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BACKGROUND: The process underlying Fontan pathophysiology is multifactorial and may include gut dysbiosis (GD). We investigated the presence of GD and elucidated its correlation with Fontan pathophysiology. METHODS AND RESULTS: Gut microbiomes of 155 consecutive patients with Fontan pathophysiology and 44 healthy individuals were analyzed using 16S rRNA sequencing of bacterial DNA extracted from fecal samples. GD was evaluated on the basis of α and ß diversities of the gut microbiome and was compared with natural log-transformed C-reactive protein, hemodynamics, von Willebrand factor antigen (a bacterial translocation marker), Mac-2 binding protein glycosylation isomer (a liver fibrosis indicator), peak oxygen uptake, and heart failure hospitalization. Patients with Fontan exhibited GD in terms of α and ß diversities as compared with controls (P<0.01). Reduced α diversity was associated with a failed hemodynamic phenotype, hypoxia, high natural log-transformed C-reactive protein levels, and elevated von Willebrand factor antigen and Mac-2 binding protein glycosylation isomer levels (P<0.05-0.01). In addition to elevated von Willebrand factor antigen and hypoxia, decreased α diversity was independently correlated with a high natural log-transformed C-reactive protein level (P<0.05), which was associated with liver imaging abnormalities and a heightened risk of heart failure hospitalization (P<0.01 for both). CONCLUSIONS: Patients with Fontan pathophysiology exhibited GD compared with healthy individuals, and GD was linked to failed hemodynamics and systemic inflammation with a poor prognosis. Therefore, GD may play a pivotal role in a failing Fontan status, including Fontan-associated liver disease, through GD-associated systemic inflammation.

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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.

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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.

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Fontan surgery is vital for infants born with a single-ventricle heart. This intervention establishes a new blood flow circuit bypassing the single ventricle, thereby the separating pulmonary and systemic circulation to preserve single ventricular function. However, it carries risks of hepatic complications, collectively termed Fontan-associated liver disease (FALD), characterized by progressive hepatic congestion and fibrosis potentially leading to an equivalent of cirrhosis. Diagnosis and staging of FALD are complex, requiring multidisciplinary management. In advanced FALD, consideration is given to heart transplantation alone or combined heart-liver transplantation, underscoring the importance of an integrated approach to optimize care for these increasingly more common patients.

La chirurgie de Fontan est vitale pour les nouveau-nés naissant avec un cœur univentriculaire. Cette intervention crée un ­nouveau circuit sanguin palliant l'absence de ventricule sous-pulmonaire en connectant les veines caves directement aux ­artères pulmonaires. Elle permet de séparer les circulations pulmonaire et ­systémique et de préserver la fonction du ventricule unique. Cela expose néanmoins les patients à des complications à moyen et long terme, parmi lesquelles l'atteinte hépatique, nommée ­Fontan-Associated Liver Disease (FALD), se caractérisant par une congestion et une fibrose hépatiques progressives pouvant conduire à l'équivalent d'une cirrhose et à ses complications. Son diagnostic ainsi que l'évaluation de sa sévérité ­impliquent différents éléments biologiques, radiologiques et ­histopathologiques ainsi qu' une expertise multidisciplinaire. Lors de FALD avancée, la transplantation cardiaque seule ou combinée cœur-foie est discutée, au cas par cas.

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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.

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BACKGROUND: Peak oxygen consumption (peak V̇O2$$ \dot{\mathrm{V}}{\mathrm{O}}_2 $$) is routinely measured in people who have congenital heart disease and is reported as a percentage of predicted value, based upon age- and sex-matched normative reference values (NRVs). This study aimed to identify which NRVs are being used, assess whether NRVs are being applied appropriately, and evaluate if recommended NRVs are valid when applied to people with congenital heart disease. METHODS AND RESULTS: A systematic scoping review identified studies that reported peak V̇O2$$ \dot{\mathrm{V}}{\mathrm{O}}_2 $$ percentage of predicted value in people with congenital heart disease. A modified risk of bias tool evaluated the included studies. Forty-five studies reported peak V̇O2$$ \dot{\mathrm{V}}{\mathrm{O}}_2 $$ percentage of predicted value, and only 21 (47%) studies described or provided a reference on how their percentage of predicted value was calculated. The most cited NRVs were from Wasserman (n=12) and Cooper and Weiler-Ravell (n=7). Risk of bias analysis judged 63% of studies as having some concerns. The NRVs recommended by the American Heart Association were applied to participants with a Fontan circulation (n=70; aged 26.5±6.4 years; 59% women) to examine validity. Predicted peak V̇O2$$ \dot{\mathrm{V}}{\mathrm{O}}_2 $$ values from the Wasserman NRV was not significantly associated to measured peak V̇O2$$ \dot{\mathrm{V}}{\mathrm{O}}_2 $$ values (men: b=0.31, R2≤0.01; women: b=0.07, R2=0.02). CONCLUSIONS: Numerous NRVs have been applied to individuals with congenital heart disease and are often poorly reported and inappropriately matched to participants. The Wasserman NRV was the most cited but showed poor validity when applied to a Fontan cohort.

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Patients born with complex congenital heart defects, not amenable for surgical repair establishing normal bi-ventricular circulation are palliated with the Fontan Circulation (FC). Here, we report new iPSC line from a patient with tricuspid and pulmonary atresia. The patient underwent series of surgeries leading to completion of Fontan circulation at the age of 13yr., and this line was generated when she was 38yr. old. The exact genetic cause of this patient's congenital heart defect is unknown, and this line will be used for studying molecular and cellular mechanisms responsible for cardiac dysfunction, along with screening for future potential therapeutic avenues.

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BACKGROUND: The Fontan circulation procedure is the palliative surgery of choice for patients with single ventricle physiology, many of whom are now reaching childbearing age due to advances in care. Our study examines the impact of pregnancy on women with Fontan circulation, assessing both short and long-term outcomes. METHODS: We retrospectively analysed pregnancies in women with Fontan circulation at our centre from 2005 to 2023, including a matched non-pregnant, nulliparous cohort for comparison. Pregnancies lost before 18 weeks were analysed separately. RESULTS: Among 26 pregnancies in 18 women, preterm births were common (73.1%), with 3 fetal losses and no maternal deaths. Neonatal complications included a 50% incidence of babies small for gestational age (SGA). Cardiac events occurred in 19.2% of pregnancies, primarily supraventricular arrhythmias, and 23% experienced postpartum haemorrhage. Over a median 6.1 [5.2-10.6]-year follow-up, no deaths, heart failure (HF), or Fontan-associated liver disease (FALD) developed, and functional status remained stable. CONCLUSIONS: Women with a Fontan-type circulation undergoing pregnancy had a few serious maternal cardiac events, though there was a high rate of post-partum haemorrhage. The rates of neonatal complications, particularly related to restricted growth and pre-term birth, were also high. Our findings indicate a generally positive medium-term outlook for these patients, though the impact of pregnancy on long-term survival remains unclear. Careful selection of patients with Fontan circulation during pre-pregnancy counselling may help to reduce complications during and after pregnancy.

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BACKGROUND: The atrium augments ventricular function, but the significance of atrial function in hypoplastic left heart syndrome (HLHS) has not been well evaluated. OBJECTIVE: We investigated the association of atrial reservoir strain (common atrial strain [CAS]) to death or need for transplantation in patients with HLHS. METHODS: In this retrospective single-center study, echocardiograms from three timepoints (pre-stage 1 palliation [S1P], 4-8 weeks post-S1P, and pre-Glenn) were analyzed in infants with classic HLHS. Patients were separated based on transplant-free survival to Fontan (survivors) versus death or heart transplant prior to Fontan (composite outcome). Echocardiographic parameters evaluated included CAS, right ventricle (RV) global longitudinal strain (RVGLS), RV fractional area change (FAC), and tricuspid annular plane systolic excursion (TAPSE). An equal variance t-test, regression, and receiver operating characteristic (ROC) analyses were performed. RESULTS: A total of 45 HLHS patients (25 survivors, 20 patients meeting endpoint) were included in this study. There were no significant differences in any of the functional parameters during the pre-stage 1 or post-stage 1 timepoints. Pre-Glenn CAS and RVGLS were significantly worse in those meeting composite endpoint compared to survivors. CAS was significantly correlated to RVGLS during the pre-S1P and pre-Glenn timepoints. A pre-Glenn CAS < 19.5 had an area under the curve of  .78 and a 75% sensitivity and 83% specificity for death or need for transplantation. CONCLUSION: Pre-Glenn CAS is significantly lower in patients with mortality or need for the transplantation prior to Fontan completion and may carry prognostic significance in patients with HLHS.

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INTRODUCTION: A variety of thromboprophylaxis regimens have been administered in patients following the Fontan procedure. However, consensus guidelines regarding the optimal thromboprophylaxis strategy have not yet been developed. METHOD: A network meta-analysis was conducted to evaluate the comparative effectiveness among available thromboprophylaxis regimens and major bleeding events associated with these regimens. RESULTS: A total of 28 comparative studies with 4430 Fontan patients were included. The incidence of thromboembolic events (TE) was significantly lower in individuals who underwent thromboprophylaxis compared to those who did not. Compared to a no-treatment strategy, nonvitamin K oral anticoagulants (NOACs) showed the largest treatment effect for preventing TE (OR = 0.08, 95 % CI 0.03 to 0.21), followed by warfarin (OR = 0.16, 95 % CI 0.10 to 0.27), and aspirin (OR = 0.23, 95 % CI 0.14 to 0.38). Indeed, NOACs were significantly more effective than aspirin in preventing TE (OR = 0.35, 95 % CI 0.14 to 0.84). Aspirin was associated with the lowest occurrence of major bleeding events, followed by NOACs, no medication, and warfarin. NOACs were shown to possess a highly favorable overall profile. CONCLUSION: Prescribing thromboprophylaxis drugs, either antiplatelets or anticoagulants, may be more effective in preventing TE after the Fontan operation than not doing so. Among the included regimens, NOACs demonstrated significantly greater efficacy than aspirin; however, they did not show statistically significant superiority over warfarin. Aspirin exhibited lower rates of major bleeding compared to both NOACs and warfarin. Overall, NOACs tended to offer the most advantageous balance of efficacy and safety. However, the findings should be interpreted considering the certainty and limitations of the evidence, including potential residual confounding in observational studies.

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We describe the safe and effective percutaneous pulmonary thrombectomy in an 18-year-old female with a Fontan circulation using the FlowTriever® device (Inari Medical®, Irvine, US). Aspiration thrombectomy of both pulmonary arteries was performed using 24 and 16 F FlowTriever® catheters retrieving large amounts of thrombus material resulting in near total angiographic recanalization.

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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.

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BACKGROUND: Liver fibrosis has been recognized as a long-term morbidity associated with Fontan circulation (Fontan-associated liver disease, FALD). The pathophysiology of FALD is not completely understood and abnormal flow dynamics may be associated with this condition. Liver hemodynamics can be quantitatively evaluated with four-dimensional phase-contrast flow magnetic resonance imaging (4D PC flow MRI). The study aimed to evaluate suitability of liver 4D PC flow MRI in Fontan patients and relate flow measurements to normal values and FALD severity. PATIENTS AND METHODS: Twenty-two Fontan patients were examined by 4D PC flow MRI at 1.5 Tesla to assess mesenteric, portal, splenic, and hepatic venous blood flow. Severity of FALD was graded based on routine screening, including abdominal ultrasound and laboratory tests. RESULTS: Median age was 18.5 (interquartile range, IQR 15.5-20.2) years. FALD was graded as "none or mild" in 16 and as "moderate to severe" in six cases. Ten patients presented at least one feature of portal hypertension (ascites, splenomegaly, or thrombocytopenia). For the entire cohort, blood flow in the superior mesenteric, splenic, and portal vein was lower than reported in the literature. No significant differences were observed in relation to FALD severity. Features of portal hypertension were associated with a higher splenic vein blood flow (0.34 ± 0.17 vs. 0.20 ± 0.07 l/min, p = 0.046). Splenic vein blood flow was negatively correlated to platelet count (r = -0.590, p = 0.005). CONCLUSIONS: 4D PC flow MRI appears suitable to assess liver hemodynamics in Fontan patients and integration into clinical follow-up might help to improve our understanding of FALD.

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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.

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BACKGROUND: To characterize global and health-related quality of life (QOL) among adults with Fontan physiology enrolled in the Australian and New Zealand Fontan Registry (ANZFR), and identify sociodemographic, clinical, psychological, and relational factors associated with outcomes. METHODS AND RESULTS: Using a cross-sectional survey design, 66 adults with Fontan physiology (58% women; mean age, 29.6±7.7 years; range, 18-50 years) completed validated self-report measures. Health-related QOL was assessed using the Pediatric Quality of Life Inventory, and global QOL was assessed using a visual analog scale (0-10). Participants reported lower total health-related QOL (P<0.001), as well as lower physical (P<0.001) and social (P=0.002) functioning compared with normative data. Median global QOL was 7.0 (interquartile range: 5.0-8.0) and most participants (71%) rated their QOL ≥6. For health-related QOL, age, sex, university education, and length of hospital stay in the past 12 months explained 27% of the variance in scores, while general psychological stress, medical traumatic stress, communication problems, and access to emotional support explained a further 44% of variance (final model: 71% of variance explained). For global QOL, sociodemographic and clinical factors explained 20% of the variance in scores, while psychological stress and sense of coherence explained a further 24% (final model: 44% of variance explained). CONCLUSIONS: Adults with Fontan physiology reported lower overall health-related QOL compared with community-based norms. Variance in QOL outcomes were predominantly attributable to psychological and relational factors. Tailored screening and assessment to identify Fontan patients at greatest risk of lower QOL, and a proactive approach to supportive care, are needed.

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