Warm ischemia provokes inflammation and regional hypercoagulability within the heart during off-pump coronary artery bypass: a possible target for serine protease inhibition.

OBJECTIVE: Accumulating evidence suggests that a hypercoagulable state influences early graft failure after off-pump coronary artery bypass (OPCAB). We hypothesized that regional myocardial ischemia caused by obligatory periods of coronary occlusion during OPCAB is an important trigger for this prothrombotic state. METHODS: Using a series of biomarkers, 60 consecutive patients undergoing OPCAB were monitored for myocardial injury (myoglobin), inflammation (TNF-alpha, IL-8) and thrombosis (thrombin generation-F1.2, contact activation pathway-FXII-a, platelet derived microparticles-via flow cytometry). The transcardiac gradients of these markers were determined by assaying both arterial and coronary sinus blood just after protamine administration. Intramyocardial pH was monitored continuously during coronary occlusion in a subset (N=30 grafts, 11 patients). The influence of management strategies affecting hemostasis (e.g. antiplatelet therapy, anti-fibrinolytics, peak activated clotting time (ACT) during heparinization) was analyzed. RESULTS: Ischemic injury, depicted by the transcardiac myoglobin gradient, significantly correlated with intramyocardial acidosis during coronary occlusion (R=0.96, p<0.0001) and predicted the transcardiac gradients of TNF-alpha (R=0.83, p<0.001) and F1.2 (R=0.72, p<0.0001). Transcardiac F1.2 strongly correlated with TNF-alpha (R=0.73, p=0.01) and IL-8 (R=0.51, p=0.02). Patients receiving aprotinin (N=20) showed significantly lower transcardiac gradients for myoglobin (4.1+/-7.5% vs 72.9+/-108.8% change, p=0.002), F1.2 (31+/-37% vs 89+/-149%, p=0.03), FXII-a (2.6+/-4.1% vs 19.2+/-34%, p=0.04) and microparticles (7+/-3.9% vs 12.9+/-8%, p=0.01). CONCLUSIONS: Strong correlations between myocardial ischemia and the transcardiac gradients of markers for inflammation and thrombosis suggest that even brief episodes of coronary occlusion in the beating heart may have pathophysiologic consequences. Aprotinin, but not other factors that influence the coagulation system, appears to mitigate this process during OPCAB.

Use of diffusion tensor imaging to predict myocardial viability after warm global ischemia: possible avenue for use of non-beating donor hearts.

BACKGROUND: The assessment of myocardial viability after global warm ischemia (WI) but before reperfusion is challenging. We hypothesized that fractional anisotropy (FA), a magnetic resonance imaging (MRI) parameter of water diffusion that characterizes cellular integrity within tissues, provides a rapid and useful method for evaluating the viability of hearts after WI. METHODS: Dog hearts were exposed to 60 minutes of WI after exanguination, explanted and preserved in a cold, non-beating state for 6 hours, using continuous perfusion (CP) or static cold storage (CS). Toward the end of preservation, a global FA assessment, acquired using MRI, was compared with analyses obtained from myocardial biopsies that included adenosine triphosphate (ATP), endothelin-1 (ET-1) and caspase-3 levels, light microscopy and tetrazolium staining. Functional recovery was analyzed after restoration of blood flow on a non-working Langendorff preparation. RESULTS: FA measured at the end of CP showed strong correlations with all parameters of functional recovery (developed pressure, R = 0.60; dP/dt, R = 0.96; -dP/dt, R = 0.96). Although FA also correlated with tissue levels of ATP, ET-1 and caspase-3 (R = 0.77, -0.84, -0.64), recovery of myocardial function did not correlate with these markers or any other conventional analyses of myocardial injury (troponin I, changes on light microscopy or tetrazolium staining). CONCLUSIONS: FA, an MRI-based parameter that indicates cellular integrity, was found to reflect better myocardial ATP stores, less induction of ET-1 and caspase-3 and improved functional recovery of hearts after global WI. As a clinically applicable tool capable of rapidly differentiating reversible from lethal injury, diffusion tensor imaging may prove useful in the eventual adoption of non-beating donor hearts for transplantation.

Heart preservation using continuous ex vivo perfusion improves viability and functional recovery.

BACKGROUND: Cold static storage (CS) is a proven preservation method for heart transplantion, yet early postoperative graft dysfunction remains prevalent, so continuous perfusion (CP) during ex vivo transport may improve viability and function of heart grafts. METHODS AND RESULTS: Canine hearts underwent CP (n=9) or CS (n=9) for 6 h while intramyocardial pH was continuously monitored. Biopsies were assayed for ATP, caspase-3, malondialdehyde (MDA), and endothelin-1 (ET-1) levels at baseline, after preservation (t1), and after 1 h of blood reperfusion on a Langendorff model (t2). Functional recovery was determined at t2 by +dP/dt, -dP/dt, developed pressure, peak pressure and end-diastolic pressure. CP resulted in higher tissue pH and ATP stores and reduced caspase-3, MDA and ET-1 levels compared with CS at both t1 and t2. Post reperfusion recovery was significantly greater in CP vs CS for all myocardial functional parameters except end-diastolic pressure. Weight gain was significantly increased in CP vs CS at t1, but not at t2. CONCLUSIONS: Low-grade tissue acidosis and energy depletion occur during CS and are associated with oxidative injury and apoptosis during reperfusion. CP attenuates these biochemical and pathologic manifestations of tissue injury, together with improved myocardial recovery, despite mild, transient edema.

Off-Pump Coronary Artery Bypass Leads to a Regional Hypercoagulable State Not Detectable Using Systemic Markers.

OBJECTIVE: It is believed that off-pump coronary artery bypass grafting (OPCAB) leads to hypercoagulability, but efforts to document such a state have been unrevealing. We hypothesized that OPCAB increases the risk of developing a regional hypercoagulable state. METHODS: Blood was obtained from the aorta and coronary sinus (CS) after CABG performed off- (N=69) or on-pump (N=35) to determine the transcardiac gradients of F1.2 (thrombin production), XIIa (coagulation activation), myoglobin (ischemia) and IL-6, IL-8 using ELISA and platelet-derived microparticles using FACS. Platelet function was measured using aggregometry. Regional myocardial pH and SVG flow were recorded intraoperatively. SVG biopsies were analyzed for endothelial integrity (EI) using immunohistochemistry and graft patency was determined by predischarge CT angiography. RESULTS: Compared with on-pump, OPCAB provoked significantly higher transcardiac F1.2 (117±200 v. 31±38%), FXII-a (14±29 v. 2±4%), microparticles (14±-9.5% v. 6.4±-4.1%), IL-6 (119±183 v. 28±39%), and a trend toward increased IL-8 (67±94 v. 24±46%, P = 0.077). Myoglobin release after OPCAB, also greater than on-pump CABG (54±89 v. 8±14%, P < 0.01), correlated with regional pH change (R=-0.96, P < 0.0001), and F1.2 release (R=0.55, P = 0.0002). In contrast, systemic changes in these markers were all less after OPCAB. SVG flow was significantly reduced in OPCAB (39.4 versus 66.5 mL/min, P = 0.0002), but EI and graft patency rates were the same. CONCLUSIONS: Through the use of transcardiac assays, we illustrated that regional coagulation was enhanced after off- compared with on-pump CABG. If the findings of this pilot study are confirmed, OPCAB may require additional antithrombotic therapies to respond to this local hypercoagulable state.

Preliminary study of a new type of energy transmission system for artificial hearts.

A transcutaneous energy transmission (TET) system is the most common way to power artificial hearts and ventricular assist devices. However, an external battery used with a TET system poses several problems, such as its heavy mass, small charge capacity, and long recharging time. The battery is indispensable when patients want to be ambulatory. This article proposes a new type of TET system that does not require an external battery because electrical energy is supplied remotely by using electromagnetic waves. For this system to operate, multiple transmitting antennas have to be mounted in a room or facility that has been shielded from electromagnetic waves, and a receiving antenna is attached to the patient. Electromagnetic waves transmit electrical power from the transmitting antennas to the receiving antenna. The received electrical power is sent to an implanted device through the TET system. The total power efficiency was plotted against the transmitter-receiver distance by measuring the power that was input to the transmitting antennas, and the final direct current (DC) power that was received by the receiving antenna. A 430-MHz frequency was applied in the experiments. The obtained efficiency was around 10% within a transmitter-receiver distance of 1 m when Yagi-Uda antennas were used for the transmitting antennas and two other types of antenna were used for the receiving antennas: a folded dipole with a reflector and a single loop with a reflector. The results suggested that the proposed system is worth considering. The proposed system would go a long way toward enhancing the patient's quality of life compared with the currently used conventional TET system.

Pathophysiologic study of goats with undulation pump total artificial heart: those that survived for more than 1 month.

The undulation pump total artificial heart is an implantable total artificial heart that is being developed at the University of Tokyo. Many advances in our system have been made by the adoption of hardware and software solutions that enabled the animals with the undulation pump total artificial hearts to survive more than 1 month. Pathophysiologic observations were performed for these goats that survived. In this article, the pathophysiologic findings are described in detail for three goats that survived for 46 (goat 9916), 54 (0030), and 63 (0107) days. The microscopic findings indicated that in goat 0107 the histologic changes in key organs occurred at the termination of the experiments. Therefore, the pathophysiologic changes in goats 9916 and 0030 were mainly investigated in this study to evaluate the chronic effect caused by our total artificial heart system. The signs of chronic ischemia and cell dystrophy were observed in both the liver and kidney. Until now, 13 goats had survived more than 1 week and 6 goats survived more than 1 month, including one that survived for 63 days, which is the longest in our experimental series. The pathophysiologic results of goats 9916 and 0030 showed that the undulation pump total artificial heart might still cause some damage to the liver and the kidney. To accomplish long-term survival with the undulation pump total artificial heart, further pathophysiologic studies are required, and the necessary modifications to the total artificial heart system will need to be made.

Functions for detecting malposition of transcutaneous energy transmission coils.

A transcutaneous energy transmission system (TETS) for artificial hearts and ventricular assist devices uses electrical coupling of power between external and implanted coils. If the position of coils changes relative to each other, the TETS cannot feed the required power of the implanted device. During activity or sleep, the coils may move accidentally. TETS users and the people around them have to pay attention to this because the range of the position where the required power can be fed efficiently is not wide. Therefore, we added functions for the position changes of the coils to the TETS. Regular, cautious, and irregular positions were introduced, and the ranges of them were decided upon in our experiments. The cautious position was determined by the area where the change of the relative position of the coils was relatively small. When the coils were in the cautious position, the circuit was tuned by way of changing the resonant point. This modulation could give good power efficiency in the cautious position. When the coils were in the irregular position, an alarm switch was turned on. These functions ease the restriction of the coil position and give better quality of life (QOL) than do the conventional TETS.

A new approach to detection of the cavitation on mechanical heart valves.

The cavitation on the mechanical heart valves (MHVs) is thought to be a cause of the mechanical failure of the occluder; also, the free radicals that would be generated when the cavitation bubbles implode might affect the patients chemically. These cavitation effects are attributed to the bubble collapse. Therefore, it is important to detect the bubble implosion behavior to analyze the cavitation on MHVs. The cavitation bubbles induce the generation of free radicals at their implosion, and the excited hydroxyl radicals emit the faint light. Based on this fact, we have tried to observe the faint light emission from a MHV to specifically capture the implosion of the cavitation bubbles. A highly sensitive CCD (charge coupled device) camera (C2400-35 VIM camera, Hamamatsu Photonics, Hamamatsu, Japan) was adopted in this study. This camera can observe low light down to the single photon counting range, and it gives two-dimensional mapping of the light. A 20 mm Björk-Shiley valve was submerged in the water tank of 10 L deionized water with luminol as a light enhancer, and then the pressure difference of 150 mm Hg was exerted on the valve at a rate of 60 bpm with a pulse duplicator. The camera and the water tank were settled in the lightproof configuration. After 2 hours of exposure, faint light images have been obtained successfully. The light emits mostly from the edge of the occluder on the inflow side in the major orifice of the valve. Therefore the results suggest that the bubbles would implode around this region and that free radicals caused by cavitation might be produced on MHV, which has coincided with our preliminary result by an electron spin resonance spectrometry.

Advance in animal experiments with the undulation pump total artificial heart: 50 and 54 day survival periods with 1/R control.

The undulation pump total artificial heart (UPTAH) is a unique, implantable, total artificial heart (TAH) that uses undulation pumps. To achieve long-term survival in animals with physiologic hemodynamic conditions, a control method based on conductance and arterial pressure was applied to UPTAH. With this control method, called 1/R control, survival periods of 50 days (No. 0016, 49.6 kg) and 54 days (No. 0030, 42.5 kg) were obtained in adult female goats. In No. 0016, 1/R control was applied to the left pump, whereas in No. 0030, it was applied to the right pump. Another pump was used for left-right balance control. The control stability was better in No. 0030 than in No. 0016. The sucking effect of the left atrium was remarkable in No. 0016, possibly because of a time delay when left-right balance control was performed with the right pump. In No. 0016, the cause of death was probably a thrombus flown from a panus in the left atrium. It is possible that the left atrial suction effect influenced the thrombus and panus formation in the left atrium. In No. 0030, the cause of death was a small rupture of the membrane in the right pump. The rupture may have been caused by excessive negative pressure inside the pump. This pressure resulted from suction of the right atrium because of an unexpected control excursion, which was probably caused by a software bug. It will be necessary to redesign the undulation pump and improve the software to achieve longer survival periods for animals with physiologic hemodynamic conditions.

Third model of the undulation pump total artificial heart.

The undulation pump is a small, continuous flow displacement type blood pump, and the undulation pump total artificial heart (UPTAH) is a unique, implantable total artificial heart based on this pump. To improve the durability of the UPTAH for investigating long-term pathophysiology with UPTAH, a third model (UPTAH3) has been developed. UPTAH3 was designed to separate the left and right undulation shafts and to be more durable. The undulation pumps were also redesigned. UPTAH3 was implemented with a diameter of 76 mm, width of 78 or 79 mm, total volume of 292 ml, and weight of 620 g. The priming volumes of the left and right pumps are 26 and 21 ml, respectively. The atrial cuffs and outflow cannulae were also redesigned for UPTAH3. The maximum output against an arterial pressure load of 100 mm Hg is about 11 L/min. The maximum pump efficiency is about 15% in the left pump and 18% in the right pump, giving a maximum total efficiency for both of about 11%. To date, UPTAH3 has been tested in 17 goats, and the longest survival period was 46 days. This third model will be useful for investigating pathophysiology with UPTAH.

Progress in the control system of the undulation pump total artificial heart.

The undulation pump total artificial heart (UPTAH) is a small implantable total artificial heart. As the UPTAH generates outflow and inflow at the same time, control of the UPTAH is very difficult. Therefore suitable control methods specifically for the UPTAH should be established. Various motor control, left-right flow balance control, and physiological control methods were examined and tried for the UPTAH control in this study. The control system is divided into seven categories. It has a hierarchical structure and all control modes work at the same time. The UPTAH with the newly developed control method has been implanted into the chest cavities of 48 goats. Until now, six goats survived for more than one month, including 63 days in the longest case. The good condition of the UPTAH implanted animal could be maintained with the newly developed control scheme, consisting of the 1/R control and several other additional controls.

A study on an energy supply method for a transcutaneous energy transmission system.

This study proposes a new type of a transcutaneous energy transmission system (TETS) that can supply electrical power for an implanted device without an external battery. In this system, the power is supplied from the floor to the shoes of the patients through coils that are set beneath the floor and the bottom of the shoes. If the patients wear the special shoes, they will be able to move freely on the specially designed floor without an external battery. Direct current (DC)-DC power efficiency was measured in the experiments, and the results showed that it varies with relative positions between the shoe and the floor coils. The results suggested that three-layered floor coils would enable the system to meet the demand for providing the required power anywhere on the floor without intermission. DC-DC power efficiency could be kept over 60% under the practical condition. It can then be concluded that the proposed system has a potential to provide better quality of life for the patients using a TETS.

Ripple reduction control of the undulation pump total artificial heart.

An undulation pump total artificial heart (UPTAH) in which the revolutions of the motor are converted to undulation motion of a disk has been developed. In an experiment, a goat using the UPTAH survived for 54 days. However, a large ripple was observed in the device's output pressure and flow waveform. In calculating the spectrum of the ripple, we found that the ripple mainly comprised 2 frequency sine waves: 1 having the same frequency as and 1 having double the frequency of the motor revolutions. To reduce the ripple, 2 sine waves, 1 having the same frequency as and 1 having double the frequency of the motor revolutions, were provided to the motor current to modulate the pulse width of the pulse width modulation controlling the motor revolutions. This ripple control method reduced the pressure ripple by 90% in a mock circulation and by 70% in animal experiments. These results revealed that the ripple generated in the UPTAH could be controlled through the use of motor control software.