Elizabeth H. Stephens

Background: Hypoplastic left heart syndrome (HLHS) is defined as “a spectrum of congenital cardiovascular malformations with normally aligned great arteries without a common atrioventricular junction, characterized by underdevelopment of the left heart with significant hypoplasia of the left ventricle including atresia, stenosis, or hypoplasia of the aortic or mitral valve, or both valves, and hypoplasia of the ascending aorta and aortic arch”. Without treatment, HLHS is usually lethal in the neonate. Many hypotheses have been advanced to explain the etiology of HLHS; however, no single theory appears to fully explain the phenotypic variability seen in HLHS. Furthermore, many of these theories offer no explanations regarding the precipitating events which lead to the development of HLHS. Objective: This review considers and critically evaluates the strengths and weaknesses of the leading theories proposed to explain the pathogenesis of HLHS—including hemodynamic disturbances, primary myocardial structural defects, valvar malformations, and genetic or epigenetic alterations that may provoke developmental and anatomic abnormalities. After presenting each model, we propose a novel, comprehensive, and data-driven framework which may assist researchers in developing models for the pathogenesis of the various subtypes of HLHS. Methods: Key findings from human fetal imaging, histopathology, genetic studies, and animal models were considered, as well as the hypothetical contribution of each in observed HLHS phenotypes. The rationales for these findings as causal factors initiating individual HLHS patterns, as well as how they might contribute to HLHS in general, were critically analyzed. Results: The flow theory is strongly supported by animal models and in utero interventions that demonstrate the impact of altered hemodynamics on cardiac morphogenesis. However, the flow theory fails to identify initial causes of disturbed flow or related histological features of HLHS like endocardial fibroelastosis. The myocardial and valve-first models suggest an important role in developmental defects, but do not necessarily have a strong experimental basis that provides explanations for how they mediate HLHS. Genetic studies in patients with HLHS have identified several candidate causal mutations. However, such genetic causes of HLHS exhibit incomplete phenotypic penetrance and clinical impact. A multifactorial framework attempts to integrate these diverse mechanisms and may provide the most coherent explanation that can accommodate the heterogeneity and variable presentation of HLHS. Such a framework may identify multiple forces that drive disease but does not provide useful pathways for future research about HLHS. Conclusions: No single hypothesis has fully explained how HLHS is initiated, progresses, and presents with the clinical conditions that are encountered by cardiac surgeons and cardiologists. The most current models suggest that the spectrum of HLHS reflects acomplex interaction between genetic susceptibility, flow-dependent cardiac remodeling, and environmental factors in utero. A multifactorial model integrates these diverse mechanisms and may provide the most coherent explanation for the various phenotypic variations in HLHS. Based on our analysis of the most current data and the strengths and weaknesses of the current theoretical frameworks, we propose a novel research strategy aimed at identifying specific cardiac progenitor cell populations whose dysregulation may represent a unifying explanation for the etiology of the various phenotypes of HLHS. Based on the arguments made throughout this manuscript that evaluate the various genetic, structural, and hemodynamic models of initiation of disease, we believe that the significant phenotypic variability across the spectrum of HLHS (i.e., the different anatomic subtypes for “classic” HLHS) most likely reflects different underlying etiologies and mechanisms. At the very least, it is very likely that the timing of the insult is critical in determining anatomic subtype. Based on the published data and the arguments within this manuscript, it seems naive to think that there is a single unifying mechanism explain all forms of HLHLS.

BACKGROUND: Fontan conversion (FC) is associated with a lower risk of atrial arrhythmias and thromboembolism, but it is unknown whether FC improves long-term survival. The purpose of this study was to assess the impact of FC on transplant-free survival. METHOD: Adults with Fontan palliation were divided into 3 groups: (1) atriopulmonary Fontan connection; (2) atriopulmonary Fontan and subsequent FC to total cavopulmonary connection (TCPC); (3) TCPC at initial Fontan operation. The risk of death/transplant was compared between the 3 groups using Cox regression analysis. RESULTS: We studied 534 patients (age 27±9 years; males [N=298; 56%]). Patients were divided into atriopulmonary Fontan group (N=199, 37%); FC-TCPC (N=138, 26%); and TCPC (N=197, 37%). The FC-TCPC and TCPC groups have similar 15-year incidence of death/transplant (42% versus 47%; P =0.8), even after excluding the 8% operative mortality in the FC-TCPC group (38% versus 47%; P =0.3). On multivariable analyses, neither FC nor the type of Fontan connection was associated with death/transplant. Rather, the risk factors for death/transplant were older age, hepatorenal dysfunction, heart failure, and higher Fontan pressures. The prevalence and severity of these comorbidities increased with age, suggesting that these factors reflect the duration of Fontan physiology, rather than the type of Fontan connection. CONCLUSIONS: These findings, in addition to the high operative mortality associated with FC, suggest that this may not be the optimal treatment option for most adults with atriopulmonary Fontan presenting with Fontan failure. Duration of Fontan physiology rather than the type of Fontan connection may be the main determinant of outcomes.

Background: Transcatheter closure of patent ductus arteriosus (PDA) in small, premature infants is increasingly performed in the contemporary practice. Data regarding optimal timing of PDA closure are scarce. We therefore decided to compare morbidity and mortality of early and late device closure in preterm infants. Methods: Hospitalizations of 166,583 newborn infants diagnosed with PDA were identified from the Kids’ Inpatient Database (KID) in 2009, 2012, 2016, and 2019. Of these, 299 preterm infants (gestational age (GA) ≤32 weeks, birth weight 30 days) ( n = 179). Results: Mean age (±standard deviation) for early PDA closure was 18.6 days ± 7 and 67.3 days ± 36.5 in late PDA closure. Comorbidities including respiratory distress syndrome/bronchopulmonary dysplasia, heart failure, and pulmonary hypertension were comparable between the two groups. There was no difference in mortality or referral for surgical ligation between early and late closure. Postprocedural vascular complications were low, but higher in patients with early PDA closure (3.3% vs 0%; p = 0.025). While the total length of hospital stay was longer in late PDA closure group (121.1 days ± 51.7 vs 81.5 days ± 48.8; p = p = 0.03). Conclusion: There was no statistical difference in in-hospital mortality; however, there is a trend toward higher mortality in the early closure group. Major periprocedural complications are comparable between early and late PDA closure, except vascular complications that were higher with early PDA closure.

Background: In recent years, transcatheter implantation devices to restrict pulmonary arterial flow have emerged as a potential alternative to surgical pulmonary artery banding.Case Presentation: A term male was diagnosed with critical aortic stenosis (AS) and severely reduced left ventricle (LV) systolic function. He underwent aortic balloon valvuloplasty on day 2 of life, resulting in some antegrade flow, but LV ejection fraction only improved to 15%. He remained ductal dependent for systemic perfusion. Pulmonary over‐circulation ensued with systemic steal evident in his second week of life. On day 14, he underwent a transcatheter stage 1 procedure including the placement of bilateral pulmonary flow restrictor (PFR) devices and ductal stenting. Post‐procedure, he improved clinically, weaned off respiratory support, and transitioned to oral feeds while awaiting cardiac transplant.Twelve days later, he received a donor heart, with an uneventful recovery. He is now 3 years post‐transplant and has excellent graft function, and his transplant course has been unremarkable.Conclusion: Transcatheter‐based palliation for a neonate with critical AS, utilizing endoluminal PFRs, proved effective in stabilizing the infant and successfully bridging him to transplant. This highlights an opportunity for the utilization of PFRs in neonatal conditions where control of pulmonary blood flow is imperative as a bridge to transplantation.