RARE DISEASE
Hypoplastic left heart syndrome
Hypoplastic left heart syndrome
Hypoplastic left heart syndrome
Synonyms: HLHS
Synonyms: HLHS
Synonyms: HLHS
Drug discovery
4
drugs
With orphan designations
Overview
Hypoplastic left heart syndrome (HLHS) is a lethal congenital heart defect characterized by underdeveloped left-sided cardiac structures, including the left ventricle, mitral/aortic valves, and aorta. Postnatal survival depends on prostaglandin E1 to maintain ductus arteriosus patency and staged palliative surgeries (Norwood, Glenn, Fontan) to reroute systemic circulation through the right ventricle. Despite advancements, patients face lifelong risks of heart failure, arrhythmias, and Fontan-associated complications [6][10].
Burden
Survival: 63.5% at 1 year, 54.6% at 10 years, and 32.6% at 15 years [2]
Complications: Ventricular dysfunction, protein-losing enteropathy, plastic bronchitis, and neurodevelopmental delays [7][11][14]
Psychosocial/financial strain on families due to complex care needs and frequent hospitalizations [16]
Therapies
Staged palliation: Norwood (neonatal), Glenn (4-6 months), and Fontan (18-36 months) procedures to reconfigure single-ventricle physiology [3][5][12]
Alternative approaches: Hybrid procedures combining catheter-based and surgical interventions [8][14]
Heart transplantation (limited by donor availability) and lifelong cardiac monitoring [3][20]
Categories: rare cardiac malformations, rare developmental anomalies during embryogenesis
Research Papers
1,907 drug discovery papers about Hypoplastic left heart syndrome, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,907 drug discovery papers about Hypoplastic left heart syndrome, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-04 | Sex-stratified trends in hypoplastic left heart syndrome-related mortality among children and young adults in the United States, 1999–2024: a pre- and post-COVID-19 analysis
Background Hypoplastic left heart syndrome (HLHS) is a congenital heart disease that accounts for approximately 3% of congenital heart defects, making it a leading cause of mortality in this population. Timely staged palliation, such as Norwood, Glenn, and Fontan, are required to reduce the incidence of adverse outcomes. Data over the long term suggest that only about 31% of patients with HLHS are alive at age 35 years after Fontan completion. However, national mortality trend data stratified by sex, extending through 2024 and spanning the COVID-19 era, have not been characterised. Methods Data for this study were obtained from the CDC WONDER (Centres for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research) Multiple Cause of Death database using ICD-10 code Q23.4 from 1999 through 2024 in individuals aged 0–24 years. Joinpoint regression was used to analyse trends. Analyses were conducted using a Poisson variation model with Monte Carlo permutation testing. Statistical significance was defined as p < 0.05 based on two-tailed testing and was stratified by sex. Results A total of 10,138 deaths were identified in the United States during the study period. Among these, 4,285 were females, and 5,853 were males. Joinpoint regression identified a declining trend from 1999 to 2021 (APC: −2.22%; 95% CI: −3.08 to −1.89; p = 0.006), with a non-significant increase from 2021 to 2024 (APC: +4.97%; p = 0.156). In 2020, total HLHS-related deaths reached their lowest point ( n = 287) before rising consecutively to 358 in 2024. Female mortality trends declined throughout the study period (APC: −1.96%; 95% CI: −2.61 to −1.33; p < 0.001) compared with males, who remained consistently high. Conclusion HLHS mortality has declined following surgical advances and perioperative care management. Persistent higher mortality rates were noted among males than females throughout both pre- and post-COVID eras. The rise in post-pandemic mortality is a new and concerning trend that warrants close national monitoring. These trends emphasise the need for uninterrupted staged palliation and continued population-level surveillance of HLHS outcomes.
2026-07-31 | Cell-Derived Therapies for Hypoplastic Left Heart Syndrome: A Meta- Analysis
Background: Hypoplastic left heart syndrome is a severe single-ventricle congenital heart disease in which the right ventricle sustains systemic circulation after staged palliation. Cell-derived therapies have been investigated as adjunctive strategies to preserve ventricular function. This meta-analysis evaluated the safety and efficacy of cell-derived therapy in patients with hypoplastic left heart syndrome. Methods: PubMed, ScienceDirect, Wiley, and Cochrane were searched from inception to January 31, 2026. Database-specific search strings combined MeSH terms and free- text keywords for hypoplastic left heart syndrome, stem cells, cell-derived therapy, cardiosphere-derived cells, umbilical cord blood mononuclear cells, and mesenchymal precursor cells. Comparative human studies in HLHS or HLHS variants were included. Pooled odds ratios or mean differences with 95% confidence intervals were calculated using fixed-effect or random-effects models according to heterogeneity. Results: Six studies involving 218 patients were included. Cell-derived therapy improved right ventricular ejection fraction (mean difference, 4.61; 95% CI 0.28 to 8.94) and weight- for-age z score (MD 1.80; 95% CI 1.72 to 1.88). Mortality and hospital length of stay did not differ significantly between groups. Cardiopulmonary bypass time appeared shorter, but this finding was based on only two heterogeneous studies and should be interpreted cautiously. Conclusion: Adjunctive cell-derived therapy may improve ventricular function and somatic growth without a detectable early mortality signal, but the current evidence remains limited by small sample sizes, heterogeneity, and early-phase study designs.
2026-07-22 | In Situ Alteplase for Rescue Recanalization After Glenn Thrombosis.
Superior vena cava (SVC) thrombosis after Glenn palliation constitutes acute cavopulmonary circuit failure. A 6-month-old boy with hypoplastic left heart syndrome developed SVC syndrome on postoperative day 13 after bidirectional Glenn, secondary to catheter-associated SVC-Glenn thrombosis with distal pulmonary embolisms. Alteplase infused in situ through the existing catheter (0.2 mg/kg/h, 72 hours) achieved complete recanalization without bleeding. Mediastinal hemorrhage and 4-day veno-arterial extracorporeal membrane oxygenation precluded thrombolysis and surgery, and mechanical disruption risked embolization into the compromised pulmonary bed. When an indwelling catheter traverses the thrombus, catheter-directed alteplase achieves complete recanalization, even after hemorrhage and extracorporeal support.
2026-07-14 | Functional improvement of heart failure in infants and children following the neonatal Norwood procedure.
Heart failure induced by systemic ventricular dysfunction after the Norwood procedure may improve with medications. This study aimed to evaluate the incidence of heart failure, medication use, and subsequent improvement after the Norwood procedure. Among the patients undergoing the Norwood procedure between 2001 and 2024, those who demonstrated heart failure (systemic ventricular dysfunction lasting > 30 days) were identified. Medical therapy and clinical outcomes were evaluated in relation to the recovery of systemic ventricular dysfunction. Among 380 patients after the Norwood procedure, heart failure was observed in 55 patients. Recovery of systemic ventricular function occurred in 21 patients with a median duration of 187 (interquartile range: 77-354) days. The cumulative incidence of recovery was 60.9% at 5 years. Recovery was more frequently observed in patients whose onset was between stage II and III palliation than in other periods (58% vs. 28%, p = .029). Survival after the onset of heart failure was better in patients who showed recovery than in those who did not (88.8% vs. 26.7% at 5 years, p < .001). At the onset of heart failure, zlog-N-terminal prohormone of brain natriuretic peptide (4.2 ± 1.3 vs. 4.5 ± 1.3, p = .55) was similar but differed at the last follow-up (2.2 ± 1.3 vs. 5.1 ± 1.5, p = .01) in patients with and without recovery. A phosphodiesterase type 5 inhibitor was identified as a factor that promoted the recovery (hazard ratio: 5.89, p < .01). In patients who developed heart failure after the Norwood procedure, survival was better in those with recovered function than in those with sustained dysfunction. Phosphodiesterase type 5 inhibitors were identified as a factor promoting the recovery.
2026-07-03 | Association of Digoxin Use at Norwood Discharge with Fontan Completion: A Study from the Pediatric Heart Network Public Dataset.
Digoxin use after the Norwood procedure has been associated with improved interstage survival in hypoplastic left heart syndrome and related conditions. Whether this benefit translates into improved longer-term outcomes through staged palliation remains unknown. We aimed to determine the association of digoxin use at Norwood discharge with transplant-free survival and Fontan completion. We conducted a retrospective cohort study using the Pediatric Heart Network (PHN) Single Ventricle Reconstruction trial public dataset, including 549 infants enrolled at 15 North American centers between 2005 and 2008. Competing risk analysis was used to evaluate Fontan completion and Cox regression to assess death or transplantation within 6 years after the Norwood procedure. Mixed-effects models compared pre-Fontan hemodynamic and echocardiographic right ventricular indices between patients treated with and without digoxin after accounting for center clustering and adjustment for sex, shunt type, heart failure medications at Norwood discharge, and census block poverty level. The 6-year cumulative incidence of Fontan completion was higher among patients discharged on digoxin than among those not receiving digoxin (82% vs 71%; p = 0.013). Competing-risk analysis accounting for death and transplant demonstrated a greater likelihood of Fontan completion among digoxin users (aHR 1.31; 95%CI 1.09-1.58; p = 0.005), without significant difference in the hazard of death or transplant (aHR 0.78; 95%CI 0.53-1.15; p = 0.208). No significant differences in pre-Fontan hemodynamic or echocardiographic indices were observed between groups. Initiation of digoxin post Stage II procedure was not associated with improved survival or likelihood to complete Fontan. Digoxin use at the time of Norwood discharge was associated with a 30% greater likelihood of Fontan completion by 6 years, without accompanying improvement in transplant-free survival. These findings extend prior observations of improved interstage outcomes associated with digoxin use and suggest that treatment may facilitate progression through staged palliation. What is new?: 1)Digoxin use during the interstage was associated with a greater likelihood of reaching Fontan completion within 6 years after Norwood discharge. However, this association was not accompanied by differences in right ventricular hemodynamic or echocardiographic indices at the time of Fontan evaluation.What are the clinical implications?: 2)These findings extend prior observations of improved interstage outcomes associated with digoxin use and provide important information for clinicians caring for patients with single-ventricle heart disease. Further studies are needed to clarify the mechanisms underlying this association and to identify patients most likely to benefit.
2026-08-04 | Sex-stratified trends in hypoplastic left heart syndrome-related mortality among children and young adults in the United States, 1999–2024: a pre- and post-COVID-19 analysis
Background Hypoplastic left heart syndrome (HLHS) is a congenital heart disease that accounts for approximately 3% of congenital heart defects, making it a leading cause of mortality in this population. Timely staged palliation, such as Norwood, Glenn, and Fontan, are required to reduce the incidence of adverse outcomes. Data over the long term suggest that only about 31% of patients with HLHS are alive at age 35 years after Fontan completion. However, national mortality trend data stratified by sex, extending through 2024 and spanning the COVID-19 era, have not been characterised. Methods Data for this study were obtained from the CDC WONDER (Centres for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research) Multiple Cause of Death database using ICD-10 code Q23.4 from 1999 through 2024 in individuals aged 0–24 years. Joinpoint regression was used to analyse trends. Analyses were conducted using a Poisson variation model with Monte Carlo permutation testing. Statistical significance was defined as p < 0.05 based on two-tailed testing and was stratified by sex. Results A total of 10,138 deaths were identified in the United States during the study period. Among these, 4,285 were females, and 5,853 were males. Joinpoint regression identified a declining trend from 1999 to 2021 (APC: −2.22%; 95% CI: −3.08 to −1.89; p = 0.006), with a non-significant increase from 2021 to 2024 (APC: +4.97%; p = 0.156). In 2020, total HLHS-related deaths reached their lowest point ( n = 287) before rising consecutively to 358 in 2024. Female mortality trends declined throughout the study period (APC: −1.96%; 95% CI: −2.61 to −1.33; p < 0.001) compared with males, who remained consistently high. Conclusion HLHS mortality has declined following surgical advances and perioperative care management. Persistent higher mortality rates were noted among males than females throughout both pre- and post-COVID eras. The rise in post-pandemic mortality is a new and concerning trend that warrants close national monitoring. These trends emphasise the need for uninterrupted staged palliation and continued population-level surveillance of HLHS outcomes.
2026-07-31 | Cell-Derived Therapies for Hypoplastic Left Heart Syndrome: A Meta- Analysis
Background: Hypoplastic left heart syndrome is a severe single-ventricle congenital heart disease in which the right ventricle sustains systemic circulation after staged palliation. Cell-derived therapies have been investigated as adjunctive strategies to preserve ventricular function. This meta-analysis evaluated the safety and efficacy of cell-derived therapy in patients with hypoplastic left heart syndrome. Methods: PubMed, ScienceDirect, Wiley, and Cochrane were searched from inception to January 31, 2026. Database-specific search strings combined MeSH terms and free- text keywords for hypoplastic left heart syndrome, stem cells, cell-derived therapy, cardiosphere-derived cells, umbilical cord blood mononuclear cells, and mesenchymal precursor cells. Comparative human studies in HLHS or HLHS variants were included. Pooled odds ratios or mean differences with 95% confidence intervals were calculated using fixed-effect or random-effects models according to heterogeneity. Results: Six studies involving 218 patients were included. Cell-derived therapy improved right ventricular ejection fraction (mean difference, 4.61; 95% CI 0.28 to 8.94) and weight- for-age z score (MD 1.80; 95% CI 1.72 to 1.88). Mortality and hospital length of stay did not differ significantly between groups. Cardiopulmonary bypass time appeared shorter, but this finding was based on only two heterogeneous studies and should be interpreted cautiously. Conclusion: Adjunctive cell-derived therapy may improve ventricular function and somatic growth without a detectable early mortality signal, but the current evidence remains limited by small sample sizes, heterogeneity, and early-phase study designs.
2026-07-22 | In Situ Alteplase for Rescue Recanalization After Glenn Thrombosis.
Superior vena cava (SVC) thrombosis after Glenn palliation constitutes acute cavopulmonary circuit failure. A 6-month-old boy with hypoplastic left heart syndrome developed SVC syndrome on postoperative day 13 after bidirectional Glenn, secondary to catheter-associated SVC-Glenn thrombosis with distal pulmonary embolisms. Alteplase infused in situ through the existing catheter (0.2 mg/kg/h, 72 hours) achieved complete recanalization without bleeding. Mediastinal hemorrhage and 4-day veno-arterial extracorporeal membrane oxygenation precluded thrombolysis and surgery, and mechanical disruption risked embolization into the compromised pulmonary bed. When an indwelling catheter traverses the thrombus, catheter-directed alteplase achieves complete recanalization, even after hemorrhage and extracorporeal support.
2026-07-14 | Functional improvement of heart failure in infants and children following the neonatal Norwood procedure.
Heart failure induced by systemic ventricular dysfunction after the Norwood procedure may improve with medications. This study aimed to evaluate the incidence of heart failure, medication use, and subsequent improvement after the Norwood procedure. Among the patients undergoing the Norwood procedure between 2001 and 2024, those who demonstrated heart failure (systemic ventricular dysfunction lasting > 30 days) were identified. Medical therapy and clinical outcomes were evaluated in relation to the recovery of systemic ventricular dysfunction. Among 380 patients after the Norwood procedure, heart failure was observed in 55 patients. Recovery of systemic ventricular function occurred in 21 patients with a median duration of 187 (interquartile range: 77-354) days. The cumulative incidence of recovery was 60.9% at 5 years. Recovery was more frequently observed in patients whose onset was between stage II and III palliation than in other periods (58% vs. 28%, p = .029). Survival after the onset of heart failure was better in patients who showed recovery than in those who did not (88.8% vs. 26.7% at 5 years, p < .001). At the onset of heart failure, zlog-N-terminal prohormone of brain natriuretic peptide (4.2 ± 1.3 vs. 4.5 ± 1.3, p = .55) was similar but differed at the last follow-up (2.2 ± 1.3 vs. 5.1 ± 1.5, p = .01) in patients with and without recovery. A phosphodiesterase type 5 inhibitor was identified as a factor that promoted the recovery (hazard ratio: 5.89, p < .01). In patients who developed heart failure after the Norwood procedure, survival was better in those with recovered function than in those with sustained dysfunction. Phosphodiesterase type 5 inhibitors were identified as a factor promoting the recovery.
2026-07-03 | Association of Digoxin Use at Norwood Discharge with Fontan Completion: A Study from the Pediatric Heart Network Public Dataset.
Digoxin use after the Norwood procedure has been associated with improved interstage survival in hypoplastic left heart syndrome and related conditions. Whether this benefit translates into improved longer-term outcomes through staged palliation remains unknown. We aimed to determine the association of digoxin use at Norwood discharge with transplant-free survival and Fontan completion. We conducted a retrospective cohort study using the Pediatric Heart Network (PHN) Single Ventricle Reconstruction trial public dataset, including 549 infants enrolled at 15 North American centers between 2005 and 2008. Competing risk analysis was used to evaluate Fontan completion and Cox regression to assess death or transplantation within 6 years after the Norwood procedure. Mixed-effects models compared pre-Fontan hemodynamic and echocardiographic right ventricular indices between patients treated with and without digoxin after accounting for center clustering and adjustment for sex, shunt type, heart failure medications at Norwood discharge, and census block poverty level. The 6-year cumulative incidence of Fontan completion was higher among patients discharged on digoxin than among those not receiving digoxin (82% vs 71%; p = 0.013). Competing-risk analysis accounting for death and transplant demonstrated a greater likelihood of Fontan completion among digoxin users (aHR 1.31; 95%CI 1.09-1.58; p = 0.005), without significant difference in the hazard of death or transplant (aHR 0.78; 95%CI 0.53-1.15; p = 0.208). No significant differences in pre-Fontan hemodynamic or echocardiographic indices were observed between groups. Initiation of digoxin post Stage II procedure was not associated with improved survival or likelihood to complete Fontan. Digoxin use at the time of Norwood discharge was associated with a 30% greater likelihood of Fontan completion by 6 years, without accompanying improvement in transplant-free survival. These findings extend prior observations of improved interstage outcomes associated with digoxin use and suggest that treatment may facilitate progression through staged palliation. What is new?: 1)Digoxin use during the interstage was associated with a greater likelihood of reaching Fontan completion within 6 years after Norwood discharge. However, this association was not accompanied by differences in right ventricular hemodynamic or echocardiographic indices at the time of Fontan evaluation.What are the clinical implications?: 2)These findings extend prior observations of improved interstage outcomes associated with digoxin use and provide important information for clinicians caring for patients with single-ventricle heart disease. Further studies are needed to clarify the mechanisms underlying this association and to identify patients most likely to benefit.
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Drug Discovery Landscape
4 orphan drug designations for Hypoplastic left heart syndrome.
4 orphan drug designations for Hypoplastic left heart syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
rexlemestrocel-L | cell therapies | FDA | 2024-02-14 | — | Mesoblast, Inc. |
Allogeneic bone marrow-derived mesenchymal stromal cells (MSCs) | cell therapies | FDA | 2021-12-02 | — | Longeveron, Inc. |
riociguat | small molecules | FDA | 2019-06-26 | — | Bayer U.S. LLC |
macitentan | small molecules | FDA | 2017-06-06 | — | Janssen Research & Development, LLC |
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