Impact of Age-Related Change in Caval Flow Ratio on Hepatic Flow Distribution in the Fontan Circulation.

BACKGROUND: The Fontan operation is a palliative technique for patients born with single ventricle heart disease. The superior vena cava (SVC), inferior vena cava (IVC), and hepatic veins are connected to the pulmonary arteries in a total cavopulmonary connection by an extracardiac conduit or a lateral tunnel connection. A balanced hepatic flow distribution (HFD) to both lungs is essential to prevent pulmonary arteriovenous malformations and cyanosis. HFD is highly dependent on the local hemodynamics. The effect of age-related changes in caval inflows on HFD was evaluated using cardiac magnetic resonance data and patient-specific computational fluid dynamics modeling. METHODS: SVC and IVC flow from 414 patients with Fontan were collected to establish a relationship between SVC:IVC flow ratio and age. Computational fluid dynamics modeling was performed in 60 (30 extracardiac and 30 lateral tunnel) patient models to quantify the HFD that corresponded to patient ages of 3, 8, and 15 years, respectively. RESULTS: SVC:IVC flow ratio inverted at ≈8 years of age, indicating a clear shift to lower body flow predominance. Our data showed that variation of HFD in response to age-related changes in caval inflows (SVC:IVC, 2, 1, and 0.5 corresponded to ages, 3, 8, and 15+, respectively) was not significant for extracardiac but statistically significant for lateral tunnel cohorts. For all 3 caval inflow ratios, a positive correlation existed between the IVC flow distribution to both the lungs and the HFD. However, as the SVC:IVC ratio changed from 2 to 0.5 (age, 3-15+) years, the correlation's strength decreased from 0.87 to 0.64, due to potential flow perturbation as IVC flow momentum increased. CONCLUSIONS: Our analysis provided quantitative insights into the impact of the changing caval inflows on Fontan's long-term HFD, highlighting the importance of SVC:IVC variations over time on Fontan's long-term hemodynamics. These findings broaden our understanding of Fontan hemodynamics and patient outcomes.

Fiberscope-Based Measurement of Coaptation Height for Intraoperative Assessment of Mitral Valve Repair.

BACKGROUND: Restoring adequate coaptation height is a key principle of mitral valve (MV) repair. This study aimed to evaluate the utility of fiberscope (FS) technology to assess MV coaptation height for intraoperative use. METHODS: Ex-vivo testing was performed on five adult porcine hearts. The left atrium (LA) was resected, and the left ventricle (LV) was pressurized retrograde to 27 ± 1mm Hg. An endoscope was inserted into the LV apex, centered under the MV orifice. An FS system (Milliscope II camera, LED light source, and 0.7 mm diameter × 15 cm long) 90° semirigid scope with 1.2 mm focal length) was mounted above the MV annulus in a custom alignment and measuring fixture. Three blinded measurements were taken at two locations on each MV, A2 and P2 segment, from the top of coaptation to the leaflet edge identified by the FS. Accurate positioning was verified using the LV endoscope. A control (metal rod of similar thickness) was used for comparison, with coaptation height recorded when the control was seen via the endoscope. RESULTS: Coaptation heights were similar for the control and FS methods across all hearts at A2 (11.6 ± 2.6 mm control vs 11.8 ± 2.2 mm FS) and P2 (13.3 ± 2.6 mm control vs 13.4 ± 2.9 mm FS) segments, with similar measurement variability (control SD 0.1-1.0 mm; FS SD 0.1-0.9 mm). One outlier was excluded from analysis (n = 19/20). The maximum absolute difference and percent error between measurement methods were less than 1.1 mm (median [IQR], 0.6 [0.3-0.9] mm) and less than 14% (4.1 [2.2-7.6]%). CONCLUSIONS: Utilization of a miniaturized FS enabled precise and accurate quantification of MV coaptation. This technique is promising for evaluating post-repair valve competence and coaptation height.

Systematic Analysis of PTFE Monocusp Leaflet Design in a Patient-Based 3D in-Vitro Model of Tetralogy of Fallot.

PURPOSE: Pulmonary valve (PV) monocusp reconstruction in transannular patch (TAP) right ventricular outflow tract (RVOT) repair for Tetralogy of Fallot has variable clinical outcomes across different surgical approaches. The study purpose was to systematically evaluate how monocusp leaflet design parameters affect valve function in-vitro. METHODS: A 3D-printed, disease-specific RVOT model was tested under three infant physiological conditions. Monocusps were sewn into models with the native main pulmonary artery (MPA) forming backwalls that constituted 40% and 50% of the reconstructed circumference for z-score zero PV annulus and MPA diameters (native PV z-score - 3.52 and - 2.99 for BSA 0.32m2). Various leaflet free edge lengths (FEL) (relative to backwall), positions (relative to PV STJ), and scallop depths were investigated across both models. Pressure gradient, regurgitation, and coaptation were analyzed with descriptive statistics and regression models. RESULTS: Increasing FEL beyond 100% of the MPA backwall decreased gradient but mildly increased regurgitation to a peak of 25%. Positioning the free edge 2 mm past the STJ mildly increased gradient for each FEL without significantly changing regurgitation compared to STJ placement. Scalloping leaflets trivially affected performance. Pre-folding leaflets improved mobility and slightly reduced gradient. CONCLUSIONS: Balancing gradient, regurgitation, and oversizing for growth, a set of leaflet designs have been selected for pre-clinical evaluation. Designs with leaflet widths 140-160% in the 40% backwall model (110-120% in the 50% backwall), positioned at or 2 mm past the STJ, demonstrated the best results. The next stage of ex-vivo testing will additionally consider native RVOT distensibility, native leaflet interactions, and TAP characteristics.

Mechanical failure analysis of patch materials used in aortic arch reconstruction: implications for clinical practice.

OBJECTIVES: Thick-patch pulmonary homograft, autologous pericardium and CardioCel Neo are common patch materials for aortic arch reconstruction. Insufficient data exist on sutured patch strength and limits of use. We evaluated failure strength of these materials to develop a failure prediction model for clinical guidance. METHODS: Patch failure strength was evaluated via sutured uniaxial and burst pressure testing. In sutured uniaxial testing, patches were sutured to aortic or Dacron tabs and pulled to failure. In burst pressure testing, patches were sewn into porcine aortas or Dacron grafts and pressurized to failure. Failure membrane tension was calculated. A prediction model of membrane tension versus vessel diameter was generated to guide clinical patch selection. RESULTS: Combining sutured uniaxial and burst pressure test data, pulmonary homograft failure strength {0.61 [interquartile range (IQR): 0.44, 0.78] N/mm, n = 21} was less than half that of autologous pericardium [2.22 (IQR: 1.65, 2.78) N/mm, n = 15] and CardioCel Neo [1.31 (IQR: 1.20, 1.42) N/mm, n = 20]. Pulmonary homograft burst pressure [245 (IQR: 202, 343) mmHg, n = 7] was significantly lower than autologous pericardium [863 (IQR: 802, 919) mmHg, n = 6] and CardioCel Neo [766 (IQR: 721, 833) mmHg, n = 6]. Our model predicts failure limits for each patch material and outlines safety margins for combinations of aortic diameter and pressure. CONCLUSIONS: Sutured failure strength of thick-patch pulmonary homograft was significantly lower than autologous pericardium and CardioCel Neo. Patient selection (predicted postoperative arch diameter and haemodynamics) and blood pressure management must be considered when choosing patch material for arch reconstruction. In older children and adolescents, autologous or bovine pericardium may be more suitable materials for aortic patch augmentation to minimize the risk of postoperative patch failure.

Transcatheter Pulmonary Artery Banding in High-Risk Neonates: In-Vitro Study Provoked by Initial Clinical Experience.

PURPOSE: Very high-risk, ductal-dependent or complex two-ventricle patients with associated comorbidities often require pulmonary blood flow restriction as bridge to a more definitive procedure, but current surgical options may not be well-tolerated. An evolving alternative utilizes a fenestrated Micro Vascular Plug (MVP) as a transcatheter, internal pulmonary artery band. In this study, we report a case series and an in-vitro evaluation of the MVP to elicit understanding of the challenges faced with device implantation. METHODS: Following single-center, retrospective review of eight patients who underwent device placement, an in-vitro flow study was conducted on MVP devices to assess impact of device and fenestration sizing on pulmonary blood flow. A mathematical model was developed to relate migration risk to vessel size. Results of the engineering analysis were compared to the clinical series for validation. RESULTS: At median follow-up of 8 months (range 1-15), survival was 63% (5/8), and 6 (75%) patients underwent subsequent target surgical intervention with relatively low mortality (1/6). Occluder-related challenges included migration (63%) and peri-device flow, which were evaluated in-vitro. The device demonstrated durability over normal and supraphysiologic conditions with minimal change in fenestration size. Smaller vessel size significantly increased pressure gradient due to reduced peri-device flow and smaller effective fenestration size. CONCLUSION: Device oversizing, with appropriate adjustment to fenestration size, may reduce migration risk and provide a clinically appropriate balance between resulting pressure gradient and Qp:Qs. Our results can guide the interventionalist in appropriately selecting the device and fenestrations based on patient-specific anatomy and desired post-implantation flow characteristics.

An In Vitro Circulatory Loop Model of the Pediatric Right Ventricular Outflow Tract as a Platform for Valve Evaluation.

PURPOSE: Tetralogy of Fallot and other conditions affecting the right ventricular outflow tract (RVOT) are common in pediatric patients, but there is a lack of quantitative comparison among techniques for repairing or replacing the pulmonary valve. The aim of this study was to develop a robust in vitro system for quantifying flow conditions after various RVOT interventions. METHODS: An infant-sized mock circulatory loop that includes a 3D-printed RVOT anatomical model was developed to evaluate flow conditions after different simulated surgical repairs. Physiologically correct flow and pressure were achieved with custom compliant tubing and a tunable flow restrictor. Pressure gradient, flow regurgitation, and coaptation height were measured for two monocusp leaflet designs after tuning the system with a 12 mm Hancock valved conduit. RESULTS: Measurements were repeatable across multiple samples of two different monocusp designs, with the wider leaflet in the 50% backwall model consistently exhibiting lower pressure gradient but higher regurgitation compared to the leaflet in the 40% backwall model. Coaptation height was measured via direct visualization with endoscopic cameras, revealing a shorter area of contact for the wider leaflet (3.3-4.0 mm) compared to the narrower one (4.3 mm). CONCLUSION: The 3D-printed RVOT anatomical model and in vitro pulmonary circulatory loop developed in this work provide a platform for planning and evaluating surgical interventions in the pediatric population. Measurements of regurgitation, pressure gradient, and coaptation provide a quantitative basis for comparison among different valve designs and positions.

The feasibility of mitral valve device foldoplasty: an in vivo study to evaluate durable retention.

OBJECTIVES: We have previously shown in experimental settings that a leaflet foldoplasty device reduces redundant leaflet area to re-establish mitral valve (MV) coaptation. The current study investigates the in vivo device retention and functional durability following foldoplasty. METHODS: The prototype is of superelastic nitinol formed into a 3-dimensional shape. It is unfolded to engage a specified area of leaflet tissue and then folded to exclude this tissue from the coaptation surface. Design modifications were made and tested in benchtop studies to determine the optimal design for durable retention within the leaflet. To evaluate in vivo performance, posterior leaflet chordae were severed in Yorkshire pigs to produce complete posterior leaflet prolapse and severe mitral regurgitation. Design modifications were then used for MV repair. Five animals that underwent repair using the optimal design were observed for 2 weeks postoperative to evaluate the functional result and implant retention. RESULTS: Device position and orientation were maintained at 2 weeks while preserving the functional MV repair in all 5 animals. Coaptation height was 5.5 ± 1.5 mm, which was not significantly different from a baseline of 4.9 ± 0.8 mm. The degree of leaflet excursion was 41.0 ± 16.0 compared to a baseline of 58.7 ± 27.5. CONCLUSIONS: Device foldoplasty is a new concept for MV repair based on the reduction of redundant leaflet tissue area. This study demonstrates the feasibility of safe maintenance of this repair without early dislodgement or embolization.

Mechanical strain triggers endothelial-to-mesenchymal transition of the endocardium in the immature heart.

BACKGROUND: Endothelial-to-mesenchymal-transition (EndMT) plays a major role in cardiac fibrosis, including endocardial fibroelastosis but the stimuli are still unknown. We developed an endothelial cell (EC) culture and a whole heart model to test whether mechanical strain triggers TGF-ß-mediated EndMT. METHODS: Isolated ECs were exposed to 10% uniaxial static stretch for 8 h (stretch) and TGF-ß-mediated EndMT was determined using the TGF-ß-inhibitor SB431542 (stretch + TGF-ß-inhibitor), BMP-7 (stretch + BMP-7) or losartan (stretch + losartan), and isolated mature and immature rats were exposed to stretch through a weight on the apex of the left ventricle. Immunohistochemical staining for double-staining with endothelial markers (VE-cadherin, PECAM1) and mesenchymal markers (αSMA) or transcription factors (SLUG/SNAIL) positive nuclei was indicative of EndMT. RESULTS: Stretch-induced EndMT in ECs expressed as double-stained ECs/total ECs (cells: 46 ± 13%; heart: 15.9 ± 2%) compared to controls (cells: 7 ± 2%; heart: 3.1 ± 0.1; p < 0.05), but only immature hearts showed endocardial EndMT. Inhibition of TGF-ß decreased the number of double-stained cells significantly, comparable to controls (cells/heart: control: 7 ± 2%/3.1 ± 0.1%, stretch: 46 ± 13%/15 ± 2%, stretch + BMP-7: 7 ± 2%/2.9 ± 0.1%, stretch + TGF-ß-inhibitor (heart only): 5.2 ± 1.3%, stretch + losartan (heart only): 0.89 ± 0.1%; p < 0.001 versus stretch). CONCLUSIONS: Endocardial EndMT is an age-dependent consequence of increased strain triggered by TGF- ß activation. Local inhibition through either rebalancing TGF-ß/BMP or with losartan was effective to block EndMT. IMPACT: Mechanical strain imposed on the immature LV induces endocardial fibroelastosis (EFE) formation through TGF-ß-mediated activation of endothelial-to-mesenchymal transition (EndMT) in endocardial endothelial cells but has no effect in mature hearts. Local inhibition through either rebalancing the TGF-ß/BMP pathway or with losartan blocks EndMT. Inhibition of endocardial EndMT with clinically applicable treatments may lead to a better outcome for congenital heart defects associated with EFE.

The Role of Elevated Wall Shear Stress in Progression of Pulmonary Vein Stenosis: Evidence from Two Case Studies.

Pulmonary vein stenosis is a serious condition characterized by restriction or blockage due to fibrotic tissue ingrowth that develops in the pulmonary veins of infants or children. It is often progressive and can lead to severe pulmonary hypertension and death. Efforts to halt or reverse disease progression include surgery and catheter-based balloon dilation and stent implantation. Its cause and mechanism of progression are unknown. In this pilot study, we propose and explore the hypothesis that elevated wall shear stress at discrete pulmonary venous sites triggers stenosis. To assess this theory, we retrospectively analyzed cardiac catheterization, lung scan, and X-ray computed tomography data to estimate wall shear stress in the pulmonary veins at multiple time points during disease progression in two patients. Results are consistent with the existence of a level of elevated wall shear stress above which the disease is progressive and below which progression is halted. The analysis also suggests the possibility of predicting the target lumen size necessary in a given vein to reduce wall shear stress to normal levels and remove the trigger for stenosis progression.

Automatic extraction of the mitral valve chordae geometry for biomechanical simulation.

PURPOSE: Mitral valve computational models are widely studied in the literature. They can be used for preoperative planning or anatomical understanding. Manual extraction of the valve geometry on medical images is tedious and requires special training, while automatic segmentation is still an open problem. METHODS: We propose here a fully automatic pipeline to extract the valve chordae architecture compatible with a computational model. First, an initial segmentation is obtained by sub-mesh topology analysis and RANSAC-like model-fitting procedure. Then, the chordal structure is optimized with respect to objective functions based on mechanical, anatomical, and image-based considerations. RESULTS: The approach has been validated on 5 micro-CT scans with a graph-based metric and has shown an [Formula: see text] accuracy rate. The method has also been tested within a structural simulation of the mitral valve closed state. CONCLUSION: Our results show that the chordae architecture resulting from our algorithm can give results similar to experienced users while providing an equivalent biomechanical simulation.

A Tribute to Ajit Yoganathan's Cardiovascular Fluid Mechanics Lab: A Survey of Its Contributions to Our Understanding of the Physiology and Management of Single-Ventricle Patients.

INTRODUCTION: Among patients with congenital heart disease, those born with only a single working ventricle represent a particularly complex sub-population, typically requiring multiple surgeries and suffering from high levels of mortality and morbidity. Their cardiac care is complex and has evolved considerably since surgical palliation was first introduced more than 50 years ago. Improvements in treatment have been driven both by growing clinical experience and by knowledge gained through experimental and computational studies of blood flow in these patients. The Cardiovascular Fluid Mechanics Lab at the Georgia Institute of Technology, founded 30 years ago by Dr. Ajit Yoganathan, has pioneered work in this field. METHODS: In this review, key contributions of Dr. Yoganathan's Cardiovascular Fluid Dynamics Lab are surveyed, including experimental flow loop studies as well as computational fluid dynamics analyses that address many of the critical challenges that cardiologists and surgeons face in treating these patients, including how to reconstruct cardiovascular anatomy to minimize power loss, balance blood flow distribution at key bifurcation points, and avoid other unfavorable hemodynamic conditions. CONCLUSIONS: Among many contributions in this field, work from the Cardiovascular Fluid Mechanics Lab has led to novel medical devices and patient-specific computational modeling workflows and software tools. These key contributions from this group have enhanced our understanding of the physiology and management of single-ventricle patients.

A geometrically adaptable heart valve replacement.

Congenital heart valve disease has life-threatening consequences that warrant early valve replacement; however, the development of a growth-accommodating prosthetic valve has remained elusive. Thousands of children continue to face multiple high-risk open-heart operations to replace valves that they have outgrown. Here, we demonstrate a biomimetic prosthetic valve that is geometrically adaptable to accommodate somatic growth and structural asymmetries within the heart. Inspired by the human venous valve, whose geometry is optimized to preserve functionality across a wide range of constantly varying volume loads and diameters, our balloon-expandable synthetic bileaflet valve analog exhibits similar adaptability to dimensional and shape changes. Benchtop and acute in vivo experiments validated design functionality, and in vivo survival studies in growing sheep demonstrated that mechanical valve expansion accommodated growth. As illustrated in this work, dynamic size adaptability with preservation of unidirectional flow in prosthetic valves thus offers a paradigm shift in the treatment of heart valve disease.

Flow disturbances and the development of endocardial fibroelastosis.

OBJECTIVES: Endothelial-to-mesenchymal transition (EndMT) has been identified as the underlying mechanism of endocardial fibroelastosis (EFE) formation. The purpose of this study was to determine whether hemodynamic alterations due to valvar defects promote EndMT and whether age-specific structural changes affect ventricular diastolic compliance despite extensive surgical resection of EFE tissue. MATERIAL AND METHODS: We analyzed EFE tissue from 24 patients with hypoplastic left heart syndrome (HLHS) who underwent left ventricular (LV) rehabilitation surgery at Boston Children's Hospital between December 2011 and March 2018. Six patients with flow disturbances across the aortic valve and/or mitral valve but no HLHS diagnosis and macroscopic appearance of "EFE-like tissue" in the LV were included for comparison. All samples were examined for amount of collagen/elastin production and degradation, and presence of active EndMT by histologic analysis. RESULTS: EFE tissue from patients with and without HLHS consisted predominantly of elastin and collagen fibers. There was no alteration in degradation activity for collagen or elastin as shown by in situ zymography. Active EndMT was found in all patients with and without HLHS with flow disturbances ("EFE-like"). In patients with HLHS, EFE infiltrated into the underlying myocardium with increasing age. CONCLUSIONS: Patients with and without HLHS with flow disturbances due to stenotic or incompetent valves develop EndMT-derived fibrotic tissue covering the LV. When EFE recurs, it is directly associated with flow disturbances and switches to an infiltrative growth pattern with increasing age, leading to increased diastolic stiffness of the LV.

Flow disturbances and progression of endocardial fibroelastosis - a case report.

Endocardial fibroelastosis (EFE) is described as thickening of the endocardium and is associated with hypoplastic left heart syndrome (HLHS). The stimulus for EFE and the mechanism for recurrence and/or progression need to be investigated. In this report, we describe the case of a 4-year-old HLHS patient who underwent several surgeries with EFE resections due to recurrence of EFE. EFE recurrence was associated with flow disturbances due to valvar defects. At her latest follow-up 7 months after the last surgery, competent valves and no EFE were identified on all imaging study.

Mechanical Properties of Autologous Pericardium Change With Fixation Time: Implications for Valve Reconstruction.

Autologous pericardium, fixed in glutaraldehyde, is a common patch material used in heart valve reconstruction. Competence of a reconstructed valve depends on patch dimensions and also on how much the patch deforms when the closed valve is pressurized. In this study, we used biaxial testing to evaluate the deformability of fixed autologous pericardium, and several commercial alternatives, under typical cardiac loads. We found that deformability of fixed autologous pericardium varies predictably with fixation time. This information can be used by surgeons in designing patches for valve repair.

An intraoperative test device for aortic valve repair.

OBJECTIVE: Aortic valve repair is currently in transition from surgical improvisation to a reproducible operation and an option for many patients with aortic regurgitation. Our research efforts at improving reproducibility include development of methods for intraoperatively testing and visualizing the valve in its diastolic state. METHODS: We developed a device that can be intraoperatively secured in the transected aorta allowing the aortic root to be pressurized and the closed valve to be inspected endoscopically. Our device includes a chamber that can be pressurized with crystalloid solution and ports for introduction of an endoscope and measuring gauges. We show use of the device in explanted porcine hearts to visualize the aortic valve and to measure leaflet coaptation height in normal valves and in valves that have undergone valve repair procedures. RESULTS: The procedure of introducing and securing the device in the aorta, pressurizing the valve, and endoscopically visualizing the closed valve is done in less than 1 minute. The device easily and reversibly attaches to the aortic root and allows direct inspection of the aortic valve under conditions that mimic diastole. It enables the surgeon to intraoperatively study the valve immediately before repair to determine mechanisms of incompetence and immediately after the repair to assess competence. We also show its use in measuring valve leaflet coaptation height in the diastolic state. CONCLUSIONS: This device enables more relevant prerepair valve assessment and also enables a test of postrepair valve competence under physiological pressures.

Three-Dimensional Mitral Valve Morphology in Children and Young Adults With Marfan Syndrome.

BACKGROUND: Mitral valve (MV) prolapse is common in children with Marfan syndrome (MFS) and is associated with varying degrees of mitral regurgitation (MR). However, the three-dimensional (3D) morphology of the MV in children with MFS and its relation to the degree of MR are not known. The goals of this study were to describe the 3D morphology of the MV in children with MFS and to compare it to that in normal children. METHODS: Three-dimensional transthoracic echocardiography was performed in 27 patients (3-21 years of age) meeting the revised Ghent criteria for MFS and 27 normal children matched by age (±1 year). The 3D geometry of the MV apparatus in midsystole was measured, and its association with clinical and two-dimensional echocardiographic parameters was examined. RESULTS: Compared with age-matched control subjects, children with MFS had larger 3D annular areas (P < .02), smaller annular height/commissural width ratios (P < .001), greater billow volumes (P < .001), and smaller tenting heights, areas, and volumes (P < .001 for all). In multivariate modeling, larger leaflet billow volume in MFS was strongly associated with moderate or greater MR (P < .01). Intra- and interuser variability of 3D metrics was acceptable. CONCLUSIONS: Children with MFS have flatter and more dilated MV annuli, greater billow volumes, and smaller tenting heights compared with normal control subjects. Larger billow volume is associated with MR. Three-dimensional MV quantification may contribute to the identification of patients with MFS and other connective tissue disorders. Further study of 3D MV geometry and its relation to the clinical progression of MV disease is warranted in this vulnerable population.