Coarctation Duration and Severity Predict Risk of Hypertension Precursors in a Preclinical Model and Hypertensive Status Among Patients.

BACKGROUND: Coarctation of the aorta (CoA) often leads to hypertension posttreatment. Evidence is lacking for the current >20 mm Hg peak-to-peak blood pressure (BP) gradient (BPGpp) guideline, which can cause aortic thickening, stiffening, and dysfunction. This study sought to find the BPGpp severity and duration that avoid persistent dysfunction in a preclinical model and test if predictors translate to hypertension status in patients with CoA. METHODS: Rabbits (n=75; 5-12/group) were exposed to mild, intermediate, or severe CoA (≤12, 13-19, ≥20 mm Hg BPGpp) for ≈1, 3, or 22 weeks using dissolvable and permanent sutures with thickening, stiffening, contraction, and endothelial function evaluated via multivariate regression. Relevance to patients with CoA (n=239; age, 0.01-46 years; median 3.7 months) was tested by retrospective review of predictors (preoperative BPGpp, surgical age, etc.) versus follow-up hypertension status. RESULTS: CoA duration and severity were predictive of aortic remodeling and active dysfunction in rabbits, and hypertension in patients with CoA. Interaction between patient age and BPGpp at surgery contributed significantly to hypertension, similar to rabbits, suggesting preclinical findings translate to patients. Machine learning decision tree analysis uncovered that preoperative BPGpp and surgical age predict risk of hypertension along with residual postoperative BPGpp. CONCLUSIONS: These findings suggest the current BPGpp threshold determined decades ago is likely too high to prevent adverse coarctation-induced aortic remodeling. The results and decision tree analysis provide a foundation for revising CoA treatment guidelines considering the interaction between CoA severity and duration to limit the risk of hypertension.

A Systems Approach to Biomechanics, Mechanobiology, and Biotransport.

The human body represents a collection of interacting systems that range in scale from nanometers to meters. Investigations from a systems perspective focus on how the parts work together to enact changes across spatial scales, and further our understanding of how systems function and fail. Here, we highlight systems approaches presented at the 2022 Summer Biomechanics, Bio-engineering, and Biotransport Conference in the areas of solid mechanics; fluid mechanics; tissue and cellular engineering; biotransport; and design, dynamics, and rehabilitation; and biomechanics education. Systems approaches are yielding new insights into human biology by leveraging state-of-the-art tools, which could ultimately lead to more informed design of therapies and medical devices for preventing and treating disease as well as rehabilitating patients using strategies that are uniquely optimized for each patient. Educational approaches can also be designed to foster a foundation of systems-level thinking.

Consistency of the continuous flow pressure gradient despite aortic arch anomalies co-existing with coarctation.

Aims: Severity assessment for coarctation of the aorta (CoA) is challenging due to concomitant morphological anomalies (complex CoA) and inaccurate Doppler-based indices. Promising diagnostic performance has been reported for the continuous flow pressure gradient (CFPG), but it has not been studied in complex CoA. Our objective was to characterize the effect of complex CoA and associated hemodynamics on CFPG in a clinical cohort. Methods and Results: Retrospective analysis identified discrete juxtaductal (n=25) and complex CoA (n=43; transverse arch and/or isthmus hypoplasia) patients with arm-leg systolic blood pressure gradients (BPG) within 24 hours of echocardiography for comparison to BPG by conventional Doppler indices (simplified Bernoulli equation and modified forms correcting for proximal kinetic energy and/or recovered pressure). Results were interpreted using the current CoA guideline (BPG ≥20 mmHg) to compare diagnostic performance indicators including receiver operating characteristic curves, sensitivity, specificity, and diagnostic accuracy, among others. Echocardiography Z-scored aortic diameters were applied with computational stimulations from a preclinical CoA model to understand aspects of the CFPG driving performance differences.Diagnostic performance was substantially reduced from discrete to complex CoA for conventional Doppler indices calculated from patient data, and by hypoplasia and/or long segment stenosis in simulations. In contrast, diagnostic indicators for the CFPG only modestly dropped for complex vs discrete CoA. Simulations revealed differences in performance due to inclusion of the Doppler velocity index and diastolic pressure half-time in the CFPG calculation. Conclusion: CFPG is less affected by aortic arch anomalies co-existing with CoA when compared to conventional Doppler indices.

Coarctation duration and severity predict the likelihood of hypertension precursors in a preclinical model and hypertensive status among patients.

Coarctation of the aorta (CoA) often leads to hypertension (HTN) post-treatment. There is limited evidence for the current ≥20 mmHg peak-to-peak blood pressure gradient (BPGpp) guideline, which can cause aortic thickening, stiffening and dysfunction. This study sought to find the BPGpp severity and duration that avoids persistent dysfunction in a preclinical model, and test if predictors identified translate to HTN status in CoA patients. Rabbits (N=75; 5-11/group; 10 weeks-old) were exposed to mild, intermediate or severe CoA (≤12, 13-19 & ≥20 mmHg BPGpp) for ~1, 3 or 22 weeks using dissolvable and permanent sutures with thickening, stiffening, contraction and endothelial function evaluated via multivariate regression analysis. The relevance of findings to CoA patients (N=239; age=0.01-46 years; mean 3.44 years) was similarly tested by retrospective review of predictors (pre-operative BPGpp, age at surgery, etc) vs follow-up HTN status. CoA duration and severity were predictive of remodeling and dysfunction in rabbits and HTN likelihood in CoA patients. Interaction between patient age and BPGpp at surgery were significant contributors to HTN, suggesting preclinical findings translate to human. Machine-learning decision tree analysis uncovered duration and severity values for precursors of HTN in the preclinical model, and HTN at follow-up in CoA patients. These findings suggest the current BPGpp threshold is likely too high to limit activation of processes leading to persistent aortic changes associated with HTN. The resulting decision tree provides a foundation for revising CoA treatment guidelines by considering the interaction between CoA severity and duration to limit the chance of HTN.

Artificial Intelligence, Computational Simulations, and Extended Reality in Cardiovascular Interventions.

Artificial intelligence, computational simulations, and extended reality, among other 21st century computational technologies, are changing the health care system. To collectively highlight the most recent advances and benefits of artificial intelligence, computational simulations, and extended reality in cardiovascular therapies, we coined the abbreviation AISER. The review particularly focuses on the following applications of AISER: 1) preprocedural planning and clinical decision making; 2) virtual clinical trials, and cardiovascular device research, development, and regulatory approval; and 3) education and training of interventional health care professionals and medical technology innovators. We also discuss the obstacles and constraints associated with the application of AISER technologies, as well as the proposed solutions. Interventional health care professionals, computer scientists, biomedical engineers, experts in bioinformatics and visualization, the device industry, ethics committees, and regulatory agencies are expected to streamline the use of AISER technologies in cardiovascular interventions and medicine in general.

Aortic Remodeling Kinetics in Response to Coarctation-Induced Mechanical Perturbations.

Background: Coarctation of the aorta (CoA; constriction of the proximal descending thoracic aorta) is among the most common congenital cardiovascular defects. Coarctation-induced mechanical perturbations trigger a cycle of mechano-transduction events leading to irreversible precursors of hypertension including arterial thickening, stiffening, and vasoactive dysfunction in proximal conduit arteries. This study sought to identify kinetics of the stress-mediated compensatory response leading to these alterations using a preclinical rabbit model of CoA. Methods: A prior growth and remodeling (G&R) framework was reformulated and fit to empirical measurements from CoA rabbits classified into one control and nine CoA groups of various severities and durations (n = 63, 5-11/group). Empirical measurements included Doppler ultrasound imaging, uniaxial extension testing, catheter-based blood pressure, and wire myography, yielding the time evolution of arterial thickening, stiffening, and vasoactive dysfunction required to fit G&R constitutive parameters. Results: Excellent agreement was observed between model predictions and observed patterns of arterial thickening, stiffening, and dysfunction among all CoA groups. For example, predicted vascular impairment was not significantly different from empirical observations via wire myography (p-value > 0.13). Specifically, 48% and 45% impairment was observed in smooth muscle contraction and endothelial-dependent relaxation, respectively, which were accurately predicted using the G&R model. Conclusions: The resulting G&R model, for the first time, allows for prediction of hypertension precursors at neonatal ages that is currently challenging to examine in preclinical models. These findings provide a validated computational tool for prediction of persistent arterial dysfunction and identification of revised severity-duration thresholds that may ultimately avoid hypertension from CoA.

3D-bioprinting of patient-derived cardiac tissue models for studying congenital heart disease.

Introduction: Congenital heart disease is the leading cause of death related to birth defects and affects 1 out of every 100 live births. Induced pluripotent stem cell technology has allowed for patient-derived cardiomyocytes to be studied in vitro. An approach to bioengineer these cells into a physiologically accurate cardiac tissue model is needed in order to study the disease and evaluate potential treatment strategies. Methods: To accomplish this, we have developed a protocol to 3D-bioprint cardiac tissue constructs comprised of patient-derived cardiomyocytes within a hydrogel bioink based on laminin-521. Results: Cardiomyocytes remained viable and demonstrated appropriate phenotype and function including spontaneous contraction. Contraction remained consistent during 30 days of culture based on displacement measurements. Furthermore, tissue constructs demonstrated progressive maturation based on sarcomere structure and gene expression analysis. Gene expression analysis also revealed enhanced maturation in 3D constructs compared to 2D cell culture. Discussion: This combination of patient-derived cardiomyocytes and 3D-bioprinting represents a promising platform for studying congenital heart disease and evaluating individualized treatment strategies.

Intravascular imaging of angioplasty balloon under-expansion during pre-dilation predicts hyperelastic behavior of coronary artery lesions.

Introduction: Stent-induced mechanical stimuli cause pathophysiological responses in the coronary artery post-treatment. These stimuli can be minimized through choice of stent, size, and deployment strategy. However, the lack of target lesion material characterization is a barrier to further personalizing treatment. A novel ex-vivo angioplasty-based intravascular imaging technique using optical coherence tomography (OCT) was developed to characterize local stiffness of the target lesion. Methods: After proper institutional oversight, atherosclerotic coronary arteries (n = 9) were dissected from human donor hearts for ex vivo material characterization <48 h post-mortem. Morphology was imaged at the diastolic blood pressure using common intravascular OCT protocols and at subsequent pressures using a specially fabricated perfusion balloon that accommodates the OCT imaging wire. Balloon under-expansion was quantified relative to the nominal balloon size at 8 ATM. Correlation to a constitutive hyperelastic model was empirically investigated (n = 13 plaques) using biaxial extension results fit to a mixed Neo-Hookean and Exponential constitutive model. Results and discussion: The average circumferential Cauchy stress was 66.5, 130.2, and 300.4 kPa for regions with <15, 15-30, and >30% balloon under-expansion at a 1.15 stretch ratio. Similarly, the average longitudinal Cauchy stress was 68.1, 172.6, and 412.7 kPa, respectively. Consequently, strong correlation coefficients >0.89 were observed between balloon under-expansion and stress-like constitutive parameters. These parameters allowed for visualization of stiffness and material heterogeneity for a range of atherosclerotic plaques. Balloon under-expansion is a strong predictor of target lesion stiffness. These findings are promising as stent deployment could now be further personalized via target lesion material characterization obtained pre-operatively.

Temporal evolution of mechanical stimuli from vascular remodeling in response to the severity and duration of aortic coarctation in a preclinical model.

Coarctation of the aorta (CoA) is one of the most common congenital cardiovascular diseases. CoA patients frequently undergo surgical repair, but hypertension (HTN) is still common. The current treatment guideline has revealed irreversible changes in structure and function, yet revised severity guidelines have not been proposed. Our objective was to quantify temporal alterations in mechanical stimuli and changes in arterial geometry in response to the range of CoA severities and durations (i.e. age of treatment) seen clinically. Rabbits were exposed to CoA resulting in peak-to-peak blood pressure gradient (BPGpp) severities of ≤ 10, 10-20, and ≥ 20 mmHg for a duration of ~ 1, 3, or 20 weeks using permanent, dissolvable, and rapidly dissolvable sutures. Elastic moduli and thickness were estimated from imaging and longitudinal fluid-structure interaction (FSI) simulations were conducted at different ages using geometries and boundary conditions from experimentally measured data. Mechanical stimuli were characterized including blood flow velocity patterns, wall tension, and radial strain. Experimental results show vascular alternations including thickening and stiffening proximal to the coarctation with increasing severity and/or duration of CoA. FSI simulations indicate wall tension in the proximal region increases markedly with coarctation severity. Importantly, even mild CoA induced stimuli for remodeling that exceeds values seen in adulthood if not treated early and using a BPGpp lower than the current clinical threshold. The findings are aligned with observations from other species and provide some guidance for the values of mechanical stimuli that could be used to predict the likelihood of HTN in human patients with CoA.

A workflow for viewing biomedical computational fluid dynamics results and corresponding data within virtual and augmented reality environments.

Researchers conducting computational fluid dynamics (CFD) modeling can spend weeks obtaining imaging data, determining boundary conditions, running simulations and post-processing files. However, results are typically viewed on a 2D display and often at one point in time thus reducing the dynamic and inherently three-dimensional data to a static image. Results from different pathologic states or cases are rarely compared in real-time, and supplementary data are seldom included. Therefore, only a fraction of CFD results are typically studied in detail, and associations between mechanical stimuli and biological response may be overlooked. Virtual and augmented reality facilitate stereoscopic viewing that may foster extraction of more information from CFD results by taking advantage of improved depth cues, as well as custom content development and interactivity, all within an immersive approach. Our objective was to develop a straightforward, semi-automated workflow for enhanced viewing of CFD results and associated data in an immersive virtual environment (IVE). The workflow supports common CFD software and has been successfully completed by novice users in about an hour, demonstrating its ease of use. Moreover, its utility is demonstrated across clinical research areas and IVE platforms spanning a range of cost and development considerations. We are optimistic that this advancement, which decreases and simplifies the steps to facilitate more widespread use of immersive CFD viewing, will foster more efficient collaboration between engineers and clinicians. Initial clinical feedback is presented, and instructional videos, manuals, templates and sample data are provided online to facilitate adoption by the community.

C Type Natriuretic Peptide Receptor Activation Inhibits Sodium Channel Activity in Human Aortic Endothelial Cells by Activating the Diacylglycerol-Protein Kinase C Pathway.

The C-type natriuretic peptide receptor (NPRC) is expressed in many cell types and binds all natriuretic peptides with high affinity. Ligand binding results in the activation or inhibition of various intracellular signaling pathways. Although NPRC ligand binding has been shown to regulate various ion channels, the regulation of endothelial sodium channel (EnNaC) activity by NPRC activation has not been studied. The objective of this study was to investigate mechanisms of EnNaC regulation associated with NPRC activation in human aortic endothelial cells (hAoEC). EnNaC protein expression and activity was attenuated after treating hAoEC with the NPRC agonist cANF compared to vehicle, as demonstrated by Western blotting and patch clamping studies, respectively. NPRC knockdown studies using siRNA's corroborated the specificity of EnNaC regulation by NPRC activation mediated by ligand binding. The concentration of multiple diacylglycerols (DAG) and the activity of protein kinase C (PKC) was augmented after treating hAoEC with cANF compared to vehicle, suggesting EnNaC activity is down-regulated upon NPRC ligand binding in a DAG-PKC dependent manner. The reciprocal cross-talk between NPRC activation and EnNaC inhibition represents a feedback mechanism that presumably is involved in the regulation of endothelial function and aortic stiffness.

Clinical, Experimental, and Computational Validation of a New Doppler-Based Index for Coarctation Severity Assessment.

BACKGROUND: Long-term morbidity including hypertension often persists in coarctation patients despite current guidelines. Coarctation severity can be invasively assessed via peak-to-peak catheter pressure gradient (PPCG), which is estimated noninvasively via simplified Bernoulli equation and conventionally reported as peak instantaneous Doppler gradient (PIDG). However, underlying simplifications of the equation limit diagnostic accuracy. We studied the diagnostic performance of a new Doppler-based diastolic index called the continuous flow pressure gradient (CFPG) versus conventional indices in assessing coarctation severity. METHODS: In a rabbit model mimicking human aortic coarctation, temporal blood pressure waveforms revealed the diastolic instantaneous pressure gradients and spectral Doppler features impacted by coarctation severity. We therefore hypothesized that CFPG provides superior correlation with coarctation gradients measured invasively. PIDG and CFPG were quantified using color flow echocardiography in humans and rabbits with discrete coarctations. Results were compared with PPCG in rabbits (n = 34) and arm-leg systolic gradients (n = 25) in humans via 1-way analysis of variance, Pearson's correlation, linear regression, and Bland-Altman analysis. RESULTS: A threshold of CFPG ≥ 4.6 mm Hg was identified via the Youden index as representative of PPCG ≥ 20 mm Hg (the current guideline value for coarctation intervention) in rabbits, while a CFPG ≥1.0 mm Hg represented an arm-leg systolic gradient ≥20 mm Hg in humans. Accuracy measures revealed superior correlation of CFPG (R2 > 0.80) and mild receiver operating characteristic improvement (area under the receiver operating characteristic curve, 0.94-0.95) compared with PIDG (R2 < 0.63; area under the receiver operating characteristic curve, 0.89-0.95). Inter-/intraobserver variability tested by intraclass correlation coefficient revealed measurement reliability with differences ≤8.2% and 10.7%, respectively. Computational simulations of anesthetized versus conscious hemodynamics showed parameters were minimally impacted by isoflurane inherent in the data used to derive CFPG. These results confirm the potential diagnostic accuracy of CFPG in echocardiography-based coarctation severity assessment. We are optimistic that CFPG will be useful for translation of results from preclinical studies that revisit current guidelines to limit morbidity in humans with aortic coarctation.

A Pilot Study Characterizing Flow Patterns in the Thoracic Aorta of Patients With Connective Tissue Disease: Comparison to Age- and Gender-Matched Controls via Fluid Structure Interaction.

Prior computational and imaging studies described changes in flow patterns for patients with Marfan syndrome, but studies are lacking for related populations. This pilot study addresses this void by characterizing wall shear stress (WSS) indices for patients with Loeys-Dietz and undifferentiated connective tissue diseases. Using aortic valve-based velocity profiles from magnetic resonance imaging as input to patient-specific fluid structure interaction (FSI) models, we determined local flow patterns throughout the aorta for four patients with various connective tissue diseases (Loeys-Dietz with the native aorta, connective tissue disease of unclear etiology with native aorta in female and male patients, and an untreated patient with Marfan syndrome, as well as twin patients with Marfan syndrome who underwent valve-sparing root replacement). FSI simulations used physiological boundary conditions and material properties to replicate available measurements. Time-averaged WSS (TAWSS) and oscillatory shear index (OSI) results are presented with localized comparison to age- and gender-matched control participants. Ascending aortic dimensions were greater in almost all patients with connective tissue diseases relative to their respective control. Differences in TAWSS and OSI were driven by local morphological differences and cardiac output. For example, the model for one twin had a more pronounced proximal descending aorta in the vicinity of the ductus ligamentum that impacted WSS indices relative to the other. We are optimistic that the results of this study can serve as a foundation for larger future studies on the connective tissue disorders presented in this article.

Do Head-Mounted Augmented Reality Devices Affect Muscle Activity and Eye Strain of Utility Workers Who Do Procedural Work? Studies of Operators and Manhole Workers.

OBJECTIVE: The objective was to determine the effect of two head-mounted display (HMD) augmented reality (AR) devices on muscle activity and eye strain of electric utility workers. The AR devices were the Microsoft HoloLens and RealWear HMT-1. BACKGROUND: The HoloLens is an optical see-through device. The HMT-1 has a small display that is mounted to the side of one eye of the user. METHOD: Twelve power plant operators and 13 manhole workers conducted their normal procedural tasks on-site in three conditions: HoloLens, HMT-1, and "No AR" (regular method). Duration of test trials ranged up to 30 s for operators and up to 10 min for manhole workers. Mean and peak values of surface electromyographic (sEMG) signals from eight neck muscles were measured. A small eye camera measured blink rate of the right eye. RESULTS: In general, there were no differences in sEMG activity between the AR and "No AR" conditions for both groups of workers. For the manhole workers, the HoloLens blink rate was 8 to 11 blinks per min lower than the HMT-1 in two tasks and 6.5 fewer than "No AR" in one task. Subjective assessment of the two AR devices did not vary in general. CONCLUSION: The decrease in blink rate with the HoloLens may expose utility manhole workers to risk of eye strain or dry-eye syndrome. APPLICATION: HMD AR devices should be tested thoroughly with respect to risk of eye strain before deployment by manhole workers for long-duration procedural work.

Computational Assessment of Hemodynamic Significance in Patients With Intramural Anomalous Aortic Origin of the Coronary Artery Using Virtually Derived Fractional Flow Reserve and Downstream Microvascular Resistance.

Anomalous aortic origin of a coronary artery (AAOCA) is the second most common cause of sudden cardiac death in young athletes. One of the hypothesized mechanisms of ischemia in these patients is the lateral compression of the anomalous artery with an intramural or interarterial course. The presence of a narrowing in the anomalous artery will cause physiologic changes in downstream resistance that should be included for computational assessment of possible clinical ramifications. In this study, we created different compression levels, i.e., proximal narrowing, in the intramural course of a representative patient model and calculated hyperemic stenosis resistance (HSR) as well as virtual fractional flow reserve (vFFR). Models also included the effect of the distal hyperemic microvascular resistance (HMR) on vFFR. Our results agreed with similar FFR studies indicating that FFR is increased with increasing HMR and that different compression levels could have similar FFR depending on the HMR. For example, vFFR at HSR: 1.0-1.3 and HMR: 2.30 mmHg/cm/s is 0.68 and close to vFFR at HSR: 0.6-0.7 and HMR: 1.6 mmHg/cm/s, which is 0.7. The current findings suggest that functional assessment of anomalous coronary arteries through FFR should consider the vascular resistance distal to the narrowing in addition to the impact of a proximal narrowing and provides computational approaches for implementation of these important considerations.

Assessment of Reflux From Needleless Connectors: Blinded Comparison of Category Designation to Benchtop Function Using a Venous Simulator.

Needleless connectors (NCs) for vascular access have limited needlestick injuries, but complications including occlusion, thrombosis, and infections have increased despite reduced needlestick injuries. These complications relate to the ability of an NC design to limit volume fluctuations that can lead to fluid reflux with potential for microbial contamination. Different NC designs requiring specific usage protocols and training, a lack of clarity in NC function relative to manufacturer-designated categories, and confounding results from a limited number of studies comparing different NCs have resulted in confusion, ultimately leading to complications from undesirable fluid movement within the vascular access. The authors therefore quantified the magnitude of reflux with current commercially available NCs using a venous stimulator. Thirteen blinded NC designs spanning the categories of negative and positive displacement, neutral, and antireflux were tested to quantify fluid movement upon disconnection and reconnection from a representative intravenous pressure (3 NCs per design; 10 trials per NC). Trials for each NC tested followed consistent displacement trends leading to tight error bars. Blinded NCs were then characterized according to their function and compared with their category designation after unblinding. All positive and negative NCs functioned in a manner consistent with their respective category designations. Conversely, all NCs categorized as neutral actually functioned with negative displacement (ie, reflux upon disconnection; 4/5 NCs) or positive displacement (1/5 NCs). Only NCs classified as antireflux functioned as neutral, which was confirmed in a blinded bidirectional flow test. These results suggest that the neutral NC-marketed category may be confusing to users unless the particular NC design has an integrated antireflux component.

Increased endothelial sodium channel activity by extracellular vesicles in human aortic endothelial cells: putative role of MLP1 and bioactive lipids.

Extracellular vesicles (EVs) contain biological molecules and are secreted by cells into the extracellular milieu. The endothelial sodium channel (EnNaC) plays an important role in modulating endothelial cell stiffness. We hypothesized EVs secreted from human aortic endothelial cells (hAoECs) positively regulate EnNaC in an autocrine-dependent manner. A comprehensive lipidomic analysis using targeted mass spectrometry was performed on multiple preparations of EVs isolated from the conditioned media of hAoECs or complete growth media of these cells. Cultured hAoECs challenged with EVs isolated from the conditioned media of these cells resulted in an increase in EnNaC activity when compared with the same concentration of media-derived EVs or vehicle alone. EVs isolated from the conditioned media of hAoECs but not human fibroblast cells were enriched in MARCKS-like protein 1 (MLP1). The pharmacological inhibition of the negative regulator of MLP1, protein kinase C, in cultured hAoECs resulted in an increase in EV size and release compared with vehicle or pharmacological inhibition of protein kinase D. The MLP1-enriched EVs increased the density of actin filaments in cultured hAoECs compared with EVs isolated from human fibroblast cells lacking MLP1. We quantified 141 lipids from glycerolipids, glycerophospholipids, and sphingolipids in conditioned media EVs that represented twice the number found in control media EVs. The concentrations of sphingomyelin, lysophosphatidylcholine and phosphatidylethanolamine were higher in conditioned media EVs. These results provide the first evidence for EnNaC regulation in hAoECs by EVs and provide insight into a possible mechanism involving MLP1, unsaturated lipids, and bioactive lipids.

Molecular and Mechanical Mechanisms of Calcification Pathology Induced by Bicuspid Aortic Valve Abnormalities.

Bicuspid aortic valve (BAV) is a congenital defect affecting 1-2% of the general population that is distinguished from the normal tricuspid aortic valve (TAV) by the existence of two, rather than three, functional leaflets (or cusps). BAV presents in different morphologic phenotypes based on the configuration of cusp fusion. The most common phenotypes are Type 1 (containing one raphe), where fusion between right coronary and left coronary cusps (BAV R/L) is the most common configuration followed by fusion between right coronary and non-coronary cusps (BAV R/NC). While anatomically different, BAV R/L and BAV R/NC configurations are both associated with abnormal hemodynamic and biomechanical environments. The natural history of BAV has shown that it is not necessarily the primary structural malformation that enforces the need for treatment in young adults, but the secondary onset of premature calcification in ~50% of BAV patients, that can lead to aortic stenosis. While an underlying genetic basis is a major pathogenic contributor of the structural malformation, recent studies have implemented computational models, cardiac imaging studies, and bench-top methods to reveal BAV-associated hemodynamic and biomechanical alterations that likely contribute to secondary complications. Contributions to the field, however, lack support for a direct link between the external valvular environment and calcific aortic valve disease in the setting of BAV R/L and R/NC BAV. Here we review the literature of BAV hemodynamics and biomechanics and discuss its previously proposed contribution to calcification. We also offer means to improve upon previous studies in order to further characterize BAV and its secondary complications.

Correlation of Computational Instantaneous Wave-Free Ratio With Fractional Flow Reserve for Intermediate Multivessel Coronary Disease.

This study computationally assesses the accuracy of an instantaneous wave-free ratio (iFR) threshold range compared to standard modalities such as fractional flow reserve (FFR) and coronary flow reserve (CFR) for multiple intermediate lesions near the left main (LM) coronary bifurcation. iFR is an adenosine-independent index encouraged for assessment of coronary artery disease (CAD), but different thresholds are debated. This becomes particularly challenging in cases of multivessel disease when sensitivity to downstream lesions is unclear. Idealized LM coronary arteries with 34 different intermediate stenoses were created and categorized (Medina) as single and multiple lesion groups. Computational fluid dynamics modeling was performed with physiologic boundary conditions using an open-source software (simvascular1) to solve the time-dependent Navier-Stokes equations. A strong linear relationship between iFR and FFR was observed among studied models, indicating computational iFR values of 0.92 and 0.93 are statistically equivalent to an FFR of 0.80 in single and multiple lesion groups, respectively. At the clinical FFR value (i.e., 0.8), a triple-lesion group had smaller CFR compared to the single and double lesion groups (e.g., triple = 3.077 versus single = 3.133 and double = 3.132). In general, the effect of additional intermediate downstream lesions (minimum lumen area > 3 mm2) was not statistically significant for iFR and CFR. A computational iFR of 0.92 best predicts an FFR of 0.80 and may be recommended as threshold criteria for computational assessment of LM stenosis following additional validation using patient-specific models.

Patient-Specific Numerical Analysis of Coronary Flow in Children With Intramural Anomalous Aortic Origin of Coronary Arteries.

Unroofing surgery for anomalous aortic origin of a coronary artery (AAOCA) alters coronary anatomy by opening the intramural segment so that the anomalous coronary orifice arises perpendicularly from appropriate aortic sinus. Computational fluid dynamics modeling (CFD) allows for quantification of hemodynamics linked to morbidity such as wall shear stress (WSS), relative to patient-specific features like the angle of origin (AO). We hypothesize that CFD will reveal abnormal WSS indices in unroofed arteries that are related to AO. Six AAOCA patients (3 left, 3 right) status post unroofing (median = 13.5 years, range 9-17) underwent cardiac magnetic resonance imaging. CFD models were created from pre (n = 2) and postunroofing (n = 6) cardiac magnetic resonance imaging data, for the anomalous and contralateral normally-arising arteries. Downstream vasculature was represented by lumped parameter networks. Time-averaged WSS (TAWSS) and oscillatory shear index (OSI) were quantified relative to AO and measured hemodynamics. TAWSS was elevated along the outer wall of the normally-arising left vs right coronary arteries, as well as along unroofed left vs right coronary arteries (n = 6/group). No significant differences were noted when comparing unroofed and same-sided normally-arising coronaries. TAWSS was reduced after unroofing (eg, 276 ± 28 dyne/cm2 vs 91 ± 15 dyne/cm2; n = 2/group). Models with more acute preoperative AO indicated lower TAWSS at the proximity of ostium. Differences in OSI were not significant. Different flow patterns exist natively between right and left coronary arteries. Unroofing may normalize TAWSS but with variance related to the AO. This study suggests CFD may help stratify risk in AAOCA.