High-Throughput Genomics Identify Novel FBN1/2 Variants in Severe Neonatal Marfan Syndrome and Congenital Heart Defects.

Fibrillin-1 and fibrillin-2, encoded by FBN1 and FBN2, respectively, play significant roles in elastic fiber assembly, with pathogenic variants causing a diverse group of connective tissue disorders such as Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCD). Different genomic variations may lead to heterogeneous phenotypic features and functional consequences. Recent high-throughput sequencing modalities have allowed detection of novel variants that may guide the care for patients and inform the genetic counseling for their families. We performed clinical phenotyping for two newborn infants with complex congenital heart defects. For genetic investigations, we employed next-generation sequencing strategies including whole-genome Single-Nucleotide Polymorphism (SNP) microarray for infant A with valvular insufficiency, aortic sinus dilatation, hydronephrosis, and dysmorphic features, and Trio whole-exome sequencing (WES) for infant B with dextro-transposition of the great arteries (D-TGA) and both parents. Infant A is a term male with neonatal marfanoid features, left-sided hydronephrosis, and complex congenital heart defects including tricuspid regurgitation, aortic sinus dilatation, patent foramen ovale, patent ductus arteriosus, mitral regurgitation, tricuspid regurgitation, aortic regurgitation, and pulmonary sinus dilatation. He developed severe persistent pulmonary hypertension and worsening acute hypercapnic hypoxemic respiratory failure, and subsequently expired on day of life (DOL) 10 after compassionate extubation. Cytogenomic whole-genome SNP microarray analysis revealed a deletion within the FBN1 gene spanning exons 7-30, which overlapped with the exon deletion hotspot region associated with neonatal Marfan syndrome. Infant B is a term male prenatally diagnosed with isolated D-TGA. He required balloon atrial septostomy on DOL 0 and subsequent atrial switch operation, atrial septal defect repair, and patent ductus arteriosus ligation on DOL 5. Trio-WES revealed compound heterozygous c.518C>T and c.8230T>G variants in the FBN2 gene. Zygosity analysis confirmed each of the variants was inherited from one of the parents who were healthy heterozygous carriers. Since his cardiac repair at birth, he has been growing and developing well without any further hospitalization. Our study highlights novel FBN1/FBN2 variants and signifies the phenotype-genotype association in two infants affected with complex congenital heart defects with and without dysmorphic features. These findings speak to the importance of next-generation high-throughput genomics for novel variant detection and the phenotypic variability associated with FBN1/FBN2 variants, particularly in the neonatal period, which may significantly impact clinical care and family counseling.

Center Volume Impacts Readmissions and Mortality after Congenital Cardiac Surgery.

OBJECTIVE: To characterize the relationship between surgical volume and postoperative outcomes in congenital heart surgery, we used a national cohort to assess the costs, readmissions, and complications in children undergoing cardiac operations. STUDY DESIGN: The Nationwide Readmissions Database was used to identify pediatric patients (≤18 years) undergoing congenital cardiac surgery from 2010 to 2017. Hospitals were categorized based on deciles and tertiles of annual caseload with high-volume categorized as the highest tertile of volume. Multivariable regression models adjusting for patient and hospital characteristics were used to study the impact of volume on 30-day nonelective readmission, mortality, home discharge, and resource use. RESULTS: Of an estimated 69 448 hospitalizations included for analysis, 56 672 (82%) occurred at high-volume centers. After adjustment for key clinical factors, each decile increase in volume was associated with a 25% relative decrease in the odds of mortality, a 14% decrease in the odds of nonhome discharge, and a 4% relative decrease in the likelihood of 30-day nonelective readmission. After risk adjustment, each incremental increase in volume decile was associated with a one-half-day decrease in the hospital length of stay, but did not alter costs of the index hospitalization. However, after including all readmissions within 30 days of the index discharge, high-volume centers were associated with significantly lower costs compared with low-volume hospitals. CONCLUSIONS: Increased congenital cardiac surgery volume is associated with improved mortality, reduced duration of hospitalization, 30-day readmissions, and resource use. These findings demonstrate the inverse relationship between hospital volume and resource use and may have implications for the centralization of care for congenital cardiac surgery.

Benefits of both physical assessment and electronic health record review to assess frailty prior to heart transplant.

INTRODUCTION: Frailty status affects outcomes after heart transplantation, but the optimal way to assess frailty prior to transplant remains unknown. METHODS: This single-center, observational study assessed 44 heart transplant candidates for frailty using three methods. The Short Physical Performance Battery (SPPB) and Fried Frailty Phenotype (FFP) were used as two physical assessments of frailty. The Frailty Risk Score (FRS) was used as a chart-review based assessment measuring 20 different biopsychosocial and functional components, including biomarkers, depression, cognitive impairment, and sleep. RESULTS: We determined the correlation between FRS, SPPB, and FFP and how each correlated with clinical outcomes. Of 44 participants, mean age was 60 years. FRS correlated with SPPB and FFP (P = .043, P < .001, respectively). Higher frailty as measured by SPPB and FRS was significantly associated with lack of achieving waitlist status (P = .022; P = .002) and not being transplanted (P = .026; P = .008). Higher frailty by SPPB and FFP was also associated with mortality (P = .010; P = .025). CONCLUSION: SPPB and chart-review FRS showed potential for predicting waitlist and transplant status of heart transplant candidates, while SPPB and FFP were associated with mortality. Additional studies may serve to validate these observations.

Discovery of non-HLA antibodies associated with cardiac allograft rejection and development and validation of a non-HLA antigen multiplex panel: From bench to bedside.

We analyzed humoral immune responses to nonhuman leukocyte antigen (HLA) after cardiac transplantation to identify antibodies associated with allograft rejection. Protein microarray identified 366 non-HLA antibodies (>1.5 fold, P < .5) from a discovery cohort of HLA antibody-negative, endothelial cell crossmatch-positive sera obtained from 12 cardiac allograft recipients at the time of biopsy-proven rejection. From these, 19 plasma membrane proteins and 10 autoantigens identified from gene ontology analysis were combined with 48 proteins identified through literature search to generate a multiplex bead array. Longitudinal sera from a multicenter cohort of adult cardiac allograft recipients (samples: n = 477 no rejection; n = 69 rejection) identified 18 non-HLA antibodies associated with rejection (P < .1) including 4 newly identified non-HLA antigenic targets (DEXI, EMCN, LPHN1, and SSB). CART analysis showed 5/18 non-HLA antibodies distinguished rejection vs nonrejection. Antibodies to 4/18 non-HLA antigens synergize with HLA donor-specific antibodies and significantly increase the odds of rejection (P < .1). The non-HLA panel was validated using an independent adult cardiac transplant cohort (n = 21 no rejection; n = 42 rejection, >1R) with an area under the curve of 0.87 (P < .05) with 92.86% sensitivity and 66.67% specificity. We conclude that multiplex bead array assessment of non-HLA antibodies identifies cardiac transplant recipients at risk of rejection.

Application of transcatheter valves for aortic valve replacement in pediatric patients: A case series.

OBJECTIVES: To describe our initial experience with pediatric transcatheter aortic valve replacement. BACKGROUND: Transcatheter aortic valve replacement (TAVR) has been approved and used to treat calcific aortic stenosis in adult patients. Select pediatric patients with congenital heart disease (CHD) who are poor candidates for conventional surgical aortic valve replacement can benefit from TAVR. METHODS: A retrospective review was performed to identify and describe pediatric patients with CHD who underwent transcatheter or hybrid aortic valve replacement using a Melody Valve (Medtronic, Minneapolis, MN), or Sapien S3/XT valve (Edwards Life sciences LLC, Irvine, CA). Patients in whom transcatheter valves were implanted on cardiopulmonary bypass were included. Imaging data, procedural elements, and clinical follow-up data were collected to evaluate acute and short-term results. RESULTS: A total of eight pediatric patients underwent treatment of aortic valvular disease using balloon expandable valves and delivery systems. Two patients had Melody valve implantation and six received a Sapien valve (one XT/five S3). In one patient, a Melody valve was placed surgically, failed, and was replaced with a Sapien valve 2 years later. Two patients were treated using a standard transfemoral route, four had the valve delivered on cardiopulmonary bypass via a median sternotomy, one was placed with a transapical approach, and one via a carotid cut down. Patients were followed for an average 16 months (range 1-208 weeks). There were no early or late deaths in this cohort. There were no embolic events, and all valves worked well in the immediate postoperative period. Both Melody implants developed moderate to severe regurgitation at 2 years and 4 years, respectively, and both required replacement at that time. One Sapien 3 valve developed a paravalvular leak that required reintervention within 6 months of implantation. CONCLUSIONS: Transcatheter valves offer a reasonable alternative to traditional surgical aortic valve replacement in certain pediatric patients who are suboptimal surgical candidates. Hybrid approaches and valve delivery on cardiopulmonary bypass has been used in smaller patients. Long-term performance of these valves in young patients has not been studied.

A minimally invasive hybrid approach for cardiac resynchronization of the systemic right ventricle.

BACKGROUND: Patients with systemic right ventricle (RV) often develop progressive heart failure and may benefit from cardiac resynchronization therapy (CRT); however, the optimal strategy for CRT has not been defined. METHODS: A retrospective review of all the patients with systemic RV failure undergoing a hybrid transcatheter-surgical approach was performed. Procedural technique and outcomes are reported. RESULTS: Six patients underwent detailed electroanatomical mapping of the systemic RV followed by a new hybrid approach targeting latest endocardial activation, which was followed by focused epicardial mapping. The exact site of latest endocardial activation was variable but localized to the basolateral RV in all cases. Sites of latest activation tended to be more superior during contralateral ventricular pacing versus intact atrioventricular conduction (P = 0.06). Latest endocardial activation at the targeted site occurred at 157 ms (interquartile range [IQR] = 120-181 ms) and corresponding epicardial activation at 174 ms (IQR = 140-198 ms), after the onset of the QRS complex. Following the hybrid CRT, the QRS duration decreased from a median of 193 to 147 ms and the fractional area of change increased from a median of 15.5% to 30% (P < 0.001). Patients were discharged to home after a median of 4 days. Of the three patients who were initially referred for transplant evaluation, two (66%) of them no longer met the criteria following CRT. CONCLUSIONS: Whereas latest endocardial activation for the systemic RV appears to localize to the basolateral region, the optimal lead position may be variable. An approach utilizing endocardial mapping followed by a limited surgical incision and confirmation of latest activation may result in minimally invasive surgery and a favorable acute CRT response.

Incidence and outcome of infective endocarditis following percutaneous versus surgical pulmonary valve replacement.

OBJECTIVES: To provide a comparison of the outcome of infective endocarditis (IE) in patients undergoing transcatheter pulmonary valve replacement (TPVR) versus surgical pulmonary valve replacement (SPVR). BACKGROUND: Although TPVR is thought to be associated with a higher risk of IE than SPVR, there is paucity of data to support this. METHODS: Patients who underwent TPVR or SPVR at UCLA between October 2010 and September 2016 were included and retrospectively analyzed. RESULTS: Three hundred forty-two patients underwent PVR at UCLA including 134 SPVR and 208 TPVR. Patients undergoing TPVR were more likely to have had a history of endocarditis than those undergoing SPVR (5.3% vs. 0.7%, P = 0.03) and a right ventricle to pulmonary artery (RV to PA) conduit (37% vs. 17%, P = 0.0001). Two SPVR and seven TPVR patients developed IE with a 4-year freedom from endocarditis of 94.0% in the SPVR versus 84% in the TPVR group (P = 0.13). In patients who underwent TPVR and developed endocarditis, the mean gradient across the RVOT prior to intervention was higher (28.1 ± 4.5 vs. 17.4 ± 0.6 mmHg, P = 0.02) and were more likely to have a conduit (71% vs. 36%, P = 0.049). CONCLUSIONS: In this study, patients undergoing TPVR were not at a higher risk of IE than patients undergoing SPVR. TPVR patients were more likely to have had a prior history of IE and RV-PA conduit. The patients at highest risk were those with stenotic RV to PA conduits who were treated with TPVR.

Lung transplantation in the Lung Allocation Score era: Medium-term analysis from a single center.

In 2005, the Lung Allocation Score (LAS) was implemented as the allocation system for lungs in the US. We sought to compare 5-year lung transplant outcomes before and after the institution of the LAS. Between 2000 and 2011, 501 adult patients were identified, with 132 from January 2000 to April 2005 (Pre-LAS era) and 369 from May 2005 to December 2011 (Post-LAS era). Kruskal-Wallis or chi-squared test was used to determine significance between groups. Survival was censored at 5 years. Overall, the post-LAS era was associated with more restrictive lung disease, higher LAS scores, shorter wait-list times, more preoperative immunosuppression, and more single lung transplantation. In addition, post-LAS patients had higher O2 requirements with greater preoperative pulmonary impairment. Postoperatively, 30-day mortality improved in post-LAS era (1.6% vs 5.3%, P = .048). During the pre- and post-LAS eras, 5-year survival was 52.3% and 55.3%, respectively (P = .414). The adjusted risk of mortality was not different in the post-LAS era (P = .139). Freedom from chronic lung allograft dysfunction was significantly higher in the post-LAS era (P = .002). In this single-center report, implementation of the LAS score has led to allocation to sicker patients without decrement in short- or medium-term outcomes. Freedom from CLAD at 5 years is improving after LAS implementation.

Heart and heart-liver transplantation in adults with failing Fontan physiology.

BACKGROUND: As the population of patients with a Fontan palliation grows so does, the number of patients with cardiac failure necessitating orthotopic heart transplant (OHT) and combined heart-liver transplant (CHLT). There is recent evidence that current era cardiac transplant in Fontan patients has improved outcomes, but most studies have a preponderance of pediatrics patients in their cohorts. We examine our institutional experience with adult OHT and CHLT transplantation for failed Fontan physiology. METHODS AND RESULTS: Retrospective analysis of patients at the Ahmanson/UCLA Adult Congenital Heart Disease Center who underwent OHT or CHLT for failing Fontan physiology from January 1, 2002 to May 31, 2017. We identified 20 patients with single-ventricle physiology and Fontan palliation who underwent OHT or CHLT. The median age was 29.5 years (range 19-44). Five patients underwent CHLT because of biopsy proven hepatic cirrhosis. The median length of hospital stay was 23 days (range 8-76) post-OHT and 51 days (range 26-77) post-CHLT. During a median follow-up of 56 months (range 2-178), there was one mortality occurring at 34 months post-OHT due to coronary vasculopathy. Most frequent early postoperative complications included bleeding and infection (55% and 20%, respectively) and surgical reintervention for bleeding complications (n = 8, 40%). One CHLT patient experienced clinically significant hepatic rejection requiring admission and steroid treatment. CONCLUSIONS: Despite inherent risks and complexities of OHT or CHLT in patients with a failed Fontan, transplant is a reasonable therapy. Peri- and postoperative complications are common and may require surgical reintervention. Continued observation of practices and unifying themes may help improve patient selection, pre- and postoperative treatment and ultimately outcomes.

Association Between Hematologic and Inflammatory Markers and 31 Thrombotic and Hemorrhagic Events in Berlin Heart Excor Patients.

Bleeding and thrombotic events remain a significant cause of morbidity in pediatric patients supported with ventricular assist devices (VADs). The objective of this study is to identify the association between markers of anticoagulation and bleeding and thrombosis events during Berlin Heart ExCor support. A retrospective, single-center analysis of 9 patients supported with the Berlin Heart ExCor was performed. Inflammatory and anticoagulation parameters including C-reactive protein, fibrinogen, partial thromboplastin time (PTT), and platelet count were measured at 48 and 24 h before and after bleeding or thrombosis events. Patients served as their own controls, and the same parameters were measured during a control period where subjects did not experience either event. All patients received the anticoagulation regimen proposed by Berlin Heart. A total of 31 bleeding or thrombotic events were identified and matched to 18 control events. Patient with predominantly thrombotic events tended to weigh less than those with bleeding events (Δ7.7 kg, p < 0.001). PTT levels were higher before and after bleeding (Δ17.36, p = 0.002) and thrombosis (Δ8.75, p < 0.001) events relative to control. Heparin dose decreased after a thrombosis event (Δ-5.67, p = 0.097), and this decrease was significantly different from control (p = 0.032). Non-collinearity between heparin dose and PTT should prompt further inflammatory and hematological investigation. In addition, heavier patients were more prone to bleeding complications. The role of inflammation in the development of thrombus or hemorrhages in the pediatric VAD population needs to be studied further.

Use of bivalirudin for anticoagulation during implantation of total artificial heart.

Heparin-induced thrombocytopenia presents a challenge for anticoagulation techniques during cardiac surgery and ventricular assist device implantation. Bivalirudin is currently recommended for use during cardiopulmonary bypass for patients with heparin-induced thrombocytopenia but requires the use of special techniques to avoid blood stagnation. We report the successful use of bivalirudin during cardiopulmonary bypass for implantation of the Total Artificial Heart with late operative bleeding likely resulting from heavy cell saver use.

Characteristics and outcomes of lung transplants performed with ex-situ lung perfusion.

BACKGROUND: Ex-situ lung perfusion (ESLP) can be used to assess and rehabilitate donor lungs, potentially expanding the donor pool. We examined the characteristics and outcomes of lung transplants performed with ESLP in the United States. METHODS: Retrospective review of the United Network for Organ Sharing registry of primary adult lung transplant recipients from February 28, 2018, to June 30, 2021, was performed, comparing baseline characteristics, in-hospital outcomes, and 1-year survival of ESLP vs no ESLP lung transplants. RESULTS: Of 8204 lung transplants, 426 (5.2%) were performed with ESLP. ESLP donors were older, more donation after circulatory death (DCD), and had lower PaO2:FiO2 (P:F) ratios. Recipients had lower lung allocation scores. ESLP lungs traveled further, had longer preservation times, and were more likely double lung transplants. Reintubation rates, extracorporeal membrane oxygenation at 72 hours, and hospital length of stay were greater in the ESLP group. On multivariable analysis, ESLP was not an independent predictor of 1-year survival. However, further analysis showed that DCD lungs managed on ESLP had worse 1-year survival compared to DCD lungs preserved with standard cold storage or with donation after brain death donor lungs. CONCLUSIONS: ESLP is used in a small percentage of lung transplants in the US and is not independently associated with 1-year survival. ESLP combined with DCD lungs, however, is associated with worse 1-year survival and warrants further investigation.

Intrahepatic Transcriptomics Differentiate Advanced Fibrosis and Clinical Outcomes in Adults With Fontan Circulation.

BACKGROUND: The molecular mechanisms underlying Fontan-associated liver disease (FALD) remain largely unknown. OBJECTIVES: This study aimed to assess intrahepatic transcriptomic differences among patients with FALD according to the degree of liver fibrosis and clinical outcomes. METHODS: This retrospective cohort study included adults with the Fontan circulation. Baseline clinical, laboratory, imaging, and hemodynamic data as well as a composite clinical outcome (CCO) were extracted from medical records. Patients were classified into early or advanced fibrosis. RNA was isolated from formalin-fixed paraffin-embedded liver biopsy samples; RNA libraries were constructed with the use of an rRNA depletion method and sequenced on an Illumina Novaseq 6000. Differential gene expression and gene ontology analyses were performed with the use of DESeq2 and Metascape. RESULTS: A total of 106 patients (48% male, median age 31 years [IQR: 11.3 years]) were included. Those with advanced fibrosis had higher B-type natriuretic peptide levels and Fontan, mean pulmonary artery, and capillary wedge pressures. The CCO was present in 23 patients (22%) and was not predicted by advanced liver fibrosis, right ventricular morphology, presence of aortopulmonary collaterals, or Fontan pressures on multivariable analysis. Samples with advanced fibrosis had 228 upregulated genes compared with early fibrosis. Samples with the CCO had 894 upregulated genes compared with those without the CCO. A total of 136 upregulated genes were identified in both comparisons and were enriched in cellular response to cytokine stimulus or oxidative stress, VEGFA-VEGFR2 signaling pathway, TGF-ß signaling pathway, and vasculature development. CONCLUSIONS: Patients with FALD and advanced fibrosis or the CCO exhibited upregulated genes related to inflammation, congestion, and angiogenesis.

Considerations of valvular heart disease in children with ventricular assist devices.

Ventricular assist devices have become a valuable tool in the treatment of heart failure in children. The use of ventricular assist devices has decreased mortality in children with end-stage heart failure awaiting transplant. It is not uncommon for children with end-stage heart failure associated with cardiomyopathy or congenital heart disease to have significant systemic semilunar and atrioventricular valve regurgitation, which can impact the efficiency and efficacy of hemodynamic support provided by a ventricular assist device. Therefore, implanting clinicians should carefully assess for valve abnormalities that may need repair and impact device selection and cannulation strategy to effectively support this diverse population. The purpose of this review is to provide an overview of this important and relevant topic and to discuss strategies for managing these patients.

Major elective non-cardiac operations in adults with congenital heart disease.

OBJECTIVE: To assess the impact of congenital heart disease (CHD) on resource utilisation and clinical outcomes in patients undergoing major elective non-cardiac operations. BACKGROUND: Due to advances in congenital cardiac management in recent years, more patients with CHD are living into adulthood and are requiring non-cardiac operations. METHODS: The 2010-2018 Nationwide Readmissions Database was used to identify all adults undergoing major elective operations (pneumonectomy, hepatectomy, hip replacement, pancreatectomy, abdominal aortic aneurysm repair, colectomy, gastrectomy and oesophagectomy). Multivariable regression models were used to categorise key clinical outcomes. RESULTS: Of an estimated 4 941 203 adults meeting inclusion criteria, 5234 (0.11%) had a previous diagnosis of CHD. Over the study period, the incidence of CHD increased from 0.06% to 0.17%, p<0.001. CHD patients were on average younger (63.3±14.8 vs 64.4±12.5 years, p=0.004), had a higher Elixhauser Comorbidity Index (3.3±2.2 vs 2.3±1.8, p<0.001) and received operations at high volume centres more frequently (66.6% vs 62.0%, p=0.003). Following risk adjustment, these patients had increased risk of in-hospital mortality (adjusted risk ratio (ARR): 1.76, 95% CI 1.25 to 2.47), experienced longer hospitalisation durations (+1.6 days, 95% CI 1.3 to 2.0) and cost more (+$8370, 95% CI $6686 to $10 055). Furthermore, they were more at risk for in-hospital complications (ARR: 1.24 95% CI 1.17 to 1.31) and endured higher adjusted risk of readmission at 30 days (ARR: 1.32 95% CI 1.13 to 1.54). CONCLUSIONS: Adults with CHD are more frequently comprising the major elective operative cohort for non-cardiac cases. Due to the inferior clinical and financial outcomes suffered by this population, perioperative risk stratification may benefit from the inclusion of CHD as a factor that portends unfavourable outcomes.

Intrahepatic transcriptomics differentiate advanced fibrosis and clinical outcomes in adults with the Fontan circulation.

Background: The molecular mechanisms underlying Fontan associated liver disease (FALD) remain largely unknown. We aimed to assess intrahepatic transcriptomic differences among patients with FALD according to the degree of liver fibrosis and clinical outcomes. Methods: This retrospective cohort study included adults with the Fontan circulation at the Ahmanson/UCLA Adult Congenital Heart Disease Center. Clinical, laboratory, imaging and hemodynamic data prior to the liver biopsy were extracted from medical records. Patients were classified into early (F1-F2) or advanced fibrosis (F3-F4). RNA was isolated from formalin-fixed paraffin embedded liver biopsy samples; RNA libraries were constructed using rRNA depletion method and sequencing was performed on Illumina Novaseq 6000. Differential gene expression and gene ontology analyses were carried out using DESeq2 and Metascape. Medical records were comprehensively reviewed for a composite clinical outcome which included decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, protein-losing enteropathy, chronic kidney disease stage 4 or higher, or death. Results: Patients with advanced fibrosis had higher serum BNP levels and Fontan, mean pulmonary artery and capillary wedge pressures. The composite clinical outcome was present in 23 patients (22%) and was predicted by age at Fontan, right ventricular morphology and presence of aortopulmonary collaterals on multivariable analysis. Samples with advanced fibrosis had 228 up-regulated genes compared to early fibrosis. Samples with the composite clinical outcome had 894 up-regulated genes compared to those without it. A total of 136 up-regulated genes were identified in both comparisons and these genes were enriched in cellular response to cytokine stimulus, response to oxidative stress, VEGFA-VEGFR2 signaling pathway, TGF-beta signaling pathway, and vasculature development. Conclusions: Patients with FALD and advanced liver fibrosis or the composite clinical outcome exhibit up-regulated genes including pathways related to inflammation, congestion, and angiogenesis. This adds further insight into FALD pathophysiology.

Whole-Exome Sequencing Identifies Homozygote Nonsense Variants in LMOD2 Gene Causing Infantile Dilated Cardiomyopathy.

As an essential component of the sarcomere, actin thin filament stems from the Z-disk extend toward the middle of the sarcomere and overlaps with myosin thick filaments. Elongation of the cardiac thin filament is essential for normal sarcomere maturation and heart function. This process is regulated by the actin-binding proteins Leiomodins (LMODs), among which LMOD2 has recently been identified as a key regulator of thin filament elongation to reach a mature length. Few reports have implicated homozygous loss of function variants of LMOD2 in neonatal dilated cardiomyopathy (DCM) associated with thin filament shortening. We present the fifth case of DCM due to biallelic variants in the LMOD2 gene and the second case with the c.1193G>A (p.W398*) nonsense variant identified by whole-exome sequencing. The proband is a 4-month male infant of Hispanic descent with advanced heart failure. Consistent with previous reports, a myocardial biopsy exhibited remarkably short thin filaments. However, compared to other cases of identical or similar biallelic variants, the patient presented here has an unusually late onset of cardiomyopathy during infancy. Herein, we present the phenotypic and histological features of this variant, confirm the pathogenic impact on protein expression and sarcomere structure, and discuss the current knowledge of LMOD2-related cardiomyopathy.

Race-based disparities in access to surgical palliation for hypoplastic left heart syndrome.

BACKGROUND: Racial disparities in outcomes have been shown to persist in many operative specialties, including the management of congenital heart disease. Using a demographic-adjusted methodology, we examined whether patient race influenced access to high-performing centers for the operative management of hypoplastic left heart syndrome. METHODS: The 2005-2017 National Inpatient Sample was queried to identify all pediatric (≤5 years) hospitalizations with an operation for hypoplastic left heart syndrome. A racial disparity index was generated for each hospital and defined as the proportion of White patients receiving operative management for hypoplastic left heart syndrome divided by the proportion of White patients admitted for respiratory failure. This methodology quantified hospital-level racial variation while adjusting for the local racial makeup of each center. RESULTS: Of the 17,275 patients who met inclusion criteria, 64.1% were managed at high-volume centers. Patients at high-volume centers had a similar distribution of operative type, age, and burden of comorbidities. The mean racial disparity index steadily grew from 1.06 at the lowest volume decile of operative volume to 1.51 at the highest, indicating an increasing proportion of White patients as volume increased. Using risk-adjusted analysis, each decile increase in hospital volume was associated with a 14% relative reduction in odds of mortality and a 0.06 increase in predicted racial disparity index. Increasing volume was further associated with reduced odds of non-home discharge but did not alter resource utilization. CONCLUSION: We demonstrate that high-volume centers disproportionally serve White patients and have superior clinical outcomes compared to low-volume centers. This study highlights the critical importance of equitable access to expert care for high-risk conditions such as hypoplastic left heart syndrome.

Venoarterial Versus Venovenous Extracorporeal Membrane Oxygenation As Bridge to Lung Transplantation.

BACKGROUND: Venovenous (VV) extracorporeal membrane oxygenation (ECMO) has been used as a bridge to lung transplantation with acceptable outcomes. We hypothesized that venoarterial (VA) ECMO, as part of a multidisciplinary ECMO program, yields similar outcomes as VV ECMO as a bridge in lung transplantation. METHODS: Records of all patients who had undergone ECMO with the intention to bridge to lung transplantation at University of California, Los Angeles, from January 1, 2012, to March 31, 2020, were reviewed. Baseline characteristics, in-hospital outcomes, long-term survival, and freedom from bronchiolitis obliterans syndrome were assessed. RESULTS: During this interval, 58 patients were placed on ECMO with the intention to bridge to lung transplantation: 27 on VV ECMO, and 31 on VA ECMO, with a median duration of 7 and 17 days of support, respectively (P = .01). Successful bridge to lung transplantation occurred in 21 VV patients (78%) and in 26 VA patients (84%). Incidence of primary graft dysfunction III at 72 hours in the VV and the VA cohorts was 0% and 4%, respectively (P = .99). In-hospital and 90-day survival of the VV and VA groups was 100% and 96%, respectively (P = .99). Survival of the 2 groups at 3 years was not significantly different from a contemporary cohort of lung transplant recipients not bridged with ECMO. CONCLUSIONS: VA and VV ECMO can both be used as a bridge to lung transplantation with high success, with short and medium-term survival similar to non-bridged lung transplant recipients. Both modes should be considered effective at bridging select candidates to lung transplantation.