Modeling Alzheimer's disease related phenotypes in the Ts65Dn mouse: impact of age on Aß, Tau, pTau, NfL, and behavior.

Introduction: People with DS are highly predisposed to Alzheimer's disease (AD) and demonstrate very similar clinical and pathological features. Ts65Dn mice are widely used and serve as the best-characterized animal model of DS. Methods: We undertook studies to characterize age-related changes for AD-relevant markers linked to Aß, Tau, and phospho-Tau, axonal structure, inflammation, and behavior. Results: We found age related changes in both Ts65Dn and 2N mice. Relative to 2N mice, Ts65Dn mice showed consistent increases in Aß40, insoluble phospho-Tau, and neurofilament light protein. These changes were correlated with deficits in learning and memory. Discussion: These data have implications for planning future experiments aimed at preventing disease-related phenotypes and biomarkers. Interventions should be planned to address specific manifestations using treatments and treatment durations adequate to engage targets to prevent the emergence of phenotypes.

Patient-specific, echocardiography compatible flow loop model of aortic valve regurgitation in the setting of a mechanical assist device.

Background: Aortic regurgitation (AR) occurs commonly in patients with continuous-flow left ventricular assist devices (LVAD). No gold standard is available to assess AR severity in this setting. Aim of this study was to create a patient-specific model of AR-LVAD with tailored AR flow assessed by Doppler echocardiography. Methods: An echo-compatible flow loop incorporating a 3D printed left heart of a Heart Mate II (HMII) recipient with known significant AR was created. Forward flow and LVAD flow at different LVAD speed were directly measured and AR regurgitant volume (RegVol) obtained by subtraction. Doppler parameters of AR were simultaneously measured at each LVAD speed. Results: We reproduced hemodynamics in a LVAD recipient with AR. AR in the model replicated accurately the AR in the index patient by comparable Color Doppler assessment. Forward flow increased from 4.09 to 5.61 L/min with LVAD speed increasing from 8,800 to 11,000 RPM while RegVol increased by 0.5 L/min (2.01 to 2.5 L/min). Conclusions: Our circulatory flow loop was able to accurately replicate AR severity and flow hemodynamics in an LVAD recipient. This model can be reliably used to study echo parameters and aid clinical management of patients with LVAD.

Safety, Tolerability, and Immunogenicity of the ACI-24 Vaccine in Adults With Down Syndrome: A Phase 1b Randomized Clinical Trial.

Importance: Individuals with Down syndrome (DS) are at high risk of developing Alzheimer disease due to an increased dose of the amyloid precursor protein gene, APP, which leads to increased levels of full-length APP and its products, including amyloid-ß (Aß). The liposome-based antiamyloid ACI-24 vaccine is intended to treat neurological disorders caused by misfolded Aß pathological protein. However, the safety, tolerability, and immunogenicity of the ACI-24 vaccine among adults with DS have not been fully examined. Objective: To assess the safety and tolerability of the ACI-24 vaccine among adults with DS as well as its ability to induce immunogenicity measured by anti-Aß immunoglobulin G titers. Design, Setting, and Participants: This multicenter double-blind placebo-controlled dose-escalation phase 1b randomized clinical trial was conducted at 3 US academic medical centers with affiliated Down syndrome clinics between March 30, 2016, and June 29, 2020. A total of 20 adults with DS were screened; of those, 16 adults were eligible to participate. Eligibility criteria included men or women aged 25 to 45 years with cytogenetic diagnosis of either trisomy 21 or complete unbalanced translocation of chromosome 21. Between April 27, 2016, and July 2, 2018, participants were randomized 3:1 into 2 dose-level cohorts (8 participants per cohort, with 6 participants receiving the ACI-24 vaccine and 2 receiving placebo) in a 96-week study. Participants received 48 weeks of treatment followed by an additional 48 weeks of safety follow-up. Interventions: Participants were randomized to receive 7 subcutaneous injections of ACI-24, 300 µg or 1000 µg, or placebo. Main Outcomes and Measures: Primary outcomes were measures of safety and tolerability as well as antibody titers. Results: Among 16 enrolled participants, the mean (SD) age was 32.6 (4.4) years; 9 participants were women, and 7 were men. All participants were White, and 1 participant had Hispanic or Latino ethnicity. Treatment adherence was 100%. There were no cases of meningoencephalitis, death, or other serious adverse events (AEs) and no withdrawals as a result of AEs. Most treatment-emergent AEs were of mild intensity (110 of 132 events [83.3%]) and unrelated or unlikely to be related to the ACI-24 vaccine (113 of 132 events [85.6%]). No amyloid-related imaging abnormalities with edema or cerebral microhemorrhage and no evidence of central nervous system inflammation were observed on magnetic resonance imaging scans. Increases in anti-Aß immunoglobulin G titers were observed in 4 of 12 participants (33.3%) receiving ACI-24 (2 receiving 300 µg and 2 receiving 1000 µg) compared with 0 participants receiving placebo. In addition, a greater increase was observed in plasma Aß1-40 and Aß1-42 levels among individuals receiving ACI-24. Conclusions and Relevance: In this study, the ACI-24 vaccine was safe and well tolerated in adults with DS. Evidence of immunogenicity along with pharmacodynamic and target engagement were observed, and anti-Aß antibody titers were not associated with any adverse findings. These results support progression to clinical trials using an optimized formulation of the ACI-24 vaccine among individuals with DS. Trial Registration: ClinicalTrials.gov Identifier: NCT02738450.

Development of 3D Printed Mitral Valve Constructs for Transcatheter Device Modeling of Tissue and Device Deformation.

Transcatheter mitral valve repair (TMVR) therapies offer a minimally invasive alternative to surgical mitral valve (MV) repair for patients with prohibitive surgical risks. Pre-procedural planning and associated medical device modeling is primarily performed in silico, which does not account for the physical interactions between the implanted TMVR device and surrounding tissue and may result in poor outcomes. We developed 3D printed tissue mimics for modeling TMVR therapies. Structural properties of the mitral annuli, leaflets, and chordae were replicated from multi-material blends. Uniaxial tensile testing was performed on the resulting composites and their mechanical properties were compared to those of their target native components. Mimics of the MV annulus printed in homogeneous strips approximated the tangent moduli of the native mitral annulus at 2% and 6% strain. Mimics of the valve leaflets printed in layers of different stiffnesses approximated the force-strain and stress-strain behavior of native MV leaflets. Finally, mimics of the chordae printed as reinforced cylinders approximated the force-strain and stress-strain behavior of native chordae. We demonstrated that multi-material 3D printing is a viable approach to the development of tissue phantoms, and that printed patient-specific geometries can approximate the local deformation force which may act upon devices used for TMVR therapies.

Beneficial Effect of ACI-24 Vaccination on Aß Plaque Pathology and Microglial Phenotypes in an Amyloidosis Mouse Model.

Amyloid-ß (Aß) deposition is an initiating factor in Alzheimer's disease (AD). Microglia are the brain immune cells that surround and phagocytose Aß plaques, but their phagocytic capacity declines in AD. This is in agreement with studies that associate AD risk loci with genes regulating the phagocytic function of immune cells. Immunotherapies are currently pursued as strategies against AD and there are increased efforts to understand the role of the immune system in ameliorating AD pathology. Here, we evaluated the effect of the Aß targeting ACI-24 vaccine in reducing AD pathology in an amyloidosis mouse model. ACI-24 vaccination elicited a robust and sustained antibody response in APPPS1 mice with an accompanying reduction of Aß plaque load, Aß plaque-associated ApoE and dystrophic neurites as compared to non-vaccinated controls. Furthermore, an increased number of NLRP3-positive plaque-associated microglia was observed following ACI-24 vaccination. In contrast to this local microglial activation at Aß plaques, we observed a more ramified morphology of Aß plaque-distant microglia compared to non-vaccinated controls. Accordingly, bulk transcriptomic analysis revealed a trend towards the reduced expression of several disease-associated microglia (DAM) signatures that is in line with the reduced Aß plaque load triggered by ACI-24 vaccination. Our study demonstrates that administration of the Aß targeting vaccine ACI-24 reduces AD pathology, suggesting its use as a safe and cost-effective AD therapeutic intervention.

Patient-specific preprocedural planning for tricuspid valve repair and replacement procedures.

PURPOSE OF REVIEW: Despite the prevalence of tricuspid valve regurgitation disorders, isolated interventions on tricuspid valves were previously infrequent due to high mortality rates and lack of advanced clinical imaging technology. Due to advancements in cardiovascular imaging and interventional technologies tricuspid valve repairs and replacement interventions became increasingly more attainable. RECENT FINDINGS: Noninvasive clinical imaging of the tricuspid valve can be challenging, providing anincomplete assessment of unique tricuspid anatomy. 3D printing technology represents an additional tool for more comprehensive preprocedural planning of tricuspid interventions and observation of tricuspid valve geometry. Patient-specific 3D printed replicas of tricuspid valve apparatus are especially useful in highly complicated cases, where physiological tricuspid replicas allow benchtop observation of individual patient's anatomy, device implantation in physiological tricuspid valves and interactions of devices with native tricuspid tissue, frequently leading to optimization or change in operational strategy. SUMMARY: Comprehensive use of clinical imaging including echocardiography, computed tomography, and cardiac magnetic resonance along with 3D printed modeling is key to successful tricuspid repair and replacements. Patient-specific 3D printed models of tricuspid anatomy can facilitate preprocedural planning, educate patients and clinicians, and improve device design, leading to the overall improvement of patients' outcomes and care.

3D Printing, Computational Modeling, and Artificial Intelligence for Structural Heart Disease.

Structural heart disease (SHD) is a new field within cardiovascular medicine. Traditional imaging modalities fall short in supporting the needs of SHD interventions, as they have been constructed around the concept of disease diagnosis. SHD interventions disrupt traditional concepts of imaging in requiring imaging to plan, simulate, and predict intraprocedural outcomes. In transcatheter SHD interventions, the absence of a gold-standard open cavity surgical field deprives physicians of the opportunity for tactile feedback and visual confirmation of cardiac anatomy. Hence, dependency on imaging in periprocedural guidance has led to evolution of a new generation of procedural skillsets, concept of a visual field, and technologies in the periprocedural planning period to accelerate preclinical device development, physician, and patient education. Adaptation of 3-dimensional (3D) printing in clinical care and procedural planning has demonstrated a reduction in early-operator learning curve for transcatheter interventions. Integration of computation modeling to 3D printing has accelerated research and development understanding of fluid mechanics within device testing. Application of 3D printing, computational modeling, and ultimately incorporation of artificial intelligence is changing the landscape of physician training and delivery of patient-centric care. Transcatheter structural heart interventions are requiring in-depth periprocedural understanding of cardiac pathophysiology and device interactions not afforded by traditional imaging metrics.

Patient-Specific Modeling for Structural Heart Intervention: Role of 3D Printing Today and Tomorrow CME.

Structural heart interventions (SHIs) are increasingly applicable in a wide range of heart defects, but the intricate and dynamic nature of cardiac structures can make SHIs challenging to perform. Three-dimensional (3D) printed modeling integrates advanced clinical imaging and 3D printing technology to replicate patient-specific anatomy for comprehensive planning and simulation of SHIs. This review discusses the basic principles of patient-specific 3D print model development, print material selection, and model fabrication and highlights how cardiovascular 3D printing can be used in preprocedural planning, device sizing, enhanced communication, and procedure simulation.

Three-Dimensional Printing Applications in Percutaneous Structural Heart Interventions.

Cardiovascular 3-dimensional printing refers to the fabrication of patients' specific cardiac anatomic replicas based on volumetric imaging data sets obtained by echocardiography, computed tomography, or magnetic resonance imaging. It enables advanced visualization and enhanced anatomic and sometimes hemodynamic understanding and also improves procedural planning and allows interventional simulation. Also, it is helpful in communication with patients and trainees. These key advantages have led to its broad use in the field of cardiology ranging from congenital to vascular and valvular disease, particularly in structural heart interventions, where many emerging technologies are being developed and tested. This review summarizes the process of 3-dimensional printing and the workflow from imaging acquisition to model generation and discusses the cardiac applications of 3-dimensional printing focusing on its use in percutaneous structural interventions, where procedural planning now commonly relies on 3-dimensional printed models.

3D Experimental and Computational Analysis of Eccentric Mitral Regurgitant Jets in a Mock Imaging Heart Chamber.

Mitral valve regurgitation (MR) is a disorder of the heart in which the mitral valve does not close properly. This causes an abnormal leaking of blood backwards from the left ventricle into the left atrium during the systolic contractions of the left ventricle. Noninvasive assessment of MR using echocardiography is an ongoing challenge. In particular, a major problem are eccentric or Coanda regurgitant jets which hug the walls of the left atrium and appear smaller in the color Doppler image of regurgitant flow. This manuscript presents a comprehensive investigation of Coanda regurgitant jets and the associated intracardiac flows by using a combination of experimental and computational approaches. An anatomically correct mock heart chamber connected to a pulsatile flow loop is used to generate the physiologically relevant flow conditions, and the influence of two clinically relevant parameters (orifice aspect ratio and regurgitant volume) on the onset of Coanda effect is studied. A two parameter bifurcation diagram showing transition to Coanda jets is obtained, indicating that: (1) strong wall hugging jets occur in long and narrow orifices with moderate to large regurgitant volumes, and (2) short orifices with moderate to large regurgitant volumes produce strong 3D flow features such as vortex rolls, giving rise to the velocities that are orthogonal to the 2D plane associated with the apical color Doppler views, making them "invisible" to the single plane color Doppler assessment of MR. This is the first work in which the presence of vortex rolls in the left atrium during regurgitation is reported and identified as one of the reasons for under-estimation of regurgitant volume. The results of this work can be used for better design of imaging strategies in noninvasive assessment of MR, and for better understanding of LA remodeling that may be associated with the presence of maladapted vortex dynamics. This introduces a new concept in clinical imaging, which emphasizes that the quality and not only the quantity of regurgitant flow matters in the assessment of severity of mitral valve regurgitation.

Cardiac 3D Printing and its Future Directions.

Three-dimensional (3D) printing is at the crossroads of printer and materials engineering, noninvasive diagnostic imaging, computer-aided design, and structural heart intervention. Cardiovascular applications of this technology development include the use of patient-specific 3D models for medical teaching, exploration of valve and vessel function, surgical and catheter-based procedural planning, and early work in designing and refining the latest innovations in percutaneous structural devices. In this review, we discuss the methods and materials being used for 3D printing today. We discuss the basic principles of clinical image segmentation, including coregistration of multiple imaging datasets to create an anatomic model of interest. With applications in congenital heart disease, coronary artery disease, and surgical and catheter-based structural disease, 3D printing is a new tool that is challenging how we image, plan, and carry out cardiovascular interventions.

3D Printed Modeling of the Mitral Valve for Catheter-Based Structural Interventions.

As catheter-based structural heart interventions become increasingly complex, the ability to effectively model patient-specific valve geometry as well as the potential interaction of an implanted device within that geometry will become increasingly important. Our aim with this investigation was to combine the technologies of high-spatial resolution cardiac imaging, image processing software, and fused multi-material 3D printing, to demonstrate that patient-specific models of the mitral valve apparatus could be created to facilitate functional evaluation of novel trans-catheter mitral valve repair strategies. Clinical 3D transesophageal echocardiography and computed tomography images were acquired for three patients being evaluated for a catheter-based mitral valve repair. Target anatomies were identified, segmented and reconstructed into 3D patient-specific digital models. For each patient, the mitral valve apparatus was digitally reconstructed from a single or fused imaging data set. Using multi-material 3D printing methods, patient-specific anatomic replicas of the mitral valve were created. 3D print materials were selected based on the mechanical testing of elastomeric TangoPlus materials (Stratasys, Eden Prairie, Minnesota, USA) and were compared to freshly harvested porcine leaflet tissue. The effective bending modulus of healthy porcine MV tissue was significantly less than the bending modulus of TangoPlus (p < 0.01). All TangoPlus varieties were less stiff than the maximum tensile elastic modulus of mitral valve tissue (3697.2 ± 385.8 kPa anterior leaflet; 2582.1 ± 374.2 kPa posterior leaflet) (p < 0.01). However, the slopes of the stress-strain toe regions of the mitral valve tissues (532.8 ± 281.9 kPa anterior leaflet; 389.0 ± 156.9 kPa posterior leaflet) were not different than those of the Shore 27, Shore 35, and Shore 27 with Shore 35 blend TangoPlus material (p > 0.95). We have demonstrated that patient-specific mitral valve models can be reconstructed from multi-modality imaging datasets and fabricated using the multi-material 3D printing technology and we provide two examples to show how catheter-based repair devices could be evaluated within specific patient 3D printed valve geometry. However, we recognize that the use of 3D printed models for the development of new therapies, or for specific procedural training has yet to be defined.

Control of respiration-driven retrograde flow in the subdiaphragmatic venous return of the Fontan circulation.

Respiration influences the subdiaphragmatic venous return in the total cavopulmonary connection (TCPC) of the Fontan circulation whereby both the inferior vena cava (IVC) and hepatic vein flows can experience retrograde motion. Controlling retrograde flows could improve patient outcomes. Using a patient-specific model within a Fontan mock circulatory system with respiration, we inserted a valve into the IVC to examine its effects on local hemodynamics while varying retrograde volumes by changing vascular impedances. A bovine valved conduit reduced IVC retrograde flow to within 3% of antegrade flow in all cases. The valve closed only under conditions supporting retrograde flow and its effects on local hemodynamics increased with larger retrograde volume. Liver and TCPC pressures improved only when the valve leaflets were closed whereas cycle-averaged pressures improved only slightly (<1 mm Hg). Increased pulmonary vascular resistance raised mean circulation pressures, but the valve functioned and cardiac output improved and stabilized. Power loss across the TCPC improved by 12%-15% (p < 0.05) with a valve. The effectiveness of valve therapy is dependent on patient vascular impedance.

Mock circulatory system of the Fontan circulation to study respiration effects on venous flow behavior.

We describe an in vitro model of the Fontan circulation with respiration to study subdiaphragmatic venous flow behavior. The venous and arterial connections of a total cavopulmonary connection (TCPC) test section were coupled with a physical lumped parameter (LP) model of the circulation. Intrathoracic and subdiaphragmatic pressure changes associated with normal breathing were applied. This system was tuned for two patients (5 years, 0.67 m2; 10 years, 1.2 m2) to physiological values. System function was verified by comparison to the analytical model on which it was based and by consistency with published clinical measurements. Overall, subdiaphragmatic venous flow was influenced by respiration. Flow within the arteries and veins increased during inspiration but decreased during expiration, with retrograde flow in the inferior venous territories. System pressures and flows showed close agreement with the analytical LP model (p < 0.05). The ratio of the flow rates occurring during inspiration to expiration were within the clinical range of values reported elsewhere. The approach used to set up and control the model was effective and provided reasonable comparisons with clinical data.

TLR4- and TRIF-dependent stimulation of B lymphocytes by peptide liposomes enables T cell-independent isotype switch in mice.

Immunoglobulin class switching from IgM to IgG in response to peptides is generally T cell-dependent and vaccination in T cell-deficient individuals is inefficient. We show that a vaccine consisting of a dense array of peptides on liposomes induced peptide-specific IgG responses totally independent of T-cell help. Independency was confirmed in mice lacking T cells and in mice deficient for MHC class II, CD40L, and CD28. The IgG titers were high, long-lived, and comparable with titers obtained in wild-type animals, and the antibody response was associated with germinal center formation, expression of activation-induced cytidine deaminase, and affinity maturation. The T cell-independent (TI) IgG response was strictly dependent on ligation of TLR4 receptors on B cells, and concomitant TLR4 and cognate B-cell receptor stimulation was required on a single-cell level. Surprisingly, the IgG class switch was mediated by TIR-domain-containing adapter inducing interferon-ß (TRIF), but not by MyD88. This study demonstrates that peptides can induce TI isotype switching when antigen and TLR ligand are assembled and appropriately presented directly to B lymphocytes. A TI vaccine could enable efficient prophylactic and therapeutic vaccination of patients with T-cell deficiencies and find application in diseases where induction of T-cell responses contraindicates vaccination, for example, in Alzheimer disease.