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Inspired Therapeutics (Merritt Island, FL) is developing a mechanical circulatory support (MCS) system designed as a single driver with interchangeable, extracorporeal, magnetically levitated pumps. The NeoMate system design features an integrated centrifugal rotary pump, motor, and controller that will be housed in a single compact unit. Conceptually, the primary innovation of this technology will be the combination of disposable, low-cost pumps for use with a single, multi-functional, universal controller to support multiple pediatric cardiopulmonary indications. In response to the paucity of clinically available pediatric devices, Inspired Therapeutics is specifically targeting the underserved neonate and infant heart failure (HF) patient population first. In this article, we present the development of the prototype Inspired Therapeutics NeoMate System for pediatric left ventricular assist device (LVAD) support, and feasibility testing in static mock flow loops (H-Q curves), dynamic mock flow loops (hemodynamics), and in an acute healthy ovine model (hemodynamics and clinical applicability). The resultant hydrodynamic and hemodynamic data demonstrated the ability of this prototype pediatric LVAD and universal controller to function over a range of rotary pump speeds (500–6000 RPM), to provide pump flow rates of up to 2.6 L/min, and to volume unload the left ventricle in acute animals. Key engineering challenges observed and proposed solutions for the next design iteration are also presented.

Objective: Rotary biventricular assist devices (BiVAD) are mechanical pumps that are implanted in the left and right ventricles of biventricular failure patients to pump blood and provide mechanical circulatory support. The objective of this paper was to develop and test a novel sensorless control algorithm that simultaneously satisfies the objectives of providing physiologic control (BiVAD flows meet cardiac demand), preventing ventricular suction, and providing balanced left–right (systemic and pulmonary) flows without the use of implantable flow or pressure sensors in the nonlinear, time varying, and discontinuous circulatory system. Methods: The control algorithm consists of two gain-scheduled proportional–integral controllers for left and right ventricular assist devices and only requires intrinsic pump parameters (speed and power) to maintain differential pump speeds ( $\Delta $ RPM $_{L}$ and $\Delta $ RPM $_{R}$ ) above user-defined thresholds to prevent ventricular suction, and average reference pressure heads ( $\Delta \text{P}_{L}$ , $\Delta \text{P}_{R}$ ) to provide physiologic perfusion and balance left–right-sided flow rates. A model-based approach with extended Kalman and Golay–Savitzky filters was used to estimate $\Delta \text{P}_{L}$ and $\Delta \text{P}_{R}$ . Efficacy and robustness of the algorithm were evaluated in silico during simulated rest and exercise test conditions for: 1) excessive $\Delta \text{P}_{L }$ and/or $\Delta \text{P}_{R}$ setpoints; 2) rapid threefold increase in pulmonary vascular or vena caval resistances; 3) transitions from exercise to rest; and 4) ventricular fibrillation. Results and Conclusion: The proposed sensorless BiVAD algorithm successfully prevented suction, restored physiologic perfusion, and inherently maintained left–right-sided balance for all test conditions. Significance: The proposed algorithm does not require any device modification and may be integrated into current clinical BiVADs.

Pediatric heart failure patients remain in critical need of a dedicated mechanical circulatory support (MCS) solution as development efforts for specific pediatric devices continue to fall behind those for the adult population. The Inspired Pediatric VAD is being developed as a pediatric specific MCS solution to provide up to 30-days of circulatory or respiratory support in a compact modular package that could allow for patient ambulation during treatment.Hydrodynamic performance (flows, pressures), impeller/rotor mechanical properties (torques, forces), and flow shear stress and residence time distributions of the latest design version, Inspired Pediatric VAD V3, were numerically predicted and investigated using computational fluid dynamics (CFD) software (SolidWorks Flow Simulator).Hydrodynamic performance was numerically predicted, indicating no change in flow and pressure head compared to the previous device design (V2), while displaying increased impeller/rotor torques and translation forces enabled by improved geometry. Shear stress and flow residence time volumetric distributions are presented over a range of pump rotational speeds and flow rates. At the lowest pump operating point (3000 RPM, 0.50 L/min, 75 mmHg), 79% of the pump volume was in the shear stress range of 0-10 Pa with1% of the volume in the critical range of 150-1000 Pa for blood damage. At higher speed and flow (5000 RPM, 3.50 L/min, 176 mmHg), 65% of the volume resided in the 0-10 Pa range compared to 2.3% at 150-1000 Pa.The initial computational characterization of the Inspired Pediatric VAD V3 is encouraging and future work will include device prototype testing in a mock circulatory loop and acute large animal model.

Pediatric heart failure (HF) patients have been a historically underserved population for mechanical circulatory support (MCS) therapy. To address this clinical need, we are developing a low cost, universal magnetically levitated extracorporeal system with interchangeable pump heads for pediatric support. Two impeller and pump designs (pump V1 and V2) for the pediatric pump were developed using dimensional analysis techniques and classic pump theory based on defined performance criteria (generated flow, pressure, and impeller diameter). The designs were virtually constructed using computer-aided design (CAD) software and 3D flow and pressure features were analyzed using computational fluid dynamics (CFD) analysis. Simulated pump designs (V1, V2) were operated at higher rotational speeds (~5,000 revolutions per minute [RPM]) than initially estimated (4,255 RPM) to achieve the desired operational point (3.5 L/min flow at 150 mm Hg). Pump V2 outperformed V1 by generating approximately 30% higher pressures at all simulated rotational speeds and at 5% lower priming volume. Simulated hydrodynamic performance (achieved flow and pressure, hydraulic efficiency) of our pediatric pump design, featuring reduced impeller size and priming volume, compares favorably to current commercially available MCS devices.

Rotary blood pumps have demonstrated superior device safety and performance compared with first-generation volume displacement pumps. The first generation of axial and centrifugal flow devices operate at constant speeds (rpm) delivering continuous end-organ blood flow, but with diminished vascular pulsatility and non-phasic volume unloading. It has been speculated that the resulting non-physiologic hemodynamics may be associated with clinically significant adverse events including thrombus, stroke, and bleeding. Subsequently, pump speed modulation algorithms are being developed in an attempt to achieve physiologic pulsatile pressures, flows, and volume unloading. This chapter presents a review of pulsatile- and continuous-flow device hemodynamics, methods for quantifying pulsatility, and engineering approaches to produce favorable flow conditions and near-physiologic hemodynamics.

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.

The structural integrity of platelet receptors is essential for platelets to play the normal hemostatic function. The high non-physiological shear stress (NPSS) commonly exists in blood contacting medical devices and has been shown to cause platelet receptor shedding. The loss of platelet receptors may impair the normal hemostatic function of platelets. The aim of this study was to quantify NPSS-induced shedding of three key receptors on the platelet surface. Human blood was subjected to the matrix of well-defined shear stresses and exposure times, generated by using a custom-designed blood shearing device. The expression of three key platelet receptors, glycoprotein (GP) Ibα, GPVI and GPIIb/IIIa in sheared blood was quantified using flow cytometry. The quantitative relationship between the loss of each of the three receptors on the platelet surface and shear condition (shear stress level and exposure time) was explored. It was found that these relationships followed well the power law functional form. The coefficients of the power law models for the shear-induced shedding of these platelet receptors were derived with coefficients of determination (R(2)) of 0.77, 0.73, and 0.78, respectively. The power law models with these coefficients may be potentially used to predict the shear-induced platelet receptor shedding of human blood.

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 controllers for left and right ventricular assist devices (LVAD, RVAD) to maintain differential pump pressure across LVAD (ΔP(L)) and RVAD (ΔP(R)) to provide left-right balance and physiologic flow. To prevent ventricular suction, LVAD and RVAD pump speed differentials (ΔRPM(L), ΔRPM(R)) 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 ΔP(L) and/or ΔP(R) setpoints, (2) rapid three-fold 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 ΔP(L) and ΔP(R). 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 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.

Thrombosis and bleeding are devastating adverse events in patients supported with blood-contacting medical devices (BCMDs). In this study, we delineated that high non-physiological shear stress (NPSS) caused platelet dysfunction that may contribute to both thrombosis and bleeding. Human blood was subjected to NPSS with short exposure time. Levels of platelet surface GPIbα and GPVI receptors as well as activation level of GPIIb/IIIa in NPSS-sheared blood were examined with flow cytometry. Adhesion of sheared platelets on fibrinogen, von Willibrand factor (VWF), and collagen was quantified with fluorescent microscopy. Ristocetin- and collagen-induced platelet aggregation was characterized by aggregometry. NPSS activated platelets in a shear and exposure time-dependent manner. The number of activated platelets increased with increasing levels of NPSS and exposure time, which corresponded well with increased adhesion of sheared platelets on fibrinogen. Concurrently, NPSS caused shedding of GPIbα and GPVI in a manner dependent on shear and exposure time. The loss of intact GPIbα and GPVI increased with increasing levels of NPSS and exposure time. The number of platelets adhered on VWF and collagen decreased with increasing levels of NPSS and exposure time, respectively. The decrease in the number of platelets adhered on VWF and collagen corresponded well with the loss in GPIbα and GPVI on platelet surface. Both ristocetin- and collagen-induced platelet aggregation in sheared blood decreased with increasing levels of NPSS and exposure time. The study clearly demonstrated that high NPSS causes simultaneous platelet activation and receptor shedding, resulting in a paradoxical effect on platelet function via two distinct mechanisms. The results from the study suggested that the NPSS could induce the concurrent propensity for both thrombosis and bleeding in patients.

Mechanical circulatory support devices (MCSDs) have gained widespread clinical acceptance as an effective heart failure (HF) therapy. The concept of harnessing the kinetic energy (KE) available in the forward aortic flow (AOF) is proposed as a novel control strategy to further increase the cardiac output (CO) provided by MCSDs. A complete mathematical development of the proposed theory and its application to an example MCSDs (two-segment extra-aortic cuff) are presented. To achieve improved device performance and physiologic benefit, the example MCSD timing is regulated to maximize the forward AOF KE and minimize retrograde flow. The proof-of-concept was tested to provide support with and without KE control in a computational HF model over a wide range of HF test conditions. The simulation predicted increased stroke volume (SV) by 20% (9 mL), CO by 23% (0.50 L/min), left ventricle ejection fraction (LVEF) by 23%, and diastolic coronary artery flow (CAF) by 55% (3 mL) in severe HF at a heart rate (HR) of 60 beats per minute (BPM) during counterpulsation (CP) support with KE control. The proposed KE control concept may improve performance of other MCSDs to further enhance their potential clinical benefits, which warrants further investigation. The next step is to investigate various assist technologies and determine where this concept is best applied. Then bench-test the combination of kinetic energy optimization and its associated technology choice and finally test the combination in animals.

Non-surgical bleeding (NSB) is the most common clinical complication in heart failure (HF) patients supported by continuous-flow left ventricular assist devices (CF-LVADs). In this study, oxidative stress and alteration of signal pathways leading to platelet apoptosis were investigated. Thirty-one HF patients supported by CF-LVADs were divided into bleeder (n = 12) and non-bleeder (n = 19) groups. Multiple blood samples were collected at pre-implant (baseline) and weekly up to 1-month post-implant. A single blood sample was collected from healthy subjects (reference). Production of reactive oxygen species (ROS) in platelets, total antioxidant capacity (TAC), oxidized low-density lipoproteins (oxLDL), expression of Bcl-2 and Bcl-xL, Bax and release of cytochrome c (Cyt.c), platelet mitochondrial membrane potential (Δψ m), activation of caspases, gelsolin cleavage and platelet apoptosis were examined. Significantly elevated ROS, oxLDL and depleted TAC were evident in the bleeder group compared to non-bleeder group (p

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

Purpose Predicting cardiac structural and functional improvement in advanced heart failure (HF) patients before durable left ventricular assist device (LVAD) implantation remains challenging. Identifying clinical predictors could improve patient selection and impact clinical management. Methods Advanced chronic HF patients (N=652) supported with continuous-flow LVADs were evaluated. After excluding patients with acute HF etiologies or without adequate post-LVAD follow up ( Results In total, 10% of the LVAD patients were R. Univariate analysis showed that R were younger, had shorter HF symptoms duration, less need for diuretics and their LV were less dilated pre-LVAD. Further, R had higher acuity disease as evidenced by the higher vasoactive agents need, higher BNP and higher incidence of abnormal liver enzymes. The multivariate Cox regression (AUC=0.74; p Conclusion Younger patients with less LV dilation and shorter duration of HF are more likely to improve their cardiac function during LVAD support. Whether these characteristics also predict sustainability of improved cardiac function after LVAD weaning warrants further investigation.

Blood can become hypercoagulable by shear-induced platelet activation and generation of microparticles. It has been reported that nonphysiological shear stress (NPSS) could induce shedding of platelet receptor glycoprotein (GP) Ibα, which may result in an opposite effect to hemostasis. The aim of this study was to investigate the influence of the NPSS on platelets and von Willebrand factor (vWF). Human blood was exposed to two levels of NPSS (25 Pa, 125 Pa) with an exposure time of 0.5 s, generated by using a novel blood-shearing device. Platelet activation (P-selectin expression, GPIIb/IIIa activation and generation of microparticles) and shedding of three platelet receptors (GPIbα, GPVI, GPIIb/IIIa) in sheared blood were quantified using flow cytometry. Aggregation capacity of sheared blood induced by ristocetin and collagen was evaluated using an aggregometer. Shear-induced vWF damage was characterized with Western blotting. Consistent with the published data, the NPSS caused significantly more platelets to become activated with increasing NPSS level. Meanwhile, the NPSS induced the shedding of platelet receptors. The loss of the platelet receptors increased with increasing NPSS level. The aggregation capacity of sheared blood induced by ristocetin and collagen decreased. There was a loss of high molecular weight multimers (HMWMs) of vWF in sheared blood. These results suggest that the NPSS induced a paradoxical effect. More activated platelets increase the risk of thrombosis, while the reduction in platelet receptors and the loss of HMWM-vWF increased the propensity of bleeding. The finding might provide a new perspective to understand thrombosis and acquired bleeding disorder in patients supported with blood contacting medical devices.

The role of oxidative stress and leukocyte activation has not been elucidated in developing systemic inflammatory response syndrome (SIRS) in heart failure (HF) patients after continuous-flow left ventricular assist device (CF-LVAD) implantation. The objective of this study was to investigate the change of plasma redox status and leukocyte activation in CF-LVAD implanted HF patients with or without SIRS. We recruited 31 CF-LVAD implanted HF patients (16 SIRS and 15 non-SIRS) and 11 healthy volunteers as the control. Pre- and postimplant blood samples were collected from the HF patients. Plasma levels of oxidized low-density lipoprotein (oxLDL), malondialdehyde (MDA), total antioxidant capacity (TAC), superoxide dismutase (SOD) in erythrocyte, myeloperoxidase (MPO), and polymorphonuclear elastase (PMN-elastase) were measured. The HF patients had a preexisting condition of oxidative stress than healthy controls as evident from the higher oxLDL and MDA levels as well as depleted SOD and TAC. Leukocyte activation in terms of higher plasma MPO and PMN-elastase was also prominent in HF patients than controls. Persistent oxidative stress and reduced antioxidant status were found to be more belligerent in HF patients with SIRS after the implantation of CF-LVAD when compared with non-SIRS patients. Similar to oxidative stress, the activation of blood leukocyte was significantly highlighted in SIRS patients after implantation compared with non-SIRS. We identified that the plasma redox status and leukocyte activation became more prominent in CF-LVAD implanted HF patients who developed SIRS. Our findings suggest that plasma biomarkers of oxidative stress and leukocyte activation may be associated with the development of SIRS after CF-LVAD implant surgery.

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.

The purpose of this study was to investigate the influence of non-physiological high shear stress on activation and shedding of platelet GP IIb/IIIa receptors. The healthy donor blood was exposed to three levels of high shear stresses (25, 75, 125 Pa) from the physiological to non-physiological status with three short exposure time (0.05, 0.5, 1.5 s), created by a specific blood shearing system. The activation and shedding of the platelet GPIIb/IIIa were analyzed using flow cytometry and enzyme-linked immunosorbent assay (ELISA). In addition, platelet P-selectin expression of sheared blood, which is a marker for activated platelets, was also analyzed. The results from the present study showed that the number of activated platelets, as indicated by the surface GPIIb/IIIa activation and P-selectin expression, increased with increasing the shear stress level and exposure time. However, the mean fluorescence of GPIIb/IIIa on the platelet surface, decreased with increasing the shear stress level and exposure time. The reduction of GPIIb/IIIa on the platelet surface was further proved by the reduction of further activated platelet GPIIb/IIIa surface expression induced by ADP and the increase in GPIIb/IIIa concentration in microparticle-free plasma with increasing the applied shear stress and exposure time. It is clear that non-physiological shear stress induced a paradoxical phenomenon, in which both activation and shedding of the GPIIb/IIIa on the platelet surface occur simultaneously. This study may offer a new perspective to explain the reason of both increased thrombosis and bleeding events in patients implanted with high shear blood contacting medical devices.

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.

In this study, the flow features and device-associated blood trauma in four clinical ventricular assist devices (VADs) (two implantable axial VADs, one implantable centrifugal VAD, and one extracorporeal VAD) were computationally analyzed under clinically relevant pulsatile flow conditions. The four VADs were operated at fixed pump speed at a mean rate of 4.5 L/min. Mean pressure difference, wall shear stress (WSS), 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 three implantable VADs was ~ 70mm Hg and the extracorporeal VAD was ~ 345 mmHg, which matched well with their reported pressure-flow curves. The axial VADs had higher mean WSS and SSS compared to the centrifugal VADs. However, the residence time of the centrifugal VADs was much longer compared to 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 one centrifugal VAD. These two 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 to at high flow rate. Subsequently, we hypothesize that in order to reduce the risk of blood trauma during VAD support, shear stress magnitude and exposure time need to be minimized.

Counterpulsation devices (CPD) 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 (IHF) 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 two of forty 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.

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.

The objective of this study was to investigate the changes in oxidative stress (OS) and circulating regulatory T cells (Tregs) of the immune system in patients supported by continuous-flow ventricular assist device (CF-VAD) with or without infection. We recruited 16 CF-VAD patients (5 with infection and 11 without infection) and 7 healthy volunteers. Generation of reactive oxygen species (ROS) from lymphocytes, superoxide dismutase (SOD) in erythrocyte, total antioxidant capacity (TAC), and oxidized low-density lipoprotein (oxLDL) in plasma were measured. Circulating Tregs were evaluated by flow cytometry. Heart failure (HF) patients had elevated OS than healthy volunteers as evident from higher lymphocyte ROS, elevated oxLDL, as well as depleted SOD and TAC levels. At baseline, HF patients had decreased percentage of Tregs (5.12 ± 1.5% vs. 8.14 ± 3.01%, p < 0.01) when compared with healthy volunteers. Postimplant patients with infection illustrated 35% and 44% rise in ROS and oxLDL, respectively, 31% decrease in TAC, and marked rise in percentage of Tregs (14.27 ± 3.17% vs. 9.38 ± 3.41%, p < 0.01) when compared with the patients without infection. Elevated OS and rise in Tregs were more prominent in CF-VAD patients with infection. In conclusion, OS and compromised immune system may be important indicators of systemic response of the body to CF-VAD among HF patients with infection.

Despite progress with adult ventricular assist devices, limited options exist to support pediatric patients with life-threatening heart disease. Extracorporeal membrane oxygenation remains the clinical standard. To characterize (patho)physiologic responses to different modes of mechanical unloading of the failing pediatric heart, extracorporeal membrane oxygenation was compared to intra-aortic balloon pump, pulsatile-flow ventricular assist device, or continuous-flow ventricular assist device support in a pediatric heart failure model.Experimental.Large animal laboratory operating room.Yorkshire piglets (n = 47; 11.7 ± 2.6 kg).In piglets with coronary ligation-induced cardiac dysfunction, mechanical circulatory support devices were implanted and studied during maximum support.Left ventricular, right ventricular, coronary, carotid, systemic arterial, and pulmonary arterial hemodynamics were measured with pressure and flow transducers. Myocardial oxygen consumption and total-body oxygen consumption were calculated from arterial, venous, and coronary sinus blood sampling. Blood flow was measured in 17 organs with microspheres. Paired Student t tests compared baseline and heart failure conditions. One-way repeated-measures analysis of variance compared heart failure, device support mode(s), and extracorporeal membrane oxygenation. Statistically significant (p0.05) findings included 1) an improved left ventricular blood supply/demand ratio during pulsatile-flow ventricular assist device, continuous-flow ventricular assist device, and extracorporeal membrane oxygenation but not intra-aortic balloon pump support, 2) an improved global myocardial blood supply/demand ratio during pulsatile-flow ventricular assist device and continuous-flow ventricular assist device but not intra-aortic balloon pump or extracorporeal membrane oxygenation support, and 3) diminished pulsatility during extracorporeal membrane oxygenation and continuous-flow ventricular assist device but not intra-aortic balloon pump and pulsatile-flow ventricular assist device support. A profile of systems-based responses was established for each type of support.Each type of pediatric ventricular assist device provided hemodynamic support by unloading the heart with a different mechanism that created a unique profile of physiological changes. These data contribute novel, clinically relevant insight into pediatric mechanical circulatory support and establish an important resource for pediatric device development and patient selection.

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.

Clinical acceptance of ventricular assist devices (VADs) as long-term heart failure therapy requires safe and effective circulatory support for a minimum of 5 years. Yet, VAD failure beyond 2 years of support is still a concern. Currently, device controllers cannot consistently predict VAD failure modes, and undetected VAD faults may lead to catastrophic device failure. To minimize this risk, a model-based algorithm for reliable VAD fault detection that only requires VAD revolutions per minute (rpm) was developed. The algorithm was tested using computer models of the human cardiovascular system simulating heart failure and axial flow (AF) or centrifugal flow (CF) VADs. Ventricular assist device rpm was monitored after a step down of motor current for normal and simulated fault conditions (>750 faults). The ability to detect fault conditions with 1%, 5%, and 10% rpm measurement noise was evaluated. All failure modes affected the VAD rpm responses to the motor current step down. Fault detection rates were >95% for AF and >89% for CF VADs, even with 10% rpm measurement noise. The VAD rpm responses were significantly altered by blood viscosity (3.5-6.2 cP), which should be accounted for in clinical application. The proposed VAD fault detection algorithm may deliver a convenient and nonintrusive way to minimize catastrophic device failures.

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.

A major limitation in the development of mechanical circulatory support (MCS) devices has been the lack of a clinically relevant, stable, and reproducible large animal chronic heart failure (HF) model. High mortality rates have been reported with large animal chronic HF models. In this study, methods of medical management to improve survival rate (SR) were investigated. Chronic ischemic HF (IHF) was induced in Jersey calves using a microembolization technique via fluoroscopy-guided injection of 90 μm microspheres into the coronary vasculature. Animals were divided into 1) Control--multiple embolization procedures with conservative therapy (n = 9); 2) treatment group 1 (TG1)--single embolization procedure with moderately aggressive therapy (n = 8); and 3) TG2--single embolization procedure with aggressive medical management (n = 20). The groups were not randomized with data analyzed retrospectively. Mean SR, body condition score, body weight, hemodynamic, echocardiography, and histopathology indices were recorded up to 60 days postembolization. SR improved from 56% (Control) to 75% (TG1) and 90% (TG2) using an aggressive medical management regimen of analgesia, diuretics, beta-blockade, antiarrhythmics, vasodilators, and inotropes. These findings support the hypothesis that a single coronary microembolization procedure and aggressive medical therapy produces a clinically relevant chronic IHF model with a significantly higher SR than conservative medical therapy.

Intra-aortic rotary blood pumps (IARBPs) have been used for partial cardiac support during cardiogenic shock, myocardial infarction, percutaneous coronary intervention, and potentially viable for long-term circulatory support. Intra-aortic rotary blood pump support continuously removes volume from the aortic root, which lowers left ventricular preload, external work (LVEW), and improves end-organ perfusion. However, IARBP support diminishes aortic root pressure and coronary artery. It may also create "coronary steal," which may produce a myocardial hypoxic state adversely affecting patient outcomes. Our objective was to develop IARBP flow modulation algorithms to eliminate coronary steal and improve the myocardial supply-demand ratio without compromising the clinical benefits of restored end-organ perfusion and reduced LVEW. The hemodynamic responses of the native ventricle, coronary, and systemic vasculature to timing and synchronization of IARBP flow modulation (cyclic variation of pump flow) were investigated using a clinical heart failure (HF) computer simulation model. A total of more than 150 combinations of varying pulse widths and time-shifts to modulate IARBP flow were tested at mean IARBP flow rates of 2, 3, and 4 L/min, and compared with HF baseline values (no IARBP support). Increasing IARBP support augmented cardiac output and diminished LVEW. Nonmodulated IARBP support significantly diminished mean diastolic coronary flow (-49%) and myocardial supply-demand ratio (-12%) compared with HF baseline. Intra-aortic rotary blood pump flow modulation increased mean diastolic coronary flow (+17%) and myocardial supply-demand ratio (+24%) compared with nonmodulated IARBP (constant flow). Modulation and synchronization of IARBP support augmented coronary artery perfusion and myocardial supply-demand ratio in simulated clinical HF while also restoring end-organ perfusion and reducing LVEW. Implementation of IARBP support with flow modulation may prevent myocardial hypoxia and improve patient outcomes. However, even with flow modulation, IARBP support provides a smaller improvement in myocardial supply demand ratio compared to ventricular assist devices and intra-aortic balloon pumps.

A growing number of elderly patients with significant co-morbidities do not meet the inclusion criteria for conventional cardiac surgical therapies, including aortic valve replacement and mechanical circulatory support. To meet this clinical need, an aortic valve bypass (AVB) system is being developed that may be implanted using subcostal or mini-thoracotomy surgical approaches without ventricular coring or cardiopulmonary bypass. The AVB system consists of an apical left ventricular (ALV) cannula made from pyrolytic carbon, a valved conduit with a locking mechanism, and a Nitinol clip for anastomosis to the descending aorta. To define design criteria and demonstrate efficacy, ALV cannulae with different diameters (7–14 mm), number of sideholes (6–12), sidehole size (1.9–4.6 mm wide) and tip shapes (tapered, straight) were designed, fabricated, and tested. Cannula efficacy was determined by quantifying flow rates and pressure drops across the ALV cannula using steady-state and dynamic mock circulation models simulating mild, moderate and severe aortic stenosis test conditions. Blood trauma testing was conducted to demonstrate hemocompatibility using the smallest diameter (7 mm) ALV cannula prototype fabricated from pyrolytic carbon (PYC). In vitro and blood trauma testing demonstrated that (1) the 7 mm PYC cannula did not produce significant hemolysis ( 4.5 L/min for

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.

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.

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.

Objective An ectopic coronary artery that courses between the aortic root and the pulmonary trunk may lead to sudden cardiac death, especially in athletes. It has been speculated that during exercise, compression of the coronary artery between the great vessels may impair coronary blood flow and produce myocardial ischemia and fatal arrhythmia. However, this hypothesis cannot be tested in humans, and little experimental data exist to explain this phenomenon. To this end, in a calf with an anomalous left coronary artery that coursed from the right sinus of Valsalva between the great vessels, we assessed for myocardial ischemia during pharmacologically induced tachycardia and hypertension. Methods We identified a juvenile male calf (103 kg) with an anomalous left coronary artery from the right sinus of Valsalva that coursed between the great vessels. Via thoracotomy, the animal was instrumented for hemodynamic measurements. Intravenous dobutamine increased heart rate and myocardial metabolic demands. Intravenous phenylephrine produced arterial hypertension and increased myocardial metabolic demands. Fluorescent-labeled microspheres were used to map regional myocardial blood flow, and hemodynamics were recorded during each condition. Masson's trichrome staining for fibrosis, wheat-germ agglutinin staining for myocyte size, terminal deoxynucleotidyl transferase dUTP nick end-label staining for apoptosis, and isolectin-B4 staining for capillary density were performed. Results For the first time, empiric data documented that an ectopic coronary artery produced myocardial ischemia during elevated myocardial metabolic demands. Left coronary artery resistance increased in a cardiac cycle–dependent pattern that was consistent with systolic compression between the great vessels. Increased cardiac fibrosis, myocyte hypertrophy, cardiac apoptosis, and capillary density indicated that regional ischemic, inflammatory-mediated myocardial remodeling was present. Conclusions These findings confirm the proposed mechanism of sudden death and support early surgical repair of coronary arteries that course between the aortic root and the pulmonary trunk.

Ventricular assist devices (VADs) have been used successfully as a bridge to transplant in heart failure patients by unloading ventricular volume and restoring the circulation. An artificial vasculature device (AVD) is being developed that may better facilitate myocardial recovery than VAD by controlling the afterload experienced by the native heart and controlling the pulsatile energy entering into the arterial system from the device, potentially reconditioning the arterial system properties. The AVD is a valveless, 80 ml blood chamber with a servo-controlled pusher plate connected to the ascending aorta by a vascular graft. Control algorithms for the AVD were developed to maintain any user-defined systemic input impedance (IM) including resistance, elastance, and inertial components. Computer simulation and mock circulation models of the cardiovascular system were used to test the efficacy of two control strategies for the AVD: 1) average impedance position control (AIPC)-to maintain an average value of resistance during left ventricular (LV) systole and 2) instantaneous impedance force feedback (IIFF) and position control (IIPC)-to maintain a desired value or profile of resistance and compliance. Computer simulations and mock loop tests were performed to predict resulting cardiovascular pressures, volumes, flows, and the resistance and compliance experienced by the native LV during ejection for simulated normal, failing, and recovering LV. These results indicate that the LV volume and pressure decreased, and the LV stroke volume increased with decreasing IM, resulting in an increased ejection fraction. Although the AIPC algorithm is more stable and can tolerate higher levels of sensor errors and noise, the IIFF and IIPC control algorithms are better suited to maintain any instantaneous IM or an IM profile. The developed AVD impedance control algorithms may be implemented with current VADs to promote myocardial recovery and facilitate weaning.

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.

A counterpulsation device (Symphony) that works synchronously with the native heart to provide partial circulatory support was developed to treat patients with advanced heart failure. Symphony is implanted in a ‘pacemaker pocket’ without entry into the chest, and requires timing with ECG for device filling and ejection. Surface leads are limited to short-term use due to signal distortion and lead management issues. Transvenous leads are a clinical standard for pacemakers and internal defibrillators, but increase the complexity of the implant procedure. In this study, the feasibility of using subcutaneous leads for synchronized timing of Symphony was investigated. ECG waveforms were simultaneously measured and recorded using epicardial (control) and subcutaneous (test) leads in a bovine model for 7-days (n = 6) and 14-days (n = 2) during daily activity and treadmill exercise. Landmark features and R-wave triggering detection rates for each lead configuration were calculated and compared. Lead placement, migration, durability, and infection were quantified using fluoroscopy and histopathological examination. There were 2,849 data epochs (30-s each) recorded at rest (133,627 analyzed beats) and 35 data epochs (20 min each) recorded during treadmill exercise (37,154 analyzed beats). The subcutaneous leads provided an accurate and reliable triggering signal during routine daily activity and treadmill exercise (99.1 ± 0.4% positive predictive value, 96.8 ± 1.5% sensitivity). The subcutaneous leads were also easily placed with minimal lead migration (0.5 ± 0.1 cm), damage (no fractures or failures), or infection. These findings demonstrate the feasibility of using subcutaneous leads for synchronized timing of mechanical circulatory support while offering the advantage of less invasive surgery and associated risk factors.

IntroductionPlatelet adhesion and activation are a significant source of clinical complications. Preventing foreign surface–platelet interaction may improve biocompatibility of implantable medical devices. This study evaluated efficacy of novel technique for electrically modifying surface of conductive biomaterial and attaching blood components to prevent thrombogenesis. Specifically, this new surface modification technology, Forcefield (ATS Medical, Inc, Minneapolis, Minn), was designed to prevent platelet adhesion on pyrolytic carbon. A modulated low-voltage current is directly applied to pyrolytic carbon surfaces to stimulate adherence of a layer of charged proteins from circulating blood components that is resistive to platelet deposition.MethodsFeasibility of Forcefield technology was tested in line with cardiopulmonary bypass circuit in patients undergoing standard cardiac surgery (n = 6). Forcefield treatment was applied to segment of pyrolytic carbon with 15 minutes (n = 3) and 30 minutes (n = 3) of electrically stimulated exposure time, and resulting segments were compared with untreated pyrolytic carbon segment. Platelet adhesion confluence was then quantified by scanning electron microscopy.ResultsConfluence of the Forcefield-treated pyrolytic carbon segments (3.3% ± 2.2%) was significantly reduced relative to untreated pyrolytic carbon control segments (81.7% ± 24%, P

The objective of this clinical study was to quantify the incidence and magnitude of intraaortic balloon pump (IABP) inflation and deflation landmark discrepancies associated with the IABP catheter arterial pressure waveform. Cardiac surgery patients with an IABP inserted prior to surgery were recruited. Following cardiac exposure, a high-fidelity pressure catheter was inserted into the aortic root for digital recording. The radial artery pressure signal was simultaneously recorded from the patient monitor along with the arterial pressure and electrocardiogram waveforms from the IABP console while operating at 1:1 and 1:2 synchronization. In selected patients, recordings were obtained with the IABP timed to the high-fidelity aortic root waveform. In all 11 patients, inflation and deflation landmark delays were observed when comparing the aortic root waveforms to the IABP arterial pressure waveforms (inflation delay = 74 ± 29 [23-117] ms; deflation delay = 71 ± 37 [24-141] ms, mean ± standard deviation [min-max]). Delays were greater when compared to the radial artery waveform (inflation delay = 175 ± 50 [100-233] ms; deflation delay = 168 ± 52 [100-274] ms). In all cases, the landmark delays were statistically different from zero (P < 0.001). Diastolic augmentation and afterload reduction varied with waveform source. Conflicting indications of afterload reduction occurred in four patients. Timing to the aortic root waveform resulted in greater diastolic pressure augmentation and afterload reduction but mixed changes in stroke volume. Delay and distortion of the arterial waveform was consistently found when measured through the IABP catheter lumen. These delays can alter IABP efficacy and may be eliminated by using high-fidelity sensing of aortic pressure.

Numerical and experimental studies are carried out to assess the hydraulic and hemodynamic performance and the biocompatibility of a viscous impeller pump (VIP) for cavopulmonary assist in patients with a univentricular Fontan circulation. Computational fluid dynamics (CFD) predictions of impeller performance are shown to be in very good agreement with measured pressure-flow data obtained in a Fontan mock-circulation system. Additional CFD and experimental design studies intending to balance pump performance and biocompatibility with the manufacturability limitations of a percutaneous expandable impeller are also reported. The numerical models and experimental studies confirm excellent performance of the VIP with augmentation of Fontan pressure up to 35 mmHg for flow rates up to 4.5 L/min and operational speeds no higher than 5000 RPM. Scalar stress predictions on the VIP surface and laboratory hemolysis measurements both demonstrate very low hemolysis potential. The impeller designs reported offer ideal performance and can meet manufacturing tolerances of a flexible, catheter-based percutaneous expandable rotary pump.

Preclinical hemolysis testing is a critical requirement toward demonstrating device safety for U.S. Food and Drug Administration (FDA) 510(k) approval of mechanical circulatory support devices (MCSD). FDA and ASTM (formerly known as the American Society for Testing and Materials) have published guidelines to assist industry with developing study protocols. However, there can be significant variability in experimental procedures, study design, and reporting of data that makes comparison of test and predicate devices a challenge. To overcome these limitations, we present a hemolysis testing protocol developed to enable standardization of hemolysis testing while adhering to FDA and ASTM guidelines. Static mock flow loops primed with fresh bovine blood (600 mL, Hematocrit = 27±5%, heparin titrated for ACT >300 sec) from a single-source donor were created as a platform for investigating test and predicate devices. MCSD differential pressure and temperature were maintained at 80 mmHg and 25°±2° C. Blood samples (3 ml) were collected at 0, 5, 90, 180, 270, 360 minutes to measure CBC and plasma free hemoglobin. This protocol led to 510(k) approval of two adult MCSD and has been used to test novel cannulae and a pediatric MCSD. Standardization of hemolysis testing procedures and transparency of results may enable better blood trauma characterization of MCS devices to facilitate the FDA 510(k) and PMA submission processes and improve clinical outcomes.

Continuous flow (CF) left ventricular assist devices (LVAD) support diminishes vascular pressure pulsatility. Despite its recent clinical success CF LVAD support has been associated with a higher incidence of gastrointestinal bleeding, aortic valve dysfunction and hemorrhagic strokes. To overcome this limitation, we are developing algorithms to provide vascular pulsatility using a CF LVAD. The effects of timing and synchronizing the CF LVAD flow modulation to the native myocardium, modulation amplitude, and modulation widths were studied on the native ventricle and vasculature using a computer simulation model of the circulatory system simulating heart failure. A total of over 150 combinations of varying pulse widths, beat frequencies, time shifts, and amplitudes to modulate CF LVAD flow were tested. All control algorithms maintained a mean CF LVAD flow of 5.0 ± 0.1 L/min (full support) or 2.5 ± 0.1 L/min (partial support). These algorithms resulted in an increased arterial pressure pulsatility of up to 59 mmHg, reduced left ventricular external work (LVEW) by 10–75%, and increased myocardial perfusion by up to 44% from baseline heart failure condition. Importantly, reduction in LVEW and increase in pulsatility may be adjusted to user-defined values while maintaining the same average CF LVAD flow rate. These methods of CF LVAD flow modulation may enable tailored unloading of the native ventricle to provide rest and rehabilitation (maximal unloading to rest followed by gradual reloading to wean), which may promote sustainable myocardial recovery. Further, these LVAD flow modulation patterns may reduce the incidence of adverse events associated with the CF LVAD therapy by increasing vascular pulsatility.