Hypoplastic left heart syndrome is a severe congenital defect involving underdeveloped left-sided cardiac structures, leading to significant mortality and morbidity. Prenatal diagnosis using fetal ultrasound and echocardiography enables early detection, family counseling, and improved clinical decision-making. Advanced prenatal interventions, such as fetal aortic valvuloplasty and atrial septostomy, show promise but require careful patient selection. A multidisciplinary approach involving obstetricians, neonatologists, and pediatric cardiologists is vital for effective management. Future directions include refining imaging techniques, such as three-dimensional ultrasound, cardiovascular magnetic resonance imaging, and exploring bioengineering solutions, stem cell therapies, and genetic research. These advancements aim to improve therapeutic options and address current limitations, including transplant scarcity and postoperative complications. Although surgical innovations have improved survival rates, challenges remain, including neurological risks and long-term hemodynamic issues. Ongoing research and technological advancements are essential to enhance outcomes and quality of life for hypoplastic left heart syndrome patients.

Hypoplastic left heart syndrome (HLHS) is a prevalent and lethal type of single ventricle anomaly. During early prenatal evaluations, left heart hypoplasia may be neglected due to its progressive features. It is a heterogeneous congenital heart disease with different phenotypes. Currently, there is no definite treatment for HLHS. This is in part due to its heterogeneous phenotypes that require different management. In addition, hindrances in recognizing the etiologic factors do not allow early preventive or therapeutic procedures. Phenotypic determination is fundamental to identifying the etiologic factors and therapeutic strategies. This review article introduces comprehensive information about different phenotypes and genotypes of HLHS and their novel molecular strategy. Genetic defects and flow-mediated mechanisms are the main known factors of HLHS. Recent studies reported additional data about its nonmendelian genetic origins associated with heterogeneous phenotypes. The genetic defects influence endocardium or cardiomyocyte development to yield early or late valve deformities and myocardial malformations. The new molecular therapeutic methods are essentially based on genetic etiologies. The principal therapeutic purpose is reinforcing the function of the right ventricle in patients with nonfunctional left ventricles. The ultimate desire is to create a biventricular heart in selected cases.

The purpose of the study is to estimate factors affecting survival in prenatally diagnosed hypoplastic left heart syndrome (HLHS) and echocardiographic features predicting poor prognosis and early neonatal death.

This study was designed as a retrospective cohort study. Cases of hypoplastic left heart syndrome diagnosed in the prenatal period between 2014 and 2023 were extracted from electronic medical records. Demographic data, echocardiographic features, results of genetic testing, pregnancy outcomes, and postnatal outcomes were analyzed.

Eighty-three prenatally diagnosed fetal HLHS cases were analyzed. Overall, survival during the study period was 26.5 %, and survival among live births was 35.4 %. Survival analysis has shown that the majority of deaths occurred during the neonatal period. Out of 62 live births, 47 had Norwood procedures, six had balloon procedures and three had hybrid procedures. Eleven out of 47 who had the Norwood procedures went on to have a Glenn operation, and only three had full Fontan palliation. The presence of additional extra-cardiac anomaly, need for extracorporeal membrane oxygenation (ECMO), bidirectional flow at pulmonary veins on color Doppler, and low birth weight are associated with survival and early neonatal death. Tricuspid regurgitation, restrictive foramen ovale, and fetal growth restriction (FGR) are not associated with survival. HLHS evolved from critical aortic stenosis has better survival rates.

Extra-cardiac anomaly, need for ECMO, bidirectional flow at pulmonary veins, and low birth weight were negatively associated with survival and early neonatal death. The survival rate was higher among HLHS cases that had evolved from critical aortic stenosis.

The univentricular heart with a predominant right ventricle morphology (uRV) has been associated with a higher rate of adverse cardiovascular events. It remains to be determined whether the specific type of uRV influences outcomes.

A North American multicenter retrospective cohort study was conducted by the Alliance for Adult Research in Congenital Cardiology on individuals with a uRV and total cavopulmonary connection Fontan. The incidence of a composite outcome consisting of all-cause mortality, cardiac transplantation, atrial arrhythmias, or thromboembolic events was compared among patients with Fontan palliation who had hypoplastic left heart syndrome (HLHS) versus other forms of uRV (non-HLHS). All components of the composite outcome were classified by a blinded adjudicating committee. Competing risks were taken into account in time-to-event analyses. A total of 171 patients with uRV of whom 76 (44.4%) had HLHS were followed for 10.2±5.7 years. The composite outcome occurred in 7.1 versus 2.1 cases per 100 person-years in patients with HLHS versus non-HLHS (P<0.0001). In multivariable analyses, HLHS was associated with a significantly higher risk of the composite outcome (hazard ratio [HR], 6.13 [95% CI, 2.92-12.69], P<0.001). Moreover, HLHS was associated with significantly higher rates of all components of the primary outcome.

Among patients with a uRV and Fontan palliation, HLHS is associated with a significantly higher rate of adverse cardiovascular events.

MYRF-related cardiac-urogenital syndrome (MYRF-CUGS) is a rare condition associated with heterozygous MYRF variants. The description of MYRF-CUGS phenotype is mostly based on postnatal cases and 36 affected individuals have been published so far. We aim now to delineate the prenatal phenotype of MYRF-CUGS by reporting clinical data from fetuses and neonates with a pathogenic MYRF variant.

Detailed radiographic, pathological, clinical, and molecular data from 12 prenatal cases were collected through an international collaborative study. Adding the five fetuses previously published, we were able to study a cohort of 17 cases.

Main ultrasound-accessible manifestations of MYRF-CUGS include congenital heart defects (13/17, 76%), congenital diaphragmatic hernia (10/17, 59%) and disorders of sexual differentiation in 46, XY fetuses (7/14; 50%). Postnatal examination and/or autopsy data highlighted additional birth defects and neurological findings with a large spectrum of severity. Molecular results revealed ten previously unpublished variants, one missense and nine predicted truncating variants (three frameshift, three nonsense and three splice site variants).

We report the first prenatal cohort of MYRF-CUGS, allowing us to further characterize the variable expressivity of this rare disorder in fetuses. Severe congenital anomalies with a poor prognosis are more frequent than previously described in postnatal cases. Our data suggest that MYRF-CUGS is characterized by a recurrent recognizable malformative association, accessible to prenatal diagnosis, with a significant intrafamilial phenotypic variability making genetic counseling challenging.

A 5-year-old female alpaca was presented with respiratory distress and lethargy. Thoracic radiographs revealed a cranioventrally distributed alveolar pattern, caudodorsal bronchial pattern, cardiomegaly, increased soft tissue opaque content in the ventral thorax, and rounded soft tissue opaque structures craniodorsal to the carina. Cardiac gated CT demonstrated a patent ductus arteriosus, ventricular septal defect, complete left atrioventricular valve atresia, partial anomalous venous connections from the cranial pulmonary veins to the azygous and cranial vena cava, severe right-sided cardiomegaly, pleural and peritoneal fluid, and severe hepatic congestion. These findings were confirmed with necropsy.

There is a paucity of data on long-term outcomes after Fontan palliation in patients with a dominant morphological univentricular right (uRV) vs left (uLV) ventricle.

The purpose of this study was to compare the incidence of atrial arrhythmias, thromboembolic events, cardiac transplantation, and death following Fontan palliation in patients with uRV vs uLV.

The Alliance for Adult Research in Congenital Cardiology conducted a multicenter retrospective cohort study on patients with total cavopulmonary connection Fontan palliation across 12 centers in North America. All components of the composite outcome, that is, atrial arrhythmias, thromboembolic events, cardiac transplantation, and death, were reviewed and classified by a blinded adjudicating committee. Time-to-event analyses were performed that accounted for competing risks.

A total of 384 patients were followed for 10.5 ± 5.9 years. The composite outcome occurred in 3.7 vs 1.7 cases per 100 person-years for uRV (N = 171) vs uLV (N = 213), respectively (P < 0.001). In multivariable analyses, uRV conferred a >2-fold higher risk of the composite outcome (HR: 2.17, 95% CI: 1.45-3.45, P < 0.001). In secondary analyses of components of the primary outcome, uRV was significantly associated with a greater risk of cardiac transplantation or death (HR: 9.09, 95% CI: 2.17-38.46, P < 0.001) and atrial arrhythmias (HR: 2.17, 95% CI: 1.20-4.00, P = 0.010) but not thromboembolic events (HR: 1.64, 95% CI: 0.86-3.16, P = 0.131).

Fontan patients with uRV vs uLV morphology have a higher incidence of adverse cardiovascular events, including atrial arrhythmia, cardiac transplantation, and all-cause mortality.

Cardiovascular magnetic resonance (CMR) has established itself as the gold standard for serial assessment of systemic right ventricular (RV) performance but due to the lack of standardized RV reference values for hypoplastic left heart syndrome (HLHS) patients, the interpretation of RV volumetric data in HLHS remains difficult. Therefore, this study aimed to close this gap by providing CMR reference values for the systemic RV in HLHS patients.

CMR scans of 160 children, adolescents, and young adults (age range 2.2-25.2 years, 106 males) with HLHS were retrospectively evaluated. All patients were studied following total cavopulmonary connection. Short-axis stacks were used to measure RV end-diastolic and end-systolic volumes (RVEDV, RVESV), RV stroke volume (RVSV), RV ejection fraction (RVEF), and RV end-diastolic myocardial mass (RVEDMM). Univariable and multiple linear regression analyses were performed to assess associations between RV parameters and demographic and anthropometric characteristics. Following the results of the regression analysis, reference graphs and tables were created with the Lambda-Mu-Sigma method.

Multiple linear regression analysis showed strong associations between body height and RVEDV, RVESV as well as RVSV. Age was highly associated with RVEDMM. Therefore, percentile curves and tables were created with respect to body height (RVEDV, RVESV, RVSV) and age (RVEDMM). The influence of demographic and anthropometric parameters on RVEF was mild, thus no percentile curves and tables for RVEF are provided.

We were able to define CMR reference values for RV volumetric variables for HLHS patients. These data might be useful for the assessment and interpretation of CMR scans in these patients and for research in this field.

To evaluate longitudinal systemic ventricular function and atrioventricular valve regurgitation in patients after the neonatal Norwood procedure.

Serial postoperative echocardiographic images before Fontan completion were assessed in neonates who underwent the Norwood procedure between 2001 and 2020. Ventricular function and atrioventricular valve regurgitation were compared between patients with modified Blalock-Taussig shunt and right ventricle to pulmonary artery conduit.

A total of 335 patients were identified including 273 hypoplastic left heart syndrome and 62 of its variants. Median age at Norwood was 8 (7-12) days. Modified Blalock-Taussig shunt was performed in 171 patients and the right ventricle to pulmonary artery conduit in 164 patients. Longitudinal ventricular function and atrioventricular valve regurgitation were evaluated using a total of 4352 echocardiograms. After the Norwood procedure, ventricular function was initially worse (1-30 days) but thereafter better (30 days to stage II) in the right ventricle to pulmonary artery conduit group (P < 0.001). After stage II, the ventricular function was inferior in the right ventricle to the pulmonary artery conduit group (P < 0.001). Atrioventricular valve regurgitation between the Norwood procedure and stage II was more frequent in the modified Blalock-Taussig shunt group (P < 0.001). After stage II, there was no significant difference in atrioventricular valve regurgitation between the groups (P = 0.171).

The effect of shunt type on haemodynamics after the Norwood procedure seems to vary according to the stage of palliation. After the Norwood, the modified Blalock-Taussig shunt is associated with poorer ventricular function and worse atrioventricular valve regurgitation compared to right ventricle to pulmonary artery conduit. Whereas, after stage II, modified Blalock-Taussig shunt is associated with better ventricular function and comparable atrioventricular valve regurgitation, compared to the right ventricle to pulmonary artery conduit.

Congenital heart disease remains one of the most frequently diagnosed congenital diseases of the newborn, with hypoplastic left heart syndrome (HLHS) being considered one of the most severe. This univentricular defect was uniformly fatal until the introduction, 40 years ago, of a complex surgical palliation consisting of multiple staged procedures spanning the first 4 years of the child's life. While survival has improved substantially, particularly in experienced centers, ventricular failure requiring heart transplant and a number of associated morbidities remain ongoing clinical challenges for these patients. Cell-based therapies aimed at boosting ventricular performance are under clinical evaluation as a novel intervention to decrease morbidity associated with surgical palliation. In this review, we will examine the current burden of HLHS and current modalities for treatment, discuss various cells therapies as an intervention while delineating challenges and future directions for this therapy for HLHS and other congenital heart diseases.