Periarteritis in lung from a continuous-flow right ventricular assist device: role of the local Renin-Angiotensin system.

BACKGROUND: We previously reported renal arterial periarteritis after implantation of a continuous-flow left ventricular assist device in calves. The purpose of the present study was to investigate whether the same periarteritis changes occur in the intrapulmonary arteries after implantation of a continuous-flow right ventricular assist device (CFRVAD) in calves and to determine the mechanism of those histologic changes. METHODS: Ten calves were implanted with a CFRVAD for 29 ± 7 days, and we compared pulmonary artery samples and hemodynamic data before and after CFRVAD implantation prospectively. RESULTS: After implantation, the pulsatility index (pulmonary arterial pulse pressure/pulmonary arterial mean pressure) significantly decreased (0.88 ± 0.40 before vs 0.51 ± 0.22 after; p < 0.05), with severe periarteritis of the intrapulmonary arteries in all animals. Periarterial pathology included hyperplasia and inflammatory cell infiltration. The number of inflammatory cells positive for the angiotensin II type 1 receptor was significantly higher after implantation (7.8 ± 6.5 pre-CFRVAD vs 313.2 ± 145.2 at autopsy; p < 0.01). Serum angiotensin-converting enzyme activity significantly decreased after implantation from 100% to 49.7 ± 17.7% at week 1 (p = 0.01). Tissue levels of angiotensin-converting enzyme also demonstrated a significant reduction (0.381 ± 0.232 before implantation vs 0.123 ± 0.096 at autopsy; p = 0.043). CONCLUSIONS: Periarteritis occurred in the intrapulmonary arteries of calves after CFRVAD implantation. The local renin-angiotensin system (not the angiotensin-converting enzyme pathway) plays an important role in such changes.

Overview of current sutureless and transcatheter mitral valve replacement technology.

Mitral valve (MV) regurgitation is the most prevalent form of heart valve disease. As it comes to surgical repair or replacement of the diseased valves, the procedure has been established as safe and effective; however, its invasiveness still carries considerable risk of significant morbidity and mortality. With aging comes increased MV dysfunction, and thus minimally invasive technology is rapidly evolving to meet the challenges of older patients' preoperative comorbidities and risks associated with surgery. In comparison, in high-risk patients with aortic stenosis, percutaneous transcatheter technologies offer a viable alternative to surgery; however, catheter-based procedures for MV disease are limited only to repair. MV surgeries have limitations and carry the potential for serious complications in high-risk elderly patients. A fast, reliable sutureless or catheter-based means of MV replacement is needed. Although transcatheter devices are still only in preclinical testing or developmental stages, the authors here review various sutureless MV and transcatheter-based concepts and devices for MV replacement.

Implantable continuous-flow right ventricular assist device: lessons learned in the development of a cleveland clinic device.

Although the need for right ventricular assist device (RVAD) support for right ventricular failure after the implantation of a continuous-flow left ventricular assist device has decreased, right ventricular failure still occurs in as many as 44% of patients after continuous-flow left ventricular assist device insertion. Cleveland Clinic's DexAide continuous-flow RVAD was implanted in 34 calves during the course of its development. This review discusses lessons learned in the design and development of an implantable continuous-flow RVAD that are drawn from the results of these in vivo studies, our clinical experience with RVAD support, and a review of previously published reports on clinical RVAD use.

Hemodynamic differences between the awake and anesthetized conditions in normal calves.

There is insufficient information in the literature about baseline circulatory parameters in normal calves in the anesthetized versus postoperative awake conditions under which a large volume of medical research is conducted. Eleven calves (mean body weight, 78.1 ± 14.3 kg) were implanted with a flow probe and fluid-filled pressure lines to measure cardiac output (CO), aortic (AoP), central venous (CVP), pulmonary arterial (PAP), and left atrial pressures (LAP). Systemic (SVR) and pulmonary vascular resistance (PVR) were also calculated. We obtained the above hemodynamic data (n = 11) and epicardial echocardiography (n = 7) during open-chest surgery under isoflurane anesthesia. After full recovery from surgery, animals were evaluated in the awake condition on postoperative days 6-9 using transthoracic echocardiography (n = 7) and the hemodynamic monitoring lines and probes noted (n = 11). CO, AoP, and PAP levels in the anesthetized condition were significantly lower than in the awake condition. Other hemodynamic parameters (CVP, LAP, SVR, and PVR) were not significantly different. In conclusion, data from this study quantify changes in CO, AoP, and PAP in anesthetized calves that may affect the hemodynamic response to experimental therapeutics such as new cardiac assist devices, prosthetic valves, and surgical interventions. Our study also provides baseline data for the translation of the hemodynamic data obtained in acute in vivo calf studies to that of an awake subject.

Performance of bioprosthetic valves after glycerol dehydration, ethylene oxide sterilization, and rehydration.

OBJECTIVE: : Most commercially available bioprosthetic valves are stored in an aldehyde solution. We report a new alternative method: Self-expanding valves composed of dehydrated tissues with a high glycerin:water ratio can be collapsed into specially designed sheaths prior to sterilization for ease of delivery and storage. MATERIALS AND METHODS: : Changes in tissue dimension of five samples of bovine pericardium were evaluated from baseline after glycerol treatment, air-drying, ethylene oxide (EtO) sterilization, and rehydration with water. Three valves fabricated from glutaraldehyde cross-linked tissues, including porcine pericardial tissue, bovine pericardial tissue, and porcine aortic valve, were dehydrated through a proprietary glycerin-based process, collapsed, placed within a catheter, EtO sterilized, stored for up to 212 days, and rehydrated with water. These valves were characterized in a mock circulation by mounting them at the inlet portion of a pneumatic pump before dehydration and after rehydration to evaluate the effects of dehydration and rehydration on the valve performance. RESULTS: : Tissues treated with glycerol solution showed no significant changes in dimension from baseline after glycerol treatment, air-drying, EtO sterilization, and rehydration with water. In all the valves, pump flows reached the maximum output capacity of the pneumatic pump after rehydration without an increase in filling pressures as compared with those before dehydration. CONCLUSIONS: : This method for storing collapsible bioprosthetic valves using a proprietary glycerin-based process demonstrated excellent valve performance.

Performance of extracorporeally adjustable ventricular assist device inflow cannula.

PURPOSE: This study evaluated the feasibility and efficacy of a newly developed adjustable left ventricular assist device inflow cannula in a short-term calf model. DESCRIPTION: In this inflow cannula, the angle between the cannula body and the inflow cannula tip can be altered extracorporeally by manipulating 2 externalized cables connected to the cannula. The cannula tip is adjustable in any plane to a maximum of ±15 degrees. EVALUATION: After initial prototyping in 4 calf cadavers, a Cleveland Heart left ventricular assist device was implanted with the adjustable inflow cannula placed in the left ventricular apex and the outlet to the descending aorta. Under hypovolemic conditions, the angle of the cannula tip could be changed to induce varying degrees of ventricular suction and then eliminate it, as evidenced by recorded pump and native left ventricular flows. Epicardial echocardiography and fluoroscopy in the closed-chest condition documented extracorporeal adjustments of the inflow cannula position. CONCLUSIONS: This extracorporeally adjustable inflow cannula was effective in preventing or controlling left ventricular suction.

Speed modulation of the continuous-flow total artificial heart to simulate a physiologic arterial pressure waveform.

This study demonstrated the concept of using speed modulation in a continuous-flow total artificial heart (CFTAH) to shape arterial pressure waveforms and to adjust pressure pulsatility. A programmable function generator was used to determine the optimum pulsatile speed profile. Three speed profiles [sinusoidal, rectangular, and optimized (a profile optimized for generation of a physiologic arterial pressure waveform)] were evaluated using the CFTAH mock circulatory loop. Hemodynamic parameters were recorded at average pump speeds of 2,700 rpm and a modulation cycle of 60 beats per minute. The effects of varying physiologically relevant vascular resistance and lumped compliance on the hemodynamics were assessed. The feasibility of using speed modulation to manipulate systemic arterial pressure waveforms, including a physiologic pressure waveform, was demonstrated in vitro. The additional pump power consumption needed to generate a physiologic pulsatile pressure was 16.2% of the power consumption in nonpulsatile continuous-flow mode. The induced pressure waveforms and pulse pressure were shown to be very responsive to changes in both systemic vascular resistance and arterial compliance. This system also allowed pulsatile pulmonary arterial waveform. Speed modulation in the CFTAH could enable physicians to obtain desired pressure waveforms by simple manual adjustment of speed control input waveforms.

In vivo biocompatibility evaluation of a new resilient, hard-carbon, thin-film coating for ventricular assist devices.

The purpose of this study was to evaluate in vivo the biocompatibility of BioMedFlex (BMF), a new resilient, hard-carbon, thin-film coating, as a blood journal bearing material in Cleveland Heart's (Charlotte, NC, USA) continuous-flow right and left ventricular assist devices (RVADs and LVADs). BMF was applied to RVAD rotating assemblies or both rotating and stator assemblies in three chronic bovine studies. In one case, an LVAD with a BMF-coated stator was also implanted. Cases 1 and 3 were electively terminated at 18 and 29 days, respectively, with average measured pump flows of 4.9 L/min (RVAD) in Case 1 and 5.7 L/min (RVAD) plus 5.7 L/min (LVAD) in Case 3. Case 2 was terminated prematurely after 9 days because of sepsis. The sepsis, combined with running the pump at minimum speed (2000 rpm), presented a worst-case biocompatibility challenge. Postexplant evaluation of the blood-contacting journal bearing surfaces showed no biologic deposition in any of the four pumps. Thrombus inside the RVAD inlet cannula in Case 3 is believed to be the origin of a nonadherent thrombus wrapped around one of the primary impeller blades. In conclusion, we demonstrated that BMF coatings can provide good biocompatibility in the journal bearing for ventricular assist devices.

In vivo evaluation of zirconia ceramic in the DexAide right ventricular assist device journal bearing.

Zirconia is a ceramic with material properties ideal for journal bearing applications. The purpose of this study was to evaluate the use of zirconium oxide (zirconia) as a blood journal bearing material in the DexAide right ventricular assist device. Zirconia ceramic was used instead of titanium to manufacture the DexAide stator housing without changing the stator geometry or the remaining pump hardware components. Pump hydraulic performance, journal bearing reliability, biocompatibility, and motor efficiency data of the zirconia stator were evaluated in six chronic bovine experiments for 14-91 days and compared with data from chronic experiments using the titanium stator. Pump performance data including average in vivo pump flows and speeds using a zirconia stator showed no statistically significant difference to the average values for 16 prior titanium stator in vivo studies, with the exception of a 19% reduction in power consumption. Indices of hemolysis were comparable for both stator types. Results of coagulation assays and platelet aggregation tests for the zirconia stator implants showed no device-induced increase in platelet activation. Postexplant evaluation of the zirconia journal bearing surfaces showed no biologic deposition in any of the implants. In conclusion, zirconia ceramic can be used as a hemocompatible material to improve motor efficiency while maintaining hydraulic performance in a blood journal bearing application.

Introduction of fixed-flow mode in the DexAide right ventricular assist device.

BACKGROUND: Although some continuous-flow left ventricular assist device algorithms have been created to respond to varying patient physiology, very little research has been conducted on control of right ventricular support in uni- or biventricular application. The purpose of this study was to develop and evaluate a simple and reliable fixed-flow algorithm for the DexAide right ventricular assist device (RVAD). This algorithm automatically adjusts speed to maintain a target flow while preventing ventricular suction when a requested target flow exceeds available tricuspid flow. METHODS: Fixed-flow control mode was evaluated in 17 DexAide RVAD long-term bovine studies, with a duration ranging from 14 to 90 days (33 +/- 24 days). Targeted fixed-flow levels ranged from 4.0 to 6.5 liters/min. Data were monitored on an hourly basis. Pump-flow data were also recorded on a weekly basis to document the speed increment required to increase pump flow from 5 to 8 liters/min at 0.5-liter/min increments. RESULTS: The fixed-flow control mode was evaluated for a total duration of 5,283 hours without complications related to pump flow or left/right circulation imbalance. The pump speed varied between 2,000 and 3,220 rpm to maintain the flow constant at each target level. The average absolute mismatch between the target flow and measured flow was 0.6 +/- 0.5 liter/min. CONCLUSIONS: Fixed-flow control mode with a pre-determined maximum automatic pump speed can be used safely and effectively in the DexAide RVAD. It can provide target flows by adjusting the pump speed while monitoring pump-flow response to automatic speed increment requests.

Use of zirconia ceramic in the DexAide right ventricular assist device journal bearing.

Our aim was to evaluate the potential use of zirconium oxide (zirconia) as a blood journal bearing material in the DexAide right ventricular assist device. The DexAide titanium stator was replaced by a zirconia stator in several blood pump builds, without changing the remaining pump hardware components. In vitro pump performance and efficiency were evaluated at a predetermined pump speed and flow. Motor power consumption decreased by 20%, and DexAide battery life was extended to over 12 h on two fully charged batteries. The zirconia stator was also successfully evaluated in a severe start/stop test pre- and postexposure of the zirconia to accelerated simulated biologic aging. This study's outcomes indicated the advantages of zirconia as an alternate journal bearing material for the DexAide device.

An innovative, sensorless, pulsatile, continuous-flow total artificial heart: device design and initial in vitro study.

BACKGROUND: We are developing a very small, innovative, continuous-flow total artificial heart (CFTAH) that passively self-balances left and right pump flows and atrial pressures without sensors. This report details the CFTAH design concept and our initial in vitro data. METHODS: System performance of the CFTAH was evaluated using a mock circulatory loop to determine the range of systemic and pulmonary vascular resistance (SVR and PVR) levels over which the design goal of a maximum absolute atrial pressure difference of 10 mm Hg is achieved for a steady-state flow condition. Pump speed was then modulated at 2,600 +/- 900 rpm to induce flow and arterial pressure pulsation to evaluate the effects of speed pulsations on the system performance. An automatic control mode was also evaluated. RESULTS: Using only passive self-regulation, pump flows were balanced and absolute atrial pressure differences were maintained at <10 mm Hg over a range of SVR (750 to 2,750 dyne.sec.cm(-5)) and PVR (135 to 600 dyne.sec.cm(-5)) values far exceeding normal levels. The magnitude of induced speed pulsatility affected relative left/right performance, allowing for an additional active control to improve balanced flow and pressure. The automatic control mode adjusted pump speed to achieve targeted pump flows based on sensorless calculations of SVR and CFTAH flow. CONCLUSIONS: The initial in vitro testing of the CFTAH with a single, valveless, continuous-flow pump demonstrated its passive self-regulation of flows and atrial pressures and a new automatic control mode.

In vivo acute performance of the Cleveland Clinic self-regulating, continuous-flow total artificial heart.

BACKGROUND: The purpose of this study was to evaluate the acute in vivo pump performance of a unique valveless, sensorless, pulsatile, continuous-flow total artificial heart (CFTAH) that passively self-balances left and right circulations without electronic intervention. METHODS: The CFTAH was implanted in two calves, with pump and hemodynamic data recorded at baseline over the full range of pump operational speeds (2,000 to 3,000 rpm) in 200-rpm increments, with pulsatility variance, and under a series of induced hemodynamic states created by varying circulating blood volume and systemic and pulmonary vascular resistance (SVR and PVR). RESULTS: Sixty of the 63 induced hemodynamic states in Case 1 and 73 of 78 states in Case 2 met our design goal of a balanced flow and maximum atrial pressure difference of 10 mm Hg. The correlation of calculated vs measured flow and SVR was high (R(2) = 0.857 and 0.832, respectively), allowing validation of an additional level of automatic active control. By varying the amplitude of sinusoidal modulation of the speed waveform, 9 mm Hg of induced pulmonary and 18 mm Hg of systemic arterial pressure pulsation were achieved. CONCLUSIONS: These results validated CFTAH self-balancing of left and right circulation, induced arterial flow and pressure pulsatility, accurate calculated flow and SVR parameters, and the performance of an automatic active control mode in an acute, in vivo setting in response to a wide range of imposed physiologic perturbations.

Development of DexAide right ventricular assist device: update II.

The DexAide right ventricular assist device (RVAD) is a magnetically and hydrodynamically levitated implantable centrifugal pump. Recent progress includes 1) redesign of the inflow/outflow conduits, which yielded two successful 3-month experiments, 2) development of alternative journal bearing materials, and 3) completion of an 18-month duration of in vitro endurance testing. Verification testing of the RVAD electronics has been completed, and a prototype biventricular assist device (BVAD) system has been tested. Acute DexAide/CorAide BVAD implantations via median sternotomy in two calves documented BVAD control algorithms and anatomical fit. A drug-induced chronic calf heart failure model, currently under development in our laboratory, resulted in a successful BVAD implantation in a calf with heart failure. Our future plans are to complete in vitro and in vivo validation of alternative bearing materials, perform preclinical DexAide in vivo and in vitro reliability studies, and obtain Food and Drug Administration (FDA) approval for an Investigational Device Exemption to conduct a clinical pilot study. In conclusion, two successful 3 month in vivo experiments and an 18-month in vitro endurance test were completed. After final bearing material selection, the DexAide design will be "frozen" so that preclinical systems can be manufactured. BVAD experiments using a chronic heart failure model are in progress.

Reduced pulsatility induces periarteritis in kidney: role of the local renin-angiotensin system.

OBJECTIVE: The need for pulsatility in the circulation during long-term mechanical support has been a subject of debate. We compared histologic changes in calf renal arteries subjected to various degrees of pulsatile circulation in vivo. We addressed the hypothesis that the local renin-angiotensin system may be implicated in these histologic changes. METHODS AND RESULTS: Sixteen calves were implanted with devices giving differing degrees of pulsatile circulation: 6 had a continuous flow left ventricular assist device (LVAD); 6 had a continuous flow right ventricular assist device (RVAD); and 4 had a pulsatile total artificial heart (TAH). Six other calves were histologic and immunohistochemical controls. In the LVAD group, the pulsatility index was significantly lower (0.28 +/- 0.07 LVAD vs 0.56 +/- 0.08 RVAD, vs 0.53 +/- 0.10 TAH; P < 0.01), and we observed severe periarteritis in all cases in the LVAD group. The number of angiotensin II type 1 receptor-positive cells and angiotensin converting enzyme-positive cells in periarterial areas was significantly higher in the LVAD group (angiotensin II type 1 receptor: 350 +/- 139 LVAD vs 8 +/- 6 RVAD, vs 3 +/- 2 TAH, vs 3 +/- 2 control; P < .001; angiotensin-converting enzyme: 325 +/- 59 LVAD vs 6 +/- 4 RVAD, vs 6 +/- 5 TAH, vs 3 +/- 1 control; P < .001). CONCLUSIONS: The reduced pulsatility produced by a continuous flow LVAD implantation induced severe periarteritis in the kidneys. The local renin-angiotensin system was up-regulated in the inflammatory cells only in the continuous flow LVAD group.

Innovative, replaceable heart valve: concept, in vitro study, and acute in vivo study.

The purpose of this study was to evaluate the feasibility of our innovative, replaceable heart valves that can be easily detached from the sewing ring at the time of repeat replacement. The prototype devices consist of the base magnet ring assembly and the valve magnet ring assembly that utilize magnetic coupling force for the locking mechanism. Magnetic coupling strength was evaluated in vitro. Prototype bioprosthetic valves were implanted acutely in three sheep to confirm the feasibility of the replaceable mitral valve. The static separation force of prototype size #25 was 12.5 lb, meeting the design goal. In situ attachment and detachment of the valve magnet ring assembly from the base magnet ring assembly were very easily accomplished in all animals. The magnetic coupling did not decouple even under extremely high left ventricular pressures. We have demonstrated the feasibility of this innovative concept of a replaceable mitral valve.

Acute in vivo evaluation of an implantable continuous flow biventricular assist system.

An implantable biventricular assist device offers a considerable opportunity to save the lives of patients with combined irreversible right and left ventricular failure. The purpose of this study was to evaluate the hemodynamic and physiologic performance of the combined implantation of the CorAide left ventricular assist device (LVAD) and the DexAide right ventricular assist device (RVAD). Acute hemodynamic responses were evaluated after simulating seven different physiological conditions in two calves. Evaluation was performed by fixing the speed of one individual pump and increasing the speed of the other. Under all conditions, increased LVAD or RVAD speed resulted in increased pump flow. The predominant pathophysiologic effect of independently varying DexAide and CorAide pump speeds was that the left atrial pressure was very sensitive to increasing RVAD speed above 2,400 rpm, whereas the right atrial pressure demonstrated much less sensitivity to increasing LVAD speed. An increase in aortic pressure and RVAD flow was observed while increasing LVAD speed, especially under low contractility, ventricular fibrillation, high pulmonary artery pressure, and low circulatory blood volume conditions. In conclusion, a proper RVAD-LVAD balance should be maintained by avoiding RVAD overdrive. Additional studies will further investigate the performance of these pumps in chronic animal models.

Progress in the development of the DexAide right ventricular assist device.

The DexAide right ventricular assist device (RVAD) is an implantable centrifugal pump modified from the CorAide left ventricular assist device. As previously published, in vitro performance testing of the DexAide RVAD has met design criteria, and the nominal operating condition of 4 l/min and 20 mm Hg pressure rise was achieved at 2,000 rpm, with a power consumption of 1.9 watts. In vivo studies in 14 calves have demonstrated acceptable hemodynamic characteristics. The calf inflow cannula design is still evolving to minimize depositions on the cannula observed in most experiments. Fitting studies were performed in 5 cadavers and 2 patients to reconfigure the cannulae for use in humans. The design and development of external electronics have been completed for the stand-alone RVAD system, and verification tests are under way in preparation for preclinical tests. Work on the external electronics design for the biventricular assist system is ongoing. In conclusion, the initial in vitro and in vivo studies have demonstrated acceptable hemodynamic characteristics of the DexAide RVAD. The design and development of the external electronic components for the stand-alone RVAD system have been completed. The calf inflow cannula is being redesigned, and chronic in vivo tests are under way.

Development of a small implantable right ventricular assist device.

The purpose of this program is to design, develop, and clinically evaluate a new, implantable right ventricular assist device (RVAD) that can be used as a component of an implantable biventricular assist device for patients with severe biventricular heart failure. The initial phase of this program resulted in a prototype RVAD, named DexAide, a modified version of the CorAide left ventricular assist device. In vitro testing was performed in a stand-alone circuit and in a true RVAD mode to evaluate pump performance. Pump flow and power were measured under various afterload and pump speed conditions. The pump performance requirements of 2 to 6 l/min and a pressure rise of 20 to 60 mm Hg were successfully met with pump speeds between 1,800 and 3,200 rpm. The nominal design point of 4 l/min and 40 mm Hg pressure rise was achieved at 2,450 +/- 70 rpm with a power consumption of 3.0 +/- 0.2 W. The initial in vitro testing met the design criteria for the new DexAide RVAD. Initial in vivo testing is under way, which will be followed by preclinical readiness testing and a pilot clinical trial in this 5-year program.

Preclinical readiness testing of the Arrow International CorAide left ventricular assist system.

BACKGROUND: Left ventricular assist system technologies are currently being developed as effective alternatives to cardiac transplantation. In this study, in vivo testing of the Arrow International CorAide left ventricular assist system was conducted to determine its preclinical readiness based on demonstrated system performance and biocompatibility. METHODS: Arrow International CorAide blood pump assemblies were implanted in 7 calves for 1-month (n = 4) and 3-month (n = 3) durations without the use of chronic anticoagulation therapy. Hemodynamic performance, physiologic pump control, end-organ function, and device-related adverse events were evaluated during the studies and at autopsy. RESULTS: Hemodynamics were stable in all cases with a mean pump flow of 4.1 +/- 0.8 L/min and a mean arterial pressure of 101 +/- 4 mm Hg. In all calves, renal and hepatic function remained normal with no incidence of hemolysis, infection, bleeding, or embolism. The CorAide physiologic control algorithm demonstrated appropriate pump speed and flow adjustments in response to physiologically induced inputs, and the system's external electronic components demonstrated no hardware or software malfunction. All 7 cases were sacrificed electively. Autopsy revealed no sign of end-organ disease on gross and histologic examinations, and no device failure, malfunction, or mechanical wear of the pump blood-bearing surfaces was found. CONCLUSIONS: The Arrow CorAide left ventricular assist system demonstrated effective pump performance and good biocompatibility with no incidence of device-related adverse events. This system has completed its preclinical readiness testing and is approved for clinical trials in Europe in 2003.