Hypoplastic Left Heart Syndrome Patients Research Articles

Abstract 15467: Bi-Leaflet Tricuspid Valve in Children With Hypoplastic Left Heart Syndrome is Rarely Incompetent, While Bi-Leaflet With a Cleft Results in Tricuspid Valve Regurgitation

Introduction: Tricuspid valve (TV) regurgitation in Hypoplastic Left Heart Syndrome (HLHS) increases the risk of death/transplantation by 2 to 3 times. Abnormalities in TV annular shape, leaflets expansion and subvalve apparatus position, have been associated in HLHS with subsequent tricuspid regurgitation (TR). As TV morphological variation is increasingly recognized, its role on tricuspid valve function remains unknown. This study aims to describe and examine the relationship between the TV leaflet morphologies in HLHS and its association with TV repair. Methods: Cross sectional study of selected 38 “classic” HLHS patients from a prospective longitudinal 3DE study of HLHS TV. TV leaflet morphology from 3DE datasets were reviewed (S.Z and N.S.K) blinded to TR grade. We adapted a previously proposed nomenclature to describe the TV leaflets (Figure 1). Using the Chi-squared test, we compared the frequencies of TV morphological types of HLHS with mild or less TR (n = 23) vs. HLHS who had TV repair (n = 15) at latest follow up. Results: Incidence of TV morphological type is summarized in Figure 2. Bi-leaflet TV was the second most common, followed by bi-leaflet with a cleft. When comparing HLHS with mild or less TR vs. HLHS with TVR, only 1 of 9 bi-leaflet TV had subsequent TVR, while all bi-leaflet TV with a cleft, underwent TVR (p<0.05). Conclusion: HLHS has considerable TV leaflet variations with bi-leaflet TV being the second most common variation. While bi-leaflet TV is more likely to be found in a competent TV, those with a bi-leaflet TV with a cleft, all required TVR. Bi-leaflet TV with a cleft, warrants further study to assess its relationship and relative role with TVR.

Abstract 15156: Statistical Modeling of Cardiac-Derived Progenitor Cell Extracellular Vesicles to Predict Clinical Trial Outcomes

Introduction: Cardiac-derived c-kit+ progenitor cells (CPCs) are under investigation in the CHILD phase I clinical trial (NCT03406884) for the treatment of hypoplastic left heart syndrome (HLHS). Therapeutic efficacy of CPCs can be attributed to the release of extracellular vesicles (EVs), carrying beneficial RNA cargo. Despite some successes with pediatric cardiac cell therapy, large variation in cell populations and patient outcomes remains a problem. To investigate these discrepancies and understand sources of cell therapy variability we took a machine learning approach: combining bulk CPC-derived EV (CPC-EV) RNA sequencing and cardiac-relevant in vitro experiments to build a predictive model. Methods: We isolated CPCs from cardiac biopsies of congenital heart disease patients (n=30) and the lead-in HLHS patients in the CHILD trial (n=7). We cultured CPCs, collected EVs from the media, and sequenced EV miRNA and total RNA. We treated cardiac endothelial cells and fibroblasts with CPC-EVs and measured inflammatory or fibrotic gene expression with qRT-PCR. We treated mesenchymal stromal cells with CPC-EVs and assessed migration in a Boyden chamber system. We treated cardiac endothelial cells seeded on Matrigel with CPC-EVs and measured tube formation. Finally, we put together the CPC-EV sequencing and experimental data in partial least squares and regularized regression models. Results: With our models we determined that the most important CPC-EV RNA signals involved in pro-reparative outcomes had significant fit to cardiac development and signaling pathways. Furthermore, using a model trained on previously collected CPC-EVs, we were able to predict in vitro outcomes for the CHILD clinical samples. Finally, we formed rank-based predictions for the CHILD lead-in patients, based on the in vitro assays. Conclusions: The CHILD phase I trial is set to conclude next year. We will validate our predictions with the release of these clinical data. With this work, we (1) investigated the EV RNA signals involved in pediatric cardiac repair and (2) will use our in vitro results to predict CHILD clinical trial outcomes. Our results highlight the importance of quantitative studies in determining the underlying variance in pediatric cardiac cell therapy.

Current state of the art in hypoplastic left heart syndrome.

Hypoplastic left heart syndrome (HLHS) is a complex congenital heart condition in which a neonate is born with an underdeveloped left ventricle and associated structures. Without palliative interventions, HLHS is fatal. Treatment typically includes medical management at the time of birth to maintain patency of the ductus arteriosus, followed by three palliative procedures: most commonly the Norwood procedure, bidirectional cavopulmonary shunt, and Fontan procedures. With recent advances in surgical management of HLHS patients, high survival rates are now obtained at tertiary treatment centers, though adverse neurodevelopmental outcomes remain a clinical challenge. While surgical management remains the standard of care for HLHS patients, innovative treatment strategies continue to be developing. Important for the development of new strategies for HLHS patients is an understanding of the genetic basis of this condition. Another investigational strategy being developed for HLHS patients is the injection of stem cells within the myocardium of the right ventricle. Recent innovations in tissue engineering and regenerative medicine promise to provide important tools to both understand the underlying basis of HLHS as well as provide new therapeutic strategies. In this review article, we provide an overview of HLHS, starting with a historical description and progressing through a discussion of the genetics, surgical management, post-surgical outcomes, stem cell therapy, hemodynamics and tissue engineering approaches.

Intrinsic myocardial defects underlie an Rbfox-deficient zebrafish model of hypoplastic left heart syndrome

Hypoplastic left heart syndrome (HLHS) is characterized by underdevelopment of left sided structures including the ventricle, valves, and aorta. Prevailing paradigm suggests that HLHS is a multigenic disease of co-occurring phenotypes. Here, we report that zebrafish lacking two orthologs of the RNA binding protein RBFOX2, a gene linked to HLHS in humans, display cardiovascular defects overlapping those in HLHS patients including ventricular, valve, and aortic deficiencies. In contrast to current models, we demonstrate that these structural deficits arise secondary to impaired pump function as these phenotypes are rescued when Rbfox is specifically expressed in the myocardium. Mechanistically, we find diminished expression and alternative splicing of sarcomere and mitochondrial components that compromise sarcomere assembly and mitochondrial respiration, respectively. Injection of human RBFOX2 mRNA restores cardiovascular development in rbfox mutant zebrafish, while HLHS-linked RBFOX2 variants fail to rescue. This work supports an emerging paradigm for HLHS pathogenesis that centers on myocardial intrinsic defects.

The outcomes of Fontan operation in patients with hypoplastic left heart syndrome (HLHS) versus other forms of univentricular heart

Abstract Background Single ventricle physiology is a rare condition but is highly represented in clinical practice due to a high prevalence of late complications and comorbidities. The Fontan operation has undergone considerable modification over the past 5 decades and is now in a superior hydrodynamic form. Purpose The purpose was to identify the potential differences in outcomes of Fontan operation between patients with hypoplastic left heart syndrome (HLHS) and with other indications to this treatment. Methods and results The study comprised 74 patients (20±6 years) after the Fontan operation (26 females) divided based on the indication to this operation as a group with HLHS (19 patients) and the group without HLHS (54 patients). Patients with HLHS had significantly more often had a fenestration between the systemic venous return and the pulmonary venous atrium (89% vs 41%; p=0.001) which was closed in further observation in 89% in HLHS versus 39% in patients without HLHS, p=0.001. Regarding complications after Fontan operation, in HLHS group more often narrowings of pulmonary arteries requiring stenting occurred (74% vs 13%; p=0.001) and Fontan-associated liver disease (37% vs 9%, p=0.05). There were no differences in stenting of the lateral tunnel connection, fistulas, enteropathy, rhythm disturbances, peacemaker implantation, vascular complications, strokes between groups. HLHS patients more often were treated with antiplatelet drugs (26% vs 0, p=0.001), spironolactone (63% vs 23%, p=0.01) and angiotensin-converting-enzyme inhibitors (89% vs 44%, p=0.01). Conclusions HLHS patients have worse outcomes of Fontan operation. This group of patients more often needs fenestrations and regular controls towards pulmonary arteries narrowings and Fontan-associated liver disease. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Polish Mother's Memorial Hospital - Research Institute

P.38 A novel splice site variant in a patient with spinal muscular atrophy and hypoplastic left heart syndrome

Spinal muscular atrophy (SMA) is an autosomal recessive disorder causing degeneration of motor neurones in the anterior horn of the spinal cord. SMA is caused by homozygous in activation of the SMN1 gene but a highly homologous copy (SMN2), which also produces a small amount of functional SMN protein, can mitigate disease severity. We present a patient with a severe SMA phenotype with hypoplastic left heart syndrome (HLHS), characterize a novel spice-site variant in the SMN1 gene and describe the unusual pathological features in muscle biopsy. The patient was born to consanguineous parents in a national heart center due to antenatal diagnosis of HLHS. Postnatal examination (day 4) revealed decreased tone, a lack of anti-gravity movements, absent deep tendon reflexes but no respiratory distress or feeding problems. Due to the combination of suspected muscle disease and HLHS, together with the results below, treatment was discontinued and the patient died on day 10 of life. Whole genome sequencing (WGS) revealed an apparently homozygous variant in SMN1 located in the donor splice-site between exon 7 and intron 7, c.*3+1G>T (NM_000344.3). MLPA identified one copy of SMN1 and SMN2. Analysis of RNA showed a transcript lacking exon 7 and western blotting of SMN protein from muscle showed reduced levels comparable to other SMA1 patients. Muscle biopsy and subsequent immunohistochemical and immunofluorescence showed unusual expression of embryonic myosin heavy chain in the patient compared to controls and other SMA patients. This case highlights the importance of rapid diagnosis of newborns to allow further treatment decisions to be made. Up to 30% of HLHS patients have associated conditions and the combination with SMA has been previously described, whether this is more than the coincidence of two relatively common conditions is unclear. A severe SMA phenotype has been previously seen in other patients with a splice site variant in intron 7.

Journey Toward Improved Long-Term Outcomes After Norwood-Sano Procedure: Focus on the Aortic Arch Reconstruction.

The disadvantage of right ventricle-to-pulmonary artery (RV-PA) shunt is the need for more unplanned interventions to address stenosis in the shunt or branch pulmonary arteries, as compared to the modified Blalock-Taussig shunt group. Ring-enforced RV-PA PTFE conduit and dunk technique minimized these complications and right ventricle (RV) damage. Aortic arch obstruction increases afterload and leads to ventricular dysfunction and tricuspid regurgitation; therefore, most surgeons prefer to use homograft, autologous pericardium, or bovine pericardium to reconstruct the neoaorta. Artificial materials decrease the elastic properties, increase wall stiffness, and decrease the distensibility of the aorta; and as a result, RV function gradually deteriorates. This inelastic reconstructed aorta may be one of the reasons why long-term outcomes after the Fontan procedure are worse in hypoplastic left heart syndrome (HLHS) patients, in comparison to non-HLHS. Reconstruction of the neoaorta without any patch materials, or at least techniques that largely minimize the use of non-autologous materials, will offer a further refinement of our ability to optimize ventriculoarterial coupling and thereby long-term RV function.

Novel Insights into the Etiology, Genetics, and Embryology of Hypoplastic Left Heart Syndrome.

Hypoplastic left heart syndrome (HLHS) is a relatively rare severe congenital heart defect (CHD) closely linked to other left ventricular outflow tract (LVOT) lesions including bicuspid aortic valve (BAV), one of the most common heart defects. While HLHS, BAV, and other LVOT lesions have a strong genetic underpinning, their genetic etiology remains poorly understood. Findings from a large-scale mouse mutagenesis screen showed HLHS has a multigenic etiology and is genetically heterogenous, explaining difficulties in identifying the genetic causes of HLHS. In Ohia mice, HLHS shows incomplete penetrance. Some mice exhibited small LV with normal aorta, and others a normal LV with hypoplastic aorta, indicating the LV hypoplasia is not hemodynamically driven. In Ohia mutants, HLHS was found to have a digenic modular construction, with mutation in a chromatin modifier causing the small LV phenotype and mutation in Pcdha9 causing the aorta/aortic valve hypoplasia. The Pcdha9 mutation alone can cause BAV, and in the human genome two common deletion copy number variants spanning PCDHA7-10 are associated with BAV. Hence the digenic etiology of HLHS can account for the close association of HLHS, a rare CHD, with BAV, one of the most common CHD. Functional analysis of Ohia HLHS heart tissue showed severe mitochondrial dysfunction in the small LV, while the normal size RV is also affected but milder, suggesting possible role in vulnerability of surgically palliated HLHS patients to heart failure. These findings suggest insights into the genetics of HLHS may yield new therapies for improving outcome for patients with HLHS.

Medical Therapies for Heart Failure in Hypoplastic Left Heart Syndrome.

Significant surgical and medical advances over the past several decades have resulted in a growing number of infants and children surviving with hypoplastic left heart syndrome (HLHS) and other congenital heart defects associated with a single systemic right ventricle (RV). However, cardiac dysfunction and ultimately heart failure (HF) remain the most common cause of death and indication for transplantation in this population. Moreover, while early recognition and treatment of single ventricle-related complications are essential to improving outcomes, there are no proven therapeutic strategies for single systemic RV HF in the pediatric population. Importantly, prototypical adult HF therapies have been relatively ineffective in mitigating the need for cardiac transplantation in HLHS, likely due to several unique attributes of the failing HLHS myocardium. Here, we discuss the most commonly used medical therapies for the treatment of HF symptoms in HLHS and other single systemic RV patients. Additionally, we provide an overview of potential novel therapies for systemic ventricular failure in the HLHS and related populations based on fundamental science, pre-clinical, clinical, and observational studies in the current literature.

Significance of α-Myosin Heavy Chain (MYH6) Variants in Hypoplastic Left Heart Syndrome and Related Cardiovascular Diseases.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) with complex genetic inheritance. HLHS segregates with other left ventricular outflow tract (LVOT) malformations in families, and can present as either an isolated phenotype or as a feature of a larger genetic disorder. The multifactorial etiology of HLHS makes it difficult to interpret the clinical significance of genetic variants. Specific genes have been implicated in HLHS, including rare, predicted damaging MYH6 variants that are present in >10% of HLHS patients, and which have been shown to be associated with decreased transplant-free survival in our previous studies. MYH6 (α-myosin heavy chain, α-MHC) variants have been reported in HLHS and numerous other CHDs, including LVOT malformations, and may provide a genetic link to these disorders. In this paper, we outline the MYH6 variants that have been identified, discuss how bioinformatic and functional studies can inform clinical decision making, and highlight the importance of genetic testing in HLHS.

Novel Protein-Protein Interactions Highlighting the Crosstalk between Hypoplastic Left Heart Syndrome, Ciliopathies and Neurodevelopmental Delays.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) affecting 1 in 5000 newborns. We constructed the interactome of 74 HLHS-associated genes identified from a large-scale mouse mutagenesis screen, augmenting it with 408 novel protein–protein interactions (PPIs) using our High-Precision Protein–Protein Interaction Prediction (HiPPIP) model. The interactome is available on a webserver with advanced search capabilities. A total of 364 genes including 73 novel interactors were differentially regulated in tissue/iPSC-derived cardiomyocytes of HLHS patients. Novel PPIs facilitated the identification of TOR signaling and endoplasmic reticulum stress modules. We found that 60.5% of the interactome consisted of housekeeping genes that may harbor large-effect mutations and drive HLHS etiology but show limited transmission. Network proximity of diabetes, Alzheimer’s disease, and liver carcinoma-associated genes to HLHS genes suggested a mechanistic basis for their comorbidity with HLHS. Interactome genes showed tissue-specificity for sites of extracardiac anomalies (placenta, liver and brain). The HLHS interactome shared significant overlaps with the interactomes of ciliopathy- and microcephaly-associated genes, with the shared genes enriched for genes involved in intellectual disability and/or developmental delay, and neuronal death pathways, respectively. This supported the increased burden of ciliopathy variants and prevalence of neurological abnormalities observed among HLHS patients with developmental delay and microcephaly, respectively.

Unlocking the Non-invasive Assessment of Conduit and Reservoir Function in the Aorta

Aortic surgeries in congenital conditions, such as hypoplastic left heart syndrome (HLHS), aim to restore and maintain the conduit and reservoir functions of the aorta. We proposed a method to assess these two functions based on 4D flow MRI, and we applied it to study the aorta in pre-Fontan HLHS. Ten pre-Fontan HLHS patients and six age-matched controls were studied to derive the advective pressure difference and viscous dissipation for conduit function, and pulse wave velocity and elastic modulus for reservoir function. The reconstructed neo-aorta in HLHS subjects achieved a good conduit function at a cost of an impaired reservoir function (69.7% increase of elastic modulus). The native descending HLHS aorta displayed enhanced reservoir (elastic modulus being 18.4% smaller) but impaired conduit function (three-fold increase in peak advection). A non-invasive and comprehensive assessment of aortic conduit and reservoir functions is feasible and has potentially clinical relevance in congenital vascular conditions.Graphical abstract

Skeletal model-based analysis of the tricuspid valve in hypoplastic left heart syndrome.

Hypoplastic left heart syndrome (HLHS) is a congenital heart disease characterized by incomplete development of the left heart. Children with HLHS undergo a series of operations which result in the tricuspid valve (TV) becoming the only functional atrioventricular valve. Many HLHS patients develop tricuspid regurgitation and right ventricle enlargement which is associated with heart failure and death without surgical intervention on the valve. Understanding the connections between the geometry of the TV and its function remains extremely challenging and hinders TV repair planning. Traditional analysis methods rely on simple anatomical measures which do not capture information about valve geometry in detail. Recently, surface-based shape representations such as SPHARM-PDM have been shown to be useful for tasks such as discriminating between valves with normal or poor function. In this work we propose to use skeletal representations (s-reps), a more feature-rich geometric representation, for modeling the leaflets of the tricuspid valve. We propose an extension to previous s-rep fitting approaches to incorporate application-specific anatomical landmarks and population information to improve correspondence. We use several traditional statistical shape analysis techniques to evaluate the efficiency of this representation: using principal component analysis (PCA) we observe that it takes fewer modes of variation compared to boundary-based approaches to represent 90% of the population variation, while distance-weighted discrimination (DWD) shows that s-reps provide for more significant classification between valves with less regurgitation and those with more. These results show the power of using s-reps for modeling the relationship between structure and function of the tricuspid valve.

Abnormal torsion and helical flow patterns of the neo-aorta in hypoplastic left heart syndrome assessed with 4D-flow MRI.

The Norwood procedure is the first stage of correction for patients with hypoplastic left heart syndrome (HLHS) and may lead to an abnormal neoaortic anatomy. We prospectively studied the neoaorta's fluid dynamics and the abnormal twist of the neoaorta by MRI examinations of HLHS patients in Fontan circulation. This study for the first time investigates the hypothesis that the neoaorta twist is associated with increased helical flow patterns, which may lead to an increased workload for the systemic right ventricle (RV) and ultimately to RV hypertrophy. A group of forty-two HLHS patients with a median age of 4.9 (2.9-17.0) years, at NYHA I was studied along with a control group of eleven subjects with healthy hearts and a median age of 12.1 (4.0-41.6). All subjects underwent MRI of the thoracic aorta including ECG-gated 2D balanced SSFP cine for an axial slice stack and 4D-flow MRI for a sagittal volume slab covering the thoracic aorta. The twist of the neoaortic arch was quantified by the effective geometric torsion, defined as the product of curvature and geometric torsion. Fluid dynamics and geometry in the neoaorta, including the flow helicity index, were evaluated using an in-house analysis software (MeVisLab-based). Myocardial mass of the systemic ventricle at end-diastole was estimated by planimetry of the short-axis stack. Compared to the control group, the neoaorta in the HLHS patients shows an increased twist (P=0.04) and higher peak helicity density (P=0.03). The maximum helicity density was correlated with maximum effective torsion of the ascending neoaorta (P<0.001). The degree of maximum twist correlated with the increase in RV myocardial mass (P<0.01). This study shows that the abnormal twist of the neoaortic arch in HLHS patients is associated with abnormal helical flow patterns, which may contribute to increased RV afterload and may adversely affect the systemic RV by stimulation of myocardial hypertrophy. These findings suggest that further improvements of surgical aortic reconstruction, guided by insights from 4D-flow MRI, could lead to better neoaortic fluid dynamics in patients with HLHS.

Insights from 3D Echocardiography in Hypoplastic Left Heart Syndrome Patients Undergoing TV Repair.

Tricuspid regurgitation (TR) in hypoplastic left heart syndrome (HLHS) is associated with morbidity and mortality. TR mechanisms and the impact of tricuspid valve repair (TVR) are unclear. We examined HLHS TR mechanisms, TVR's impact on tricuspid valve (TV), and features of poor TVR durability. We retrospectively compared 35 HLHS TVR cases and 35 age/stage-matched HLHS controls who do not undergo TVR. Pre-operative 3-dimensional echocardiography (3DE) assessed overall TV morphology (prolapse, normal, tethered), leaflet morphology, vena contracta area, and TR location. Two-dimensional echocardiography measured TV annulus diameter, RV fractional area change (RVFAC), sphericity, and TR grade at three time points (pre-op, early post-op, and latest follow-up). Pre-op, TVR group, and controls had no difference in age, RV function or shape, or TV dimension. TVR group most commonly had anterior leaflet prolapse followed by septal leaflet prolapse or tethering. TR jet arises centrally (63%) and anterior septally (26%). Posterior annuloplasty (69%), commissuroplasty (37%), and leaflet repair (37%) were surgical techniques commonly performed. At early post-op, TR grade and TV annulus decreased. At latest follow-up, TV annulus remained reduced; however, 50% had significant TR. 25% required TV reoperation. Larger vena contracta at TVR was associated with significant TR. HLHS patients undergoing TVR had more anterior leaflet prolapse and central TR. While TVR initially reduces annular size and TR grade, 50% redevelop significant TR despite maintained annular reduction. The association of greater TR severity prior to repair with post-op recurrence raises the consideration for earlier repair of TR in HLHS patients.

Abstract 10723: Fetal Echocardiographic Assessment of Right Ventricular and Tricuspid Valve Function in Hypoplastic Left Heart Syndrome: Correlation with Postnatal Outcomes

Introduction: Hypoplastic left heart syndrome (HLHS) carries significant morbidity and mortality. Transthoracic echocardiogram (echo) assessment of right ventricular (RV) function and tricuspid regurgitation (TR) correlate with HLHS outcomes. There are limited reports on RV function and TR in fetal HLHS and postnatal outcomes. We aim to correlate RV function and TR on fetal-echo (F-echo) with transplant-free survival (survival), hospital length of stay after initial surgery (LOS), and timing of Glenn (BDG) in HLHS patients. Methods: Imaging and clinical data of fetuses diagnosed with HLHS between February 2014 and September 2020 at our institution were retrospectively reviewed. Measurements of RV myocardial performance index (MPI) and fractional area change (FAC) were made on initial F-echo. The RV shortening fraction (SF), presence/degree of TR, and RV size by diastolic short-axis dimension were recorded. Postnatal outcomes included survival, LOS and age at BDG. Early BDG was a repair at &lt;4 months. Mann-Whitney U test correlated F-echo measures and postnatal outcomes. Results: F-echo was available in 69 subjects; 22 excluded for termination/fetal demise, 9 for genetic syndromes, resulting in 38 subjects. Mean age at initial F-echo was 31.4±0.9wks, 11 referred &gt;30 weeks from regional cardiologists (adjusted mean age 23.1±0.4wks). Subject age at time of review ranged from 7 months to 6.5 years. Eight subjects died (median age 2 months) and 3 required transplant (median age 8 months). F-echo RV MPI was significantly higher (0.372±0.09;p=0.005) and RV FAC was significantly lower (43%±6.4%;p=0.016) in HLHS non-survivors versus survivors. Fetal RV size and presence of TR were not significantly different. Subjects with initial LOS &gt;30 days were more likely to have fetal TR (p&lt;0.001) and RV dilation (p=0.019), but no significant RV MPI and FAC difference. No fetal measures correlated with need for an early BDG. Conclusion: F-echo evaluation of RV MPI and FAC in HLHS correlates with transplant-free survival. Presence of fetal TR and RV dilation correlate with a longer LOS. F-echo measures of RV function and TR function may inform prenatal counseling and postnatal outcomes for fetal HLHS.

Abstract 8911: Incidence and Risk Factors of Aortic Arch Obstruction After the Comprehensive Stage II Procedure

Introduction: Minimal data exist about the incidence and risk factors for arch intervention after Comprehensive Stage II (CSII). Goal of this study was to document incidence of arch interventions after CSII and determine if any differences existed between those that underwent an arch intervention (aiCSII) versus those did not have an intervention. Methods: Retrospective chart review of all hypoplastic left heart syndrome patients that underwent a CSII between 6/1/2005 through 2/1/2020 was performed. Univariate analysis was conducted in addition to principal components analysis (PCA). Results: One hundred patients were evaluated. Sixteen patients underwent 24 arch interventions. Age at initial arch reintervention was 1.3 + 1.2 years (median 1.0 years, range 0.5 - 2.2 years). Univariate analysis showed that the aiCSII group were more likely to be female, to have had a retrograde arch intervention post-hybrid procedure, and to be younger at time of CSII. On echocardiograms, aiCSII group had significantly higher pre-CSII patent ductus arteriosus velocities, arch velocities on their 1 st post-operative and discharge study post-CSII, and arch velocities pre-Fontan. Gradients were higher in the aiCSII via pre-Fontan catheterization. With PCA, echocardiographic and catheterization data remained significantly associated with aiCSII versus those that did not undergo an arch intervention (OR = 4.5 (1.9, 19.8), p &lt; 0.01). Mortality was not associated with arch intervention. Conclusions: Incidence of arch intervention post-CSII was 16%. Echocardiographic arch gradients during the CSII hospitalization were the strongest predictors for subsequent aortic arch interventions. Further studies are needed to determine any modifiable variables that may reduce the incidence of arch interventions.

Abstract 13734: Biomechanical Comparison of Atrioventricular Valve Repair Strategies in Hypoplastic Left Heart Syndrome

Purpose: Atrioventricular valve (AV) regurgitation in hypoplastic left heart syndrome (HLHS) remains a challenging problem with no clear consensus on optimal repair strategies. We sought to evaluate the effect of AV repairs on leaflet biomechanics. Methods: Explanted fetal bovine tricuspid valves and right ventricles were sutured onto annular and ventricular mounts derived from imaging data of HLHS patients. The annulus underwent an average areal dilation of 21% with preferential dilation of the free wall (Fig 1A). The specimens were then placed in a previously validated univentricular heart simulator and subjected to the typical flows and pressures seen at Norwood, Glenn, early Fontan, and late Fontan stages. The valves underwent repair via De Vega suture annuloplasty (AP) or anteroseptal commissuroplasty (CP). Leaflet forces pre- and post-repair were measured using optical strain sensors (fiber Bragg grating) sutured to each leaflet edge. Statistical significance was determined using paired t-test. Results: A total of 8 AP and 7 CP specimens underwent testing. Regurgitation decreased from 2+ to &lt;1+ following both repairs. With AP, forces in the tricuspid valve anterior (TVAL), posterior (TVPL), and septal leaflets (TVSL) as a percentage change from pre-repair were [TVAL:-12.6%, p&lt;0.001 Conclusions: Force reduction was seen only in the anterior and posterior leaflets with CP in contrast to the global reduction seen in AP. This difference may compound with cardiac cycling and impact the longevity of the repair. Future studies with more complex pathologies and repair strategies can help develop more tailored techniques.

Serial assessment of right ventricular function and deformation in patients with hypoplastic left heart syndrome: a cardiovascular magnetic resonance study

Abstract Background In patients with hypoplastic left heart syndrome (HLHS), right ventricular (RV) dysfunction and failure is a major cause of adverse outcome. Most studies have assessed RV function and size during staged palliation but serial data about RV deformation and function after completion of the Fontan circulation are rare. We assessed RV function and deformation by analysing serial cardiovascular magnetic resonance (CMR) studies in a large cohort of HLHS patients after completion of the total cavopulmonary connection (TCPC). Methods CMR examinations of 105 HLHS patients (female: 31, male: 74) were retrospectively analysed. Short axis cine images were used to measure RVEF and end-diastolic myocardial mass indexed to body surface area (RVMMi). 2-dimensional CMR feature tracking (2D-CMR-FT) was performed using long-axis and short axis cine images to measure myocardial global longitudinal, circumferential and radial strain (GLS, GCS, GRS) values. Results From 105 patients, all had at least two CMR examinations after TCPC completion (mean age at TCPC: 2.7±0.8 years; mean interval between examinations 5.4±1.6 years). 36 patients had three examinations (mean interval between first and third scan 9.9±2.2 years). The first scan was performed at a mean age of 5.6±2.9 years. Global strain values and RVEF decreased from the first to the third examination with a significant decline in GLS from the first examination to the second examination (median and interquartile range (IQR): −18.6%, IQR −20.4 to −16.3 vs. −16.8%, IQR −19.2 to −14.7) and from the first to the third examination in 36 patients (−18.6%, IQR −20.8 to −16.1 vs. −15.9%, IQR −18.3 to −12.4) (all p-values &amp;lt;0.004). RVEF decreased significantly from the first to the third examination (55.9%, IQR 50.2–59.8 vs. 50.4%, IQR 45.0–57.6; p&amp;lt;0.002) and from the second to the third examination (55.1%, IQR 47.1–58.7 vs. 50.4%, IQR 45.0–57.6; p&amp;lt;0.0004). The decrease in RVEF between the first and second scan and the changes in GCS and GRS across the examinations did not reach statistical significance. Median RVMMi increased significantly between the first and second scan (47.4 g/m2, IQR 39.0–55.3 vs. 50.2 g/m2, IQR 42.6–61.7; p&amp;lt;0.0007) and slightly but not significantly between the first and third scan in patients with three examinations (47.4 g/m2, IQR 39.5–56.2 vs. 50.1 g/m2, IQR 45.3–60.4). Negative correlations between GCS and RVEF (r=−0.57 to −0.76; p all &amp;lt;0.0001) as well as between GLS and RVEF (r=−0.31 to −0.59; p all &amp;lt;0.002) at all three time points could be demonstrated. Conclusion Serial assessment of CMR studies in HLHS patients after TCPC completion demonstrates a significant reduction in global strain values and RVEF at mid-term follow-up. The significant reduction in GLS between the first two examinations with non-significant changes in RVEF suggest that 2D-CMR-FT might be a suitable technique for the detection of early myocardial dysfunction. Funding Acknowledgement Type of funding sources: None.

Incidence of and Risk Factors for Aortic Arch Interventions After the Comprehensive Stage II Procedure for Hypoplastic Left Heart Syndrome.

Minimal data exist about the incidence and risk factors for arch intervention after comprehensive stage II (CSII). Goal of this study was to document incidence of arch interventions after CSII and determine if any differences existed between those who underwent an arch intervention (aiCSII) versus those did not have an intervention. Single-center retrospective chart review of all hypoplastic left heart syndrome patients who underwent a CSII between 6/1/2005 and 2/1/2020 was performed. Univariate analysis was conducted in addition to principal components analysis (PCA). One hundred patients were evaluated. Sixteen patients underwent 24 arch interventions. Age at initial arch reintervention was 1.3±1.2years (median 1.0years, range 0.5-2.2years). Univariate analysis showed that the aiCSII group were more likely to be female, to have had a retrograde arch intervention post-hybrid procedure, and to be younger at time of CSII. On echocardiograms, aiCSII group had significantly higher pre-CSII patent ductus arteriosus velocities, arch velocities on their 1st post-operative and discharge study post-CSII, and arch velocities pre-Fontan. Gradients were higher in the aiCSII via pre-Fontan catheterization. With PCA, echocardiographic and catheterization data remained significantly associated with aiCSII versus those who did not undergo an arch intervention (OR = 4.5 (1.9, 19.8), p = 0.008). Incidence of arch intervention post-CSII was 16%. Echocardiographic arch velocities during the CSII hospitalization were the strongest predictors for subsequent aortic arch interventions. Further studies are needed to determine any modifiable variables that may reduce the incidence of arch interventions.