Feasibility of an animal model for long-term mechanical circulatory support with Impella 5.5 implanted through carotid artery access in sheep.

Impella is a mechanical circulatory support device of a catheter-based intravascular microaxial pump for left ventricular support and unloading. However, nonclinical studies assessing the effects of the extended duration of left ventricular unloading on cardiac recovery are lacking. An animal model using Impella implanted with a less invasive procedure to enable long-term support is required. This study aimed to evaluate the feasibility of an animal model for long-term support with Impella 5.5 implanted through carotid artery access in sheep.Impella 5.5 was implanted in four sheep through the proximal region of the left carotid artery without a thoracotomy, and myocardial injuries were induced by coronary microembolization. Support by Impella 5.5 was maintained for 4 weeks, and the animals were observed. The position of Impella 5.5 and cardiac function was evaluated using cardiac computer tomography at 2 and 4 weeks after implantation.All four animals completed the 4-week study without major complications. The discrepancy in the Impella 5.5 flow rate between the conscious and anesthetized states was observed depending on the device's position. Animals in whom the inflow was above the left ventricular papillary muscle had a relatively high flow rate under the maximum performance level without a suction alarm during the conscious state. Pathological changes in the aortic valve were observed. Cardiac function under the minimum performance level was observed with no remarkable deterioration.The animal model with myocardial injuries supported for 4 weeks by Impella 5.5 implanted through carotid artery access in sheep was feasible.

Hemodynamic Evaluation of Asynchronous Speed Modulation of a Continuous-Flow Left Ventricular Assist Device in an Acute-Myocardial Injury Sheep Model.

Asynchronous rotational-speed modulation of a continuous-flow left ventricular assist device (LVAD) can increase pulsatility; however, the feasibility of hemodynamic modification by asynchronous modulation of an LVAD has not been sufficiently verified. We evaluated the acute effect of an asynchronous-modulation mode under LVAD support and the accumulated effect of 6 consecutive hours of driving by the asynchronous-modulation mode on hemodynamics, including both ventricles, in a coronary microembolization-induced acute-myocardial injury sheep model. We evaluated 5-min LVAD-support hemodynamics, including biventricular parameters, by switching modes from constant-speed to asynchronous-modulation in the same animals ("acute-effect evaluation under LVAD support"). To determine the accumulated effect of a certain driving period, we evaluated hemodynamics including biventricular parameters after weaning from 6-hour (6 h) LVAD support by constant-speed or asynchronous-modulation mode ("6h-effect evaluation"). The acute-effect evaluation under LVAD support revealed that, compared to the constant-speed mode, the asynchronous-modulation mode increased vascular pulsatility but did not have significantly different effects on hemodynamics, including both ventricles. The 6 h-effect evaluation revealed that the hemodynamics did not differ significantly between the two groups except for some biventricular parameters which did not indicate negative effects of the asynchronous-modulation mode on both ventricles. The asynchronous-modulation mode could be feasible to increase vascular pulsatility without causing negative effects on hemodynamics including both ventricles. Compared to the constant-speed mode, the asynchronous-modulation mode increased pulsatility during LVAD support without negative effects on hemodynamics including both ventricles in the acute phase. Six hours of LVAD support with the asynchronous-modulation mode exerted no negative effects on hemodynamics, including both ventricles, after weaning from the LVAD.

Feasibility study of an artificial placenta system consisting of a loop circuit configuration extracorporeal membrane oxygenation with a bridge circuit in the form of the umbilical arterial-venous connection.

We developed a new artificial placenta (AP) system consisting of a loop circuit configuration extracorporeal membrane oxygenation (ECMO) with a bridge circuit designed to be applied to the fetus in the form of an umbilical arterial-venous connection. We aimed to evaluate the feasibility of the AP system by performing a hydrodynamic simulation using a mechanical mock circulation system and fetal animal experiment. The effect of the working condition of the AP system on the fetal hemodynamics was evaluated by hydrodynamic simulation using a mechanical mock circulation system, assuming the weight of the fetus to be 2 kg. The AP system was introduced to two fetal goats at a gestational age of 135 days. The general conditions of the experimental animals were evaluated. The mock simulation showed that in an AP system with ECMO in the form of an umbilical arterial-venous connection in series, it could be difficult to maintain fetal hemodynamics when high ECMO flow was applied. The developed AP system could have high ECMO flow with less umbilical blood flow; however, the possibility of excessive load on the fetal right-sided heart should be noted. In the animal experiment, kid 1 (1.9 kg) was maintained on the AP system for 12 days and allowed to grow to term. In kid 2 (1.6 kg), the AP system could not be established because of the occlusion of the system by a thrombus. The developed AP system was feasible under both in vitro and in vivo conditions. Improvements in the AP system and management of the general fetal conditions are essential.

Coronary microembolization sheep model by adjusting the number of microspheres based on coronary blood flow.

BACKGROUND: A heart failure (HF) model using coronary microembolization in large animals is indispensable for medical research. However, the heterogeneity of myocardial response to microembolization is a limitation. We hypothesized that adjusting the number of injected microspheres according to coronary blood flow could stabilize the severity of HF. This study aimed to evaluate the effect of microsphere injection based on the left coronary artery blood flow in an animal model. METHODS: Microembolization was induced by injecting different numbers of microspheres (polystyrene, diameter: 90 µm) into the left descending coronary artery of the two groups of sheep (400 and 600 times coronary blood flow [ml/min]). Hemodynamic parameters, the pressure-volume loop of the left ventricle, and echocardiography findings were examined at 0.5, 1.5, 3.5, and 6.5 h after microembolization. RESULTS: End-diastolic pressure and normalized heart rate increased over time, and were significantly higher in 600 × coronary blood flow group than those in 400 × coronary blood flow group (p = 0.04 and p < 0.01, respectively). The maximum rate of left-ventricular pressure rise and normalized stroke volume decreased over time, and were significantly lower in 600 × coronary blood flow group than those in 400 × coronary blood flow group (p < 0.01 and p < 0.01, respectively). The number of microspheres per coronary blood flow was significantly correlated with the decrease in stroke volume and the maximum rate of left ventricular pressure rise in 6.5 h (r = 0.74, p = 0.01 and r = 0.71, p = 0.02, respectively). CONCLUSIONS: Adjusting the number of injected microspheres based on the coronary blood flow enabled the creation of HF models with different degrees of severity.

Assessment of ocular blood flow in continuous-flow ventricular assist device by laser speckle flowgraphy.

Although the influence of continuous-flow left ventricular assist device (CF-LVAD) support on peripheral circulation has been widely discussed, its monitoring modalities are limited. The aim of this study was to assess the peripheral circulation using the laser speckle flowgraph (LSFG) which can quantitatively measure the ocular blood flow. We implanted a centrifugal CF-LVAD (EVAHEART®; Sun Medical Technology Research Corporation, Nagano, Japan) in five adult goats (body weight 44.5 ± 2.9 kg) under general anesthesia. The waveform of the central retinal artery using the mean blur rate (MBR) for ocular blood velocity and fluctuations as a parameter of pulsatility were obtained before LVAD implantation and after LVAD full-bypass support. The MBR waveform and LSFG fluctuation data were compared with the waveform and pulsatility index of the external carotid artery using an ultrasonic flow meter to evaluate circulatory patterns at different levels. The MBR waveform pattern of the central retinal artery was pulsatile before LVAD implantation and less pulsatile under LVAD full bypass. The fluctuation was 14.7 ± 1.86 before LVAD implantation and 3.85 ± 0.61 under LVAD full bypass (p < 0.01), respectively. The fluctuations of LSFG showed a strong correlation with the pulsatility index of the external carotid artery meaning that similar changes in circulatory pattern were observed at two different levels. Measuring the ocular blood flow using LSFG has potential utility for the assessment of the status of the peripheral circulation and its pulsatility during CF-LVAD.

Evaluation of cardiac beat synchronization control for a rotary blood pump on valvular regurgitation with a mathematical model.

We have studied the cardiac beat synchronization (CBS) control for a rotary blood pump (RBP) and revealed that it can promote pulsatility and reduce cardiac load. Besides, patients with LVAD support sometimes suffer from aortic and mitral regurgitation (AR and MR). A control method for the RBP should be validated in wider range of conditions to clarify its benefits and pitfalls prior to clinical application. In this study, we evaluated pulsatility and cardiac load reduction obtained with the CBS control on valvular failure conditions with a mathematical model. Diastolic assist could reduce cardiac load on the left ventricle by decreasing external work of the ventricle even in MR cases while it was not so effective in AR cases. Systolic assist can still promote pulsatility in AR and MR cases; however, aortic valve function should be carefully confirmed since pulse pressure can be wider not due to systolic assist but to AR.

Preclinical biocompatibility study of ultra-compact durable ECMO system in chronic animal experiments for 2 weeks.

Although the innovation has come in ECMO field, many problems remain unresolved. One of the main problems is about long-term durability and biocompatibility. Another is the system's size, weight, and its complicated equipment. For the former problem, we have previously developed ECMO system which consists of a tiny, hydrodynamically levitated centrifugal pump (BIOFLOAT-NCVC), a membrane oxygenator with hollow polyolefin fibers (BIOCUBE-NCVC), and the circuit treated with a heparin-bonding material (T-NCVC coating), and reported three cases of animal experiments for 30-day heparin-free drive. For the latter problem, we have integrated these elements to the compact system with sensors of temperature, pressure, and SvO2, and blood flow. Its installation area is 595 cm2, weighs 8.9 kg with attachable oxygen cassette, and battery which could last an hour at least. To evaluate the biocompatibility of this system, this ECMO was installed in four goats. Scheduled duration was 14 days. Heparin was continuously infused to control their ACT between 150 and 200 s except one 2-week experiment without systemic heparinization. All of the four goats survived till the scheduled termination. Function of the pump and the oxygenator during ECMO was stable. No obvious adverse events were observed. All lab data were of normal range after 1 week. Small infarctions were found at kidneys, but they were not clinically significant. No thrombus was found in the pump system. The oxygenators were extremely clean except a little thrombus formation; while, the heparin-free examination revealed acceptable cleanliness. The present study revealed good anti-thrombogenicity of this ultra-compact durable ECMO system with heparinization. Our system encourages awake and extubated management, rehabilitation, inter-hospital transfer, and prehospital initiation of ECMO.

A Novel Extracorporeal Continuous-Flow Ventricular Assist System for Patients With Advanced Heart Failure　- Initial Clinical Experience.

BACKGROUND: Bridge-to-decision (BTD) devices providing temporary mechanical circulatory support should be introduced to patients with advanced heart failure. This study evaluated the effectiveness and safety of a BTD device comprising an innovative extracorporeal continuous-flow temporary ventricular assist device (VAD) driven by a novel hydrodynamically levitated centrifugal flow blood pump.Methods and Results:Nine patients, comprising 3 with dilated cardiomyopathy, 3 with fulminant myocarditis, and 3 with ischemic heart disease, and 6 males, whose mean age was 47.7±8.1 years, were enrolled into the study. Six patients had Interagency Registry for Mechanically Assisted Circulatory Support profile 1, and 3 were profile 2. The primary endpoint was a composite of survival free from device-related serious adverse events and complications during circulatory support. Eight patients received left ventricular support, of whom 3 received concomitant right ventricular support using extracorporeal membrane oxygenation circuits, as a consequence of severe respiratory failure. One patient with fulminant myocarditis received biventricular support using the novel VAD system. After 19.0±13.5 days, 3 patients were weaned from circulatory support, because their native cardiac function recovered, and 6 patients required conversion to a durable device as a bridge-to-transplantation. One patient had non-disabling ischemic stroke episodes, and no patients died. CONCLUSIONS: This novel extracorporeal VAD system with a hydrodynamically levitated centrifugal pump can safely and successfully bridge patients with advanced heart failure to subsequent therapeutic stages.

Mathematical evaluation of cardiac beat synchronization control used for a rotary blood pump.

We studied a control method of rotary blood pumps (RBPs), which is called as the cardiac beat synchronization (CBS) system. Usually, RBPs operate at constant target rotational speed, meanwhile, the CBS system modulates target speed synchronizing with cardiac beat. We built a computer simulation method to evaluate the CBS system. This simulator acquires a mathematical model of a circulatory system including a RBP and can provide us the theoretical hemodynamics when our control method is applied. We compared theoretical results with experimental ones with the model focusing on both pulsatility and aortic valve (AV) opening interval enhanced by the CBS system. Our simulator could reproduce behavior of the circulatory system whether the RBP is connected or not. Comparison among no RBP, constant assist, systolic assist, and diastolic assist modes indicated that pulsatility is enhanced with systolic assist theoretically. While systolic assist decreased AV opening interval, diastolic assist made it longer than the ones in other control strategies.

Interventricular dyssynchrony during continuous-flow left ventricular assist device support: observation using the conductance method.

The purpose of this study was to observe and clarify the interventricular dysscynchrony caused by continuous-flow left ventricular assist device (CF-LVAD) support using the conductance method. During CF-LVAD support, the systolic phase of the left ventricle (LV) becomes shorter than that of the right ventricle (RV). Accordingly, timing of the systole and diastole during the cardiac cycle is not synchronous between the LV and RV. In this study, we evaluated this phenomenon in a normal heart model using the adult goat (n = 5, body weight 44.5 ± 2.9 kg). A centrifugal LVAD was implanted under general anesthesia. We inserted the conductance catheter into the RV and LV to obtain the pressure-volume relationship of the two ventricles simultaneously. We defined the dyssynchronous status as the sign (plus or minus) of the LV volume-change opposite to that of RV volume-change. Dyssynchronous phase of the cardiac cycle was observed in 5.6 ± 0.65% of hearts under LVAD pump-off and 25.3 ± 3.3% under LVAD full bypass, respectively (p < 0.05). To the best of our knowledge, this is the first experimental report clarifying interventricular dyssynchrony during CF-LVAD support using the conductance method. Quantification of this phenomenon under various support conditions and assessment of influences on the right ventricular function will be studied in future studies.

Quantification of interventricular dyssynchrony during continuous-flow left ventricular assist device support.

Under continuous-flow left ventricular assist device (CF-LVAD) support, the ventricular volume change and cardiac cycle between the left ventricle (LV) and right ventricle (RV) become dyssynchronous due to the shortening of the LV systole. The purpose of this study was to quantify interventricular dyssynchrony based on different CF-LVAD support conditions and assess its relationship with LV unloading. In this study, we evaluated seven goats (body weight 44.5 ± 6.5 kg) with normal hearts. A centrifugal LVAD was implanted under general anesthesia. We inserted the conductance catheters into the left ventricle (LV) and right ventricle (RV) to assess the volume signal simultaneously. We defined the interventricular dyssynchrony as a signal (increase or decrease) of LV volume (LVV) change opposite to that of RV volume (RVV) (i.e., (dLVV/dt) × (dRVV/dt) < 0). The duration of interventricular dyssynchrony (DYS) was reported as the percentage of time that a heart was in a dyssynchronous state within a cardiac cycle. The mean DYS of normal hearts, hearts with LVAD clamp and hearts supported by LVADs with a bypass rate of 50%, 75% and 100% were 5.6 ± 1.6%, 8.7 ± 2.4%, 8.6 ± 2.8%, 15.1 ± 5.1%, and 25.6 ± 8.0%, respectively. Furthermore, the DYS was found to be associated with the degree of LV stroke volume reduction caused by LV unloading. These findings may be useful for understanding interventricular interactions and physiology during CF-LVAD support. Influences on the right ventricular function and heart failure models warrant further study.

Miniaturized centrifugal ventricular assist device for bridge to decision: Preclinical chronic study in a bovine model.

We developed a novel miniaturized extracorporeal centrifugal pump "BIOFLOAT NCVC (Nipro Corporation Osaka, Japan) as a ventricular assist device (VAD) and performed a preclinical study that is part of the process for its approval as a bridge to decision by the pharmaceutical and medical device agencies. The aim of this study was to assess the postoperative performance, hemocompatibility, and anticoagulative status during an extended period of its use. A VAD system, consisting of a hydrodynamically levitated pump, measuring 64 mm by 131 mm in size and weighing 635 g, was used. We installed this assist system in 9 adult calves (body weight, 90 ± 13 kg): as left ventricular assist device (LVAD) in 6 calves and right ventricular assist device (RVAD) in 3 calves, for over 30 days. Perioperative hemodynamic, hematologic, and blood chemistry measurements were obtained and end-organ effects on necropsy were investigated. All calves survived for over 30 days, with a good general condition. The blood pump was operated at a mean rotational speed and a mean pump flow of 3482 ± 192 rpm and 4.08 ± 0.15 L/min, respectively, for the LVAD and 3902 ± 210 rpm and 4.24 ± 0.3 L/min, respectively, for the RVAD. Major adverse events, including neurological or respiratory complications, bleeding events, and infection were not observed. This novel VAD enabled a long-term support with consistent and satisfactory hemodynamic performance and hemocompatibility in the calf model. The hemodynamic performance, hemocompatibility, and anticoagulative status of this VAD system were reviewed.

Humoral factors secreted from adipose tissue-derived mesenchymal stem cells ameliorate atherosclerosis in Ldlr-/- mice.

AIMS: Atherosclerosis is a chronic inflammatory disease of the vasculature. Mesenchymal stem cells (MSCs) exert immunomodulatory and immunosuppressive effects by secreting humoral factors; however, the intravascular MSC administration presents a risk of vascular occlusion. Here, we investigated both the effect of conditioned medium from cultured MSCs (MSC-CM) on atherosclerosis and the underlying mechanism. METHODS AND RESULTS: Low-density lipoprotein receptor-deficient (Ldlr-/-) mice were fed a high-fat diet and received intravenous injections of either MSC-CM from adipose tissue-derived MSCs or control medium 2×/week for 13 weeks. MSC-CM treatment decreased the atherosclerotic plaque area in the aorta and aortic root of Ldlr-/- mice by 41% and 30%, respectively, with no change in serum lipoprotein levels. Histopathologically, the MSC-CM treatment decreased the expression of cell adhesion molecules (CAMs) and the accumulation of macrophages on the vascular walls. Extracellular vesicles (EVs) and supernatant (MSC-CM supernatant) were separated from the MSC-CM by ultracentrifugation. In tumour necrosis factor-α stimulated human aortic endothelial cells (HAOECs), both the MSC EVs and MSC-CM supernatant decreased CAM expression by inhibiting the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NFκB) pathways. In macrophages, the MSC-CM supernatant decreased the lipopolysaccharide-induced increases in M1 marker expression by inhibiting both the MAPK and NFκB pathways and increased the expression of M2 markers by activating the signal transducer and activator of transcription 3 pathway. In co-culture, inflamed HAOECs pretreated with MSC-CM supernatant and MSC EVs exhibited decreased monocyte adhesion to HAOECs. In addition, the neutralization of hepatocyte growth factor (HGF) in MSC-CM or MSC-CM supernatant attenuated their abilities to suppress monocyte adhesion to HAOECs in co-culture. CONCLUSION: MSC-CM ameliorated atherosclerosis in Ldlr-/- mice and suppressed CAM expression and macrophage accumulation in the vascular walls. Humoral factors, including HGF and EVs from MSCs, hold promise as therapeutic agents to reduce the residual risk of coronary artery diseases.

Accurate Method of Quantification of Aortic Insufficiency During Left Ventricular Assist Device Support by Thermodilution Analysis: Proof of Concept and Validation by a Mock Circulatory System.

Aortic insufficiency (AI) is an intractable complication during long term left ventricular assist device (LVAD) support. Conventional evaluation of AI depends on ultrasound evaluation, which is mainly a qualitative, not a quantitative method. The pathophysiology of AI during LVAD is shunt formation. Conversely, the methods to quantify the shunt of congenital heart disease are already established, and among these is the thermodilution technique. To develop an accurate quantification method for AI (namely, a shunt), we have adopted this conventional thermodilution technique. The purpose of this study was to determine whether this technique could calculate the shunt magnitude accurately in a simulated cardiac circuit. The magnitude of AI was represented by the recirculation rate (RR), defined by regurgitant flow (RF) divided by pump flow (PF). A mock circulatory system for an LVAD endurance test (Laboheart NCVC; Iwaki & Co., Ltd, Tokyo, Japan) was used. A centrifugal LVAD was equipped in the Laboheart in parallel from the left ventricle to the aorta. A parallel shunt circuit was created across the aortic valve to mimic AI. To control the magnitude of AI, the resistance of the AI circuit was changed. Heart failure was simulated by controlling the parameters of the Laboheart. The LVAD was driven in full bypass condition, confirming that the heart did not eject forward flow via the aortic valve. PF, RF, and the temperatures of two points of the outflow graft measured with two thermistors were monitored. Analyses were started after confirming that circuit water temperature was the same as room temperature. Hot water was injected from a port between the two thermistors of the outflow conduit. The time-temperature curves of both thermistors were recorded, and RR was calculated. Two values of RR calculated in two different ways (by analyzing thermistors and by calculating from flowmeter values) were compared. Multiple measurements were done by changing the magnitude of AI. The existence of AI could be easily confirmed by analyzing the temperature data. There was a good correlation between RR by thermistor and RR by flowmeter data (r = 0.984). Furthermore, the two RR values were almost the same. This novel technique could provide an accurate method for quantifying AI during LVAD support. This method can be clinically applied by left-sided cardiac catheterization if a dedicated catheter with two thermistors and an injection hole is developed.

The angle of the outflow graft to the aorta can affect recirculation due to aortic insufficiency under left ventricular assist device support.

Aortic insufficiency (AI) is a crucial complication during continuous-flow left ventricular assist device (LVAD) support. Our previous clinical study suggested that a larger angle between the outflow graft and the aorta (O-A angle) could cause AI progression. This study examined the effect of the O-A angle on the hemodynamics of AI under LVAD support in an acute animal experimental model. An LVAD was installed in seven calves, with the inflow cannula inserted from the LV apex and with the outflow graft sutured at the ascending aorta. The AI model was made using a temporary inferior vena cava filter inserted from the LV apex and placed at the aortic valve. Cardiac dysfunction was induced by continuous beta-blocker infusion. Hemodynamic values and the myocardial oxygen extraction rate (O2ER) were evaluated at three O-A angles (45°, 90°, and 135°) over three levels of AI (none, Sellers I-II AI, and Sellers III-IV AI). The recirculation rate, defined as the percentage of regurgitation flow to LVAD output, was calculated. Systemic flow tended to decrease with a larger O-A angle. The recirculation rate was significantly increased with a larger O-A angle (22, 23, and 31% at 45°, 90°, and 135° in Sellers III-IV AI, respectively). Coronary artery flow was decreased at a larger O-A angle (86, 76 and 75 mL/min at 45°, 90°, and 135° in Sellers I-II AI, respectively, and 77, 67, and 56 mL/min at 45°, 90°, and 135° in Sellers III-IV AI, respectively). O2ER tended to increase with a larger O-A angle (40, 43, and 49% at 45°, 90°, and 135° in Sellers III-IV AI, respectively). A larger O-A angle can increase the recirculation due to AI and can be disadvantageous to LVAD-AI hemodynamics and myocardial oxygen metabolism.

Evaluation of the Novel Centrifugal Pump, CAPIOX SL, in Chronic Large Animal Experiments.

In the development of a new device for extracorporeal circulation, long-term durability and biocompatibility are required. The CAPIOX SL Pump (SL pump, Terumo Corporation, Tokyo, Japan), which is a centrifugal pump using a two-pivot bearing, was developed with the hope of suppressing pump thrombus formation around the bearings. This study aimed to evaluate the in vivo performance of the SL pump in the condition assumed severe clinical situation for long-term extracorporeal membrane oxygenation (ECMO) support. Extracorporeal circulation using the SL pump was installed in three goats, with drainage from the inferior vena cava and infusion into the right jugular artery. The animals were maintained with target pump flow of 2.0-3.0 L/min for 3 or 7 days. Anticoagulation was performed by continuous infusion of heparin with a target activated coagulation time (ACT) of 200 ± 50 s. Blood tests were performed regularly. After 3 or 7 days, autopsies were performed on all animals. The pumps were disassembled and observed for thrombus formation. The results were compared with those of our previous study of the current model of the centrifugal pump (SP pump). All animals were successfully managed within target pump flows and ACT values during the scheduled period, with no adverse events. No thrombus formation was found around the bearing of the SL pump. The blood tests showed normal major organ functions, and platelet consumption and hemolysis were significantly lower in this study compared to the previous study of the SP pump. The CAPIOX SL Pump showed excellent durability and biocompatibility in a large animal experiment.

Novel temporary left ventricular assist system with hydrodynamically levitated bearing pump for bridge to decision: initial preclinical assessment in a goat model.

The management of heart failure patients presenting in a moribund state remains challenging, despite significant advances in the field of ventricular assist systems. Bridge to decision involves using temporary devices to stabilize the hemodynamic state of such patients while further assessment is performed and a decision can be made regarding patient management. We developed a new temporary left ventricular assist system employing a disposable centrifugal pump with a hydrodynamically levitated bearing. We used three adult goats (body weight, 58-68 kg) to investigate the 30-day performance and hemocompatibility of the newly developed left ventricular assist system, which included the pump, inflow and outflow cannulas, the extracorporeal circuit, and connectors. Hemodynamic, hematologic, and blood chemistry measurements were investigated as well as end-organ effect on necropsy. All goats survived for 30 days in good general condition. The blood pump was operated at a rotational speed of 3000-4500 rpm and a mean pump flow of 3.2 ± 0.6 L min. Excess hemolysis, observed in one goat, was due to the inadequate increase in pump rotational speed in response to drainage insufficiency caused by continuous contact of the inflow cannula tip with the left ventricular septal wall in the early days after surgery. At necropsy, no thrombus was noted in the pump, and no damage caused by mechanical contact was found on the bearing. The newly developed temporary left ventricular assist system using a disposable centrifugal pump with hydrodynamic bearing demonstrated consistent and satisfactory hemodynamic performance and hemocompatibility in the goat model.

Differences in clotting parameters between species for preclinical large animal studies of cardiovascular devices.

Several species of domestic animals are used in preclinical studies evaluating the safety and feasibility of medical devices; however, the relevance of animal models to human health is often not clear. The purpose of this study was to compare the clotting parameters of animal models to determine which animals most adequately mimic human clotting parameters. The clotting parameters of the different species were assessed in whole blood by in vitro thromboelastography using the clotting activators, such as tissue factor (extrinsic clotting screening test, EXTEM®) and partial thromboplastin phospholipid (intrinsic clotting screening test, IINTEM®). The measurements were performed using normal blood samples from humans (n = 13), calves (n = 18), goats (n = 56) and pigs (n = 8). Extrinsic clotting time (CT) and the intrinsic CT were significantly prolonged in calves compared to humans (249.9 ± 91.3 and 376.4 ± 124.4 s vs. 63.5 ± 11.8 and 192.5 ± 29.0 s, respectively, p < 0.01). The maximum clot firmness (MCF) in domestic animals (EXTEM®: 77-87 mm, IINTEM®: 66-78 mm) was significantly higher than that of humans (EXTEM®: 59.1 ± 6.0 mm, IINTEM®: 58.8 ± 1.5 mm, p < 0.01), and calves and goats exhibited longer time to MCF (MCF-t) than did humans and pigs (p < 0.01). Our results show that there are relevant differences in the four species' extrinsic and intrinsic clotting parameters. These cross-comparisons indicate that it is necessary to clarify characteristics of clotting properties in preclinical animal studies.

Preclinical animal study of the NIPRO-ventricular assist device for use in pediatric patients.

Although the outcomes of patients with end-stage heart failure treated with implantable left ventricular assist devices have improved, extracorporeal left ventricular assist devices continue to play an important role, especially in pediatric patients. The present study aimed to examine the long-term biocompatibility of a small-sized extracorporeal pneumatic left ventricular assist device (NIPRO-LVAD) used in a 30- to 90-day animal experiment. The NIPRO-LVAD was designed for pediatric patients or small-sized adults. The left ventricular assist device system was installed in four adult Shiba goats weighing 25.7 ± 4.78 kg via a left thoracotomy. The outflow graft was sewn to the descending aorta and the inflow cannula was placed in the left ventricle through the left ventricular apex. Oral antiplatelet (aspirin) and oral anticoagulation therapies (warfarin) were also administered. Three out of four animals survived for a 30-day period and two goats survived for 90 days. One animal was killed early because of low pump flow due to obstruction of the inflow cannula by a left ventricular endocardial vegetation. The blood pump exhibited sufficient hydrodynamic performance with blood flows of 1.5-2.0 L/min. The animals' laboratory values were within normal limits by postoperative day 7. There was no significant thrombus formation on the housing, diaphragm, or valves of the explanted pumps. Based on the biocompatibility demonstrated in this animal study, the explanted small-sized pump may be suitable for use in left ventricular assist device systems for pediatric patients.

Changing pulsatility by delaying the rotational speed phasing of a rotary left ventricular assist device.

Continuous-flow left ventricular assist devices (LVADs) have improved the prognosis of end-stage heart failure. However, continuous-flow LVADs diminish pulsatility, which possibly result in bleeding, aortic insufficiency, and other adverse effects. We previously developed a novel control system for a continuous-flow LVAD (EVAHEART®; Sun Medical), and demonstrated that we could create sufficient pulsatility by increasing its rotational speed (RS) in the systolic phase (Pulsatile Mode) in the normal heart model. Here, we aimed to evaluate differences between systolic assist with advanced and delayed loads by shifting the timing of increased RS. We implanted EVAHEART in six goats (55.3 ± 4.3 kg) with normal hearts. We reduced their heart rates to <60 bpm using propranolol and controlled the heart rates at 80 and 120 bpm using ventricular pacing. We shifted the timing of increasing RS from -60 to +60 ms in the systolic phase. We found significant increases in all the following parameters when assessments of delayed timing (+60 ms) were compared with assessments of advanced timing (-60 ms): pulse pressure, mean dP/dt max of aortic pressure, and energy-equivalent pulse pressure. During continuous-flow LVAD support, pulsatility can be controlled using a rotary pump. In particular, pulsatility can be shifted by delaying increased RS.