Language：Japanese   Publisher：北海道外科学会  

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Language：Japanese   Publisher：北海道外科学会  

J-GLOBAL

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Language：Japanese   Publisher：北海道外科学会  

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Language：Japanese   Publisher：北海道外科学会  

J-GLOBAL

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Language：Japanese   Publisher：北海道外科学会  

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Language：Japanese   Publisher：北海道外科学会  

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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.

DOI： 10.1007/s10047-021-01265-5

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publisher：北海道外科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Japan  

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.

DOI： 10.1007/s10047-020-01180-1

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Language：Japanese   Publisher：(一社)日本人工臓器学会  

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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.

DOI： 10.1111/aor.13795

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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.

DOI： 10.1253/circj.CJ-19-1122

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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© 2020 International Center for Artificial Organs (ICAOT) and Transplantation and Wiley Periodicals LLC. 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.

DOI： 10.1111/aor.13795

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

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© 2019, The Japanese Society for Artificial Organs. 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.

DOI： 10.1007/s10047-019-01117-3

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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.

DOI： 10.1007/s10047-019-01117-3

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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.

DOI： 10.1007/s10047-019-01109-3

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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.

DOI： 10.1007/s10047-019-01115-5

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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.

DOI： 10.1111/aor.13459

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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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.

DOI： 10.1111/aor.13158

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Aortic insufficiency (AI) is a worrisome complication under left ventricular assist device (LVAD) support. AI progression causes LVAD-left ventricular (LV) recirculation and can require surgical intervention to the aortic valve. However, the limitations of LVAD support are not well known. Using an animal model of LVAD with AI, the effect of AI progression on hemodynamics and myocardial oxygen metabolism were investigated. Five goats (Saanen 48 ± 2 kg) underwent centrifugal type LVAD, EVAHEART, implantation. The AI model was established by placing a vena cava filter in the aortic valve. Cardiac dysfunction was induced by continuous beta-blockade (esmolol) infusion. Hemodynamic values and myocardial oxygen extraction ratio (O2ER) were evaluated while changing the degree of AI which was expressed as the flow rate of LVAD-LV recirculation (recirculation rate). Diastolic aortic pressure was decreased with AI progression and correlated negatively with the recirculation rate (p = 0.00055). Systolic left ventricular pressure (LVP) and mean left atrial pressure (LAP) were increased with AI progression and correlated positively with the recirculation rate (p = 0.010, 0.023, respectively). LVP and LAP showed marked exponential increases when the recirculation rate surpassed 40%. O2ER was also increased with AI progression and had a significant positive correlation with the recirculation rate (p = 0.000043). O2ER was increased linearly, with no exponential increase. AI progression made it difficult to reduce the cardiac pressure load, worsening myocardial oxygen metabolism. The exponential increase of left heart pressures could be the key to know the limitation of LVAD support against AI progression.

DOI： 10.1007/s10047-018-1027-4

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INTRODUCTION:: Recently, the use of veno-venous extracorporeal membrane oxygenation for adult patients with severe acute respiratory failure has increased. We previously investigated the optimal return cannula position; however, the optimal drainage cannula position has not yet been fully clarified. The aim of this study was to investigate the optimal drainage cannula position. METHODS:: Veno-venous extracorporeal membrane oxygenation was performed in four adult goats (mean body weight 59.6 ± 0.6 kg). The position of the drainage cannula was varied among the right atrium, the upper inferior vena cava, and the lower inferior vena cava, whereas the position of the return cannula was fixed in the superior vena cava. The recirculation fraction and arterial oxygen saturation and pressure (SaO2, PaO2) were measured in all drainage cannula positions. RESULTS:: In the lower inferior vena cava drainage cannula position, the recirculation fraction was the lowest. In the lower inferior vena cava, upper inferior vena cava, and right atrium drainage cannula positions at 3 L/min, SaO2 and PaO2 after 20 min were 92.9% ± 4.9% and 75.1 ± 26.0 mm Hg, 99.5% ± 0.5% and 113.8 ± 20.9 mm Hg, and 93.8% ± 6.2% and 91.9 ± 17.7 mm Hg, respectively. CONCLUSION:: With respect to blood oxygenation, the optimal position for the drainage cannula was the upper inferior vena cava. These findings suggested that blood from the superior vena cava, inferior vena cava, and hepatic vein was most efficiently drained in the upper inferior vena cava cannula position.

DOI： 10.1177/0391398818795357

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BACKGROUND: 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. The purpose of this study (NCVC-BTD_01, National Cerebral and Cardiovascular Center-Bridge to Dicision_01) is to assess the safety and effectiveness of the newly developed extracorporeal continuous-flow ventricular assist system employing a disposable centrifugal pump with a hydrodynamically levitated bearing (BR16010) use as a bridge-to-decision therapy for patients with severe heart failure or refractory cardiogenic shock. METHOD/DESIGN: NCVC-BTD_01 is a single-center, single-arm, open-label, exploratory, medical device, investigator-initiated clinical study. It is conducted at the National Cerebral and Cardiovascular Center in Japan. A total of nine patients will be enrolled in the study. The study was planned using Simon's minimax two-stage phase design. The primary endpoint is a composite of survival free of device-related serious adverse events and complications during device support. For left ventricular assistance, withdrawal of a trial device due to cardiac function recovery or exchange to other ventricular assist devices (VADs) for the purpose of bridge to transplantation (BTT) during 30 days after implantation will be considered study successes. For right ventricular assistance, withdrawal of tal device due to right ventricular function recovery within 30 days after implantation will be considered a study success. Secondary objectives include changes in brain natriuretic peptide levels (7 days after implantation of a trial device and the day of withdrawal of a trial device), period of mechanical ventricular support, changes in left ventricular ejection fraction (7 days after implantation of a trial device and the day of withdrawal of a trial device), and changes in left ventricular diastolic dimension (7 days after implantation of a trial device and the day of withdrawal of a trial device). ETHICS AND DISSEMINATION: We will disseminate the findings through regional, national, and international conferences and through peer-reviewed journals. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR; R000033243) registered on 8 September 2017.

DOI： 10.1007/s10557-018-6796-8

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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.

DOI： 10.1111/aor.13100

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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.

DOI： 10.1007/s10047-018-1064-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer New York LLC  

Background: 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. The purpose of this study (NCVC-BTD_01, National Cerebral and Cardiovascular Center-Bridge to Dicision_01) is to assess the safety and effectiveness of the newly developed extracorporeal continuous-flow ventricular assist system employing a disposable centrifugal pump with a hydrodynamically levitated bearing (BR16010) use as a bridge-to-decision therapy for patients with severe heart failure or refractory cardiogenic shock. Method/Design: NCVC-BTD_01 is a single-center, single-arm, open-label, exploratory, medical device, investigator-initiated clinical study. It is conducted at the National Cerebral and Cardiovascular Center in Japan. A total of nine patients will be enrolled in the study. The study was planned using Simon’s minimax two-stage phase design. The primary endpoint is a composite of survival free of device-related serious adverse events and complications during device support. For left ventricular assistance, withdrawal of a trial device due to cardiac function recovery or exchange to other ventricular assist devices (VADs) for the purpose of bridge to transplantation (BTT) during 30 days after implantation will be considered study successes. For right ventricular assistance, withdrawal of tal device due to right ventricular function recovery within 30 days after implantation will be considered a study success. Secondary objectives include changes in brain natriuretic peptide levels (7 days after implantation of a trial device and the day of withdrawal of a trial device), period of mechanical ventricular support, changes in left ventricular ejection fraction (7 days after implantation of a trial device and the day of withdrawal of a trial device), and changes in left ventricular diastolic dimension (7 days after implantation of a trial device and the day of withdrawal of a trial device). Ethics and Dissemination: We will disseminate the findings through regional, national, and international conferences and through peer-reviewed journals. Trial Registration: UMIN Clinical Trials Registry (UMIN-CTR
R000033243) registered on 8 September 2017.

DOI： 10.1007/s10557-018-6796-8

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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 &lt
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 &lt
0.01), and calves and goats exhibited longer time to MCF (MCF-t) than did humans and pigs (p &lt
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.

DOI： 10.1007/s10047-017-1003-4

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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.

DOI： 10.1007/s10047-017-1009-y

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Tissue-engineered heart valves (TEHVs) are expected to be viable grafts. However, it is unknown whether they transit their histological structure after implantation. We developed a novel autologous TEHV (named stent biovalve) for transcatheter implantation, using in-body tissue engineering based on a tissue encapsulation phenomenon. In this study, a time-course histological transition of implanted biovalves was investigated in goats. Three types of stent biovalves were prepared by 2 month embedding of plastic molds mounted with metallic stents, in the subcutaneous spaces. After extracting the molds with tissue and removing the molds only, stent biovalves were constituted entirely from the connective tissues. Stent biovalves were implanted in the aortic or pulmonary valve position of other goats with transcatheter technique. In each animal, the stent biovalve was explanted at 1 month step (from 1 to 6 months) or as long as possible. Total 12 goats (five for aortic and seven for pulmonary) were successfully implanted. The maximum duration became 19 months as a result. Even then the leaflets of the biovalves kept their shape and elasticity, and neither calcification nor thrombi were observed in any cases and duration. Histology showed the recipients' cells covering the laminar surface of the leaflets like the endothelium even after 1 month. The cells have also migrated in the leaflets gradually and finally constructed characteristic 3 layered tissues like native leaflets. Implanted stent biovalves can adapt their histological structure to the environment. They have a potential as viable grafts keeping better function and biocompatibility.

DOI： 10.1097/MAT.0000000000000769

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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.

DOI： 10.1007/s10047-017-0989-y

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Language：Japanese   Publisher：(一社)日本集中治療医学会  

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OBJECTIVES: Continuous-flow left ventricular assist devices (CF-LVADs) are widely used to treat patients with end-stage heart failure. Although continuous flow is different from physiological flow, patients show improved outcomes after CF-LVAD implantation. A novel rotational speed (RS) modulation system used with CF-LVAD (EVAHEART) has been developed, which can change RS in synchronization with the native cardiac cycle. We conducted the present study to investigate the influence of the system on pulsatility in peripheral perfusion. METHODS: We implanted EVAHEART devices at the left ventricular apex drainage and the descending aortic perfusion via a left thoracotomy in 7 adult goats (56.8 ± 8.1 kg). Cardiogenic shock was induced by a beta-adrenergic antagonist. We evaluated the pulsatility index and maximal time derivative of flow rate (max dQ/dt) of the carotid, mesenteric and renal arteries. These data were collected with a bypass rate of 100% under 4 conditions: circuit clamp, continuous mode, co-pulse mode (increased RS during systole) and counter-pulse mode (increased RS during diastole). RESULTS: The pulsatility indexes of the carotid and renal artery in the co-pulse mode were significantly higher than in the other modes. Max dQ/dt of the carotid and mesenteric arteries were significantly higher in the co-pulse mode than in the counter-pulse mode. CONCLUSIONS: The co-pulse mode of this novel RS modulation system may provide better pulsatility not only in the large vessels but also in the peripheral vasculature.

DOI： 10.1093/icvts/ivx236

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Background. Femoral venoarterial extracorporeal membrane oxygenation (VA-ECMO) is widely used to maintain blood flow in patients with cardiogenic shock. However, retrograde blood flow increases left ventricular (LV) afterload during femoral VA-ECMO. Additional support by means of an intraaortic balloon pump (IABP) alleviates LV afterload but is associated with significant adverse events. We previously developed a system for rotational speed modulation in synchrony with the native cardiac cycle, for use with implantable continuous-flow LV assist devices. Here, we aimed to evaluate whether our novel rotation speed modulation system can improve coronary artery flow and reduce LV during femoral VA-ECMO.& para;& para;Methods. VA-ECMO was installed by means of right atrial drainage and distal abdominal aortic perfusion in six adult goats. Cardiogenic shock was induced with beta-adrenergic antagonist infusion. An IABP was placed in the descending aorta. LV stroke work, LV end-systolic pressure, and coronary arterial flow were evaluated. Data were collected under five conditions (modes): baseline, circuit-clamp (cardiogenic shock), continuous mode (constant rotational speed), counterpulse mode (increasing rotational speed during diastole), and continuous mode with IABP support.& para;& para;Results. LV stroke work and LV end-systolic pressure tended to be lower in the counterpulse mode, indicating decreased LV work load and afterload in this mode. Furthermore, coronary arterial flow tended to be higher in the counterpulse mode.& para;& para;Conclusions. Our system enabled an increase in coronary arterial flow and a decrease in LV work load and afterload during VA-ECMO. The system offers the effects of VA-ECMO and an IABP in a single device. (C) 2017 by The Society of Thoracic Surgeons

DOI： 10.1016/j.athoracsur.2017.04.045

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Cardiopulmonary bypass (CPB) preserves patients' lives during open heart surgery by providing sufficient oxygen delivery and blood supply to vital organs. However, previous studies have suggested that the interaction of hemodilution and vascular hyperpermeability induces tissue edema and an inflammatory response during CPB. In this study, we hypothesized the suppression of the systemic inflammatory response and tissue edema during CPB by a plasma substitute (hydroxyethyl starch [HES]). Rats (450-500 g) were divided into a SHAM group (n = 5), a Ringer's acetate CPB group (n = 7), and an HES CPB group (n = 7). In the Ringer's acetate group, the CPB circuit was primed with Ringer's acetate solution, and in the HES CPB group, it was primed with HES formulation (6% HES 130/0.4). Blood samples were collected before (baseline) and 30, 60, 90 and 120 min after initiation of CPB. Plasma cytokine levels of tumor necrosis factor-a, interleukin (IL)-6, and IL-10, and biochemical markers (lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, creatinine, liver-type fatty acid-binding protein, and colloid osmotic pressure [COP]) were measured before and 30, 60, 90, and 120 min after the initiation of CPB. In the Ringer's acetate CPB group, the inflammatory cytokines and biochemical markers increased significantly during CPB compared with the SHAM group, but such increases were significantly suppressed in the HES CPB group. In addition, during CPB, it was possible to preserve normal plasma COP in the HES CPB group. The data suggest that 6% HES 130/0.4 is effective for suppressing the inflammatory response during CPB.

DOI： 10.1097/MAT.0000000000000543

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Aortic valve regurgitation (AR) is a serious complication under left ventricular assist device (LVAD) support. AR causes LVAD-left ventricular (LV) recirculation, which makes it difficult to continue LVAD support. However, the hemodynamics and myocardial oxygen metabolism of LVAD support with AR have not been clarified, especially, how pump rotation speed influences them. An animal model of LVAD with AR was newly developed, and how pump rotation speed influences hemodynamics and myocardial oxygen metabolism was examined in acute animal experiments. Five goats (55 +/- 9.3 kg) underwent centrifugal type LVAD, EVAHEART implantation. The AR model was established by placing a vena cava filter in the aortic valve. Hemodynamic values and the myocardial oxygen consumption, delivery, and oxygen extraction ratio (O2ER) were evaluated with changing pump rotation speeds with or without AR (AR+, AR-). AR+ was defined as Sellers classification 3 or greater. AR was successfully induced in five goats. Diastolic aortic pressure was significantly lower in AR+ than AR- (p = 0.026). Central venous pressure, mean left atrial pressure, and diastolic left ventricular pressure were significantly higher in AR+ than AR- (p = 0.010, 0.047, and 0.0083, respectively). Although systemic flow did not improve with increasing pump rotation speed, LVAD pump flow increased over systemic flow in AR+, which meant increasing pump rotation speed increased LVAD-LV recirculation and did not contribute to effective systemic circulation. O2ER in AR- decreased with increasing pump rotation speed, but O2ER in AR+ was hard to decrease. The O2ER in AR+ correlated positively with the flow rate of LVAD-LV recirculation (p = 0.012). AR caused LVAD-LV recirculation that interfered with the cardiac assistance of LVAD support and made it ineffective to manage with high pump rotation speed.

DOI： 10.1007/s10047-017-0960-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

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 &lt
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.

DOI： 10.1007/s10047-016-0920-y

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Language：Japanese   Publisher：(一社)日本体外循環技術医学会編集委員会  

成人におけるveno-venous extracorporeal membrane oxygenation(VV ECMO)は送脱血カニューレをそれぞれ挿入する方法で行われることが多かった。近年、ゲティンゲグループ社より成人ECMO用ダブルルーメンカテーテル(Avalon-DLC)が開発された。1ヶ所の穿刺で済むため出血や感染のリスクが少ないなど、いくつかの利点がある。一方で、内頸静脈に挿入できるAvalon-DLCサイズには限りがあり、十分なECMO補助流量を得られず、適切な酸素化と脱炭酸ガス化ができない可能性がある。本研究ではAvalon-DLCを用いて十分に酸素化と脱炭酸ガス化が可能かを動物実験にて検討した。成ヤギ8頭(60.2±0.4kg)にAvalon-DLCを挿入後、VV ECMOを確立した。人工呼吸器を停止させ、補助流量を1〜4L/minで維持しECMO開始から20分間の動脈血の酸素飽和度(SaO2)、酸素分圧(PaO2)、二酸化炭素分圧(PaCO2)を計測した。補助流量が2L/min以上のときSaO2を80%以上で維持することができた。VV ECMO開始から20分後のPaO2は補助流量1、2、3、4L/minのとき、それぞれ28.6±4.5、62.6±9.3、127.9±21.5、183.9±30.1mmHgだった。PaCO2は補助流量が2L/min以上のとき45mmHg以下で維持できた。Avalon-DLCを用いたVV ECMOでは2L/min以上の補助流量を維持することで良好な酸素化・脱炭酸ガス化が得られ、有用性が高いと考えられる。(著者抄録)

DOI： 10.7130/jject.44.1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

We have previously developed a native heart load control system for a continuous-flow left ventricular assist device (LVAD) ((EVAHEART®
Sun Medical) and demonstrated that the rotational speed (RS) in synchronization with the cardiac cycle can alter pulsatility and left ventricular (LV) load under general anesthesia. In this study, we assessed the effects of different levels of increase in RS on pulsatility and LV load in the chronic awake phase. We implanted the EVAHEART via left thoracotomy in 7 normal goats (59.3 ± 4.6 kg). Two weeks after implantation, we examined the effects of co-pulse mode (increased RS in the systolic phase) and counter-pulse mode (increased RS in the diastolic phase), as well as shifting the change in RS from 250 to 500 rpm, and 750 rpm in both modes on pulsatility and LV load. Pulsatility was assessed using pulse pressure and mean dP/dt max of aortic pressure. LV load was assessed using stroke work and left ventricle end-diastolic volume determined from LV pressure–volume loops. In the co-pulse mode, pulsatility values increased as the change in RS increased. By contrast, in the counter-pulse mode, these values decreased as the change in RS increased. LV load increased significantly in the co-pulse mode compared with the counter-pulse mode, but there were no significant differences among the three levels of RS increase in either mode. Increasing RS to varying degrees with our newly developed system could contribute to pulsatility. However, it appeared to have little effect on LV load in normal hearts.

DOI： 10.1007/s10047-016-0906-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

This study evaluates a newly designed autologous heart valve-shaped tissue with a stent [stent-biovalve (SBV)] for transcatheter pulmonary valve implantation using the "in-body tissue architecture" technology. In the previously developed SBV with flat-shaped leaflets (FS-SBV), the valve could not close rapidly, because the leaflets were fixed in the open position, which induced regurgitant volume in the closing phase. Therefore, a novel mold to fabricate an SBV with round-shaped leaflets (RS-SBV) was developed, and its hydrodynamic performance with different valve diameters was evaluated in this study. A specially designed, self-expandable, stent-mounted, acrylic mold, which has 3 hemispheres, was placed in dorsal subcutaneous pouches of goats for 2 months. After extraction, the acrylic mold was removed from the implant, and a tubular tissue impregnated with the stent strut was obtained. Half of the tubular tissue with 3 hemispheres was completely folded in half inwards. The acrylic mold was designed, such that the folded half of the tubular tissue became the round-shaped leaflets. The 3 commissure parts were connected to form 3 leaflets, resulting in the preparation of the RS-SBV (internal diameter 25 mm). The RS-SBV closed more rapidly than the FS-SBV in a pulsatile mock circulation circuit under the pulmonary circulation conditions. The regurgitant fraction of the RS-SBV was approximately 6 %, which was lower than that of the FS-SBV. The appropriate pulmonary annulus diameter of the RS-SBV was from 24 to 25 mm based on the pressure difference and effective orifice area.

DOI： 10.1007/s10047-016-0909-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Excessive left ventricular (LV) volume unloading can affect right ventricular (RV) function by causing a leftward shift of the interventricular septum in patients with mitral regurgitation (MR) receiving left ventricular assist device (LVAD) support. Optimal settings for the LVAD should be chosen to appropriately control the MR without causing RV dysfunction. In this study, we assessed the utility of our electrocardiogram-synchronized rotational speed (RS) modulation system along with a continuous-flow LVAD in a goat model of MR. We implanted EVAHEART devices after left thoracotomy in six adult goats weighing 66.4 +/- 10.7 kg. Severe MR was induced through inflation of a temporary inferior vena cava filter placed within the mitral valve. We evaluated total flow (TF; the sum of aortic flow and pump flow [PF]), RV fractional area change (RVFAC) calculated by echocardiography, left atrial pressure (LAP), LV end-diastolic pressure (LVEDP), LV end-diastolic volume (LVEDV), and LV stroke work (LVSW) with a bypass rate (PF divided by TF) of 100% under four conditions: circuit-clamp, continuous mode, co-pulse mode (increased RS during systole), and counter-pulse mode (increased RS during diastole). TF tended to be higher in the counter-pulse mode. Moreover, RVFAC was significantly higher in the counter-pulse mode than in the co-pulse mode, whereas LAP was significantly lower in all driving modes than in the circuit-clamp condition. Furthermore, LVEDP, LVEDV, and LVSW were significantly lower in the counter-pulse mode than in the circuit-clamp condition. The counter-pulse mode of our RS modulation system used with a continuous-flow LVAD may offer favorable control of MR while minimizing RV dysfunction.

DOI： 10.1111/aor.12702

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Completely autologous in vivo tissue-engineered connective tissue tubes (Biotubes) have promise as arterial vascular grafts in animal implantation studies. In this clinical study of patients undergoing peritoneal dialysis (PD) (n = 11; age: 39-83 years), we evaluated human Biotubes' (h-Biotubes) mechanical properties to determine whether Biotubes with feasibility as vascular grafts could be formed in human bodies. We extracted PD catheters, embedded for 4-47 months, and obtained tubular connective tissues as h-Biotubes (internal diameter: 5 mm) from around the catheter' silicone tubular parts. h-Biotubes were composed mainly of collagen with smooth luminal surfaces. The average wall thickness was 278 ± 178 μm. No relationship was founded between the tubes' mechanical properties and patients' ages or PD catheter embedding periods statistically. However, the elastic modulus (2459 ± 970 kPa) and tensile strength (623 ± 314 g) of h-Biotubes were more than twice as great as those from animal Biotubes, formed from the same PD catheters by embedding in the beagle subcutaneous pouches for 1 month, or beagle arteries. The burst strength (6338 ± 1106 mmHg) of h-Biotubes was almost the same as that of the beagle thoracic or abdominal aorta. h-Biotubes could be formed in humans over a 4-month embedding period, and they satisfied the mechanical requirements for application as vascular grafts. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1431-1437, 2016.

DOI： 10.1002/jbm.b.33495

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

We have developed a rotational speed (RS) modulation system for a continuous-flow left ventricular assist device (EVAHEART) that can change RS in synchronization with a patient's electrocardiogram. Although EVAHEART is considered not to cause significant acquired von Willebrand syndrome, there remains a concern that the repeated acceleration and deceleration of the impeller may degrade von Willebrand factor (vWF) multimers. Accordingly, we evaluated the influence of our RS modulation system on vWF dynamics. A simple mock circulation was used. The circulation was filled with whole bovine blood (650mL), and the temperature was maintained at 37 +/- 1 degrees C. EVAHEART was operated using the electrocardiogram-synchronized RS modulation system with an RS variance of 500rpm and a pulse frequency of 60bpm (EVA-RSM; n=4). The pumps were operated at a mean flow rate of 5.0 +/- 0.2L/min against a mean pressure head of 100 +/- 3mmHg. The continuous-flow mode of EVAHEART (EVA-C; n=4) and ROTAFLOW (ROTA; n=4) was used as controls. Whole blood samples were collected at baseline and every 60min for 6h. Complete blood counts (CBCs), normalized indexes of hemolysis (NIH), vWF antigen (vWF:Ag), vWF ristocetin cofactor (vWF:Rco), the ratio of vWF:Rco to vWF:Ag (Rco/Ag), and high molecular weight multimers (HMWM) of vWF were evaluated. There were no significant changes in CBCs throughout the 6-h test period in any group. NIH levels of EVA-RSM, EVA-C, and ROTA were 0.0035 +/- 0.0018, 0.0031 +/- 0.0007, and 0.0022 +/- 0.0011g/100L, respectively. Levels of vWF:Ag, vWF:Rco, and Rco/Ag did not change significantly during the test. Immunoblotting analysis of vWF multimers showed slight degradation of HMWM in all groups, but there were no significant differences between groups in the ratios of HMWM to low molecular weight multimers, calculated by densitometry. This study suggests that our RS modulation system used with EVAHEART does not have marked adverse influences on vWF dynamics. The low NIH and the absence of significant decreases in CBCs indicate that EVAHEART is hemocompatible, regardless of whether it is operated with the RS modulation system.

DOI： 10.1111/aor.12666

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We have developed a rotational speed (RS) modulation system for a continuous-flow left ventricular assist device (EVAHEART) that can change RS in synchronization with a patient's electrocardiogram. Although EVAHEART is considered not to cause significant acquired von Willebrand syndrome, there remains a concern that the repeated acceleration and deceleration of the impeller may degrade von Willebrand factor (vWF) multimers. Accordingly, we evaluated the influence of our RS modulation system on vWF dynamics. A simple mock circulation was used. The circulation was filled with whole bovine blood (650 mL), and the temperature was maintained at 37 ± 1°C. EVAHEART was operated using the electrocardiogram-synchronized RS modulation system with an RS variance of 500 rpm and a pulse frequency of 60 bpm (EVA-RSM; n = 4). The pumps were operated at a mean flow rate of 5.0 ± 0.2 L/min against a mean pressure head of 100 ± 3 mm Hg. The continuous-flow mode of EVAHEART (EVA-C; n = 4) and ROTAFLOW (ROTA; n = 4) was used as controls. Whole blood samples were collected at baseline and every 60 min for 6 h. Complete blood counts (CBCs), normalized indexes of hemolysis (NIH), vWF antigen (vWF:Ag), vWF ristocetin cofactor (vWF:Rco), the ratio of vWF:Rco to vWF:Ag (Rco/Ag), and high molecular weight multimers (HMWM) of vWF were evaluated. There were no significant changes in CBCs throughout the 6-h test period in any group. NIH levels of EVA-RSM, EVA-C, and ROTA were 0.0035 ± 0.0018, 0.0031 ± 0.0007, and 0.0022 ± 0.0011 g/100 L, respectively. Levels of vWF:Ag, vWF:Rco, and Rco/Ag did not change significantly during the test. Immunoblotting analysis of vWF multimers showed slight degradation of HMWM in all groups, but there were no significant differences between groups in the ratios of HMWM to low molecular weight multimers, calculated by densitometry. This study suggests that our RS modulation system used with EVAHEART does not have marked adverse influences on vWF dynamics. The low NIH and the absence of significant decreases in CBCs indicate that EVAHEART is hemocompatible, regardless of whether it is operated with the RS modulation system.

DOI： 10.1111/aor.12666

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For the continued development of improved mechanical circulatory systems, longer term evaluation of new devices in animal model experiments may be critical. The effects of anticoagulants in adult goats have not been well studied. We assessed the effects of oral warfarin in three adult goats during fasting or after feeding. The goats [weighing 57.8 ± 8.1 kg (53.0-67.2 kg)] were administered warfarin orally beginning at a dose of 5 mg/day and then increasing to 10, 20, 40, and 60 mg every 2 weeks. One goat (receiving 10 mg/day warfarin) was killed on day 27 because of the inability to stand. After administration of 60 mg warfarin, the remaining goat received no warfarin for 4 days to return to coagulated state. The goats were then fasted and treated with 40 mg warfarin. During warfarin administration, both goats required a dose of 60 mg/day to achieve International Normalized Ratios (INRs) of approximately 2.5; however, when, the animals were in the fasted condition, precipitous extension of INR was observed in 5 days. After resuming feeding, the INR was reduced to the proper range. We showed the tendency that warfarin therapy in goats required higher doses than the doses administered to human patients and that the effects of therapy were related to the feeding state. The results of this study provide important information for development of anticoagulation protocols to assess mechanical circulatory support devices for long-term use in preclinical examination.

DOI： 10.1007/s10047-016-0885-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

We previously developed a novel control system for a continuous-flow left ventricular assist device (LVAD), the EVAHEART, and demonstrated that sufficient pulsatility can be created by increasing its rotational speed in the systolic phase (pulsatile mode) in a normal heart animal model. In the present study, we assessed this system in its reliability and ability to follow heart rate variability. We implanted an EVAHEART via left thoracotomy into five goats for the Study for Fixed Heart Rate with ventricular pacing at 80, 100, 120 and 140 beats/min and six goats for the Study for native heart rhythm. We tested three modes: the circuit clamp, the continuous mode and the pulsatile mode. In the pulsatile mode, rotational speed was increased during the initial 35 % of the RR interval by automatic control based on the electrocardiogram. Pulsatility was evaluated by pulse pressure and dP/dt max of aortic pressure. As a result, comparing the pulsatile mode with the continuous mode, the pulse pressure was 28.5 +/- 5.7 vs. 20.3 +/- 7.9 mmHg, mean dP/dt max was 775.0 +/- 230.5 vs 442.4 +/- 184.7 mmHg/s at 80 bpm in the study for fixed heart rate, respectively (P &lt; 0.05). The system successfully determined the heart rate to be 94.6 % in native heart rhythm. Furthermore, pulse pressure was 41.5 +/- 7.9 vs. 27.8 +/- 5.6 mmHg, mean dP/dt max was 716.2 +/- 133.9 vs 405.2 +/- 86.0 mmHg/s, respectively (P &lt; 0.01). In conclusion, our newly developed the pulsatile mode for continuous-flow LVADs reliably provided physiological pulsatility with following heart rate variability.

DOI： 10.1007/s10047-015-0875-4

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A cardiopulmonary bypass (CPB) can preserve life. However, interactions between blood and large artificial surfaces might help to provoke a series of chain reactions during CPB that result in the formation and release of numerous powerful inflammatory mediators including hormones and autacoids. We postulated that small CPB circuits with reduced priming volumes and less surface areas that come into contact with blood would attenuate systemic inflammatory responses by reducing the levels of cytokines and organ tissue damage during CPB. Rats were assigned to groups that underwent CPB with a high priming volume (PV) of 15 ml and a surface area of 0.044 m or a low PV of 7 ml and a surface area of 0.034 m. We measured serum levels of cytokines and biochemical markers during CPB. Levels of proinflammatory cytokines and biochemical markers were significantly elevated in the group with a high PV, than low PV at 60 min, whereas none of these factors significantly differed between the groups at 120 min. These data suggested that in addition to blood being in contact with surfaces, the duration of CPB exposure is also an important factor for nonlinear time variances in damage caused by the systemic inflammatory response.

DOI： 10.1097/MAT.0000000000000347

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer-Verlag Tokyo  

An extracorporeal centrifugal blood pump with a hydrodynamically levitated impeller was developed for use in a durable extracorporeal membrane oxygenation (ECMO) system. The present study examined the biocompatibility of the blood pump during long-term use by conducting a series of 30-day chronic animal experiments. The ECMO system was used to produce a percutaneous venoarterial bypass between the venae cavae and carotid artery in adult goats. No anticoagulation or antiplatelet therapy was administered during the experiments. Three out of four animals survived for the scheduled 30-day period, and the blood pumps and membrane oxygenators both exhibited sufficient hydrodynamic performance and good antithrombogenicity, while one animal died of massive bleeding from the outflow cannulation site. The animals’ plasma free hemoglobin had returned to within the normal range by 1 week after the surgical intervention, and their hemodynamic and biochemistry parameters remained within their normal ranges throughout the experiment. The explanted centrifugal blood pumps did not display any trace of thrombus formation. Based on the biocompatibility demonstrated in this study, the examined centrifugal blood pump, which includes a hydrodynamically levitated impeller, is suitable for use in durable ECMO systems.

DOI： 10.1007/s10047-015-0842-0

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We have been developing an autologous heart valve-shaped tissue with a stent (stent-biovalve) for transcatheter pulmonary valve implantation (TPVI) using "in-body tissue architecture" technology. In this study, the hydrodynamic performance of a stent-biovalve with tubular leaflets was evaluated by changing its leaflet height in an in vitro test in order to determine the appropriate stent-biovalve form for the pulmonary valve. A specially designed, self-expandable, stent-mounted, cylindrical acrylic mold was placed in a dorsal subcutaneous pouch of goat, and the implant was extracted 2 months later. Only the cylindrical acrylic mold was removed from the implant, and a tubular hollow structure of membranous connective tissue impregnated with the stent strut was obtained. Half of tubular tissue was completely folded in half inwards, and 3 commissure parts were connected to form 3 leaflets, resulting in the preparation of a stent-biovalve with tubular leaflets (25-mm ID). The stent-biovalve with adjusting leaflet height (13, 14, 15, 17, 20, and 25 mm) was fixed to a specially designed pulsatile mock circulation circuit under pulmonary valve conditions using 37 °C saline. The mean pressure difference and effective orifice area were better than those of the biological valve. The lowest and highest leaflet heights had a high regurgitation rate due to lack of coaptation or prevention of leaflet movement, respectively. The lowest regurgitation (ca. 11%) was observed at a height of 15 mm. The leaflet height was found to significantly affect the hydrodynamics of stent-biovalves, and the existence of an appropriate leaflet height became clear.

DOI： 10.1007/s10047-015-0851-z

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Language：Japanese   Publisher：医学図書出版(株)  

【目的】心臓手術時や急性循環不全時などに使用される補助循環では、血液が異物と接触することで炎症反応が惹起されることが知られている。われわれは補助循環中の炎症抑制を目指し、ポリプロピレン製ネット(スクリム)、ポリスチレン製極細繊維およびポリプロピレン製繊維から構成された不織布3層構造を有し、顆粒球・単球を選択的に除去可能な新型の白血球除去カラムを開発した。今回、ラット補助循環モデルを用い、炎症抑制効果について検討した。【方法】ラットを補助循環中にカラム非使用群、カラム使用群に分けた。カラム使用群では、補助循環開始後30分の時点からカラムに血液を灌流し、白血球除去を行った。補助循環前、補助循環開始後30分、60分で動脈血を採取し、白血球数、サイトカイン、生化学マーカーを計測し、さらに、実験終了後に組織浮腫の指標となる肺乾湿重量比を計測した。【結果】カラム使用で、サイトカインの上昇が45.8〜58.5%抑制され、肝逸脱酵素の上昇も52.2〜92.3%抑制された。また、肺乾湿重量比も低下した。【まとめ】開発した新型の白血球除去カラムの使用により、補助循環中の炎症反応、肝逸脱酵素の上昇および肺組織浮腫が抑制された。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer-Verlag Tokyo  

In this study, self-expanding valved stents were prepared by in-body tissue architecture technology. As molds, plastic rods (outer diameter
14 or 25 mm), mounted with specially designed self-expanding stents, whose strut was a combination of two wavy rings and three pillars, were embedded into the subcutaneous pouches of goats or beagles for 1 month. Upon harvesting, the molds were fully encapsulated with membranous connective tissues, in which the stent strut was completely embedded. The tubular tissues with the stents were obtained by removing the internal rods. About a half of the tubular tissues as a leaflet part was folded inside the remaining tubular tissues having ring strut as a conduit part. When the overlapped tubular tissues were fixed at the three pillars, two different-sized self-expanding valved stents (internal diameter
14 or 25 mm) with autologous tubular leaflet tissues were obtained as Stent-Biovales. After shape formation of the leaflets at the closed form, regurgitation rate was approximately 5 and 22 % at pulmonary and aortic condition, respectively. The Stent-Biovalves developed here may be useful as a heart valve for patients undergoing transcatheter heart valve implantation.

DOI： 10.1007/s10047-015-0820-6

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Language：English   Publishing type：Research paper (scientific journal)  

Cardiopulmonary bypass (CPB) is indispensable for cardiac surgery. Since the ethical and technical difficulties associated with clinical research limit the acquisition of new knowledge, it is desirable to have a miniature extracorporeal circulation (ECC) system for small animals. We aimed to establish a miniature ECC system and apply the system to the rat for investigating systemic inflammatory response changes during and after CPB. The ECC system consisted of a membranous oxygenator (polypropylene, 0.03 m(2)), tubing line (polyvinyl chloride) and a roller pump. Priming volume of this system is only 7 ml. Rats were divided into the SHAM (received surgical preparation only without CPB) group and the CPB group. ECC pump flow was initiated and maintained at 70 ml/kg/min. We measured the serum cytokine levels of tumor necrosis factor-α, interleukin (IL)-6, and IL-10, and biochemical markers (lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase) before, 30, and 60 min after the initiation of CPB, in addition, 30, 60, and 120 min after the CPB weaning. During CPB, blood pressure and hemoglobin were maintained around 80 mmHg and 10g/dl, the serum cytokine levels and biochemical markers were significantly elevated in the CPB group compared with the SHAM group. These data suggest that CPB promotes organ damage and a systemic inflammatory response. This rat ECC model is considered to be equivalent to the already established human CPB and useful for studying the mechanism of pathophysiological changes during and after CPB.

DOI： 10.1109/EMBC.2015.7318522

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

OBJECTIVES: Right ventricular failure after left ventricular assist device (LVAD) implantation is associated with high mortality. This study was designed to evaluate the effectiveness of an atrial septostomy with a membrane oxygenator incorporated in an LVAD as a novel approach for right ventricular failure after LVAD implantation. METHODS: The outflow and inflow cannulae were placed in the carotid artery and left ventricular apex, respectively. A centrifugal pump and an oxygenator were sequentially placed between the inflow and outflow cannulae in seven anesthetized goats. While right ventricular failure was induced by pulmonary artery banding, a balloon atrial septostomy was performed using a 19-mm balloon catheter under echocardiographic guidance. We investigated the effects of the interatrial shunt on LVAD flow and haemodynamics. RESULTS: Development of right ventricular failure decreased LVAD flow (2.7 ± 0.6-0.9 ± 0.6 l/min), causing a state of shock [mean arterial pressure (MAP) of 41 ± 12 mmHg]. Following a balloon atrial septostomy, LVAD flow and MAP were significantly improved to 2.7 ± 0.4 l/min (P < 0.001) and 53 ± 18 mmHg (P = 0.006), respectively, while right atrial pressure decreased from 18 ± 5 to 15 ± 5 mmHg (P = 0.001). Furthermore, arterial blood oxygenation was maintained by the membrane oxygenator incorporated in the LVAD. CONCLUSIONS: In the present model of right ventricular failure after LVAD implantation, LVAD flow was significantly increased and haemodynamics improved without compromising systemic oxygenation by the use of an interatrial shunt and a membrane oxygenator incorporated in the LVAD. Our results indicate that this novel approach may be less invasive for a right ventricular failure after LVAD implantation.

DOI： 10.1093/ejcts/ezu364

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Our research institute has been working on the development of a compact wearable drive unit for an extracorporeal ventricular assist device (VAD) with a pneumatically driven pump. A method for checking the pump blood flow on the side of the drive unit without modifying the existing blood pump and impairing the portability of it will be useful. In this study, to calculate the pump flow rate indirectly from measuring the flow rate of the driving air of the VAD air chamber, we conducted experiments using a mock circuit to investigate the correlation between the air flow rate and the pump flow rate as well as its accuracy and error factors. The pump flow rate was measured using an ultrasonic flow meter at the inflow and outflow tube, and the air flow was measured using a thermal mass flow meter at the driveline. Similarity in the instantaneous waveform was confirmed between the air flow rate in the driveline and the pump flow rate. Some limitations of this technique were indicated by consideration of the error factors. A significant correlation was found between the average pump flow rate in the ejecting direction and the average air flow rate in the ejecting direction (R (2) = 0.704-0.856), and the air flow rate in the filling direction (R (2) = 0.947-0.971). It was demonstrated that the average pump flow rate was estimated exactly in a wide range of drive conditions using the air flow of the filling phase.

DOI： 10.1007/s10047-014-0811-z

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Language：English   Publishing type：Research paper (scientific journal)  

We developed an autologous, trileaflet tissue valve ("biovalve") using in-body tissue architecture technology to overcome the disadvantages of current bioprosthetic valves. We designed a novel biovalve with a balloon-expandable stent: the stent biovalve (SBV). This study evaluated the technical feasibility of sutureless aortic valve replacement using the SBV in an orthotopic position, as well as the functionality of the SBV under systemic circulation, in an acute experimental goat model. Three adult goats (54.5-56.1 kg) underwent sutureless AVR under cardiopulmonary bypass (CPB). The technical feasibility and functionality of the SBVs were assessed using angiography, pressure catheterization, and two-dimensional echocardiography. The sutureless AVR was successful in all goats, and all animals could be weaned off CPB. The mean aortic cross-clamp time was 45 min. Angiogram, after weaning the animals off CPB, showed less than mild paravalvular leakage and central leakage was not detected in any of the goats. The mean peak-to-peak pressure gradient was 6.3 ± 5.0 mmHg. Epicardial two-dimensional echocardiograms showed smooth leaflet movement, including adequate closed positions with good coaptation; the open position demonstrated a large orifice area (average aortic valve area 2.4 ± 0.1 cm2). Sutureless AVR, using SBVs, was feasible in a goat model. The early valvular functionalities of the SBV were sufficient; future long-term experiments are needed to evaluate its durability and histological regeneration potential.

DOI： 10.1007/s10047-015-0817-1

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Language：English   Publishing type：Research paper (scientific journal)  

The clinical use of veno-venous extracorporeal membrane oxygenation (VVECMO) in adult patients with respiratory failure is rapidly increasing. However, recirculation of blood oxygenated by ECMO back into the circuit may occur in VVECMO, resulting in insufficient oxygenation. The cannula position and bypass flow rate are two major factors influencing recirculation, but the relationship and ideal configuration of these factors are not fully understood. In the present study, we attempted to clarify these parameters for effective gas exchange. VVECMO was performed in eight adult goats under general anesthesia. The position of the drainage cannula was fixed in the inferior vena cava (IVC), but the return cannula position was varied between the IVC, right atrium (RA), and superior vena cava (SVC). At each position, the recirculation rates calculated, and the adequacy of oxygen delivery by ECMO in supplying systemic oxygen demand was assessed by measuring the arterial oxygen saturation (SaO2) and pressure (PaO2). Although the recirculation rates increased as the bypass flow rates increased, SaO2 and PaO2 also increased in any position of return cannula. The recirculation rates and PaO2 were 27 ± 2% and 162 ± 16 mmHg, 36 ± 6% and 139 ± 11 mmHg, and 63 ± 6% and 77 ± 9 mmHg in the SVC, RA and IVC position at 4 L/min respectively. In conclusion, the best return cannula position was the SVC, and a high bypass flow rate was advantageous for effective oxygenation. Both the bypass flow rates and cannula position must be considered to achieve effective oxygenation.

DOI： 10.1007/s10047-014-0810-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Japan  

Biovalves, autologous tri-leaflet valved conduits, are formed in the subcutaneous spaces of animals. The valves are formed using molds encapsulated with autologous connective tissues. However, tissue migration into the small apertures in the molds for leaflet formation is generally slower than that for conduit formation around the molds. In this study, the formation of the leaflet tissues was directly and non-invasively observed using a wireless capsule endoscope. The molds were assembled from 6 parts, one of which was impregnated with the endoscope, and embedded into subcutaneous pouches in goats (n = 30). Tissue ingrowth into the apertures gradually occurred from the edges of the leaflet parts. Tissue formation was accompanied by capillary formation. At 63.1 ± 17.1 days after embedding, the apertures were completely replaced with autologous connective tissue, forming the leaflet tissues. Leaflet formation was enhanced by including fat tissue (46.7 ± 4.2 days) or blood (41.1 ± 6.9 days) in the apertures before embedding. The creation of slit openings, in conjunction with addition of blood to the apertures, further enhanced leaflet formation (37.0 ± 2.8 days). Since leaflet formation could be observed endoscopically, the appropriate embedding period for complete biovalve formation could be determined.

DOI： 10.1007/s10047-014-0793-x

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Language：English   Publishing type：Research paper (scientific journal)  

Extracorporeal circulation (ECC) is indispensable for cardiac surgery. Despite the fact that ECCcauses damage to blood components and is non-physiologic, its pathophysiology has not been fully elucidated. This is because difficulty in clinical research and animal experiments keeps the knowledge insufficient. Therefore, it is desirable to have a miniature ECC model for small animals, which enables repetitive experiments, to study the mechanism of pathophysiological changes during ECC. We developed a miniature ECC system and applied it to the rat. We measured changes in hemodynamics, blood gases and hemoglobin (Hb) concentration, serum cytokines (TNF-α, IL-6, IL-10), biochemical markers (LDH, AST, ALT), and the wet-to-dry weight (W/D) ratio of the lung for assessing whether the rat ECC model is comparable to the human ECC. The ECC system consisted of a membranous oxygenator (polypropylene, 0.03 m(2)), tubing line (polyvinyl chloride), and roller pump. Priming volume of this system is only 8 ml. Rats (400-450 g) were divided into the SHAM group (n = 7) and the ECC group (n = 7). Blood samples were collected before, 60 and 120 min after initiation of ECC. During ECC, blood pressure and Hb were maintained around 80 mmHg and 10 g/dL, respectively. The levels of the inflammatory and biochemical markers and the W/D ratio were significantly elevated in the ECC group, indicating some organ damages and systemic inflammatory responses during ECC. We successfully established the ECC for the rat. This miniature ECC model could be a useful approach for studying the mechanism of pathophysiology during ECC and basic assessment of the ECC devices.

DOI： 10.1007/s10047-014-0804-y

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Language：English   Publishing type：Research paper (scientific journal)  

In-body tissue architecture--a novel and practical regeneration medicine technology--can be used to prepare a completely autologous heart valve, based on the shape of a mold. In this study, a three-dimensional (3D) printer was used to produce the molds. A 3D printer can easily reproduce the 3D-shape and size of native heart valves within several processing hours. For a tri-leaflet, valved conduit with a sinus of Valsalva (Biovalve type VII), the mold was assembled using two conduit parts and three sinus parts produced by the 3D printer. Biovalves were generated from completely autologous connective tissue, containing collagen and fibroblasts, within 2 months following the subcutaneous embedding of the molds (success rate, 27/30). In vitro evaluation, using a pulsatile circulation circuit, showed excellent valvular function with a durability of at least 10 days. Interposed between two expanded polytetrafluoroethylene grafts, the Biovalves (N = 3) were implanted in goats through an apico-aortic bypass procedure. Postoperative echocardiography showed smooth movement of the leaflets with minimal regurgitation under systemic circulation. After 1 month of implantation, smooth white leaflets were observed with minimal thrombus formation. Functional, autologous, 3D-shaped heart valves with clinical application potential were formed following in-body embedding of specially designed molds that were created within several hours by 3D printer.

DOI： 10.1002/jbm.b.33186

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Language：Japanese   Publisher：The Institute of Electrical Engineers of Japan  

We have been developing a pneumatic total artificial heart (PTAH) system which was driven by a wearable pneumatic drive unit (WPD). The WPD which have driven one blood pump by one actuator, called as WPD100, had problems such as high power consumption, large size and excessive negative air pressure. To solve these problems, we developed a WPD twin head type (WPD TH) equipped with a mechanism to drive two pumps by one actuator and relief valves to avoid excessive negative pressure. In this study, we evaluated the performance and characteristics of the WPD TH in a mock circulation test and numerical calculation. As a result, the maximum flow rates of the left and right pumps driven by the WPD TH were 7.9 L/min and 9.3 L/min even under the pressure release in diastole. The maximum power consumption and the efficiency were 27.6 W and 6.6% in the case of right and left pumps driven from side to side, and these were improved in comparison with WPD100. The alternate drive method had advantages of suppressing vibration and a mechanical load in the numerical calculation. These results indicated that the WPD TH had a basic performance to realize a wearable PTAH system.

DOI： 10.1541/ieejeiss.135.1376

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Other Link： https://jlc.jst.go.jp/DN/JLC/20016812213?from=CiNii

Language：English   Publishing type：Research paper (scientific journal)  

© 2014, The Japanese Society for Artificial Organs. We developed a novel controller for a continuous-flow left ventricular assist device (EVAHEART) that can change the pump’s rotational speed (RS) in synchronization with a patient’s myocardial electrocardiogram (ECG) with the aim of facilitating cardiac recovery. We previously presented various applications of this system in animal models, but there remained a concern that the repeated acceleration and deceleration of the impeller may induce additional hemolysis. In this study, we evaluated the blood trauma and motor power consumption induced by our system in a mock circulation. We evaluated our system with a 60-bpm pulse frequency and a variance between the high and low RSs of 500 rpm (EVA-P; n = 4). The continuous modes of EVAHEART (EVA-C; n = 4) and ROTAFLOW (n = 4) were used as controls. The pumps were examined at a mean flow rate of 5.0 ± 0.2 L/min against a mean pressure head of 100 ± 3 mmHg for a 4-h period. As a result, the normalized indexes of the hemolysis levels of EVA-P and EVA-C were 0.0023 ± 0.0019 and 0.0023 ± 0.0025, respectively, and their difference was not significant. The estimated mean motor power consumptions of EVA-C and EVA-P were 6.24 ± 0.33 and 7.19 ± 0.93 W, respectively. When a novel ECG-synchronized RS-change system was applied to EVAHEART, the periodic RS change with a 500-rpm RS variance did not affect the hemolysis at a 60-bpm pulse frequency.

DOI： 10.1007/s10047-014-0787-8

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Soc. of Med. Electronics and Biol. Engineering  

A pneumatic ventricular assist device (PVAD) and a pneumatic total artificial heart (PTAH) system were developed. The size and weight of the driver with 2 battery pack are 250 × 110 × 210 mm and 4.3 kg, respectively. The PVAD with Nipro VAD blood pump using the driver achieved the mean pump flow ranging from 3.4 to 6.7 L/min and the mean electric power consumption ranging from 8.0 to 19.7 W in the overflow type circulation mock test. The PVAD was also examiend for 28 days in the chronic animal test using calf. The bypass flow and the electric power consumption were maintained at 4.1+/-0.4 L/min and 13.3+/-0.4 W, respectively. The PTAH using the 2 drive unit was evaluated in the acute animal test using calf. The mean pump flow ranging from 3.9 to 5.4 L/min and the mean electric power consumption ranging from 5.3 to 17.6 W were achieved.

DOI： 10.11239/jsmbe.52.OS-19

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY-ELSEVIER  

Objective: We previously developed a native heart load control system for a continuous-flow left ventricular assist device and demonstrated that the rotational speed synchronized with the cardiac cycle can alter left ventricular preload and myocardial oxygen consumption. In the present study, we assessed this system in a conscious goat model of chronic heart failure.
Methods: Chronic heart failure was induced by coronary microsphere embolization of the left ascending artery and subsequent rapid ventricular pacing in 6 goats. After 4 to 6 weeks of rapid pacing, the goats showed a decreased ejection fraction (from 89.7% +/- 3.1% to 53.3% +/- 5.4%) measured during sinus rhythm. The assist device was implanted by way of a left thoracotomy, and we examined the effects of the continuous, co-pulse, and counterpulse mode on the end-diastolic volume and stroke work, determined from the left ventricular pressure-volume loops.
Results: Significant decreases were found in the end-diastolic volume and stroke work in the counterpulse mode relative to the values observed with 0% bypass (63.4% +/- 15.2% and 39.1% +/- 18.2%, respectively; P &lt; .01). Furthermore, both increased in the co-pulse mode (82.1% +/- 17.6% and 68.3% +/- 22.2%; P &lt; .01) compared with those in the continuous mode (69.6% +/- 15.4% and 54.6% +/- 21.6%) with 100% bypass.
Conclusions: The system offers the possibility to control the left ventricular load by changing the rotational speed of a continuous-flow assist device in synchronization with the cardiac cycle. This system should provide the most favorable left ventricular loading conditions for recovery of the native heart.

DOI： 10.1016/j.jtcvs.2013.12.049

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Language：English   Publishing type：Research paper (scientific journal)  

We designed a novel method for constructing an autologous heart valve with a stent, called a stent-biovalve. In constructing completely autologous heart valves, named biovalves, which used in-body tissue architecture technology, tissues for leaflets were formed via ingrowths into narrow apertures in the preparation molds, frequently leading to delayed or incomplete biovalve preparation. In this technique, self-expandable nitinol stents after everting were mounted on an acrylic column-shaped part and partially covered with an acrylic cylinder-shaped part with three slits. This assembled mold was placed into subcutaneous abdominal pouches in beagles or goats for 4 weeks. Upon removing the acrylic parts after harvesting and trimming of capsulated tissues, a tubular hollow structure with three pocket-flaps of membranous tissue rigidly fixed to the stent's outer surface was obtained. Then, the stent was turned inside out to the original form, thus moving the pocket-flaps from outside to the inside. Stent-biovalves with a sufficient coaptation area were thus obtained with little tissue damage in all cases. The valve opened smoothly, and high aperture ratio was noted. This novel technique was thus highly effective in constructing a robust, completely autologous stent-biovalve with adequate valve function.

DOI： 10.1002/jbm.b.33086

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Language：English   Publishing type：Research paper (scientific journal)  

Right ventricular (RV) failure is a potentially fatal complication after treatment with a left ventricular assist device (LVAD). Ventricular septal shift caused by such devices is an important factor in the progress of RV dysfunction. We developed a control system for a rotary blood pump that can change rotational speed (RS) in synchrony with the cardiac cycle. We postulated that decreasing systolic RS using this system would alter ventricular septal movement and thus prevent RV failure. We implanted the EVAHEART ventricular assist device into seven adult goats weighing 54.1 ± 2.1 kg and induced acute bi-ventricular dysfunction by coronary embolization. Left and RV pressure was monitored, and ventricular septal movement was echocardiographically determined. We evaluated circuit-clamp mode as the control condition, as well as continuous and counter-pulse modes, both with full bypass. As a result, a leftward ventricular septal shift occurred in continuous and counter-pulse modes. The septal shift was corrected as a result of decreased RS during the systolic phase in counter-pulse mode. RV fractional area change improved in counter-pulse (59.0 ± 4.6%) compared with continuous (44.7 ± 4.0%) mode. In conclusion, decreased RS delivered during the systolic phase using the counter-pulse mode of our new system holds promise for the clinical correction of ventricular septal shift resulting from a LVAD and might confer a benefit upon RV function.

DOI： 10.1007/s10047-014-0757-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

We have used in-body tissue architecture technology to develop an autologous valved conduit with intact sinuses of Valsalva (biovalve). In this study, we fabricated three different forms of biovalves and evaluated their function in vitro using a mock circulation model to determine the optimal biovalve form for aortic valve replacement. A cylindrical mold for biovalve organization was placed in a dorsal subcutaneous pouch of a goat, and the implant that was encapsulated with connective tissue was extracted 2 months later. The cylindrical mold was removed to obtain the biovalve (16 mm inside diameter) that consisted of pure connective tissue. The biovalve was connected to a pulsatile mock circulation system in the aortic valve position. The function of the three biovalves (biovalve A: normal leaflets with the sinuses of Valsalva; biovalve B: extended leaflets with the sinuses of Valsalva; biovalve C: extended leaflets without the sinuses of Valsalva) was examined under pulsatile flow conditions using saline. In addition, the mock circuit was operated continuously for 40 days to evaluate the durability of biovalve C. The regurgitation rate (expressed as a percent of the mean aortic flow rate during diastole) was 46% for biovalve A but only 3% for biovalves B and C. The durability test demonstrated that even after biovalve C pulsated more than four million times (heart rate, 70 bpm; mean flow rate, 5.0 L/min; mean aortic pressure, 92 mm Hg), stable continuous operation was possible without excessive reduction of the flow rate or bursting. The developed biovalve demonstrated good function and durability in this initial in vitro study.

DOI： 10.1111/aor.12173

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Language：English   Publisher：KARGER  

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Language：English   Publisher：Institute of Electrical Engineers of Japan  

We have been developing a wearable pneumatic total artificial heart (PTAH) system for bridge to transplant, and we evaluated its fundamental performance in in vitro and in vivo experiments. The PTAH system consists of left and right diaphragm-type blood pumps and a compact wearable pneumatic drive (WPD-100) unit. The WPD-100 unit can generate a fixed systole ratio by the non-circular gears. The prototype WPD-100 units with fixed systolic ratio of 35, 40 and 44 % were developed. 25 mm and 23 mm Bicarbon valves were mounted in the inlet and outlet ports of the left and right blood pumps. As a result of an overflow-type mock circulation test, more than 8.0 l/min of pump output was obtained at 100 bpm for after load of 80, 100 and 120 mm Hg in all WPD-100 units. An acute animal experiment was also performed using WPD-100 units with fixed systolic ratio of 35 and 44% in a calf weighing 98 kg. The cardiac output ranged between 4.3 and 5.2 l/min at the mean aortic pressures of 108-115 mm Hg at beating rates of 60 to 100 bpm. These results indicated that our PTAH system consisting of two blood pumps and WPD-100 units have sufficient performance for total cardiac replacement. © 2014 The Institute of Electrical Engineers of Japan.

DOI： 10.1541/ieejeiss.134.839

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：IEEE  

A ventricular assist device (VAD) is a device with mechanical pumps implanted adjacent to the patient's native heart to support the blood flow. Mechanical circulatory support using VADs has been an essential therapeutic tool for patients with severe heart failure waiting for a heart transplant in clinical site. Adaptive control of VADs that automatically adjust the pump output with changes in a patient state is one of the important approaches for enhanced therapeutic efficacy, prevention of complications and quality of life improvement. However adaptively controlling a VAD in the realistic situation would be difficult because it is necessary to model the whole including the VAD and the cardiovascular dynamics. To solve this problem, we propose an application of attractor selection algorithm using stochastic behavior to a VAD control system. In this study, we sought to investigate whether this proposed method can be used to adaptively control of a VAD in the simple case of a continuous flow VAD. The flow rate control algorithm was constructed on the basis of a stochastically searching algorithm as one example of application. The validity of the constructed control algorithm was examined in a mock circuit. As a result, in response to a low-flow state with the different causes, the flow rate of the pump reached a target value with self adaptive behavior without designing the detailed control rule based on the experience or the model of the control target.

DOI： 10.1109/EMBC.2014.6943586

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：IEEE  

Extracorporeal circulation (ECC) is indispensable for cardiac surgery. Since difficulty in clinical research keeps the knowledge insufficient, it is desirable to have a miniature ECC system for small animals. We aimed to establish a miniature ECC system and apply the system to the rat for investigating biochemical changes. The ECC system consisted of a membranous oxygenator (polypropylene, 0.03 m(2)), tubing line (polyvinyl chloride) and roller pump. Priming volume of this system is only 15 ml. Rats were divided into the SHAM group and the ECC group. ECC pump flow was initiated and maintained at 70 ml/kg/min. We measured the serum cytokine levels of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-10, and biochemical markers (lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase) before, 60, and 120 min after the initiation of ECC. In addition, we measured the wet-to-dry weight (W/D) ratio of the left lung tissues. During ECC, blood pressure and Hb were maintained around 80 mmHg and 10g/dl, the serum cytokine levels and biochemical markers were significantly elevated in the ECC group compared with the SHAM group. The W/D ratio increased significantly more in the ECC group compared with that in the SHAM group. These data suggest that ECC promotes organ damages and systemic inflammatory response. This rat ECC model is considered to be equivalent to the already established human ECC and useful for studying the mechanism of pathophysiological changes during artificial perfusion.

DOI： 10.1109/EMBC.2014.6944619

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Systemic inflammatory responses in patients receiving cardiac surgery supported by cardiopulmonary bypass (CPB) significantly contribute to CPB-associated morbidity and mortality. We hypothesized that hyperoxia insufflation aggravates the inflammatory responses and organ damage during CPB. To verify this hypothesis, we investigated the inflammatory responses at high and normal levels of arterial pressure of oxygen (PaO2 ) in the rat CPB model. Rats were divided into a SHAM group, a hyperoxia CPB group (PaO2  > 400 mm Hg), and a normoxia CPB group (PaO2 : 100-150 mm Hg). We measured the serum cytokine levels of tumor necrosis factor-α, interleukin (IL)-6, and IL-10, and biochemical markers (lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase) before, 60, and 120 min after the initiation of CPB. We also measured the wet-to-dry weight (W/D) ratio of the left lung and performed dihydroethidium (DHE) stain reflecting superoxide generation in the lung and liver tissues 120 min after the CPB initiation. In the hyperoxia group, the pro-inflammatory cytokines and biochemical markers significantly increased during the CPB compared with the SHAM, but such increases were significantly suppressed in the normoxia group. However, the increase in anti-inflammatory cytokines was more suppressed in the hyperoxia group than in the normoxia group. The W/D ratio increased significantly more in the hyperoxia group than in the normoxia group. In addition, the DHE fluorescence predominantly increased in the hyperoxia group compared with that in the normoxia group. These data suggest that it is better to avoid too much oxygen insufflation for attenuating organ damage associated with the superoxide production and inflammatory responses during CPB.

DOI： 10.1111/aor.12125

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper (scientific journal)  

Aortic insufficiency (AI) is a serious complication for patients on long-term support with left ventricular assist devices (LVAD). Postoperative aortic valve opening is an important predictor of AI. A system is presently available that can promote native aortic flow by reducing rotational speed (RS) for defined intervals. However, this system can cause a reduction in pump flow and lead to insufficient support. We therefore developed a novel "delayed copulse mode" to prevent AI by providing both minimal support for early systole and maximal support shortly after aortic valve opening by changing the RS in synchronization with heartbeat. To evaluate whether our drive mode could open the aortic valve while maintaining a high total flow (sum of pump flow and native aortic flow), we installed a centrifugal LVAD (EVAHEART(®); Sun Medical) in seven goats each with normal hearts and acute LV dysfunction created by micro-embolization of the coronary artery. We intermittently switched the drive mode from continuous (constant RS) with 100 % bypass to delayed copulse mode with 90 % bypass. Total flow did not significantly change between the two modes. The aortic valve opened when the delayed copulse mode was activated. The delayed copulse mode allowed the aortic valve to open while maintaining a high total flow. This novel drive mode may considerably benefit patients with severe heart failure on long-term LVAD support by preventing AI.

DOI： 10.1007/s10047-012-0685-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

We developed a novel endurance test system that can arbitrarily set various circulatory conditions and has durability and stability for long-term continuous evaluation of ventricular assist devices (VADs), and we evaluated its fundamental performance and prolonged durability and stability. The circulation circuit of the present endurance test system consisted of a pulsatile pump with a small closed chamber (SCC), a closed chamber, a reservoir and an electromagnetic proportional valve. Two duckbill valves were mounted in the inlet and outlet of the pulsatile pump. The features of the circulation circuit are as follows: (1) the components of the circulation circuit consist of optimized industrial devices, giving durability; (2) the pulsatile pump can change the heart rate and stroke length (SL), as well as its compliance using the SCC. Therefore, the endurance test system can quantitatively reproduce various circulatory conditions. The range of reproducible circulatory conditions in the endurance test circuit was examined in terms of fundamental performance. Additionally, continuous operation for 6 months was performed in order to evaluate the durability and stability. The circulation circuit was able to set up a wide range of pressure and total flow conditions using the SCC and adjusting the pulsatile pump SL. The long-term continuous operation test demonstrated that stable, continuous operation for 6 months was possible without leakage or industrial device failure. The newly developed endurance test system demonstrated a wide range of reproducible circulatory conditions, durability and stability, and is a promising approach for evaluating the basic characteristics of VADs.

DOI： 10.1007/s10047-013-0687-3

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Using simple, safe, and economical in-body tissue engineering, autologous valved conduits (biovalves) with the sinus of Valsalva and without any artificial support materials were developed in animal recipients' bodies. In this study, the feasibility of the biovalve as an aortic valve was evaluated in a goat model. Biovalves were prepared by 2-month embedding of the molds, assembled using two types of specially designed plastic rods, in the dorsal subcutaneous spaces of goats. One rod had three projections, resembling the protrusions of the sinus of Valsalva. Completely autologous connective tissue biovalves (type VI) with three leaflets in the inner side of the conduit with the sinus of Valsalva were obtained after removing the molds from both terminals of the harvested implants with complete encapsulation. The biovalve leaflets had appropriate strength and elastic characteristics similar to those of native aortic valves; thus, a robust conduit was formed. Tight valvular coaptation and a sufficient open orifice area were observed in vitro. Biovalves (n = 3) were implanted in the specially designed apico-aortic bypass for 2 months as a pilot study. Postoperative echocardiography showed smooth movement of the leaflets with little regurgitation under systemic circulation (2.6 ± 1.1 l/min). α-SMA-positive cells appeared significantly with rich angiogenesis in the conduit and expanded toward the leaflet tip. At the sinus portions, marked elastic fibers were formed. The luminal surface was covered with thin pseudointima without thrombus formation. Completely autologous biovalves with robust and elastic characteristics satisfied the higher requirements of the systemic circulation in goats for 2 months with the potential for valvular tissue regeneration.

DOI： 10.1007/s10047-012-0679-8

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Other Link： http://orcid.org/0000-0001-6862-8046

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CIRCULATION SOC  

Background: A novel control system for the EVAHEART left ventricular assist device (LVAD), known as the Native Heart Load Control System (NHLCS), can change the device's rotational speed (RS) in synchrony with the heartbeat. The system enhanced coronary flow (CoF) with the counter-pulse mode in normal goats' hearts, so we examined the change in CoF in goats with acute ischemic heart failure (HF).
Methods and Results: We studied 14 goats (56.1 +/- 6.9 kg) with acute ischemic HF induced by coronary microsphere embolization. We installed EVAHEART and ran the device in 4 modes [continuous support, circuit-clamp, counter-pulse (raise RS in diastole), and co-pulse (raise RS in systole)] with 50% or 100% bypass in each mode. In comparison with the circuit-clamp mode, CoF was 121.0 +/- 14.1% in the counter-pulse mode and 102.9 +/- 7.9% in the co-pulse mode, whereas it was 113.5 +/- 10.6% in the continuous mode, with 100% bypass (P&lt;0.05). The same difference was confirmed with 50% bypass. The results indicated that a LVAD in an acute ischemic heart enhanced CoF, and that CoF was greater in the counter-pulse mode and smaller in the co-pulse mode relative to the continuous mode.
Conclusions: By using NHLCS to change CoF, recovery of native heart function with a LVAD has a better prognosis. (Circ J 2013; 77: 995-1000)

DOI： 10.1253/circj.CJ-12-0676

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Systemic inflammatory responses in patients receiving cardiac surgery with the use of the cardiopulmonary bypass (CPB) significantly contribute to CPB-associated morbidity and mortality. We hypothesized that insufflated hydrogen gas (H₂) would provide systemic anti-inflammatory and anti-apoptotic effects during CPB, therefore reducing proinflammatory cytokine levels. In this study, we examined the protective effect of H₂ on a rat CPB model. Rats were divided into three groups: the sham operation (SHAM) group, received sternotomy only; the CPB group, which was initiated and maintained for 60 min; and the CPB + H₂ group in which H₂ was given via an oxygenator during CPB for 60 min. We collected blood samples before, 20 min, and 60 min after the initiation of CPB. We measured the serum cytokine levels of (tumor necrosis factor-α, interleukin-6, and interleukin-10) and biochemical markers (lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase). We also measured the wet-to-dry weight (W/D) ratio of the left lung 60 min after the initiation of CPB. In the CPB group, the cytokine and biochemical marker levels significantly increased 20 min after the CPB initiation and further increased 60 min after the CPB initiation as compared with the SHAM group. In the CPB + H₂ group, however, such increases were significantly suppressed at 60 min after the CPB initiation. Although the W/D ratio in the CPB group significantly increased as compared with that in the SHAM group, such an increase was also suppressed significantly in the CPB + H₂ group. We suggest that H₂ insufflation is a possible new potential therapy for counteracting CPB-induced systemic inflammation.

DOI： 10.1111/j.1525-1594.2012.01535.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Japan  

Aiming the 'Bridge to Recovery' course, we have developed a novel left ventricular assist device (LVAD) controlling system. It can change the rotational speed of the continuous flow LVAD, EVAHEART, synchronized with the cardiac beat. Employing this system, we have already demonstrated that myocardial oxygen consumption (MVO2), which is considered to be equivalent to native heart load, changes in the hearts of normal goats. Herein, we examined changes in goats with acute ischemic heart failure. We studied 14 goats (56.1 ± 6.9 kg) with acute ischemic heart failure due to coronary microsphere embolization. We installed the EVAHEART and drive in four modes: "circuit-clamp", "continuous support", "counter- pulse", and "co-pulse", with 50 and 100 % bypass. In comparison to the circuit-clamp mode, MVO2 was reduced to 70.4 ± 17.9 % in the counter-pulse mode and increased to 90.3 ± 14.5 % in the co-pulse mode, whereas it was 80.0 ± 14.5 % in the continuous mode, with 100 % bypass (p &lt
0.05). The same difference was confirmed with 50 % bypass. This means that we may have a chance to change the native heart load by controlling the LVAD rotation in synchrony with the cardiac rhythm, so we named our controller as the Native Heart Load Control System (NHLCS). Employing changeable MVO2 with NHLCS according to the patient's condition may provide more opportunity for native heart recovery with LVAD, especially for patients with ischemic heart diseases. © 2013 The Japanese Society for Artificial Organs.

DOI： 10.1007/s10047-012-0682-0

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AIMS: Mammalian myocardium has a finite but limited capacity to regenerate. Experimentally stimulating proliferation of cardiomyocytes with extracellular regeneration factors like periostin enhances cardiac repair in rodents. The aim of this study was to develop a safe method for delivering regeneration factors to the heart and to test the functional and structural effects of periostin peptide treatment in a large animal model of myocardial infarction (MI). METHODS AND RESULTS: We developed a controlled release system to deliver recombinant periostin peptide into the pericardial space. A single application of this method was performed two days after experimental MI in swine. Animals were randomly assigned to receive either saline or periostin peptide. Experimental groups were compared at baseline, day 2, 1 month and 3 months. Treatment with periostin peptide increased the EF from 31% to 41% and decreased by 22% the infarct size within 12 weeks. Periostin peptide-treated animals had newly formed myocardium strips within the infarct scar, leading to locally improved myocardial function. In addition the capillary density was increased in animals receiving periostin. However, periostin peptide treatment increased myocardial fibrosis in the remote region at one week and 12 weeks post-treatment. CONCLUSION: Our study shows that myocardial regeneration through targeted peptides is possible. However, in the case of periostin the effects on cardiac fibrosis may limit its clinical application as a viable therapeutic strategy.

DOI： 10.1371/journal.pone.0059656

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publisher：Hamad bin Khalifa University Press ({HBKU} Press)  

DOI： 10.5339/qproc.2012.heartvalve.4.80

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

The technique for assisting renal blood circulation may be a useful therapeutic method in acute cardiorenal syndrome (ACRS), because renal ischemic dysfunction due to the reduced renal blood circulation is a powerful negative prognostic factor in ACRS. We constructed a circuit assisting renal arterial pressure and flow, and performed renal-selective blood perfusion (RSP) to the left kidney in a goat model of ACRS induced by right ventricular rapid pacing (n = 8), with the right kidney left intact as an internal control. Upon induction of ACRS, renal arterial flow (RAF), creatinine clearance (CCr), and renal oxygen consumption (RVO2) of the left kidney decreased to 49, 48, and 63% of the respective baseline values accompanied by a significant increase in renal vascular resistance (RVR), and similar results were observed in the right kidney. Then, RSP improved RVR and increased left RAF, CCr, and RVO2 up to 91, 86, and 93% of baseline values, respectively, without a significant change in systemic hemodynamics. The RSP-treated kidney showed significantly higher CCr and urinary excretion of water and sodium compared to the contralateral kidney. Additional infusion of prostaglandin E-1 with RSP decreased RVR further and enabled the left RAF to increase up to 129% of the baseline value, without a significant change in systemic hemodynamic parameters. The CCr and RVO2 did not change significantly, and urinary excretion of water and sodium showed a tendency to increase. These findings suggest that the technique for assisting renal blood circulation for both kidneys may offer a new treatment strategy for patients with ACRS.

DOI： 10.1007/s10047-011-0613-5

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Objective: Recent developments in adjunctive therapy have enabled us to remove once-implanted left ventricular assist devices. For successful device removal, appropriate patient selection and precise evaluation of cardiac function are essential. However, with rotary pumps, pump weaning inevitably creates diastolic retrograde pump flow, and this flow may overload the native heart. We developed a novel "off-test mode" for weaning, which increases revolutions per minute just in diastole. The present study evaluated the effect of this mode on retrograde pump flow and ventricular workload. Methods: The EVAHEART device (Sun Medical Technology Research Corporation, Nagano, Japan) was installed in 8 goats (63.0 ± 7.3 kg). We evaluated myocardial oxygen consumption, pressure volume area, and retrograde pump flow under 3 conditions: circuit clamp, continuous mode, and off-test mode. In continuous mode, revolution per minute was set for a mean net pump flow of zero, whereas in off-test mode, systolic revolution per minute was kept at a minimum level and diastolic revolution per minute was adjusted to ensure near-zero diastolic retrograde pump flow. Results: In off-test mode, the pressure volume loop shapes were similar to those under circuit-clamp conditions, with both myocardial oxygen consumption and pressure volume area approximately equal to those under clamp conditions. Retrograde pump flow was significantly decreased in off-test compared with continuous mode (P = .005). Conclusions: Off-test mode decreased retrograde flow during weaning while keeping ventricular workload similar to baseline. This mode is potentially valuable for establishing a safe and appropriate pump weaning protocol after myocardial recovery. Investigations on heart failure models are ongoing. Copyright © 2012 by The American Association for Thoracic Surgery.

DOI： 10.1016/j.jtcvs.2011.07.065

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Coronary circulation is closely linked to myocardial oxygen consumption (MVO(2)), and previous reports have suggested decreased coronary flow (CoF) under left ventricular assist device support. Decreased CoF itself under support is not unfavorable because the native heart can be well unloaded and myocardial oxygen demand is also decreased. There should be an autoregulatory system that would maintain optimal CoF according to oxygen demand; however, the detailed mechanism is still unclear. The aim of the current study is to evaluate the effect of centrifugal pumps on CoF under varied bypass rates in relation to left ventricle workload. A centrifugal pump, EVAHEART (Sun Medical Technology Research Corporation, Nagano, Japan), was installed in an adult goat (n = 10, 61.3 +/- 6.5 kg). We set up the following conditions, including Circuit-Clamp (i.e., no pump support), 50% bypass, and 100% bypass. In these settings, CoF, MVO(2), pressure-volume area (PVA), and coronary vascular resistance (CVR) were measured. In 100% bypass, CoF, MVO(2), and PVA were all decreased significantly from clamp. While in 50% bypass, CoF and MVO(2) decreased from clamp, but not PVA. There was a significant 40% increase in CVR in 100% bypass from clamp. This CVR increase in 100% bypass was possibly due to mechanical collapse of coronary vascular bed itself by pump support or increased vascular tone through autoregulatory system. In clinical settings, we should adjust optimal pump speed so as not to cause this vascular collapse. However, to clarify autoregulatory system of the coronary perfusion, further investigation is ongoing in ischemic and heart failure models.

DOI： 10.1111/j.1525-1594.2011.01298.x

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Continuous-flow left ventricular assist devices (LVADs) have greatly improved the prognosis of patients with end-stage heart failure, even if continuous flow is different from physiological flow in that it has less pulsatility. A novel pump controller of continuous-flow LVADs has been developed, which can change its rotational speed (RS) in synchronization with the native cardiac cycle, and we speculated that pulsatile mode, which increases RS just in the systolic phase, can create more pulsatility than the current system with constant RS does. The purpose of the present study is to evaluate the effect of this pulsatile mode of continuous-flow LVADs on pulsatility in in vivo settings. Experiments were performed on eight adult goats (61.7±7.5kg). A centrifugal pump, EVAHEART (Sun Medical Technology Research Corporation, Nagano, Japan), was installed by the apex drainage and the descending aortic perfusion. A pacing lead for the detection of ventricular electrocardiogram was sutured on the anterior wall of the right ventricle. In the present study, we compared pulse pressure or other parameters in the following three conditions, including Circuit-Clamp (i.e., no pump support), Continuous mode (constant RS), and Pulsatile mode (increase RS in systole). Assist rate was calculated by dividing pump flow (PF) by the sum of PF and ascending aortic flow (AoF). In continuous and pulsatile modes, these assist rates were adjusted around 80-90%. The following three parameters were used to evaluate pulsatility, including pulse pressure, dp/dt of aortic pressure (AoP), and energy equivalent pulse pressure (EEP=(∫PF*AoP dt)/(∫PF dt), mmHg). The percent difference between EEP and mean AoP is used as an indicator of pulsatility, and normally it is around 10% of mean AoP in physiological pulse. Both pulse pressure and mean dp/dt max were decreased in continuous mode compared with clamp condition, while those were regained by pulsatile mode nearly to clamp condition (pulse pressure, clamp/continuous/pulsatile, 25.0±7.6/11.7±6.4/22.6± 9.8mmHg, mean dp/dt max, 481.9±207.6/75.6±36.2/351.1±137.8mmHg/s, respectively). In clamp condition, %EEP was 10% higher than mean AoP (P=0.0078), while in continuous mode, %EEP was nearly equivalent to mean AoP (N.S.). In pulsatile mode, %EEP was 9% higher than mean AoP (P=0.038). Our newly developed pulsatile mode of continuous-flow LVADs can produce pulsatility comparable to physiological pulsatile flow. Further investigation on the effect of this novel drive mode on organ perfusion is currently ongoing. © 2011, the Authors. Artificial Organs © 2011, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

DOI： 10.1111/j.1525-1594.2011.01205.x

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A number of promising therapies for ischemic cardiomyopathy are emerging, and the role of translational research in testing the efficacy and safety of these agents in relevant clinical models has become important. The goal of this study was to develop a chronic model of ischemic cardiomyopathy in a large animal model. In this study, 40 consecutive pigs were initially enrolled. To induce progressive stenosis, a plastic occluder with a fixed diameter of 1.0 mm fitted with an 18-gauge copper wire was placed around the proximal left anterior descending (LAD) coronary artery. Coronary angiography, hemodynamic measurements, and echocardiography were performed at 2 wk and 1, 2, and 3 mo. Overall mortality was 26% at 3 mo, and up to 80% of the pigs showed total occlusion of LAD at 1 mo. A significant depression of peak LV pressure rate of rise (+dP/dt(max)) was observed in the animals showing total artery occlusion throughout the study. Left ventricular ejection fraction was also impaired, and the left ventricular volumes tended to be larger in the pigs with occlusion. Approximately 10% of scar tissue was found in the LAD occluded pigs, whereas the coronary flow pattern in the rest of the area took the pattern of hibernating myocardium. At the same time, histological and protein analysis established the presence of fibrosis and ongoing apoptosis in the ischemic area. In this model, the timing and incidence of total occlusion and low mortality offer significant advantages over other ischemic cardiomyopathy models in conducting preclinical studies.

DOI： 10.1152/ajpheart.01103.2010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Recent progress in the development of implantable rotary blood pumps realized long-term mechanical circulatory support (MCS) for bridge to transplant, bridge to recovery, or a destination therapy. Meanwhile, a short-term MCS system is becoming necessary for bridge to decision. We developed a novel inflow cannula for the short-term MCS system, which gives sufficient bypass flow with minimal invasion at insertion, and evaluated its hydrodynamic characteristics. The novel inflow cannula, named the Lantern cannula, is made of elastic silicone reinforced with metal wires. The cannula tip has six slits on the side. This cannula tip can be extended to the axial direction by using an introducer and can be reduced in diameter, and the Lantern cannula enables easy insertion into the left ventricle apex with minimal invasion. The sufficient bypass flow rate can be obtained due to low pressure loss. Moreover, this Lantern shape also resists suction complication around the cannula tip. The pressure loss through the Lantern cannula was measured using a mock circulation and compared with two commercially available venous cannulae (Sarns4882, Terumo, Tokyo, Japan and Stockert V122-28, Sorin Group, Tokyo, Japan), which have almost same diameter as the Lantern cannula. Moreover, the flow patterns around the cannula tip were numerically analyzed by computational fluid dynamics (CFD). Acute animal experiment was also performed to confirm the practical effectiveness of the Lantern cannula. The pressure loss of the Lantern cannula was the lowest compared with those of the commercially available venous cannulae in in vitro experiment. CFD analysis results demonstrated that the Lantern cannula has low pressure loss because of wide inflow orifice area and a bell mouth, which were formed via Lantern shape. The highest bypass flow was obtained in the Lantern cannula because of the low pressure loss under pulsatile condition in in vivo experiments. The Lantern cannula demonstrated superior hydrodynamic characteristics as the inflow cannula in terms of pressure loss due to its specially designed Lantern shape.

DOI： 10.1111/j.1525-1594.2011.01319.x

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Recent developments in adjunct therapeutic options for end-stage heart failure have enabled us to remove implanted left ventricular assist devices (LVADs) from more patients than before. However, a safe and proper protocol for pump-off trials is yet to be established, because diastolic backward flow in a pump circuit turns up when it is driven at low-flow conditions. We have developed a novel drive mode of centrifugal pumps that can change its rotational speed in synchronization with the cardiac cycle of the native heart. The purpose of this study was to test-drive this novel system of a centrifugal pump in a mock circulation and to evaluate the effect of the counterpulse mode, which increases pump speed just in diastole, on the amount of this nonphysiological intracircuit retrograde flow. A rotary pump (EVAHEART, Sun Medical Technology Research Corporation) was connected to the mock circulation by left ventricular uptake and ascending aortic return. We drove it in the following four conditions: (A) continuous mode at 1500 rpm, (B) counterpulse mode (systolic 1500 rpm, diastolic 2500 rpm), (C) continuous mode at 2000 rpm, and (D) counterpulse mode (systolic 2000 rpm, diastolic 2500 rpm). Data concerning the rotation speed, pump flow, left ventricular pressure, aortic pressure, and pressure head (i.e., aortic pressure-left ventricular pressure) in each condition were collected. After data collection, we analyzed pump flow, and calculated its forward and backward flow. Counterpulse mode decreased the amounts of pump backward flow compared with the continuous mode [mean backward flow, -4, -1, -0.5, 0 l/min, in (A), (B), (C), and (D) conditions, respectively]. The actual amounts of mean backward flow can be different from those in clinical situations; however, this novel drive mode for rotary pumps can relatively decrease pump backward flow during pump weaning and can be beneficial for safe and proper pump-off trials. Further investigations in in vivo settings are currently ongoing.

DOI： 10.1007/s10047-010-0544-6

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Bridge to recovery has become a major goal after left-ventricular-assist- device (LVAD) implantation thanks to recent development in adjunctive therapies. Precise assessment of native heart function under minimum LVAD support is the key for successful LVAD explantation. However, weaning of centrifugal LVADs normally generates diastolic intracircuit backward flow. This retrograde flow may become excessive load for the native heart during off-pump test. The flow itself is an inevitable characteristic of centrifugal pumps. Therefore, evaluating this retrograde flow in vitro is of considerable significance, even if its amount is different from that in clinical settings. The purpose of this study was to assess diastolic backflow of continuous-flow centrifugal LVADs in a mock circulation model. A centrifugal LVAD (EVAHEART, Sun Medical Technology) was installed in a mock circulation model by the left ventricle uptake and the ascending aortic return. Pump flow was measured at the pump rotational speed of 1000, 1500, 2000, and 2500 rpm, and pulse rate of the virtual native heart was varied to 60, 90, and 120 beats/min. After data collection, pump flow was integrated, and forward and backward intracircuit flow were calculated. As a result, nonphysiological reverse flow of approximately 2.0 L/min exists at the rotational speed, providing 0 L/min mean pump flow. An ideal off-test trial condition should be realizing both ±0 L/min pump flow and no intracircuit backward flow at the same time. We are developing a novel EVAHEART drive mode that can change its rotational speed in synchronization with cardiac cycle with the aim of controlling this retrograde flow with the new drive mode and creating an ideal off-test condition. © 2011 The Japanese Society for Artificial Organs.

DOI： 10.1007/s10047-010-0543-7

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Recent developments in adjunct therapeutic options for end-stage heart failure have enabled us to remove implanted left ventricular assist devices (LVADs) from more patients than before. However, a safe and proper protocol for pump-off trials is yet to be established, because diastolic backward flow in a pump circuit turns up when it is driven at low-flow conditions. We have developed a novel drive mode of centrifugal pumps that can change its rotational speed in synchronization with the cardiac cycle of the native heart. The purpose of this study was to test-drive this novel system of a centrifugal pump in a mock circulation and to evaluate the effect of the counterpulse mode, which increases pump speed just in diastole, on the amount of this nonphysiological intracircuit retrograde flow. A rotary pump (EVAHEART, Sun Medical Technology Research Corporation) was connected to the mock circulation by left ventricular uptake and ascending aortic return. We drove it in the following four conditions: (A) continuous mode at 1500 rpm, (B) counterpulse mode (systolic 1500 rpm, diastolic 2500 rpm), (C) continuous mode at 2000 rpm, and (D) counterpulse mode (systolic 2000 rpm, diastolic 2500 rpm). Data concerning the rotation speed, pump flow, left ventricular pressure, aortic pressure, and pressure head (i.e., aortic pressure-left ventricular pressure) in each condition were collected. After data collection, we analyzed pump flow, and calculated its forward and backward flow. Counterpulse mode decreased the amounts of pump backward flow compared with the continuous mode [mean backward flow, -4, -1, -0.5, 0 l/min, in (A), (B), (C), and (D) conditions, respectively]. The actual amounts of mean backward flow can be different from those in clinical situations; however, this novel drive mode for rotary pumps can relatively decrease pump backward flow during pump weaning and can be beneficial for safe and proper pump-off trials. Further investigations in in vivo settings are currently ongoing. © 2011 The Japanese Society for Artificial Organs.

DOI： 10.1007/s10047-010-0544-6

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Bridge to recovery has become a major goal after left-ventricular-assist-device (LVAD) implantation thanks to recent development in adjunctive therapies. Precise assessment of native heart function under minimum LVAD support is the key for successful LVAD explantation. However, weaning of centrifugal LVADs normally generates diastolic intracircuit backward flow. This retrograde flow may become excessive load for the native heart during off-pump test. The flow itself is an inevitable characteristic of centrifugal pumps. Therefore, evaluating this retrograde flow in vitro is of considerable significance, even if its amount is different from that in clinical settings. The purpose of this study was to assess diastolic backflow of continuous-flow centrifugal LVADs in a mock circulation model. A centrifugal LVAD (EVAHEART, Sun Medical Technology) was installed in a mock circulation model by the left ventricle uptake and the ascending aortic return. Pump flow was measured at the pump rotational speed of 1000, 1500, 2000, and 2500 rpm, and pulse rate of the virtual native heart was varied to 60, 90, and 120 beats/min. After data collection, pump flow was integrated, and forward and backward intracircuit flow were calculated. As a result, nonphysiological reverse flow of approximately 2.0 L/min exists at the rotational speed, providing 0 L/min mean pump flow. An ideal off-test trial condition should be realizing both ± 0 L/min pump flow and no intracircuit backward flow at the same time. We are developing a novel EVAHEART drive mode that can change its rotational speed in synchronization with cardiac cycle with the aim of controlling this retrograde flow with the new drive mode and creating an ideal off-test condition.

DOI： 10.1007/s10047-010-0543-7

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A series of star-shaped cationic polymers, termed star vectors (SVs), has been developed as effective nonviral gene delivery carriers. In this study, we separated SVs into several fractions having different molecular weights with very narrow molecular weight distributions in order to examine in detail the influence of the molecular weight of the SVs on the gene transfection efficiency. As a model compound for several types of SVs, 4-branched poly(N,N-dimethylaminopropyl acrylamide) having a molecular weight (M n) of approximately 35 kDa and polydispersity of 1.6 was prepared by iniferter-based radical polymerization. The SVs were separated using size-exclusion chromatography to obtain seven fractions having M n ranging from 27 kDa to 73 kDa with polydispersity ranging from 1.1 to 1.2. All the fractionated SVs have similar pH of 10.2-10.4 and were able to interact with and condense luciferase-encoding plasmid deoxyribonucleic acid (DNA) to yield SV/DNA polyplexes. A water-soluble tetrazolium-1 (WST) assay showed that all SVs had minimal cellular cytotoxicity under an N/P charge ratio of 10. The critical micellar concentration decreased with an increase in the M n of the fractionated SVs
however, the particle size of the polyplexes, exclusion activity of ethidium bromide, and ζ-potential of the polyplexes increased. An in vitro evaluation using COS-1 cells at an N/P ratio of 10 showed that transfection activity increased almost linearly with M n. The highest transfection activity was obtained for SVs with the highest M n (73 kDa), which was over 7 times that for the SVs with the lowest M n (27 kDa), the nonfractionated original SV, or PEI standard. The transfection efficiency was more correlated with the amphiphilicity or hydrophobicity of the SVs and the surface potential and condensate density of the polyplexes than with the particle size. © 2009 American Chemical Society.

DOI： 10.1021/bc900283h

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AIMS: There are few data comparing the fate of multipotent progenitor cells (MPCs) used in cardiac cell therapy after myocardial infarction (MI). To document in vivo distribution of MPCs delivered by intracoronary (IC) injection. METHODS AND RESULTS: Using an anterior MI swine model, near-infrared (NIR) fluorescence was used for in vivo tracking of labelled MPCs [mesenchymal stromal (MSCs), bone marrow mononuclear (BMMNCs), and peripheral blood mononuclear (PBMNCs)] cells early after IC injection. Signal intensity ratios (SIRs) of injected over non-injected (reference) zones were used to report NIR fluorescence emission. Following IC injection, significant differences in mean SIR were documented when MSCs were compared with BMMNCs [1.28 +/- 0.10 vs. 0.77 +/- 0.11, P < 0.001; 95% CI (0.219, 0.805), respectively] or PBMNCs [1.28 +/- 0.10 vs. 0.80 +/- 0.14, P = 0.005; 95% CI (0.148, 0.813), respectively]. Differences were maintained during the 60 min tracking period, with only the MSC-injected groups continuously emitting NIR fluorescence (SIR>1). This is correlated with greater cell retention for MSCs relative to mononuclear cells. However, there was evidence of MSC-related vessel plugging in some swine. CONCLUSION: Our in vivo NIR fluorescence findings suggest that MPC distribution and retention immediately after intracoronary delivery vary depending on cell population and could potentially impact the clinical efficacy of cardiac cell therapy.

DOI： 10.1093/eurheartj/ehp322

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Eccentric cardiac remodeling seen in dilated cardiomyopathy or regurgitant valvular disease is a well-known process of heart failure progression, but its mechanoenergetic profile has not been yet established. We made a volume overload (VO) heart failure model in rats and for the first time investigated left ventricular (LV) mechanical work and energetics in cross-circulated whole heart preparations. Laparotomy was performed in 14 Wistar male rats, and abdominal aortic-inferior vena caval shunt was created in seven rats (VO group). Another seven rats underwent a sham operation without functional shunt (Sham group). LV dimensions changes were followed with weekly transthoracic echocardiography. Three months after surgery, we measured LV pressure and volume and myocardial O 2 consumption in isolated heart cross circulation. LV internal dimensions in both systolic and diastolic phases were significantly increased in the VO group versus the Sham group (P &lt
0.05). LV pressure was markedly decreased in the VO group versus in the Sham group (P &lt
0.05). LV end-systolic pressure- volume relation shifted downward, and myocardial O 2 consumption related to Ca 2+ handling significantly decreased. The contractile response to Ca 2+ infusion was attenuated. Nevertheless, the increase in Ca 2+ handling-related O 2 consumption per unit change in LV contractility in the VO group was significantly higher than that in the Sham group (P &lt
0.05). The levels of sarco(endo)plasmic reticulum Ca 2+-ATPase 2a protein were reduced in the VO group (P &lt
0.01). In conclusion, VO failing rat hearts had a character of marked contractile dysfunction accompanied with less efficient energy utilization in the Ca 2+ handling processes. These results suggest that restoring Ca 2+ handling in excitation-contraction coupling would improve the contractility of the myocardium after eccentric cardiac remodeling. Copyright © 2009 the American Physiological Society.

DOI： 10.1152/ajpheart.01120.2008

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

The purpose of this study was to develop a compact wearable pneumatic drive unit for a ventricular assist device (VAD). This newly developed drive unit, 20 x 8.5 x 20 cm in size and weighing approximately 1.8 kg, consists of a brushless DC motor, noncircular gears, a crankshaft, a cylinder-piston, and air pressure regulation valves. The driving air pressure is generated by the reciprocating motion of the piston and is controlled by the air pressure regulation valves. The systolic ratio is determined by the noncircular gears, and so is fixed for a given configuration. As a result of an overflow-type mock circulation test, a drive unit with a 44% systolic ratio connected to a Toyobo VAD blood pump with a 70-ml stroke volume achieved a pump output of more than 7 l/min at 100 bpm against a 120 mmHg afterload. Long-term animal tests were also performed using drive units with systolic ratios of 45% and 53% in two Holstein calves weighing 62 kg and 74 kg; the tests were terminated on days 30 and 39, respectively, without any malfunction. The mean aortic pressure, bypass flow, and power consumption for the first calf were maintained at 90 x 13 mmHg, 3.9 x 0.9 l/min, and 12 x 1 W, and those for the second calf were maintained at 88 x 13 mmHg, 5.0 x 0.5 l/min, and 16 x 2 W, respectively. These results indicate that the newly developed drive unit may be used as a wearable pneumatic drive unit for the Toyobo VAD blood pump.

DOI： 10.1007/s10047-008-0433-4

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OBJECTIVES: The aim of this study was to examine the effects of sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) gene transfer in a swine heart failure (HF) model. BACKGROUND: Reduced expression and activity of SERCA2a have been documented in HF. Prior studies have reported the beneficial effects of short-term SERCA2a overexpression in rodent models. However, the effects of long-term expression of SERCA2a in pre-clinical large animal models are not known. METHODS: Yorkshire-Landrace pigs were used (n = 16) to create volume overload by percutaneously severing chordae tendinae of the mitral apparatus with a bioptome to induce mitral regurgitation. At 2 months, pigs underwent intracoronary delivery of either recombinant adeno-associated virus type 1 (rAAV1) carrying SERCA2a under a cytomegalovirus promoter (rAAV1.SERCA2a) (n = 10; group 1) or saline (n = 6; group 2). RESULTS: At 2 months, study animals were found to be in a compensated state of volume-overload HF (increased left ventricular internal diastolic and systolic diameters [LVIDd and LVIDs]). At 4 months, gene transfer resulted in: 1) positive left ventricular (LV) inotropic effects (adjusted peak left ventricular pressure rate of rise (dP/dt)max/P, 21.2 +/- 3.2 s(-1) group 1 vs. 15.5 +/- 3.0 s(-1) group 2; p < 0.01); 2) improvement in LV remodeling (% change in LVIDs -3.0 +/- 10% vs. +15 +/- 11%, respectively; p < 0.01). At follow-up, brain natriuretic peptide levels remained stable in group 1 after gene transfer, in contrast to rising levels in group 2. Further, cardiac SERCA2a expression was significantly decreased in group 2 whereas in group 1 it was restored to normal levels. There was no histopathological evidence of acute myocardial inflammation or necrosis. CONCLUSIONS: Using a large-animal, volume-overload model of HF, we report that long-term overexpression of SERCA2a by in vivo rAAV1-mediated intracoronary gene transfer preserved systolic function, potentially prevented diastolic dysfunction, and improved ventricular remodeling.

DOI： 10.1016/j.jacc.2007.12.014

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1. The aim of the present study was to examine the acute and chronic effects of adenoviral gene transfer on cardiac function in terms of left ventricular (LV) mechanoenergetic function. Recombinant adenoviral vector carrying beta-galactosidase and green fluorescent protein genes (Ad.betagal-GFP) was used. Cardiac function was examined in cross-circulated rat heart preparations, where end-systolic/diastolic pressure-volume relationships (ESPVR/EDPVR), systolic pressure-volume area (PVA), LV relaxation rate, equivalent maximal elastance at mid-range LV volume (eE(max) at mLVV), coronary blood flow, coronary vascular resistance and myocardial oxygen consumption (VO(2)) were also measured. 2. To examine the ex vivo acute effects of the adenoviral vector, data were obtained before and 30-90 min after intracoronary infusion of Ad.betagal-GFP in the excised, cross-circulated hearts that underwent serotonin pretreatment. To examine the in vivo chronic effects of adenoviral gene transfer, normal rat hearts received Ad.betagal-GFP or saline by a catheter-based technique and data were obtained 3 days after the injection of Ad.betagal-GFP or saline. 3. The ESPVR, EDPVR, LV relaxation rate, eE(max) at mLVV, coronary blood flow and coronary vascular resistance remained unchanged in Ad.betagal-GFP-transfected hearts in both ex vivo acute and in vivo chronic experiments. Moreover, the ex vivo and in vivo transfection caused no change in the slope and VO(2) intercept of the VO(2)-PVA relationship, VO(2) for basal metabolism and for Ca(2+) handling in excitation-contraction coupling and O(2) costs of LV contractility. 4. These results indicate that adenoviral gene transfer has neither acute nor chronic toxic effects on LV mechanical and energetic function. A special combination of in vivo adenoviral gene transfer and a cross-circulation experimental system may provide a useful novel strategy to explore the functional and mechanoenergetic role of specifically targeted genes in the diseased heart.

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The aim of this study was to examine how global cardiac gene transfer of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) can influence left ventricular (LV) mechanical and energetic function, especially in terms of O(2) cost of LV contractility, in normal rats. Normal rats were randomized to receive an adenovirus carrying the SERCA2a (SERCA) or beta-galactosidase (beta-Gal) gene or saline by a catheter-based technique. LV mechanical and energetic function was measured in cross-circulated heart preparations 2-3 days after the infection. The end-systolic pressure-volume relation was shifted upward, end-systolic pressure at 0.1 ml of intraballoon water volume was higher, and equivalent maximal elastance, i.e., enhanced LV contractility, was higher in the SERCA group than in the normal, beta-Gal, and saline groups. Moreover, the LV relaxation rate was faster in the SERCA group. There was no significant difference in myocardial O(2) consumption per beat-systolic pressure-volume area relation among the groups. Finally, O(2) cost of LV contractility was decreased to subnormal levels in the SERCA group but remained unchanged in the beta-Gal and saline groups. This lowered O(2) cost of LV contractility in SERCA hearts indicates energy saving in Ca(2+) handling during excitation-contraction coupling. Thus overexpression of SERCA2a transformed the normal energy utilization to a more efficient state in Ca(2+) handling and superinduced the supranormal contraction/relaxation due to enhanced Ca(2+) handling.

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The aim of this study was to examine whether short- and long-term gene transfer of Ca(2+) handling proteins restore left ventricular (LV) mechanoenergetics in aortic banding-induced failing hearts. Aortic-banded rats received recombinant adenoviruses carrying sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) (Banding+SERCA), parvalbumin (Banding+Parv) or beta-galactosidase (Banding+betagal), or an adeno-associated virus carrying SERCA2a (Banding+AAV.SERCA) by a catheter-based technique. LV mechanoenergetic function was measured in cross-circulated hearts. "Banding", "Banding+betagal" and "Banding+saline" groups showed lower end-systolic pressure at 0.1 ml intraballoon water (ESP(0.1)), higher end-diastolic pressure at 0.1 ml intraballoon water (EDP(0.1)) and slower LV relaxation rate, compared with "Normal" and "Sham". However, "Banding+SERCA" and "Banding+Parv" showed high ESP(0.1), low EDP(0.1) and fast LV relaxation rate. In "Banding", "Banding+betagal" and "Banding+saline", slope of relation between cardiac oxygen consumption and systolic pressure-volume area, O(2) cost of total mechanical energy, was twice higher than normal value, whereas slope in "Baning+SERCA" and "Banding+Parv" was similar to normal value. Furthermore, O(2) cost of LV contractility in the 3 control banding groups was approximately 3 times higher than normal value, whereas O(2) cost of contractility in "Banding+SERCA", "Banding+AAV.SERCA" and "Banding+Parv" was as low as normal value. Thus, high O(2) costs of total mechanical energy and of LV contractility in failing hearts indicate energy wasting both in chemomechanical energy transduction and in calcium handling. Improved calcium handling by both short- and long-term overexpression of SERCA2a and parvalbumin transforms the inefficient energy utilization into a more efficient state. Therefore enhancement of calcium handling either by resequestration into the SR or by intracellular buffering improves not only mechanical but energetic function in failing hearts.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY, INC  

Background: Although a left ventricular assist device is often used to provide circulatory support until transplantation in severe heart failure, the mortality of long-term use of left ventricular assist devices remains high. We have shown that hepatocyte growth factor causes angiogenesis, antifibrosis, and antiapoptosis in the myocardium. Therefore, gene therapy with hepatocyte growth factor-complementary DNA plasmids may enhance the chance of "bridge to recovery." In this study, we performed gene therapy with hepatocyte growth factor in the impaired goat heart with a left ventricular assist device.
Methods: Cardiac impairment was induced in 6 adult goats (56-65 kg) by ligation of the coronary artery, and ventricular assist devices were installed. The hepatocyte growth factor group (HGF; n = 3) was administered human hepatocyte growth factor-complementary DNA plasmid (2.0 mg) in the myocardium. The control group (n = 3) was similarly administered beta-galactosidase plasmid. Four weeks after gene transfection, we attempted to wean all goats from the ventricular assist device.
Results: The myocardia transfected with human hepatocyte growth factor-complementary DNA contained human hepatocyte growth factor protein at levels as high as 1.0 +/- 0.3 ng/g tissue 3 days after transfection. After weaning from the ventricular assist device, the HGF group showed good hemodynamics, whereas the control group showed deterioration. The percentage of fractional shortening was significantly higher in the HGF group than the control group (HGF vs control, 37.9% +/- 1.7% vs 26.4% +/- 0.3%, respectively; P &lt; .01). Left ventricular dilatation associated with myocyte hypertrophy and fibrotic changes was detected in the control group but not in the HGF group. Vascular density was markedly increased in the HGF group.
Conclusions: These results suggest that gene therapy with human hepatocyte growth factor may enhance the chance of bridge to recovery in the impaired heart supported with a ventricular assist device.

DOI： 10.1016/j.jtcvs.2004.02.045

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Language：English   Publishing type：Part of collection (book)   Publisher：Springer  

Cardiac regeneration therapy was recently attempted for recovering heart failure. However it is not clear whether the therapy is effective for severe failing hearts that need mechanical circulatory assistance. We examined a gene therapy for angiogenesis after acute myocardial infarction in goats under ventricular assist system (VAS). Six adult goats (56-65kg) were created with impaired hearts by ligating the coronary artery and installing pulsatile bi-ventricular assist devices (VADs). Hepatocyte Growth Factor (HGF) was selected as a gene for an angiogenesis factor, which also has cardio-protective activities. The HGF group (n=3) were administered 2.0mg human HGF-cDNA plasmid in myocardium. The control group (n=3) were similarly administered beta-galactosidase plasmid. Four weeks after gene transfection, we tried to wean all goats from VADs. The myocardia transfected with the hHGF-cDNA contained hHGF protein at levels as high as 1.0+/-0.3ng/g tissue 3 days after transfection. After weaning from VADs, the HGF group showed good hemodynamics, while the control group showed deterioration. The percent fractional shortening was significantly higher in the HGF group than the control group (HGF vs. control, 37.9+/-1.7% vs. 26.4+/-0.3%, p&lt
0.01). LV dilatation associated with myocytes hypertrophy and fibrotic changes were detected in the control group, but not in the HGF group. Vascular density was markedly increased in the HGF group. These results suggest that gene therapy using hHGF may enhance the chance of bridge to recovery in the impaired heart under VAS. © 2005 Springer-Verlag Tokyo.

DOI： 10.1007/4-431-27378-6_13

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

The purpose of this study was to try to reconstitute three-dimensional cardiac tissue using a thermoresponsive artificial extracellular matrix, poly (N-isopropylacrylamide)-grafted gelatin (PNIPAM-gelatin), as the scaffold. PNIPAM-gelatin solution gels almost immediately when heated above 34degreesC. We thought this property could become advantageous as scaffolding for reconstituting three-dimensional tissue. Because PNIPAM-gelatin solution gels so quickly, all seeded cells in PNIPAM-gelatin solution would become entrapped and uniformly distributed toward three dimensions. Thus it would be possible to reconstitute three-dimensional tissue by a very simple method of mixing cells and PNIPAM-gelatin solution. Fetal rat cardiac cells were mixed with PNIPAM-gelatin solution, incubated at 37degreesC to allow the mixture to gel, and cultured in vitro. To define suitable culture conditions the following parameters were tested: (1) PNIPAM-gelatin concentration, 0.04similar to0.125 mg/ml; (2) cell seeding density, 1similar to50 X 10(6) cells/ml; and (3) addition or not of hyaluronic acid. With a PNIPAM-gelatin concentration of 0.05 mg/ml, a cell seeding density of 50 X 10(6) cells/ml, and the addition of hyaluronic acid, tissue was reconstituted and it contracted synchronously. After hematoxylin and eosin staining, the cells reconstituted three-dimensional tissue, and the tissue cross-section was approximately 60 mum thick.

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Recently, cavitation on the surface of mechanical heart valves has been studied as a cause of fractures occurring in implanted mechanical heart valves. The cause of cavitation in mechanical heart valves was investigated using the 25 mm Medtronic Hall valve and the 23 mm Omnicarbon valve. Closing of these valves in the mitral position was simulated in an electrohydraulic totally artificial heart. Tests were conducted under physiologic pressures at heart rates from 60 to 100 beats per minute with cardiac outputs from 4.8 to 7.7 L/min. The disk closing motion was measured by a laser displacement sensor. A high-speed video camera was used to observe the cavitation bubbles in the mechanical heart valves. The maximum closing velocity of the Omnicarbon valve was faster than that of the Medtronic Hall valve. in both valves, the closing velocity of the leaflet, used as the cavitation threshold, was approximately 1.3-1.5 m/s. In the case of the Medtronic Hall valve, cavitation bubbles were generated by the squeeze flow and by the effects of the venturi and the water hammer. With the Omnicarbon valve, the cavitation bubbles were generated by the squeeze flow and the water hammer. The mechanism leading to the development of cavitation bubbles depended on the valve closing velocity and the valve stop geometry. Most of the cavitation bubbles were observed around the valve stop and were generated by the squeeze flow. ASAIO Journal 2004; 50:205-210.

DOI： 10.1097/01.MAT.0000123639.59051.C9

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：SOC INSTRUMENT CONTROL ENGINEERS JAPAN  

We have been developing an electrohydraulic total artificial heart (EHTAH) system. The system consists of diaphragm-type blood pumps, an electrohydraulic energy converter, an internal control unit, a transcutaneous energy transfer (TET) system, a transcutaneous optical telemetry (TOT) system, and an internal battery. The energy converter reciprocates and delivers hydraulic silicone oil to the alternate blood pumps. The displacement volume and the weight of the system are 872 ml and 2492 g, respectively. The maximum flow rate was 12 L/min and the maximum efficiency was 15.4 %. The system performance was examined in a series of in vivo experiments. The system was successfully implanted in 16 calves in the range of 60 kg or more. Four of the 16 calves survived for more than I month approximately. One of them lived for 70 days. The system was basically driven by the TET system, and was driven by the internal battery for 40 minutes everyday. The internal battery was fully charged within 3 hours after usage. DC-DC transmission efficiency of around 80 % was maintained during operation with the TET system. These results indicate that EHTAH has the potential to be a totally implantable system.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING INC  

Aortic wall thinness was one of the most characteristic changes observed in experimental animals under prolonged continuous flow left heart bypass. The goal of this study was to determine the roles of smooth muscle cells in the vascular remodeling process in cases demonstrating aortic wall thinness under prolonged continuous flow left heart bypass. The aortic samples from three goats in which continuous flow left heart bypass was performed were subjected to histological and immunohistochemical analyses. After 4 weeks of observation, the pulse pressure in the goats under the continuous flow left heart bypass was clearly lower than that in the normal healthy goats. The aortic walls of these goats became thinner, an effect caused by the dilation of their internal diameter. These aortic smooth muscle cells maintained contractile formation due to the fact that they contained abundant alpha-smooth muscle actin (SMA) and smooth muscle myosin heavy chain (SMMS). These cells also synthesized redundant matrix metalloproteinase-2 and -9, and the ratio of the SMMS-positive to the SMA-positive area was significantly lower (0.76) than that observed in the control goat (1.00; P &lt; 0.05). The smooth muscle cells demonstrated synthetic-dedifferentiated formation, which is one of the phenotypes of smooth muscle cell function. In conclusion, aortic wall thinness under prolonged continuous flow left heart bypass is caused by over-synthesis of matrix metalloproteinase in smooth muscle cells, and this refers the vascular remodeling process of the extracellular matrix.

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The integrated heart lung assist device (IHLAD) has been developed to overcome the problems of currently available extracorporeal membrane oxygenation devices. The integrated structure of a centrifugal blood pump and cylindrical bundle of polyolefin hollow-fibers has allowed a remarkably compact size for the device. This study deals with the design change of the IHLAD that added to the vaned diffuser between the impeller of the centrifugal pump and the hollow-fiber bundle with a view to enhancing the gas-transfer performance. Ex vivo gas-transfer performance tests were carried out, as well as hydrodynamic characteristics and hemolysis test using fresh goat blood. The oxygen transfer rate was generally improved, and the carbon dioxide removal rate was slightly improved. Intolerable amount of hemolysis (index of hemolysis= 0.177) was caused by the IHLAD, which must be resolved by improving the design in the future.

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The configuration of the vaned diffuser of the integrated heart lung assist device (IHLAD) has been revised to reduce mechanical blood trauma caused by the device. The flow visualization study of the flow near the diffuser vanes revealed the existence of a rotating stall which deteriorates the hydrodynamic performance of the device and augments the chance for blood cells to pass through the regions with intense shearing forces. Design changes of the diffuser included decrease in vane number from 7 to 5 and decrease in passage width from 3 mm to 2 mm. This design change was effective to suppress initiation of a rotating stall. Improvement of hydrodynamic performance and antihemolytic properties was confirmed with the newly designed configuration based on the flow visualization study.

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We investigated morphological changes of the arterial systems in the kidneys under prolonged continuous flow left heart bypass. Twelve goats were subjected to 2 weeks of pulsatile left heart bypass followed by 4 weeks of continuous flow left heart bypass (group CF). After autopsy, the kidneys underwent pathological evaluation. Six normal healthy goats were used as controls. The media of the afferent arterioles of group CF were frequently thickened by an increase in the number of the mature smooth muscle cells (SMCs). The juxtaglomerular areas (JGA) were expanded because of an increase in the number and size of SMCs and/or SMC-like cells. Furthermore, the percentage of anti-proliferating cell nuclear antigen antibody-positive cells in the JGA of group CF (9.9 +/- 1.9%) was significantly higher (p = 0.025) than that of the control group (4.6 +/- 3.4%), indicating active proliferation in group CF. We concluded that prolonged continuous flow left heart bypass causes proliferation of SMCs and/or SMC-like cells in the afferent arterioles and their perivascular tissue.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

In the mechanism of damage to red blood cells (RBCs) caused by a centrifugal pump, the prolonged effects to the RBC membrane caused by exposure to shear stress remain unclear. We focused on the band 3 protein (B3), one of the major proteins in the membrane skeleton, and investigated the ultrastructural alterations of the RBC membrane with loaded shear stress. Using flow cytometry, the relative amount of B3 was examined in relation to RBC deformability. The results, with continuous exposure to low shear stress, showed cell downsizing, an increase in B3 density, and a decrease in the deformability of the RBC membrane. Exposure to high shear stress does not appear to exert any influence on the membrane skeleton of the RBC. Therefore, in addition to conventional processes including the instantaneous destruction of a cell due to intense shear stresses, the results of the present study indicate the presence of another process based on changes in membrane proteins leading to cell fragmentation. Under low shear stress, the RRC membrane skeleton shows delayed destruction, which is exhibited as a disorder of B3 distribution, and the related membrane dysfunction includes decreases in RBC deformability and stability.

DOI： 10.1097/01.MAT.0000033867.03197.BA

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Aortic pressure declines during cardiopulmonary bypass (CPB), particularly at normothermia. it has been reported that administering vasoconstrictors during normothermic CPB (NCPB) to restore perfusion pressure might induce hypoperfusion of splanchnic organs. We have reported that prostaglandin (PG), metabolized in the lung but increased during CPR, might have played a substantial role in hypotension, and that a PG synthesis inhibitor (PGSI) could improve hypotension during CPR. This study was designed to examine whether regional perfusion of splanchnic organs was reduced when PGSI restored systemic perfusion pressure during NCPB. NCPB was performed in eight adult goats for 60 minutes (body weight 57.0 +/- 5.9 kg). PGSI was administered in group P (n = 4), while norepinephrine was administered in group C (n = 4), to keep aortic pressure in the range of 50 to 80 mm Hg. The total systemic flow was maintained at approximately 70 ml/kg/min. Tissue blood flow was measured by means of the colored microsphere method before and 30 and 60 minutes after the start of CPR. In group P, gut blood flows after the start of CPR were higher than those before CPR, significantly in the stomach and jejunum at 30 minutes (p &lt; 0.05), whereas gut blood flows in group C were decreased or not changed. In conclusion, PGSI prevents hypotension without impairing gut perfusion during NCPB.

DOI： 10.1097/01.MAT.0000026352.66193.22

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We have reported that infusion of prostaglandin synthesis inhibitor (PGSI) reduced the severity of hypotension during normothermic cardiopulmonary bypass (CPB). In the present study, we investigated the effects of PGSI on humoral conditions and whole body oxygen metabolism during normothermic CPB conducted for 60 min in 8 adult goats. The PGSI group (n = 4) was administered 100 to 150 mg of flurbiprofen, a potent PGSI, before and during CPB, and the control group (n = 4) was administered noradrenaline (NA) to restore hypotension. The prostaglandin E-2 (PGE(2)) and NA concentrations in the PGSI group were significantly lower than those of the control group (PGE(2) 8.8 +/- 1.0 versus 30.3 +/- 11.5 pg/ml, NA 431 +/- 197 versus 3847 +/- 2,153 pg/ml). The adrenaline concentration was not significantly different between the groups. The oxygen consumption and the oxygen extraction rate were not significantly different between the groups, but the blood lactate level in the PGSI group was lower than that of the control group (34.3 +/- 7.6 versus 43.7 +/- 3.8 mg/dl). In conclusion, PGSI improves humoral disorder and thus prevents inadequate tissue oxygen delivery.

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We developed an extracorporeal membrane oxygenation (ECMO) system with high antithrombogenicity and durability characteristics for prolonged continuous cardiopulmonary support. The oxygenator consists of a special hollow-fiber-type polyolefin gas-exchange membrane, which has an ultrathin dense layer in contact with the blood, in order to prevent plasma leakage during protracted use (Platinum Cube NCVC). The centrifugal pump (RotaFlow) is free of seals. The entire blood-contacting surface of the system is coated with a newly developed heparin material (Toyobo-NCVC coating). We performed a venoarterial bypass in a goat, and the ECMO system was driven for 34 days without systemic anticoagulants. Plasma leakage from the oxygenator did not occur, and sufficient gas exchange performance was maintained. Thrombus formation was hardly observed in the ECMO system except in the casing margins of the oxygenator. This ECMO system showed potential for long-term cardiopulmonary support with minimal or no use of systemic anticoagulants.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Hypotension is a major systemic side effect during cardiopulmonary bypass (CPB), especially at normothermia. We previously reported that prostaglandin (PG) might play a substantial role in hypotension. The purpose of this study was to clarify whether a PG synthesis inhibitor (PGSI) could improve hypotension during CPB. Thirty-six patients undergoing cardiac surgery with normothermic CPB (35-37 degreesC) were divided into two groups: a PGSI group (n = 18), whose members were given a PGSI before and during CPB, and a control group (n = 18). In both groups, perfusion flow was sufficient and pressure was maintained at above 45 mm Hg by infusion of metaraminol, a vasoconstrictor. The mean arterial pressure throughout CPB was significantly higher in the PGSI group than in the control group (57 +/- 4 vs. 48 +/- 3 mm Hg, p &lt; 0.01), whereas the dose of infused metaraminol was significantly lower in the PGSI group (13 +/- 7 vs. 21 +/- 6 mg, p &lt; 0.01). The blood base excess was not significantly different (1.0 +/- 1.6 vs. 1.7 +/- 1.9 mmol/L, p = 0.28), and urine output was significantly higher in the PGSI group (503 +/- 179 vs. 354 +/- 112 ml/hr, p &lt; 0.01). In conclusion, PGSI can improve hypotension during CPB and increase urine output without impairing peripheral circulation.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WICHTIG EDITORE  

Despite its wide clinical application, patient recovery from cardiopulmonary support (CPS) is not necessarily satisfactory. To clarify what influence CPS has on organ perfusion, we investigated the oxygen metabolism under various bypass flow (BF) conditions in a series of chronic animal CPS experiments.
The CPS system, which consists of a pulsatile ventricular assist device and a compact artificial lung was installed without anesthesia in 6 adult goats weighing 49-51 kg. BF was adjusted stepwise from 0% to 50%, 75%, 90%, and 100% of total systemic blood flow (TSF) by balancing the pulmonary arterial flow. The animals' TSF and oxygen delivery (DO2) were sufficiently maintained throughout the experiments.
The oxygen consumption (VO2) and the oxygen extraction rate (ExO(2)) increased from 178 +/- 14 to 342 +/- 19 ml/min, and from 28 +/- 2% to 64 +/- 1%, respectively in proportion to the increase of CPBF dependency from 0% to 100%. The blood lactate level did not change appreciably even at 90% BF from 5.7 +/- 0.3 to 11.2 +/- 1.2 mg/dl, but drastically elevated to 23.5 +/- 4.6 mg/dl at the total bypass.
This indicates that CPS leads to a relative lack of oxygen and can induce organ dysfunction due to increasing VO2 and ExO(2) in proportion to the increase of BF dependence even if TSF and DO2 are sufficiently maintained.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Lippincott-Raven Publ  

In this study, an attempt was made to investigate whether prostaglandin (PG) synthesis inhibitor (PGSI) can improve hypotension during cardiopulmonary bypass (CPB). The mean systemic blood pressure (SBP), the blood base excess (BE), the urine output and the dose of metaraminol were estimated. Administration of PGSI during CPB improved hypotension and increased urine output without impairing peripheral circulation.

DOI： 10.1097/00002480-200003000-00049

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE INC  

We investigated the morphological changes in the aorta due to reduced systemic pulse pressure in prolonged nonpulsatile left heart bypass (LHB). Nineteen adult goats were divided into 3 groups, the nonpulsatile group in which nonpulsatile LHB was conducted, the pulsatile group in which pulsatile LHB was conducted, and the control group used as the normal control. The average aortic pulse pressures were 12, 47, and 37 mm Hg, respectively. The descending aorta was subjected to morphological examination. In the nonpulsatile group, the wall was significantly thinner, and the volume ratio of smooth muscle cells (SMCs) was much lower. In terms of the SMC type classification, the proportion of SMCs with low activity and low contractility was higher, and the cell density of the SMCs was increased compared to those in the other groups. These results indicate that prolonged nonpulsatile LHB causes morphological atrophic changes in the aorta.

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOCIETY FOR ARTIFICIAL ORGANS  

We evaluated the basic performance of an interatrial shunt (IAS), which was made by punching a hole in the atrial septum, in accommodating the left-right imbalance in our electrohydraulic total artificial heart (EHTAH) system. In an in vitro study conducted in a closed mock circuit connected with the EHTAH, the interatrial pressure gradient changed in proportion to the amount of bronchial flow and the size of the IAS. The IAS of 4.4mm in diameter or larger maintained the interatrial pressure gradient within physiologically permissible limits when the amount of bronchial flow was 5% of cardiac output or less. A left-to-right one-way valve made of a piece of pericardium, a possible option in our IAS method, successfully prevented right-to-left reverse shunt flow through the IAS. In a chronic in vivo study using a calf implanted with the EHTAH for 10 days, a 4.5mm IAS without the one-way valve demonstrated satisfactory dynamic left-right balancing capacity with a stable interatrial pressure gradient of 4±1mmHg over a wide range of atrial pressures. No thrombus was found in or around the IAS at autopsy. We conclude that the IAS is a simple and promising means of left-right balancing in the EHTAH system

DOI： 10.11392/jsao1972.27.31

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOCIETY FOR ARTIFICIAL ORGANS  

We evaluated the heat transfer characteristics of an electrohydraulic total artificial heart (EH-TAH) that have been developed at our institute. In two in vitro experiments, the heat dissipation way of the TAH was investigated. First, we simulated heat transfer of the calf circulation by using a heat exchanger. The amount of heat dissipating directly from the TAH surface and that to the blood chamber were estimated to be almost the same. Second, the temperature of the actuator examined with thermography was found to be almost uniform, and no prominent high temperature area was observed. In an to vivo study, the TAH was implanted in a calf weighing 62kg for 10 days. The input power to the device was 18±2 W, the temperature of the actuator-tissue contacting surface was 39-41°C. This slight temperature elevation was thought to be attributable to the heat dissipation to the blood. Upon histological study of the chest wall and the lung in contact with the actuator, vascularized connective tissue envelopes were observed and unfavorable side effects such as tissue necrosis were not observed. These results suggest that the thermal effect of this system is acceptable at this input power

DOI： 10.11392/jsao1972.27.3

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Other Link： http://search.jamas.or.jp/link/ui/1998162896

Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT-RAVEN PUBL  

Mixed venous oxygen saturation (SvO(2)) and physical activity (PhyAc) are practical candidates as parameters of total artificial heart (TAH) control because SvO(2) can be measured through a transparent blood pump housing with infrared rays and PhyAc can be calculated from signals of an accelerometer used for rate response pacemakers. Although the methods for measurement of the parameters have already been developed, characteristics of these parameters for TAH control, such as during exercise, are still unclear and were examined in this study. SvO(2), cardiac output (CO), and PhyAc were measured as parameters. Multi-stage treadmill exercise tests were performed. Difference values (DVs) from the value at the start of exercise showed better correlation than did absolute values. Correlation coefficients between DV in CO and DV in SvO(2) and between DV in CO and PhyAc were high at -0.82 and 0.72, while the time constants for the change of SvO(2) and CO to the PhyAc change were 26 and 32 sec. Although the correlation coefficient between the CO and SvO(2) was higher than that between CO and PhyAc, PhyAc responded more quickly to the speed change compared with the response of SvO(2) and CO. It was concluded that SvO(2) and PhyAc were useful parameters with different characteristics for TAH control during exercise.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT-RAVEN PUBL  

The morphologic changes of the aortic wall due to reduced systemic pulse pressure in prolonged non pulsatile left heart bypass (LHB) were investigated. Sixteen adult goats were divided into three groups: the non pulsatile group in which non pulsatile LHB was conducted for 137 days on average, the pulsatile group in which pulsatile LHB was conducted for 79 days on average, and the control group used as the normal control. The average aortic pulse pressures were 12, 48, and 37 mmHg, respectively. At the end of the experiments, the descending aorta was excised and subjected to morphologic examination. The wall thickness of the aorta in the non pulsatile group (1.4 mm) was significantly thinner than that in the pulsatile group (2.2 mm) and the control group (2.0 mm), and the volume ratio of smooth muscle cells (SMC) in the non pulsatile group (37%) was lower than that in the pulsatile group (48%) and the control group (49%). In SMC classification, the proportion of SMC with low activity and low contractility in the non pulsatile group (57%) was high as compared with that in the pulsatile (2%) and control (5%) groups. These results strongly indicate that prolonged non pulsatile LHB causes substantial morphologic changes in the aorta.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT-RAVEN PUBL  

The effects of reduced pulmonary arterial blood flow (PAF) during venoarterial bypass (VAB) on hemodynamic and humoral conditions were investigated in a series of experiments in a chronic animal model. A biventricular bypass system was installed in five adult goats weighing 49.8 +/- 1.1 kg. Two weeks later, the extracorporeal circuitry was changed to VAB without anesthesia. The PAF was reduced stepwise from 100% to 50, 25, 10, and 0% of total systemic flow. The mean aortic pressure and systemic vascular resistance decreased from 110 +/- 14 to 66 +/- 3 mmHg and from 1,288 +/- 77 to 740 +/- 73 dyne.sec/cm(5), respectively, in proportion to the decrease in PAF from 100 to 0%. The prostaglandin E-2 concentration increased from 1.5 +/- 0.6 to 8.8 +/- 0.6 pg/ml following the decrease in PAF from 100 to 0%. The renin-angiotensin system increased in proportion to the decrease in PAF. In contrast, the epinephrine and norepinephrine concentrations (60 +/- 10 and 227 +/- 80 pg/ml, respectively, at 100% PAF) did not change appreciably even at 10% PAF, but were markedly elevated to 335 +/- 117 and 2,088 +/- 1,503 pg/ml at 0% PAF. The antidiuretic hormone level similarly changed. In conclusion, decrease in PAF during VAB exerts significant effects on hemodynamics in a proportional manner and on vasoactive humoral factors in a diverse manner.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT-RAVEN PUBL  

The authors evaluated the basic performance of an interatrial shunt (IAS) made by punching a hole in the atrial septum, in accommodating the left-right imbalance in our electrohydraulic total artificial heart (EHTAH) system. In an in vitro study conducted in a closed mock circuit connected with the EHTAH, the interatrial pressure gradient changed in compliance with the amount of bronchial flow and the size of the IAS. The IAS of 4.4 mm diameter or larger maintained the interatrial pressure gradient within physiologically permissible limits when the amount of bronchial flow was 5% of cardiac output or less. A left-to-right one-way valve made of a piece of pericardium, a possible option in this IAS method, successfully prevented right-to-left reverse shunt flow through the IAS. In a chronic in vivo study using a calf implanted with the EHTAH for 10 days, a 4.5 mm IAS without the one-way valve demonstrated satisfactory dynamic left-right balancing capacity with a stable interatrial pressure gradient of 4 +/- 1 mmHg over a wide range of atrial pressures. No thrombus was found in or around the IAS at autopsy. The authors conclude that the IAS is a simple and promising means of left-right balancing in the EHTAH system.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT-RAVEN PUBL  

The authors evaluated the heat transfer characteristics of an electrohydraulic totally implantable artificial heart (EH-TAH) developed at our institute. In three in vitro experiments, the heat dissipation of the EH-TAH was investigated. First, the EH-TAH was connected to a closed mock circuit filled with 1 L of saline, and driven at an input power of 20 W. The estimated heat conducted to the blood was similar to 10.3 W, which was almost half of the input power. Second, we simulated heat transfer with the circulation of a calf by using a heat exchanger. The amount of heat dissipating directly from the EH-TAH surface was calculated to be 10 W. Third, the temperature of the actuator examined with thermography was found to be almost uniform, and no prominent high temperature area was observed. In an in vivo study, the EH-TAH was implanted for 10 days in a calf weighing 62 kg. The input power was 18 +/- 2 W, the temperature of the actuator-tissue contacting surface was 39.5 +/- 0.8 degrees C, and that of the pump blood chamber was 39.8 +/- 0.4 degrees C. This slight temperature elevation was thought to be attributable to heat dissipation to the blood. On histologic study of the chest wall and the lung in contact with the actuator, vascularized connective tissue envelopes were observed, but unfavorable side effects, such as tissue necrosis, were not observed. These results suggest that the thermal effect of this system is acceptable at the input power used.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE INC  

A flow rate estimating method was investigated for a centrifugal blood pump developed in our institute. The estimated flow rate was determined by the power consumption, the rotating speed of the motor, and the hematocrit value. The power consumption and the rotating speed of the motor were measured with a wattmeter. The examinations were performed in a closed mock loop filled with goat blood with hematocrit values of 21.5%, 28%, 34%, and 42%. Measured values of blood viscosity were 2.47, 3.09, 3.71, and 5.07 mPa . s at a share rate of 37.5/s, respectively. A linear correlation between the power consumption and the pump flow rate was observed in all hematocrit values. But variations in hematocrit caused a difference in the flow rate up to 1.1 L/min at the same power consumption and rotating speed. Effects of blood viscosity on the flow estimation were corrected by the hematocrit value. The value of the coefficient of determination, RP between the estimated flow rate and the measured now rate was 0.988. These results may indicate that the now estimating method calculated by the power consumption of the motor, the rotating speed, and the hematocrit value is useful in the clinical situation.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE INC  

Antithrombogenicity of a centrifugal pump (CP) developed in our institute is provided by a central balancing hole (BH) in the impeller. A current CP, the National Cardiovascular Center (NCVC)-2, was ameliorated to improve antithrombogenicity, whereby the BH diameter was widened to improve self washout flow velocity, and an edge of the thrust bearing was rounded off to minimize flow separation. Effects of these modifications were assessed in a long-term in vivo experiment. The antithrombogenicity, hemolytic property, and mechanical durability of the NCVC-2 were investigated in 3 goats. The NCVC-2 was installed paracorporeally between the left atrium and the aorta and driven as long as possible at rotating speeds of about 2,800 rpm. The NCVC-2 ran for 50, 200, and 367+ days. The mean bypass flow rates were 6.8, 5.0, and 5.3 L/min, respectively. Creatinine, blood urea nitrogen (BUN), glutamic-oxaloacetic transaminase (GOT), and glutamic-pyruvic transaminase (GPT) did not increase until one week before termination. Plasma free hemoglobin was kept to a level less than 15 mg/dl, except for the last week of the second case. These results indicate that the NCVC-2 has excellent antithrombogenicity, an acceptable hemolytic property and the necessary durability for prolonged use.

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Language：Japanese   Publisher：JAPANESE SOCIETY FOR ARTIFICIAL ORGANS  

We investigated morphological changes of the aortic wall after long-term high flow nonpulsatile left heart bypass using nine adult goats weighing from 46 to 71kg. High flow left heart bypass was performed with a nonpulsatile pump in three goats for 32-381 days (Group-N), and with a pulsatile ventricular assist device in the other three goats for 24-130 days (Group-P). Three healthy goats were used as a normal control (Group-C). Morphological changes of the descending aorta were evaluated in: 1) the wall thickness, 2) the volume ratio of collagen, elastin and smooth muscle cell (SMC) and, 3) the relative proportion of the three SMC cell types least active (type I), moderately active (type II), and most active (type III). The wall thickness in Group-N (1.4±0.2mm) was considerably thin as compared with those in Group-P (2.3±0.4mm) and in Group-C (2.4±0.1mm). The volume ratio of SMC in the aortic matrix in Group-N (38±2%) was significantly lower than those in Group-P (47±3%) and in Group-C (50±2%). In SMC cell type categorization, the relative proportion of type I cell in Group-N (67±12%) was higher than those in Group-P (4±5%) and in Group-C (5±2%), whereas that of type III cell in Group-P (49±4%) was higher than those in Group-N (4±1%) and in Group-C (16±2%). In conclusion, prolonged high flow left heart bypass with a nonpulsatile pump causes significant morphological changes in the aortic wall.

DOI： 10.11392/jsao1972.26.93

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Other Link： http://search.jamas.or.jp/link/ui/1997156275

Language：Japanese   Publisher：JAPANESE SOCIETY FOR ARTIFICIAL ORGANS  

DOI： 10.11392/jsao1972.26.Supplement_S100

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT-RAVEN PUBL  

The authors developed a new membrane oxygenator (MO) for long-term respiratory support and evaluated its performance in animal experiments for as long as 336 hr. The MO, with a membrane area of 1.2 m(2) and priming volume of 140 ml, is compact and designed to be interposed in a ventricular assist system (VAS) conduit. It is made with a novel hollow fiber membrane, in which micropores are blind-ended so that serum leakage can be prevented during prolonged use. The blood contacting surface of the MO is heparinized with a newly developed covalent bonding technique that ensures good thrombus resistance. In vivo evaluation with five adult goats was performed by installing the MO into a venoarterial or venovenous bypass circuit. No systemic anticoagulant therapy was used, except for a heparin-added fluid infusion to keep the pressure monitoring lines open (2-3 U/kg/hr). Throughout the experiments, no plasma leakage was observed, and gas transfer rates were maintained in a satisfactory range. Platelet counts did not decrease to less than 60% of levels before bypass, and hemolysis was negligible. The levels of coagulation parameters including fibrinogen, fibrin degradation products (FDP), antithrombin III (AT III), antiplasmin, prothrombin time (PT) and activated partial thromboplastic time (APTT) remained within physiologic ranges and relatively constant. At the end of the evaluation, no thrombus formation was noted in three of five MOs. These results suggest that this MO is a promising device for long-term respiratory support.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT-RAVEN PUBL  

It is generally considered that the natural lung metabolizes various vasoactive substances through the pulmonary circulation. However, the influences of bypassing or eliminating the pulmonary circulation have not been fully elucidated, especially for prolonged periods. In this study, we performed total cardiopulmonary bypass and exclusion of the pulmonary circulation for up to 336 hr in awake goats to clarify the importance of the metabolic function of the lung. In seven adult goats, biventricular bypass with a pulsatile ventricular assist system was first established. After 2 weeks, the biventricular bypass was converted to total cardiopulmonary bypass without anesthesia. Adequate gas exchange and perfusion support were achieved in all animals. However, the institution of total cardiopulmonary bypass led to marked decreases in the mean aortic pressure and systemic vascular resistance, and they remained low thereafter. The arterial levels of prostaglandin E(2) and norepinephrine, which are inactivated naturally through the pulmonary circulation, increased remarkably. These results indicate that the natural lung plays an important role in controlling systemic circulation by metabolizing various vasoactive substances. Understanding the non respiratory function of the natural lung is of prime importance for advancement of lung and heart-lung support.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE INC  

When operating turbo blood pumps in tandem, the strength of shear stress is reduced, but the exposure duration of the stress is increased. The purpose of this experiment was to compare the degree of contribution of these two factors on hemolysis as well as to evaluate the effectiveness of the tandem operation of turbo blood pumps. Tandem operation of two Bio-pumps (BP-80; Medtronics Bio-medicus, Inc., Eden Prairie, Minnesota, U.S.A.) were compared with single operation of a BP-80 in in vitro hemolysis tests in three different driving conditions, that is, pumping heads of 200, 350, and 500 mm Hg under a pump flow rate of 5 L/min. The Allen's hemolytic indexes of the tandem operation at pumping heads of 200, 350, and 500 mm Hg were 0.014, 0.020, and 0.080 mg/dl, respectively. The hemolytic indexes of the single operation at pumping heads of 200, 350, and 500 mm Hg were 0.014, 0.056, and 0.12 mg/dl, respectively. These results indicate that tandem operation is a useful method of reducing hemolysis with the BP-80 under high pumping heads and that the effect on hemolysis of exposure to higher shear stresses may be more serious than that of longer durations of exposure to shear stress in turbo blood pumps.

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

DOI： 10.1016/j.healun.2019.01.1093

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：KARGER  

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Language：Japanese   Publisher：The Japan Society of Mechanical Engineers  

A new technique for assisting renal selective blood circulation using an extracorporeal circuit to the kidney in acute cardiorenal syndrome was proposed and this technique have shown sufficient effectiveness for the renal function in a goat model in our previous study. However, this technique requires an invasive surgery to install the extracorporeal circuit. We are developing a catheter-based intravascular rotary blood pump for assisting renal blood circulation (Renal-RBP). The purpose of this study is to evaluate the appropriate pump casing geometry to improve the hydraulic performance in Renal-RBP using the computational fluid dynamics (CFD) analysis. The Renal-RBP consists of an impeller, a pump casing, a brushless DC motor, a motor housing and a catheter. The Renal-RBP is positioned in the abdominal aorta near the renal artery and it perfuses blood to both kidneys. Therefore, the Renal-RBP has two outlet ports against one inlet port. Multiple pump casing geometries were estimated in order to obtain the necessity performance using CFD analysis. The results of CFD analysis, it was showed that the outer diameter of pump casing contributed to the increase in pressure head of Renal-RBP.

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Language：Japanese   Publisher：The Japan Society of Mechanical Engineers  

Mechanical circulatory support using a ventricular assist device (VAD) has been an essential therapeutic tool for patients with severe heart failure waiting for a heart transplant. To the enhancement of the therapeutic efficacy or safety and prevention of complications, advanced software functionality such as VAD drive control may be equally important as hardware improvements. However, controlling VADs in the realistic situation would be difficult because it is necessary to model the whole including the VAD and the cardiovascular dynamics. To solve this problem, we have proposed an autonomous VAD control method based on stochastic model. In this study, we sought to investigate whether a flow control application of our method can be used to adaptively control a continuous flow VAD. To evaluate behaviors based on the implemented algorithm, control testing on a mock circulation loop simulated a left heart bypass support and inflow sucking (unexpected event). These were compared with the linear flow rate control. As a result, the flow rate of the VAD reached a target value in both methods to changes of the circuit resistance. The behaviors to inflow sucking were found as follows: linear control failed by increasing rotational speed for the sucking. On the other hand, the proposed method reduced frequency of the sucking up to 12% by behaviors to searchingly decrease rotational speed.

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Language：Japanese   Publisher：The Japan Society of Mechanical Engineers  

Extracorporeal circulation (ECC) is indispensable for cardiac surgery and cardiopulmonary support. Despite the fact that ECC is traumatic to blood components and non-physiologic, its influence has not been fully explored. However, difficulty in clinical research and animal experiments keeps the knowledge insufficient. Therefore, it is desirable to have a miniature ECC system for small animals, which enables repetitive experiments, to study the mechanism of pathophysiological changes during ECC. We establish a miniature ECC system and apply the system to the rat for investigating biochemical changes, and assess whether the rat ECC model is comparable to the human ECC. The ECC system consisted of a membranous oxygenator (polypropylene, 0.03 m^2), tubing line (polyvinyl chloride, φ2.0 mm) and roller pump. Priming volume of this system is only 8 ml. During CPB, the MAP and the Hb levels were maintained around 70 mmHg and 10 g/dl, respectively. Pump flow and blood gases were normally maintained in the both groups. On the other hand, TNF-α, IL-6 and IL-10 levels were significantly elevated in the ECC group, indicating some organ damages and systemic inflammatory responses during ECC. We successfully established the ECC for the rat. This miniature ECC model could be a very useful approach for studying the mechanism of pathophysiology during ECC and basic assessment of the ECC devices.

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