSIONS: This pilot phase-1 clinical trial indicates that low-dose MSO therapy is safe and well tolerated in pregnancies diagnosed with fetal SVP. However, our protocol was not associated with an increase in fetal cerebral oxygen delivery or improvements in early neurological or neurodevelopmental outcomes. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Arginine-NO metabolites are associated with morbidity in single ventricle infants undergoing stage 2 palliation.

BACKGROUND: Infants with single ventricle heart disease (SVHD) suffer morbidity from insufficient pulmonary blood flow, which may be related to impaired arginine metabolism. No prior study has reported quantitative mapping of arginine metabolites to evaluate the relationship between circulating metabolite levels and outcomes. METHODS: Prospective cohort study of 75 SVHD cases peri-Stage 2 and 50 healthy controls. We targeted pre- and post-op absolute serum quantification of 9 key members of the arginine metabolism pathway by tandem mass spectrometry. Primary outcomes were length of stay (LOS) and post-Stage 2 hypoxemia. RESULTS: Pre-op cases showed alteration in 6 metabolites including decreased arginine and increased asymmetric dimethyl arginine (ADMA) levels compared to controls. Post-op cases demonstrated decreased arginine and citrulline levels persisting through 48 h. Adjusting for clinical variables, lower pre-op and 2 h post-op concentrations of multiple metabolites, including arginine and citrulline, were associated with longer post-op LOS (p < 0.01). Increased ADMA at 24 h was associated with greater post-op hypoxemia burden (p < 0.05). CONCLUSION: Arginine metabolism is impaired in interstage SVHD infants and is further deranged following Stage 2 palliation. Patients with greater metabolite alterations experience greater post-op morbidity. Decreased arginine metabolism may be an important driver of pathology in SVHD. IMPACT: Interstage infants with SVHD have significantly altered arginine-nitric oxide metabolism compared to healthy children with deficiency of multiple pathway intermediates persisting through 48 h post-Stage 2 palliation. After controlling for clinical covariates and classic catheterization-derived predictors of Stage 2 readiness, both lower pre-operation and lower post-operation circulating metabolite levels were associated with longer post-Stage 2 LOS while increased post-Stage 2 ADMA concentration was associated with greater post-op hypoxemia. Arginine metabolism mapping offers potential for development using personalized medicine strategies as a biomarker of Stage 2 readiness and therapeutic target to improve pulmonary vascular health in infants with SVHD.