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:
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.
2026-05-29 | 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.
2026-05-01 | 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.
2026-04-16 | 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.
2026-07-21 | 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.
2026-05-29 | 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.
2026-05-01 | 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.
2026-04-16 | 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.
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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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