RARE DISEASE
Univentricular heart
Univentricular heart
Univentricular heart
Synonyms: Double inlet atrioventricular connection
Synonyms: Double inlet atrioventricular connection
Synonyms: Double inlet atrioventricular connection
Drug discovery
4
drugs
With orphan designations
Overview
Univentricular Heart (UVH) encompasses congenital cardiac defects where both atria connect to a single functional ventricle, often accompanied by complex anatomic variations. Clinical manifestations include congestive heart failure, cyanosis, and systemic hypoxemia due to unbalanced circulations. Management involves staged palliative surgeries (e.g., Fontan procedure) to optimize hemodynamics, though long-term complications like arrhythmias, ventricular dysfunction, and multiorgan impacts persist [1][6][11].
Burden
Mortality: Up to 61% in untreated cases; 5-year survival post-palliation ~77%, with attrition from arrhythmias and heart failure [4][7][9].
Long-term morbidity: 40–50% develop heart failure, 7–39% arrhythmias, and protein-losing enteropathy [9][13][14].
Psychosocial strain: Families report high stress due to neurodevelopmental delays and recurrent hospitalizations [14][16].
Therapies
Staged surgical palliation (Norwood, Glenn, Fontan) to establish passive pulmonary blood flow [3][8][16].
Adjuvant therapies: Pulmonary artery banding, Damus-Kaye-Stansel anastomosis, and mechanical circulatory support for high-risk cases [3][6][15].
Heart transplantation reserved for Fontan failure or end-stage disease [9][13].
Categories: rare cardiac malformations, rare developmental anomalies during embryogenesis
Research Papers
1,966 drug discovery papers about Univentricular heart, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,966 drug discovery papers about Univentricular heart, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-07-21 | Interstage outcomes in single ventricle neonates: ductal stenting versus modified Blalock-Taussig shunt.
To compare outcomes of ductal stenting (DS) with those of modified Blalock-Taussig shunt (mBTS) as initial palliation in neonates with functionally univentricular heart and duct-dependent pulmonary blood flow, up to bidirectional cavopulmonary connection (BCPC). We retrospectively analyzed 192 neonates with functionally univentricular heart and duct-dependent pulmonary blood flow undergoing initial palliation with DS (n = 39) or mBTS (n = 153) between 2005 and 2025, using Cox proportional hazards models. The median follow-up was 6.3 months, including follow-up after BCPC. Low birth weight was more frequent in the DS group (28.2% vs 11.1%; P = .01). Survival after initial palliation, during the interstage period, and post-BCPC was 85.7% (95%CI, 81.9-91.5), 83.3% (95%CI, 76.9-88.1), and 79.7% (95%CI, 71.9-85.5), respectively, with no between-group differences (log-rank P > .8). Early postoperative morbidity, including neonatal intensive care unit length of stay, duration of inotropic support, and mechanical ventilation was greater after mBTS (all P = .01). Reintervention rates were similar between DS and mBTS (approximately 23% overall), with no difference in time to reintervention, even for unplanned procedures. Patients initially palliated with DS underwent BCPC earlier (5.3 [3.6-8.6] vs 7.3 [6.0-11.2] months, P = .05) and at lower body weight (5.9 [5.0-7.9] vs 6.9 [5.7-8.2] kg, P = .02). Branch pulmonary artery stenosis before BCPC was more frequent after mBTS (P = .01). After adjustment, overall mortality and reintervention before BCPC were numerically higher in the mBTS group, although these differences were not statistically significant. DS provided safe and effective palliation and was associated with improved early postoperative recovery. Although mortality and reintervention before BCPC were numerically lower after DS, these differences were not statistically significant.
2026-05-01 | The Benefits of a Standardized Approach in Fontan Patients–an Effective Approach for Tailoring Treatment to Individual Needs
Although being a great achievement for patients with univentricular heart (UVH), the Fontan circulation remains a matter of discussion. As a standardized and reproducible surgical method, the extracardiac conduit using a PTFE conduit (TCPC) has demonstrated excellent results.1 Patients with UVH have the prospect of living a long and satisfying life with the Fontan pathway. However, the variety of diagnoses, the type of systemic ventricle and additional burden such as neurologic sequelae, render it difficult to predict the outcome of an individual patient. Furthermore, unresolved questions remain, such as the need for a fenestration or the optimal size of the extracardiac conduit. Most large studies analysing long-term data of patients after TCPC do not find consistent results for all patients. Knowing this discrepancy in results and acknowledging the heterogeneity of patients, it seems more than logic to treat patients depending on their personal underlying physiology. What seems evident can be a challenge in the everyday care of patients with UVH. Benli et al.2 have designed a protocol, structuring the treatment of patients undergoing a TCPC depending on preoperative haemodynamic findings. Starting with a congenital cardiac surgery registry used at 4 centres in 2 countries, the procedure involved a physiology-anchored assessment before Fontan completion, a haemodynamic-driven intraoperative decision on selective fenestration, and a standardised perioperative management protocol including an escalation strategy regarding pleural effusion.
2026-04-14 | Biological tissue engineering for Fontan failure using decellularized extracellular matrix: a systematic review.
BACKGROUND: Functional univentricular heart disease is the most severe congenital condition, managed by Fontan surgery, which is life-sustaining by creating a non-contractile conduit yet limited by long-term complications. Decellularized ECM (dECM) scaffolds reseeded with contractile human cells offer a promising solution, but key factors for such a biological tube remain undefined. AIM: To evaluate the potential of cardiac dECM as a scaffold for recellularization in the development of a contractile Fontan conduit. METHODS: A systematic review was performed of studies identified in PubMed, Embase, Web of Science, and the Cochrane Library on human or porcine cardiac tissue engineering. Decellularization outcome parameters included efficiency of DNA removal, ECM preservation, and cytocompatibility; recellularization parameters focused on cell viability, co-culture strategies, maturation, and contractility. RESULTS: Fifty-eight studies on decellularization of porcine or human cardiac tissue were included; 13 also investigated recellularization. Most studies reported more than 90% reduced DNA content and preserved ECM architecture, though quantitative ECM analyses and toxicity assessments were not often reported. Recellularization with cardiomyocyte (like) cells showed high viability, especially in slice monocultures. Co-culture with other cell types improved organization and sarcomere maturation. Functionality assessment in most studies showed spontaneous and synchronized contractions however remaining under normal physiological values. CONCLUSION: Cardiac dECM scaffolds hold promise for contractile Fontan conduits; however, standardized decellularization protocols, enhanced recellularization strategies, and integration of vascular and supportive cells are needed to advance clinical translation.
2025-07-10 | Ductus arteriosus obstruction induced by vertical vein stenting in single-ventricle physiology with supracardiac total anomalous pulmonary venous connection.
A newborn with right atrial isomerism, single-ventricle physiology, supracardiac total anomalous pulmonary venous connection, and pulmonary atresia underwent vertical vein stenting, resulting in ductus arteriosus compression. Subsequent ductal stenting restored patency, preventing haemodynamic compromise and ensuring survival. This case highlights the risk of secondary ductal obstruction in vertical vein stenting and the importance of early recognition and intervention.
2025-04-29 | Establishment and Hemodynamic Assessment of the Superior Cavopulmonary Anastomosis in a Reproducible Porcine Model.
Background: Palliative surgery for the treatment of functionally univentricular heart malformations consists of a staged approach to separation of the pulmonary and systemic circulation, including the creation of a superior cavopulmonary connection. Literature on the superior cavopulmonary connection in porcine models lacks information on details of the procedure as well as data on its acute hemodynamic effects. In preliminary experiments, we were unable to reproduce an already published porcine model. Therefore, we used a conduit extension and cardiopulmonary bypass in order to achieve hemodynamic stability and still employ the commonly used straight downward pathway for the superior caval vein onto the right pulmonary artery, as in the human clinical setting. This model of a univentricular circulation utilising the superior cavopulmonary anastomosis is intended to be applied in the setting of unilateral diaphragmatic palsy. Hence, we aim to investigate the effect of unilateral diaphragmatic pacing in a reproducible model of univentricular physiology. Methods: Therefore, we constructed an anastomosis between the superior caval vein and the right pulmonary artery (RPA) in 14 pigs on cardiopulmonary bypass using a 12 mm expanded polytetrafluorethylene interposition graft. Six pigs received a bidirectional cavopulmonary connection with unrestricted atrial septal communication (BDCPC), while eight pigs received a unidirectional cavopulmonary connection (UDCPC) to the excluded RPA. Results: The BDCPC resulted in an impaired cardiopulmonary state (cardiac output dropped from 3.15 ± 0.21 to 2.17 ± 0.19 L/min; p < 0.01), mean arterial pressure plummeted (from 80.8 ± 3.7 to 49.3 ± 7.3 mmHg; p = 0.02), arterial lactate concentration rose (from 0.82 ± 0.09 to 4.36 ± 0.96 mmol/L; p = 0.01), arterial oxygen saturation dropped (from 95.8 ± 1.1 to 60.9 ± 10.4%; p < 0.01), and right ventricular function deteriorated (tricuspid annular plane systolic excursion decreased from 12 ± 0.7 to 5 ± 0.7 mm; p < 0.01). In contrast, in the UDCPC group, the cardiopulmonary parameters indicated a stable condition. Conclusions: Consequently, a UDCPC is a more suitable acute model in pigs for a univentricular circulation. The model's reproducibility may aid in future research on partial cavopulmonary connection.
small molecules
2026-05-29 | Perinatal brain development in congenital heart disease
This thesis shows that children with critical congenital heart disease (CCHD) have altered brain growth trajectories that begin during fetal life and continue after neonatal cardiac surgery. These changes are not limited to a single brain region, but affect multiple brain structures. The timing and pattern of altered brain growth differ between CCHD subtypes. In transposition of the great arteries, brain growth abnormalities are diffuse and already visible early in the third trimester of pregnancy. In contrast, in univentricular heart defects and aortic arch anomalies, cerebral vulnerability appears to be more region-specific and emerges later in development. The mechanisms underlying delayed brain development are likely complex and multifactorial. Besides altered oxygen delivery and cerebral blood flow, both during fetal life and around the time of cardiac surgery, placental dysfunction, disruption of the insulin-like growth factor axis, and maternal health and stress may also contribute. Importantly, disturbances in early brain development appear to have long-term consequences, as neonatal brain volumes and brain injury are strongly associated with brain structure at school-age. At the same time, some regions, particularly the white matter, remain vulnerable beyond the neonatal period, especially in children who undergo additional cardiac interventions. The findings of this thesis highlight the importance of the perinatal period as a window for neuroprotection. Prenatally, optimizing placental function, treating maternal conditions, and reducing maternal stress may help support fetal brain development. Postnatally, allopurinol may offer opportunities to reduce brain injury around birth and neonatal cardiac surgery. In the future, it will also be important to investigate neuroprotective strategies for cardiac interventions beyond the neonatal period.
2026-05-25 | Real-world experience with sodium-glucose cotransporter 2 inhibitors in adults with Fontan circulatory failure.
Patients with Fontan physiology frequently develop Fontan circulatory failure (FCF), but there are no evidence-based pharmacological treatment options. This study evaluated the safety and efficacy of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in FCF. A real-world, multicenter study of all adult FCF patients included in the international ACHIEVE-SGLT2i registry (NCT06932081) was conducted. Data on side effects, treatment discontinuation, and clinical outcomes were collected. Longitudinal changes in serum biomarkers and clinical parameters from one year before to one year after SGLT2i initiation were evaluated using linear mixed models. Responses between patients with reduced (FCFrEF) vs. preserved ventricular function (FCFpEF) were compared. Thirty-three FCF patients were started on SGLT2i between January 2017 and October 2024. The median age was 32 [20.5-42] years, 17 (51.5%) were female, 11 (33.3%) had FCFrEF, and 22 (66.7%) FCFpEF. Over a median follow-up of 8.0 [3.2-12.2] months, 5 (15.2%) patients reported side effects, of whom 3 (9.1%) permanently discontinued SGLT2i. There were 11 FCF-related hospitalizations in the year before SGLT2i and 7 during follow-up in 9 patients. Blood pressure and renal function remained stable. NT-proBNP increased from 186.3 [116.8-297.1] to 272.6 [180.7-411.3] ng/L in the year before treatment (+46.4%, p = 0.022). In the year after starting SGLT2i, NT-proBNP levels decreased significantly to 200.4 [126.5-317.4] ng/L (-26.5%, p = 0.010), in both FCFrEF and FCFpEF patients. SGLT2i were safe and well-tolerated in adult patients with FCF. SGLT2i treatment was associated with a reduction in NT-proBNP, regardless of FCF phenotype. ClinicalTrials.gov, identifier NCT06932081.
2026-04-16 | Long-Term Outcomes of Antithrombotic Treatment in a Cohort of 864 Patients With Fontan Circulation.
An effective antithrombotic strategy for patients with univentricular heart is required. We determined the prevalence of antithrombotic treatment and survival in patients with Fontan circulation, with secondary outcomes mortality, cardiovascular disease, acute myocardial infarction, and ischemic stroke. We retrospectively included patients with univentricular heart born in Sweden between January 1, 1970, and December 31, 2017. Data from the National Patient Register, the Cause of Death Register, and the Prescribed Drug Register were used. Patients who underwent total cavopulmonary connection surgery, resulting in Fontan circulation, were included and divided into groups based on treatment: anticoagulation, antiplatelets, and no antithrombotic therapy. In total, 864 patients (median [interquartile range] 14.4 [3.9-24.9] years follow-up) were included, 511 of whom (59%) were men. Thirty-six percent received no antithrombotic treatment, and the mortality rate during the follow-up was 58%. Among the patients treated with antithrombotic treatment, 75% received antiplatelets, with a 4% mortality rate. The mortality incidence rate was 2.40 (95% CI, 1.49-3.67) for antithrombotic treatment and 49.42 (95% CI, 42.50-57.15) without. The hazard ratio for mortality was 22.32 (95% CI, 14.04-35.48) without antithrombotic treatment. The incidence rate of ischemic stroke was 2.45 (95% CI, 1.52-3.75) with antithrombotic treatment and 2.47 (95% CI, 1.13-4.68) without. The incidence rate of acute myocardial infarction was 0.69 (95% CI, 0.25-1.50) with antithrombotic treatment and 2.76 (95% CI, 1.32-5.07) without treatment. Treatment with antiplatelets was associated with lower mortality compared with no antithrombotic treatment.
2026-03-25 | Effects of ACE inhibitor and afterload reduction in single ventricles following bidirectional Glenn.
Patients with single ventricles after bidirectional Glenn (BDG) are placed on ACE inhibitors (ACEIs) to reduce afterload and to decrease systemic to pulmonary collateral flow (SPC). The objective is to determine if ACEI use in BDG patients improves SPC and ventricular function. Single-centre retrospective study of BDG patients who underwent cardiac magnetic resonance (CMR) from 2010 to 2024. Demographics, medication, ventricular function and flow data were collected. Patients included were >1 year old and on ACEI for >3 months prior to CMR. A total of 320 BDG patients were studied, 137 were treated with ACEI with no difference in age, sex, medications (except for ACEI) or body surface area. SPC as a percentage of aortic flow was not different in the ACEI group, whether right (RV) or left ventricle (LV) dominant. Ejection fraction (EF) was lower and end- diastolic volume (EDV) was higher in BDG on ACEI for the entire group and for RV dominant. Although LV EDV was higher with those on ACEI, there was no difference in EF. There was no difference in ventricular dilation or EF on echocardiogram prior to starting drug. SPC positively correlated with EDV. SVC flow was lower for those on ACEI. BDG patients treated with ACEI did not demonstrate decreased SPC. There was a suggestion of no improvement of ventricular performance. Cerebral blood flow is decreased in BDG on ACEI using SVC flow. Findings suggest that routine ACEI use in single ventricle patients post BDG should be considered with caution and age-appropriate and clear indications along with measurable therapeutic targets should be considered.
2026-03-16 | Clinical improvement of protein-losing enteropathy after SGLT2 inhibitor therapy in an adult with failing Fontan circulation: a case report.
Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) have proven benefits in patients with biventricular heart failure; however, their role in patients with univentricular physiology and failing Fontan circulation (FC) remains largely unexplored. A 21-year-old male with failing FC, preserved ejection fraction, and protein-loosing enteropathy (PLE) presented to our Adult Congenital Heart Disease Unit for evaluation. Born with a L-transposition of the great vessels with an interventricular septal defect and antero-superior rudimentary chamber, he underwent a Fontan completion at age 5. Since he was 16 years old, he had multiple admissions for FC failure complicated by PLE and ascites, which did not respond to conventional treatments including diuretics, corticosteroids, albumin, and immunoglobulin infusions. Despite the stenosis of the extracardiac conduit, treated by the placement of a covered stent and a further conduit balloon dilation and stenting in a stent procedure performed after 3 years, the patient continued to experience ascites and hypoalbuminemia. To better understand the extent of his lymphatic dysfunction, magnetic resonance lymphoscintigraphy was performed. The study showed significant lymphatic congestion, with leakage into the duodenal lumen and prominent stasis in the thoracic duct. Based on these findings, therapy with SGLT-2i was initiated. Over the following 18 months, there was marked clinical improvement with a reduction in ascites and stabilization of serum protein and albumin levels. This case highlights the potential benefit of SGLT-2i in managing Fontan failure complicated by PLE. Multicenter studies are needed to further investigate the efficacy, safety, and mechanism of action of SGLT-2i in this unique patient population.
proteins
2026-01-01 | Enhanced myocardial perfusion in late gestation fetal lambs with impaired left ventricular inflow
Manuscript abstract: Robust preclinical models of asymmetric ventricular loading in late gestation reflecting conditions such as hypoplastic left heart syndrome are lacking. We characterized the morphometry and microvascular function of the hypoplastic left ventricle (LV) and remaining right ventricle (RV) in a sham-controlled late gestation fetal lamb model of impaired left ventricular inflow (ILVI). Singleton fetuses were instrumented at ∼120 days gestational age (dGA; term is ∼147 days) with vascular catheters, an aortic flow probe and a deflated left atrial balloon. Balloons in ILVI fetuses were inflated over the 8 day study until aortic output was eliminated; Sham balloons remained deflated. At the study end-point (∼134 dGA), cardiac function was assessed by echocardiography, microvascular perfusion of each free wall was measured by myocardial contrast echocardiography (MCE) and terminal morphometric data were collected. During the chronic study, flow through the ascending aorta of ILVI fetuses fell from 389 to -48 mL min-1 with minimal changes to other haemodynamics or blood chemistry. End-point echocardiography and morphometry similarly showed significant and meaningful reductions in ILVI LV chamber volume and wall mass without statistically significant changes in RV size relative to Shams. MCE revealed modestly increased LV perfusion and profoundly increased RV perfusion in ILVI fetuses. Our model displays effective LV hypoplasia with preserved overall fetal health, and our finding of increased RV myocardial perfusion may indicate active vascular remodelling in response to the experimental lesion. KEY POINTS: Hypoplastic left heart syndrome can be caused by insufficient inflow of blood to the fetal left ventricle. We found that eliminating fetal left ventricular input for 8 days reduced left ventricular size and volume, with minimal effects on the right ventricle or overall fetal health. Blood and oxygen delivery increased significantly in the right ventricle and slightly in the hypoplastic left ventricle. Our results suggest functional and anatomical adaptation of the fetal coronary microvasculature to univentricular right heart conditions.
2025-10-16 | Contemporary outcomes and health care costs associated with single-ventricle heart failure admissions in adults in the United States.
Advances in surgical and medical therapies have enabled patients with single-ventricle (SV) physiology to survive into adulthood, leading to a growing population of adults with SV congenital heart disease (SV-ACHD). This study aims to characterize contemporary SV-ACHD health care utilization and outcomes in comparison to acquired heart failure (HF). The National Inpatient Sample was queried for the years 2016-2021 to identify all nonelective hospital admissions for HF or cardiogenic shock in patients aged 18 years or older. Patients with a diagnosis of common ventricle, double-inlet ventricle, tricuspid atresia, or hypoplastic left heart syndrome were identified as SV-ACHD. Patients with 2-ventricle congenital diagnoses were excluded, leaving a control group of acquired HF. Demographics, comorbidities, procedure utilization, in-hospital mortality, and total hospital costs were assessed. There were 28,402 843 HF admissions identified, of which 3375 (0.01%) were SV-ACHD. SV-ACHD admissions were younger and had differing comorbidities. Patients with SV-ACHD had prolonged length of stay, increased rates of advanced HF therapy, and increased hospital cost. There was no absolute difference in in-hospital mortality (5.8% vs 5.7%; P = .908); mortality rates decreased over time in SV-ACHD patients (odds ratio, 0.79; 95% CI, 0.66-0.96; P = .017). However, in multivariable analysis, SV-ACHD was associated with increased risk of mortality (odds ratio, 1.876; 95% CI, 1.210-2.907; P = .005). SV-ACHD represents a small proportion of adult HF admissions, although they have increased rates of procedure utilization and increased total costs. Risk of in-hospital mortality has improved over time in SV-ACHD patients, but there remains an increased risk of mortality relative to patients with acquired HF.
2024-05-16 | Native aortic root thrombus leading to myocardial infarction in a single ventricle patient.
We report a 14-month-old male with hypoplastic left heart syndrome, mitral stenosis, and aortic stenosis with native aortic root thrombus. He developed a wide complex ventricular tachycardia and ST-segment elevation myocardial infarction with troponin I levels peaking at 388 ng/mL. He was treated safely with systemic alteplase with a resolution of his regional wall motion abnormality 18 hours later.
2021-12-29 | Imposition of Fontan physiology: Effects on strain and global measures of ventricular function.
We sought to evaluate contractile function in single-ventricle patients before and after imposition of Fontan physiology. Single right ventricle (SRV; n = 38) and single left ventricle (SLV; n = 11) patients underwent cardiac magnetic resonance imaging pre and post Fontan operation. Global radial strain (GRS), global circumferential strain (GCS), and global longitudinal strain were measured along with ejection fraction (EF) and atrioventricular valve regurgitation (AVVR). Age at cardiac magnetic resonance imaging before the Fontan operation was 3.1 ± 1.3 years and after the Fontan procedure was 5.8 ± 2.7 years. There were no significant EF differences between SRV and SLV patients before and after the Fontan procedure, and EF did not deteriorate significantly after the Fontan operation. GRS was significantly lower for SRV patients than for SLV patients before (24.3% vs 32.1%; P = .048) and after (21.8% vs 29.7%; P = .045) the Fontan procedure. GRS and GCS of the SRV patients deteriorated significantly after the Fontan operation (GRS, P = .01; GCS, P = .009). Strains showed positive correlations before and after the Fontan operation with positive correlations among each strain. Within all patients, strains correlated positively with EF. Strains and EF negatively correlated with AVVR (GRS P = .03, r = -0.22; GCS P = .03, r = -0.23; EF P < .001, r = -0.37). Strains were lower for SRV than for SLV patients before and after the Fontan operation and deteriorated after the Fontan operation. Our study suggests that strain measures might detect ventricular deterioration earlier than EF. Because strains before and after the Fontan operation were positively correlated, and negatively correlated with AVVR, the early institution of myocardial protective therapy including AVVR management, especially for SRV patients, might have benefit.
2021-11-29 | Can Erythropoietin Reduce Hypoxemic Neurological Damages in Neonates With Congenital Heart Defects?
Congenital heart defects (CHD), the most common cause of birth defects with increasing birth prevalence, affect nearly 1% of live births worldwide. Cyanotic CHD are characterized by hypoxemia, with subsequent reduced oxygen delivery to the brain, especially critical during brain development, beginning in the fetus and continuing through the neonatal period. Therefore, neonates with CHD carry a high risk for neurological comorbidities, even more frequently when there are associated underlying genetic disorders. We review the currently available knowledge on potential prevention strategies to reduce brain damage induced by hypoxemia during fetal development and immediately after birth, and the role of erythropoietin (EPO) as a potential adjunctive treatment. Maternal hyper-oxygenation had been studied as a potential therapeutic to improve fetal oxygenation. Despite demonstrating some effectiveness, maternal hyper-oxygenation has proven to be impractical for extensive clinical application, thus prompting the investigation of specific pathways for pharmacological intervention. Among those, the role of antioxidant pathways and Hypoxia Inducible Factors (HIF) have been studied for their involvement in the protective response to hypoxic injury. One of the proteins induced by HIF, EPO, has properties of being anti-apoptotic, antioxidant, and protective for neurons, astrocytes, and oligodendrocytes. In human trials, EPO administration in neonates with hypoxic ischemic encephalopathy (HIE) significantly reduced the neurological hypoxemic damages in several reported studies. Currently, it is unknown if the mechanisms of pathophysiology of cyanotic CHD are like HIE. Neonates with cyanotic CHD are exposed to both chronic hypoxemia and episodes of acute ischemia-reperfusion injury when undergo cardiopulmonary bypass surgery requiring aortic cross-clamp and general anesthesia. Our review supports future trials to evaluate the potential efficiency of EPO in reducing the hypoxemic neurologic damages in neonates with CHD. Furthermore, it suggests the need to identify early biomarkers of hypoxia-induced neurological damage, which must be sensitive to the neuroprotective effects of EPO.
gene therapies
2026-01-07 | MATERNAL SOCIO-ENVIRONMENTAL EXPOSURES DURING EARLY PREGNANCY AND MORTALITY AMONG CHILDREN BORN WITH CRITICAL CONGENITAL HEART DEFECTS
Background: Children with critical congenital heart defects (CCHDs) experience high infant mortality (~25%). While various factors like severity and prenatal diagnosis impact survival, the role of environmental exposures remain understudied. We evaluated the associations between maternal neighborhood-level socioeconomic position (nSEP) and air pollution exposure during early pregnancy and survival in children with CCHDs. Methods: Children with CCHDs in the National Birth Defects Prevention Study (1999–2011) classified as univentricular (UVHDs; more severe) or biventricular (BVHDs) were linked to vital records for 1-year and 5-year mortality. To characterize nSEP, we applied principal component analysis to construct the Neighborhood Deprivation Index (NDI) [low (reference), moderate, or high deprivation] based on maternal addresses reported via interview. To evaluate per-IQR increases in ambient air pollutants, we assigned weekly averages (gestational weeks 2-8) using the nearest air monitor ≤50 kilometers. We estimated survival probabilities and hazard ratios (HRs) with 95% confidence intervals (CIs), adjusting for maternal and infant characteristics. Results: One-year survival was high (87-92%), though lower among children with UVHDs (60-75%) than BVHDs (93-95%). Among all CCHDs, survival differed significantly by deprivation (p<0.001), with the lowest survival among those living in highdeprivation areas. Compared to living in areas characterized as having low deprivation, living in areas characterized as having high deprivation was associated with an increased risk of 1-year mortality for all CCHDs (1.18 [0.83, 1.68]) and UVHDs (1.19 [0.73, 1.95]), though non-significant. Estimates for BVHDs were null (1.01 [0.58, 1.77]). For pollutant exposures, per-IQR increases in carbon monoxide (CO) were associated with increased mortality risk (1.25-1.36) across weeks 2-8. No associations were observed among children with UVHDs, but increased mortality risk was observed among children with BVHDs for CO (1.30-1.72) and sulfur dioxide (1.37-1.38). Associations with 5-year mortality were stronger in magnitude for both exposures, with greater deprivation-related disparities among BVHDs and higher CO-related mortality in UVHDs. Conclusion: These observations suggest that the socio-environmental context during pregnancy is associated with childhood mortality risk, with differences observed across severity of CCHDs. Further research could inform underlying structural, environmental, and/or physiological factors that contribute to increased early childhood mortality.
2025-12-07 | Living with a univentricular heart: the journey of surviving on borrowed time.
A univentricular heart is a rare congenital heart defect usually diagnosed prenatelly or at the time of birth. Early intervention and continuous monitoring are crucial, especially when the condition is diagnosed later in life. A man in his 20 s with a known univentricular heart defect presented to a hospital seeking asylum. He showed signs of cyanosis, affecting his lips, nose, and hands. An echocardiogram revealed functional single-ventricle physiology due to a hypoplastic non-functional right ventricle and malposition of the great arteries. Given his complex condition, he was scheduled for a central transplantation evaluation. However, three days after admission, he developed a severe respiratory infection, significantly complicating his treatment and requiring urgent intervention. This case underscores the rarity of complex congenital heart defects in adults, such as functional single-ventricle physiology with malposition of the great arteries. Double inlet left ventricle occurs in approximately 0.05–0.1 per 1,000 live births (J Am Coll Cardiol. 2004;43(1):113–9). while transposition of the great arteries affects 1 in 3,500-5,000 live births (Orphanet J Rare Dis. 2008;3:27). when occuring in isolation. The coexistence of these anomalies represents an exceptionally rare and complex subset of congenital heart disease. Although many children with these defects undergo early interventions, such as the Fontan procedure, some cases are not identified or addressed until adulthood. As these patients age, the challenges of managing congenital heart defects increase, highlighting the need for a more refined, multi-disciplinary approach to care in adult congenital heart disease.
2025-11-17 | Genetic Burden in Congenital Anomalies of the Mitral and Tricuspid Valves: A Case-Control Study.
Congenital heart disease (CHD) is the most common congenital malformation, with most cases exhibiting a multifactorial etiology involving genetic and environmental factors. Congenital anomalies of the atrioventricular valve or septum (CAAVAS) and functionally univentricular heart (FUH) are complex subtypes of CHD, where disruptions in key molecular pathways are implicated. This study investigates the genetic burden contributing to these anomalies. This case-control study included 48 participants: 24 patients diagnosed with CAAVAS or FUH and 24 healthy controls. Whole-exome sequencing (WES) was conducted to assess genetic burden by evaluating minor allele frequencies (MAF) using gnomAD and predicting functional impact of variants with REVEL scores. A secondary filtration was performed, focusing on 349 genes associated with abnormal heart valve morphology (HP:0001654) as defined by the Human Phenotype Ontology (HPO) database, to identify pathogenic variants exclusive to the case group. Genetic burden risk (GBR) analysis revealed a significantly higher median number of common variants in the case group compared to controls (p = 0.035). Genetic analysis identified variants in genes involved in contractile cardiac and cytoskeletal proteins (MYH3, ACTC1), extracellular matrix proteins (FBN1, FREM1, HSPG2), ciliary proteins (EVC2, PKD1L1), enzymes (POLG, DNASE1L3), Cell-signaling proteins (TGFB2, CCDC22) and transcription factors (NKX2-5, NONO). This study highlights the significant role of genetic burden and gene variants associated with congenital mitral and tricuspid valve anomalies. Our findings reinforce the strong genetic predisposition underlying these malformations, as evidenced by the increased genetic burden in affected individuals compared to controls without CHD.
2025-06-24 | Thirty-Year Prevalence of Spontaneous Hemoptysis in Palliated Single Ventricle Circulation.
Spontaneous hemoptysis is a well-recognized risk of palliated single ventricle circulation, yet published literature is limited to case reports and small case series. In this study, we sought to determine the long-term prevalence of spontaneous hemoptysis among patients with palliated single ventricle circulation at a single institution. Secondarily, we sought to characterize the clinical outcomes after spontaneous hemoptysis. We conducted a retrospective study of patients with a history of Glenn or Fontan palliation seen from January 1, 1990 to January 21, 2023. Episodes of spontaneous hemoptysis were identified through 2 independent database screens that queried International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) codes and electronic medical records for "pulmonary hemorrhage" and "hemoptysis." Positive screens were subsequently confirmed or reclassified by manual chart review. Of 799 patients with palliated single ventricle circulation, 10.9% (87/799) screened positive for hemoptysis. Following verification with manual chart review, 3.4% (27/799) of patients with palliated single ventricle circulation had spontaneous hemoptysis. A total of 61 episodes of spontaneous hemoptysis occurred in 27 patients. Of all hemoptysis episodes, 83.6% (51/61) occurred after Fontan palliation. Of patients with hemoptysis, 51.9% (14/27) had multiple episodes of hemoptysis with recurrence at a median of 0.6 years (range 1 day-8.5 years) after the first episode. To our knowledge, this is the first study that quantifies prevalence of hemoptysis in a large cohort of patients with palliated single ventricle circulation. Overall, prevalence of spontaneous hemoptysis was low (3.4%) among patients with palliated single ventricle circulation and there was a moderate rate of recurrence (51.9%).
2025-01-09 | Extracorporeal cardiopulmonary resuscitation outcomes in pre-Glenn single ventricle infants: Analysis of a ten-year dataset.
While several studies have reported on outcomes of extracorporeal membrane oxygenation (ECMO) in patients with single ventricle physiology, few studies have described outcomes of extracorporeal cardiopulmonary resuscitation (ECPR) in this unique population. The objective of this study was to determine survival and risk factors for mortality after ECPR in single ventricle patients prior to superior cavopulmonary anastomosis, using a large sample from the Extracorporeal Life Support Organization (ELSO) Registry. We included single ventricle patients who underwent ECPR for in-hospital cardiac arrest (IHCA) between January 2012 and December 2021. We excluded patients who had undergone a superior cavopulmonary anastomosis, inferior cavopulmonary anastomosis, or who were older than 180 days at the time of ECPR. We collected data on mortality, ECMO course and ECMO complications. Subjects who survived to hospital discharge after ECPR were compared to subjects who did not survive to hospital discharge. We then performed univariate logistic regression followed by multivariable logistic regression analysis for associations with survival to hospital discharge. There were 420 subjects included who had index ECPR events. Median age was 14 (IQR 7,44) days and median weight was 3.14 (IQR 2.8, 3.8) kg.. Hypoplastic left heart syndrome was the most common diagnosis (354/420; 84.2%), and 47.4% of the cohort (199/420) had undergone a Norwood operation. Survival to hospital discharge occurred in 159/420 (37.9%) of subjects. Median number of hours on ECMO (122 vs. 93 h; p < 0.001), presence of seizures by electroencephalography (24% vs. 15%; p = 0.033), and need for renal replacement therapy (45% vs. 34%; p = 0.023) were significantly higher among non-survivors compared to survivors. In the subgroup of Norwood patients, survival was 43.2% after ECPR. Presence of Norwood variable was 54% among ECPR survivors in the overall cohort, compared to 43% among non-survivors (p = 0.032). In a multivariable logistic regression model to test association with survival to discharge, number of ECMO hours and presence of seizures were associated with decreased odds of survival to hospital discharge [adjusted odds ratio 0.95 (95% C.I. 0.92-0.98) and 0.57 (95% C.I. 0.33-0.97) respectively]. The odds ratio for ECMO hours demonstrated a decrease in odds of survival by 5% for every 12 h on ECMO. Presence of Norwood operation pre-arrest was associated with increased odds of survival [adjusted odds ratio 1.53 (95% C.I. 1.01-2.32)]. In our cohort of pre-Glenn single ventricle infants, survival after ECPR for in-hospital cardiac arrest was 37.9%. Number of hours on ECMO and seizures post-ECMO cannulation were associated with decreased odds of survival. Single ventricle infants who had undergone Norwood palliation pre-arrest were more likely to survive to hospital discharge.
other
2025-04-23 | Are We Getting Better?: Ongoing Challenges of Atrioventricular Valve Repair in Children With Single Ventricle Physiology.
This study aimed to assess impact of atrioventricular valve (AVV) regurgitation onset, timing of AVV repair (AVVr), ventricular morphology, and era effect on AVVr outcomes in a single ventricle population. A retrospective review of 155 patients with single ventricle physiology who underwent AVVr between 1998 and 2022 was conducted. Transplant-free survival, discharge alive, and AVV reoperation were assessed using the Kaplan-Meier survival method, stratified by the timing of AVVr (Group1 [G1], prebidirectional cavopulmonary shunt, N=33; G2, at or post-shunt, N=93; G3, at or post-Fontan, N=29). Cox proportional hazard models were used to assess the association of the timing of AVVr with death or transplant. Transplant-free survival at 10 years was lowest in G1 (G1, 16% [95% CI, 4%-35%]; G2, 65% [95% CI, 53%-74%]; G3, 85% [95% CI, 65%-94%], P<0.001). In the multivariate analysis, AVVr prebidirectional cavopulmonary shunt was an independent risk factor for failure to be discharged alive (P<0.001) but not for overall survival (P=0.12). Meanwhile, the likelihood of discharge alive improved over the period in the entire cohort (P<0.001), and right ventricle morphology (P=0.02) and weight <5 kg (P<0.01) at AVVr were significantly associated with death. In the multistate model, persistent or recurrent AVV regurgitation and ventricular dysfunction post-sAVVr were significantly associated with death, with hazard ratios of 3.8 (95% CI, 2.0-7.3, P<0.001) and 32 (95% CI, 13-77, P<0.001), respectively. Patients with single ventricles who required AVVr, particularly before bidirectional cavopulmonary shunt, have poorer transplant-free survival with no meaningful improvement over the past 2 decades. Small weight and morphologic right ventricle were strongly associated with increased mortality. Alternative treatment strategies should be considered for this high-risk subgroup.
2023-06-22 | The Role of Galectin-3 in Predicting Congenital Heart Disease Outcome: A Review of the Literature
Galectin-3 (Gal-3) is a novel pro-fibrotic biomarker that can predict both right and left cardiac dysfunction caused by various cardiovascular conditions. Its expression seems to be progressively altered with evolving cardiac remodeling processes, even before the onset of heart failure. Hence, Gal-3 has been found to be an individual predictor of acute and chronic heart failure or to serve as part of an integrated biomarker panel that can foresee adverse cardiac outcomes. In congenital heart disease (CHD), Gal-3 correlates with cardiac mortality and complications in both children and adults and is proposed as a therapeutic target in order to reverse the activation of pro-fibrosis pathways that lead to heart failure. Positive associations between serum Gal-3 levels, post-operatory hospitalization rates, complications and ventricular dysfunction have also been reported within studies conducted on patients with CHD who underwent corrective surgery. Thus, this review tried to address the potential utility of Gal-3 in patients with CHD and particularly in those who undergo corrective surgery. The heterogeneity of the literature data and the lack of validation of the results obtained by the current studies on larger cohorts cannot be neglected, though. Further longitudinal research is required to establish how Gal-3 can relate to long-term outcomes in pediatric CHD.
2023-04-01 | Preterm Birth Is Associated With Adverse Cardiac Remodeling and Worse Outcomes in Patients With a Functional Single Right Ventricle
ObjectiveTo assess the effects of preterm birth on cardiac structure and function and transplant-free survival in patients with hypoplastic left heart syndrome and associated anomalies throughout the staged palliation process.Study designData from the Single Ventricle Reconstruction trial were used to assess the impact of prematurity on echocardiographic measures at birth, Norwood, Stage II, and 14 months in 549 patients with a single functional right ventricle. Medical history was recorded once a year using medical records or telephone interviews. Cox regression models were applied to analyze transplant-free survival to age 6 years. Causal mediation analysis was performed to estimate the mediating effect of birth weight within this relationship.ResultsOf the 549 participants, 64 (11.7%) were born preterm. Preterm-born participants had lower indexed right ventricle end-diastolic volumes at birth but higher volumes than term-born participants by age 14 months. Preterm-born participants had an increased risk of death or heart transplantation from birth to age 6 years, with an almost linear increase in the observed risk as gestational age decreased below 37 weeks. Of the total effect of preterm birth on transplant-free survival, 27.3% (95% CI 2.5-59.0%) was mediated through birth weight.ConclusionsPreterm birth is associated with adverse right ventricle remodeling and worse transplant-free survival throughout the palliation process, in part independently of low birth weight. Further investigation into this vulnerable group may allow development of strategies that mitigate the impact of prematurity on outcomes in patients with hypoplastic left heart syndrome. To assess the effects of preterm birth on cardiac structure and function and transplant-free survival in patients with hypoplastic left heart syndrome and associated anomalies throughout the staged palliation process. Data from the Single Ventricle Reconstruction trial were used to assess the impact of prematurity on echocardiographic measures at birth, Norwood, Stage II, and 14 months in 549 patients with a single functional right ventricle. Medical history was recorded once a year using medical records or telephone interviews. Cox regression models were applied to analyze transplant-free survival to age 6 years. Causal mediation analysis was performed to estimate the mediating effect of birth weight within this relationship. Of the 549 participants, 64 (11.7%) were born preterm. Preterm-born participants had lower indexed right ventricle end-diastolic volumes at birth but higher volumes than term-born participants by age 14 months. Preterm-born participants had an increased risk of death or heart transplantation from birth to age 6 years, with an almost linear increase in the observed risk as gestational age decreased below 37 weeks. Of the total effect of preterm birth on transplant-free survival, 27.3% (95% CI 2.5-59.0%) was mediated through birth weight. Preterm birth is associated with adverse right ventricle remodeling and worse transplant-free survival throughout the palliation process, in part independently of low birth weight. Further investigation into this vulnerable group may allow development of strategies that mitigate the impact of prematurity on outcomes in patients with hypoplastic left heart syndrome.
2023-01-11 | Prophylaxis protects infants with congenital heart disease from severe forms of RSV infection: an Italian observational retrospective study
Abstract Background In children with congenital heart disease (CHD) respiratory syncytial virus (RSV) infection may have a severe course, with increased risk of morbidity and mortality, requiring hospital admission and intensive care. The aim of the present study was to evaluate the effect of prophylaxis with palivizumab in preventing RSV-associated hospitalization in infants with CHD. Methods We carried out an observational, retrospective study in a paediatric cardiology division at a secondary-care centre in Italy, extracting from the database children with CHD who, from November 2004 to March 2022, matched the criteria for palivizumab prophylaxis, to evaluate the hospitalization rate in CHD patients with and without palivizumab prophylaxis and their RSV-related hospitalization characteristics compared with a group of children without CHD and no other underlying clinical conditions (control group, CG), hospitalized for RSV infection. Results One hundred twenty-eight children with CHD were enrolled in the study, mainly (71.9%) with increased pulmonary flow, and received palivizumab prophylaxis. Twenty-seven received hospital care for bronchiolitis. Almost all CHD patients hospitalized for bronchiolitis (26 out of 27) received partial prophylaxis (≤ 3 doses). CHD patients with bronchiolitis stay longer in the hospital than control (14.4 ± 21.7 days vs 6.2 ± 2.3 days) some of which require intensive care ( n = 4). Conclusions Our study provides evidence of the efficacy of palivizumab in protecting patients with hemodynamically significant CHD under the age of 2 years from RSV disease and its life-threatening complications. Reducing hospitalisation rate, morbidity, and mortality in this category of patients, passive immune prophylaxis with palivizumab may impact healthcare resource availability and utilisation.
2016-09-29 | Secondary Combined Immunodeficiency in Pediatric Patients after the Fontan Operation: Three Case Reports
The Fontan operation or total cavopulmonal connection (TCPC) is a palliative surgical correction of rare and complex inborn cardiac malformations that are characterized by univentricular circulation. Protein-losing enteropathy (PLE) develops in 4-13% of patients after the Fontan procedure. Fontan-related PLE leads to secondary combined immunodeficiency marked by hypogammaglobulinemia and predominantly CD4+ lymphocytopenia. Here, we present 3 case reports of patients with secondary immunodeficiency after the Fontan operation. The severity of hypogammaglobulinemia correlated with the nature of the infectious complications; however, clinical manifestations of T cell deficiency such as severe viral or opportunistic infections were not observed. The clinical consequences of the secondary combined immunodeficiency were modified by immunoglobulin replacement treatment and antibiotic prophylaxis. Heart transplantation led to the resolution of PLE signs and the restitution of IgG levels in 1 transplanted patient. Our experience shows that the immunological follow-up was delayed in all 3 patients. We suggest that all patients should be followed regularly by a clinical immunologist after the Fontan surgery.
cell therapies
2026-07-21 | Interstage outcomes in single ventricle neonates: ductal stenting versus modified Blalock-Taussig shunt.
To compare outcomes of ductal stenting (DS) with those of modified Blalock-Taussig shunt (mBTS) as initial palliation in neonates with functionally univentricular heart and duct-dependent pulmonary blood flow, up to bidirectional cavopulmonary connection (BCPC). We retrospectively analyzed 192 neonates with functionally univentricular heart and duct-dependent pulmonary blood flow undergoing initial palliation with DS (n = 39) or mBTS (n = 153) between 2005 and 2025, using Cox proportional hazards models. The median follow-up was 6.3 months, including follow-up after BCPC. Low birth weight was more frequent in the DS group (28.2% vs 11.1%; P = .01). Survival after initial palliation, during the interstage period, and post-BCPC was 85.7% (95%CI, 81.9-91.5), 83.3% (95%CI, 76.9-88.1), and 79.7% (95%CI, 71.9-85.5), respectively, with no between-group differences (log-rank P > .8). Early postoperative morbidity, including neonatal intensive care unit length of stay, duration of inotropic support, and mechanical ventilation was greater after mBTS (all P = .01). Reintervention rates were similar between DS and mBTS (approximately 23% overall), with no difference in time to reintervention, even for unplanned procedures. Patients initially palliated with DS underwent BCPC earlier (5.3 [3.6-8.6] vs 7.3 [6.0-11.2] months, P = .05) and at lower body weight (5.9 [5.0-7.9] vs 6.9 [5.7-8.2] kg, P = .02). Branch pulmonary artery stenosis before BCPC was more frequent after mBTS (P = .01). After adjustment, overall mortality and reintervention before BCPC were numerically higher in the mBTS group, although these differences were not statistically significant. DS provided safe and effective palliation and was associated with improved early postoperative recovery. Although mortality and reintervention before BCPC were numerically lower after DS, these differences were not statistically significant.
2026-05-01 | The Benefits of a Standardized Approach in Fontan Patients–an Effective Approach for Tailoring Treatment to Individual Needs
Although being a great achievement for patients with univentricular heart (UVH), the Fontan circulation remains a matter of discussion. As a standardized and reproducible surgical method, the extracardiac conduit using a PTFE conduit (TCPC) has demonstrated excellent results.1 Patients with UVH have the prospect of living a long and satisfying life with the Fontan pathway. However, the variety of diagnoses, the type of systemic ventricle and additional burden such as neurologic sequelae, render it difficult to predict the outcome of an individual patient. Furthermore, unresolved questions remain, such as the need for a fenestration or the optimal size of the extracardiac conduit. Most large studies analysing long-term data of patients after TCPC do not find consistent results for all patients. Knowing this discrepancy in results and acknowledging the heterogeneity of patients, it seems more than logic to treat patients depending on their personal underlying physiology. What seems evident can be a challenge in the everyday care of patients with UVH. Benli et al.2 have designed a protocol, structuring the treatment of patients undergoing a TCPC depending on preoperative haemodynamic findings. Starting with a congenital cardiac surgery registry used at 4 centres in 2 countries, the procedure involved a physiology-anchored assessment before Fontan completion, a haemodynamic-driven intraoperative decision on selective fenestration, and a standardised perioperative management protocol including an escalation strategy regarding pleural effusion.
2026-04-14 | Biological tissue engineering for Fontan failure using decellularized extracellular matrix: a systematic review.
BACKGROUND: Functional univentricular heart disease is the most severe congenital condition, managed by Fontan surgery, which is life-sustaining by creating a non-contractile conduit yet limited by long-term complications. Decellularized ECM (dECM) scaffolds reseeded with contractile human cells offer a promising solution, but key factors for such a biological tube remain undefined. AIM: To evaluate the potential of cardiac dECM as a scaffold for recellularization in the development of a contractile Fontan conduit. METHODS: A systematic review was performed of studies identified in PubMed, Embase, Web of Science, and the Cochrane Library on human or porcine cardiac tissue engineering. Decellularization outcome parameters included efficiency of DNA removal, ECM preservation, and cytocompatibility; recellularization parameters focused on cell viability, co-culture strategies, maturation, and contractility. RESULTS: Fifty-eight studies on decellularization of porcine or human cardiac tissue were included; 13 also investigated recellularization. Most studies reported more than 90% reduced DNA content and preserved ECM architecture, though quantitative ECM analyses and toxicity assessments were not often reported. Recellularization with cardiomyocyte (like) cells showed high viability, especially in slice monocultures. Co-culture with other cell types improved organization and sarcomere maturation. Functionality assessment in most studies showed spontaneous and synchronized contractions however remaining under normal physiological values. CONCLUSION: Cardiac dECM scaffolds hold promise for contractile Fontan conduits; however, standardized decellularization protocols, enhanced recellularization strategies, and integration of vascular and supportive cells are needed to advance clinical translation.
2025-07-10 | Ductus arteriosus obstruction induced by vertical vein stenting in single-ventricle physiology with supracardiac total anomalous pulmonary venous connection.
A newborn with right atrial isomerism, single-ventricle physiology, supracardiac total anomalous pulmonary venous connection, and pulmonary atresia underwent vertical vein stenting, resulting in ductus arteriosus compression. Subsequent ductal stenting restored patency, preventing haemodynamic compromise and ensuring survival. This case highlights the risk of secondary ductal obstruction in vertical vein stenting and the importance of early recognition and intervention.
2025-04-29 | Establishment and Hemodynamic Assessment of the Superior Cavopulmonary Anastomosis in a Reproducible Porcine Model.
Background: Palliative surgery for the treatment of functionally univentricular heart malformations consists of a staged approach to separation of the pulmonary and systemic circulation, including the creation of a superior cavopulmonary connection. Literature on the superior cavopulmonary connection in porcine models lacks information on details of the procedure as well as data on its acute hemodynamic effects. In preliminary experiments, we were unable to reproduce an already published porcine model. Therefore, we used a conduit extension and cardiopulmonary bypass in order to achieve hemodynamic stability and still employ the commonly used straight downward pathway for the superior caval vein onto the right pulmonary artery, as in the human clinical setting. This model of a univentricular circulation utilising the superior cavopulmonary anastomosis is intended to be applied in the setting of unilateral diaphragmatic palsy. Hence, we aim to investigate the effect of unilateral diaphragmatic pacing in a reproducible model of univentricular physiology. Methods: Therefore, we constructed an anastomosis between the superior caval vein and the right pulmonary artery (RPA) in 14 pigs on cardiopulmonary bypass using a 12 mm expanded polytetrafluorethylene interposition graft. Six pigs received a bidirectional cavopulmonary connection with unrestricted atrial septal communication (BDCPC), while eight pigs received a unidirectional cavopulmonary connection (UDCPC) to the excluded RPA. Results: The BDCPC resulted in an impaired cardiopulmonary state (cardiac output dropped from 3.15 ± 0.21 to 2.17 ± 0.19 L/min; p < 0.01), mean arterial pressure plummeted (from 80.8 ± 3.7 to 49.3 ± 7.3 mmHg; p = 0.02), arterial lactate concentration rose (from 0.82 ± 0.09 to 4.36 ± 0.96 mmol/L; p = 0.01), arterial oxygen saturation dropped (from 95.8 ± 1.1 to 60.9 ± 10.4%; p < 0.01), and right ventricular function deteriorated (tricuspid annular plane systolic excursion decreased from 12 ± 0.7 to 5 ± 0.7 mm; p < 0.01). In contrast, in the UDCPC group, the cardiopulmonary parameters indicated a stable condition. Conclusions: Consequently, a UDCPC is a more suitable acute model in pigs for a univentricular circulation. The model's reproducibility may aid in future research on partial cavopulmonary connection.
small molecules
2026-05-29 | Perinatal brain development in congenital heart disease
This thesis shows that children with critical congenital heart disease (CCHD) have altered brain growth trajectories that begin during fetal life and continue after neonatal cardiac surgery. These changes are not limited to a single brain region, but affect multiple brain structures. The timing and pattern of altered brain growth differ between CCHD subtypes. In transposition of the great arteries, brain growth abnormalities are diffuse and already visible early in the third trimester of pregnancy. In contrast, in univentricular heart defects and aortic arch anomalies, cerebral vulnerability appears to be more region-specific and emerges later in development. The mechanisms underlying delayed brain development are likely complex and multifactorial. Besides altered oxygen delivery and cerebral blood flow, both during fetal life and around the time of cardiac surgery, placental dysfunction, disruption of the insulin-like growth factor axis, and maternal health and stress may also contribute. Importantly, disturbances in early brain development appear to have long-term consequences, as neonatal brain volumes and brain injury are strongly associated with brain structure at school-age. At the same time, some regions, particularly the white matter, remain vulnerable beyond the neonatal period, especially in children who undergo additional cardiac interventions. The findings of this thesis highlight the importance of the perinatal period as a window for neuroprotection. Prenatally, optimizing placental function, treating maternal conditions, and reducing maternal stress may help support fetal brain development. Postnatally, allopurinol may offer opportunities to reduce brain injury around birth and neonatal cardiac surgery. In the future, it will also be important to investigate neuroprotective strategies for cardiac interventions beyond the neonatal period.
2026-05-25 | Real-world experience with sodium-glucose cotransporter 2 inhibitors in adults with Fontan circulatory failure.
Patients with Fontan physiology frequently develop Fontan circulatory failure (FCF), but there are no evidence-based pharmacological treatment options. This study evaluated the safety and efficacy of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in FCF. A real-world, multicenter study of all adult FCF patients included in the international ACHIEVE-SGLT2i registry (NCT06932081) was conducted. Data on side effects, treatment discontinuation, and clinical outcomes were collected. Longitudinal changes in serum biomarkers and clinical parameters from one year before to one year after SGLT2i initiation were evaluated using linear mixed models. Responses between patients with reduced (FCFrEF) vs. preserved ventricular function (FCFpEF) were compared. Thirty-three FCF patients were started on SGLT2i between January 2017 and October 2024. The median age was 32 [20.5-42] years, 17 (51.5%) were female, 11 (33.3%) had FCFrEF, and 22 (66.7%) FCFpEF. Over a median follow-up of 8.0 [3.2-12.2] months, 5 (15.2%) patients reported side effects, of whom 3 (9.1%) permanently discontinued SGLT2i. There were 11 FCF-related hospitalizations in the year before SGLT2i and 7 during follow-up in 9 patients. Blood pressure and renal function remained stable. NT-proBNP increased from 186.3 [116.8-297.1] to 272.6 [180.7-411.3] ng/L in the year before treatment (+46.4%, p = 0.022). In the year after starting SGLT2i, NT-proBNP levels decreased significantly to 200.4 [126.5-317.4] ng/L (-26.5%, p = 0.010), in both FCFrEF and FCFpEF patients. SGLT2i were safe and well-tolerated in adult patients with FCF. SGLT2i treatment was associated with a reduction in NT-proBNP, regardless of FCF phenotype. ClinicalTrials.gov, identifier NCT06932081.
2026-04-16 | Long-Term Outcomes of Antithrombotic Treatment in a Cohort of 864 Patients With Fontan Circulation.
An effective antithrombotic strategy for patients with univentricular heart is required. We determined the prevalence of antithrombotic treatment and survival in patients with Fontan circulation, with secondary outcomes mortality, cardiovascular disease, acute myocardial infarction, and ischemic stroke. We retrospectively included patients with univentricular heart born in Sweden between January 1, 1970, and December 31, 2017. Data from the National Patient Register, the Cause of Death Register, and the Prescribed Drug Register were used. Patients who underwent total cavopulmonary connection surgery, resulting in Fontan circulation, were included and divided into groups based on treatment: anticoagulation, antiplatelets, and no antithrombotic therapy. In total, 864 patients (median [interquartile range] 14.4 [3.9-24.9] years follow-up) were included, 511 of whom (59%) were men. Thirty-six percent received no antithrombotic treatment, and the mortality rate during the follow-up was 58%. Among the patients treated with antithrombotic treatment, 75% received antiplatelets, with a 4% mortality rate. The mortality incidence rate was 2.40 (95% CI, 1.49-3.67) for antithrombotic treatment and 49.42 (95% CI, 42.50-57.15) without. The hazard ratio for mortality was 22.32 (95% CI, 14.04-35.48) without antithrombotic treatment. The incidence rate of ischemic stroke was 2.45 (95% CI, 1.52-3.75) with antithrombotic treatment and 2.47 (95% CI, 1.13-4.68) without. The incidence rate of acute myocardial infarction was 0.69 (95% CI, 0.25-1.50) with antithrombotic treatment and 2.76 (95% CI, 1.32-5.07) without treatment. Treatment with antiplatelets was associated with lower mortality compared with no antithrombotic treatment.
2026-03-25 | Effects of ACE inhibitor and afterload reduction in single ventricles following bidirectional Glenn.
Patients with single ventricles after bidirectional Glenn (BDG) are placed on ACE inhibitors (ACEIs) to reduce afterload and to decrease systemic to pulmonary collateral flow (SPC). The objective is to determine if ACEI use in BDG patients improves SPC and ventricular function. Single-centre retrospective study of BDG patients who underwent cardiac magnetic resonance (CMR) from 2010 to 2024. Demographics, medication, ventricular function and flow data were collected. Patients included were >1 year old and on ACEI for >3 months prior to CMR. A total of 320 BDG patients were studied, 137 were treated with ACEI with no difference in age, sex, medications (except for ACEI) or body surface area. SPC as a percentage of aortic flow was not different in the ACEI group, whether right (RV) or left ventricle (LV) dominant. Ejection fraction (EF) was lower and end- diastolic volume (EDV) was higher in BDG on ACEI for the entire group and for RV dominant. Although LV EDV was higher with those on ACEI, there was no difference in EF. There was no difference in ventricular dilation or EF on echocardiogram prior to starting drug. SPC positively correlated with EDV. SVC flow was lower for those on ACEI. BDG patients treated with ACEI did not demonstrate decreased SPC. There was a suggestion of no improvement of ventricular performance. Cerebral blood flow is decreased in BDG on ACEI using SVC flow. Findings suggest that routine ACEI use in single ventricle patients post BDG should be considered with caution and age-appropriate and clear indications along with measurable therapeutic targets should be considered.
2026-03-16 | Clinical improvement of protein-losing enteropathy after SGLT2 inhibitor therapy in an adult with failing Fontan circulation: a case report.
Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) have proven benefits in patients with biventricular heart failure; however, their role in patients with univentricular physiology and failing Fontan circulation (FC) remains largely unexplored. A 21-year-old male with failing FC, preserved ejection fraction, and protein-loosing enteropathy (PLE) presented to our Adult Congenital Heart Disease Unit for evaluation. Born with a L-transposition of the great vessels with an interventricular septal defect and antero-superior rudimentary chamber, he underwent a Fontan completion at age 5. Since he was 16 years old, he had multiple admissions for FC failure complicated by PLE and ascites, which did not respond to conventional treatments including diuretics, corticosteroids, albumin, and immunoglobulin infusions. Despite the stenosis of the extracardiac conduit, treated by the placement of a covered stent and a further conduit balloon dilation and stenting in a stent procedure performed after 3 years, the patient continued to experience ascites and hypoalbuminemia. To better understand the extent of his lymphatic dysfunction, magnetic resonance lymphoscintigraphy was performed. The study showed significant lymphatic congestion, with leakage into the duodenal lumen and prominent stasis in the thoracic duct. Based on these findings, therapy with SGLT-2i was initiated. Over the following 18 months, there was marked clinical improvement with a reduction in ascites and stabilization of serum protein and albumin levels. This case highlights the potential benefit of SGLT-2i in managing Fontan failure complicated by PLE. Multicenter studies are needed to further investigate the efficacy, safety, and mechanism of action of SGLT-2i in this unique patient population.
proteins
2026-01-01 | Enhanced myocardial perfusion in late gestation fetal lambs with impaired left ventricular inflow
Manuscript abstract: Robust preclinical models of asymmetric ventricular loading in late gestation reflecting conditions such as hypoplastic left heart syndrome are lacking. We characterized the morphometry and microvascular function of the hypoplastic left ventricle (LV) and remaining right ventricle (RV) in a sham-controlled late gestation fetal lamb model of impaired left ventricular inflow (ILVI). Singleton fetuses were instrumented at ∼120 days gestational age (dGA; term is ∼147 days) with vascular catheters, an aortic flow probe and a deflated left atrial balloon. Balloons in ILVI fetuses were inflated over the 8 day study until aortic output was eliminated; Sham balloons remained deflated. At the study end-point (∼134 dGA), cardiac function was assessed by echocardiography, microvascular perfusion of each free wall was measured by myocardial contrast echocardiography (MCE) and terminal morphometric data were collected. During the chronic study, flow through the ascending aorta of ILVI fetuses fell from 389 to -48 mL min-1 with minimal changes to other haemodynamics or blood chemistry. End-point echocardiography and morphometry similarly showed significant and meaningful reductions in ILVI LV chamber volume and wall mass without statistically significant changes in RV size relative to Shams. MCE revealed modestly increased LV perfusion and profoundly increased RV perfusion in ILVI fetuses. Our model displays effective LV hypoplasia with preserved overall fetal health, and our finding of increased RV myocardial perfusion may indicate active vascular remodelling in response to the experimental lesion. KEY POINTS: Hypoplastic left heart syndrome can be caused by insufficient inflow of blood to the fetal left ventricle. We found that eliminating fetal left ventricular input for 8 days reduced left ventricular size and volume, with minimal effects on the right ventricle or overall fetal health. Blood and oxygen delivery increased significantly in the right ventricle and slightly in the hypoplastic left ventricle. Our results suggest functional and anatomical adaptation of the fetal coronary microvasculature to univentricular right heart conditions.
2025-10-16 | Contemporary outcomes and health care costs associated with single-ventricle heart failure admissions in adults in the United States.
Advances in surgical and medical therapies have enabled patients with single-ventricle (SV) physiology to survive into adulthood, leading to a growing population of adults with SV congenital heart disease (SV-ACHD). This study aims to characterize contemporary SV-ACHD health care utilization and outcomes in comparison to acquired heart failure (HF). The National Inpatient Sample was queried for the years 2016-2021 to identify all nonelective hospital admissions for HF or cardiogenic shock in patients aged 18 years or older. Patients with a diagnosis of common ventricle, double-inlet ventricle, tricuspid atresia, or hypoplastic left heart syndrome were identified as SV-ACHD. Patients with 2-ventricle congenital diagnoses were excluded, leaving a control group of acquired HF. Demographics, comorbidities, procedure utilization, in-hospital mortality, and total hospital costs were assessed. There were 28,402 843 HF admissions identified, of which 3375 (0.01%) were SV-ACHD. SV-ACHD admissions were younger and had differing comorbidities. Patients with SV-ACHD had prolonged length of stay, increased rates of advanced HF therapy, and increased hospital cost. There was no absolute difference in in-hospital mortality (5.8% vs 5.7%; P = .908); mortality rates decreased over time in SV-ACHD patients (odds ratio, 0.79; 95% CI, 0.66-0.96; P = .017). However, in multivariable analysis, SV-ACHD was associated with increased risk of mortality (odds ratio, 1.876; 95% CI, 1.210-2.907; P = .005). SV-ACHD represents a small proportion of adult HF admissions, although they have increased rates of procedure utilization and increased total costs. Risk of in-hospital mortality has improved over time in SV-ACHD patients, but there remains an increased risk of mortality relative to patients with acquired HF.
2024-05-16 | Native aortic root thrombus leading to myocardial infarction in a single ventricle patient.
We report a 14-month-old male with hypoplastic left heart syndrome, mitral stenosis, and aortic stenosis with native aortic root thrombus. He developed a wide complex ventricular tachycardia and ST-segment elevation myocardial infarction with troponin I levels peaking at 388 ng/mL. He was treated safely with systemic alteplase with a resolution of his regional wall motion abnormality 18 hours later.
2021-12-29 | Imposition of Fontan physiology: Effects on strain and global measures of ventricular function.
We sought to evaluate contractile function in single-ventricle patients before and after imposition of Fontan physiology. Single right ventricle (SRV; n = 38) and single left ventricle (SLV; n = 11) patients underwent cardiac magnetic resonance imaging pre and post Fontan operation. Global radial strain (GRS), global circumferential strain (GCS), and global longitudinal strain were measured along with ejection fraction (EF) and atrioventricular valve regurgitation (AVVR). Age at cardiac magnetic resonance imaging before the Fontan operation was 3.1 ± 1.3 years and after the Fontan procedure was 5.8 ± 2.7 years. There were no significant EF differences between SRV and SLV patients before and after the Fontan procedure, and EF did not deteriorate significantly after the Fontan operation. GRS was significantly lower for SRV patients than for SLV patients before (24.3% vs 32.1%; P = .048) and after (21.8% vs 29.7%; P = .045) the Fontan procedure. GRS and GCS of the SRV patients deteriorated significantly after the Fontan operation (GRS, P = .01; GCS, P = .009). Strains showed positive correlations before and after the Fontan operation with positive correlations among each strain. Within all patients, strains correlated positively with EF. Strains and EF negatively correlated with AVVR (GRS P = .03, r = -0.22; GCS P = .03, r = -0.23; EF P < .001, r = -0.37). Strains were lower for SRV than for SLV patients before and after the Fontan operation and deteriorated after the Fontan operation. Our study suggests that strain measures might detect ventricular deterioration earlier than EF. Because strains before and after the Fontan operation were positively correlated, and negatively correlated with AVVR, the early institution of myocardial protective therapy including AVVR management, especially for SRV patients, might have benefit.
2021-11-29 | Can Erythropoietin Reduce Hypoxemic Neurological Damages in Neonates With Congenital Heart Defects?
Congenital heart defects (CHD), the most common cause of birth defects with increasing birth prevalence, affect nearly 1% of live births worldwide. Cyanotic CHD are characterized by hypoxemia, with subsequent reduced oxygen delivery to the brain, especially critical during brain development, beginning in the fetus and continuing through the neonatal period. Therefore, neonates with CHD carry a high risk for neurological comorbidities, even more frequently when there are associated underlying genetic disorders. We review the currently available knowledge on potential prevention strategies to reduce brain damage induced by hypoxemia during fetal development and immediately after birth, and the role of erythropoietin (EPO) as a potential adjunctive treatment. Maternal hyper-oxygenation had been studied as a potential therapeutic to improve fetal oxygenation. Despite demonstrating some effectiveness, maternal hyper-oxygenation has proven to be impractical for extensive clinical application, thus prompting the investigation of specific pathways for pharmacological intervention. Among those, the role of antioxidant pathways and Hypoxia Inducible Factors (HIF) have been studied for their involvement in the protective response to hypoxic injury. One of the proteins induced by HIF, EPO, has properties of being anti-apoptotic, antioxidant, and protective for neurons, astrocytes, and oligodendrocytes. In human trials, EPO administration in neonates with hypoxic ischemic encephalopathy (HIE) significantly reduced the neurological hypoxemic damages in several reported studies. Currently, it is unknown if the mechanisms of pathophysiology of cyanotic CHD are like HIE. Neonates with cyanotic CHD are exposed to both chronic hypoxemia and episodes of acute ischemia-reperfusion injury when undergo cardiopulmonary bypass surgery requiring aortic cross-clamp and general anesthesia. Our review supports future trials to evaluate the potential efficiency of EPO in reducing the hypoxemic neurologic damages in neonates with CHD. Furthermore, it suggests the need to identify early biomarkers of hypoxia-induced neurological damage, which must be sensitive to the neuroprotective effects of EPO.
gene therapies
2026-01-07 | MATERNAL SOCIO-ENVIRONMENTAL EXPOSURES DURING EARLY PREGNANCY AND MORTALITY AMONG CHILDREN BORN WITH CRITICAL CONGENITAL HEART DEFECTS
Background: Children with critical congenital heart defects (CCHDs) experience high infant mortality (~25%). While various factors like severity and prenatal diagnosis impact survival, the role of environmental exposures remain understudied. We evaluated the associations between maternal neighborhood-level socioeconomic position (nSEP) and air pollution exposure during early pregnancy and survival in children with CCHDs. Methods: Children with CCHDs in the National Birth Defects Prevention Study (1999–2011) classified as univentricular (UVHDs; more severe) or biventricular (BVHDs) were linked to vital records for 1-year and 5-year mortality. To characterize nSEP, we applied principal component analysis to construct the Neighborhood Deprivation Index (NDI) [low (reference), moderate, or high deprivation] based on maternal addresses reported via interview. To evaluate per-IQR increases in ambient air pollutants, we assigned weekly averages (gestational weeks 2-8) using the nearest air monitor ≤50 kilometers. We estimated survival probabilities and hazard ratios (HRs) with 95% confidence intervals (CIs), adjusting for maternal and infant characteristics. Results: One-year survival was high (87-92%), though lower among children with UVHDs (60-75%) than BVHDs (93-95%). Among all CCHDs, survival differed significantly by deprivation (p<0.001), with the lowest survival among those living in highdeprivation areas. Compared to living in areas characterized as having low deprivation, living in areas characterized as having high deprivation was associated with an increased risk of 1-year mortality for all CCHDs (1.18 [0.83, 1.68]) and UVHDs (1.19 [0.73, 1.95]), though non-significant. Estimates for BVHDs were null (1.01 [0.58, 1.77]). For pollutant exposures, per-IQR increases in carbon monoxide (CO) were associated with increased mortality risk (1.25-1.36) across weeks 2-8. No associations were observed among children with UVHDs, but increased mortality risk was observed among children with BVHDs for CO (1.30-1.72) and sulfur dioxide (1.37-1.38). Associations with 5-year mortality were stronger in magnitude for both exposures, with greater deprivation-related disparities among BVHDs and higher CO-related mortality in UVHDs. Conclusion: These observations suggest that the socio-environmental context during pregnancy is associated with childhood mortality risk, with differences observed across severity of CCHDs. Further research could inform underlying structural, environmental, and/or physiological factors that contribute to increased early childhood mortality.
2025-12-07 | Living with a univentricular heart: the journey of surviving on borrowed time.
A univentricular heart is a rare congenital heart defect usually diagnosed prenatelly or at the time of birth. Early intervention and continuous monitoring are crucial, especially when the condition is diagnosed later in life. A man in his 20 s with a known univentricular heart defect presented to a hospital seeking asylum. He showed signs of cyanosis, affecting his lips, nose, and hands. An echocardiogram revealed functional single-ventricle physiology due to a hypoplastic non-functional right ventricle and malposition of the great arteries. Given his complex condition, he was scheduled for a central transplantation evaluation. However, three days after admission, he developed a severe respiratory infection, significantly complicating his treatment and requiring urgent intervention. This case underscores the rarity of complex congenital heart defects in adults, such as functional single-ventricle physiology with malposition of the great arteries. Double inlet left ventricle occurs in approximately 0.05–0.1 per 1,000 live births (J Am Coll Cardiol. 2004;43(1):113–9). while transposition of the great arteries affects 1 in 3,500-5,000 live births (Orphanet J Rare Dis. 2008;3:27). when occuring in isolation. The coexistence of these anomalies represents an exceptionally rare and complex subset of congenital heart disease. Although many children with these defects undergo early interventions, such as the Fontan procedure, some cases are not identified or addressed until adulthood. As these patients age, the challenges of managing congenital heart defects increase, highlighting the need for a more refined, multi-disciplinary approach to care in adult congenital heart disease.
2025-11-17 | Genetic Burden in Congenital Anomalies of the Mitral and Tricuspid Valves: A Case-Control Study.
Congenital heart disease (CHD) is the most common congenital malformation, with most cases exhibiting a multifactorial etiology involving genetic and environmental factors. Congenital anomalies of the atrioventricular valve or septum (CAAVAS) and functionally univentricular heart (FUH) are complex subtypes of CHD, where disruptions in key molecular pathways are implicated. This study investigates the genetic burden contributing to these anomalies. This case-control study included 48 participants: 24 patients diagnosed with CAAVAS or FUH and 24 healthy controls. Whole-exome sequencing (WES) was conducted to assess genetic burden by evaluating minor allele frequencies (MAF) using gnomAD and predicting functional impact of variants with REVEL scores. A secondary filtration was performed, focusing on 349 genes associated with abnormal heart valve morphology (HP:0001654) as defined by the Human Phenotype Ontology (HPO) database, to identify pathogenic variants exclusive to the case group. Genetic burden risk (GBR) analysis revealed a significantly higher median number of common variants in the case group compared to controls (p = 0.035). Genetic analysis identified variants in genes involved in contractile cardiac and cytoskeletal proteins (MYH3, ACTC1), extracellular matrix proteins (FBN1, FREM1, HSPG2), ciliary proteins (EVC2, PKD1L1), enzymes (POLG, DNASE1L3), Cell-signaling proteins (TGFB2, CCDC22) and transcription factors (NKX2-5, NONO). This study highlights the significant role of genetic burden and gene variants associated with congenital mitral and tricuspid valve anomalies. Our findings reinforce the strong genetic predisposition underlying these malformations, as evidenced by the increased genetic burden in affected individuals compared to controls without CHD.
2025-06-24 | Thirty-Year Prevalence of Spontaneous Hemoptysis in Palliated Single Ventricle Circulation.
Spontaneous hemoptysis is a well-recognized risk of palliated single ventricle circulation, yet published literature is limited to case reports and small case series. In this study, we sought to determine the long-term prevalence of spontaneous hemoptysis among patients with palliated single ventricle circulation at a single institution. Secondarily, we sought to characterize the clinical outcomes after spontaneous hemoptysis. We conducted a retrospective study of patients with a history of Glenn or Fontan palliation seen from January 1, 1990 to January 21, 2023. Episodes of spontaneous hemoptysis were identified through 2 independent database screens that queried International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) codes and electronic medical records for "pulmonary hemorrhage" and "hemoptysis." Positive screens were subsequently confirmed or reclassified by manual chart review. Of 799 patients with palliated single ventricle circulation, 10.9% (87/799) screened positive for hemoptysis. Following verification with manual chart review, 3.4% (27/799) of patients with palliated single ventricle circulation had spontaneous hemoptysis. A total of 61 episodes of spontaneous hemoptysis occurred in 27 patients. Of all hemoptysis episodes, 83.6% (51/61) occurred after Fontan palliation. Of patients with hemoptysis, 51.9% (14/27) had multiple episodes of hemoptysis with recurrence at a median of 0.6 years (range 1 day-8.5 years) after the first episode. To our knowledge, this is the first study that quantifies prevalence of hemoptysis in a large cohort of patients with palliated single ventricle circulation. Overall, prevalence of spontaneous hemoptysis was low (3.4%) among patients with palliated single ventricle circulation and there was a moderate rate of recurrence (51.9%).
2025-01-09 | Extracorporeal cardiopulmonary resuscitation outcomes in pre-Glenn single ventricle infants: Analysis of a ten-year dataset.
While several studies have reported on outcomes of extracorporeal membrane oxygenation (ECMO) in patients with single ventricle physiology, few studies have described outcomes of extracorporeal cardiopulmonary resuscitation (ECPR) in this unique population. The objective of this study was to determine survival and risk factors for mortality after ECPR in single ventricle patients prior to superior cavopulmonary anastomosis, using a large sample from the Extracorporeal Life Support Organization (ELSO) Registry. We included single ventricle patients who underwent ECPR for in-hospital cardiac arrest (IHCA) between January 2012 and December 2021. We excluded patients who had undergone a superior cavopulmonary anastomosis, inferior cavopulmonary anastomosis, or who were older than 180 days at the time of ECPR. We collected data on mortality, ECMO course and ECMO complications. Subjects who survived to hospital discharge after ECPR were compared to subjects who did not survive to hospital discharge. We then performed univariate logistic regression followed by multivariable logistic regression analysis for associations with survival to hospital discharge. There were 420 subjects included who had index ECPR events. Median age was 14 (IQR 7,44) days and median weight was 3.14 (IQR 2.8, 3.8) kg.. Hypoplastic left heart syndrome was the most common diagnosis (354/420; 84.2%), and 47.4% of the cohort (199/420) had undergone a Norwood operation. Survival to hospital discharge occurred in 159/420 (37.9%) of subjects. Median number of hours on ECMO (122 vs. 93 h; p < 0.001), presence of seizures by electroencephalography (24% vs. 15%; p = 0.033), and need for renal replacement therapy (45% vs. 34%; p = 0.023) were significantly higher among non-survivors compared to survivors. In the subgroup of Norwood patients, survival was 43.2% after ECPR. Presence of Norwood variable was 54% among ECPR survivors in the overall cohort, compared to 43% among non-survivors (p = 0.032). In a multivariable logistic regression model to test association with survival to discharge, number of ECMO hours and presence of seizures were associated with decreased odds of survival to hospital discharge [adjusted odds ratio 0.95 (95% C.I. 0.92-0.98) and 0.57 (95% C.I. 0.33-0.97) respectively]. The odds ratio for ECMO hours demonstrated a decrease in odds of survival by 5% for every 12 h on ECMO. Presence of Norwood operation pre-arrest was associated with increased odds of survival [adjusted odds ratio 1.53 (95% C.I. 1.01-2.32)]. In our cohort of pre-Glenn single ventricle infants, survival after ECPR for in-hospital cardiac arrest was 37.9%. Number of hours on ECMO and seizures post-ECMO cannulation were associated with decreased odds of survival. Single ventricle infants who had undergone Norwood palliation pre-arrest were more likely to survive to hospital discharge.
other
2025-04-23 | Are We Getting Better?: Ongoing Challenges of Atrioventricular Valve Repair in Children With Single Ventricle Physiology.
This study aimed to assess impact of atrioventricular valve (AVV) regurgitation onset, timing of AVV repair (AVVr), ventricular morphology, and era effect on AVVr outcomes in a single ventricle population. A retrospective review of 155 patients with single ventricle physiology who underwent AVVr between 1998 and 2022 was conducted. Transplant-free survival, discharge alive, and AVV reoperation were assessed using the Kaplan-Meier survival method, stratified by the timing of AVVr (Group1 [G1], prebidirectional cavopulmonary shunt, N=33; G2, at or post-shunt, N=93; G3, at or post-Fontan, N=29). Cox proportional hazard models were used to assess the association of the timing of AVVr with death or transplant. Transplant-free survival at 10 years was lowest in G1 (G1, 16% [95% CI, 4%-35%]; G2, 65% [95% CI, 53%-74%]; G3, 85% [95% CI, 65%-94%], P<0.001). In the multivariate analysis, AVVr prebidirectional cavopulmonary shunt was an independent risk factor for failure to be discharged alive (P<0.001) but not for overall survival (P=0.12). Meanwhile, the likelihood of discharge alive improved over the period in the entire cohort (P<0.001), and right ventricle morphology (P=0.02) and weight <5 kg (P<0.01) at AVVr were significantly associated with death. In the multistate model, persistent or recurrent AVV regurgitation and ventricular dysfunction post-sAVVr were significantly associated with death, with hazard ratios of 3.8 (95% CI, 2.0-7.3, P<0.001) and 32 (95% CI, 13-77, P<0.001), respectively. Patients with single ventricles who required AVVr, particularly before bidirectional cavopulmonary shunt, have poorer transplant-free survival with no meaningful improvement over the past 2 decades. Small weight and morphologic right ventricle were strongly associated with increased mortality. Alternative treatment strategies should be considered for this high-risk subgroup.
2023-06-22 | The Role of Galectin-3 in Predicting Congenital Heart Disease Outcome: A Review of the Literature
Galectin-3 (Gal-3) is a novel pro-fibrotic biomarker that can predict both right and left cardiac dysfunction caused by various cardiovascular conditions. Its expression seems to be progressively altered with evolving cardiac remodeling processes, even before the onset of heart failure. Hence, Gal-3 has been found to be an individual predictor of acute and chronic heart failure or to serve as part of an integrated biomarker panel that can foresee adverse cardiac outcomes. In congenital heart disease (CHD), Gal-3 correlates with cardiac mortality and complications in both children and adults and is proposed as a therapeutic target in order to reverse the activation of pro-fibrosis pathways that lead to heart failure. Positive associations between serum Gal-3 levels, post-operatory hospitalization rates, complications and ventricular dysfunction have also been reported within studies conducted on patients with CHD who underwent corrective surgery. Thus, this review tried to address the potential utility of Gal-3 in patients with CHD and particularly in those who undergo corrective surgery. The heterogeneity of the literature data and the lack of validation of the results obtained by the current studies on larger cohorts cannot be neglected, though. Further longitudinal research is required to establish how Gal-3 can relate to long-term outcomes in pediatric CHD.
2023-04-01 | Preterm Birth Is Associated With Adverse Cardiac Remodeling and Worse Outcomes in Patients With a Functional Single Right Ventricle
ObjectiveTo assess the effects of preterm birth on cardiac structure and function and transplant-free survival in patients with hypoplastic left heart syndrome and associated anomalies throughout the staged palliation process.Study designData from the Single Ventricle Reconstruction trial were used to assess the impact of prematurity on echocardiographic measures at birth, Norwood, Stage II, and 14 months in 549 patients with a single functional right ventricle. Medical history was recorded once a year using medical records or telephone interviews. Cox regression models were applied to analyze transplant-free survival to age 6 years. Causal mediation analysis was performed to estimate the mediating effect of birth weight within this relationship.ResultsOf the 549 participants, 64 (11.7%) were born preterm. Preterm-born participants had lower indexed right ventricle end-diastolic volumes at birth but higher volumes than term-born participants by age 14 months. Preterm-born participants had an increased risk of death or heart transplantation from birth to age 6 years, with an almost linear increase in the observed risk as gestational age decreased below 37 weeks. Of the total effect of preterm birth on transplant-free survival, 27.3% (95% CI 2.5-59.0%) was mediated through birth weight.ConclusionsPreterm birth is associated with adverse right ventricle remodeling and worse transplant-free survival throughout the palliation process, in part independently of low birth weight. Further investigation into this vulnerable group may allow development of strategies that mitigate the impact of prematurity on outcomes in patients with hypoplastic left heart syndrome. To assess the effects of preterm birth on cardiac structure and function and transplant-free survival in patients with hypoplastic left heart syndrome and associated anomalies throughout the staged palliation process. Data from the Single Ventricle Reconstruction trial were used to assess the impact of prematurity on echocardiographic measures at birth, Norwood, Stage II, and 14 months in 549 patients with a single functional right ventricle. Medical history was recorded once a year using medical records or telephone interviews. Cox regression models were applied to analyze transplant-free survival to age 6 years. Causal mediation analysis was performed to estimate the mediating effect of birth weight within this relationship. Of the 549 participants, 64 (11.7%) were born preterm. Preterm-born participants had lower indexed right ventricle end-diastolic volumes at birth but higher volumes than term-born participants by age 14 months. Preterm-born participants had an increased risk of death or heart transplantation from birth to age 6 years, with an almost linear increase in the observed risk as gestational age decreased below 37 weeks. Of the total effect of preterm birth on transplant-free survival, 27.3% (95% CI 2.5-59.0%) was mediated through birth weight. Preterm birth is associated with adverse right ventricle remodeling and worse transplant-free survival throughout the palliation process, in part independently of low birth weight. Further investigation into this vulnerable group may allow development of strategies that mitigate the impact of prematurity on outcomes in patients with hypoplastic left heart syndrome.
2023-01-11 | Prophylaxis protects infants with congenital heart disease from severe forms of RSV infection: an Italian observational retrospective study
Abstract Background In children with congenital heart disease (CHD) respiratory syncytial virus (RSV) infection may have a severe course, with increased risk of morbidity and mortality, requiring hospital admission and intensive care. The aim of the present study was to evaluate the effect of prophylaxis with palivizumab in preventing RSV-associated hospitalization in infants with CHD. Methods We carried out an observational, retrospective study in a paediatric cardiology division at a secondary-care centre in Italy, extracting from the database children with CHD who, from November 2004 to March 2022, matched the criteria for palivizumab prophylaxis, to evaluate the hospitalization rate in CHD patients with and without palivizumab prophylaxis and their RSV-related hospitalization characteristics compared with a group of children without CHD and no other underlying clinical conditions (control group, CG), hospitalized for RSV infection. Results One hundred twenty-eight children with CHD were enrolled in the study, mainly (71.9%) with increased pulmonary flow, and received palivizumab prophylaxis. Twenty-seven received hospital care for bronchiolitis. Almost all CHD patients hospitalized for bronchiolitis (26 out of 27) received partial prophylaxis (≤ 3 doses). CHD patients with bronchiolitis stay longer in the hospital than control (14.4 ± 21.7 days vs 6.2 ± 2.3 days) some of which require intensive care ( n = 4). Conclusions Our study provides evidence of the efficacy of palivizumab in protecting patients with hemodynamically significant CHD under the age of 2 years from RSV disease and its life-threatening complications. Reducing hospitalisation rate, morbidity, and mortality in this category of patients, passive immune prophylaxis with palivizumab may impact healthcare resource availability and utilisation.
2016-09-29 | Secondary Combined Immunodeficiency in Pediatric Patients after the Fontan Operation: Three Case Reports
The Fontan operation or total cavopulmonal connection (TCPC) is a palliative surgical correction of rare and complex inborn cardiac malformations that are characterized by univentricular circulation. Protein-losing enteropathy (PLE) develops in 4-13% of patients after the Fontan procedure. Fontan-related PLE leads to secondary combined immunodeficiency marked by hypogammaglobulinemia and predominantly CD4+ lymphocytopenia. Here, we present 3 case reports of patients with secondary immunodeficiency after the Fontan operation. The severity of hypogammaglobulinemia correlated with the nature of the infectious complications; however, clinical manifestations of T cell deficiency such as severe viral or opportunistic infections were not observed. The clinical consequences of the secondary combined immunodeficiency were modified by immunoglobulin replacement treatment and antibiotic prophylaxis. Heart transplantation led to the resolution of PLE signs and the restitution of IgG levels in 1 transplanted patient. Our experience shows that the immunological follow-up was delayed in all 3 patients. We suggest that all patients should be followed regularly by a clinical immunologist after the Fontan surgery.
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Drug Discovery Landscape
4 orphan drug designations for Univentricular heart.
4 orphan drug designations for Univentricular heart.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Macitentan [Opsumit] | small molecules | EMA | 2021-05-20 | — | Janssen Cilag International |
autologous mononuclear cells derived from umbilical cord blood | cell therapies | FDA | 2017-07-13 | — | HeartWorks |
Udenafil | small molecules | EMA | 2016-12-12 | — | ICON Clinical Research Limited |
udenafil | small molecules | FDA | 2015-08-31 | — | Mezzion Pharma Co. Ltd. |
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