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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: Accurate segmentation of retinal layers of the eye in 3D Optical Coherence Tomography (OCT) data provides relevant information for clinical diagnosis. This manuscript describes a 3D segmentation approach that uses an adaptive patient‐specific retinal atlas, as well as an appearance model for 3D OCT data. Methods: To reconstruct the atlas of 3D retinal scan, the central area of the macula (macula mid‐area) where the fovea could be clearly identified, was segmented initially. Markov Gibbs Random Field (MGRF) including intensity, spatial information, and shape of 12 retinal layers were used to segment the selected area of retinal fovea. A set of coregistered OCT scans that were gathered from 200 different individuals were used to build a 2D shape prior. This shape prior was adapted subsequently to the first order appearance and second order spatial interaction MGRF model. After segmenting the center of the macula "foveal area", the labels and appearances of the layers that were segmented were utilized to segment the adjacent slices. The final step was repeated recursively until a 3D OCT scan of the patient was segmented. Results: This approach was tested in 50 patients with normal and with ocular pathological conditions. The segmentation was compared to a manually segmented ground truth. The results were verified by clinical retinal experts. Dice Similarity Coefficient (DSC), 95% bidirectional modified Hausdorff Distance (HD), Unsigned Mean Surface Position Error (MSPE), and Average Volume Difference (AVD) metrics were used to quantify the performance of the proposed approach. The proposed approach was proved to be more accurate than the current state‐of‐the‐art 3D OCT approaches. Conclusions: The proposed approach has the advantage of segmenting all the 12 retinal layers rapidly and more accurately than current state‐of‐the‐art 3D OCT approaches. [ABSTRACT FROM AUTHOR]

Purpose: Early assessment of renal allograft function post‐transplantation is crucial to minimize and control allograft rejection. Biopsy — the gold standard — is used only as a last resort due to its invasiveness, high cost, adverse events (e.g., bleeding, infection, etc.), and the time for reporting. To overcome these limitations, a renal computer‐assisted diagnostic (Renal‐CAD) system was developed to assess kidney transplant function. Methods: The developed Renal‐CAD system integrates data collected from two image‐based sources and two clinical‐based sources to assess renal transplant function. The imaging sources were the apparent diffusion coefficients (ADCs) extracted from 47 diffusion‐weighted magnetic resonance imaging (DW‐MRI) scans at 11 different b‐values (b0, b50, b100,..., b1000 s/mm2), and the transverse relaxation rate (R2*) extracted from 30 blood oxygen level‐dependent MRI (BOLD‐MRI) scans at 5 different echo times (TEs = 2, 7, 12, 17, and 22 ms). Serum creatinine (SCr) and creatinine clearance (CrCl) were the clinical sources for kidney function evaluation. The Renal‐CAD system initially performed kidney segmentation using the level‐set method, followed by estimation of the ADCs from DW‐MRIs and the R2* from BOLD‐MRIs. ADCs and R2* estimates from 30 subjects that have both types of scans were integrated with their associated SCr and CrCl. The integrated biomarkers were then used as our discriminatory features to train and test a deep learning‐based classifier, namely stacked autoencoders (SAEs) to differentiate non‐rejection (NR) from acute rejection (AR) renal transplants. Results: Using a leave‐one‐subject‐out cross‐validation approach along with SAEs, the Renal‐CAD system demonstrated 93.3% accuracy, 90.0% sensitivity, and 95.0% specificity in differentiating AR from NR. Robustness of the Renal‐CAD system was also confirmed by the area under the curve value of 0.92. Using a stratified tenfold cross‐validation approach, the Renal‐CAD system demonstrated its reproducibility and robustness by a diagnostic accuracy of 86.7%, sensitivity of 80.0%, specificity of 90.0%, and AUC of 0.88. Conclusion: The obtained results demonstrate the feasibility and efficacy of accurate, noninvasive identification of AR at an early stage using the Renal‐CAD system. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Mechanical circulatory assist devices that provide temporary support in heart failure patients are needed to enable recovery or provide a bridge to decision. Minimizing risk of blood damage (i.e., hemolysis) with these devices is critical, especially if the length of support needs to be extended. Hematologic responses of the RotaFlow (Maquet) and CentriMag (Thoratec) temporary support devices were characterized in an in vitro feasibility study. Paired static mock flow loops primed with fresh bovine blood (700 mL, hematocrit [Hct] = 25 ± 3%, heparin titrated for activated clotting time >300 s) pooled from a single-source donor were used to test hematologic responses to RotaFlow ( n = 2) and CentriMag ( n = 2) simultaneously. Pump differential pressures, temperature, and flow were maintained at 250 ± 10 mm Hg, 25 ± 2°C, and 4.2 ± 0.25 L/min, respectively. Blood samples (3 mL) were collected at 0, 60, 120, 180, 240, 300, and 360 min after starting pumps in accordance with recommended Food and Drug Administration and American Society for Testing and Materials guidelines. The CentriMag operated at a higher average pump speed (3425 rpm) than the RotaFlow (3000 rpm) while maintaining similar constant flow rates (4.2 L/min). Hematologic indicators of blood trauma (hemoglobin, Hct, platelet count, plasma free hemoglobin, and white blood cell) for all measured time points as well as normalized and modified indices of hemolysis were similar (RotaFlow: normalized index of hemolysis [NIH] = 0.021 ± 0.003 g/100 L, modified index of hemolysis [MIH] = 3.28 ± 0.52 mg/mg compared to CentriMag: NIH = 0.041 ± 0.010 g/100 L, MIH = 6.08 ± 1.45 mg/mg). In this feasibility study, the blood trauma performance of the RotaFlow was similar or better than the CentriMag device under clinically equivalent, worst-case test conditions. The RotaFlow device may be a more cost-effective alternative to the CentriMag. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is increasing worldwide and represents a major burden in terms of health care resources and costs. Despite advances in medical care, prognosis with HF remains poor, especially in advanced stages. The large patient population with advanced HF and the limited number of donor organs stimulated the development of mechanical circulatory support (MCS) devices as a bridge to transplant and for destination therapy. However, MCS devices require a major operative intervention, cardiopulmonary bypass, and blood component exposure, which have been associated with significant adverse event rates, and long recovery periods. Miniaturization of MCS devices and the development of an efficient and reliable transcutaneous energy transfer system may provide the vehicle to overcome these limitations and usher in a new clinical paradigm in heart failure therapy by enabling less invasive beating heart surgical procedures for implantation, reduce cost, and improve patient outcomes and quality of life. Further, it is anticipated that future ventricular assist device technology will allow for a much wider application of the therapy in the treatment of heart failure including its use for myocardial recovery and as a platform for support for cell therapy in addition to permanent long-term support. [ABSTRACT FROM AUTHOR]

A counterpulsation device (Symphony) is being developed to provide long-term circulatory support for advanced heart failure (HF) patients. In acute animal experiments, flow waveform patterns in the aortic, carotid, and coronary arteries were compared during Symphony and intra-aortic balloon pump (IABP) support. Human data were examined for similarities. The 30-mL Symphony was compared to a 40-mL IABP in calves with cardiac dysfunction (80-100 kg, n = 8). Aortic pressures and aortic, carotid, and coronary artery flows were simultaneously recorded at baseline (devices off) and during 1:1 and 1:2 support. Forward, retrograde, and mean flows were calculated and compared for each test condition. Findings were also compared to aortic flow measurements recorded in HF patients ( n = 21) supported by 40-mL IABP. IABP caused significant retrograde flows in the aorta, coronary (IABP: −24 ± 8 mL/min, Symphony: −6 ± 2 mL/min, baseline: −2 ± 1 mL/min, P < 0.05), and carotid arteries (IABP: −30 ± 5 mL/min, Symphony: −0 ± 0 mL/min, baseline: −0 ± 0 L/min, P < 0.05) during ventricular systole compared to the Symphony. IABP support produced higher diastolic pressure and flow augmentation compared to Symphony. Due to retrograde flows during IABP support, Symphony provided higher overall coronary, carotid, and aortic flows. Similar reduction in total aortic flows due to retrograde flow was observed in HF patients during IABP support. Counterpulsation with an IABP via aortic volume displacement produces retrograde flows during rapid balloon deflation that reduces total flow. Counterpulsation with Symphony via volume removal eliminates retrograde flow and improves total flow more than that achieved with IABP. The Symphony may provide long-term hemodynamic benefits in HF patients. [ABSTRACT FROM AUTHOR]

The miniaturization of mechanical assist devices and less invasive implantation techniques may lead to earlier intervention in patients with heart failure. As such, we evaluated the effectiveness of a novel, minimally invasive, implantable counterpulsation device (CPD) in augmenting cardiac function during impaired hemodynamics. We compared the efficacy of a 32-mL stroke volume CPD with a standard 40-mL intra-aortic balloon pump (IABP) over a range of clinically relevant pathophysiological conditions. Male calves were instrumented via thoracotomy, the CPD was anastomosed to the left carotid artery, and the IABP was positioned in the descending aorta. Hemodynamic conditions of hypertension, hypotension, and heart failure were pharmacologically simulated and data were recorded during CPD and IABP support (off, 1:2, 1:1 modes) for each condition. In all three pathophysiological conditions, the CPD and IABP produced similar and statistically significant ( P < 0.05) increases in coronary artery blood flow normalized to the left ventricular (LV) workload. During hypotension and heart failure conditions, however, the CPD produced significantly greater reductions in LV workload and myocardial oxygen consumption as compared with the IABP. A novel 32-mL CPD connected to a peripheral artery produced equivalent or greater hemodynamic benefits than a standard 40-mL IABP during pharmacologically induced hypertension, hypotension, and heart failure conditions. [ABSTRACT FROM AUTHOR]

Implantable flow and pressure sensors, used to control rotary blood pumps, are unreliable in the long term. It is, therefore, desirable to develop a physiological control system that depends only on readily available measurements of the intrinsic pump parameters, such as measurements of the pump current, voltage, and speed (in revolutions per minute). A previously proposed Δ P control method of ventricular assist devices (VADs) requires the implantation of two pressure sensors to measure the pressure difference between the left ventricle and aorta. In this article, we propose a model-based method for estimating Δ P, which eliminates the need for implantable pressure sensors. The developed estimator consists of the extended Kalman filter in conjunction with the Golay–Savitzky filter. The performance of the combined estimator–VAD controller system was evaluated in computer simulations for a broad range of physical activities and varying cardiac conditions. The results show that there was no appreciable performance degradation of the estimator–controller system compared to the case when Δ P is measured directly. The proposed approach effectively utilizes a VAD as both a pump and a differential pressure sensor, thus eliminating the need for dedicated implantable pressure and flow sensors. The simulation results show that different pump designs may not be equally effective at playing a dual role of a flow actuator and Δ P sensor. [ABSTRACT FROM AUTHOR]

Although continuous flow (CF) and pulsatile flow (PF) ventricular assist devices (VADs) are being clinically used, their effects on aortic blood flow, as a measure of overall blood distribution, remain unclear. In acute VAD support animal experiments, our group has described a zone of turbulent mixing in the aortic arch. The objective of this study was to confirm this finding in the controlled setting of an adult mock circulation, simulating ventricular pathophysiologic states (normal and failing ventricle). CF and PF flow VADs were connected to ventricular apical inflow and ascending aorta (AA) or descending aorta (DA) outflow cannulae. Cardiovascular pressure and flow waveforms were recorded at varying levels of VAD bypass resulting in four test conditions: (i) CF-AA; (ii) CF-DA; (iii) PF-AA; and (iv) PF-DA. Confirming the animal data, no differences in mean aortic flow between CF and PF VADs were found, and significantly lower mean aortic arch flow with DA cannulation was noted. Mean aortic root flow decreased with increasing VAD bypass flow. As in the animal studies, despite similar mean flow rates, significant differences in waveform morphology were observed for AA and DA outflow graft locations and varying levels of VAD bypass. At 100% VAD support in the failing heart, PF restored waveform pulsatility to normal baseline while CF resulted in little pulsatility. These results confirm our earlier findings in the animal model, suggesting that outflow graft location may have a significant effect on aortic blood flow distribution. The long-term implications of these findings are being examined in ongoing studies. [ABSTRACT FROM AUTHOR]

We present arguments and simulation results in favor of a novel strategy for control of rotary blood pumps. We suggest that physiological perfusion is achieved when the blood pump is controlled to maintain an average reference differential pressure. In the case of rotary left ventricular assist devices, our simulations show that maintaining a constant average pressure difference between the left ventricle and aorta results in physiological perfusion over a wide range of physical activities and clinical cardiac conditions. We simulated rest, light, and strenuous exercise conditions, corresponding to cardiac demands of 4.92, 7.98, and 14.62 L/min, respectively. For different exercise levels, the clinical conditions ranged from normal to failing to asystolic heart. By maintaining a constant pressure difference of 75 mm Hg between the left ventricle and aorta, with either an axial or a centrifugal blood pump, a total cardiac output close to the physiological cardiac demand was achieved, irrespective of the heart condition. The simulations of the transitions between different levels of exercise indicate that with the same reference differential pressure, the proposed approach leads to rapid adaptation of the total cardiac output to physiological levels, while avoiding suction. Comparison with the traditional control strategy of maintaining a reference rotational speed (rpm) of the pump indicates that though the traditional approach has some degree of adaptability, it is only adequate over a narrow range of cardiac demand and clinical conditions of the patient. Our results indicate that the proposed approach is superior to the alternatives in providing an adequate and autonomous adaptation of the total cardiac output over a broad range of exercise conditions (expected when an assist device is used as a destination therapy) and clinical statuses of the native heart (such as further deterioration or recovery of cardiac function), while having the potential to improve... [ABSTRACT FROM AUTHOR]

This paper presents the design of a gain-scheduled proportional integral (PI) feedback controller for ventricular assist devices to maintain physiologically motivated perfusion. The selected control objective is to maintain an average differential pressure ΔP between the left ventricle and the aorta. Computer simulations for different pathological conditions, ranging from the normal heart to left heart asystole, and a wide range of physiological scenarios, ranging from rest to strenuous exercise, were used to validate the performance of the controller and the effectiveness of the selected control objective in ensuring physiologically adequate perfusion under different clinical and cardiac demand conditions. [ABSTRACT FROM AUTHOR]

A response by Carlo R. Bartoli and colleagues to a letter to the editor about their article "A Novel Subcutaneous Counterpulsation Device: Acute Hemodynamic Efficacy During Pharmacologically Induced Hypertension, Hypotension, and Heart Failure," in the 2010 issue is presented.