Hemocompatibility and biophysical interface of left ventricular assist devices and total artificial hearts.

ABSTRACT: Over the past 2 decades, there has been a significant increase in the utilization of long-term mechanical circulatory support (MCS) for the treatment of cardiac failure. Left ventricular assist devices (LVADs) and total artificial hearts (TAHs) have been developed in parallel to serve as bridge-to-transplant and destination therapy solutions. Despite the distinct hemodynamic characteristics introduced by LVADs and TAHs, a comparative evaluation of these devices regarding potential complications in supported patients, has not been undertaken. Such a study could provide valuable insights into the complications associated with these devices. Although MCS has shown substantial clinical benefits, significant complications related to hemocompatibility persist, including thrombosis, recurrent bleeding, and cerebrovascular accidents. This review focuses on the current understanding of hemostasis, specifically thrombotic and bleeding complications, and explores the influence of different shear stress regimens in long-term MCS. Furthermore, the role of endothelial cells in protecting against hemocompatibility-related complications of MCS is discussed. We also compared the diverse mechanisms contributing to the occurrence of hemocompatibility-related complications in currently used LVADs and TAHs. By applying the existing knowledge, we present, for the first time, a comprehensive comparison between long-term MCS options.

Role of tissue biomechanics in the formation and function of myocardial trabeculae in zebrafish embryos.

Cardiac trabeculae are uneven ventricular muscular structures that develop during early embryonic heart development at the outer curvature of the ventricle. Their biomechanical function is not completely understood, and while their formation is known to be mechanosensitive, it is unclear whether ventricular tissue internal stresses play an important role in their formation. Here, we performed imaging and image-based cardiac biomechanics simulations on zebrafish embryonic ventricles to investigate these issues. Microscopy-based ventricular strain measurements show that the appearance of trabeculae coincided with enhanced deformability of the ventricular wall. Image-based biomechanical simulations reveal that the presence of trabeculae reduces ventricular tissue internal stresses, likely acting as structural support in response to the geometry of the ventricle. Passive ventricular pressure-loading experiments further reveal that the formation of trabeculae is associated with a spatial homogenization of ventricular tissue stiffnesses in healthy hearts, but gata1 morphants with a disrupted trabeculation process retain a spatial stiffness heterogeneity. Our findings thus suggest that modulating ventricular wall deformability, stresses, and stiffness are among the biomechanical functions of trabeculae. Further, experiments with gata1 morphants reveal that a reduction in fluid pressures and consequently ventricular tissue internal stresses can disrupt trabeculation, but a subsequent restoration of ventricular tissue internal stresses via vasopressin rescues trabeculation, demonstrating that tissue stresses are important to trabeculae formation. Overall, we find that tissue biomechanics is important to the formation and function of embryonic heart trabeculation. KEY POINTS: Trabeculations are fascinating and important cardiac structures and their abnormalities are linked to embryonic demise. However, their function in the heart and their mechanobiological formation processes are not completely understood. Our imaging and modelling show that tissue biomechanics is the key here. We find that trabeculations enhance cardiac wall deformability, reduce fluid pressure stresses, homogenize wall stiffness, and have alignments that are optimal for providing load-bearing structural support for the heart. We further discover that high ventricular tissue internal stresses consequent to high fluid pressures are needed for trabeculation formation through a rescue experiment, demonstrating that myocardial tissue stresses are as important as fluid flow wall shear stresses for trabeculation formation.

Flow assessment as a function of pump timing of tubular pulsatile pump for use as a ventricular assist device in a left heart simulator.

INTRODUCTION: Although mechanical circulatory support saved many lives during the last decade, clinical observations have shown that the continuous flow pumps are associated with a much higher incidence of gastrointestinal bleeding and kidney problems, among others, compared with the earlier generation pulsatile pumps. However, the presence of several moving mechanical components made pulsatile pumps less durable, bulky, and prone to malfunction, ultimately leading to bias in favor of continuous flow designs. OBJECTIVE: The aim of the current work is to create a prototype tubular pulsatile pump and to test the timing of the pump in a left heart simulator. METHODS: A left heart simulator to mimic pumping from a failing heart was created. This was used to experimentally test the output of a prototype ventricular assist device relative to a failing heart in the form of flow and pressure. The effect of pulsation timing was quantified. RESULTS: A failing heart was simulated with an average flow rate of 1.1 L/min and a systolic pressure of 47 mm Hg. With the pump, the flow rate increases to 4.8 L/min and a systolic pressure of 110 mm Hg, in a copulsation mode, while activating for 300-400 ms. If the activation time is reduced, or increased, the pump becomes less effective. Load on the heart is reduced when the pump operates in a counterpulsation mode. CONCLUSION: A pulsatile pump, like the one proposed, provides adequate output for mechanical circulatory support, while minimizing the number of moving parts that could otherwise lead to tribological wear.

TNF-α-driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging.

Aging and chronic inflammation are independent risk factors for the development of atherothrombosis and cardiovascular disease. We hypothesized that aging-associated inflammation promotes the development of platelet hyperreactivity and increases thrombotic risk during aging. Functional platelet studies in aged-frail adults and old mice demonstrated that their platelets are hyperreactive and form larger thrombi. We identified tumor necrosis factor α (TNF-α) as the key aging-associated proinflammatory cytokine responsible for platelet hyperreactivity. We further showed that platelet hyperreactivity is neutralized by abrogating signaling through TNF-α receptors in vivo in a mouse model of aging. Analysis of the bone marrow compartments showed significant platelet-biased hematopoiesis in old mice reflected by increased megakaryocyte-committed progenitor cells, megakaryocyte ploidy status, and thrombocytosis. Single-cell RNA-sequencing analysis of native mouse megakaryocytes showed significant reprogramming of inflammatory, metabolic, and mitochondrial gene pathways in old mice that appeared to play a significant role in determining platelet hyperreactivity. Platelets from old mice (where TNF-α was endogenously increased) and from young mice exposed to exogenous TNF-α exhibited significant mitochondrial changes characterized by elevated mitochondrial mass and increased oxygen consumption during activation. These mitochondrial changes were mitigated upon TNF-α blockade. Similar increases in platelet mitochondrial mass were seen in platelets from patients with myeloproliferative neoplasms, where TNF-α levels are also increased. Furthermore, metabolomics studies of platelets from young and old mice demonstrated age-dependent metabolic profiles that may differentially poise platelets for activation. Altogether, we present previously unrecognized evidence that TNF-α critically regulates megakaryocytes resident in the bone marrow niche and aging-associated platelet hyperreactivity and thrombosis.

Pilot-scale open-channel raceways and flat-panel photobioreactors maintain well-mixed conditions under a wide range of mixing energy inputs.

Turbulent mixing in pilot-scale cultivation systems influences the productivity of photoautotrophic cultures. We studied turbulent mixing by applying particle image velocimetry and acoustic doppler velocimetry to pilot-scale, flat-panel photobioreactor, and open-channel raceway. Mixing energy inputs were varied from 0.1 to 2.1 W·m-3 . The experimental results were used to quantify turbulence and to validate computational fluid dynamics models, from which Lagrangian representations of the fluid motion in these reactors were derived. The results of this investigation demonstrated that differences in mixing energy input do not significantly impact the structure of turbulence and the light/dark cycling frequencies experienced by photoautotrophic cells within the reactors. The experimental and computational results of our research demonstrated that well-mixed conditions exist in pilot-scale, flat-panel photobioreactors and open-channel raceways, even for relatively low mixing energy inputs.

Turbulent Flow Promotes Cleavage of VWF (von Willebrand Factor) by ADAMTS13 (A Disintegrin and Metalloproteinase With a Thrombospondin Type-1 Motif, Member 13).

Objective- Acquired von Willebrand syndrome is defined by excessive cleavage of the VWF (von Willebrand Factor) and is associated with impaired primary hemostasis and severe bleeding. It often develops when blood is exposed to nonphysiological flow such as in aortic stenosis or mechanical circulatory support. We evaluated the role of laminar, transitional, and turbulent flow on VWF cleavage and the effects on VWF function. Approach and Results- We used a vane rheometer to generate laminar, transitional, and turbulent flow and evaluate the effect of each on VWF cleavage in the presence of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type-1 motif, member 13). We performed functional assays to evaluate the effect of these flows on VWF structure and function. Computational fluid dynamics was used to estimate the flow fields and forces within the vane rheometer under each flow condition. Turbulent flow is required for excessive cleavage of VWF in an ADAMTS13-dependent manner. The assay was repeated with whole blood, and the turbulent flow had the same effect. Our computational fluid dynamics results show that under turbulent conditions, the Kolmogorov scale approaches the size of VWF. Finally, cleavage of VWF in this study has functional consequences under flow as the resulting VWF has decreased ability to bind platelets and collagen. Conclusions- Turbulent flow mediates VWF cleavage in the presence of ADAMTS13, decreasing the ability of VWF to sustain platelet adhesion. These findings impact the design of mechanical circulatory support devices and are relevant to pathological environments where turbulence is added to circulation.

Human fetal hearts with tetralogy of Fallot have altered fluid dynamics and forces.

Studies have suggested the effect of blood flow forces in pathogenesis and progression of some congenital heart malformations. It is therefore of interest to study the fluid mechanic environment of the malformed prenatal heart, such as the tetralogy of Fallot (TOF), especially when little is known about fetal TOF. In this study, we performed patient-specific ultrasound-based flow simulations of three TOF and seven normal human fetal hearts. TOF right ventricles (RVs) had smaller end-diastolic volumes (EDVs) but similar stroke volumes (SVs), whereas TOF left ventricles (LVs) had similar EDVs but slightly increased SVs compared with normal ventricles. Simulations showed that TOF ventricles had elevated systolic intraventricular pressure gradient (IVPG) and required additional energy for ejection but IVPG elevations were considered to be mild relative to arterial pressure. TOF RVs and LVs had similar pressures because of equalization via ventricular septal defect (VSD). Furthermore, relative to normal, TOF RVs had increased diastolic wall shear stresses (WSS) but TOF LVs were not. This was caused by high tricuspid inflow that exceeded RV SV, leading to right-to-left shunting and chaotic flow with enhanced vorticity interaction with the wall to elevate WSS. Two of the three TOF RVs but none of the LVs had increased thickness. As pressure elevations were mild, we hypothesized that pressure and WSS elevation could play a role in the RV thickening, among other causative factors. Finally, the endocardium surrounding the VSD consistently experienced high WSS because of RV-to-LV flow shunt and high flow rate through the over-riding aorta. NEW & NOTEWORTHY Blood flow forces are thought to cause congenital heart malformations and influence disease progression. We performed novel investigations of intracardiac fluid mechanics of tetralogy of Fallot (TOF) human fetal hearts and found essential differences from normal hearts. The TOF right ventricle (RV) and left ventricle had similar and elevated pressure but only the TOF RV had elevated wall shear stress because of elevated tricuspid inflow, and this may contribute to the observed RV thickening. TOF hearts also expended more energy for ejection.

Decoding thrombosis through code: a review of computational models.

From the molecular level up to a blood vessel, thrombosis and hemostasis involves many interconnected biochemical and biophysical processes over a wide range of length and time scales. Computational modeling has gained eminence in offering insights into these processes beyond what can be obtained from in vitro or in vivo experiments, or clinical measurements. The multiscale and multiphysics nature of thrombosis has inspired a wide range of modeling approaches that aim to address how a thrombus forms and dismantles. Here, we review recent advances in computational modeling with a focus on platelet-based thrombosis. We attempt to summarize the diverse range of modeling efforts straddling the wide-spectrum of physical phenomena, length scales, and time scales; highlighting key advancements and insights from existing studies. Potential information gleaned from models is discussed, ranging from identification of thrombus-prone regions in patient-specific vasculature to modeling thrombus deformation and embolization in response to fluid forces. Furthermore, we highlight several limitations of current models, future directions in the field, and opportunities for clinical translation, to illustrate the state-of-the-art. There are a plethora of opportunity areas for which models can be expanded, ranging from topics of thromboinflammation to platelet production and clearance. Through successes demonstrated in existing studies described here, as well as continued advancements in computational methodologies and computer processing speeds and memory, in silico investigations in thrombosis are poised to bring about significant knowledge growth in the years to come.

Recommendations for defining disturbed flow as laminar, transitional, or turbulent in assays of hemostasis and thrombosis: communication from the ISTH SSC Subcommittee on Biorheology.

Blood flow is vital to life, yet disturbed flow has been linked to atherosclerosis, thrombosis, and endothelial dysfunction. The commonly used hemodynamic descriptor "disturbed flow" found in disease and medical devices is not clearly defined in many studies. However, the specific flow regime-laminar, transitional, or turbulent-can have very different effects on hemostasis, thrombosis, and vascular health. Therefore, it remains important to clinically identify turbulence in cardiovascular flow and to have available assays that can be used to study effects of turbulence. The objective of the current communication was to 1) provide clarity and guidance for how to clinically identify turbulence, 2) define standard measures of turbulence that can allow the recreation of flow conditions in a benchtop assay, and 3) review how cells and proteins in the blood can be impacted by turbulence based on current literature.

Clinical Impact of an AI Decision Support System for Detection of Intracranial Hemorrhage in CT Scans.

This study aimed to evaluate the predictive value and clinical impact of a clinically implemented artificial neural network software model. The software detects intracranial hemorrhage (ICH) from head computed tomography (CT) scans and artificial intelligence (AI)-identified positive cases are then annotated in the work list for early radiologist evaluation. The index test was AI detection by the program Zebra Medical Vision-HealthICH+. Radiologist-confirmed ICH was the reference standard. The study compared whether time benefits from using the AI model led to faster escalation of patient care or surgery within the first 24 h. A total of 2,306 patients were evaluated by the software, and 288 AI-positive cases were included. The AI tool had a positive predictive value of 0.823. There was, however, no significant time reduction when comparing the patients who required escalation of care and those who did not. There was also no significant time reduction in those who required acute surgery compared with those who did not. Among the individual patients with reduced time delay, no cases with evident clinical benefit were identified. Although the clinically implemented AI-based decision support system showed adequate predictive value in identifying ICH, there was no significant clinical benefit for the patients in our setting. While AI-assisted detection of ICH shows great promise from a technical perspective, there remains a need to evaluate the clinical impact and perform external validation across different settings.

LRRC8 complexes are adenosine nucleotide release channels regulating platelet activation and arterial thrombosis.

Platelet shape and volume changes are early mechanical events contributing to platelet activation and thrombosis. Here, we identify single-nucleotide polymorphisms in Leucine-Rich Repeat Containing 8 (LRRC8) protein subunits that form the Volume-Regulated Anion Channel (VRAC) which are independently associated with altered mean platelet volume. LRRC8A is required for functional VRAC in megakaryocytes (MKs) and regulates platelet volume, adhesion, and agonist-stimulated activation, aggregation, ATP secretion and calcium mobilization. MK-specific LRRC8A cKO mice have reduced arteriolar thrombus formation and prolonged arterial thrombosis without affecting bleeding times. Mechanistically, platelet LRRC8A mediates swell-induced ATP/ADP release to amplify agonist-stimulated calcium and PI3K-AKT signaling via P2X1, P2Y 1 and P2Y 12 receptors. Small-molecule LRRC8 channel inhibitors recapitulate defects observed in LRRC8A-null platelets in vitro and in vivo . These studies identify the mechanoresponsive LRRC8 channel complex as an ATP/ADP release channel in platelets which regulates platelet function and thrombosis, providing a proof-of-concept for a novel anti-thrombotic drug target.

Platelet transport rates and binding kinetics at high shear over a thrombus.

Thrombus formation over a ruptured atherosclerotic plaque cap can occlude an artery with fatal consequences. We describe a computational model of platelet transport and binding to interpret rate-limiting steps seen in experimental thrombus formation over a collagen-coated stenosis. The model is used to compute shear rates in stenoses with growing boundaries. In the model, moving erythrocytes influence platelet transport based on shear-dependent enhanced diffusivity and a nonuniform platelet distribution. Adhesion is modeled as platelet-platelet binding kinetics. The results indicate that observed thrombus growth rates are limited by platelet transport to the wall for shear rates up to 6000 s(-1). Above 7000 s(-1), the thrombus growth rate is likely limited by binding kinetics (10(-4) m/s). Thrombus growth computed from these rate-limiting steps match the thrombus location and occlusion times for experimental conditions if a lag time for platelet activation is included. Using fitted parameters, the model is then used to predict thrombus size and shape at a higher Reynolds number flow consistent with coronary artery disease.

Maximizing flow rate in single paper layer, rapid flow microfluidic paper-based analytical devices.

Small, single-layer microfluidic paper-based analytical devices (µPADs) offer potential for a range of point-of-care applications; however, they have been limited to low flow rates. Here, we investigate the role of laser cutting paper channels in maximizing flow rate in small profile devices with limited fluid volumes. We demonstrate that branching, laser-cut grooves can provide a 59.23-73.98% improvement in flow rate over a single cut, and a 435% increase over paper alone. These design considerations can be applied to more complex microfluidic devices with the aim of increasing the flow rate, and could be used in stand-alone channels for self-pumping. Supplementary Information: The online version contains supplementary material available at 10.1007/s10404-023-02679-8.

The in vivo study of cardiac mechano-electric and mechano-mechanical coupling during heart development in zebrafish.

In the adult heart, acute adaptation of electrical and mechanical activity to changes in mechanical load occurs via feedback processes known as "mechano-electric coupling" and "mechano-mechanical coupling." Whether this occurs during cardiac development is ill-defined, as acutely altering the heart's mechanical load while measuring functional responses in traditional experimental models is difficult, as embryogenesis occurs in utero, making the heart inaccessible. These limitations can be overcome with zebrafish, as larvae develop in a dish and are nearly transparent, allowing for in vivo manipulation and measurement of cardiac structure and function. Here we present a novel approach for the in vivo study of mechano-electric and mechano-mechanical coupling in the developing zebrafish heart. This innovative methodology involves acute in vivo atrial dilation (i.e., increased atrial preload) in larval zebrafish by injection of a controlled volume into the venous circulation immediately upstream of the heart, combined with optical measurement of the acute electrical (change in heart rate) and mechanical (change in stroke area) response. In proof-of-concept experiments, we applied our new method to 48 h post-fertilisation zebrafish, which revealed differences between the electrical and mechanical response to atrial dilation. In response to an acute increase in atrial preload there is a large increase in atrial stroke area but no change in heart rate, demonstrating that in contrast to the fully developed heart, during early cardiac development mechano-mechanical coupling alone drives the adaptive increase in atrial output. Overall, in this methodological paper we present our new experimental approach for the study of mechano-electric and mechano-mechanical coupling during cardiac development and demonstrate its potential for understanding the essential adaptation of heart function to acute changes in mechanical load.

Correlation of thrombosis growth rate to pathological wall shear rate during platelet accumulation.

Local hemodynamics may strongly influence atherothrombosis, which can lead to acute myocardial infarction and stroke. The relationship between hemodynamics and thrombosis during platelet accumulation was studied through an in vitro flow system consisting of a stenosis. Specifically, wall shear rates (WSR) ranging from 0 to 100,000 s(-1) were ascertained through computations and compared with thrombus growth rates found by image analysis for over 5,000 individual observation points per experiment. A positive correlation (P < 0.0001) was found between thrombus accumulation rates and WSR up to 6,000 s(-1), with a decrease in growth rates at WSR >6,000 s(-1) (P < 0.0001). Furthermore, growth rates at pathological shear rates were found to be two to four times greater than for physiological arterial shear rates below 400 s(-1). Platelets did not accumulate for the first minute of perfusion. The initial lag time, before discernible thrombus growth could be found, diminished with shear (P < 0.0001). These studies show the quantitative increase in thrombus growth rates with very high shear rates in stenoses onto a collagen substrate.

Myocardial Afterload Is a Key Biomechanical Regulator of Atrioventricular Myocyte Differentiation in Zebrafish.

Heart valve development is governed by both genetic and biomechanical inputs. Prior work has demonstrated that oscillating shear stress associated with blood flow is required for normal atrioventricular (AV) valve development. Cardiac afterload is defined as the pressure the ventricle must overcome in order to pump blood throughout the circulatory system. In human patients, conditions of high afterload can cause valve pathology. Whether high afterload adversely affects embryonic valve development remains poorly understood. Here we describe a zebrafish model exhibiting increased myocardial afterload, caused by vasopressin, a vasoconstrictive drug. We show that the application of vasopressin reliably produces an increase in afterload without directly acting on cardiac tissue in zebrafish embryos. We have found that increased afterload alters the rate of growth of the cardiac chambers and causes remodeling of cardiomyocytes. Consistent with pathology seen in patients with clinically high afterload, we see defects in both the form and the function of the valve leaflets. Our results suggest that valve defects are due to changes in atrioventricular myocyte signaling, rather than pressure directly acting on the endothelial valve leaflet cells. Cardiac afterload should therefore be considered a biomechanical factor that particularly impacts embryonic valve development.

Valveless pumping behavior of the simulated embryonic heart tube as a function of contractile patterns and myocardial stiffness.

During development, the heart begins pumping as a valveless multilayered tube capable of driving blood flow throughout the embryonic vasculature. The mechanical properties and how they interface with pumping function are not well-defined at this stage. Here, we evaluate pumping patterns using a fluid-structure interaction computational model, combined with experimental data and an energetic analysis to investigate myocardial mechanical properties. Through this work, we propose that a myocardium modeled as a Neo-Hookean material with a material constant on the order of 10 kPa is necessary for the heart tube to function with an optimal pressure and cardiac output.

Calcific Aortic Stenosis-A Review on Acquired Mechanisms of the Disease and Treatments.

Calcific aortic stenosis is a progressive disease that has become more prevalent in recent decades. Despite advances in research to uncover underlying biomechanisms, and development of new generations of prosthetic valves and replacement techniques, management of calcific aortic stenosis still comes with unresolved complications. In this review, we highlight underlying molecular mechanisms of acquired aortic stenosis calcification in relation to hemodynamics, complications related to the disease, diagnostic methods, and evolving treatment practices for calcific aortic stenosis.

In Vivo Pressurization of the Zebrafish Embryonic Heart as a Tool to Characterize Tissue Properties During Development.

Cardiac morphogenesis requires an intricate orchestration of mechanical stress to sculpt the heart as it transitions from a straight tube to a multichambered adult heart. Mechanical properties are fundamental to this process, involved in a complex interplay with function, morphology, and mechanotransduction. In the current work, we propose a pressurization technique applied to the zebrafish atrium to quantify mechanical properties of the myocardium under passive tension. By further measuring deformation, we obtain a pressure-stretch relationship that is used to identify constitutive models of the zebrafish embryonic cardiac tissue. Two-dimensional results are compared with a three-dimensional finite element analysis based on reconstructed embryonic heart geometry. Through these steps, we found that the myocardium of zebrafish results in a stiffness on the order of 10 kPa immediately after the looping stage of development. This work enables the ability to determine how these properties change under normal and pathological heart development.

Wall shear rates in human and mouse arteries: Standardization of hemodynamics for in vitro blood flow assays: Communication from the ISTH SSC subcommittee on biorheology.

Hemodynamics play a central role in hemostasis and thrombosis by affecting all aspects linked to platelet functions and coagulation. In vitro flow devices are extensively used in basic research, pharmacological studies, antiplatelet agent screening, and development of diagnostic tools. Because hemodynamic conditions vary tremendously throughout the vascular tree and among different (patho)physiological processes, it is important to use flow conditions based on relevant biorheological reference ranges. Surprisingly, it is particularly difficult to find a concise overview of relevant hemodynamic parameters in various human and mouse vessels. To our knowledge, this is the first time an inventory of flow conditions in healthy, non-diseased, human and mouse vessels has been created. The objective of providing such a repertoire is to aid researchers in the field of hemostasis and thrombosis in choosing rheological conditions relevant in in vitro flow experiments and to promote harmonization of flow-based assays to facilitate comparative evaluations between studies. With reference to the human, we discuss relevant similarities and discrepancies in wall shear rates in the mouse, which are typically one order of magnitude greater in agreement with allometric scaling laws between species. Importantly, we bring the attention of the researchers to the fact that the relevant range of average wall shear rates in human arteries where clinically relevant arterial thrombosis occurs may fall as low as 100 to 200 s-1, thus significantly overlapping with what are considered "venous" shear rates. The same range for the murine arteries used for arterial thrombosis models may significantly exceed 1000 s-1 reaching values considered to be "pathological."