Stephens, Elizabeth H.

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.

Abstract Background DDX3X- syndrome is a rare neurodevelopmental disorder characterized by varying degrees of intellectual disability, predominantly affecting females. We present an institutional cohort supplemented by a systematic literature review, expanding the cardiovascular phenotype of DDX3X- syndrome. Methods We conducted a retrospective chart review of patients diagnosed with DDX3X -syndrome at Mayo Clinic. Additionally, we performed a systematic literature review to identify studies reporting cardiovascular abnormalities in patients with DDX3X -syndrome. Results A total of 200 patients with DDX3X -syndrome were analyzed, comprising 14 patients from our institutional cohort and 186 patients identified through a systematic review of 9 published studies. Our institutional cohort included 14 patients (12 females and 2 males) from 13 unrelated families diagnosed with DDX3X -syndrome, at a median age of 4.5 years (IQR 1.2–9.5). Echocardiogram was performed on nine patients, and cardiovascular abnormalities were found in 7 out of 9 patients who underwent echocardiography (78%), two of whom had major congenital heart defect (CHD) requiring surgical intervention. At the time of assessment, 13 individuals were still alive, while one had died at age six due to extracardiac complications. The systematic review included 9 studies involving 186 patients, of whom 32 (17.4%, 25 females and 7 males) had reported cardiovascular abnormalities, ranging from simple CHDs to more complex defects. Conclusion DDX3X -syndrome carries a significant cardiovascular burden, which is possibly higher than previously reported, including complex congenital heart disease requiring surgical repair. A thorough cardiovascular assessment, including an electrocardiogram and echocardiogram, should be universally recommended for all patients at the time of diagnosis.

OBJECTIVES: Vasoplegia is a common complication of cardiac surgery that uses cardiopulmonary bypass and contributes to morbidity and mortality, yet a consensus definition does not exist. The objective of this study was to evaluate the diagnostic criteria and definitions used to characterize vasoplegia and how different criteria influence incidence estimates. DATA SOURCES: Ovid Embase, Ovid MEDLINE, Scopus, Web of Science Core Collection, ClinicalTrials.gov, Ovid Cochrane Central Register of Controlled Trials, and the World Health Organization’s International Clinical Trials Registry Platform clinical trials registry. STUDY SELECTION: Randomized clinical trials and observational studies reporting on vasoplegia in adults undergoing any type of cardiac surgery that used cardiopulmonary bypass. DATA EXTRACTION: Proportional meta-analysis using a random-effects model and the inverse variance method was used to calculate the pooled incidence of vasoplegia and its clinical outcomes. DATA SYNTHESIS: A total of 68 studies encompassing 56,580 patients were identified, from which 63 unique vasoplegia definitions were used. Blood pressure ( n = 57 studies, 84%) and cardiac output ( n = 50 studies, 74%) were among the most common criteria used in vasoplegia definitions; however, there was a vast variety of threshold values applied within these criteria and all other criteria comprising the definitions. The pooled incidence of vasoplegia was 21% (95% CI, 17–25%), acute kidney injury was 32% (95% CI, 21–45%), and mortality was 12% (95% CI, 9–16%). Subgroup analysis revealed that transplantation and left ventricular assist device implantation surgeries, and those with baseline left ventricular ejection fraction less than 40% had a significantly greater incidence of vasoplegia. CONCLUSIONS: The published literature varies greatly in the criteria used to define vasoplegia associated with on-pump cardiac surgery. Generation and adoption of a unified definition for vasoplegia must be an international priority.

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 <1500 grams) underwent percutaneous PDA closure. Characteristics and periprocedural outcomes were compared between early (≤30 days) ( n = 120) and late PDA closure (>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 = <0.01), postprocedural length of stay was paradoxically longer in the early closure group (69 days ± 43.6 vs 57.5 days ± 43, 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.

ABSTRACT Introduction Improving organ preservation is essential for expanding the donor pool and enhancing outcomes for pediatric transplant recipients. This report presents three pediatric patients who received donor hearts preserved using the Organ Care System (OCS). All donor hearts were prepared, placed, and monitored on OCS according to standard protocols. Heart function and myocardial edema were visually assessed during monitoring. Case Reports Patient 1: A 17‐year‐old female patient with hypertrophic cardiomyopathy utilized OCS technology due to donor distance. She experienced an uncomplicated post‐transplant course and was discharged on post‐transplant day 10. Patient 2: A 14‐year‐old male patient with complex congenital heart disease, palliated with Fontan circulation, underwent orthotopic heart transplantation (OHT) with OCS support due to both the complexity of the procedure and donor heart distance. His post‐transplant course was complicated by a revision of the ascending aorta anastomosis and prolonged milrinone infusion for diastolic dysfunction. He was discharged on post‐transplant day 31. Patient 3: A 16‐year‐old male patient with hypoplastic left heart syndrome, also palliated with Fontan circulation, underwent OHT using OCS technology due to the complexity of the surgical procedure. His post‐transplant recovery was unremarkable, and he was discharged on post‐transplant day 15. Conclusions All three pediatric patients demonstrated favorable short‐term outcomes using OCS technology. The OCS system facilitated shorter ischemic times despite the need for extended transport distances or complex surgical procedures. However, further studies with larger patient cohorts and longer follow‐up are needed to better understand the long‐term impact of OCS on pediatric heart transplantation outcomes.

ABSTRACT 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.

Solitary myofibromas are rare, benign, mesenchymal tumors typically found in the head and neck regions. We report an exceptionally rare case of a solitary cardiac myofibroma and its short-term management and outcome. A two-month-old infant was referred due to a murmur. Echocardiography revealed a 2 × 1 cm solitary mass originating from a mitral papillary muscle, causing severe regurgitation. Magnetic resonance imaging showed the mass to be homogeneous on T1, hyperintense on T2, and hypointense on first-pass perfusion imaging with no enhancement on delayed postcontrast imaging. The mass was surgically excised partially due to its involvement with the mitral valve. Postoperative recovery was uneventful, with echocardiography four months later showing no tumor recurrence and trivial mitral regurgitation. This report provides valuable imaging and pathology examples to aid in the recognition of this rare tumor and demonstrates that successful surgical excision is possible, even with significant cardiac involvement.

Abstract Introduction Cardiopulmonary exercise testing (CPET) parameters such as peak VO2 ≤ 14ml/kg/min, percentage predicted peak VO2 (ppVO2) ≤ 50% and ventilation equivalent of carbon dioxide (Ve/VCO2) &gt;35 l/min/l/min are recommended thresholds to list for isolated heart transplant. There is minimal data on clinical events after listing to guide clinical management or priority in organ allocation. Purpose To assess the effect of peak VO2, ppVO2, Ve/VCO2 on clinical events after listing for isolated heart transplant. Methods In a single centre retrospective study, we identified patients who were status 6 or status 2 prior to 2018 at time of listing for isolated heart transplant between 2007 and 2021. Clinical data were collected by chart review. Primary outcome of progressive heart failure was defined as death or upgrade in transplant priority status (new inotropes or mechanical circulatory support). Comparison was made between peak VO2 strata (&gt; 14 vs ≤ 14 ml/kg/min), ppVO2 strata (&gt; 50% vs 40-50% vs &lt;40%) and Ve/VCO2 strata (&lt;35 vs &gt;35 l/min/l/min). Secondary outcome was time dependent survival after listing for heart transplant. Results We identified 141 patients of which 133 underwent CPET and follow up was available for 130 who were included in the analysis. Median age was 53 years (interquartile range 41-59 years), 29.1% of patients were female. Median peak VO2 was 14.0 ml/kg/min (11.2-15.7), ppVO2 was 44% (36-52), Ve/VCO2 slope was 34.0 (31.0-37.0) and RER was 1.1 (1.1-1.2). 87 patients had progressive heart failure consisting of 34 deaths and 83 patients having upgrade in priority status. There was a significant difference in risk of progressive heart failure comparing peak VO2 strata (Figure 1) (freedom from event at one year 71.4% with peak VO2 &gt; 14 vs 46.5% with peak VO2 ≤ 14, p=0.00061) and ppVO2 strata (Figure 2) (freedom from event at one year 75.0% with ppVO2 &gt;50% vs 61.2% with ppVO2 40-50% vs 42.6% with ppVO2 &lt;40%, p=0.0015). There was no significant difference with Ve/VCO2 strata (freedom from event at one year 59.8% with Ve/VCO2 &lt;34 vs 54.9% with Ve/VCO2 &gt;34, p=0.52). There were 34 deaths before transplant and 23 deaths after transplant. 87 patients underwent transplant. In a time dependent survival analysis, age, gender and ppVO2&lt;50% (HR 1.65 (0.87-3.12)) were not significant predictors of mortality. Both early transplant (defined as &lt; 1 year after listing, HR 0.14 (0.06-0.34) and late transplant (defined as &gt; 1 year after listing, HR 0.16 (0.08-0.32)) were significant predictors of lower mortality whilst Ve/VCO2&gt;35 (HR 2.09 (1.19-3.68)) was a significant predictor of higher mortality. Conclusions Peak VO2 and ppVO2 stratify risk of progressive heart failure in ambulatory patients awaiting isolated heart transplant. However, Ve/VCO2 is a predictor of significantly higher mortality. These findings should affect clinical management and transplant priority status; and influence revision of future guidelines.Freedom from event by peak VO2 strataFreedom from event by ppVO2 strata

Background The purpose of this study was to describe the correlates and outcomes in adults with unrepaired partial anomalous pulmonary venous return and intact atrial septum (PAPVR‐IAS). Methods and Results We identified adults with PAPVR‐IAS who received care at the Mayo Clinic, while those with unrepaired PAPVR‐IAS comprised the reference group. Clinical indices (New York Heart Association class, peak oxygen consumption, and NT‐proBNP [N‐terminal pro‐B‐type natriuretic peptide]) and echo‐derived right heart indices (right atrial [RA] volume, RA reservoir strain, right ventricular [RV] free wall strain, RV end‐diastolic area, and RV systolic pressure) were assessed at baseline and 3‐year and 5‐year follow‐up. There were 80 patients and 38 patients with unrepaired versus repaired PAPVR‐IAS, respectively. The clinical predictors of surgical repair were the number of anomalous veins, RA volume, and RV end‐diastolic area. The PAPVR‐IAS risk score, derived from these clinical predictors, was associated with surgical repair (adjusted odds ratio, 1.37 [95% CI, 1.24–1.65] per unit increase in risk score; area under the curve, 0.742). Among patients with unrepaired PAPVR‐IAS with 3‐year (n=73) and 5‐year follow‐up (n=36), there was no temporal change in clinical indices (New York Heart Association class, predicted peak oxygen consumption, and NT‐proBNP) and right heart indices (RA volume index, RA reservoir strain, RV end‐diastolic area index, RV free wall strain, and RV systolic pressure). Conclusions The PAPVR‐IAS risk score can be used to assess the odds of requiring surgical repair. Furthermore, there was no temporal deterioration in clinical and right heart indices during follow‐up in adults with unrepaired PAPVR‐IAS.