Lightning Round: Breaking Science in Single Ventricle Disease Modeling


A computational model of cardiac growth and remodeling: Initial results and potential applications in Fontan patients

Amadeus M. Gebauer, Graduate Student at the Institute for Computational Mechanics of the Technical University of Munich

Abstract: Cardiac growth and remodeling (G&R) patterns change ventricular size, shape, and function. Biomechanical, neurohormonal, and genetic stimuli drive these patterns through changes in myocyte dimension and fibrosis. Adaptive G&R can stabilize short-term cardiac performance. Yet, by early adulthood, up to 50% of patients with a Fontan circulation are in heart failure, hypothesized to be caused by adverse G&R. We propose a novel microstructure-motivated computational model of organ- scale G&R in the heart based on the homogenized constrained mixture theory. Previous models reproduced consequences of G&R in bulk myocardial tissue by prescribing the direction and extent of growth but neglected underlying cellular mechanisms. In our model, the direction and extent of G&R emerge naturally from micromechanical turnover processes in myocardial tissue constituents and their homeostatic mechanical state. We tested our model on an idealized 3D left ventricular geometry and demonstrated that our model aims to maintain tensional homeostasis in hypertension conditions. We identified adaptive (stable) and adverse (unstable) G&R regions from varying systolic pressures and growth factors in a stability map. Further- more, we showed that our model also inherently captures the reversal of G&R after returning the systolic pressure to baseline following hypertension. The Fontan procedure dramatically improved the survival of children with single ventricle (SV) physiology, but the mechanisms of long-term heart failure remain poorly understood. Our microstructure-motivated G&R model could form the basis for a computational prediction of heart failure in SV patients. Furthermore, it could quantify the therapeutic potential of reversing remodeling, e.g., through left ventricular assist devices.

Cerebrovascular Accidents In Patients With A Left Ventricle Assist Device – The Role of Quantitative In Silico Models

Akshita Sahni, Graduate Student at the University of Colorado Boulder

Abstract: Left Ventricle Assist Devices (LVAD) have become a primary treatment choice for advanced heart failure, both as bridge-to-transplant as well as destination therapy. LVADs offer mechanical circulation support by shunting blood from failed left ventricle through a pump directly into the aorta. Despite advances in LVAD design and overall survival, they are associated with significant levels of morbidity and mortality. Stroke and cerebrovascular complications remain a leading cause of adverse outcomes post-LVAD implantation. The altered state of hemodynamics due to the LVAD pump action is intimately linked to the etiology and mechanism of stroke in LVAD patients. Yet, in-depth pre-implant understanding of stroke risks and propensity post-implant remains challenge. Here, we address this challenge through development of custom in silico models for stroke risks and mechanisms of cerebrovascular accidents, and integration of quantitative model outcomes with clinical data and patient outcomes data. We will present parametric in silico studies on the underlying mechanisms of stroke in LVAD patients, discuss results from a systematic patient cohort study for patients on LVAD support, and present perspectives on integration of such models into surgical decision making.

Shear and hydrostatic stress regulate heart valve remodeling through YAP-mediated mechanotransduction

Mingkun Wang, PhD, Postdoctoral Fellow at The Nancy E. and Peter C. Meinig School of Biomedical Engineering at Cornell University

Abstract: Congenital heart valve defects account for over 25% of all congenital heart disease, therapeutic options beyond surgical valve replacement are currently limited. Biomechanics is a driving force in valve development and disease, but how to harness it for preventing the defective development is largely unknown. Here we show that YAP, a key mechanotransduction mediator and Hippo pathway effector, responds to various mechanical forces during valvulogenesis. We first examined YAP expression during later stages of valve remodeling and found a spatiotemporal pattern correlated to the changes in mechanical environments. We then applied the shear stress on a monolayer of valvar endothelial cells (VEC) cultured in-vitro and hydrostatic stress on isolated valve explants. We found the low oscillatory shear stress and hydrostatic compressive stress promote YAP nuclear localization in VEC and valvar interstitial cells (VIC), while the high laminar shear stress and hydrostatic tensile stress restrict YAP entering nuclei in VEC and VIC. By inhibiting YAP, we altered the morphology of valve explants by limiting the VIC proliferation and enhancing the cell-cell junction of VEC. To verify the role of YAP in-vivo, we performed left and right atrial ligation in chick embryonic hearts. The surgery restricted or amplified blood flows in-vivo and induced a hypoplastic or hypertrophic valve phenotype. An inhibited YAP expression was found in the hypoplastic phenotype while a sustained YAP expression was observed in the hypertrophic phenotype. Together, we identified a mechanobiological role YAP in valve remodeling, wherein shear stress controls valve shape via YAP mediated VEC junction while the hydrostatic stress controls valve size through YAP mediated VIC proliferation.

A cardio-respiratory benchtop model which integrates respiratory biomechanics to investigate the effects of breathing on the venous flow of the Fontan circulation

Markus Horvath, Graduate Student in the Harvard-MIT Health Sciences and Technology Program

Abstract: The current preferred treatment for single ventricle physiology culminates in the Fontan circulation which connects the systemic and pulmonic vasculature in series. While it allows patients to survive with a single ventricle, the relentless hemodynamic burden triggers severe pathophysiological consequences. Despite great interest, understanding of the physiological interactions and development of support strategies remain limited which results in continuously high mid- to long term mortality rates over the past 20 years. One important example of limitation is highlighted in the current Fontan models; animal, benchtop, and computational. Recently, respiratory mechanics have been identified as a governing contributor to Fontan flow patterns and resulting reverse flow in the systemic venous return, yet currently available animal models fail to recreate the impact of respiration on the hemodynamics. Similarly, sophisticated models have been developed in vitro and in silico, but a physiologically relevant interaction of respiratory pressures is still lacking. This limits the development of therapeutic solutions. We present the development of quantitative tools that recreate the impact of respiration on the hemodynamics and serve as test platforms for interventions. In this work we introduce a physical and computational model of the Fontan physiology which mimics our natural breathing and flow mechanics to recreate the venous blood flow in the Fontan circulation. This will allow to study the effects of different breathing patterns and particular physiologies on the flow characteristics. Finally, it will serve as a platform to test different support strategies to improve the Fontan circulation.

Self-Powered Injection-Jet Fontan Circulation to Effectively Drop Caval Pressure in a Failing Fontan

Ray Prather, PhD, Senior Research Associate at the Arnold Palmer Hospital for Children

Abstract: The Fontan circulation is a fragile system in which imperfections at any one of multiple levels may compromise quality of life. Elevated inferior vena caval (IVC) pressure plays a key role in “Fontan failure”. We hypothesize that the Fontan circulation can be energized with an injection jet shunt (IJS) drawing flow directly from the aortic arch balanced by a fenestration. The IJS causes flow entrainment, leading to a clinically significant IVC pressure reduction of >3mmHg. We describe a tightly coupled multi-scale lumped parameter/computational fluids dynamics model to validate this hypothesis. A synthetic 3D-CAD model of the fenestrated total cavopulmonary connection (TCPC) was generated, with average dimensions matching those of a 2-4yo patient. The prescribed cardiac output is of about 2.3L/min with a body surface area of 0.7m2. Hemodynamics are modeled as unsteady, incompressible, turbulent, and blood is assumed non-Newtonian. Potential optimal IJS configurations were determined through a parametric sweep of several geometric design parameters such as TCPC morphology, shunt and fenestration diameter and location. A set of baseline simulations representing a failing Fontan with elevated IVC pressure (17.8mmHg) is first subjected to a fenestration enlargement to 7mm resulting in a 3mmHg IVC pressure drop but also significant reduction in systemic oxygen saturation. Addition of an IJS (2mm nozzle) to this model preserves the IVC pressure drop of 3.2mmHg and improves systemic oxygen saturation with only a small additional volume load to the ventricle (CO/Qs=1.2). Our current models demonstrate the potential salutary effect of the IJS on the Fontan circulation.

Modeling Ventricular Hypoplasia in Pulmonary Atresia with Intact Ventricular Septum Using Patient-Specific iPSCs

Yang Yu, PhD, Postdoctoral Fellow at Nationwide Children’s Hospital

Abstract: Pulmonary atresia with intact ventricular septum (PA-IVS) is a detrimental congenital heart disease where the pulmonary valve is not appropriately developed. Several hypotheses speculated to explain the pathogenesis of this disorder contains abnormal coronary arterial development, atypical blood flow through the venous valve, and atretic pulmonary valve formation. The conventional treatment strategy is pulmonary valve perforation and PA-IVS patients after treatment present with varying degrees of ventricular hypoplasia: from single ventricle palliation (1v) to 1½-ventricle palliation (1.5v) and bi-ventricle repair (2v). Mechanistic studies are required to further explain the different levels of RV hypoplasia in PA-IVS patients. Here, we generated PA-IVS-specific induced pluripotent stem cells (iPSCs) from patients with a spectrum of RV hypoplasia. PA-IVS iPSC-derived cardiomyocytes (iPSC-CMs) contracted normally and displayed sarcomeric structures with intercalated cardiac troponin T and α-actinin. Early-stage PA-IVS iPSC-CMs exhibited a variety of compromised proliferation activities, which could not be rescued by Wnt signaling pathway activation. Transcriptomic profiling by bulk RNA seq suggested that pathways involved in the cell cycle and mitosis were downregulated in day13 PA-IVS-1v iPSC-CMs, but not in PA-IVS-2v iPSC-CMs. However, at a later stage (day20), pathways involved in the regulation of cell division and mitosis were upregulated in PA-IVS-1v cardiomyocytes, indicating a possible developmental delay in the cardiomyocyte proliferation for PA-IVS-1v. Intriguingly, differentially expressed genes between PA-IVS-2v and control cardiomyocytes were primarily enriched in the pathways relevant to glucose metabolism, mitochondrial biogenesis, and muscle contraction. We conclude that patient iPSC-CMs can recapitulate cardiomyocyte proliferation defects involved in ventricular hypoplasia in PA-IVS.

Biventricular Shape Modes Discriminate Pulmonary Valve Replacement in Tetralogy of Fallot Better Than Imaging Indices

Sachin Govil, Graduate Student in the Department of Bioengineering at University of California San Diego 

Abstract: Current indications for pulmonary valve replacement (PVR) in repaired tetralogy of Fallot (rTOF) rely on cardiovascular magnetic resonance (CMR) image-based indices but are inconsistently applied, lead to mixed outcomes, and remain debated. This study aimed to test the hypothesis that specific markers of biventricular shape may discriminate differences between rTOF patients who did and did not require subsequent PVR better than standard imaging indices. In this cross-sectional retrospective study, biventricular shape models were customized to CMR images from 84 rTOF patients. A statistical atlas of end-diastolic shape was constructed using principal component analysis. Multivariate regression and clustering analysis were used to test the ability of shape modes and imaging indices to discriminate PVR status as evaluated by a Matthews correlation coefficient (MCC). Geometric strain analysis was conducted to assess shape mode associations with systolic function. PVR status correlated significantly with shape modes associated with right ventricular (RV) apical dilation and left ventricular (LV) dilation (p<0.01), RV basal bulging and LV conicity (p<0.05), and pulmonary valve dilation (p<0.01). Shape modes discriminated subsequent PVR better than standard imaging indices (MCC=0.49 and MCC=0.28, respectively) and were significantly associated with RV and LV radial systolic strain. Biventricular shape modes discriminated differences between patients who did and did not require subsequent PVR better than standard imaging indices in current use. These regional features of cardiac morphology may provide insight into adaptive vs. maladaptive types of structural remodeling and point toward an improved quantitative, patient-specific assessment tool for clinical use.

Persistent Ventricle Partitioning in the Adult Zebrafish Heart

Hannah Moran, Graduate Student at the University of Colorado Anschutz Medical Campus

Abstract: The heart is the first functional organ to form in the developing vertebrate embryo. The zebrafish provides an accessible vertebrate system to study early heart morphogenesis and to gain new insights into the mechanisms of congenital disease. Although composed of only two chambers compared to the four-chambered mammalian heart, the zebrafish heart integrates the core processes and cellular lineages that are central to cardiac development across vertebrates. The vertebrate heart integrates cells from the early-differentiating first heart field (FHF) and the later-differentiating second heart field (SHF), both emerging from the lateral plate mesoderm. In mammals, this process forms the basis for the development of the left and right ventricle chambers and subsequent chamber septation. The single ventricle-forming zebrafish heart also integrates FHF and SHF lineages during embryogenesis, yet the contributions of these two myocardial lineages to the adult zebrafish heart remain incompletely understood. Here, we characterize the myocardial labeling of FHF descendants in both the developing and adult zebrafish ventricle. Expanding previous findings, late gastrulation-stage labeling using drl-driven CreERT2 recombinase with a myocardium-specific, myl7-controlled, loxP reporter results in the predominant labeling of FHF-derived outer curvature and the right side of the embryonic ventricle. Raised to adulthood, such lineage-labeled hearts retain broad areas of FHF cardiomyocytes in a region of the ventricle that is positioned at the opposite side to the atrium and encompasses the apex. Our findings are consistent with the hypothesis that integration of distinct cardiomyocyte lineages is an evolutionarily ancient trait that predates the formation of multi-chambered ventricles.

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