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Continuous-flow ventricular assist devices (CFVAD) and counterpulsation devices (CPD) are used to treat heart failure (HF). CFVAD can diminish pulsatility, but pulsatile modes have been implemented to increase vascular pulsatility. The effects of CFVAD in a pulsatile mode and CPD support on the function of endothelial cells (ECs) are yet to be investigated. In this study, two in vitro microfluidic models for culturing ECs are proposed to reproduce blood pressure (BP) and wall shear stress (WSS) on the arterial endothelium while using these medical devices. The layout and parameters of the two microfluidic systems were optimized based on the principle of hemodynamic similarity to efficiently simulate physiological conditions. Moreover, the unique design of the double-pump and double afterload systems could successfully reproduce the working mode of CPDs in an in vitro microfluidic system. The performance of the two systems was verified by numerical simulations and in vitro experiments. BP and WSS under HF, CFVAD in pulsatile modes, and CPD were reproduced accurately in the systems, and these induced signals improved the expression of Ca 2+ , NO, and reactive oxygen species in ECs, proving that CPD may be effective in normalizing endothelial function and replacing CFVAD to a certain extent to treat non-severe HF. This method offers an important tool for the study of cell mechanobiology and a key experimental basis for exploring the potential value of mechanical circulatory support devices in reducing adverse events and improving outcomes in the treatment of HF in the future.

Rotary blood pumps (RBPs) operating at a constant speed generate non-physiologic blood pressure and flow rate, which can cause endothelial dysfunction, leading to adverse clinical events in peripheral blood vessels and other organs. Notably, pulsatile working modes of the RBP can increase vascular pulsatility to improve arterial endothelial function. However, the laws and related mechanisms of differentially regulating arterial endothelial function under different pulsatile working modes are still unclear. This knowledge gap hinders the optimal selection of the RBP working modes. To address these issues, this study developed a multi-element in vitro endothelial cell culture system (ECCS), which could realize in vitro cell culture effectively and accurately reproduce blood pressure, shear stress, and circumferential strain in the arterial endothelial microenvironment. Performance of this proposed ECCS was validated with numerical simulation and flow experiments. Subsequently, this study investigated the effects of four different pulsation frequency modes that change once every 1-4-fold cardiac cycles (80, 40, 80/3, and 20 cycles per min, respectively) of the RBP on the expression of nitric oxide (NO) and reactive oxygen species (ROS) in endothelial cells. Results indicated that the 2-fold and 3-fold cardiac cycles significantly increased the production of NO and prevented the excessive generation of ROS, potentially minimizing the occurrence of endothelial dysfunction and related adverse events during the RBP support, and were consistent with animal study findings. In general, this study may provide a scientific basis for the optimal selection of the RBP working modes and potential treatment options for heart failure.

Continuous flow (CF) left ventricular assist devices (LVAD) operate at a constant speed mode, which could result in increased risk of adverse events due to reduced vascular pulsatility. Consequently, pump speed modulation algorithms have been proposed to augment vascular pulsatility. However, the quantitative local hemodynamic effects on the aorta when the pump is operating with speed modulation using different types of CF-LVADs are still under investigation. The computational fluid dynamics (CFD) study was conducted to quantitatively elucidate the hemodynamic effects on a clinical patient-specific aortic model under different speed patterns of CF-LVADs. Pressure distribution, wall shear stress (WSS), time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), relative residence time (RRT), and velocity were calculated to compare their differences at constant and pulsatile speeds under centrifugal and axial LVAD support. Results showed that pulse pressure on the aorta was significantly larger under pulsatile speed mode than that under constant speed mode for both CF-LVADs, indicating enhanced aorta pulsatility, as well as the higher peak blood flow velocity on some representative slices of aorta. Pulsatile speed modulation enhanced peak WSS compared to constant speed; high TAWSS region appeared near the branch of left common carotid artery and distal aorta regardless of speed modes and CF-LVADs but these regions also had low OSI; RRT was almost the same for all the cases. This study may provide a basis for the scientific and reasonable selection of the pulsatile speed patterns of CF-LVADs for treating heart failure patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Testing drugs in vivo and in vitro have been essential elements for the discovery of new therapeutics. Due to the recent advances in in vitro cell culture models, such as human-induced pluripotent stem cell-derived cardiomyocytes and 3D multicell type organoid culture methods, the detection of adverse cardiac events prior to human clinical trials has improved. However, there are still numerous therapeutics whose adverse cardiac effects are not detected until human trials due to the inability of these cell cultures to fully model the complex multicellular organization of an intact human myocardium. Cardiac tissue slices are a possible alternative solution. Myocardial slices are a 300-micron thin snapshot of the myocardium, capturing a section of the adult heart in a 1 × 1 cm section. Using a culture method that incorporates essential nutrients and electrical stimulation, tissue slices can be maintained in culture for 6 days with full viability and functionality. With the addition of mechanical stimulation and humoral cues, tissue slices can be cultured for 12 days. Here we provide detailed methods for how to culture cardiac tissue slices under continuous mechanical stimulation in the cardiac tissue culture model (CTCM) device. The CTCM incorporates four essential factors for maintaining tissue slices in culture for 12 days: mechanical stimulation, electrical stimulation, nutrients, and humoral cues. The CTCM can also be used to model disease conditions, such as overstretch-induced cardiac hypertrophy. The versatility of the CTCM illustrates its potential to be a medium-throughput screening platform for personalized drug testing., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Autism Spectrum Disorder (ASD) is characterized as a neurodevelopmental disorder with a heterogeneous nature, influenced by genetics and exhibiting diverse clinical presentations. In this study, we dissect Autism Spectrum Disorder (ASD) into its behavioral components, mirroring the diagnostic process used in clinical settings. Morphological features are extracted from magnetic resonance imaging (MRI) scans, found in the publicly available dataset ABIDE II, identifying the most discriminative features that differentiate ASD within various behavioral domains. Then, each subject is categorized as having severe, moderate, or mild ASD, or typical neurodevelopment (TD), based on the behavioral domains of the Social Responsiveness Scale (SRS). Through this study, multiple artificial intelligence (AI) models are utilized for feature selection and classifying each ASD severity and behavioural group. A multivariate feature selection algorithm, investigating four different classifiers with linear and non-linear hypotheses, is applied iteratively while shuffling the training-validation subjects to find the set of cortical regions with statistically significant association with ASD. A set of six classifiers are optimized and trained on the selected set of features using 5-fold cross-validation for the purpose of severity classification for each behavioural group. Our AI-based model achieved an average accuracy of 96%, computed as the mean accuracy across the top-performing AI models for feature selection and severity classification across the different behavioral groups. The proposed AI model has the ability to accurately differentiate between the functionalities of specific brain regions, such as the left and right caudal middle frontal regions. We propose an AI-based model that dissects ASD into behavioral components. For each behavioral component, the AI-based model is capable of identifying the brain regions which are associated with ASD as well as utilizing those regions for diagnosis. The proposed system can increase the speed and accuracy of the diagnostic process and result in improved outcomes for individuals with ASD, highlighting the potential of AI in this area., (© 2023. Springer Nature Limited.)

Patients with single ventricle defects undergoing the Fontan procedure eventually face Fontan failure. Long-term cavopulmonary assist devices using rotary pump technologies are currently being developed as a subpulmonary power source to prevent and treat Fontan failure. Low hydraulic resistance is a critical safety requirement in the event of pump failure (0 RPM) as a modest 2 mmHg cavopulmonary pressure drop can compromise patient hemodynamics. The goal of this study is therefore to assess the passive performance of a viscous impeller pump (VIP) we are developing for Fontan patients, and validate flow simulations against in-vitro data. Two different blade heights (1.09 mm vs 1.62 mm) and a blank housing model were tested using a mock circulatory loop (MCL) with cardiac output ranging from 3 to 11 L/min. Three-dimensional flow simulations were performed and compared against MCL data. In-silico and MCL results demonstrated a pressure drop of < 2 mmHg at a cardiac output of 7 L/min for both blade heights. There was good agreement between simulation and MCL results for pressure loss (mean difference - 0.23 mmHg 95% CI [0.24-0.71]). Compared to the blank housing model, low wall shear stress area and oscillatory shear index on the pump surface were low, and mean washout times were within 2 s. This study demonstrated the low resistance characteristic of current VIP designs in the failed condition that results in clinically acceptable minimal pressure loss without increased washout time as compared to a blank housing model under normal cardiac output in Fontan patients., (© 2023. Springer Nature Limited.)

Nonsurgical bleeding occurs in a significant proportion of patients implanted with continuous-flow ventricular assist devices (CF-VADs) and is associated with nonphysiologic flow with diminished pulsatility. An in vitro vascular pulse perfusion model seeded with adult human aortic endothelial cells (HAECs) was used to identify biomarkers sensitive to changes in pulsatility. Diminished pulsatility resulted in an ~45% decrease in von Willebrand factor (vWF) levels from 9.80 to 5.32 ng/ml (n = 5, p < 0.05) and a threefold increase in angiopoietin-2 (ANGPT-2) levels from 775.29 to 2471.93 pg/ml (n = 5, p < 0.05) in cultured HAECs. These changes are in agreement with evaluation of patient blood samples obtained pre-CF-VAD implant and 30-day postimplant: a decrease in plasma vWF level by 50% from ~45.59 to ~22.49 μg/ml (n = 15, p < 0.01) and a 64% increase in plasma ANGPT-2 level from 7,073 to 11,615 pg/ml (n = 8, p < 0.05). This study identified vWF and ANGPT-2 as highly sensitive to changes in pulsatility, in addition to interleukin-6 (IL-6), IL-8, and tumor necrosis-α (TNF-α). These biomarkers may help determine the optimal level of pulsatility and help identify patients at high risk of nonsurgical bleeding., Competing Interests: Disclosure: G.A.G. has served as a consultant for NuPulseCV, but this manuscript does not directly pertain to the device of NuPulseCV. The other authors have no conflicts of interest to report., (Copyright © ASAIO 2023.)

Continuous flow rotary blood pumps (RBP) operating clinically at constant rotational speeds cannot match cardiac demand during varying physical activities, are susceptible to suction, diminish vascular pulsatility, and have an increased risk of adverse events. A sensorless, physiologic feedback control strategy for RBP was developed to mitigate these limitations. The proposed algorithm used intrinsic pump speed to obtain differential pump speed (Δ RPM ). The proposed gain-scheduled proportional-integral controller, switching of setpoints between a higher pump speed differential setpoint (Δ RPM Hr ) and a lower pump speed differential setpoint (Δ RPM Lr ), generated pulsatility and physiologic perfusion, while avoiding suction. The switching between Δ RPM Hr and Δ RPM Lr setpoints occurred when the measured Δ RPM reached the pump differential reference setpoint. In-silico tests were implemented to assess the proposed algorithm during rest, exercise, a rapid 3-fold pulmonary vascular resistance increase, rapid change from exercise to rest, and compared with maintaining a constant pump speed setpoint. The proposed control algorithm augmented aortic pressure pulsatility to over 35 mmHg during rest and around 30 mmHg during exercise. Significantly, ventricular suction was avoided, and adequate cardiac output was maintained under all simulated conditions. The performance of the sensorless algorithm using estimation was similar to the performance of sensor-based method. This study demonstrated that augmentation of vascular pulsatility was feasible while avoiding ventricular suction and providing physiological pump outflows. Augmentation of vascular pulsatility can minimize adverse events that have been associated with diminished pulsatility. Mock circulation and animal studies would be conducted to validate these results., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Patients on continuous flow ventricular assist devices (CF-VADs) are at high risk for the development of Acquired von-Willebrand Syndrome (AVWS) and non-surgical bleeding. von Willebrand Factor (vWF) plays an essential role in maintaining hemostasis via platelet binding to the damaged endothelium to facilitate coagulation. In CF-VAD patients, degradation of vWF into low MW multimers that are inefficient in facilitating coagulation occurs and has been primarily attributed to the supraphysiological shear stress associated with the CF-VAD impeller., Methods: In this review, we evaluate information from the literature regarding the unraveling behavior of surface-immobilized vWF under pulsatile and continuous flow pertaining to: (A) the process of arterial endothelial vWF production and release into circulation, (B) the critical shear stress required to unravel surface bound versus soluble vWF which leads to degradation, and (C) the role of pulsatility in on the production and degradation of vWF., Results and Conclusion: Taken together, these data suggests that the loss of pulsatility and its impact on arterial endothelial cells plays an important role in the production, release, unraveling, and proteolytic degradation of vWF into low MW multimers, contributing to the development of AVWS. Restoration of pulsatility can potentially mitigate this issue by preventing AVWS and minimizing the risk of non-surgical bleeding., (© 2022 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Bladder cancer (BC) is the 10th most common cancer globally and has a high mortality rate if not detected early and treated promptly. Non-muscle-invasive BC (NMIBC) is a subclassification of BC associated with high rates of recurrence and progression. Current tools for predicting recurrence and progression on NMIBC use scoring systems based on clinical and histopathological markers. These exclude other potentially useful biomarkers which could provide a more accurate personalized risk assessment. Future trends are likely to use artificial intelligence (AI) to enhance the prediction of recurrence in patients with NMIBC and decrease the use of standard clinical protocols such as cystoscopy and cytology. Here, we provide a comprehensive survey of the most recent studies from the last decade (N = 70 studies), focused on the prediction of patient outcomes in NMIBC, particularly recurrence, using biomarkers such as radiomics, histopathology, clinical, and genomics. The value of individual and combined biomarkers is discussed in detail with the goal of identifying future trends that will lead to the personalized management of NMIBC.

There is need for a reliable in vitro system that can accurately replicate the cardiac physiological environment for drug testing. The limited availability of human heart tissue culture systems has led to inaccurate interpretations of cardiac-related drug effects. Here, we developed a cardiac tissue culture model (CTCM) that can electro-mechanically stimulate heart slices with physiological stretches in systole and diastole during the cardiac cycle. After 12 days in culture, this approach partially improved the viability of heart slices but did not completely maintain their structural integrity. Therefore, following small molecule screening, we found that the incorporation of 100 nM tri-iodothyronine (T3) and 1 μM dexamethasone (Dex) into our culture media preserved the microscopic structure of the slices for 12 days. When combined with T3/Dex treatment, the CTCM system maintained the transcriptional profile, viability, metabolic activity, and structural integrity for 12 days at the same levels as the fresh heart tissue. Furthermore, overstretching the cardiac tissue induced cardiac hypertrophic signaling in culture, which provides a proof of concept for the ability of the CTCM to emulate cardiac stretch-induced hypertrophic conditions. In conclusion, CTCM can emulate cardiac physiology and pathophysiology in culture for an extended time, thereby enabling reliable drug screening., (© 2022. The Author(s).)

Background: Patients with continuous flow ventricular assist devices (CF-VADs) are at high risk for non-surgical bleeding, speculated to associate with the loss of pulsatility following CF-VAD placement. It has been hypothesized that continuous shear stress causes elongation and increased enzymatic degradation of von Willebrand Factor (vWF), a key player in thrombus formation at sites of vascular damage. However, the role of loss of pulsatility on the unravelling behavior of vWF has not been widely explored., Methods: vWF molecules were immobilized on the surface of microfluidic devices and subjected to various pulsatile flow profiles, including continuous flow and pulsatile flow of different magnitudes, dQ/dt (i.e., first derivative of flow rate) of pulsatility and pulse frequencies to mimic in vivo shear flow environments with and without CF-VAD support. VWF elongation was observed using total internal reflection fluorescence (TIRF) microscopy. Besides, the vWF level is measured from the patients' blood sample before and after CF-VAD implantation from a clinical perspective. To our knowledge, this work is the first in providing direct, visual observation of single vWF molecule extension under controlled-pulsatile shear flow., Results: Unravelling of vWF (total sample size n ~ 200 molecules) is significantly reduced under pulsatile flow (p < 0.01) compared to continuous flow. An increase in the magnitude of pulsatility further reduces unravelling lengths, while lower frequency of pulsatility (20 vs. 60 pulses per min) does not have a major effect on the maximum or minimum unravelling lengths. Evaluation of CF-VAD patient blood samples (n = 13) demonstrates that vWF levels decreased by ~40% following CF-VAD placement (p < 0.01), which correlates to single-molecule observations from a clinical point of view., Conclusions: Pulsatile flow reduces unfolding of vWF compared to continuous flow and a lower pulse frequency of 20 pulses/minute yielded comparable vWF unfolding to 60 pulses/minute. These findings could shed light on non-surgical bleeding associated with the loss of pulsatility following CF-VAD placement., (© 2021 International Center for Artificial Organs and Transplantation and Wiley Periodicals LLC.)

Cardiopulmonary bypass (CPB) results in short-term (3-5 h) exposure to flow with diminished pulsatility often referred to as "continuous flow". It is unclear if short-term exposure to continuous flow influences endothelial function, particularly, changes in levels of pro-inflammatory and pro-angiogenic cytokines. In this study, we used the endothelial cell culture model (ECCM) to evaluate if short-term (≤5 h) reduction in pulsatility alters levels of pro-inflammatory/pro-angiogenic cytokine levels. Human aortic endothelial cells (HAECs) cultured within the ECCM provide a simple model to evaluate endothelial cell function in the absence of confounding factors. HAECs were maintained under normal pulsatile flow for 24 h and then subjected to continuous flow (diminished pulsatile pressure and flow) as observed during CPB for 5 h. The ECCM replicated pulsatility and flow morphologies associated with normal hemodynamic status and CPB as seen with clinically used roller pumps. Levels of angiopoietin-2 (ANG-2), vascular endothelial growth factor-A (VEGF-A), and hepatocyte growth factor were lower in the continuous flow group in comparison to the pulsatile flow group whereas the levels of endothelin-1 (ET-1), granulocyte colony stimulating factor, interleukin-8 (IL-8) and placental growth factor were higher in the continuous flow group in comparison to the pulsatile flow group. Immunolabelling of HAECs subjected to continuous flow showed a decrease in expression of ANG-2 and VEGF-A surface receptors, tyrosine protein kinase-2 and Fms-related receptor tyrosine kinase-1, respectively. Given that the 5 h exposure to continuous flow is insufficient for transcriptional regulation, it is likely that pro-inflammatory/pro-angiogenic signaling observed was due to signaling molecules stored in Weible-Palade bodies (ET-1, IL-8, ANG-2) and via HAEC binding/uptake of soluble factors in media. These results suggest that even short-term exposure to continuous flow can potentially activate pro-inflammatory/pro-angiogenic signaling in cultured HAECs and pulsatile flow may be a successful strategy in reducing the undesirable sequalae following continuous flow CPB., (© 2021 S. Karger AG, Basel.)

Rotary left ventricular assist devices (LVAD) have emerged as a long-term treatment option for patients with advanced heart failure. LVADs need to maintain sufficient physiological perfusion while avoiding left ventricular myocardial damage due to suction at the LVAD inlet. To achieve these objectives, a control algorithm that utilizes a calculated suction index from measured pump flow (SIMPF) is proposed. This algorithm maintained a reference, user-defined SIMPF value, and was evaluated using an in silico model of the human circulatory system coupled to an axial or mixed flow LVAD with 5-10% uniformly distributed measurement noise added to flow sensors. Efficacy of the SIMPF algorithm was compared to a constant pump speed control strategy currently used clinically, and control algorithms proposed in the literature including differential pump speed control, left ventricular end-diastolic pressure control, mean aortic pressure control, and differential pressure control during (1) rest and exercise states; (2) rapid, eight-fold augmentation of pulmonary vascular resistance for (1); and (3) rapid change in physiologic states between rest and exercise. Maintaining SIMPF simultaneously provided sufficient physiological perfusion and avoided ventricular suction. Performance of the SIMPF algorithm was superior to the compared control strategies for both types of LVAD, demonstrating pump independence of the SIMPF algorithm.

Patients with heart failure (HF) or undergoing cardiogenic shock and percutaneous coronary intervention require short-term cardiac support. Short-term cardiac support using a left ventricular assist device (LVAD) alters the pressure and flows of the vasculature by enhancing perfusion and improving the hemodynamic performance for the HF patients. However, due to the position of the inflow and outflow of the LVAD, the local hemodynamics within the aorta is altered with the LVAD support. Specifically, blood velocity, wall shear stress, and pressure difference are altered within the aorta. In this study, computational fluid dynamics (CFD) was used to elucidate the effects of a short-term LVAD for hemodynamic performance in a patient-specific aorta model. The three-dimensional (3D) geometric models of a patient-specific aorta and a short-term LVAD, Impella CP, were created. Velocity, wall shear stress, and pressure difference in the patient-specific aorta model with the Impella CP assistance were calculated and compared with the baseline values of the aorta without Impella CP support. Impella CP support augmented cardiac output, blood velocity, wall shear stress, and pressure difference in the aorta. The proposed CFD study could analyze the quantitative changes in the important hemodynamic parameters while considering the effects of Impella CP, and provide a scientific basis for further predicting and assessing the effects of these hemodynamic signals on the aorta., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Wang, Peng, Huo, Yang, Giridharan, Luan and Qin.)

Liver cancer is a major cause of morbidity and mortality in the world. The primary goals of this manuscript are the identification of novel imaging markers (morphological, functional, and anatomical/textural), and development of a computer-aided diagnostic (CAD) system to accurately detect and grade liver tumors non-invasively. A total of 95 patients with liver tumors (M = 65, F = 30, age range = 34-82 years) were enrolled in the study after consents were obtained. 38 patients had benign tumors (LR1 = 19 and LR2 = 19), 19 patients had intermediate tumors (LR3), and 38 patients had hepatocellular carcinoma (HCC) malignant tumors (LR4 = 19 and LR5 = 19). A multi-phase contrast-enhanced magnetic resonance imaging (CE-MRI) was collected to extract the imaging markers. A comprehensive CAD system was developed, which includes the following main steps: i) estimation of morphological markers using a new parametric spherical harmonic model, ii) estimation of textural markers using a novel rotation invariant gray-level co-occurrence matrix (GLCM) and gray-level run-length matrix (GLRLM) models, and iii) calculation of the functional markers by estimating the wash-in/wash-out slopes, which enable quantification of the enhancement characteristics across different CE-MR phases. These markers were subsequently processed using a two-stages random forest-based classifier to classify the liver tumor as benign, intermediate, or malignant and determine the corresponding grade (LR1, LR2, LR3, LR4, or LR5). The overall CAD system using all the identified imaging markers achieved a sensitivity of 91.8%±0.9%, specificity of 91.2%±1.9%, and F[Formula: see text] score of 0.91±0.01, using the leave-one-subject-out (LOSO) cross-validation approach. Importantly, the CAD system achieved overall accuracies of [Formula: see text], 85%±2%, 78%±3%, 83%±4%, and 79%±3% in grading liver tumors into LR1, LR2, LR3, LR4, and LR5, respectively. In addition to LOSO, the developed CAD system was tested using randomly stratified 10-fold and 5-fold cross-validation approaches. Alternative classification algorithms, including support vector machine, naive Bayes classifier, k-nearest neighbors, and linear discriminant analysis all produced inferior results compared to the proposed two stage random forest classification model. These experiments demonstrate the feasibility of the proposed CAD system as a novel tool to objectively assess liver tumors based on the new comprehensive imaging markers. The identified imaging markers and CAD system can be used as a non-invasive diagnostic tool for early and accurate detection and grading of liver cancer.

In the US, the most significant morbidity and mortality associated with non-valvular atrial fibrillation (NVAF) is embolic stroke, with 90% of thrombus originating from the left atrial appendage (LAA). Anticoagulation is the preferred treatment for the prevention of stroke in NVAF patients, but clinical studies have demonstrated high levels of non-compliance and increased risk of bleeding or ineligibility for anticoagulation therapy, especially in the elderly population where the incidence of NVAF is highest. Alternatively, stroke may be preventing using clinically approved surgical and catheter-based devices to exclude or occlude the LAA, but these devices continue to be plagued by peri-device leaks and thrombus formation because of residual volume. To overcome these limitations, Cor Habere (Louisville, KY) and the University of Louisville are developing a LAA closure device (StrokeShield) that completely occludes and collapses the LAA to minimize the risk of stroke. The StrokeShield device is a collapsible occluder (nitinol reinforced membrane) that completely covers the LAA orifice with an expandable conical coil anchor that attaches to the myocardium. The device is designed for catheter-based delivery and expands to completely occlude the LAA orifice and collapse the LAA. The primary advantages of the StrokeShield system are a completely sealed LAA (no peri-device flow or residual space) and smooth endothelialized connection to the left atrial wall with minimal risk of cardiac bleeding and tamponade. We tested proof-of-concept of a prototype StrokeShield device in acute (n = 2) and chronic 60-day (n = 2) healthy canine models. Acute results demonstrated that the conical coil securely attached to the myocardium (5N pull-out force) and the Nitinol umbrella fully deployed and covered the LAA ostium. Results from the chronic implants demonstrated long-term feasibility of device placement with no procedural or device-related intra- or post-operative complications, secure placement and correct positioning of the device with no device migration. The device successfully occluded the LAA ostium and collapsed the LAA with no interference with the mitral valve, circumflex coronary artery, or pulmonary veins. Necropsy demonstrated no gross signs of thrombus or end-organ damage and the device was encapsulated in the LAA. Histology demonstrated mature neointima covering the device with expected foreign body inflammatory response. These early positive results will help to guide the iterative design process for the continued development of the StrokeShield system., Competing Interests: Financial • Two US patents awarded related to the research presented in this manuscript, and a third University of Louisville (UofL) invention disclosure was filed February 1, 2021, but is not presented in this manuscript Slaughter MS, Giridharan GA, Sobieski MA, Soucy KG, and Koenig SC. Atrial appendage closure device and related methods (US Patent 10,531,878 awarded January 14, 2020) Slaughter MS, Giridharan GA, Sobieski MA, Soucy KG, and Koenig SC. Atrial appendage closure device and related methods (US Patent 10,898,202 awarded January 26, 2021) Slaughter MS, Monreal G, Koenig SC, Jimenez J, Tompkins L. Left Atrial Appendage (LAA) device, delivery tool, and related methods (UofL Invention Disclosure no. 21038, filed February 1, 2021) • Research presented in this manuscript was funded as an internal project subaward (PI: Guruprasad Giridharan) from a 5-yr Coulter Foundation grant awarded to University of Louisville (PIs: Robert Keynton, PhD and Mark Slaughter, MD) • Co-authors Jimenez, Koenig, Slaughter are co-founders of Cor Habere (Louisville KY), and are continuing the research and development of the StrokeShield system (LAA device) presented in this manuscript. Note: Cor Habere was founded after the research and development presented in this manuscript had been completed. • Cor Habere was awarded a NIH SBIR phase I grant (R43HL142337-01) to continue development of the StrokeShield system (LAA device, delivery tool) but none of the work supported by the SBIR phase I grant is presented in this manuscript. Co-authors (Giridharan, Koenig, Slaughter) were awarded US Patent 10,531,878 (January 14, 2020) and US Patent 10,898,202 (January 26, 2021). All of the co-authors are continuing with the development of the StrokeShield device and are listed as co-inventors on our recent UofL invention disclosure (no. 21038, filed Feb 1, 2021) and co-investigators of NIH SBIR phase I grant (R43HL142337-01, awarded Sep 30, 2019). This information does NOT alter our adherence to PLOS ONE policies on sharing data and materials.

The primary goal of this manuscript is to develop a computer assisted diagnostic (CAD) system to assess pulmonary function and risk of mortality in patients with coronavirus disease 2019 (COVID-19). The CAD system processes chest X-ray data and provides accurate, objective imaging markers to assist in the determination of patients with a higher risk of death and thus are more likely to require mechanical ventilation and/or more intensive clinical care.To obtain an accurate stochastic model that has the ability to detect the severity of lung infection, we develop a second-order Markov-Gibbs random field (MGRF) invariant under rigid transformation (translation or rotation of the image) as well as scale (i.e., pixel size). The parameters of the MGRF model are learned automatically, given a training set of X-ray images with affected lung regions labeled. An X-ray input to the system undergoes pre-processing to correct for non-uniformity of illumination and to delimit the boundary of the lung, using either a fully-automated segmentation routine or manual delineation provided by the radiologist, prior to the diagnosis. The steps of the proposed methodology are: (i) estimate the Gibbs energy at several different radii to describe the inhomogeneity in lung infection; (ii) compute the cumulative distribution function (CDF) as a new representation to describe the local inhomogeneity in the infected region of lung; and (iii) input the CDFs to a new neural network-based fusion system to determine whether the severity of lung infection is low or high. This approach is tested on 200 clinical X-rays from 200 COVID-19 positive patients, 100 of whom died and 100 who recovered using multiple training/testing processes including leave-one-subject-out (LOSO), tenfold, fourfold, and twofold cross-validation tests. The Gibbs energy for lung pathology was estimated at three concentric rings of increasing radii. The accuracy and Dice similarity coefficient (DSC) of the system steadily improved as the radius increased. The overall CAD system combined the estimated Gibbs energy information from all radii and achieved a sensitivity, specificity, accuracy, and DSC of 100%, 97% ± 3%, 98% ± 2%, and 98% ± 2%, respectively, by twofold cross validation. Alternative classification algorithms, including support vector machine, random forest, naive Bayes classifier, K-nearest neighbors, and decision trees all produced inferior results compared to the proposed neural network used in this CAD system. The experiments demonstrate the feasibility of the proposed system as a novel tool to objectively assess disease severity and predict mortality in COVID-19 patients. The proposed tool can assist physicians to determine which patients might require more intensive clinical care, such a mechanical respiratory support.

The limited availability of human heart tissue and its complex cell composition are major limiting factors for the reliable testing of drug efficacy and toxicity. Recently, we developed functional human and pig heart slice biomimetic culture systems that preserve the viability and functionality of 300 μm heart slices for up to 6 days. Here, we tested the reliability of this culture system for testing the cardiotoxicity of anti-cancer drugs. We tested three anti-cancer drugs (doxorubicin, trastuzumab, and sunitinib) with known different mechanisms of cardiotoxicity at three concentrations and assessed the effect of these drugs on heart slice viability, structure, function and gene expression. Slices incubated with any of these drugs for 48 h showed diminished in viability as well as loss of cardiomyocyte structure and function. Mechanistically, RNA sequencing of doxorubicin-treated tissues demonstrated a significant downregulation of cardiac genes and upregulation of oxidative stress responses. Trastuzumab treatment downregulated cardiac muscle contraction-related genes consistent with its clinically known effect on cardiomyocytes. Interestingly, sunitinib treatment resulted in significant downregulation of angiogenesis-related genes, in line with its mechanism of action. Similar to hiPS-derived-cardiomyocytes, heart slices recapitulated the expected toxicity of doxorubicin and trastuzumab, however, slices were superior in detecting sunitinib cardiotoxicity and mechanism in the clinically relevant concentration range of 0.1-1 μM. These results indicate that heart slice culture models have the potential to become a reliable platform for testing and elucidating mechanisms of drug cardiotoxicity., Competing Interests: Declaration of Competing Interest TMAM, holds equities in Tenaya Therapeutics. GAG, is consultant for NuPulseCV. The other authors report no conflicts., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cardiac magnetic resonance (MR) imaging is one of the most rigorous form of imaging to assess cardiac function in vivo. Strain analysis allows comprehensive assessment of diastolic myocardial function, which is not indicated by measuring systolic functional parameters using with a normal cine imaging module. Due to the small heart size in mice, it is not possible to perform proper tagged imaging to assess strain. Here, we developed a novel deep learning approach for automated quantification of strain from cardiac cine MR images. Our framework starts by an accurate localization of the LV blood pool center-point using a fully convolutional neural network (FCN) architecture. Then, a region of interest (ROI) that contains the LV is extracted from all heart sections. The extracted ROIs are used for the segmentation of the LV cavity and myocardium via a novel FCN architecture. For strain analysis, we developed a Laplace-based approach to track the LV wall points by solving the Laplace equation between the LV contours of each two successive image frames over the cardiac cycle. Following tracking, the strain estimation is performed using the Lagrangian-based approach. This new automated system for strain analysis was validated by comparing the outcome of these analysis with the tagged MR images from the same mice. There were no significant differences between the strain data obtained from our algorithm using cine compared to tagged MR imaging. Furthermore, we demonstrated that our new algorithm can determine the strain differences between normal and diseased hearts.

Objective: Fontan circulatory inefficiency can be addressed by replacing the missing subpulmonary power source to reverse the Fontan paradox. An implantable cavopulmonary assist device is described that will simultaneously reduce systemic venous pressure and increase pulmonary arterial pressure, improving preload and cardiac output, in a univentricular Fontan circulation on a long-term basis., Methods: A rotary blood pump that was based on the von Karman viscous pump was designed for implantation into the total cavopulmonary connection (TCPC). It will impart modest pressure energy to augment Fontan flow without risk of obstruction. In the event of rotational failure, it is designed to default to a passive flow diverter. Pressure-flow performance was characterized in vitro in a Fontan mock circulatory loop with blood analog., Results: The pump performed through the fully specified operating range, augmenting flow in all 4 directions of the TCPC. Pressure rise of 6 to 8 mm Hg was readily achieved, ranging to 14 mm Hg at highest speed (5600 rpm). Performance was consistent across a wide range of cardiac outputs. In stalled condition (0 rpm), there was no discernible pressure loss across the TCPC., Conclusions: A blood pump technology is described that can reverse the Fontan paradox and may permit a surgical strategy of long-term biventricular maintenance of a univentricular Fontan circulation. The technology is intended for Fontan failure in which right-sided circulatory inefficiencies predominate and ventricular systolic function is preserved. It may also apply before clinical Fontan failure as health maintenance to preempt the progression of Fontan disease., (Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Continuous-flow ventricular assist devices (CF-VADs) produce non-physiologic flow with diminished pulsatility, which is a major risk factor for development of adverse events, including gastrointestinal (GI) bleeding and arteriovenous malformations (AVMs). Introduction of artificial pulsatility by modulating CF-VAD flow has been suggested as a potential solution. However, the levels of pulsatility and frequency of CF-VAD modulation necessary to prevent adverse events are currently unknown and need to be evaluated., Methods: The purpose of this study was to use human aortic endothelial cells (HAECs) cultured within an endothelial cell culture model (ECCM) to: (i) identify and validate biomarkers to determine the effects of pulsatility; and (ii) conclude whether introduction of artificial pulsatility using flow-modulation approaches can mitigate changes in endothelial cells seen with diminished pulsatile flow. Nuclear factor erythroid 2-related factor 2 (Nrf-2)-regulated anti-oxidant genes and proteins and the endothelial nitric oxide synthase/endothelin-1 (eNOS/ET-1) signaling pathway are known to be differentially regulated in response to changes in pulsatility., Results: Comparison of HAECs cultured within the ECCM (normal pulsatile vs CF-VAD) with aortic wall samples from patients (normal pulsatile [n = 5] vs CF-VADs [n = 5]) confirmed that both the Nrf-2-activated anti-oxidant response and eNOS/ET-1 signaling pathways were differentially regulated in response to diminished pulsatility. Evaluation of 2 specific CF-VAD flow-modulation protocols to introduce artificial pulsatility, synchronous (SYN, 80 cycles/min, pulse pressure 20 mm Hg) and asynchronous (ASYN, 40 cycles/min, pulse pressure 45 mm Hg), suggested that both increased expression of Nrf-2-regulated anti-oxidant genes and proteins along with changes in levels of eNOS and ET-1 can potentially be minimized with ASYN and, to a lesser extent, with SYN., Conclusions: HAECs cultured within the ECCM can be used as an accurate model of large vessels in patients to identify biomarkers and select appropriate flow-modulation protocols. Pressure amplitude may have a greater effect in normalizing anti-oxidant response compared with frequency of modulation., (Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Modulation of pump speed has been proposed and implemented clinically to improve vascular pulsatility in continuous flow ventricular assist device patient. The flow dynamics of the HVAD with a promising asynchronous pump speed modulation and its potential risk for device-induced blood trauma was investigated numerically. The boundary conditions at the pump inlet and outlet were defined using the pressure waveforms adapted from the experimentally recorded ventricular and arterial pressure waveforms in a large animal ischemic heart failure (IHF) model supported by the HVAD operated at constant and modulated pump speeds. Shear stress fields and hemolysis indices were derived from the simulated flow fields. The overall features of the computationally generated flow waveforms at simulated constant and pulse-modulated speed operations matched with those of the experimentally recorded flow waveforms. The simulations showed that the shear stress field and hemolysis index vary throughout the cardiac cycle under the constant speed operation, and also as a function of modulation profile under modulated speed operation. The computational model did not demonstrate any differences in the time average hemolysis index between constant and modulated pump speed operations, thereby predicting pulse-modulated speed operation may help to restore vascular pulsatility without any further increased risk of blood trauma. Graphical abstract The streamline inside the HVAD pump and the wall shear stress distribution on the impeller surface at six discrete time instants over one cardiac cycle under constant speed operation (3000 rpm) (a) and under pulse-modulated speed operation (b). c Computationally predicted flow rate waveform under pulse-modulated speed operation. d Computationally predicted time-varying HI generated by the HVAD pump under the two operation modes constant speed (dash line) and pulse-modulated speed (solid line). These figures indicate that the pulse-modulated speed operation may help to restore vascular pulsatility without any further increased risk of blood trauma.

Rotary biventricular assist devices (BiVAD) are becoming a clinically accepted treatment option for end-stage biventricular failure. To improve BiVAD efficacy and safety, we propose a control algorithm to achieve the clinical objectives of maintaining left-right-sided balance, restoring physiologic flows, and preventing ventricular suction. The control algorithm consists of two proportional-integral (PI) controllers for left and right ventricular assist devices (LVAD and RVAD) to maintain differential pump pressure across LVAD (ΔPL) and RVAD (ΔPR) to provide left-right balance and physiologic flow. To prevent ventricular suction, LVAD and RVAD pump speed differentials (ΔRPML, ΔRPMR) were maintained above user-defined thresholds. Efficacy and robustness of the proposed algorithm were tested in silico for axial and centrifugal flow BiVAD using 1) normal and excessive ΔPL and/or ΔPR setpoints, 2) rapid threefold increase in pulmonary vascular or vena caval resistances, 3) transient responses from exercise to rest, and 4) ventricular fibrillation. The study successfully demonstrated that the proposed BiVAD algorithm achieved the clinical objectives but required pressure sensors to continuously measure ΔPL and ΔPR. The proposed control algorithm is device independent, should not require any modifications to the pump or inflow/outflow cannulae/grafts, and may be directly applied to current rotary blood pumps for biventricular support.

In this study, the flow features and device-associated blood trauma in 4 clinical ventricular assist devices (VADs; 2 implantable axial VADs, 1 implantable centrifugal VAD, and 1 extracorporeal VAD) were computationally analyzed under clinically relevant pulsatile flow conditions. The 4 VADs were operated at fixed pump speed at a mean rate of 4.5 L/min. Mean pressure difference, wall shear stress, volume distribution of scalar shear stress (SSS), and shear-induced hemolysis index (HI) were derived from the flow field of each VAD and were compared. The computationally predicted mean pressure difference across the 3 implantable VADs was ~70 mmHg, and the extracorporeal VAD was ~345 mmHg, which matched well with their reported pressure-flow curves. The axial VADs had higher mean wall shear stress and SSS compared with the centrifugal VADs. However, the residence time of the centrifugal VADs was much longer compared with the axial VADs because of the large volume of the centrifugal VADs. The highest SSS was observed in one axial VAD, and the longest exposure time was observed in 1 centrifugal VAD. These 2 VADs generated the highest HI. The shear-induced HI varied as a function of flow rate within each cardiac cycle. At fixed pump speed, the HI was greatest at low flow rate due to longer exposure time to shear stress compared with at high flow rate. Subsequently, we hypothesize that to reduce the risk of blood trauma during VAD support, shear stress magnitude and exposure time need to be minimized., (Copyright © 2017 John Wiley & Sons, Ltd.)

Mechanical circulatory support (MCS) devices have become a standard therapy for heart failure (HF) patients. MCS device designs may differ by level of support, inflow and/or outflow cannulation sites, and mechanism(s) of cardiac unloading and blood flow delivery. Investigation and direct comparison of hemodynamic parameters that help characterize performance of MCS devices has been limited. We quantified cardiac and vascular hemodynamic responses for different types of MCS devices. Continuous flow (CF) left ventricular (LV) assist devices (LVAD) with LV or left atrial (LA) inlet, counterpulsation devices, percutaneous CF LVAD, and intra-aortic rotary blood pumps (IARBP) were quantified using established computer simulation and mock flow loop models. Hemodynamic data were analyzed on a beat-to-beat basis at baseline HF and over a range of MCS support. Results demonstrated that all LVAD greatly diminished vascular pulsatility (P) and LV external work (LVEW). LVAD with LA inflow provided a greater reduction in LVEW compared to LVAD with LV inflow, but at the potential risk for blood stasis/thrombosis in the LV at high support. Counterpulsation provided greater coronary flow (CoF) augmentation, but had a lower reduction in LVEW compared to partial percutaneous LVAD support. IARBP diminished LVEW, but at the expense of diminished CoF due to coronary steal. The hemodynamic benefits for each type of mechanical circulatory support system are unique and clinical decisions on device selection to maximize end organ perfusion and minimize invasiveness needs to be considered for an individual patients' presentation.

Continuous-flow left ventricular assist devices (CF LVADs) are rotary blood pumps that improve mean blood flow, but with potential limitations of non-physiological ventricular volume unloading and diminished vascular pulsatility. In this study, we tested the hypothesis that left ventricular unloading with increasing CF LVAD flow increases myocardial flow normalized to left ventricular work. Healthy (n = 8) and chronic ischemic heart failure (IHF, n = 7) calves were implanted with CF LVADs. Acute hemodynamics and regional myocardial blood flow were measured during baseline (LVAD off, clamped), partial (2-4 L/min) and full (>4 L/min) LVAD support. IHF calves demonstrated greater reduction of cardiac energy demand with increasing LVAD support compared to healthy calves, as calculated by rate-pressure product. Coronary artery flows (p < 0.05) and myocardial blood flow (left ventricle (LV) epicardium and myocardium, p < 0.05) decreased with increasing LVAD support in normal calves. In the IHF model, blood flow to the septum, LV, LV epicardium, and LV myocardium increased significantly with increasing LVAD support when normalized to cardiac energy demand (p < 0.05). In conclusion, myocardial blood flow relative to cardiac demand significantly increased in IHF calves, thereby demonstrating that CF LVAD unloading effectively improves cardiac supply and demand ratio in the setting of ischemic heart failure.

Counterpulsation devices (CPDs) require an accurate, reliable electrocardiogram (ECG) waveform for triggering inflation and deflation. Surface electrodes are for short-term use, and transvenous/epicardial leads require invasive implant procedure. A subcutaneous ECG lead configuration was developed as an alternative approach for long-term use with timing mechanical circulatory support (MCS) devices. In this study, efficacy testing was completed by simultaneously recording ECG waveforms from clinical-grade epicardial (control) and subcutaneous (test) leads in chronic ischemic heart failure calves implanted with CPD for up to 30 days. Sensitivity and specificity of CPD triggering by R-wave detection was quantified for each lead configuration. The subcutaneous leads provided 98.9% positive predictive value and 98.9% sensitivity compared to the epicardial ECG leads. Lead migration (n = 1) and fracture (n = 1) were observed in only 2 of 40 implanted leads, without adversely impacting triggering efficacy due to lead redundancy. These findings demonstrate the efficacy of subcutaneous ECG leads for long-term CPD timing and potential use as an alternative method for MCS device timing.

Continuous flow (CF) left ventricular assist devices (LVAD) diminish vascular pressure pulsatility, which may be associated with clinically reported adverse events including gastrointestinal bleeding, aortic valve insufficiency, and hemorrhagic stroke. Three candidate CF LVAD pump speed modulation algorithms designed to augment aortic pulsatility were evaluated in mock flow loop and ischemic heart failure (IHF) bovine models by quantifying hemodynamic performance as a function of mean pump speed, modulation amplitude, and timing. Asynchronous and synchronous copulsation (high revolutions per minute [RPM] during systole, low RPM during diastole) and counterpulsation (low RPM during systole, high RPM during diastole) algorithms were tested for defined modulation amplitudes (±300, ±500, ±800, and ±1,100 RPM) and frequencies (18.75, 37.5, and 60 cycles/minute) at low (2,900 RPM) and high (3,200 RPM) mean LVAD speeds. In the mock flow loop model, asynchronous, synchronous copulsation, and synchronous counterpulsation algorithms each increased pulse pressure (ΔP = 931%, 210%, and 98% and reduced left ventricular external work (LVEW = 20%, 22%, 16%). Similar improvements in vascular pulsatility (1,142%) and LVEW (40%) were observed in the IHF bovine model. Asynchronous modulation produces the largest vascular pulsatility with the advantage of not requiring sensor(s) for timing pump speed modulation, facilitating potential clinical implementation.

Background: Ex vivo lung perfusion (EVLP) has the potential to increase the donor pool for lung transplantation by facilitating resuscitation and extended evaluation of marginal organs. Current EVLP methodology employs continuous flow (CF) pumps that produce non-pulsatile EVLP hemodynamics. In this feasibility study, we tested the hypothesis that a pulsatile flow (PF) pump will provide better EVLP support than a CF pump through delivery of physiologic hemodynamics., Methods: Porcine lungs were supported in an EVLP model by centrifugal CF (n = 3) or PF (n = 4) left ventricular assist devices. Lungs were ventilated at 4 to 5 mL/kg, 0.21 fraction of inspired oxygen (FiO2), and perfused with an acellular, albumin-based solution corrected for osmolarity, acid-base balance, and carbon dioxide pressure (≤20 hours at 30°C) for a minimum of 12 hours support. Prostaglandin E1 and 30% albumin were infused continuously. Hemodynamic, respiratory, and blood gas parameters were continuously monitored and digitally recorded hourly. Parenchymal biopsies were used for quantification of wet to dry weight ratio., Results: All lungs maintained function in the EVLP circuit for a minimum of 12 hours (mean 14.7 ± 1 hours) and demonstrated minimal edema formation. The PF EVLP produced higher pulsatility as demonstrated by greater energy equivalent pressure and surplus hemodynamic energy compared with CF EVLP (p < 0.05). There were no statistically significant differences in pulmonary impedance, arterial partial pressure of oxygen/fraction of inspired oxygen, wet to dry weight ratio, and peak airway pressure between CF and PF EVLP., Conclusions: The CF and PF EVLP systems successfully maintained lungs 12+ hours using a modified Steen perfusate (XVIVO Perfusion, Inc, Goteborg, Sweden); however, there were no statistically significant differences between CF and PF groups despite higher pulsatility, suggesting that PF may not offer immediate benefits over CF for prolonged ex vivo lung preservation., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

In the event of left ventricular assist device (LVAD) failure, we hypothesized that rotary blood pumps will experience significant retrograde flow and induce adverse physiologic responses. Catastrophic LVAD failure was investigated in computer simulation with pulsatile, axial, and centrifugal LVAD, mock flow loop with pulsatile (PVAD) and centrifugal (ROTAFLOW), and healthy and chronic ischemic heart failure bovine models with pulsatile (PVAD), axial (HeartMate II), and centrifugal (HVAD) pumps. Simulated conditions were LVAD "off" with outflow graft clamped (baseline), LVAD "off" with outflow graft unclamped (LVAD failure), and LVAD "on" (5 L/min). Hemodynamics (aortic and ventricular blood pressures, LVAD flow, and left ventricular volume), echocardiography (cardiac volumes), and end-organ perfusion (regional blood flow microspheres) were measured and analyzed. Retrograde flow was observed with axial and centrifugal rotary pumps during LVAD failure in computer simulation (axial = -3.4 L/min, centrifugal = -2.8 L/min), mock circulation (pulsatile = -0.1 L/min, centrifugal = -2.7 L/min), healthy (pulsatile = -1.2 ± 0.3 L/min, axial = -2.2 ± 0.2 L/min, centrifugal = -1.9 ± 0.3 L/min), and ischemic heart failure (centrifugal = 2.2 ± 0.7 L/min) bovine models for all test conditions (p < 0.05). Differences between axial and centrifugal LVAD were statistically indiscernible. Retrograde flow increased ventricular end-systolic and end-diastolic volumes and workload, and decreased myocardial and end-organ perfusion during LVAD failure compared with baseline, LVAD support, and pulsatile LVAD failure.

Axial (AX) and centrifugal (CFG) rotary blood pumps have gained clinical acceptance for the treatment of advanced heart failure. Differences between AX and CFG designs and mechanism of blood flow delivery may offer clinical advantages. In this study, pump characteristics, and acute physiologic responses during support with AX (HeartMate II) and CFG (HVAD) left ventricular assist devices (LVAD) were investigated in mock loop and chronic ischemic heart failure bovine models. In the mock loop model, pump performance was characterized over a range of pump speeds (HeartMate II: 7,000-11,000 rpm, HVAD: 2,000-3,600 rpm) and fluid viscosities (2.7 cP, 3.2 cP, 3.7 cP). In the ischemic heart failure bovine model, hemodynamics, echocardiography, and end-organ perfusion were investigated. CFG LVAD had a flatter HQ curve, required less power, and had a more linear flow estimation relation than AX LVAD. The flow estimation error for the AX LVAD (±0.9 L/min at 2.7 cP, ±0.7 L/min at 3.2 cP, ±0.8 L/min at 3.7 cP) was higher than the CFG LVAD (±0.5 L/min at 2.7 cP, ±0.2 L/min at 3.2 cP, ±0.5 L/min at 3.7 cP). No differences in acute hemodynamics, echocardiography, or end-organ perfusion between AX and CFG LVAD over a wide range of support were statistically discernible. These findings suggest no pronounced acute differences in LV volume unloading between AX and CFG LVAD.

The risk for left ventricular (LV) suction during left ventricular assist devices (LVAD) support has been a clinical concern. Current development efforts suggest LVAD suction prevention and physiologic control algorithms may require chronic implantation of pressure or flow sensors, which can be unreliable because of baseline drift and short lifespan. To overcome this limitation, we designed a sensorless suction prevention and physiologic control (eSPPC) algorithm that only requires LVAD intrinsic parameters (pump speed and power). Two gain-scheduled, proportional-integral controllers maintain a differential pump speed (ΔRPM) above a user-defined threshold to prevent LV suction while maintaining an average reference differential pressure (ΔP) between the LV and aorta. ΔRPM is calculated from noisy pump speed measurements that are low-pass filtered, and ΔP is estimated using an extended Kalman filter. Efficacy and robustness of the eSPPC algorithm were evaluated in silico during simulated rest and exercise test conditions for 1) excessive ΔP setpoint (ES); 2) rapid eightfold increase in pulmonary vascular resistance (PVR); and 3) ES and PVR. Simulated hemodynamic waveforms (LV pressure and volume; aortic pressure and flow) using only intrinsic pump parameters showed the feasibility of our proposed eSPPC algorithm in preventing LV suction for all test conditions.

Myocardial recovery with left ventricular assist device (LVAD) support is uncommon and unpredictable. We tested the hypothesis that injectable particulate extracellular matrix (P-ECM) with LVAD support promotes cell proliferation and improves cardiac function. LVAD, P-ECM, and P-ECM + LVAD therapies were investigated in chronic ischemic heart failure (IHF) calves induced using coronary embolization. Particulate extracellular matrix emulsion (CorMatrix, Roswell, GA) was injected intramyocardially using a 7 needle pneumatic delivery tool. Left ventricular assist devices (HVAD, HeartWare) were implanted in a left ventricle (LV) apex to proximal descending aorta configuration. Cell proliferation was identified using BrdU (5 mg/kg) injections over the last 45 treatment days. Echocardiography was performed weekly. End-organ regional blood flow (RBF) was quantified at study endpoints using fluorescently labeled microspheres. Before treatment, IHF calves had an ejection fraction (EF) of 33 ± 2% and left ventricular end-diastolic volume of 214 ± 18 ml with cardiac cachexia (0.69 ± 0.06 kg/day). Healthy weight gain was restored in all groups (0.89 ± 0.03 kg/day). EF increased with P-ECM + HVAD from 36 ± 5% to 75 ± 2%, HVAD 38 ± 4% to 58 ± 5%, and P-ECM 27 ± 1% to 66 ± 6%. P-ECM + HVAD demonstrated the largest increase in cell proliferation and end-organ RBF. This study demonstrates the feasibility of combined LVAD support with P-ECM injection to stimulate new cell proliferation and improve cardiac function, which warrants further investigation.

Hemodynamic mechanical cues play a critical role in the early development and functional maturation of cardiomyocytes (CM). Therefore, tissue engineering approaches that incorporate immature CM into functional cardiac tissues capable of recovering or replacing damaged cardiac muscle require physiologically relevant environments to provide the appropriate mechanical cues. The goal of this work is to better understand the subcellular responses of immature cardiomyocytes using an in vitro cardiac cell culture model that realistically mimics in vivo mechanical conditions, including cyclical fluid flows, chamber pressures, and tissue strains that could be experienced by implanted cardiac tissues. Cardiomyocytes were cultured in a novel microfluidic cardiac cell culture model (CCCM) to achieve accurate replication of the mechanical cues experienced by ventricular CM. Day 10 chick embryonic ventricular CM (3.5 × 10(4) cell clusters per cell chamber) were cultured for 4 days in the CCCM under cyclic mechanical stimulation (10 mmHg, 8-15% stretch, 2 Hz frequency) and ventricular cells from the same embryo were cultured in a static condition for 4 days as controls. Additionally, ventricular cell suspensions and ventricular tissue from day 16 chick embryo were collected and analyzed for comparison with CCCM cultured CM. The gene expressions and protein synthesis of calcium handling proteins decreased significantly during the isolation process. Mechanical stimulation of the cultured CM using the CCCM resulted in an augmentation of gene expression and protein synthesis of calcium handling proteins compared to the 2D constructs cultured in the static conditions. Further, the CCCM conditioned 2D constructs have a higher beat rate and contractility response to isoproterenol. These results demonstrate that early mechanical stimulation of embryonic cardiac tissue is necessary for tissue proliferation and for protein synthesis of the calcium handling constituents required for tissue contractility. Thus, physiologic mechanical conditioning may be essential for generating functional cardiac patches for replacement of injured cardiac tissue.

Background: Rotary blood pumps operate at a constant speed (rpm) that diminishes vascular pulsatility and variation in ventricular end-systolic and end-diastolic volumes, which may contribute to adverse events, including aortic insufficiency and gastrointestinal bleeding. In this study, pump speed modulation algorithms for generating pulsatility and variation in ventricular end-systolic and end-diastolic volumes were investigated in an ischemic heart failure (IHF) bovine model (n = 10) using a clinically implanted centrifugal-flow left ventricular assist device (LVAD)., Methods: Hemodynamic and hematologic measurements were recorded during IHF baseline, constant pumps speeds, and asynchronous (19-60 cycles/min) and synchronous (copulse and counterpulse) pump speed modulation profiles using low relative pulse speed (±25%) of 3,200 ± 800 rpm and high relative pulse speed (±38%) of 2,900 ± 1,100 rpm. End-organ perfusion, hemodynamics, and pump parameters were measured to characterize pulsatility, myocardial workload, and LVAD performance for each speed modulation profile., Results: Speed modulation profiles augmented aortic pulse pressure, surplus hemodynamic energy, and end-organ perfusion (p < 0.01) compared with operation at constant speed. Left ventricular external work and myocardial oxygen consumption were significantly reduced compared with IHF baseline (p < 0.01) but at the expense of higher LVAD power consumption., Conclusions: Pump speed modulation increases pulsatility and improves cardiac function and end-organ perfusion, but the asynchronous mode provides the technologic advantage of sensorless control. Investigation of asynchronous pump speed modulation during long-term support is warranted to test the hypothesis that operating an LVAD with speed modulation will minimize adverse events in patients supported by an LVAD that may be associated with long-term operation at a constant pump speed., (Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

The risk for left ventricular (LV) suction while maintaining adequate perfusion over a range of physiologic conditions during continuous flow LV assist device (LVAD) support is a significant clinical concern. To address this challenge, we developed a suction prevention and physiologic control (SPPC) algorithm for use with axial and centrifugal LVADs. The SPPC algorithm uses two gain-scheduled, proportional-integral controllers that maintain a differential pump speed (ΔRPM) above a user-defined threshold to prevent LV suction, while maintaining an average reference differential pressure (ΔP) between the LV and aorta to provide physiologic perfusion. Efficacy and robustness of the proposed algorithm were evaluated in silico during simulated rest and exercise test conditions for (1) ΔP/ΔRPM excessive setpoint (ES); (2) rapid eightfold increase in pulmonary vascular resistance (PVR); and (3) ES and PVR. Hemodynamic waveforms (LV pressure and volume; aortic pressure and flow) were simulated and analyzed to identify suction event(s), quantify total flow output (pump + cardiac output), and characterize the performance of the SPPC algorithm. The results demonstrated that the proposed SPPC algorithm prevented LV suction while maintaining physiologic perfusion for all simulated test conditions, and warrants further investigation in vivo.

Type 2 diabetes significantly elevates the risk of cardiovascular disease. This can be largely attributed to the adverse effects of hyperglycemic conditions on normal endothelial cell (EC) function. ECs in both large and small vessels are influenced by hyperglycemic conditions, which increase susceptibility to EC dysfunction and atherosclerotic lesion formation. Fluid shear stress and flow patterns play an essential role in atherogenesis: lesions form only at locations where fluid flow behavior can be classified as "disturbed flow" (i.e., low shear stress recirculation and/or retrograde flow). Since regions of disturbed flow are the focal points of atherosclerotic cardiovascular disease, we hypothesized that the combinatorial effects of high glucose and disturbed flow conditions elicit significantly different responses from ECs than high glucose alone. To validate our hypothesis, we used our endothelial cell culture model (ECCM) to establish vascular niches associated with "normal" and "disturbed" flow conditions typically seen in vivo along with physiological pressure and stretch. We subjected human aortic endothelial cells (HAECs) to hyperglycemic conditions under both "normal" and "disturbed" flow. Our results confirm significant and quantifiable differences in phenotypic and functional markers between cells cultured under conditions of "normal" and "disturbed flow" under hyperglycemic conditions suggesting that elevated glucose in conjunction with "disturbed" flow conditions results in significantly higher level of EC dysfunction. The ECCM can therefore be used as a physiologically relevant model to study early stage hyperglycemia induced atherosclerosis for basic research, drug discovery, and screening and toxicity studies.

Biomaterials with direct intramyocardial injection devices have been developed and are being investigated as a potential cardiac regenerative therapy for end-stage ischemic heart failure. Decellularized extracellular matrix (ECM) has been shown to improve cardiac function and attenuate or reverse pathologic remodeling cascades. CorMatrix Cardiovascular, Inc. has developed a porcine small intestinal submucosa-derived particulate extracellular matrix (P-ECM) and ECM Delivery System to provide uniform and controlled intramyocardial delivery of the injectable P-ECM material into infarcted regions. The CorMatrix ECM Delivery System is composed of a Multi-Needle P-ECM Syringe Assembly, Automated Injection Controller, and Tissue Depth Measurement System (portable ultrasound). Feasibility of the P-ECM delivery system was tested intraoperatively in a chronic ischemic heart failure bovine model (n = 11), and demonstrated the ability to control injection volume (0.1-1.0 ml) and depth of penetration (3-5 mm) under regulated injection pressure (150 psi CO2) into the ischemic region. Targeted intramyocardial delivery of P-ECM may improve efficacy and enable development of novel patient-specific therapy.

Mechanical circulatory support--either ventricular assist device (VAD, left-sided systemic support) or cavopulmonary assist device (CPAD, right-sided support)--has been suggested as treatment for Fontan failure. The selection of left- versus right-sided support for failing Fontan has not been previously defined. Computer simulation and mock circulation models of pediatric Fontan patients (15-25 kg) with diastolic, systolic, and combined systolic and diastolic dysfunction were developed. The global circulatory response to assisted Fontan flow using VAD (HeartWare HVAD, Miami Lakes, FL) support, CPAD (Viscous Impeller Pump, Indianapolis, IN) support, and combined VAD and CPAD support was evaluated. Cavopulmonary assist improves failing Fontan circulation during diastolic dysfunction but preserved systolic function. In the presence of systolic dysfunction and elevated ventricular end-diastolic pressure (VEDP), VAD support augments cardiac output and diminishes VEDP, while increased preload with cavopulmonary assist may worsen circulatory status. Fontan circulation can be stabilized to biventricular values with modest cavopulmonary assist during diastolic dysfunction. Systemic VAD support may be preferable to maintain systemic output during systolic dysfunction. Both systemic and cavopulmonary support may provide best outcome during combined systolic and diastolic dysfunction. These findings may be useful to guide clinical cavopulmonary assist strategies in failing Fontan circulations.

APK Advanced Medical Technologies (Atlanta, GA) is developing a sutureless beating heart (SBH) left ventricular assist device (LVAD) connector system consisting of anchoring titanium coil, titanium cannula with integrated silicone hemostatic valve, coring and delivery tool, and LVAD locking mechanism to facilitate LVAD inflow surgical procedures. Feasibility testing was completed in human cadavers (n = 4) under simulated normal and hypertensive conditions using saline to observe seal quality in degraded human tissue and assess anatomic fit; acutely in ischemic heart failure bovine model (n = 2) to investigate short-term performance and ease of use; and chronically for 30 days in healthy calves (n = 2) implanted with HeartWare HVAD to evaluate performance and biocompatibility. Complete hemostasis was achieved in human cadavers and animals at LV pressures up to 170 mm Hg. In animals, off-pump (no cardiopulmonary bypass) anchoring of the connector was accomplished in less than 1 minute with no residual bleeding after full delivery and locking of the LVAD; and implant of connector and LVAD were successfully completed in under 10 minutes with total procedure blood loss less than 100 ml. In chronic animals before necropsy, no signs of leakage or disruption at the attachment site were observed at systolic LV pressures >200 mm Hg.

Implantation of ventricular assist devices (VADs) for the treatment of end-stage heart failure (HF) falls decidedly short of clinical demand, which exceeds 100,000 HF patients per year. Ventricular assist device implantation often requires major surgical intervention with associated risk of adverse events and long recovery periods. To address these limitations, HeartWare, Inc. has developed a platform of miniature ventricular devices with progressively reduced surgical invasiveness and innovative patient peripherals. One surgical implant concept is a transapical version of the miniaturized left ventricular assist device (MVAD). The HeartWare MVAD Pump is a small, continuous-flow, full-support device that has a displacement volume of 22 ml. A new cannula configuration has been developed for transapical implantation, where the outflow cannula is positioned across the aortic valve. The two primary objectives for this feasibility study were to evaluate anatomic fit and surgical approach and efficacy of the transapical MVAD configuration. Anatomic fit and surgical approach were demonstrated using human cadavers (n = 4). Efficacy was demonstrated in acute (n = 2) and chronic (n = 1) bovine model experiments and assessed by improvements in hemodynamics, biocompatibility, flow dynamics, and histopathology. Potential advantages of the MVAD Pump include flow support in the same direction as the native ventricle, elimination of cardiopulmonary bypass, and minimally invasive implantation.

In vivo preclinical testing of left ventricular assist devices (LVADs) warrants a large animal model that faithfully simulates human etiology. Although LVAD recipients are in end-stage heart failure (HF), healthy, young animals have served as the experimental platform for most LVAD research and development (R&D) to demonstrate device safety, reliability, and biocompatibility. The rapidly growing HF epidemic, donor heart shortage, and clinical acceptance of LVAD for bridge-to-transplant therapy (BTT) has led to the expanded role of LVAD for destination therapy and bridge-to-recovery therapy. New paradigms for the clinical care of these emerging patient populations are needed. Clinically relevant, robust, and reproducible large animal models of HF are required to demonstrate efficacy, investigate physiologic responses, elucidate genetic, molecular, and cellular mechanism(s), and develop LVAD control strategies. The animal model must be comparable in size, anatomical structure, and phenotype; the technique used to initiate HF must reflect the clinical portrait, should be technically and financially feasible, result in predictable, stable, and irreversible HF, and demonstrate bidirectionality of the remodeling cascade. In this review, large animal species commonly used in cardiac research, techniques used to create chronic HF, and the combined applicability to preclinical LVAD R&D studies are presented.

Ventricular assist devices (VADs) have emerged as a successful treatment option for advanced heart failure. The objective of this study was to develop a clinically relevant model of chronic ischemic cardiomyopathy to investigate functional, histological, and molecular changes during mechanical circulatory support. In calves (n = 17, 94 ± 7 kg), 90 μm microspheres were injected percutaneously into the left coronary artery. Serial echocardiography was performed weekly to evaluate cardiac function. Sixty days after coronary microembolization, a terminal study was performed via thoracotomy to measure hemodynamics. Regional myocardial and end-organ blood flows were quantified with 15-μm fluorescent-labeled microspheres. Myocardial fibrosis, myocyte size, and myocardial apoptosis were quantified with histological stains. Eleven animals survived coronary microembolization and exhibited clinical and statistically significant echocardiographic and hemodynamic signs of severe systolic dysfunction. Statistically significant decreases in regional myocardial blood flow and increases in myocardial fibrosis, myocyte size, total myocardial apoptosis, and cardiac myocyte-specific apoptosis were observed. End-organ hypoperfusion was observed. Coronary microembolization induced stable and reproducible chronic left ventricular failure in calves. The anatomical size and physiology of the bovine heart and thorax are appropriate to study novel interventions for the clinical management of heart failure. This model is an appropriate physiological substrate in which to test VAD and adjunctive biological therapies., (© 2013 Wiley Periodicals, Inc. and International Center for Artificial Organs and Transplantation.)

Ventricular assist devices (VADs) have been successfully used as a bridge to heart transplant and destination therapy (DT) for congestive heart failure (HF) patients. Recently, continuous flow VAD (CVAD) has emerged as an attractive clinical option for long-term mechanical support of HF patients, with bridge-to-transplant outcomes comparable with pulsatile flow VAD (PVAD). Continuous flow VADs are smaller, more reliable, and less complex than the first-generation PVAD. Despite the widespread clinical use, CVAD support has been associated with gastrointestinal bleeding, hemorrhagic strokes, and aortic valve insufficiency. Speculation that diminished arterial pressure pulsatility associated with continuous flow devices may be contributing to these complications has sparked much debate over CVAD support. Studies comparing pulsatile flow and continuous flow (CF) support have presented conflicting findings, and the relevance to CVAD as DT is uncertain due to variations in device operation, support duration, and the criteria used to quantify pulsatility. Currently, there is interest in developing control algorithms for CVAD to increase the delivered pulsatility as a strategy to mitigate adverse event risks associated with CVAD therapy. There may also be the added benefit of specific control strategies for managing CVAD therapy, potentially improving the rate of myocardial recovery and successful weaning of mechanical circulatory support.