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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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

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. [ABSTRACT FROM AUTHOR]

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

Continuous-flow ventricular assist devices (CVADs) have gained widespread use as an effective clinical therapy for patients with advanced-stage heart failure. Axial and centrifugal CVADs have been successfully used as bridge-to-transplant and destination therapy. CVADs are smaller, more reliable, and less complex than the first-generation pulsatile-flow ventricular assist devices. Despite their recent clinical success, arteriovenous malformations, gastrointestinal bleeding, hemorrhagic strokes, aortic valve insufficiency, and valve fusion have been reported in heart failure patients supported by CVADs. It has been hypothesized that diminished arterial pressure and flow pulsatility delivered by CVAD may be a contributing factor to these adverse events. Subsequently, the clinical significance of vascular pulsatility continues to be highly debated. Studies comparing pulsatile-flow and continuous-flow support have presented conflicting findings, largely due to variations in device operation, support duration, and the criteria used to quantify pulsatility. Traditional measurements of pulse pressure and pulsatility index are less effective at quantifying pulsatility for mechanically derived flows, particularly with the growing trend of CVAD speed modulation to achieve various pulsatile flow patterns. Kinetic measurements of energy equivalent pressure and surplus hemodynamic energy can better quantify pulsatile energies, yet technologic and conceptual challenges are impeding their clinical adaption. A review of methods for quantifying vascular pulsatility and their application as a research tool for investigating physiologic responses to CVAD support are presented. [ABSTRACT FROM AUTHOR]

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

Background: Left ventricular assist devices are increasingly used to treat patients with advanced and otherwise refractory heart failure as bridge to transplant or destination therapy. We evaluated a new miniaturized left ventricular assist device that requires minimal surgery for implantation, potentially allowing implantation in earlier stage heart failure. Methods: HeartWare (Miami Lakes, Fla) developed transapical miniaturized ventricular assist device. Acute (n = 4), 1-week (n = 2), and 30-day (n = 4) bovine model experiments evaluated hemodynamic efficacy and biocompatibility of the device, which was implanted through small left thoracotomy with single insertion at apex of left ventricle without cardiopulmonary bypass. The device outflow cannula was positioned across the aortic valve. The international normalized ratio was maintained between 2.0 and 2.5 with warfarin. Hemodynamic, echocardiographic, fluoroscopic, hematologic, and blood chemistry measurements were evaluated. Results: The device was successfully implanted through the left ventricular apex in all 10 animals. The device was operated at 15,000 ± 1000 rpm (power consumption, 3.5–6.0 W). The device maintained normal end-organ perfusion with no significant hemolysis (0–30 mg/dL). There were no pump failures or device-related complications. At autopsy, no abnormalities were seen in endocardium, aortic valve leaflets, or aortic root. There was no evidence of thromboembolism or abnormalities in any peripheral end organs. Conclusions: We successfully demonstrated feasibility of a novel intraventricular assist device that can be completely implanted through left ventricular apex. This transapical surgical approach eliminates needs for sternotomy, device pocket, cardiopulmonary bypass, ventricular coring, and construction of an outflow graft anastomosis. [ABSTRACT FROM AUTHOR]