Heart Model Research Articles

Mitochondrial MICOS complex genes, implicated in hypoplastic left heart syndrome, maintain cardiac contractility and actomyosin integrity.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) with a likely oligogenic etiology, but our understanding of the genetic complexities and pathogenic mechanisms leading to HLHS is limited. We performed whole genome sequencing (WGS) on 183 HLHS patient-parent trios to identify candidate genes, which were functionally tested in the Drosophila heart model. Bioinformatic analysis of WGS data from an index family of a HLHS proband born to consanguineous parents prioritized 9 candidate genes with rare, predicted damaging homozygous variants. Of them, cardiac-specific knockdown (KD) of mitochondrial MICOS complex subunit dCHCHD3/6 resulted in drastically compromised heart contractility, diminished levels of sarcomeric actin and myosin, reduced cardiac ATP levels, and mitochondrial fission-fusion defects. These defects were similar to those inflicted by cardiac KD of ATP synthase subunits of the electron transport chain (ETC), consistent with the MICOS complex's role in maintaining cristae morphology and ETC assembly. Five additional HLHS probands harbored rare, predicted damaging variants in CHCHD3 or CHCHD6. Hypothesizing an oligogenic basis for HLHS, we tested 60 additional prioritized candidate genes from these patients for genetic interactions with CHCHD3/6 in sensitized fly hearts. Moderate KD of CHCHD3/6 in combination with Cdk12 (activator of RNA polymerase II), RNF149 (goliath, E3 ubiquitin ligase), or SPTBN1 (β-Spectrin, scaffolding protein) caused synergistic heart defects, suggesting the likely involvement of diverse pathways in HLHS. Further elucidation of novel candidate genes and genetic interactions of potentially disease-contributing pathways is expected to lead to a better understanding of HLHS and other CHDs.

Novel mitral/tricuspid annuloplasty sizing device and technique: Proof of concept using a cadaveric porcine heart model.

Novel mitral/tricuspid annuloplasty sizing device and technique: Proof of concept using a cadaveric porcine heart model.

Multiplatform modeling of atrial fibrillation identifies phospholamban as a central regulator of cardiac rhythm.

Atrial fibrillation (AF) is a common and genetically inheritable form of cardiac arrhythmia; however, it is currently not known how these genetic predispositions contribute to the initiation and/or maintenance of AF-associated phenotypes. One major barrier to progress is the lack of experimental systems to investigate the effects of gene function on rhythm parameters in models with human atrial and whole-organ relevance. Here, we assembled a multi-model platform enabling high-throughput characterization of the effects of gene function on action potential duration and rhythm parameters using human induced pluripotent stem cell-derived atrial-like cardiomyocytes and a Drosophila heart model, and validation of the findings using computational models of human adult atrial myocytes and tissue. As proof of concept, we screened 20 AF-associated genes and identified phospholamban loss of function as a top conserved hit that shortens action potential duration and increases the incidence of arrhythmia phenotypes upon stress. Mechanistically, our study reveals that phospholamban regulates rhythm homeostasis by functionally interacting with L-type Ca2+ channels and NCX. In summary, our study illustrates how a multi-model system approach paves the way for the discovery and molecular delineation of gene regulatory networks controlling atrial rhythm with application to AF.

Site-specific prolongation of repolarization prevents postmyocardial infarction tachycardia.

Site-specific prolongation of repolarization prevents postmyocardial infarction tachycardia.

A Coordinate-Regression-Based Deep Learning Model for Catheter Detection during Structural Heart Interventions

With a growing geriatric population estimated to triple by 2050, minimally invasive procedures that are image-guided are becoming both more popular and necessary for treating a variety of diseases. To lower the learning curve for new procedures, it is necessary to develop better guidance systems and methods to analyze procedure performance. Since fluoroscopy remains the primary mode of visualizations, the ability to perform catheter tracking from fluoroscopic images is an important part of this endeavor. This paper explores the use of deep learning to perform the landmark detection of a catheter from fluoroscopic images in 3D-printed heart models. We show that a two-stage deep-convolutional-neural-network-based model architecture can provide improved performance by initially locating a region of interest before determining the coordinates of the catheter tip within the image. This model has an average error of less than 2% of the image resolution and can be performed within 4 milliseconds, allowing for its potential use for real-time intraprocedural tracking. Coordinate regression models have the advantage of directly outputting values that can be used for quantitative tracking in future applications and are easier to create ground truth values (~50× faster), as compared to semantic segmentation models that require entire masks to be made. Therefore, we believe this work has better long-term potential to be used for a broader class of cardiac devices, catheters, and guidewires.

Cell to whole organ global sensitivity analysis on a four-chamber heart electromechanics model using Gaussian processes emulators.

Cardiac pump function arises from a series of highly orchestrated events across multiple scales. Computational electromechanics can encode these events in physics-constrained models. However, the large number of parameters in these models has made the systematic study of the link between cellular, tissue, and organ scale parameters to whole heart physiology challenging. A patient-specific anatomical heart model, or digital twin, was created. Cellular ionic dynamics and contraction were simulated with the Courtemanche-Land and the ToR-ORd-Land models for the atria and the ventricles, respectively. Whole heart contraction was coupled with the circulatory system, simulated with CircAdapt, while accounting for the effect of the pericardium on cardiac motion. The four-chamber electromechanics framework resulted in 117 parameters of interest. The model was broken into five hierarchical sub-models: tissue electrophysiology, ToR-ORd-Land model, Courtemanche-Land model, passive mechanics and CircAdapt. For each sub-model, we trained Gaussian processes emulators (GPEs) that were then used to perform a global sensitivity analysis (GSA) to retain parameters explaining 90% of the total sensitivity for subsequent analysis. We identified 45 out of 117 parameters that were important for whole heart function. We performed a GSA over these 45 parameters and identified the systemic and pulmonary peripheral resistance as being critical parameters for a wide range of volumetric and hemodynamic cardiac indexes across all four chambers. We have shown that GPEs provide a robust method for mapping between cellular properties and clinical measurements. This could be applied to identify parameters that can be calibrated in patient-specific models or digital twins, and to link cellular function to clinical indexes.

A role for ultra-high resolution three-dimensional printed human heart models.

Echocardiography is essential for diagnosing and assessing the severity of perioperative structural and functional heart disease. Yet, educational opportunities to better understand echocardiography-based cardiac anatomy remain limited by the two-dimensional display, lack of anatomic details, variability of heart models, and costs and global access of training. We performed micro computed tomography of human heart specimens not suitable for orthotopic transplantation. We created high-resolution computational 3D models of different human hearts, sliced them in the different recommended American Society of Echocardiography views, and 3D printed them using different materials. We scanned, 3D modeled, and 3D printed a variety of human hearts both healthy and diseased. We have made the models available in the cardiac operating rooms and routinely use them for teaching anesthesia residents and cardiothoracic anesthesia fellows about basic and advanced echocardiographic views, cardiopulmonary bypass cannulation strategies, and valvular pathology and planned interventions. We have generated a library of 3D printed hearts to display the recommended echocardiographic views as a unique educational tool designed to safely accelerate the understanding of absolute and relative human cardiac anatomy and pathology, especially related to gaining advanced appreciation of clinically employed perioperative echocardiography.

Diastolic dysfunction inhibits mechanical dyssynchrony in cardiac resynchronization therapy patients: a combined clinical-computational study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This work was supported by the European Union's Horizon 2020 Research and Innovation program under the Marie Skłodowska-Curie grant agreement No. 860745. Background In heart failure patients treated with cardiac resynchronization therapy (CRT), both the presence of typical left bundle branch block (LBBB) mechanics and a relatively preserved diastolic function are associated with better clinical outcomes. However, the mechanistic interaction between both phenomena has never been investigated. Aim In this combined clinical-computational study, we explored the potential interaction between LBBB mechanics and the severity of diastolic dysfunction. Methods In 219 CRT candidates, left atrial pressure (LAP) was retrospectively estimated using the multiparametric guideline approach, where patients were classified into elevated (eLAP, 49%), normal (nLAP, 40%) and undetermined (uLAP, 11%) LAP. nLAP and uLAP were together referred to as non-elevated LAP (non-eLAP, 51%). Typical LBBB mechanical behavior was quantified using two speckle-tracking echocardiography-based indices, being systolic stretch index (SSI) and global myocardial wasted work (GWW). Both indices positively correlate with the mechanical interaction between septal and lateral walls in typical LBBB as previously shown. CRT response was quantified as change of LV end-systolic volume (LVESV) at follow-up (12±6 months) relative to baseline. We used the CircAdapt computer model of the human heart and circulation to investigate the effects of eccentric remodeling and diastolic dysfunction (i.e. myocardial stiffening) on SSI and GWW in virtual hearts with a constant LBBB-like septal-to-lateral conduction delay, i.e. a 25-ms and 75-ms mechanical activation delay of the septum and LV free wall with respect to the right ventricular free wall. Results Before CRT, patients with non-eLAP showed more typical LBBB mechanical behavior (Fig. 1), as suggested by higher SSI and higher GWW compared to patients with non-eLAP (SSI: 4.6±3.2 vs 3.4±3.5 %, P=0.02, GWW: 368±131 vs 309±127 mmHg*%, P=0.03). At follow-up, patients with eLAP showed significantly less LV reverse remodeling compared to patients with non-eLAP (relative decrease of LVESV: 30±26% vs 46±34 P=0.001). Our simulations (Fig. 2) revealed that eccentric remodeling amplifies mechanical dyssynchrony, characterized by increased septal rebound stretch (second row) and increased wasted work (third and bottom rows), while LAP remained normal (top row). In contrast, increasing myocardial stiffness led to elevated LAP (top row), but a pronounced reduction of mechanical dyssynchrony (second, third and bottom rows). Conclusion The presented combination of clinical data and virtual patient simulations revealed that diastolic dysfunction, in particular myocardial stiffening, inhibits mechanical dyssynchrony induced by LBBB. In contrast, eccentric remodeling amplifies the LBBB mechanical substrate. These data further explain why baseline dyssynchrony measures like septal rebound stretch and wasted work are well associated with reverse remodeling and clinical outcome after CRT.

Flexible 3D printing of the mitral valve apparatus and left coronary artery for patients with complex anatomical variations in mitral valve surgery

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Injury to the left circumflex artery (LCA) occurs in an estimated 2.7% of patients undergoing mitral valve (MV) surgery. The average distance from the LCA to the MV varies substantially between patients but is on average 3.1 ± 1.3mm. In unfavorable anatomical variations, a 3D print of relevant anatomical structures could be helpful for a surgeon to be aware of the situation and determine a surgical strategy. In this case such a 3D print is made of a 66 year old patient with mitral valve regurgitation and a P2 prolapse assessed in the heart team for MVS. Purpose To create a flexible heart model using Computed tomography (CT) and Transesophageal echocardiography (TEE) scans of this patient that utilizes the synergistic information derived from both modalities and provides an improved method for surgical preparation in cases with unfavorable anatomical variations. Method CT and TEE scans of the heart and mitral valve are acquired and fused using Mutual information registration. Both modalities are used in the print as TEE is the gold standard for evaluating the MV prior to surgery while on CT the LCA can be visualized and the ventricle can be imaged with a higher spatial resolution. The combined reconstructions are hollowed and smoothed using Meshmixer and the Poisson disk sampling tool of Meshlab to make the reconstruction suitable for 3D printing, enhance visibility of the relevant anatomy and achieve the desired flexibility of the model. Results A flexible 3D model of the left side of the heart of a patient is created. The model consists of reconstructions of the left coronary artery (CT), the left side of the heart (CT), and the mitral valve (TEE). To expose the LCA, an indent in the tissue surrounding the LCA was made. At the apex of the heart and at the left lateral side a small window in the ventricle was created for visibility. A flexibility resembling the flexibility of tissue was created by hollowing a with walls of 1.2mm thickness and printing with Agilus 30 Clear (with a shore A value of 30) . Conclusion To our knowledge this is the first 3D print for the planning of mitral valve surgery in which CT and TEE scans are combined into one flexible print. The flexible 3D print with exposed coronary arteries allows for assessment of the mitral valve regurgitation deficit and determine a surgical strategy because of the flexibility of the model, and as the LCA is exposed in this model, the surgeon can adapt his surgical approach based on the location of the LCA.

Prevalence and correlates of low-flow state by 3-dimensional automated echocardiography in aortic stenosis with normal ejection fraction

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Measurement of left ventricular (LV) stroke volume normalized for the body surface area (SVi) is required in aortic stenosis (AS) to calculate aortic valve area (AVA) and determine flow status. However, the LV outflow tract in most patients is hourglass rather than cylindrical, leading to a significant overestimation of the low-flow state and AS severity. Therefore, an accurate LV volumetric approach may potentially outperform the standard linear method in SVi measurement. Aims To investigate the prevalence of low-flow state (SVi ≤35 ml/m2) in patients with AS and normal ejection fraction (EF) by automated machine learning 3D echocardiography based on an adaptive analytics algorithm. Materials and Methods Consecutive patients with AS (peak velocity>2.5 m/s) and EF>50% underwent Dynamic Heart Model (DHM) using the larger settings of the boundary detection sliders (end-diastolic position = 60/60; end-systolic position = 30/30). Exclusion criteria were > moderate aortic or mitral regurgitation, rheumatic valve disease or endocarditis, and previous valve repair or replacement. Results We included 68 patients (mean 75 ± 12 years; 60% men, mean AVA 1,12 ± 0,40 cm2). On DHM, 10/68 patients (15%) demonstrated low SVi. The LVEDVi, LVESVi, AVA, LV mass, and EFLA were significantly lesser in patients with low SVi (Table). Conclusions When quantified with the modern 3D volumetric method, the prevalence of low-flow state in patients with AS and normal EF may be significantly lower than previously reported. The phenotypic profile of patients with low SVi can be refined when new metrics by DHM are employed.

Auto left atrial strain by speckle tracking echocardiography and auto left atrial volumes by 3D transthoracic echocardiography after electrical cardioversion for atrial fibrillation

Abstract Funding Acknowledgements Type of funding sources: None. Introduction We have evidence that left atrial dysfunction and stunning occur after electric cardioversion for atrial fibrillation (CAF). Additionally, after successful cardioversion to sinus rhythm, a dissociation between electrical and mechanical recovery may be observed. Traditional pulsed Doppler and tissue Doppler imaging parameters demonstrate reduced atrial contractility immediately after cardioversion. Improvement in atrial function occurs within the first 4 weeks after sinus rhythm is restored. Recent advances in the assessment of myocardial function have facilitated the direct measurement of auto left atrial strain using speckle tracking echocardiography, and auto left atrial volumes measurements using dynamic heart model modern 3D transthoracic echo logistics. Purpose Aim of this study was to determine whether auto left atrial strain (auto LAs) by speckle tracking echocardiography, and auto left atrial volumes measurements, auto left atrial volume indices calculations (auto LAVI), could be used to evaluate global left atrial function and when a main improvement occurs after electrical cardioversion for CAF. Methods Auto LAs was measured from transthoracic echocardiography in 25 patients with CAF who had been cardioverted to sinus rhythm and followed up for 4 weeks, and in a cohort of 25 healthy individuals. Left atrial contractile strain (LACTS), conduit strain (LACDS) and reservoir strain (LARSS) were measured. Conventional measures of atrial function derived from transmitral pulsed wave doppler (PW) and tissue doppler imaging (TDI) of lateral mitral annulus were included, such as A wave velocity, A wave velocity time integral, A' wave velocity and A' velocity time integral. Results Immediately after cardioversion all PW, TDI and all three auto LAs parameters were significantly lower than in controls. On the other hand, auto LAVI was significantly higher in patients compared to controls immediately after cardioversion Atrial function was improved over time with maximal change observed 4 weeks after cardioversion and restoration to sinus rhythm. Auto LAs parameters were significantly higher in the group of patients. Auto LA volumes and auto LAVI with dynamic heart model logistics were lower in the same group, but with no statistical significance. Three patients with the lowest auto LAs values immediately after cardioversion, suffered recurrence of atrial fibrillation during the 4 weeks follow up. Conclusions Although left atrial electrical function is immediately restored after cardioversion in CAF patients, a persistent degree of atrial dysfunction remains for up to 4 weeks. This difference could explain the increased propensity for these patients to develop recurrent atrial fibrillation. Additional this dysfunction could indicate the longer-term use of antiarrhythmic and antithrombotic medication in the CAF cohort.

Kir1.1 and SUR1 are not implicated as subunits of an adenosine triphosphate-sensitive potassium channel involved in diazoxide cardioprotection

ObjectiveThe adenosine triphosphate-sensitive potassium channel opener diazoxide mimics ischemic preconditioning and is cardioprotective. Clarification of diazoxide's site and mechanism of action could lead to targeted pharmacologic therapies for patients undergoing cardiac surgery. Several mitochondrial candidate proteins have been investigated as potential adenosine triphosphate-sensitive potassium channel components. Renal outer medullary potassium (Kir1.1) and sulfonylurea sensitive regulatory subunit 1 have been suggested as subunits of a mitochondrial adenosine triphosphate-sensitive potassium channel. We hypothesized that pharmacologic blockade or genetic deletion (knockout) of renal outer medullary potassium and sensitive regulatory subunit 1 would result in loss of diazoxide cardioprotection in models of global ischemia with cardioplegia. MethodsMyocyte volume and contractility were compared after Tyrode's physiologic solution (20 minutes), stress (hyperkalemic cardioplegia ± diazoxide, ± VU591 (Kir1.1 inhibitor), N = 9 to 23 each, 20 min), and Tyrode's (20 minutes). Isolated mouse (wild-type, sensitive regulatory subunit 1 [−/−], and cardiac knockout renal outer medullary potassium) hearts were given cardioplegia ± diazoxide (N = 9-16 each) before global ischemia (90 minutes) and 30 minutes reperfusion. Left ventricular pressures were compared before and after ischemia. ResultsStress (cardioplegia) was associated with reduced myocyte contractility that was prevented by diazoxide. Isolated myocytes were not responsive to diazoxide in the presence of VU591. In isolated hearts, diazoxide improved left ventricular function after prolonged ischemia compared with cardioplegia alone in wild-type and knockout (sensitive regulatory subunit 1 [−/−] and cardiac knockout renal outer medullary potassium) mice. ConclusionsIsolated myocyte and heart models may measure independent and separate actions of diazoxide. By definitive genetic deletion, these data indicate that sensitive regulatory subunit 1 and renal outer medullary potassium are not implicated in cardioprotection by diazoxide.

Cardiomyocyte peroxisome proliferator-activated receptor α prevents septic cardiomyopathy via improving mitochondrial function.

Clinically, cardiac dysfunction is a key component of sepsis-induced multi-organ failure. Mitochondria are essential for cardiomyocyte homeostasis, as disruption of mitochondrial dynamics enhances mitophagy and apoptosis. However, therapies targeted to improve mitochondrial function in septic patients have not been explored. Transcriptomic data analysis revealed that the peroxisome proliferator-activated receptor (PPAR) signaling pathway in the heart was the most significantly decreased inthe cecal ligation puncture-treated mouse heart model, and PPARα was the most notably decreased among the three PPAR family members. Male Pparafl/fl (wild-type), cardiomyocyte-specific Ppara-deficient (PparaΔCM), and myeloid-specific Ppara-deficient (PparaΔMac) mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce endotoxic cardiac dysfunction. PPARα signaling was decreased in LPS-treated wild-type mouse hearts. To determine the cell type in which PPARα signaling was suppressed, the cell type-specific Ppara-null mice were examined. Cardiomyocyte- but not myeloid-specific Ppara deficiency resulted in exacerbated LPS-induced cardiac dysfunction. Ppara disruption in cardiomyocytes augmented mitochondrial dysfunction, as revealed by damaged mitochondria, lowered ATP contents, decreased mitochondrial complex activities, and increased DRP1/MFN1 protein levels. RNA sequencing results further showed that cardiomyocyte Ppara deficiency potentiated the impairment of fatty acid metabolism in LPS-treated heart tissue. Disruption of mitochondrial dynamics resulted in increased mitophagy and mitochondrial-dependent apoptosis in Ppara△CM mice. Moreover, mitochondrial dysfunction caused an increase of reactive oxygen species, leading to increased IL-6/STAT3/NF-κB signaling. 3-Methyladenine (3-MA, an autophagosome formation inhibitor) alleviated cardiomyocyte Ppara disruption-induced mitochondrial dysfunction and cardiomyopathy. Finally, pre-treatment with the PPARα agonist WY14643 lowered mitochondrial dysfunction-induced cardiomyopathy in hearts from LPS-treated mice. Thus, cardiomyocyte but not myeloid PPARα protects against septic cardiomyopathy by improving fatty acid metabolism and mitochondrial dysfunction, thus highlighting that cardiomyocyte PPARα may be a therapeutic target for the treatment of cardiac disease.

A multiphysical computational model of myocardial growth adopted to human pathological ventricular remodelling

We present a novel three-dimensional constitutive model that describes an electro-visco-elastic-growth response on the myocardium with a fully implicit staggered solution procedure for the strong electromechanical coupling. The novel formulations of the myocardium allows us to simulate and analyze the remodelling of actively contracting human ventricular heart models which consist of growing viscoelastic myocardium where the growth direction is determined based on its mechanical state at each time step. The total deformation gradient is multiplicatively decomposed into a mechanical-active part and a growth part, where the mechanical-active part is further split into elastic, viscous, and active components. Unconditional stability of time integration is ensured by a backward Euler integration scheme. With the developed model, the myocardium can experience stretch-driven longitudinal (fibre) growth and stress-driven transverse (cross-fibre) growth. To validate the developed approach, two simulations regarding pathological ventricular remodelling are implemented: two divergent types of remodelling of a left ventricular model driven by hemodynamic overloads and ventricular remodelling triggered by acute myocardial ischemia in a biventricular heart model.

Prediction of experimental cardiac magnetostimulation thresholds using pig-specific body models.

Modern high-amplitude gradient systems can be limited by the International Electrotechnical Commission 60601-2-33 cardiac stimulation (CS) limit, which was set in a conservative manner based on electrode experiments and E-field simulations in uniform ellipsoidal body models. Here, we show that coupled electromagnetic-electrophysiological modeling in detailed body and heart models can predict CS thresholds, suggesting that such modeling might lead to more detailed threshold estimates in humans. Specifically, we compare measured and predicted CS thresholds in eight pigs. We created individualized porcine body models using MRI (Dixon for the whole body, CINE for the heart) that replicate the anatomy and posture of the animals used in our previous experimental CS study. We model the electric fields induced along cardiac Purkinje and ventricular muscle fibers and predict the electrophysiological response of these fibers, yielding CS threshold predictions in absolute units for each animal. Additionally, we assess the total modeling uncertainty through a variability analysis of the 25 main model parameters. Predicted and experimental CS thresholds agree within 19% on average (normalized RMS error), which is smaller than the 27% modeling uncertainty. No significant difference was found between the modeling predictions and experiments (p < 0.05, paired t-test). Predicted thresholds matched the experimental data within the modeling uncertainty, supporting the model validity. We believe that our modeling approach can be applied to study CS thresholds in humans for various gradient coils, body shapes/postures, and waveforms, which is difficult to do experimentally.

Designing a Bioreactor to Improve Data Acquisition and Model Throughput of Engineered Cardiac Tissues.

Heart failure remains the leading cause of death worldwide, creating a pressing need for better preclinical models of the human heart. Tissue engineering is crucial for basic science cardiac research; in vitro human cell culture eliminates the interspecies differences of animal models, while a more tissue-like 3D environment (e.g., with extracellular matrix and heterocellular coupling) simulates in vivo conditions to a greater extent than traditional two-dimensional culture on plastic Petri dishes. However, each model system requires specialized equipment, for example, custom-designed bioreactors and functional assessment devices. Additionally, these protocols are often complicated, labor-intensive, and plagued by the failure of the small, delicate tissues. This paper describes a process for generating a robust human engineered cardiac tissue (hECT) model system using induced pluripotent stem-cell-derived cardiomyocytes for the longitudinal measurement of tissue function. Six hECTs with linear strip geometry are cultured in parallel, with each hECTsuspended from a pair of force-sensing polydimethylsiloxane (PDMS) posts attached to PDMS racks. Each post is capped with a black PDMS stable post tracker (SPoT), a new feature that improves the ease of use, throughput, tissue retention, and data quality. The shape allows for the reliable optical tracking of post deflections, yielding improved twitch force tracings with absolute active and passive tension. The cap geometry eliminates tissue failure due to hECTs slipping off the posts, and as they involve a second step after PDMS rack fabrication, the SPoTs can be added to existing PDMS post-based designs without major changes to the bioreactor fabrication process. The system is used to demonstrate the importance of measuring hECT function at physiological temperatures and shows stable tissue function during data acquisition. In summary, we describe a state-of-the-art model system that reproduces key physiological conditions to advance the biofidelity, efficiency, and rigor of engineered cardiac tissues for in vitro applications.

P12: Mechanical Characterization of Synthetic Tissues for Cardiac Surgical Training

Background: Synthetic heart models are commonly used for surgical training, especially for complex procedures. However, current models are expensive and poorly mimic heart tissue mechanics and anatomy. 3D printing unconventional materials can produce more realistic models at a more affordable price; therefore, this study investigates the potential of several 3D printed materials as a synthetic tissue for surgical heart models. Methods: Three synthetic cardiac tissues were fabricated: hydrogel samples (3Dresyn SAE1) on a Form2 laser printer, soft polymer samples (3Dresyn SEA10) on a Form2 laser printer, and silicone samples (Dragon Skin Fast 10A) on an Eazao Zero liquid deposition printer. Synthetic tissues were compared to fresh bovine cardiac tissues in terms of puncture resistance, suture retention, and tensile strength using an AEL universal testing machine and 20N PCE Instruments force gauge. Results: There are no significant differences between the mechanical properties of cardiac tissue and the hydrogel-printed SAE1 samples according to ANOVA with a Tukey’s HSD test (Fig1A). There are significant differences between the SEA10 soft polymer sample and cardiac tissue for the puncture and tension tests, but not for the suture retention test (Fig1A). All mechanical test results are significantly different between the 10A silicone and cardiac samples (Fig1A). An example heart is printed with the hydrogel material to demonstrate usability (Fig1B). Conclusion: The 3D printed hydrogel samples better matched the mechanical properties of cardiac tissue than the other printed samples. Although the hydrogel material proved adequate for surgical simulation, other synthetic tissues should be explored to reduce the cost and time of printing, and to better mimic cardiac tissue.

P53: Dynamics of Intracardiac Carbon Dioxide Concentration During Insufflation

Background: Insufflation of Carbon Dioxide (Co2) during cardiac surgery is a common practice during open chamber cardiac surgery. Co2 fills the pericardial space, displaces the air and due to its high solubility in blood and tissues the risk of air embolism is significantly reduced. Previous studies have measured the Co2 or oxygen (O2) in the surgical field only. In this study concentration of Co2 and O2 inside the heart and in the field were measured in different insufflation scenarios. Methods: A phantom of the chest with a pericardial cavity and a heart model was constructed to simulate the adult heart surgery. To simulate an open chamber heart procedure, the aorta of the model was tunneled towards left ventricle chamber to achieve open communication. Co2 and O2 concentration were measured in the left ventricle by sensors implanted in the left ventricle chamber and then in the field during the study. Results: In the standard Co2 insufflation of 5 L/min in the lower midline corner of the pericardial well, the intracardiac Co2 reached to 40000 ppm (the upper range of the sensor) in 17 seconds and O2 reached to lowest level of 5.6% in 130 seconds. The Co2 and O2 concentrations were not different on lower insufflation of Co2 of 2 and 1 L/min. After discontinuation of Co2 insufflation, Co2 and O2 concentration were back to baseline in 3min. Placement of Co2 line in other locations of the pericardial well did not change the above parameters (Figure 1A). Despite the common belief, while using a strong suction in the field, intracardiac Co2 and O2 concertation did not change significantly, 40000 ppm and 7.5%, respectively. Co2 concentration measured at 10, 20 and 30cm above the surgical field were 2580, 1130 and 922 ppm, respectively and at the level of surgeon’s face was similar to that of ambient air (Figure 1B). Conclusion: This study provides information on intracardiac Co2 concentration in different Co2 insufflation settings. Lower than 5 L/min, different locations of Co2 cannula, and using suction does not affect the efficiency of Co2 insufflation. It takes up to 3 minutes for Co2 to be cleared from the heart chamber. The risk of breathing Co2 from insufflation of Co2 in the field is negligible.Figure 1. A: Co2 insufflation in the phantom of pericardial cavity, locations a-d: Indicate different positions of Co2 line placement: a= standard location, b-d: variations; star: Co2 and O2 sensors implanted in the heart chamber, connected to microprocessors; arrow: opening in the aorta, connecting to left ventricle. B: Co2 concentration changes and dissipation from the field up to the surgeon’s face level. ppm: parts per million Co2: Carbon dioxide, O2: Oxygen

Fast-Track Virtual Reality to Facilitate 3D Reconstruction in Congenital Heart Disease.

A limitation of the clinical use of 3D reconstruction and virtual reality (VR) systems is the relatively high cost and experience required to use hardware and software to effectively explore medical images. We have tried to simplify the process and validate a new tool developed for this purpose with a novel software. Five patients with right partial anomalous pulmonary venous return with adequate preoperative imaging acquired by magnetic resonance were enrolled. Five volunteers with no previous experience in the field of 3D reconstruction were instructed to use the software after a short video tutorial. Users were then asked to create a 3D model of each patient's heart with DIVA and their results were compared quantitatively and qualitatively with a benchmark reconstruction performed by an experienced user. All our participants recreated 3D models in a relatively short time, maintaining a good overall quality (average quality score ≥ 3 on a scale of 1-5). The overall trend of all the parameters analysed showed a statistical improvement between Case 1 and Case 5, as users become more and more experienced. DIVA is a very simple software that allows accurate 3D reconstruction in a relatively short time ("fast-track" VR). In this study, we demonstrated the potential use of DIVA by inexperienced users, with a significant improvement in quality and time after a few cases were performed. Further studies are needed to confirm the potential application of this technology on a larger scale.

Parallel use of human stem cell lung and heart models provide insights for SARS-CoV-2 treatment.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily infects the respiratory tract, but pulmonary and cardiac complications occur in severe coronavirus disease 2019 (COVID-19). To elucidate molecular mechanisms in the lung and heart, we conducted paired experiments in human stem cell-derived lung alveolar type II (AT2) epithelial cell and cardiac cultures infected with SARS-CoV-2. With CRISPR-Cas9-mediated knockout of ACE2, we demonstrated that angiotensin-converting enzyme 2 (ACE2) was essential for SARS-CoV-2 infection of both cell types but that further processing in lung cells required TMPRSS2, while cardiac cells required the endosomal pathway. Host responses were significantly different; transcriptome profiling and phosphoproteomics responses depended strongly on the cell type. We identified several antiviral compounds with distinct antiviral and toxicity profiles in lung AT2 and cardiac cells, highlighting the importance of using several relevant cell types for evaluation of antiviral drugs. Our data provide new insights into rational drug combinations for effective treatment of a virus that affects multiple organ systems.