Left Ventricular Assist Device Pump Obstruction Reduces Native Heart Efficiency.

Obstruction of the LVAD flow path can occur when blood clots or tissue overgrowth form within the inflow cannula, pump body, or outflow graft, and it can lead to thrombus, embolism, and stroke. The goal of this study was to measure the impact of progressive pump inflow obstruction on the pressure and flow dynamics of the LVAD-supported heart using a mock circulatory loop. Pump obstruction (PO) was produced by progressively blocking a fraction of the LVAD inlet area. Pressures, flows, and the midplane velocity field of the LV were measured for three LVAD speeds and six PO levels. Pressure and flow decreased with PO, shifting more of the flow through the aortic valve such that the total flow decreased by 6-11% and decreased the efficiency of the work of the native heart up to 60%. PO restricts diastolic flow through the LVAD, which reduces mitral inflow and decreases the strength and energy of the intraventricular vortices. The changes in flow architecture produced by PO include flow stasis and increased shear, which predispose the system to thromboembolic risk. Analysis of the contributions to external work may enable early detection, which allows time for therapeutic intervention, reducing the likelihood of pump replacement and the risk of complications.

Benchtop Models of Patient-Specific Intraventricular Flow During Heart Failure and LVAD Support.

The characterization of intraventricular flow is critical to evaluate the efficiency of fluid transport and potential thromboembolic risk but challenging to measure directly in advanced heart failure (HF) patients with left ventricular assist device (LVAD) support. The study aims to validate an in-house mock loop (ML) by simulating specific conditions of HF patients with normal and prosthetic mitral valves (MV) and LVAD patients with small and dilated left ventricle volumes, then comparing the flow-related indices result of vortex parameters, residence time (RT), and shear-activation potential (SAP). Patient-specific inputs for the ML studies included heart rate, end-diastolic and end-systolic volumes, ejection fraction, aortic pressure, E/A ratio, and LVAD speed. The ML effectively replicated vortex development and circulation patterns, as well as RT, particularly for HF patient cases. The LVAD velocity fields reflected altered flow paths, in which all or most incoming blood formed a dominant stream directing flow straight from the mitral valve to the apex. RT estimation of patient and ML compared well for all conditions, but SAP was substantially higher in the LVAD cases of the ML. The benchtop system generated comparable and reproducible hemodynamics and fluid dynamics for patient-specific conditions, validating its reliability and clinical relevance. This study demonstrated that ML is a suitable platform to investigate the fluid dynamics of HF and LVAD patients and can be utilized to investigate heart-implant interactions.

A Mathematical Model of Artificial Pulse Synchronization for the HeartMate3 Left Ventricular Assist Device.

Constant speed control of rotary LVADs attenuates vascular pulsatility, which has been linked to clinical complications such as thrombus formation, bleeding, and valvular dysfunction. Speed modulation can improve pulsatility and washout, but optimization requires coordination with the native heartbeat. A simple mathematical model of the left ventricle-left ventricular assist device (LV-LVAD) flow interaction was developed that sums the individual contributions of the native LV and the HeartMate3 artificial pulse (AP) to predict the total systemic flow. The model flow and pulsatility predictions results were in good agreement with experimental data from a mock circulatory loop measured for full bypass support conditions. The model was used to evaluate three schemes for optimizing the synchronization of the AP with the native heart. The optimized interaction occurred when the AP speed increase occurred during contraction, resulting in a doubling of flow pulsatility, and corresponded to an increase in the area enclosed by the dynamic pressure-flow relation. The model provides a simple tool for exploring the optimization of LVAD speed modulation that can reduce the time and expense of mock loop studies during the development process.

Design and execution of a verification, validation, and uncertainty quantification plan for a numerical model of left ventricular flow after LVAD implantation.

BACKGROUND: Left ventricular assist devices (LVADs) are implantable pumps that act as a life support therapy for patients with severe heart failure. Despite improving the survival rate, LVAD therapy can carry major complications. Particularly, the flow distortion introduced by the LVAD in the left ventricle (LV) may induce thrombus formation. While previous works have used numerical models to study the impact of multiple variables in the intra-LV stagnation regions, a comprehensive validation analysis has never been executed. The main goal of this work is to present a model of the LV-LVAD system and to design and follow a verification, validation and uncertainty quantification (VVUQ) plan based on the ASME V&V40 and V&V20 standards to ensure credible predictions. METHODS: The experiment used to validate the simulation is the SDSU cardiac simulator, a bench mock-up of the cardiovascular system that allows mimicking multiple operation conditions for the heart-LVAD system. The numerical model is based on Alya, the BSC's in-house platform for numerical modelling. Alya solves the Navier-Stokes equation with an Arbitrary Lagrangian-Eulerian (ALE) formulation in a deformable ventricle and includes pressure-driven valves, a 0D Windkessel model for the arterial output and a LVAD boundary condition modeled through a dynamic pressure-flow performance curve. The designed VVUQ plan involves: (a) a risk analysis and the associated credibility goals; (b) a verification stage to ensure correctness in the numerical solution procedure; (c) a sensitivity analysis to quantify the impact of the inputs on the four quantities of interest (QoIs) (average aortic root flow [Formula: see text], maximum aortic root flow [Formula: see text], average LVAD flow [Formula: see text], and maximum LVAD flow [Formula: see text]); (d) an uncertainty quantification using six validation experiments that include extreme operating conditions. RESULTS: Numerical code verification tests ensured correctness of the solution procedure and numerical calculation verification showed a grid convergence index (GCI)95% <3.3%. The total Sobol indices obtained during the sensitivity analysis demonstrated that the ejection fraction, the heart rate, and the pump performance curve coefficients are the most impactful inputs for the analysed QoIs. The Minkowski norm is used as validation metric for the uncertainty quantification. It shows that the midpoint cases have more accurate results when compared to the extreme cases. The total computational cost of the simulations was above 100 [core-years] executed in around three weeks time span in Marenostrum IV supercomputer. CONCLUSIONS: This work details a novel numerical model for the LV-LVAD system, that is supported by the design and execution of a VVUQ plan created following recognised international standards. We present a methodology demonstrating that stringent VVUQ according to ASME standards is feasible but computationally expensive.

Dynamic pressure-flow curve analysis of the native heart and left ventricular assist device for full and partial bypass conditions.

BACKGROUND: During left ventricular assist device (LVAD) support, the external work performed by the native heart combines with the work performed by the rotary LVAD to provide cyclic flow through the LVAD and, in some conditions, through the aortic valve. In this study, a balance of external work was developed and validated for both full and partial bypass conditions that includes valve opening and aortic compliance. METHODS: The theory assumes a steady-state contribution of external work from the rotary LVAD and a dynamic portion from the heart. Cyclic flow may be ejected through either the LVAD or ascending aorta, and an energy absorption term accounts for aortic compliance. Mock loop studies were performed for LV ejection fractions of 10%-28% combined with HeartMate II LVAD support at 8 and 11 krpm to produce a range of full and partial bypass conditions. The external work of the LVAD and native heart was computed from the experimental pressure-flow (H-Q) relations and compared to the theory. RESULTS: Native heart contraction produces a counterclockwise loop in the pressure-flow relation of the LVAD which increased with ejection fraction, and during full bypass conditions the external work was preserved in the total systemic flow. During partial bypass conditions, forward flow through the ascending aorta was accompanied by a reversal during aortic valve closure resulting in a reduction in energy in the downstream flow. CONCLUSIONS: The study presents a balance of external work during full and partial bypass LVAD support. Experimental data validated the additional terms corresponding to forward flow and aortic compliance that contribute to the system balance. This expanded theory can be applied to LVAD design and control to improve pulsatility and aortic valve biomechanics.

Left Ventricular Flow Dynamics with the HeartMate3 Left Ventricular Assist Device: Effect of Inflow Cannula Position and Speed Modulation.

Improper left ventricular assist device (LVAD) inflow cannula (IC) positioning creates areas of stasis and low pulsatility that predispose thromboembolism, but may be mitigated with LVAD speed modulation. A mock loop study was performed to assess the sensitivity of left ventricle (LV) flow architecture to IC position and speed modulation during HeartMate3 support. System pressure, flow, and the time-resolved velocity field were measured within a transparent silicone LV for three IC angles and three IC insertion depths at matched levels of cardiac function and LVAD speed. Inflow cannula angulation towards the septum increased the resistance to LVAD flow as well as increasing the size and energy of the counter-clockwise (CCW) vortex. Apical velocity was reduced compared to IC angulation towards the mitral valve, but regional pulsatility was maintained across all angles and LVAD speeds. Increased IC protrusion decreased LVAD flow resistance, increasing velocity within the IC but reducing flow and pulsatility in the adjacent apical region. Increasing LVAD flow resistance improves aortic valve opening and strengthens the CCW vortex which directs inflow towards the septum, producing higher blood residence time and shear activation potential. Despite this impact on flow architecture, pulsatility reduction with increased LVAD speed was minimal with the HeartMate3 speed modulation feature.

Manual Carotid Compression is a Viable Alternative for Reduction of Cerebral Microemboli.

BACKGROUND: Stroke is a devastating complication of cardiovascular surgeries, and the risk is particularly high for those requiring cardiopulmonary bypass (CPB). Embolic particles generated during the unclamping of the aortic cross-clamp may enter the cerebral circulation, lodging in small vessels. External manual compression of the carotid arteries is a non-invasive technique that has been proposed for cerebral protection during CPB procedures but is not widely deployed. METHODS: The aim of this study is to assess the potential for cerebral emboli reduction with carotid compression using an in vitro model. Experiments were performed with a glass aortic arch model in a mock cardiovascular circuit. Small fluorescent particles were released into the circulation with and without carotid compression, and the particles visualized in the aortic midplane. The number of particles in the aorta and arch branch vessels were counted from the images before, during and following the release of carotid compression for durations of 10, 15 and 20 s. A gamma variate function was fit to the data to describe the bolus dynamics. RESULTS: Carotid compression for 10 s reduces the number of embolic articles entering the carotid arteries by over 75%. A compression duration of 15-20 s does not result in greater particle reduction than one of 10 s. CONCLUSION: Brief compression of the common carotid arteries during cardiovascular interventions has the potential to dramatically reduce the number of cerebral emboli and should be investigated further.

Intraventricular Flow Patterns in Patients Treated with Left Ventricular Assist Devices.

The success of left ventricular assist device (LVAD) therapy is hampered by complications such as thrombosis and bleeding. Understanding blood flow interactions between the heart and the LVAD might help optimize treatment and decrease complication rates. We hypothesized that LVADs modify shear stresses and blood transit in the left ventricle (LV) by changing flow patterns and that these changes can be characterized using 2D echo color Doppler velocimetry (echo-CDV). We used echo-CDV and custom postprocessing methods to map blood flow inside the LV in patients with ongoing LVAD support (Heartmate II, N = 7). We compared it to healthy controls (N = 20) and patients with dilated cardiomyopathy (DCM, N = 20). We also analyzed intraventricular flow changes during LVAD ramp tests (baseline ± 400 rpm). LVAD support reversed the increase in blood stasis associated with DCM, but it did not reduce intraventricular shear exposure. Within the narrow range studied, the ventricular flow was mostly insensitive to changes in pump speed. Patients with significant aortic insufficiency showed abnormalities in blood stasis and shear indices. Overall, this study suggests that noninvasive flow imaging could potentially be used in combination with standard clinical methods for adjusting LVAD settings to optimize flow transport and minimize stasis on an individual basis.

New partnerships, new perspectives: The relevance of sexual and reproductive health and rights for sustainable development.

In the light of the opportunities presented by the Sustainable Development Goals (SDGs) debate is being reignited to understand the connections between human population dynamics (including rapid population growth) and sustainable development. Sustainable development is seriously affected by human population dynamics yet programme planners too often fail to consider them in development programming, casting doubt on the sustainability of such programming. Some innovative initiatives are attempting to cross sector boundaries once again, such as the Population Health and Environment (PHE) programmes, which are integrated programmes encompassing family planning service provision with broader public health services and environmental conservation activities. These initiatives take on greater prominence in the context of the SDGs since they explicitly seek to provide cross-sector programming and governance to improve both human and planetary wellbeing. Yet such initiatives remain under-researched and under promoted.

Reducing regional flow stasis and improving intraventricular hemodynamics with a tipless inflow cannula design: An in vitro flow visualization study using the EVAHEART LVAD.

Due to the high stroke rate of left ventricular assist device (LVAD) patients, reduction of thrombus has emerged as an important target for LVAD support. Left ventricular blood flow patterns with areas of flow stasis and recirculation are associated with platelet aggregation, which is worsened by exposure to high shear stress. Previous reports of intraventricular thrombus in LVAD patients have identified the outside of the LVAD inflow cannula as a nidus for LV thrombus formation. Previous studies of LVAD inflow cannula design have shown a region of low blood velocity and pulsatility at the apex, adjacent to the cannula. One unresolved question is whether the standard practice of inserting the LVAD inflow cannula several mm into the LV could be revised to reduce thrombus formation. To address this, a "tipless" inflow cannula was designed for the EVAHEART LVAS, and assessed in a mock circulatory loop of the LVAD-supported heart. Customized transparent silicone models of a dilated LV were connected to the EVAHEART LVAS at the apex with a clear polycarbonate inflow cannula for flow visualization using particle image velocimetry (PIV). The "tipless" cannula was inserted flush with the endocardial border and did not protrude into the LV. This condition was compared to the standard cannula position with a 1-cm insertion into the LV. The Pre-LVAD condition corresponded to a severe heart failure patient (ejection fraction of 24%) with a dilated LV (180 mL). LVAD support was provided at speeds of 1.8 and 2.3 krpm. At the lower LVAD speed, 63% of the flow passed through the LVAD, with the remainder ejecting through the aortic valve. When LVAD speed was increased, nearly all flow (98%) left the LV through the LVAD. Both LVAD speed conditions produced a vortex ring similar to the Pre-LVAD condition in diastole. However, the protruding inflow cannula interrupted the growth and restricted the movement of the vortex, and produced areas of low velocity and pulsatility adjacent to the cannula. The tipless cannula exhibited an uninterrupted pattern of the mitral jet toward the LV apex, which allowed the diastolic vortex to grow and aid in the washout of this region. In addition, the tipless cannula increased aortic valve flow, which reduces stasis in the left ventricular outflow tract. The EVAHEART LVAS tipless inflow cannula design improved regional velocity, pulsatility, and vortex formation compared to the standard protruding design, which all reduce the risk of thrombus formation. The clinical significance of the differences observed in the flow field will be dependent on other factors such as the cannula material and surface characteristics, as well as the patients' coagulation status.

Bileaflet Prosthesis Design and Orientation Affect Fluid Shear, Residence Time, and Thrombus Formation.

The orientation and design of bileaflet valve prosthesis in the mitral position affects the intraventricular blood flow and exposure to shear. The combination of the anatomic orientation and a small gap size of the St. Jude Medical valve produces an increase in shear exposure and blood residence time, which both predispose the formation of thrombus in the high shear gaps of the valve hinges.

Mitral Valve Prosthesis Design Affects Hemodynamic Stasis and Shear In The Dilated Left Ventricle.

Dilated cardiomyopathy produces abnormal left ventricular (LV) blood flow patterns that are linked with thromboembolism (TE). We hypothesized that implantation of mechanical heart valves non-trivially influences TE risk in these patients, exacerbating abnormal LV flow dynamics. The goal of this study was to assess how mitral valve design impacts flow and hemodynamic factors associated with TE. The mid-plane velocity field of a silicone dilated LV model was measured in a mock cardiovascular loop for three different mitral prostheses, two with multiple orientations, and used to characterize LV vortex properties through the cardiac cycle. Blood residence time and a platelet shear activation potential index (SAP) based on the cumulative exposure to shear were also computed. The porcine bioprosthesis (BP) and the bileaflet valve in the anti-anatomical (BL-AA) position produced the most natural flow patterns. The bileaflet valves experienced large shear in the valve hinges and recirculating shear-activated flow, especially in the anatomical (BL-A) and 45-degree (BL-45) positions, thus exhibited high SAP. The tilting disk valve in the septal orientation (TD-S) produced a complete reversal of flow and vortex properties, impairing LV washout and retaining shear-activated fluid, leading to the highest residence time and SAP. In contrast, the tilting disk valve in the free-wall position (TD-F) exhibited mid-range values for residence time and SAP. Hence, the thrombogenic potential of different MHV models and configurations can be collectively ranked from lowest to highest as: BP, BL-AA, TD-F, BL-A, BL-45, and TD-S. These findings provide new insight about the effect of fluid dynamics on LV TE risk, and suggest that the bioprosthesis valve in the mitral position minimizes this risk by producing more physiological flow patterns in patients with dilated cardiomyopathy.

The Effect of Inflow Cannula Angle on the Intraventricular Flow Field of the Left Ventricular Assist Device-Assisted Heart: An In Vitro Flow Visualization Study.

Previous studies have identified left ventricular assist device (LVAD) inflow cannula (IC) malposition as a significant risk for pump thrombosis. Thrombus development is a consequence of altered flow dynamics, which can produce areas of flow stasis or high shear that promote coagulation. The goal of this study was to measure the effect of IC orientation on the left ventricle (LV) flow field using a mock circulatory loop, and identify flow-based indices that are sensitive measures of cannula malposition. Experimental studies were performed with a customized silicone model of the dilated LV and the EVAHEART Centrifugal LVAS (Evaheart, Inc.; Houston TX). The velocity field of the LV midplane was measured for a transparent IC oriented parallel to and rotated 15° toward the septum under matched hemodynamic conditions. Vortex structures were analyzed and localized stasis calculated within the IC and combined with a map of normalized pulsatile velocity. The velocity fields revealed increased apical stasis and lower pulsatility with a small angulation of the IC. A significant change in vortex dynamics with the angled IC was observed, doubling the size of the counterclockwise (CCW) vortex while reducing the kinetic energy provided by LVAD support. A significant decrease in average and systolic velocities within the IC was found with cannula angulation, suggesting an increased resistance that affects primarily systolic flow and is worsened with increased LVAD support. These common echocardiographic indices offer the opportunity for immediate clinical application during ramp study assessment. Optimized IC positioning may be determined preoperatively using imaging techniques to develop patient-specific surgical recommendations.

Combined functions of two RRMs in Dead-end1 mimic helicase activity to promote nanos1 translation in the germline.

Dead-end1 (Dnd1) expression is restricted to the vertebrate germline where it is believed to activate translation of messenger RNAs (mRNAs) required to protect and promote that unique lineage. Nanos1 is one such germline mRNA whose translation is blocked by a secondary mRNA structure within the open reading frame (ORF). Dnd1 contains a canonical RNA recognition motif (RRM1) in its N-terminus but also contains a less conserved RRM2. Here we provide a mechanistic picture of the nanos1 mRNA-Dnd1 interaction in the Xenopus germline. We show that RRM1, but not RRM2, is required for binding nanos1. Similar to the zebrafish homolog, Xenopus Dnd1 possesses ATPase activity. Surprisingly, this activity appears to be within the RRM2, different from the C-terminal region where it is found in zebrafish. More importantly, we show that RRM2 is required for nanos1 translation and germline survival. Further, Dnd1 functions as a homodimer and binds nanos1 mRNA just downstream of the secondary structure required for nanos1 repression. We propose a model in which the RRM1 is required to bind nanos1 mRNA while the RRM2 is required to promote translation through the action of ATPase. Dnd1 appears to use RRMs to mimic the function of helicases.

A Tool to Identify Key Behaviors and Attributes of High-Performing Nurses.

OBJECTIVE: The purpose of this project was to identify key behaviors and attributes that distinguish high-performing nurses to develop a tool for employment screening, staff development, and performance management. BACKGROUND: Selecting nurses who will complement an organization's mission and philosophy is a key step toward achieving quality and safety goals, ensuring patient and family satisfaction, and improving retention rates and overall costs. METHODS: Focus group methodology was used to determine perceptions of high-performing nurses' behaviors and attributes. Content analysis of the meeting transcripts was performed to aggregate data into categories and items. RESULTS: Following several phases of testing with various groups, a 16-item scale has been developed. CONCLUSIONS: This tool has received positive ratings from nurse managers currently using it to interview nurse applicants who best "fit" into the organization's nursing culture. Results will be monitored over time including hiring decisions, preceptor ratings, and retention rates.

Microinjection of Xenopus Oocytes.

Microinjection of Xenopus oocytes has proven to be a valuable tool in a broad array of studies that require expression of DNA or RNA into functional protein. These studies are diverse and range from expression cloning to receptor-ligand interaction to nuclear programming. Oocytes offer a number of advantages for such studies, including their large size (∼1.2 mm in diameter), capacity for translation, and enormous nucleus (0.3-0.4 mm). They are cost effective, easily manipulated, and can be injected in large numbers in a short time period. Oocytes have a large maternal stockpile of all the essential components for transcription and translation. Consequently, the investigator needs only to introduce by microinjection the specific DNA or RNA of interest for synthesis. Oocytes translate virtually any exogenous RNA regardless of source, and the translated proteins are folded, modified, and transported to the correct cellular locations. Here we present procedures for the efficient microinjection of oocytes and their subsequent care.

Isolation of Xenopus Oocytes.

Xenopus oocytes and oocyte extracts are the starting material for a variety of experimental approaches. Oocytes are obtained by surgical removal of the ovary from anesthetized females. Although oocytes may be used while they remain within their ovarian follicle, it is more practical to work with defolliculated oocytes. Defolliculation can be performed either manually or enzymatically. Here we present a protocol for the isolation and separation of Xenopus oocytes at various developmental stages, and guidelines for maintaining oocytes in culture.

The Effect of Inflow Cannula Length on the Intraventricular Flow Field: An In Vitro Flow Visualization Study Using the Evaheart Left Ventricular Assist Device.

Left ventricular assist device (LVAD) inflow cannula malposition is a significant risk for pump thrombosis. Thrombus development is influenced by altered flow dynamics, such as stasis or high shear that promote coagulation. The goal of this study was to measure the intraventricular flow field surrounding the apical inflow cannula of the Evaheart centrifugal LVAD, and assess flow stasis, vortex structures, and pulsatility for a range of cannula insertion depths and support conditions. Experimental studies were performed using a mock loop with a customized silicone left ventricle (LV) and the Evaheart LVAD. A transparent inflow cannula was positioned at 1, 2, or 3 cm insertion depth into the LV and the velocity field in the LV midplane was measured for 2 levels of LVAD support: 1800 and 2300 rpm. The LV velocity field exhibits a diastolic vortex ring whose size, path, and strength are affected by the flow conditions and cannula position. During diastole, the large clockwise midplane vortex grows, but its circulation and kinetic energy are reduced with cannula insertion depth. The counterclockwise vortex is smaller and exhibits more complex behavior, reflecting a flow split at 3 cm. Overall, the 1 cm cannula insertion depth produces the flow pattern that exhibits the least apical flow stasis and greatest pulsatility and should correlate to a lower risk of thrombus formation.