Applying the Hybrid Concept as a Bridge to Transplantation in Infants Without Hypoplastic Left Heart Syndrome.

Therapies to support small infants in decompensated heart failure that are failing medical management are limited. We have used the hybrid approach, classically reserved for high-risk infants with single ventricle physiology, in patients with biventricular physiology with left ventricular failure. This approach secures systemic circulation, relieves left atrial hypertension, protects the pulmonary vasculature, and allows the right ventricle to support cardiac output. This approach can be used as a bridge to transplantation in select individuals. Infants without single ventricle congenital heart disease who were treated with the hybrid approach between 2008 and 2021 were included in analysis. Eight patients were identified. At the time of hybrid procedure, the median weight was 3.2 kg (range 2.4-3.6 kg) and the median age was 18 days (range 1-153 days). Seventy five percent were mechanically ventilated and 88% were on inotropic support. The median duration from hybrid procedure to transplant was 63 days (range 4-116 days). All patients experienced a good outcome (delisted for improvement or transplanted). The hybrid procedure is an appropriate therapeutic bridge to transplantation in a carefully selected subset of critically ill infants without single ventricle congenital heart disease in whom alternate therapies may confer increased risk for morbidity and mortality.

Dissemination and implementation analysis of the Ross procedure in adults: time to update the guidelines?

Background: The science of dissemination and implementation (D&I) aims to improve the quality and effectiveness of care by addressing the challenges of incorporating research and evidence-based practice into routine clinical practice. This lens of D&I has challenged the interpretation and incorporation of data, noting that failure of a given therapy may not reflect lack of efficacy, but instead reflect an imperfect implementation. The aim of this manuscript is to review the influence of the Ross procedure's historical context on its D&I. Methods: A contextual baseline of the Ross procedure was defined from the procedure's original description in the literature to major publications since the 2017 valvular heart disease guidelines. D&I evaluation was conducted using the Consolidated Framework for Implementation Research (CFIR), using constructs from each of the five respective domains to define the main determinants. Results: Each of the five CFIR domains appears to be correlated with a factor influencing the Ross procedure's varied history of enthusiasm and acceptance. The complex nature of Ross required adaptation for optimization, with a strong correlation of center volume on outcomes that were not considered in non-contemporary studies. Outcomes later published from those studies influenced social and cultural contexts within the aortic surgery community, and led to further organizational uncertainty, resulting in slow guideline incorporation. Conclusions: The D&I of the Ross procedure was a result of inadequate appreciation of technical complexity, effect of patient selection, and complex aortic surgery experience, resulting in dismissal of an efficacious procedure due to a misunderstanding of effectiveness.

Biventricular Support Using ProtekDuo Cannula in a Child.

We report a successful pediatric bridge to transplant following application of the ProTekDuo Cannula to provide right ventricular support in a 12-year-old child with biventricular cardiomyopathy and on left ventricular assist device support. We are unaware of any other reports of pediatric use of this device in the medical literature.

Ebstein's Anomaly of the Tricuspid Valve: an Overview of Pathology and Management.

PURPOSE OF REVIEW: Ebstein's anomaly (EA) is a rare, but complex form of congenital heart disease consisting of a right ventricular myopathy and morphologic tricuspid valve disease leading to a high incidence of right ventricular dysfunction and arrhythmias. This review offers an updated overview of the current understanding and management of patients with EA with a focus on the adult population. RECENT FINDINGS: Increased understanding of anatomic accessory atrioventricular pathways in EA has resulted in an improvement in ablation techniques and long-term freedom of atrial arrhythmia recurrence. Despite an improvement in understanding and recognition of EA, significant disease heterogeneity and complex treatment options continue to challenge providers, with the best outcomes achieved at expert congenital heart disease centers.

Surgical Management of Heterotaxy Syndrome: Current Challenges and Opportunities.

INTRODUCTION: Heterotaxy syndrome presents a unique challenge in surgical management, even in the current era. We hypothesized that certain anatomic subsets merit novel strategies. METHODS: We analyzed morphologic details, surgeries, comorbidities, subsequent admissions, and survival using Kaplan-Meier methods and multivariable risk models from a single-institution experience of 103 consecutive patients with heterotaxy who underwent cardiac surgery between January 1, 1990, and May 31, 2016. RESULTS: Of the 103 patients (50 males and 53 females), 31 had left atrial isomerism, 64 had right atrial isomerism (RAI), and 8 patients' isomerism was indeterminate (IND), with first cardiac operation at a mean 1.0 year (standard deviation ±3.0 years) of age. Kaplan-Meier overall survival estimate was 83.1% at six months, 77.8% at one year, 65.9% at five years, and 52.1% at ten years. Survival was particularly low among RAI following repair of total anomalous pulmonary venous connection (TAPVC) at first operation, with one- and five-year survival of 57% and 46%, respectively. By multivariable analysis, the only risk factor for death during the early phase (hazard model) was repair of TAPVC at the first cardiac operation (hazard ratio [HR]: 4.4, P = .01), and risk factors during the longer term constant phase were atrioventricular valve (AVV) regurgitation (HR: 4.2, P < .01), male gender (HR: 3.7, P < .01), and two-ventricle repair (HR: 3.0, P = .02). Patients with heterotaxy undergoing the Fontan procedure had excellent subsequent survival (85% at ten years). CONCLUSIONS: This analysis of over 100 patients with heterotaxy identified TAPVC requiring initial repair as the major risk factor for early death and important AVV regurgitation as the major risk factor in the longer term. Survival with RAI and early repair of TAPVC were poor, with one-year mortality exceeding 40%. Patients with single ventricle completing the Fontan operation enjoyed outstanding ten-year survival (85%). Initial management of RAI requiring early repair of TAPVC remains challenging. For this high-risk subset, alternative strategies such as early referral for cardiac transplantation evaluation warrant consideration.

Repair of Rare Vascular Ring: Circumflex Aortic Arch with Associated Hypoplasia and Coarctation.

We describe a neonate with an unusual vascular ring formed by a right-sided aortic arch with associated coarctation and distal hypoplasia in the presence of an aberrant left subclavian artery. The descending aorta traveled behind the esophagus to descend on the left side of the spine. A left ductus arteriosus connected to the descending aorta completing the vascular ring, with notable esophageal compression. Surgical correction was accomplished through median sternotomy, resection of the hypoplastic circumflex arch, aortic arch advancement, and end-to-side anastomosis.

Anti-Pig Antibody in Infants: Can a Genetically Engineered Pig Heart Bridge to Allotransplantation?

BACKGROUND: Patients with congenital heart disease have high heart transplant waitlist mortality, and mechanical support is suboptimal. To evaluate feasibility of cardiac grafts from a genetically engineered triple-knockout pig as a bridge to allotransplantation, preformed anti-pig antibodies were measured in pediatric and adult patients. METHODS: Flow cytometry measured serum immunoglobulin M (IgM) or IgG binding to wild-type and triple-knockout red blood cells (RBCs), with binding to human O-negative RBCs as a negative control. Group 1 comprise 84 pediatric patients and 64 healthy adults' sera with no previous cardiac surgery. Group 2 comprised 25 infant's sera postcardiac surgery, including 10 after palliation for hypoplastic left heart syndrome. RESULTS: In group 1, IgM binding to wild-type RBCs occurred in 80% of sera and IgG binding occurred in in 91% of sera. Only 3% of sera showed IgM binding to triple-knockout RBCs, and 1 (<1%) was weakly positive for IgG binding. In group 2, all 25 infants demonstrated increased IgM and IgG binding to wild-type RBCs. One patient showed minimal IgM and another showed low IgG binding to triple-knockout RBCs. No infant after stage 1 Norwood demonstrated any IgG or IgM binding. CONCLUSIONS: Preformed anti-pig antibodies may not be a barrier to heart xenotransplantation in infants, even after cardiac surgery. With adequate immunosuppressive therapy, a triple-knockout pig heart transplant might function successfully as a bridge to allotransplantation.

Comparison of Transcatheter Pulmonic Valve Implantation With Surgical Pulmonic Valve Replacement in Adults (from the National Inpatient Survey Dataset).

There are no large reports of comparative outcomes of transcatheter pulmonic valve implantation (TPVI) and surgical pulmonic valve replacement (SPVR). Prospective studies are unlikely to be feasible in the future also. Thus, we utilized a large adult inpatient database to compare the two with respect to temporal trends, in hospital outcomes and costs. Data from the National Inpatient Sample database from 2003 to 2014 was analyzed to extract patients who underwent TPVI and SPVR using unique ICD 9-CM codes. In-hospital outcomes and charges were then analyzed. All charges were converted to 2018 dollars and a loss of wages analysis was performed using the Bureau of Labor Statistics published median weekly wages. A total of 8,449 and 555 SPVR and TPVI discharges were identified. 5.8% SPVR procedures were done in rural setting versus 1.8% of TPVI. Complications including in-hospital mortality (2.3 vs 0.9%; p = 0.02) were higher in SPVR group. Length of stay was significantly shorter for the TPVI group (1 vs 5 days; p <0.001), which also contributed to lower loss of wages ($1028.57 vs $6042.86; p <0.001) with similar hospital charges. In conclusion, volumes of both TPVI and SPVR are increasing across adult hospitals in the United States, reflecting an overall increase in the adult congenital heart disease population. TPVI offers improved short-term outcomes and decreased loss of wages through shorter recovery time in this real-world database analysis.

Congenitally Corrected Transposition Presenting in the First Year of Life: Survival and Fate of the Systemic Right Ventricle.

INTRODUCTION: Knowledge gaps exist in the life expectancy and functional outcome of patients with congenitally corrected transposition (ccTGA) presenting early in life, which is relevant in the evaluation of early anatomic repair. METHODS: In a single-center analysis, 91 patients with ccTGA were identified over 25 years, of which 31 presented with biventricular anatomy in the first year of life and formed the study cohort. End points for analysis included survival, moderate or worse tricuspid valve regurgitation, and systemic right ventricle (RV) dysfunction. Median follow-up was 4.9 years (range: 7 days to 20 years). RESULTS: Among 31 patients presenting in the first year of life, 9 (29%) never received cardiac surgery, while 22 (71%) underwent 36 cardiac operations. Overall freedom from moderate or severe systemic RV dysfunction was 75% at 10 years. Overall survival was 82% at 10 years. Surgical mortality was 5.6% (2/36). Among survivors with a systemic RV, 23 (100%) of 23 were Ross or NYHA class I or II at last follow-up. CONCLUSIONS: Congenitally corrected transposition presenting in the first year of life and maintaining a systemic RV can expect (1) long-term survival of more than 80% at 10 years, (2) low expected surgical mortality (overall 6%), and (3) 75% late freedom from major RV dysfunction at 10 years. Pending multi-institutional analyses, this experience with a systemic RV in ccTGA provides an initial benchmark for comparison when considering early elective anatomic correction.

Evaluation of flow-modulation approaches in ventricular assist devices using an in-vitro endothelial cell culture model.

BACKGROUND: Continuous-flow ventricular assist devices (CF-VADs) produce non-physiologic flow with diminished pulsatility, which is a major risk factor for development of adverse events, including gastrointestinal (GI) bleeding and arteriovenous malformations (AVMs). Introduction of artificial pulsatility by modulating CF-VAD flow has been suggested as a potential solution. However, the levels of pulsatility and frequency of CF-VAD modulation necessary to prevent adverse events are currently unknown and need to be evaluated. METHODS: The purpose of this study was to use human aortic endothelial cells (HAECs) cultured within an endothelial cell culture model (ECCM) to: (i) identify and validate biomarkers to determine the effects of pulsatility; and (ii) conclude whether introduction of artificial pulsatility using flow-modulation approaches can mitigate changes in endothelial cells seen with diminished pulsatile flow. Nuclear factor erythroid 2-related factor 2 (Nrf-2)-regulated anti-oxidant genes and proteins and the endothelial nitric oxide synthase/endothelin-1 (eNOS/ET-1) signaling pathway are known to be differentially regulated in response to changes in pulsatility. RESULTS: Comparison of HAECs cultured within the ECCM (normal pulsatile vs CF-VAD) with aortic wall samples from patients (normal pulsatile [n = 5] vs CF-VADs [n = 5]) confirmed that both the Nrf-2-activated anti-oxidant response and eNOS/ET-1 signaling pathways were differentially regulated in response to diminished pulsatility. Evaluation of 2 specific CF-VAD flow-modulation protocols to introduce artificial pulsatility, synchronous (SYN, 80 cycles/min, pulse pressure 20 mm Hg) and asynchronous (ASYN, 40 cycles/min, pulse pressure 45 mm Hg), suggested that both increased expression of Nrf-2-regulated anti-oxidant genes and proteins along with changes in levels of eNOS and ET-1 can potentially be minimized with ASYN and, to a lesser extent, with SYN. CONCLUSIONS: HAECs cultured within the ECCM can be used as an accurate model of large vessels in patients to identify biomarkers and select appropriate flow-modulation protocols. Pressure amplitude may have a greater effect in normalizing anti-oxidant response compared with frequency of modulation.

The Case for Cardiac Xenotransplantation in Neonates: Is Now the Time to Reconsider Xenotransplantation for Hypoplastic Left Heart Syndrome?

Neonatal cardiac transplantation for hypoplastic left heart syndrome (HLHS) is associated with excellent long-term survival compared to older recipients. However, heart transplantation for neonates is greatly limited by the critical shortage of donor hearts, and by the associated mortality of the long pre-transplant waiting period. This led to the development of staged surgical palliation as the first-line surgical therapy for HLHS. Recent advances in genetic engineering and xenotransplantation have provided the potential to replicate the excellent results of neonatal cardiac allotransplantation while eliminating wait-list-associated mortality through genetically modified pig-to-human neonatal cardiac xenotransplantation. The elimination of the major pig antigens in addition to the immature B-cell response in neonates allows for the potential to induce B-cell tolerance. Additionally, the relatively mature neonatal T-cell response could be reduced by thymectomy at the time of operation combined with donor-specific pig thymus transplantation to "reprogram" the host's T-cells to recognize the xenograft as host tissue. In light of the recent significantly increased graft survival of genetically-engineered pig-to-baboon cardiac xenotransplantation, we propose that now is the time to consider devoting research to advance the potential clinical application of cardiac xenotransplantation as a treatment option for patients with HLHS. Employing cardiac xenotransplantation could revolutionize therapy for complex congenital heart defects and open a new chapter in the field of pediatric cardiac transplantation.

Transplantation in the Fontan patient.

The failing Fontan circulation presents difficult treatment challenges. When Fontan revision and or intervention for treatable arrhythmias is not feasible, heart transplantation is the only therapeutic option. Particular challenges presented by these patients include limited ability to assess hemodynamics, complex anatomy, multiple prior procedures, and unique underlying pathologic states. These issues complicate the decision-making process for further surgical intervention verses transplantation. The pre-transplant evaluation, transplant operation, and post-operative management are more problematic for these patients compared with most patients undergoing transplantation. Consequently, failing Fontan patients constitute one of the highest risk heart transplant subsets.

Current estimate of costs of lung cancer screening in the United States.

The United States Preventive Services Task Force recently endorsed the use of low-dose computed tomography for lung cancer screening in high-risk patients because of the potential to reduce deaths. Before implementation on a national level, it will be important to ensure that a safe, high-quality, and accessible service can be adequately provided. It will also be important to make sure that screening is cost-effective. This article summarizes the published analyses of lung cancer screening cost, provides a contemporary estimation of the annual cost of screening in the United States, and identifies areas for improvement in the future.

Cancer stem cell phenotype is supported by secretory phospholipase A2 in human lung cancer cells.

BACKGROUND: Lung cancer stem cells (CSCs) are a subpopulation of cells that drive growth, invasiveness, and resistance to therapy. Inflammatory eicosanoids are critical to maintain this malignant subpopulation. Secretory phospholipase A2 group IIa (sPLA2) is an important mediator of the growth and invasive potential of human lung cancer cells and regulates eicosanoid production. We hypothesized that sPLA2 plays a role in the maintenance of lung CSCs. METHODS: Cancer stem cells from lung adenocarcinoma cell lines H125 and A549 were isolated using aldehyde dehydrogenase activity and flow cytometry. Protein and mRNA levels for sPLA2 were compared between sorted cells using Western blotting and quantitative reverse transcriptase-polymerase chain reaction techniques. Chemical inhibition of sPLA2 and short-hairpin RNA knockdown of sPLA2 were used to evaluate effects on tumorsphere formation. RESULTS: Lung CSCs were isolated in 8.9%±4.1% (mean±SD) and 4.1%±1.6% of H125 and A549 cells respectively. Both sPLA2 protein and mRNA expression were significantly elevated in the CSC subpopulation of H125 (p=0.002) and A549 (p=0.005; n=4). Knockdown of sPLA2 significantly reduced tumorsphere formation in H125 (p=0.026) and A549 (p=0.001; n=3). Chemical inhibition of sPLA2 resulted in dose-dependent reduction in tumorsphere formation in H125 (p=0.003) and A549 (p=0.076; n=3). CONCLUSIONS: Lung CSCs express higher levels of sPLA2 than the non-stem cell population. Our findings that viral knockdown and chemical inhibition of sPLA2 reduce tumorsphere formation in lung cancer cells demonstrate for the first time that sPLA2 plays an important role in CSCs. These findings suggest that sPLA2 may be an important therapeutic target for human lung cancer.

Pulmonary resection and lung transplantation for bronchiectasis.

The purpose of this article is to update specialists in pulmonary medicine on the role of surgical resection and lung transplantation for bronchiectasis. The focus is on pre-operative workup, the technical details of surgical resection, complications, and outcomes.

The 5-lipoxygenase pathway is required for acute lung injury following hemorrhagic shock.

The cellular and biochemical mechanisms leading to acute lung injury (ALI) and subsequent multiple organ failure are only partially understood. To study the potential role of eicosanoids, particularly leukotrienes, as possible mediators of ALI, we used a murine experimental model of ALI induced by hemorrhagic shock after blood removal via cardiac puncture. Neutrophil sequestration, as shown by immunofluorescence and protein leakage into the alveolar space were measured as markers of injury. We used liquid chromatography coupled to tandem mass spectrometry to unequivocally identify several eicosanoids in the bronchoalveolar lavage fluid of experimental animals. MK886, a specific inhibitor of the 5-lipoxygenase (5-LO) pathway, and transgenic mice deficient in 5-LO were used to determine the role of this enzymatic pathway in this model. Leukotriene B4 and leukotriene C4 were consistently elevated in shock-treated mice compared with sham-treated mice. MK886 attenuated neutrophil infiltration and protein extravasation induced by hemorrhagic shock. 5-Lipoxygenase-deficient mice showed reduced neutrophil infiltration and protein extravasation after shock treatment, indicating greatly reduced lung injury. These results support the hypothesis that 5-LO, most likely through the generation of leukotrienes, plays an important role in the pathogenesis of ALI induced by hemorrhagic shock in mice. This pathway could represent a new target for pharmacological intervention to reduce lung damage following severe primary injury.

Bone morphogenic protein 2 induces Runx2 and osteopontin expression in human aortic valve interstitial cells: role of Smad1 and extracellular signal-regulated kinase 1/2.

OBJECTIVE: Bone morphogenic protein 2 is found in calcified areas of stenotic aortic valves, and prolonged stimulation of aortic valve interstitial cells with bone morphogenic protein 2 results in increased expression of alkaline phosphatase, indicating a mechanistic role for bone morphogenic protein 2 in aortic valve calcification. The purposes of this study were to assess the effect of bone morphogenic protein 2 on the expression of the osteogenic factors Runx2 and osteopontin in human aortic valve interstitial cells and to determine the signaling mechanisms that mediate the expression of these early osteogenic factors. METHODS: Interstitial cells were isolated from normal and stenotic human aortic valve leaflets, and cellular bone morphogenic protein 2 levels were analyzed by means of immunoblotting. Cultured interstitial cells from normal aortic valves were stimulated with bone morphogenic protein 2 to determine its effect on cellular Runx2 and osteopontin levels. RESULTS: Interstitial cells from stenotic aortic valves express greater levels of bone morphogenic protein 2 than cells from normal valves. Stimulation of human aortic valve interstitial cells with bone morphogenic protein 2 induced marked increases in Runx2 and osteopontin levels at 48 hours. The changes in Runx2 and osteopontin levels were preceded by phosphorylation of Smad1 and extracellular signal-regulated kinase 1/2 but not p38 mitogen-activated protein kinase. Silencing Smad1 reduced Runx2 and osteopontin levels, whereas inhibition of extracellular signal-regulated kinase 1/2 reduced osteopontin expression without an influence on Runx2 expression. CONCLUSIONS: Interstitial cells of stenotic human aortic valves are characterized by increased bone morphogenic protein 2 levels. A short period of exposure of human aortic valve interstitial cells to bone morphogenic protein 2 induces the expression of Runx2 and osteopontin. The extracellular signal-regulated kinase 1/2 pathway modulates bone morphogenic protein 2-induced osteopontin expression, and the Smad1 pathway plays a role in regulating the expression of both Runx2 and osteopontin induced by bone morphogenic protein 2.

Clinical utility and cost-effectiveness of routine preoperative computed tomography scanning in patients with colon cancer.

BACKGROUND: The aims of this study were to assess the clinical utility of the practice of routine preoperative CT scanning and to determine its cost-effectiveness in colon cancer patients. METHODS: A 6-year database of colon cancer patients treated at a veterans affairs medical was reviewed to determine the influence of preoperative CT scanning on clinical management. Cost analysis involved comparison of the institutional cost of CT scanning with the cost savings provided by avoiding nontherapeutic operations. RESULTS: CT scans were obtained in 130 consecutive patients. CT scans provided information that was used in treatment planning in 43 (33%) patients and definitively altered the mode of treatment in 21 (16%) patients. The practice saved the institution $24,018 over 6 years. CONCLUSION: Routine preoperative CT scanning definitively alters treatment in a small number of cases and is cost-effective.