Reduced morbidity with early surgical ligation of patent ductus arteriosus in extremely low birth weight infants: a retrospective single-centre study.

INTRODUCTION: Failure of the patent ductus arteriosus to close is common among extremely low birth weight neonates and has been associated with increased morbidities. The objective of this study was to compare outcomes between early and late surgical ligation in extremely low birth weight patients. METHODS: This was a single-centre retrospective cohort study of infants who required surgical closure of patent ductus arteriosus between January 2017 and August 2022. RESULTS: A total of 43 neonates were identified with birth weight less than 1 kg that underwent surgical patent ductus arteriosus ligation. Compared to the late ligation group, the early ligation group experienced fewer total days of mechanical ventilation (43.9 days vs. 97.2 days, p < 0.05) and a shorter length of hospital stay (114.2 days vs. 169.0 days, p < 0.05). CONCLUSION: Early surgical ligation of haemodynamically significant patent ductus arteriosus in extremely low birth weight neonates may improve hospital morbidity, including improved ventilatory outcomes and a shorter length of stay.

Bayesian Optimization-Based Inverse Finite Element Analysis for Atrioventricular Heart Valves.

Inverse finite element analysis (iFEA) of the atrioventricular heart valves (AHVs) can provide insights into the in-vivo valvular function, such as in-vivo tissue strains; however, there are several limitations in the current state-of-the-art that iFEA has not been widely employed to predict the in-vivo, patient-specific AHV leaflet mechanical responses. In this exploratory study, we propose the use of Bayesian optimization (BO) to study the AHV functional behaviors in-vivo. We analyzed the efficacy of Bayesian optimization to estimate the isotropic Lee-Sacks material coefficients in three benchmark problems: (i) an inflation test, (ii) a simplified leaflet contact model, and (iii) an idealized AHV model. Then, we applied the developed BO-iFEA framework to predict the leaflet properties for a patient-specific tricuspid valve under a congenital heart defect condition. We found that the BO could accurately construct the objective function surface compared to the one from a [Formula: see text] grid search analysis. Additionally, in all cases the proposed BO-iFEA framework yielded material parameter predictions with average element errors less than 0.02 mm/mm (normalized by the simulation-specific characteristic length). Nonetheless, the solutions were not unique due to the presence of a long-valley minima region in the objective function surfaces. Parameter sets along this valley can yield functionally equivalent outcomes (i.e., closing behavior) and are typically observed in the inverse analysis or parameter estimation for the nonlinear mechanical responses of the AHV. In this study, our key contributions include: (i) a first-of-its-kind demonstration of the BO method used for the AHV iFEA; and (ii) the evaluation of a candidate AHV in-silico modeling approach wherein the chordae could be substituted with equivalent displacement boundary conditions, rendering the better iFEA convergence and a smoother objective surface.

An investigation of how specimen dimensions affect biaxial mechanical characterizations with CellScale BioTester and constitutive modeling of porcine tricuspid valve leaflets.

Biaxial mechanical characterizations are the accepted approach to determine the mechanical response of many biological soft tissues. Although several computational and experimental studies have examined how experimental factors (e.g., clamped vs. suture mounting) affect the acquired tissue mechanical behavior, little is known about the role of specimen dimensions in data acquisition and the subsequent modeling. In this study, we combined our established mechanical characterization framework with an iterative size-reduction protocol to test the hypothesis that specimen dimensions affect the observed mechanical behavior of biaxial characterizations. Our findings indicated that there were non-significant differences in the peak equibiaxial stretches of tricuspid valve leaflets across four specimen dimensions ranging from 4.5×4.5mm to 9 × 9mm. Further analyses revealed that there were significant differences in the low-tensile modulus of the circumferential tissue direction. These differences resulted in significantly different constitutive model parameters for the Tong-Fung model between different specimen dimensions of the posterior and septal leaflets. Overall, our findings demonstrate that specimen dimensions play an important role in experimental characterizations, but not necessarily in constitutive modeling of soft tissue mechanical behavior during biaxial testing with the commercial CellScale BioTester.

PROX1 Inhibits PDGF-B Expression to Prevent Myxomatous Degeneration of Heart Valves.

BACKGROUND: Cardiac valve disease is observed in 2.5% of the general population and 10% of the elderly people. Effective pharmacological treatments are currently not available, and patients with severe cardiac valve disease require surgery. PROX1 (prospero-related homeobox transcription factor 1) and FOXC2 (Forkhead box C2 transcription factor) are transcription factors that are required for the development of lymphatic and venous valves. We found that PROX1 and FOXC2 are expressed in a subset of valvular endothelial cells (VECs) that are located on the downstream (fibrosa) side of cardiac valves. Whether PROX1 and FOXC2 regulate cardiac valve development and disease is not known. METHODS: We used histology, electron microscopy, and echocardiography to investigate the structure and functioning of heart valves from Prox1ΔVEC mice in which Prox1 was conditionally deleted from VECs. Isolated valve endothelial cells and valve interstitial cells were used to identify the molecular mechanisms in vitro, which were tested in vivo by RNAScope, additional mouse models, and pharmacological approaches. The significance of our findings was tested by evaluation of human samples of mitral valve prolapse and aortic valve insufficiency. RESULTS: Histological analysis revealed that the aortic and mitral valves of Prox1ΔVEC mice become progressively thick and myxomatous. Echocardiography revealed that the aortic valves of Prox1ΔVEC mice are stenotic. FOXC2 was downregulated and PDGF-B (platelet-derived growth factor-B) was upregulated in the VECs of Prox1ΔVEC mice. Conditional knockdown of FOXC2 and conditional overexpression of PDGF-B in VECs recapitulated the phenotype of Prox1ΔVEC mice. PDGF-B was also increased in mice lacking FOXC2 and in human mitral valve prolapse and insufficient aortic valve samples. Pharmacological inhibition of PDGF-B signaling with imatinib partially ameliorated the valve defects of Prox1ΔVEC mice. CONCLUSIONS: PROX1 antagonizes PDGF-B signaling partially via FOXC2 to maintain the extracellular matrix composition and prevent myxomatous degeneration of cardiac valves.

Tricuspid Valve Regurgitation in Hypoplastic Left Heart Syndrome: Current Insights and Future Perspectives.

Hypoplastic Left Heart Syndrome (HLHS) is a congenital heart defect that requires a three-stage surgical palliation to create a single ventricle system in the right side of the heart. Of patients undergoing this cardiac palliation series, 25% will develop tricuspid regurgitation (TR), which is associated with an increased mortality risk. Valvular regurgitation in this population has been extensively studied to understand indicators and mechanisms of comorbidity. In this article, we review the current state of research on TR in HLHS, including identified valvular anomalies and geometric properties as the main reasons for the poor prognosis. After this review, we present some suggestions for future TR-related studies to answer the central question: What are the predictors of TR onset during the three palliation stages? These studies involve (i) the use of engineering-based metrics to evaluate valve leaflet strains and predict tissue material properties, (ii) perform multivariate analyses to identify TR predictors, and (iii) develop predictive models, particularly using longitudinally tracked patient cohorts to foretell patient-specific trajectories. Regarded together, these ongoing and future efforts will result in the development of innovative tools that can aid in surgical timing decisions, in prophylactic surgical valve repair, and in the refinement of current intervention techniques.

Bilateral pulmonary artery banding in higher risk neonates with hypoplastic left heart syndrome.

Objectives: Limited data on performing bilateral pulmonary artery banding (BPAB) before stage 1 Norwood procedure suggest that some patients may benefit through the postponement of the major cardiopulmonary bypass procedure. The objective of this study was to evaluate the effectiveness of BPAB in the surgical management of high-risk patients with hypoplastic left heart syndrome (HLHS). Methods: A retrospective review of all high-risk neonates with HLHS who underwent BPAB at our institution was performed. No patients, including those with intact or highly restrictive atrial septum (IAS), were excluded. Results: Between October 2015 and April 2021, 49 neonates with HLHS (including 6 with IAS) underwent BPAB, 40 of whom progressed to the Norwood procedure. Risk factors for not progressing to the Norwood procedure after BPAP include low birth weight (P = .043), the presence of multiple extracardiac anomalies (P = .005), and the presence of genetic disorders (P = .028). Operative mortality was 7.5% (3/40). IAS was associated with operative mortality (P = .022). Conclusions: The strategy of BPAB prestage 1 Norwood procedure was successful in identifying at-risk patients and improving Norwood survival. Although not all patients will need this hybrid approach, a significant number can be expected to benefit from this tactic. These results support the need for a substantial hybrid strategy, in addition to a primary stage 1 Norwood surgical strategy, in the management of HLHS.

Sinus of Valsalva aneurysm: Defining the optimal approach.

Sinus of Valsalva aneurysm (SVA) is relatively rare, especially in Western countries, and reports on long-term results after surgical SVA repair in a sizable patient cohort are scarce. In this issue of the Journal of Cardiac Surgery, Chaganti and colleagues publish their surgical experience over the past 30 years in 216 patients with SVA. SVAs were closed via a dual approach, with (1) patch closure (80%) or direct closure (20%) of the base of the fistula through aortotomy and (2) direct closure of the ruptured tip through the chamber of rupture. Aortic valve replacement (9.7%) or repair (6.5%) was performed for moderate to severe aortic regurgitation (AR). There was no hospital mortality. During a mean follow-up of 10 years, no patient had residual/recurrent shunting. The actual survival at 10 years was 99%, with only two deaths. Freedom from moderate or severe AR was 98.5% at 10 years. Early and long-term results after surgical repair of SVA were excellent in their 216 patients with a mean follow-up of 10 years. Their dual approach for SVA was effective in preventing residual/recurrent shunting. The need for AVR in 10% of the patients speaks to the importance of follow-up. The current report provides strong support for surgical repair being the preferred management for SVA.

Autologous Umbilical Cord Blood-Derived Mononuclear Cell Therapy Promotes Cardiac Proliferation and Adaptation in a Porcine Model of Right Ventricle Pressure Overload.

Congenital heart diseases, including single ventricle circulations, are clinically challenging due to chronic pressure overload and the inability of the myocardium to compensate for lifelong physiological demands. To determine the clinical relevance of autologous umbilical cord blood-derived mononuclear cells (UCB-MNCs) as a therapy to augment cardiac adaptation following surgical management of congenital heart disease, a validated model system of right ventricular pressure overload due to pulmonary artery banding (PAB) in juvenile pigs has been employed. PAB in a juvenile porcine model and intramyocardial delivery of UCB-MNCs was evaluated in three distinct 12-week studies utilizing serial cardiac imaging and end-of-study pathology evaluations. PAB reproducibly induced pressure overload leading to chronic right ventricular remodeling including significant myocardial fibrosis and elevation of heart failure biomarkers. High-dose UCB-MNCs (3 million/kg) delivered into the right ventricular myocardium did not cause any detectable safety issues in the context of arrhythmias or abnormal cardiac physiology. In addition, this high-dose treatment compared with placebo controls demonstrated that UCB-MNCs promoted a significant increase in Ki-67-positive cardiomyocytes coupled with an increase in the number of CD31+ endothelium. Furthermore, the incorporation of BrdU-labeled cells within the myocardium confirmed the biological potency of the high-dose UCB-MNC treatment. Finally, the cell-based treatment augmented the physiological adaptation compared with controls with a trend toward increased right ventricular mass within the 12 weeks of the follow-up period. Despite these adaptations, functional changes as measured by echocardiography and magnetic resonance imaging did not demonstrate differences between cohorts in this surgical model system. Therefore, this randomized, double-blinded, placebo-controlled pre-clinical trial establishes the safety of UCB-MNCs delivered via intramyocardial injections in a dysfunctional right ventricle and validates the induction of cardiac proliferation and angiogenesis as transient paracrine mechanisms that may be important to optimize long-term outcomes for surgically repaired congenital heart diseases.

Benchtop characterization of the tricuspid valve leaflet pre-strains.

The pre-strains of biological soft tissues are important when relating their in vitro and in vivo mechanical behaviors. In this study, we present the first-of-its-kind experimental characterization of the tricuspid valve leaflet pre-strains. We use 3D photogrammetry and the reproducing kernel method to calculate the pre-strains within the central 10×10 mm region of the tricuspid valve leaflets from n=8 porcine hearts. In agreement with previous pre-strain studies for heart valve leaflets, our results show that all the three tricuspid valve leaflets shrink after being explanted from the ex vivo heart. These calculated strains are leaflet-specific and the septal leaflet experiences the most compressive changes. Furthermore, the strains observed after dissection of the central 10×10 mm region of the leaflet are smaller than when the valve is explanted, suggesting that our computed pre-strains are mainly due to the release of in situ annulus and chordae connections. The leaflets are then mounted on a biaxial testing device and preconditioned using force-controlled equibiaxial loading. We show that the employed preconditioning protocol does not 100% restore the leaflet pre-strains as removed during tissue dissection, and future studies are warranted to explore alternative preconditioning methods. Finally, we compare the calculated biomechanically oriented metrics considering five stress-free reference configurations. Interestingly, the radial tissue stretches and material anisotropies are significantly smaller compared to the post-preconditioning configuration. Extensions of this work can further explore the role of this unique leaflet-specific leaflet pre-strains on in vivo valve behavior via high-fidelity in-silico models. STATEMENT OF SIGNIFICANCE: This study provides a first of its kind benchtop characterization of tricuspid valve leaflet pre-strains. We used 3D photogrammetry to reconstruct the central region of the tricuspid valve leaflets in three configurations. The associated configurational changes revealed compressive, leaflet-specific strains after dissection of the valve from its in situ environment. Interestingly, we found that biaxial preconditioning did not restore the measured pre-strains of the leaflets. Depending on the selection of the stress-free reference configuration, this led to substantial differences in the leaflet mechanics. Our findings and methodology are crucial when it comes to relating in vitro mechanical behaviors to valve function in vivo. Future studies can integrate our quantified pre-strains into in-silico simulations to get more realistic predictions about the valve function.

A pilot investigation of the tricuspid valve annulus in newborns with hypoplastic left heart syndrome.

Objective: Hypoplastic left heart syndrome (HLHS) is a congenital disease characterized by an underdevelopment of the anatomical components inside the left heart. Approximately 30% of HLHS newborns will develop tricuspid regurgitation (TR), and it is currently unknown how the valve annulus mechanics and geometry are associated with regurgitation. Thus, we present an engineering mechanics-based analysis approach to quantify the mechanics and geometry of the HLHS-afflicted tricuspid valve (TV), using 4-dimensional echocardiograms. Methods: Infants born with hypoplastic left heart syndrome (n=8) and healthy newborns (n=4) had their tricuspid valves imaged, and the data was imported to the 3D Slicer. The annular curves were defined at five points in the cardiac cycle. The geometry and deformation (strain) of the TV annulus were calculated to elucidate the mechanics of this critical structure, and compare them between HLHS and normal neonates. Results: For the annular geometry, HLHS-afflicted newborns had significantly larger annular circumferences (20-30%) and anterior-posterior diameters (35-45%) than the healthy patients. From a biomechanics perspective, the HLHS patients had significantly smaller strains in the anterior segments (-0.1±2.6%) during end diastolic and end isovolumetric relaxation (1.7±3.0%) compared to the healthy counterparts (-13.3±2.9% and 6.8±0.9%, respectively). Conclusions: The image-based analysis in this study may provide novel insights into the geometric and mechanistic differences in the TV annulus between healthy and HLHS newborns. Future longitudinal studies of the biomechanics of TV annulus and other subvalvular structures may inform our understanding of the initiation and development of TR and the design of optimal repairs in this challenging population.

Isolated ostial left main coronary artery stenosis causing ischemic cardiomyopathy in a child with bicuspid aortic valve: Role of echocardiography in diagnosis and follow-up.

Bicuspid aortic valve (BAV) is the most common congenital cardiac defect, commonly associated with valve dysfunction and coarctation of aorta. Rarely, BAV can be associated with abnormalities of the coronary arteries, the most common of which are ectopic coronary origins. In this report, we present a case of a 2-year-old child with BAV, without coexisting supravalvular aortic stenosis, who was found to have a left main coronary ostio-proximal stenosis, leading to ischemic cardiomyopathy and congestive heart failure.

Clinical Characteristics and Potential Pathogenesis of Cardiac Necrotizing Enterocolitis in Neonates with Congenital Heart Disease: A Narrative Review.

Neonates with congenital heart disease (CHD) are at an increased risk of developing necrotizing enterocolitis (NEC), an acute inflammatory intestinal injury most commonly associated with preterm infants. The rarity of this complex disease, termed cardiac NEC, has resulted in a dearth of information on its pathophysiology. However, a higher incidence in term infants, effects on more distal regions of the intestine, and potentially a differential immune response may distinguish cardiac NEC as a distinct condition from the more common preterm, classical NEC. In this review, risk factors, differentiated from those of classical NEC, are discussed according to their potential contribution to the disease process, and a general pathogenesis is postulated for cardiac NEC. Additionally, biomarkers specific to cardiac NEC, clinical outcomes, and strategies for achieving enteral feeds are discussed. Working towards an understanding of the mechanisms underlying cardiac NEC may aid in future diagnosis of the condition and provide potential therapeutic targets.

Tracheobronchial Release for Left Bronchus Compression After Aortic Arch Repair.

Narrowing of the retroaortic space after repair of common arterial trunk (CAT) with interrupted aortic arch (IAA) is a well-known issue. We present a newborn with CAT, IAA, and functionally univentricular heart (tricuspid atresia) who underwent repair of CAT, IAA, and left ventricle-to-pulmonary artery (LV-to-PA) conduit placement with the Lecompte maneuver. The patient suffered from left bronchus compression postoperatively, which was relieved by tracheobronchial release.

Staged unifocalization revisited.

BACKGROUND: A staged thoracotomy unifocalization approach has not been the dominant option over the past 20 years primarily due to the introduction of midline one-stage complete unifocalization. METHODS: In this issue of the Journal of Cardiac Surgery, van de Woestijne et al. publish their experience over the past 30 years in 39 consecutive patients with "consistent" staged unifocalization through a lateral thoracotomy in patients with pulmonary atresia, ventricular septal defect, and major aortopulmonary collateral arteries (PA/VSD/MAPCA). RESULTS: They report definitive repair completion in 76.3% of the patients and an overall survival after definitive repair of 96% at 20 years despite the study period ranging from 1989 to the present. CONCLUSION: Given the multiple variations one could have with PA/VSD/MPACA, a midline unifocalization approach may not always be possible. Surgeons should be familiar with the lateral thoracotomy unifocalization staged approach to PA/VSD/MAPCA.