Hypoplastic Left Heart Syndrome Research Articles

Mortality and Heart Transplantation After Hybrid Palliation of Hypoplastic Left Heart Syndrome: A Systematic Review and Meta-Analysis.

Newborns with hypoplastic left heart syndrome (HLHS) who are considered at increased risk for death following Norwood/Sano surgery often undergo hybrid palliation (HP) as initial surgery. We aimed to compile the HP experience in HLHS and its variants and assess the rates of, and risk factors for, death and heart transplantation. CINAHL, CINAHL PLUS, PubMed/MEDLINE, and SCOPUS were systematically searched for HP outcome studies of death or heart transplantation in HLHS between 1998 and 2022. Pooled incidence was estimated, and potential risk factors were identified using random-effects meta-analysis and reconstructed time-to-event data from Kaplan-Meier curves. Thirty-three publications were included in our review. Overall, of 1,162 patients 417 died and 57 underwent heart transplantation, resulting in a combined outcome of 40.7%, (474/1,162). There was a trend toward decreasing mortality risk across the stages of palliation. Pooled mortality between HP and comprehensive stage 2 palliation was 25%, after stage 2 up to Fontan palliation was 16%, and 6% post-Fontan. The incidence of death or heart transplantation was higher in high-risk patients-43% died and 10% received heart transplantation. Our systematic review and meta-analysis found high rates of death or heart transplantation in HP of HLHS patients between HP and Fontan surgeries. All patients should be closely followed during the initial interstage period, which is associated with the highest hazard. Prospective studies on appropriate patient selection, indications, and / or alternatives, as well as refining HP strategies for managing newborns with HLHS are needed to improve outcomes.

Effect of patient factors, center, and era on Fontan timing: An observational study using the Pediatric Health Information Systems Database

BackgroundThere are no consensus guidelines defining optimal timing for the Fontan operation, the last planned surgery in staged palliation for single-ventricle heart disease. ObjectivesIdentify patient-level characteristics, center-level variation, and secular trends driving Fontan timing. MethodsA retrospective observational study of subjects who underwent Fontan from 2007-2021 at centers in the Pediatric Health Information Systems database was performed using linear mixed-effects modeling in which age at Fontan was regressed on patient characteristics and date of operation with center as random effect. ResultsWe included 10,305 subjects (40.4% female, 44% non-white) at 47 centers. Median age at Fontan was 3.4 years (IQR 2.6-4.4). Hypoplastic left heart syndrome (-4.4 months, 95% CI -5.5 to -3.3) and concomitant conditions (-2.6 months, 95% CI -4.1 to -1.1) were associated with younger age at Fontan. Subjects with technology-dependence (+4.6 months, 95% CI 3.1 to 6.1) were older at Fontan. Black (+4.1 months, 95% CI 2.5 to 5.7) and Asian (+8.3 months, 95% CI 5.4 to 11.2) race were associated with older age at Fontan. There was significant variation in Fontan timing between centers. Center accounted for 10% of variation (ICC 0.10, 95% CI 0.07 to 0.14). Center surgical volume was not associated with Fontan timing (p=0.21). Operation year was associated with age at Fontan, with a 3.1 month increase in age for every 5 years (+0.61 months, 95% CI 0.48 to 0.75). ConclusionsAfter adjusting for patient-level characteristics there remains significant inter-center variation in Fontan timing. Age at Fontan has increased. Future studies addressing optimal Fontan timing are warranted.

Using machine learning to predict five-year transplant-free survival among infants with hypoplastic left heart syndrome

Hypoplastic left heart syndrome (HLHS) is a congenital malformation commonly treated with palliative surgery and is associated with significant morbidity and mortality. Risk stratification models have often relied upon traditional survival analyses or outcomes data failing to extend beyond infancy. Individualized prediction of transplant-free survival (TFS) employing machine learning (ML) based analyses of outcomes beyond infancy may provide further valuable insight for families and healthcare providers along the course of a staged palliation. Data from both the Pediatric Heart Network (PHN) Single Ventricle Reconstruction (SVR) trial and Extension study (SVR II), which extended cohort follow up for five years was used to develop ML-driven models predicting TFS. Models incrementally incorporated features corresponding to successive phases of care, from pre-Stage 1 palliation (S1P) through the stage 2 palliation (S2P) hospitalization. Models trained with features from Pre-S1P, S1P operation, and S1P hospitalization all demonstrated time-dependent area under the curves (td-AUC) beyond 0.70 through 5 years following S1P, with a model incorporating features through S1P hospitalization demonstrating particularly robust performance (td-AUC 0.838 (95% CI 0.836–0.840)). Machine learning may offer a clinically useful alternative means of providing individualized survival probability predictions, years following the staged surgical palliation of hypoplastic left heart syndrome.

Longitudinal analysis of systemic ventricular function and atrioventricular valve function after the Norwood procedure.

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.

Two-dimensional speckle tracking echocardiography in fetuses with critical aortic stenosis before and after fetal aortic valvuloplasty.

Critical aortic stenosis (AS) in fetuses may progress to hypoplastic left heart syndrome (HLHS) with need for postnatal single ventricular (SV) palliation. Fetal aortic valvuloplasty (FAV) is performed to achieve postnatal biventricular (BV) circulation. However, the impact of FAV on fetal myocardial function is difficult to measure. Prediction of postnatal circulatory status and, therefore, counseling is challenging. Retrospective study of fetuses with critical AS who underwent FAV. Global Longitudinal Peak Systolic Strain (GLPSS) of the left ventricle (LV) and right ventricle (RV) were retrospectively analyzed before and after intervention. Fisher's Exact Test and Mann-Whitney-U Test were used for univariant statistical analysis. 23 fetuses with critical AS were included. After intervention fetuses demonstrated more negative LV-GLPSS mean values post- vs. pre-intervention (-5.36% vs. -1.57%; p < 0.05). RV-GLPSS was decreased in all fetuses, there was no peri-interventional change. 20 fetuses were born alive. Postnatally, 10 had BV and 10 SV circulation. Improved post-interventional LV-GLPSS strain values correlated with BV outcome (p < 0.05). Pre-interventional continuous LV-GLPSS values correlated with postnatal SV vs. BV outcome (p < 0.05). In some fetuses, LV myocardial function assessed by speckle tracking echocardiography (STE) improves after FAV. Improved post-interventional LV-GLPSS correlates with biventricular postnatal outcome. Furthermore, pre-interventional LV- and RV-GLPSS correlate with postnatal outcome. Further studies are needed to asses, if pre-interventional STE parameters might predict which fetuses will benefit from FAV with postnatal BV circulation.

Investigation of infant deaths associated with critical congenital heart diseases; 2018–2021, Türkiye

BackgroundThe aim of this study was to examine the characteristics of infant mortality associated with critical congenital heart disease (CCHD).MethodsIn a cross-sectional study, data for the study were obtained through Death Notification System, Birth Notification System and Turkish Statistical Institute birth statistics.ResultsOf all infant deaths, 9.8% (4083) were associated with CCHD, and the infant mortality rate specific to CCHD was 8.8 per 10,000 live births. CCHD-related infant deaths accounted for 8.0% of all neonatal deaths, while the CCHD specific neonatal death rate was 4.6 per 10,000 live births. Of the deaths 21.7% occurred in the early neonatal, 30.3% in the late neonatal and 48.0% in the post neonatal period. Group 1 diseases accounted for 59.1% (n = 2415) of CCHD related infant deaths, 40.5% (n = 1652) were in Group 2 and 0.4% (n = 16) were in the unspecified group. Hypoplastic left heart syndrome was the most common CCHD among infant deaths (n = 1012; 24.8%). The highest CCHD related mortality rate was found in infants with preterm birth and low birth-weight while multiparity, maternal age ≥ 35 years, twin/triplet pregnancy, male gender, maternal education in secondary school and below, and cesarean delivery were also associated with higher CCHD related infant mortality rate. There was at least one non-cardiac congenital anomaly/genetic disorder in 26.1% of all cases.ConclusionCCHD holds a significant role in neonatal and infant mortality in Türkiye. To mitigate CCHD-related mortality rates, it is crucial to enhance prenatal diagnosis rates and promote widespread screening for neonatal CCHD.

Impact of preoperative left pulmonary artery stenting on the Fontan procedure: a retrospective multicentre study.

Left pulmonary artery (LPA) or bifurcation stenoses at Fontan palliation can be very challenging to treat and may also require cardioplegia and aortic transection. Moreover, the low pressure of Fontan circulation and the bulkiness of the aorta increase the risk of a patch angioplasty collapse. Pre-Fontan LPA stenting of stenotic LPAs overcomes those drawbacks therefore the present study aimed to evaluate its advantageous impact on Fontan surgery. A multicentre retrospective analysis was performed on 304 consecutive Fontan patients. The study population was divided into 2 groups (LPA stented, n = 62 vs not stented, n = 242); pre-and postoperative data were compared. LPA-stented patients had a higher prevalence of systemic right ventricle (P = 0.01), hypoplastic left heart syndrome (P = 0.042), complex neonatal palliations (Norwood/Damus-Kaye-Stansel) and surgical LPA patch repair at Glenn (P < 0.001). No differences were found in cross-clamp rates, early (P = 0.29) and late survival (94.6% vs 98.4, P = 0.2) or complications (P = 0.14). Complex palliations on ascending aorta/aortic arch (P = 0.013) and surgical LPA repair at Glenn (P < 0.001) proved to be risk factors for LPA stenting before Fontan at multivariable analysis. The LPA-stented group showed similar outcomes in terms of survival and complications rate compared to patients without LPA stenosis; however, they significantly differ in their higher preoperative risk profile and in their more complex anatomy. Complex neonatal palliations involving ascending aorta or aortic arch may increase the risk of pulmonary branches stenosis requiring stenting; therefore, preoperative stenting of LPA stenoses could help to reduce the surgical risk of complex Fontan procedure by avoiding the need for cross-clamp or complex mediastinal dissections to perform a high-risk surgical repair.

Pre-intervention myocardial stress is a good predictor of aortic valvoluplasty outcome for fetal critical aortic stenosis and evolving HLHS.

Fetal critical aortic stenosis with evolving hypoplastic left heart syndrome (CAS-eHLHS) causes biomechanical and functional aberrations, leading to a high risk of progression to hypoplastic left heart syndrome (HLHS) at birth. Fetal aortic valvuloplasty (FAV) can resolve outflow obstruction and may reduce progression risk. However, it is currently difficult to accurately predict which patients will respond to the intervention and become functionally biventricular (BV) at birth, as opposed to becoming functionally univentricular (UV). This prediction is important for patient selection, parental counselling, and surgical planning. Therefore, we investigated whether biomechanics parameters from pre-FAV image-based computations could robustly distinguish between CAS-eHLHS cases with BV or UV outcomes in a retrospective cohort. To do so we performed image-based finite element biomechanics modelling of nine CAS-eHLHS cases undergoing intervention and six healthy fetal control hearts, and found that a biomechanical parameter, peak systolic myofibre stress, showed a uniquely large difference between BV and UV cases, which had a larger magnitude effect than echocardiography parameters. A simplified equation was derived for quick and easy estimation of myofibre stress from echo measurements via principal component analysis. When tested on a retrospective cohort of 37 CAS-eHLHS cases, the parameter outperformed other parameters in predicting UV versus BV outcomes, and thus has a high potential of improving outcome predictions, if incorporated into patient selection procedures. Physiologically, high myocardial stresses likely indicate a healthier myocardium that can withstand high stresses and resist pathological remodelling, which can explain why it is a good predictor of BV outcomes. KEY POINTS: Predicting the morphological birth outcomes (univentricular versus biventricular) of fetal aortic valvuloplasty for fetal aortic stenosis with evolving HLHS is important for accurate patient selection, parental counselling and management decisions. Computational simulations show that a biomechanics parameter, pre-intervention peak systolic myofibre stress, is uniquely robust in distinguishing between such outcomes, outperforming all echo parameters. An empirical equation was developed to quickly compute peak systolic myofibre stress from routine echo measurements and was the best predictor of outcomes among a wide range of parameters tested.

Antifungal medication use during early pregnancy and the risk of congenital heart defects in the National Birth Defects Prevention Study, 1997-2011.

Fungal infections are common among pregnant people. Recent studies suggest positive associations between oral antifungals used to treat fungal infections and congenital heart defects (CHDs). We estimated associations between first trimester antifungal use and 20 major, specific CHDs using data from the National Birth Defects Prevention Study (NBDPS), a multi-site, case-control study that included pregnancies with estimated delivery dates from October 1997 through December 2011. Infants with CHDs ("cases") were ascertained from 10 birth defect surveillance programs. Live born infants without major birth defects ("controls") were randomly selected from birth records or hospital discharge lists. First trimester antifungal use was self-reported via maternal interview. We estimated adjusted odds ratios (AORs) and 95% confidence intervals (CIs) using logistic regression with Firth's penalized likelihood. First trimester antifungal use was reported by 148/11,653 (1.3%) case and 123/11,427 (1.1%) control participants. We estimated AORs for 12 CHDs; six had AORs >1.5 (tetralogy of Fallot, double outlet right ventricle with transposition of the great arteries [DORV-TGA], atrioventricular septal defect, hypoplastic left heart syndrome, pulmonary atresia, muscular ventricular septal defect), and one (pulmonary valve stenosis) had an AOR <0.7. All CIs included the null, except for DORV-TGA. First trimester antifungal use was rare. We observed some positive associations for several specific CHDs in our analysis, although the CIs largely included the null. Results do not support a large increase in risk, but smaller increases in risk for certain CHD cannot be ruled out.

Association Between Neighborhood Socioeconomic Factors and Length of Stay After Surgery for Congenital Heart Disease.

Neighborhood socioeconomic status, as measured by area deprivation index (ADI) is associated with longer length of stay (LOS) after surgery for hypoplastic left heart syndrome. We tested the hypothesis that LOS is associated with ADI in a large cohort of congenital heart disease (CHD) surgical cases of varying severity and sought to determine which other components of the ADI accounted for any associations. Retrospective analysis of a curated dataset. The Brokamp ADI was determined using residential addresses. Overall, ADI and each of its six individual components were dichotomized, and LOS compared between groups above versus below the median for the entire cohort and after stratifying by surgical The Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STAT) severity category. Single-center academic pediatric teaching hospital. CHD patients who underwent surgical repair/palliation between September 2007 and August 2022. None. A total of 2462 patients (52.7% male) were included. Median age was 254 (interquartile range [IQR] 95-1628) days and median LOS in the hospital was 8 (IQR 5-18) days. We failed to identify an association between Brokamp ADI, above versus below the median for the entire cohort, and LOS; nor in STAT categories 1-4. However, in STAT category 5 ( n = 129) those with ADI above the median (more deprived) had a significantly longer LOS (48 [20-88] vs. 36 [18-49] d, p = 0.034). Of the individual components of the ADI, only percent below poverty level and percent vacant houses were associated with LOS in STAT category 5. LOS after CHD surgery is associated with Brokamp ADI in STAT category 5 cases, we failed to identify an association in lower-risk cardiac operations.

The expanded spectrum of human disease associated with GREB1L likely includes complex congenital heart disease.

GREB1L has been linked prenatally to Potter's sequence, as well as less severe anomalies of the kidney, uterus, inner ear, and heart. The full phenotypic spectrum is unknown. The purpose of this study was to characterize known and novel pre- and postnatal phenotypes associated with GREB1L. We solicited cases from the Fetal Sequencing Consortium, screened a population-based genomic database, and conducted a comprehensive literature search to identify disease cases associated with GREB1L. We present a detailed phenotypic spectrum and molecular changes. One hundred twenty-seven individuals with 51 unique pathogenic or likely pathogenic GREB1L variants were identified. 24 (47%) variants were associated with isolated kidney anomalies, 19 (37%) with anomalies of multiple systems, including one case of hypoplastic left heart syndrome, five (10%) with isolated sensorineural hearing loss, two (4%) with isolated uterine agenesis; and one (2%) with isolated tetralogy of Fallot. GREB1L may cause complex congenital heart disease (CHD) in humans. Clinicians should consider GREB1L testing in the setting of CHD, and cardiac screening in the setting of GREB1L variants.

Ablation of atrial flutter in a patient after Fontan procedure: a case report of challenging access to the common atrium

Abstract Background In patients with a total cavopulmonary connection in Fontan circulation, the access to the common atrium (CA) during a catheter ablation can be challenging, even in the presence of fenestration in an intra-atrial lateral tunnel (IALT). In our department, the fenestration is typically marked with metal clips (MCs). To the best of our knowledge, there is no previous report of balloonoplasty of clipped fenestration. Case summary A 19-year-old male with hypoplastic left heart syndrome (HLHS) was scheduled for catheter ablation of recurrent atrial tachycardia. He was diagnosed with HLHS prenatally and underwent a stepwise surgical palliation. Fontan circulation was completed with the creation of a fenestrated IALT. The fenestration was marked by four MCs. During the ablation procedure, the passage of the steerable sheath with mapping catheter to the CA was prevented by a small fenestration size and rigidness of the edges of the fenestration caused by the MCs. Multiple attempts to dilate the fenestration using a peripheric angioplasty balloon failed. Only angioplasty with the ‘balloon-against-dilator’ technique was finally successful. Activation map showed a counterclockwise atrial flutter in the CA; successful ablation was performed. Discussion We present a case of challenging access to the CA through a clipped fenestration in a polytetrafluoroethylene baffle for atrial tachycardia ablation. Even though a tunnel fenestration in Fontan patients facilitates access to the CA, the passage of a steerable introducer with a mapping catheter may be challenging due to diameter mismatch and the rigidity of its edges caused by MCs. The balloon-against-dilator technique might be helpful when conventional balloon angioplasty fails.

Paediatric heart transplantation: life-saving but not yet a cure.

In the 1980s, heart transplantation was the first successful treatment for infants born with hypoplastic left heart syndrome. Infants who have required heart transplantation benefit from immunologic "advantages," including long-term survival free from cardiac allograft vasculopathy. Currently ∼ 90% of children undergoing a heart transplant are reaching their first-year anniversary and the clinical practices of paediatric heart transplantation have dramatically improved. These successes are largely attributed to research sponsored by the Pediatric Heart Transplant Study Group, the International Society of Heart and Lung Transplantation and, more recently, the Non-profits Enduring Hearts and Additional Ventures. Despite these successes, the field is challenged to increase progress to achieve long-term survival into adulthood. The wait-list mortality, especially among infants, is unacceptably high often leading to palliative measures that can increase post-transplant mortality. Cardiac allograft vasculopathy remains a major cause for progressive graft loss of function and sudden death. The relative tolerance seen in immature recipients has not been translated to modifying older recipients' post-transplant outcomes. The modifiable cause(s) for the increased risks of transplantation in children of different ethnicities and races require definition. Addressing these challenges faces the reality that for-profit research favours funding adult recipients, with ∼ 10-fold greater numbers, and their more modest longevity goals. Advocacy for funding "incentives" such as the Orphan Drug rules in the United States and upholding principles of equity and inclusion are critical to addressing the challenges of paediatric heart transplant recipients worldwide.

Ethical Attitudes and Handling in Prenatal Conflict Situations - A Survey among Obstetricians and Prenatal Diagnosticians in Germany

Various studies have shown that belonging to a professional group has an influence on ethical attitudes. The aim of this study was to assess and compare the attitudes and approaches of obstetrical specialists and prenatal diagnosticians in prenatal conflict situations. Explorative cross-sectional online survey among tertiary perinatal care centers and prenatal diagnosticians with DEGUM Level II/III in Germany. The questionnaire included questions on ethical attitudes in the perinatal context and a case presentation of a fetal hypoplastic left heart syndrome. The response rate was 57.1% (310/543). 55.5% of the respondents practiced both obstetrics and prenatal diagnostics, 24.5% exclusively prenatal diagnostics, and 14.2% purely obstetrics. 27% agreed with the statement "An uncertain prognosis justifies pregnancy termination". For complex fetal malformations joint interdisciplinary counseling was advocated by 98.3%. Addressing the option of postnatal palliative treatment in a case of a hypoplastic left heart syndrome was accepted by 84.3% across all professional groups, while mentioning fetocide was more frequently cited as an option by prenatal diagnosticians than by obstetricians (57.7% vs. 34.1%). Interdisciplinary prenatal parental counseling in complex fetal malformations is uniformly advocated by prenatal diagnosticians and obstetricians in Germany. However, different ethical attitudes appear among specialists groups with regard to the option of termination of pregnancy.

Detection of hypoplastic left heart syndrome anatomy from cardiovascular magnetic resonance images using machine learning

ObjectiveThe prospect of being able to gain relevant information from cardiovascular magnetic resonance (CMR) image analysis automatically opens up new potential to assist the evaluating physician. For machine-learning-based classification of complex congenital heart disease, only few studies have used CMR.Materials and methodsThis study presents a tailor-made neural network architecture for detection of 7 distinctive anatomic landmarks in CMR images of patients with hypoplastic left heart syndrome (HLHS) in Fontan circulation or healthy controls and demonstrates the potential of the spatial arrangement of the landmarks to identify HLHS. The method was applied to the axial SSFP CMR scans of 46 patients with HLHS and 33 healthy controls.ResultsThe displacement between predicted and annotated landmark had a standard deviation of 8–17 mm and was larger than the interobserver variability by a factor of 1.1–2.0. A high overall classification accuracy of 98.7% was achieved.DiscussionDecoupling the identification of clinically meaningful anatomic landmarks from the actual classification improved transparency of classification results. Information from such automated analysis could be used to quickly jump to anatomic positions and guide the physician more efficiently through the analysis depending on the detected condition, which may ultimately improve work flow and save analysis time.

The impact of specialty training and physician attitudes on fetal cardiac counseling

Objective Fetal cardiac anomalies are the most commonly diagnosed structural anomalies. In these cases, Maternal-Fetal Medicine (MFM) specialists are tasked with counseling patients on a spectrum of diagnoses as well as their prognostic implications. A recent study of pediatric cardiologists demonstrated that personal beliefs regarding termination impact the counseling provided to patients. Our objective was to study whether the personal beliefs of MFMs impact counseling of patients with severe fetal cardiac anomalies and to compare these providers to their cardiology counterparts. Methods We conducted an anonymous cross-sectional survey of MFMs in New England that assessed personal beliefs and counseling practices when diagnosing hypoplastic left heart syndrome (HLHS). We subsequently compared these providers to the previously surveyed cardiologists. Results A total of 34 respondents representing a broad spectrum of age and experience across several states in New England were analyzed. When presented with the statement “some life is always better than no life at all,” 79% (n = 27) of respondents disagreed and all respondents (n = 34) offered termination, palliative care, and treatment options when counseling patients with HLHS. Additionally, while 74% (n = 25) of providers would personally support a decision to terminate a pregnancy with HLHS, 94% (n = 32) would professionally support the decision to pursue termination. MFMs and cardiologists differed in their responses to “some life is better than no life” and the belief that termination should be offered, though differences did not reach statistical significance. However, with respect to the providers’ personal and professional support of the decision to terminate the pregnancy, the groups of respondents varied significantly in their level of support, both professionally and personally with fewer cardiologists supporting this decision. Conclusion When diagnosing a severe and potentially fatal congenital cardiac anomaly, counseling by MFMs was largely unaffected by personal beliefs regarding termination of pregnancy. While this is consistent with previously published data on counseling practices among pediatric cardiology specialists, some important differences between the specialties were seen.

Human Genetics of Hypoplastic Left Heart Syndrome.

Hypoplastic left heart syndrome (HLHS) is a severe congenital cardiovascular malformation characterized by hypoplasia of the left ventricle, aorta, and other structures on the left side of the heart. The pathologic definition includes atresia or stenosis of both the aortic and mitral valves. Despite considerable progress in clinical and surgical management of HLHS, mortality and morbidity remain concerns. One barrier to progress in HLHS management is poor understanding of its cause. Several lines of evidence point to genetic origins of HLHS. First, some HLHS cases have been associated with cytogenetic abnormalities (e.g., Turner syndrome). Second, studies of family clustering of HLHS and related cardiovascular malformations have determined HLHS is heritable. Third, genomic regions that encode genes influencing the inheritance of HLHS have been identified. Taken together, these diverse studies provide strong evidence for genetic origins of HLHS and related cardiac phenotypes. However, using simple Mendelian inheritance models, identification of single genetic variants that "cause" HLHS has remained elusive, and in most cases, the genetic cause remains unknown. These results suggest that HLHS inheritance is complex rather than simple. The implication of this conclusion is that researchers must move beyond the expectation that a single disease-causing variant can be found. Utilization of complex models to analyze high-throughput genetic data requires careful consideration of study design.

Molecular Pathways and Animal Models of Hypoplastic Left Heart Syndrome.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) with underdevelopment of left-sided heart structures. While previously uniformly fatal, surgical advances now provide highly effective palliation that allows most HLHS patients to survive their critical CHD. Nevertheless, there remains high morbidity and mortality with high risk of heart failure. As hemodynamic compromise from restricted aortic blood flow has been suggested to underlie the poor LV growth, this suggests the possibility of prenatal fetal intervention to recover LV growth. As such interventions have yielded ambiguous results, the optimization of therapy will require more mechanistic insights into the developmental etiology for HLHS. Clinical studies have shown high heritability for HLHS, with an oligogenic etiology indicated in conjunction with genetic heterogeneity. This is corroborated with the recent recovery of mutant mice with HLHS. With availability-induced pluripotent stem cell (iPSC)-derived cardiomyocytes from HLHS mice and patients, new insights have emerged into the cellular and molecular etiology for the LV hypoplasia in HLHS. Cell proliferation defects were observed in conjunction with metaphase arrest and the disturbance of Hippo-YAP signaling. The left-sided restriction of the ventricular hypoplasia may result from epigenetic perturbation of pathways regulating left-right patterning. These findings suggest new avenues for fetal interventions with therapies using existing drugs that target the Hippo-YAP pathway and/or modulate epigenetic regulation.

Cardiovascular magnetic resonance reference values of right ventricular volumetric variables in patients with hypoplastic left heart syndrome

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 2.2-25.2years, 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.

Successful treatment of dumping syndrome with diazoxide in an infant with hypoplastic left heart syndrome.

Dumping syndrome is a rare but potentially serious condition that causes inappropriate postprandial hyperinsulinemia leading to hypoglycemia in children following gastrointestinal surgeries. While dietary modifications are often the first line of treatment, severe cases may require pharmacological intervention to prevent severe hypoglycemia. We present a case of successful treatment of dumping syndrome with diazoxide. A 2-month-old infant with left hypoplastic heart syndrome who underwent single ventricle palliation pathway and developed feeding intolerance that required Nissen fundoplication. Postprandial hypoglycemia was detected following the procedure, with glucose level down to 12 mg/dL, and the diagnosis of dumping syndrome was established. The patient was successfully managed with diazoxide, which effectively resolved postprandial hypoglycemia without any major adverse events. The patient was eventfully weaned off the medication at the age of 5 months. This case highlights the potential role of diazoxide in the management of pediatric patients with postprandial hyperinsulinemic hypoglycemia secondary to dumping syndrome. Dumping syndrome is a possible complication of gastrointestinal surgeries and should be suspected in children with abnormal glucose levels. Postprandial hyperglycemia should be monitored closely for significant subsequent hypoglycemia. Diazoxide might be considered as part of the treatment plan for dumping syndrome.