Modulation of Graft Anastomosis Orifice Opening by Graft Stiffness: A Computational Study 

Ehsan Ban, PhD, Postdoctoral Researcher at Yale University (Jay Humphrey Lab)

Abstract: Blood flow is commonly redirected from the systemic to pulmonary arteries in procedures that palliate congenital cardiovascular defects, such as the Blalock–Taussig shunt procedure. Previous clinical and biomechanical studies reported the critical role of graft diameter in the balance of perfusion in the systemic and pulmonary circulations. However, the process of the formation of such anastomoses has not been the subject of biomechanics studies. Here, we developed a computational algorithm that starts from the host and graft represented by cylindrical vessels and predicts the anastomosis geometry and wall stresses resulting from the attachment of the axial cut in the host to the circular end of the shunt. We observed that anastomosis orifice opening increased by increasing shunt stiffness, following a Hill-type function. The host artery conforms to stiff synthetic grafts, whereas soft vein grafts conform to the host, accompanied by changes in attachment forces. We expect that the variation of orifice opening leads to significant hemodynamic and circulatory changes. In the future, we plan to apply this approach to specific patients and grafts and study the related clinical consequence. 

Material properties are important for patch sizing in aortic arch reconstruction for single ventricle patients

Shannen Kizilski, PhD, Research Fellow at Boston Children’s Hospital (David Hoganson)

Abstract: Patch augmentation of the hypoplastic aortic arch is often a challenging part of Stage 1 single ventricle palliation. During this procedure, a biologic patch is manually shaped and sewn into the open aorta to increase its diameter to a normal size with smooth tapering to the unpatched sections. This procedure, however, is conducted when the aorta is unpressurized, so the reconstructed diameter at physiologic blood pressures is unknown until blood flow is restored after the procedure. Depending on stiffness of the patch material relative to the highly compliant aorta, the reconstructed segment might be significantly undersized or oversized compared to the surrounding vessel when pressurized. Diameter mismatch in the aorta is associated with abnormal flow and early ventricular failure. Prospective patch design to achieve the correct pressurized dimensions is achievable through computational modeling with accurate estimates of the mechanical properties of the vessel and patch. We have been developing this patch planning workflow through extensive tissue characterization and application of fundamental mechanical principles. Our growing database of aortic and biologic patch mechanical properties enables estimation of the zero-pressure configuration of patient-specific hypoplastic aortas. With this information, and with a target pressurized diameter for the reconstructed vessel, we calculate dimensions of the patch to be sewn in at the unpressurized state. Calculated patch sizes for pulmonary homograft versus pericardium are compared to dimensions obtained through the current technique of matching the unpressurized vessel diameter. Our results demonstrate the importance of considering both aortic and patch properties for proper patch sizing.

Prediction of Impending Central Line Associated Bloodstream Infections in Hospitalized Cardiac Patients: Development and Testing of a Machine-Learning Model

Siva Emani, Medical Student at Harvard Medical School and Boston Children’s Hospital (John Kheir Lab)

Abstract: To build a prediction model which identifies patients who will develop a positive central line-associated blood stream infection (CLABSI) in the next 24 hours. We collected variables potentially related to infection identification, including vital sign parameters, lab results, medication and nutrition information, prior microbiology results, and features of CVC use. Predictors were selected according to a forward stepwise approach using cross-validated area under the curve (AUC) as the inclusion metric. Logistic regression, lasso regression and random forest classifiers were built using standard machine learning techniques. We assessed model performance based on area under the curve (AUC), sensitivity, and false positive rate (FPR) of models run on an independent testing set (40%). 104,035 patient days with 399 positive cultures corresponding to 7,468 unique patients were included in the analysis. Major predictors included a prior history of infection, elevated maximum heart rate, elevated maximum temperature, elevated C reactive protein, exposure to total parenteral nutrition, and exposure to alteplase as predictors. The model identified 25% of positive cultures with an FPR of 0.11% (AUC = 0.82). A machine learning model can be used to predict 25% of patients who will develop a positive blood culture in the coming 24 hours with only 1.1/1,000 of these predictions being incorrect. Once prospectively validated, this tool may be used to diminish the incidence and duration of CLABSIs through timely removal of at-risk CVLs or earlier institution of antimicrobials.  

The role of embryonic senescence in cardiac trabeculation and compaction 

Audrey Ibre, PhD Student at INSERM (Michel Pucéat Lab)

Abstract: Embryonic senescence is a novel process uncovered over the last decade and found as essential for proper embryonic development. We investigated whether this cell process could occur during heart development. We detected senescent cells at different stages of mouse cardiac development. γH2AX+ and then p21+ cells were enriched in trabeculae and the number of senescent cells transiently increased from early to late stages of trabeculation/compaction. We performed single cell RNA-sequencing of high tomato+ trabeculae myocytes dissociated from E13.5 and E16.5 hearts from embryos generated by breeding SmaCreERT2 with Rosa26tdtomato mice. We identified several clusters of senescent cells in trabeculae myocytes. We uncovered news genes as well as specific cell processes and signaling pathways involved in cardiac senescence. Next, we used drugs that inhibit (Navitoclax) or exacerbate (Palbociclib) senescence to look at its impact on cardiac trabeculation and or compaction. High Resolution Episcopic Microscopy combined with Fractal analysis of embryonic hearts show that senescence has a major impact on ventricular compaction. We are using mice with cardiac conditional deletion of VHL, which feature impaired metabolic switch at mid-gestation. It will allow us to identify whether O2, mitochondrial ROS and metabolism underlie trabeculae myocyte senescence. Embryonic cardiac senescence is likely at the origin of ventricular compaction. If dysregulated, the cell process may be at the origin, of cardiac congenital diseases such as hypoplastic left ventricle and non-compaction syndrome often observed in rare metabolic diseases. 

3D Bioprinted Platforms to Study Cellular and Molecular Mechanisms of Pulmonary Vein Stenosis 

Martin Tomov, PhD, Research Scientist at Emory University (Vahid Serpooshan Lab)

Abstract: Pulmonary vein stenosis (PVS) is an acute pediatric cardiovascular disease that is always lethal if not treated early. While current clinical interventions (stenting and angioplasties) have shown promising results in treating PVS, they require multiple re-interventions that can lead to re-stenosis and diminished long-term efficacy. Thus, there is an unmet need to develop functional in vitro models of PVS that can enable study of its developmental triggers, provide a drug screen platform, or a phantom for clinical interventions. Patient-inspired 3D bioprinted tissue models provide a unique model to recapitulate and analyze the complex tissue microenvironment impacted by PVS and other cardiovascular pathologies. Here, we developed perfusable in vitro models of healthy and stenotic pulmonary vein by 3D reconstruction and bioprinting inspired by patient CT data. Models were seeded with human endothelial cells (ECs) to study cell state in healthy and stenotic geometries and analyzed via fluorescence microscopy and bioinformatics. Flow hemodynamics through the bioprinted vessels were quantified via Computational Fluid Dynamics (CFD) modeling and analyzed by Particle Image Velocimetry (4D-PIV). Cell growth and endothelialization were analyzed in detail and mechanical properties of the phantoms were characterized in detail. Our work here demonstrates the feasibility of bioprinting various cardiovascular cells, to create perfusable, patient inspired vascular constructs that can model in vivo geometries. Deeper understanding of vascular cell behavior in in vitro biomimetic models that incorporate tissue-like geometrical, chemical, and biomechanical ques could offer substantial insights etymology, prevention, and treatment of PVS, as well as other cardiovascular diseases. 

Design of a Fetal Valve Prototype for Implantation in utero 

Sanchita Bhat, MS, PhD Student at Georgia Tech, Cardiovascular Fluid Mechanics Laboratory (Lakshmi Prasad Dasi Lab)

Abstract: Single ventricle physiology (SVP) treatment consists of interventions that are palliative and not curative. Recently, prenatal intervention rates to prevent SVP have improved, but even patients who avoid SVP require or eventual valve replacement, limited by poor durability and somatic outgrowth. Thus, this project aims to develop a fully biodegradable tissue-engineered heart valve (TEHV) that will normalize the fetal hemodynamics to prevent SVP and allow the valve to grow with the patient. We manufactured a prototype using a cobalt chromium metal stent and biodegradable polycaprolactone leaflets and tested this prototype in our fetal pulse duplicator using physiological conditions using a 60/40 water/glycerin mixture. We conducted preliminary animal studies to establish the deployment system for the prototypes. Our prototype fetal valve was tested for 100 consecutive cardiac cycles and had a regurgitant fraction of 3.9% with an effective orifice area of 0.18 cm2 and a mean transvalvular pressure gradient of 3.84 mmHg. We had moderate success with the valves in animal models with minimal paravalvular leakage and mild to no stenosis as measured from echocardiography. There was trivial flow acceleration through the stent with peak velocity ~1.6 m/s. We are also experimenting with different stent designs and leaflet materials to optimize the prototype. This project is the first step to design to develop and manufacture a fully biodegradable tissue-engineered valve for use in utero. The current drawback in the lack of interventional techniques for congenital anomalies can be overcome with the progress of such a replacement device.