Eisuke Tatsumi

A novel counterpulsation mode of rotary left ventricular assist devices can enhance myocardial perfusion

The effect of rotary left ventricular assist devices (LVADs) on myocardial perfusion has yet to be clearly elucidated, and several studies have shown decreased coronary flow under rotary LVAD support. We have developed a novel pump controller that can change its rotational speed (RS) in synchronization with the native cardiac cycle. The aim of our study was to evaluate the effect of counterpulse mode, which increases the RS in diastole, during coronary perfusion. Experiments were performed on ten adult goats. The EVAHEART LVAD was installed by the left ventricular uptake and the descending aortic return. Ascending aortic flow, pump flow, and coronary flow of the left main trunk were monitored. Coronary flow was compared under four conditions: circuit-clamp, continuous mode (constant pump speed), counterpulse mode (increased pump speed in diastole), and copulse mode (increased pump speed in systole). There were no significant baseline changes between these groups. In counterpulse mode, coronary flow increased significantly compared with that in continuous mode. The waveform analysis clearly revealed that counterpulse mode mainly resulted in increased diastolic coronary flow. In conclusion, counterpulse mode of rotary LVADs can enhance myocardial perfusion. This novel drive mode can provide great benefits to the patients with end-stage heart failure, especially those with ischemic etiology.

Electrocardiogram‐Synchronized Rotational Speed Change Mode in Rotary Pumps Could Improve Pulsatility

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 ± 7.5 kg). 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), mm Hg). 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 ± 9.8 mm Hg, mean dp/dt max, 481.9 ± 207.6/75.6 ± 36.2/351.1 ± 137.8 mm Hg/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.

In-body tissue-engineered aortic valve (Biovalve type VII) architecture based on 3D printer molding

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.

Morphologic Changes of the Aortic Wall Due to Reduced Systemic Pulse Pressure in Prolonged Non Pulsatile Left Heart Bypass

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 plus.

Three-dimensional cardiac tissue engineering using a thermoresponsive artificial extracellular matrix.

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 34°C. 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 37°C to allow the mixture to gel, and cultured in vitro. To define suitable culture conditions the following parameters were tested: (1) PNIPAM-gelatin concentration, 0.04±0.125 mg/ml; (2) cell seeding density, 1~50 × 106 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 × 106 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 μm thick.

Treatment of acute myocardial infarction with cardiogenic shock using left ventricular assist device

We have treated ten cardiogenic shock patients after acute myocardial infarction (AMI) with a left ventricular assist device (LVAD). These patients were later divided into three groups: the first group with ventricular septal perforation, the second with aorto-coronary bypass grafting (ACBG) before LVAD implantation and the third group without ACBG. LVAD maintained the systemic circulation in each group, and cardiac function recovered enough to remove LVAD in 70% of the total patients. Two of three patients in the first group were discharged from hospital. Two weaned cases in the second group died of multiple organ failure and one was discharged, and hemorrhagic necrosis was seen in the bypassed area of the myocardium. One patient of the third group could not be weaned from LVAD because of respiratory failure though his heart function began to recover. Another case in the third group underwent bypass grafting after removal of LVAD. However ACBG surgery should be done very carefully because a patient in shock is occasionally intolerant to major surgery. In all groups, the major cause of death was multiple organ failure which was probably caused by the prolonged low output condition prior to LVAD application. In the light of this experience, it appears that LVAD should be applied before irreversible damage occurs to major organs, including the heart itself. To ensure the timely application of LVAD, some way must be found to introduce systematic application of LVAD into the normal course of AMI treatment.

Influences of nonpulsatile pulmonary flow on pulmonary function: Evaluation in a chronic animal model

To clarify the influences of nonpulsatile blood flow on the physiologic function of the lung, we established nonpulsatile pulmonary circulation with a centrifugal pump in a chronic animal model (adult goats, n = 6). As the initial phase, a pulsatile right ventricular assist device was implanted to bypass the whole blood supply from both the right atrium and right ventricle to the pulmonary artery. After 2 weeks of pumping, the pulsatile pump was replaced with a centrifugal pump without anesthesia, and nonpulsatile pulmonary circulation was instituted. In this experimental model, no significant change was observed in either mean pulmonary arterial pressure or pulmonary vascular resistance index during the pulsatile pumping compared with that on the fourteenth day of nonpulsatile pumping. Blood gas data, extravascular lung water content, and serum level of angiotensin-converting enzyme were maintained within normal ranges. There was also no significant change in the ventral to dorsal blood perfusion ratio of the lower lobe of the right lung. These results indicate that pulmonary functions are not affected by nonpulsatile pulmonary circulation for a period of 14 days in this animal model.

Impact of Systemic Depulsation on Tissue Perfusion and Sympathetic Nerve Activity

BACKGROUND We postulated that pathophysiologic processes under nonpulsatile circulation are related to the behavior of the sympathetic nerve activity that regulates tissue perfusion. METHODS Pulsatile and nonpulsatile pumps were installed in parallel in the left heart bypass circuit of anesthetized goats (n = 9) so that pulsatile circulation could be converted to nonpulsatile circulation instantly. At 5 minutes before and after systemic depulsation, we measured hemodynamic indices, renal nerve activity, and regional blood flow of the brain, heart, and renal cortex. RESULTS Renal nerve activity was significantly elevated after systemic depulsation (15.6 +/- 9.3 versus 19.4 +/- 9.8 microV), when mean aortic pressure remained almost constant. The renal cortical flow was significantly reduced after depulsation (3.61 +/- 1.23 versus 2.93 +/- 1.19 mL.min-1.g-1), whereas no significant difference was found in the regional blood flow of the brain or the heart. CONCLUSIONS The significant reduction of renal cortical blood flow after systemic depulsation is associated with a significant increase in renal nerve activity. Our results suggest that increased renal nerve activity plays an important role in the reduction of renal function after systemic depulsation.

Up to 151 days of continuous animal perfusion with trivial heparin infusion by the application of a long-term durable antithrombogenic coating to a combination of a seal-less centrifugal pump and a diffusion membrane oxygenator

We developed a new coating material (Toyobo-National Cardiovascular Center coating) for medical devices that delivers high antithrombogenicity and long-term durability. We applied this coating to an extracorporeal membrane oxygenation (ECMO) system, including the circuit tube, cannulae, a seal-less centrifugal pump, and a diffusion membrane oxygenator, to realize prolonged cardiopulmonary support with trivial anticoagulant infusion. The oxygenator consisted of a hollow-fiber membrane made of polymethylpentene, which allows the transfer of gas by diffusion through the membrane. The centrifugal pump was free of seals and had a pivot bearing. We performed a venoarterial bypass in a goat using this ECMO system, and the system was driven for 151 days with trivial anticoagulant infusion. Plasma leakage from the oxygenator did not occur and sufficient gas-exchange performance was well maintained. In the oxygenator, thrombus formation was present around the top and the distributor of the inlet portion and was very slight in the outlet portion. In the centrifugal blood pump, there was some wear in the female pivot region and quite small amounts of thrombus formation on the edge of the shroud; the pivot wear seemed to be the cause of the hemolysis observed after 20 weeks of perfusion and which resulted in the termination of the perfusion. However, no significant amounts of thrombus were observed in other parts of the system. This ECMO system showed potential for long-term cardiopulmonary support with minimal use of systemic anticoagulants.

Prolonged nonpulsatile left heart bypass diminishes vascular contractility

We investigated possible functional changes in the vascular system accompanying the morphological change in prolonged nonpulsatile left heart bypass (LHB). Three adult goats underwent pulsatile LHB. Two weeks postoperatively, the pulsatile ventricular assist device was replaced with a centrifugal pump and nonpulsatile LHB was subsequently conducted for 4 weeks. The mean aortic pulse pressure was 39 and 16 mmHg during the pulsatile and nonpulsatile LHB, respectively. Systemic vascular resistance (SVR) and plasma norepinephrine levels were measured at the end of pulsatile LHB (PUL), and at the end of 1st, 2nd, 3rd, and 4th week of nonpulsatile LHB (NP1w, NP2w, NP3w, NP4w, respectively). At each point, 50 μg/kg nitroglycerin and 1μg/kg norepinephrine were injected and the minimal and maximal values of SVR after injection were calculated as parameters reflecting the vascular tonus and contractility. The SVR and plasma nor epinephrine level did not significantly change during the entire course (SVR: 1106, 895, 982, 920, and 938 dyne·sec·cm−5; norepinephrine level: 0.3, 0.2, 0.1, 0.2, and 0.1 ng/ml; at PUL, NP1w, NP2w, NP3w, and NP4w, respectively). The minimal value of SVR after nitroglycerin injection remained unchanged, indicating that vascular tonus was stable during the entire course (618, 687, 623, 560, 653 dyne·sec·cm−5, respectively). In contrast, the maximal value of SVR after norepinephrine injection at NP3w and NP4w (1695 and 1759 yne·sec·cm−5) became significantly reduced compared to that at PUL (2346 dyne·sec·cm−5). These results indicated that prolonged nonpulsatile left heart bypass did not affect the vascular tonus, but significantly diminished the vascular contractility.