Hybrid Stenting of Pulmonary Venous Baffle Stenosis: Subxiphoid Approach in Transposition of the Great Arteries.

A 31-year-old woman with transposition of the great arteries status post-Senning operation presents with severe pulmonary venous baffle obstruction. Both standards of care (percutaneous stenting or open repair) were deemed suboptimal and/or high risk. A multidisciplinary, hybrid approach via subxiphoid incision, guided by 3-dimensional modeling, provided a lower risk and minimally invasive intervention.

Evaluating threshold for donor fraction cell-free DNA using clinically available assay for rejection in pediatric and adult heart transplantation.

BACKGROUND: The aims of the study were to assess the performance of a clinically available cell-free DNA (cfDNA) assay in a large cohort of pediatric and adult heart transplant recipients and to evaluate performance at specific cut points in detection of rejection. METHODS: Observational, non-interventional, prospective study enrolled pediatric and adult heart transplant recipients from seven centers. Biopsy-associated plasma samples were used for cfDNA measurements. Pre-determined cut points were tested for analytic performance. RESULTS: A total of 487 samples from 160 subjects were used for the analysis. There were significant differences for df-cfDNA values between rejection [0.21% (IQR 0.12-0.69)] and healthy samples [0.05% (IQR 0.01-0.14), p < .0001]. The pediatric rejection group had a median df-cfDNA value of 0.93% (IQR 0.28-2.84) compared to 0.09% (IQR 0.04-0.23) for healthy samples, p = .005. Overall negative predictive value was 0.94 while it was 0.99 for pediatric patients. Cut points of 0.13% and 0.15% were tested for various types of rejection profiles and were appropriate to rule out rejection. CONCLUSION: The study suggests that pediatric patients with rejection show higher levels of circulating df-cfDNA compared to adults and supports the specific cut points for clinical use in pediatric and adult patients with overall acceptable performance.

Postoperative Morbidity and Interstage Hemodynamics Following Stage I Palliation in Patients with Turner Syndrome and Hypoplastic Left Heart Syndrome.

BACKGROUND: Turner syndrome (TS) is associated with left-sided cardiac lesions, including hypoplastic left heart syndrome (HLHS). Mortality as high as 80-90% has been reported following stage I single-ventricle palliation (S1P) in patients with TS and HLHS (TS + HLHS). The specific factors that relate to poor outcomes are not well understood. METHODS: This is a single-center, retrospective cohort study that includes 197 patients with HLHS who underwent S1P between 2008 and 2022. The clinical outcomes and interstage hemodynamics of TS + HLHS patients (N = 11) were compared with HLHS without TS (TS-HLHS), (N = 186). RESULTS: Of the 11 TS + HLHS patients, 10 underwent S1P; 4 underwent Glenn and 1 had hemodynamics considered prohibitive for Glenn; only 1 survived to Fontan palliation. Post-S1P mortality was higher in TS + HLHS (60 v 25%, p = 0.017). Following S1P, TS + HLHS had higher rates of postoperative ECMO (70 v 28%, p = 0.006), surgical necrotizing enterocolitis (20 v 3%, p = 0.007), peritoneal drain placement (70 v 31%, p = 0.012), urinary tract infection (30 v 9%, p = 0.035), and ICU readmissions (median 5 v 1, p = 0.035). Interstage hemodynamics demonstrated higher right ventricular end diastolic, (11 v 8mmHg, p = 0.033), mean pulmonary artery (20 v 13mmHg) (p = 0.002), and left atrial pressures (9 v 6mmHg, p = 0.047) in TS + HLHS. CONCLUSION: High mortality rates are described in TS + HLHS patients following S1P. In our cohort, despite most surviving more than 30 days post-S1P, long-term survival remained poor. Interstage catheterization data suggest poor physiologic candidacy for subsequent stages of single-ventricle palliation. Understanding the clinical and hemodynamic factors related to poor outcomes in TS + HLHS will help inform management for this population.

Impaired Reorganization of Centrosome Structure Underlies Human Infantile Dilated Cardiomyopathy.

BACKGROUND: During cardiomyocyte maturation, the centrosome, which functions as a microtubule organizing center in cardiomyocytes, undergoes dramatic structural reorganization where its components reorganize from being localized at the centriole to the nuclear envelope. This developmentally programmed process, referred to as centrosome reduction, has been previously associated with cell cycle exit. However, understanding of how this process influences cardiomyocyte cell biology, and whether its disruption results in human cardiac disease, remains unknown. We studied this phenomenon in an infant with a rare case of infantile dilated cardiomyopathy (iDCM) who presented with left ventricular ejection fraction of 18% and disrupted sarcomere and mitochondria structure. METHODS: We performed an analysis beginning with an infant who presented with a rare case of iDCM. We derived induced pluripotent stem cells from the patient to model iDCM in vitro. We performed whole exome sequencing on the patient and his parents for causal gene analysis. CRISPR/Cas9-mediated gene knockout and correction in vitro were used to confirm whole exome sequencing results. Zebrafish and Drosophila models were used for in vivo validation of the causal gene. Matrigel mattress technology and single-cell RNA sequencing were used to characterize iDCM cardiomyocytes further. RESULTS: Whole exome sequencing and CRISPR/Cas9 gene knockout/correction identified RTTN, the gene encoding the centrosomal protein RTTN (rotatin), as the causal gene underlying the patient's condition, representing the first time a centrosome defect has been implicated in a nonsyndromic dilated cardiomyopathy. Genetic knockdowns in zebrafish and Drosophila confirmed an evolutionarily conserved requirement of RTTN for cardiac structure and function. Single-cell RNA sequencing of iDCM cardiomyocytes showed impaired maturation of iDCM cardiomyocytes, which underlie the observed cardiomyocyte structural and functional deficits. We also observed persistent localization of the centrosome at the centriole, contrasting with expected programmed perinuclear reorganization, which led to subsequent global microtubule network defects. In addition, we identified a small molecule that restored centrosome reorganization and improved the structure and contractility of iDCM cardiomyocytes. CONCLUSIONS: This study is the first to demonstrate a case of human disease caused by a defect in centrosome reduction. We also uncovered a novel role for RTTN in perinatal cardiac development and identified a potential therapeutic strategy for centrosome-related iDCM. Future study aimed at identifying variants in centrosome components may uncover additional contributors to human cardiac disease.

Validation of donor fraction cell-free DNA with biopsy-proven cardiac allograft rejection in children and adults.

OBJECTIVES: Donor-specific cell-free DNA shows promise as a noninvasive marker for allograft rejection, but as yet has not been validated in both adult and pediatric recipients. The study objective was to validate donor fraction cell-free DNA as a noninvasive test to assess for risk of acute cellular rejection and antibody-mediated rejection after heart transplantation in pediatric and adult recipients. METHODS: Pediatric and adult heart transplant recipients were enrolled from 7 participating sites and followed for 12 months or more with plasma samples collected immediately before all endomyocardial biopsies. Donor fraction cell-free DNA was extracted, and quantitative genotyping was performed. Blinded donor fraction cell-free DNA and clinical data were analyzed and compared with a previously determined threshold of 0.14%. Sensitivity, specificity, negative predictive value, positive predictive value, and receiver operating characteristic curves were calculated. RESULTS: A total of 987 samples from 144 subjects were collected. After applying predefined clinical and technical exclusions, 745 samples from 130 subjects produced 54 rejection samples associated with the composite outcome of acute cellular rejection grade 2R or greater and pathologic antibody-mediated rejection 2 or greater and 323 healthy samples. For all participants, donor fraction cell-free DNA at a threshold of 0.14% had a sensitivity of 67%, a specificity of 79%, a positive predictive value of 34%, and a negative predictive value of 94% with an area under the curve of 0.78 for detecting rejection. When analyzed independently, these results held true for both pediatric and adult cohorts at the same threshold of 0.14% (negative predictive value 92% and 95%, respectively). CONCLUSIONS: Donor fraction cell-free DNA at a threshold of 0.14% can be used to assess for risk of rejection after heart transplantation in both pediatric and adult patients with excellent negative predictive value.

Severe aortopulmonary collaterals are associated with lower transplant-free survival in patients undergoing staged single ventricle palliation.

Objective: To identify risk factors for aortopulmonary collateral (APC) development and assess the impact of severe APCs in children undergoing staged single ventricle palliation. Methods: Children undergoing a bidirectional Glenn operation between January 1, 2016, and March 31, 2021, at our center were included. All underwent angiography prior to Glenn and Fontan; APC flow was graded on a scale of 0 (no appreciable collateral flow) to 4 (severe burden). Demographic data, congenital diagnosis, clinical history, and outcomes were stratified by Glenn assessment; Fontan outcomes were stratified by pre-Fontan grade. Results: Sixty patients met the inclusion criteria, all of whom had angiographic evidence of APCs. There were 7 transplants and 9 deaths in the cohort. There were no significant differences in demographics among the patients. Right ventricular morphology was more common in patients with severe pre-Glenn collaterals (24 of 44 vs 2 of 6 vs 7 of 8; P = .014). Longer stage 1 aortic cross-clamp duration was associated with greater severity pre-Glenn (44 minutes vs 34 minutes vs 66 minutes; P = .023). Patients with grade 3 pre-Glenn collaterals more commonly required transplantation than those with grade 1 collaterals (P < .001) and had lower overall transplant-free survival than those with grade 1 (P = .005) or grade 2 (P = .04) collaterals. Conclusions: The ubiquity of APCs in this study demonstrates their prevalence in single ventricle disease. Right ventricular morphology and prolonged aortic cross-clamp duration are associated with higher burden. Greater severity was associated with decreased transplant-free survival. These data emphasize the negative long-term impact of these collaterals.

Congenitally Corrected Transposition Cardiac Surgery: Society of Thoracic Surgeons Database Analysis.

BACKGROUND: Congenitally corrected transposition of the great arteries (ccTGA) has many management strategies, with the emergence of anatomic repair increasing the available surgical options. Contemporary surgical practices have not been described in multicenter analyses. This study describes the distribution of heart surgery in patients with ccTGA and defines contemporary outcomes in a large multicenter cohort. METHODS: Index cardiovascular operations in patients with primary or fundamental diagnosis of ccTGA were identified in The Society of Thoracic Surgeons Congenital Heart Surgery Database from 2010 to 2019. Operations of interest were combined into mutually exclusive groups designating overall ccTGA management strategies. Outcomes were defined with standard Society of Thoracic Surgeons Congenital Heart Surgery Database definitions. Pearson χ2 and Kruskal-Wallis tests were used for statistical comparisons. RESULTS: One hundred one centers performed 985 index operations, with anatomic repair the most common approach. Twenty-six centers performed more than 10 operations. Atrial switch plus Rastelli operations had the highest rate of operative mortality (8.4%) and major complications (38.2%). Heart transplant operations had the longest postoperative length of stay among survivors (18 days [interquartile range, 13.5-26]). CONCLUSIONS: Patients with ccTGA remain a challenging cohort, with significant diversity in the operations used and a substantial burden of operative mortality and morbidity.

Relationship between donor fraction cell-free DNA and clinical rejection in heart transplantation.

BACKGROUND: Clinical rejection (CR) defined as decision to treat clinically suspected rejection with change in immunotherapy based on clinical presentation with or without diagnostic biopsy findings is an important part of care in heart transplantation. We sought to assess the utility of donor fraction cell-free DNA (DF cfDNA) in CR and the utility of serial DF cfDNA in CR patients in predicting outcomes of clinical interest. METHODS: Patients with heart transplantation were enrolled in two sequential, multi-center, prospective observational studies. Blood samples were collected for surveillance or clinical events. Clinicians were blinded to the results of DF cfDNA. RESULTS: A total of 835 samples from 269 subjects (57% pediatric) were included for this analysis, including 28 samples associated with CR were analyzed. Median DF cfDNA was 0.43 (IQR 0.15, 1.36)% for CR and 0.10 (IQR 0.07, 0.16)% for healthy controls (p < .0001). At cutoff value of 0.13%, the area under curve (AUC) was 0.82, sensitivity of 0.86, specificity of 0.67, and negative predictive value of 0.99. There was serial decline in DF cfDNA post-therapy, however, those with cardiovascular events (cardiac arrest, need for mechanical support or death) showed significantly higher levels of DF cfDNA on Day 0 (2.11 vs 0.31%) and Day 14 (0.51 vs 0.22%) compared to those who did not have such an event (p < .0001). CONCLUSION: DF cfDNA has excellent agreement with clinical rejection and, importantly, serial measurement of DF cfDNA predict clinically significant outcomes post treatment for rejection in these patients.

Misclassification of Pulmonary Hypertension in Partial Anomalous Pulmonary Venous Return.

Partial anomalous pulmonary venous return is a rare congenital heart defect that can escape detection until adulthood and can be misdiagnosed as pulmonary hypertension and managed with vasodilators before the anomaly is identified. This report describes the cases of 3 patients with pulmonary hypertension whose hemodynamics and symptoms improved after repair of anomalous veins. Anomalous pulmonary veins are difficult to identify on a transthoracic echocardiogram, so a high index of suspicion and early use of additional imaging modalities are important to avoid a delayed diagnosis and progression to irreversible disease.

Impact of obesity on post-operative arrhythmias after congenital heart surgery in children and young adults.

BACKGROUND: Obesity increases the risk of post-operative arrhythmias in adults undergoing cardiac surgery, but little is known regarding the impact of obesity on post-operative arrhythmias after CHD surgery. METHODS: Patients undergoing CHD surgery from 2007 to 2019 were prospectively enrolled in the parent study. Telemetry was assessed daily, with documentation of all arrhythmias. Patients aged 2-20 years were categorised by body mass index percentile for age and sex (underweight <5, normal 5-85, overweight 85-95, and obese >95). Patients aged >20 years were categorised using absolute body mass index. We investigated the impact of body mass index category on arrhythmias using univariate and multivariate analysis. RESULTS: There were 1250 operative cases: 12% underweight, 65% normal weight, 12% overweight, and 11% obese. Post-operative arrhythmias were observed in 38%. Body mass index was significantly higher in those with arrhythmias (18.8 versus 17.8, p = 0.003). There was a linear relationship between body mass index category and incidence of arrhythmias: underweight 33%, normal 38%, overweight 42%, and obese 45% (p = 0.017 for trend). In multivariate analysis, body mass index category was independently associated with post-operative arrhythmias (p = 0.021), with odds ratio 1.64 in obese patients as compared to normal-weight patients (p = 0.036). In addition, aortic cross-clamp time (OR 1.007, p = 0.002) and maximal vasoactive-inotropic score in the first 48 hours (OR 1.03, p = 0.04) were associated with post-operative arrhythmias. CONCLUSION: Body mass index is independently associated with incidence of post-operative arrhythmias in children after CHD surgery.

Increase in nuclear cell-free DNA is associated with major adverse events in adult and pediatric heart transplant recipients.

BACKGROUND: Cell-free DNA is an emerging biomarker. While donor fraction may detect graft events in heart transplant recipients, the prognostic value of total nuclear cell-free DNA (ncfDNA) itself is largely unexplored. OBJECTIVE: Explore the relationship between ncfDNA and clinical events in heart transplant recipients. METHODS: We conducted a multi-center prospective study to investigate the value of cell-free DNA in non-invasive monitoring following heart transplantation. Over 4000 blood samples were collected from 388 heart transplant patients. Total ncfDNA and donor fraction were quantified. Generalized linear models with maximum likelihood estimation for repeated measures with subjects as clusters were used to explore the relationship of ncfDNA and major adverse events. Receiver operating characteristic curves were used to help choose cutpoints. RESULTS: A ncfDNA threshold (50 ng/ml) was identified that was associated with increased risk of major adverse events. NcfDNA was elevated in patients who suffered cardiac arrest, required mechanical circulatory support or died post heart transplantation as well as in patients undergoing treatment for infection. CONCLUSIONS: Elevated ncfDNA correlates with risk for major adverse events in adult and pediatric heart transplant recipients and may indicate a need for enhanced surveillance after transplant.

An Anomalous Cause of Portal Hypertension.

Portal hypertension is a syndrome marked by an increase in the pressure of the portal vein. Portal hypertension can be diagnosed clinically or if the measurement of the hepatic venous pressure gradient is greater than 5 mm Hg. Cirrhosis is the most common etiology in Western countries, but there are other causes which lead to presinusoidal portal hypertension. We present a patient with a rare cause of portal hypertension.