In Vivo Hemodynamic Evaluation of CH-VAD in a Bovine Model for 14 Days.

The CH-VAD is a centrifugal-flow magnetically levitated (maglev) left ventricular assist device (LVAD) used to treat end-stage heart failure. It is implanted in the chest cavity; the inflow cannula is inserted into the apex of the left ventricle, and the outflow graft is anastomosed to the aorta. Among several key VAD system improvements, the CH-VAD has a smaller body size than other LVADs and its maglev system offers a large-gap design that makes it superior in terms of hemocompatibility. In this study, we implanted the CH-VAD in a calf and evaluated the hemodynamic and hemocompatibility characteristics over a 14-day period. The hemodynamic parameters, the pump data, and blood test results were recorded throughout the study. The results showed that the CH-VAD provided hemodynamic stability. Hemocompatibility testing indicated negligible hemolysis throughout the study, and no signs of infection were seen. On necropsy, the results showed only expected focal mild-to-moderate adhesions between the pericardial sac (along the pump) and the adjacent rib cage, and between the pericardial sac and the heart. Gross examination of internal organs was unremarkable. Examination of the CH-VAD after explantation revealed no evidence of thrombus formation internally or around the inflow or outflow cannulas.

In Vivo Feasibility Study of an Intra-Atrial Blood Pump for Partial Support of the Left Ventricle.

We are designing an intra-atrial pump (IAP) that will be affixed to the atrial septum and support the compromised left ventricle (LV) in patients with early-stage heart failure without harming the ventricular tissue. It will operate in parallel with the LV, drawing blood from the left atrium and unloading the LV. In previous hydraulic and hemodynamic studies, different blade geometries were tested for the IAP, and the hemodynamic results obtained using a mock circulatory loop showed that the IAP can successfully reduce end-diastolic volume and increase the total systemic flow rate. In the current study, we used a bovine model to validate the in vitro hemodynamic results and better understand how the IAP interacts with the cardiovascular system in vivo. Because this was the first study assessing the complete device in a living system, it was also necessary to determine the best manufacturing techniques and ideal sensor placements. In the bovine model, we were able to successfully implant the IAP across the atrial septum with the outflow graft connected to a peripheral artery. The implanted IAP was capable of providing partial support (1-3 L/min) in vivo. These results indicate that atrial cannulation is feasible and creates a beneficial hemodynamic environment.

The miniaturized pediatric continuous-flow device: Preclinical assessment in the chronic sheep model.

BACKGROUND: The Infant Jarvik 2015 is an implantable axial-flow ventricular assist device (VAD) that has undergone the major evolutionary design modifications to improve hemocompatibility. This study was conducted in anticipation of data submission to the US Food and Drug Administration to obtain Investigational Device Exemption approval. METHODS: The VAD was implanted via a left thoracotomy in Barbado sheep (n = 10, 26 (19-34] kg). Anticoagulation was maintained with coumadin, with a target international normalized ratio of greater than the individual sheep's baseline values. The VAD was managed at the highest possible speed as clinically tolerable. Complete necropsy was performed at the end of the study. RESULTS: There were 2 early mortalities: tension pneumothorax (n = 1) and shower emboli of the fragmented myocardium (n = 1). The remaining 8 sheep (2 with 30-day and 6 with 60-day protocols) completed the anticipated study duration in excellent condition, with the 6 completing 60-day sheep showing appropriate weight gain during support. There were no signs of clinically significant hemolysis, with the final plasma-free hemoglobin of 2 (1-17) mg/dL. Necropsy showed old renal infarction in 7 sheep. Although thromboembolism can be the potential etiology, given the mild anticoagulation regimen, other sources of emboli were identified in 2 sheep (graft coating material and fragmented myocardium). Flow study demonstrated favorable increase in flow (up to 3.0 L/min) in proportion to change in pump speed. CONCLUSIONS: This study has demonstrated that the Infant Jarvik 2015 VAD is capable of maintaining its functionality for an extended period of time with minimal hemolysis.

In Vivo Evaluation of a Pneumatic Extracorporeal Ventricular Assist Device for up to 90 Day Support.

In a previous study, we showed that the Vitalmex Extracorporeal Ventricular Assist Device-Pneumatic (EVAD-P)-a low-cost, pneumatically actuated, pulsatile blood pump-is easy to implant and safe for short-term in vivo support (30 ± 5 days). In the current study, we included additional 30 day experiments and assessed the safety and durability of the EVAD-P for up to 90 days of support. Using the same surgical procedure as in the previous study, we implanted the device into 14 healthy sheep. Group I subjects (n = 7) were evaluated for up to 30 days, and group II (n = 2) and group III (n = 5) subjects were evaluated for up to 49 and 93 days, respectively. After a system redesign, two of the five sheep in group III reached the scheduled end-point without device-related problems at a fixed beat rate of 56 bpm, a stroke volume (SV) of 58.0 ± 2.3 ml, and a flow of 3.5 ± 0.2 L/min. This study shows that the EVAD-P can provide safe pulsatile mechanical circulatory support (MCS) for up to 93 days. To further confirm that the system can consistently provide MCS for this duration, additional studies are recommended.

Ninety-day survival of a calf implanted with a continuous-flow total artificial heart.

We evaluated the effects of steady state flow and perfusion on end-organ function in a long-term calf model. The animal received a continuous-flow total artificial heart (CFTAH) that we created from two axial-flow ventricular assist devices. Pump flow, blood pressure, and other pump parameters were monitored throughout the study, as were arterial blood gas and hematologic values, including neurohormone levels. Some hematologic values were mildly abnormal transiently after surgery but returned to acceptable levels within the first week. During the 90-day study, the calf showed no signs of hemolysis or thrombosis. Its mental function remained normal, as evidenced by the animal's interest in its surroundings and response to stimuli. End-organ and vasomotor function was not adversely affected by 90 days of steady state flow. This was the first study in which CFTAH support of an animal model was maintained for this duration.

In vivo testing of an intra-annular aortic valve annuloplasty ring in a chronic calf model.

OBJECTIVE: To increase applicability and stability of aortic valve repair, a three-dimensional aortic annuloplasty ring has been developed for intra-annular placement. The goal of this study was to test the safety of this device with in vivo implantation in the calf model. METHODS: In 10 chronic calves, the HAART annuloplasty ring was sutured to the aortic valve annulus using cardiopulmonary bypass. The animals were recovered and followed for 1-2 months. Serial echocardiography was used to evaluate valve competence, and contrast aortograms and CT angiograms were obtained in selected animals. After completion of follow-up, each animal was euthanized, and aortic endoscopy was performed under water distension in five. Full autopsies with histologic examinations were performed. RESULTS: All animals survived surgery. Two were euthanized in the first week for complications, and the remaining eight calves were followed uneventfully for the 1-2 months. Serial echocardiography showed completely competent valves in all but one animal, in which the ring was intentionally up-sized to test the sizing strategy. Contrast aortographic and CT angiographic findings were similar to the echocardiograms. Postmortem examination showed proper seating of all rings with endothelialization at 1-2 months. All valves demonstrated good leaflet coaptation and no abnormalities. CONCLUSIONS: In vivo testing of a three-dimensional aortic annuloplasty ring in a chronic calf model proved to be very successful and safe. Using the sizing and implant strategies developed, human trials seem indicated.

Elective tracheotomy facilitates total artificial heart implantation in calves.

Chronic ventilatory support may be required for survival after total artificial heart (TAH) implantation in calves. However, prolonged or repeated intubation may negatively affect a calf's ability to eat, drink, ruminate, and stand after surgery. To mitigate these limitations, we performed tracheotomies on 23 consecutive calves at the time of TAH implantation. The tracheostomies served as the primary route for ventilatory support and airway management. Tracheostomies were left in place for up to 25 days (mean, 7 +/- 7 days) and were well tolerated. Prolonged presence of a tracheostomy facilitated cleaning of the airway secretions and did not inhibit the calf's ability to stand, eat, or drink. The calves survived from 2 to 49 days (mean, 8 days). Twenty-two calves that maintained their tracheostomies died of causes unrelated to airway management. The calf that had the tracheostomy removed on day 25 died of respiratory arrest on day 49. At necropsy, we found that severe tracheal stenosis had developed at the tracheostomy site. In calves, an elective tracheotomy can be a valuable adjunct to TAH implantation or other procedures that might require prolonged ventilatory support or airway access, but care should be exercised if the tracheostomy is removed to ensure that the calf does not develop late tracheal stenosis.

Preclinical testing of the Levitronix Ultramag pediatric cardiac assist device in a lamb model.

We evaluated the effects of the Levitronix UltraMag pediatric ventricular assist system on healthy animals during 29- to 90-day periods by assessing hemocompatibility and hepatic and renal functions while operating the device in a flow range suitable for pediatric patients. Nine lambs (weight, 15 to 24 kg) received the Levitronix UltraMag with an outflow cannula anastomosed to the descending aorta and an inflow cannula inserted into the left ventricular apex. Pump function data were collected at 1-hour intervals, and postoperative hematology and clinical chemistry tests were performed weekly throughout the study. Complete necropsy and histopathologic examinations were performed at study termination. Pump and circuit were thoroughly inspected for evidence of thrombi. All animals reached the scheduled endpoint of 29 to 90 days without device-related problems. Mean flow was maintained at 1.14 +/- 0.19 L/min. Hematologic values were within normal range in all animals except in one lamb that had a severe hemolytic reaction after cefazolin sodium administration. In all animals, serum glutamic-oxaloacetic transaminase and creatinine kinase levels increased after surgery but gradually returned to normal limits within 1 week. Postmortem examination of the explanted organs revealed small infarcted areas in five lamb kidneys, but renal function was unaffected. All other major organs were unremarkable. In one explanted pump (a 30-day study), a small thrombus was seen within the impeller blade. The other eight pumps were free of thrombus. The Levitronix UltraMag successfully operated in pediatric flow ranges without device-related adverse events.

The effect of intermittent low speed mode upon aortic valve opening in calves supported with a Jarvik 2000 axial flow device.

We assessed the effects of an axial flow left ventricular assist device (LVAD) upon aortic valve opening, pump outflow, and biologic and hematologic parameters when operated in intermittent low speed (ILS) mode. An ILS controller equipped Jarvik 2000 LVAD was implanted in six calves. Pump speed was maintained at 10,000 rpm, and pump outflow was measured throughout the study period (71 +/- 6 days [mean +/- SD]). Hematologic and biochemical parameters were analyzed daily for the first 10 days, weekly for the first month, and biweekly thereafter to monitor for kidney or liver dysfunction, hemolysis, bleeding, or infection. Before study termination, esmolol hydrochloride was infused to induce low cardiac output and totally impair aortic valve opening. Radiopaque cineaortography was performed over 30 second intervals (10 seconds before, 10 seconds during, and 10 seconds immediately after ILS controller activation) to assess the effect of ILS mode upon aortic valve opening. After study termination, major end organs and the major vascular tree were removed and examined macroscopically and histologically for thrombus formation and infarction; the aortic valve was examined for thickening and fusion. All pumps were explanted and examined for thrombus formation. All six calves recovered without surgical or mechanical complications. Hematologic and biochemical parameters did not change significantly between baseline and study termination. The aortic valve successfully opened when ILS mode was activated, even under low cardiac output conditions. No thrombus was detected in the major end organs and vascular tree, except for some small renal infarcts in three calves that did not affect renal function. These results indicate that operating an axial flow LVAD in ILS mode allows aortic valve opening and aortic root washout.

Effect of pump flow mode of novel left ventricular assist device upon end organ perfusion in dogs with doxorubicin induced heart failure.

End organ effects of nonpulsatile (NP) and pulsatile (P) left ventricular assist device (LVAD) flow were compared in a canine model of doxorubicin-induced heart failure. After heart failure induction, a prototype bimodal LVAD was implanted. Hemodynamics, cardiac dimensions, and myocardial metabolism were monitored with the LVAD off (baseline) and on (in NP and P modes at 70% or 100% power). End organ perfusion was assessed by colored microsphere analysis. Seven dogs were used: two died before pump implantation and were excluded from analysis, and the remaining five survived to study termination. At 70% NP, ascending aortic flow and myocardial oxygen consumption (MVO2) decreased significantly. At 100% NP, LV dimensions decreased, aortic systolic, pulse, and LV pressures decreased but not significantly, and ascending aorta flow reversed. At 100% NP, coronary blood flow, MVO2, and LV free wall subepicardial and subendocardial blood flows decreased significantly. However, as NP support increased, the subepicardial/subendocardial blood flow ratio remained near baseline. At 100% NP, right ventricular perfusion decreased but not significantly, cerebral perfusion decreased significantly, and renal perfusion stayed constant. P mode results were similar, except that ascending aorta flow decreased significantly at 100% P instead of reversing as at 100% NP. These results suggest that end organ perfusion is not differentially affected by LVAD flow mode during chronic heart failure.

Evaluation of myocardial function in patients with end-stage heart failure during support with the Jarvik 2000 left ventricular assist device.

In 2 patients with the Jarvik 2000 left ventricular assist device (LVAD), we assessed left ventricular systolic function through pressure-volume loops and E(max) at the beginning and end of the support period to potentially predict the possibility of pump removal without transplantation. Immediately before LVAD implantation and explantation, pressure and volume measurements were made with catheters and echocardiography, respectively, the E(max) being calculated from the slope of the pressure-volume loops, and the left ventricular ejection fraction (LVEF) being estimated by echocardiography. Transplantation was performed after 14 and 62 days, respectively, during which the LVEF increased by 75% (from 12% to 21%) in Patient 1 and remained unchanged (from 16% to 18%) in Patient 2, whereas the E(max) increased from 0.63 and 0.42 mm Hg/ml, respectively, to 1.31 and 1.07 mm Hg/ml, reflecting a 107% and 155% improvement. In these 2 cases, the E(max) was a more reliable indicator of intrinsic myocardial contractility than was the LVEF.

Biventricular support with the Jarvik 2000 ventricular assist device in a calf model of pulmonary hypertension.

The Jarvik 2000 ventricular assist device (VAD) is clinically efficacious for treating end-stage left ventricular failure. Because simultaneous right ventricular support is also occasionally necessary, we developed a biventricular Jarvik 2000 technique and tested it in a calf model. One VAD was implanted in the left ventricle with outflow-graft anastomosis to the descending aorta. The other VAD was implanted in the right ventricle with outflow-graft anastomosis to the pulmonary artery. Throughout the 30 day study, hemodynamic values were continuously monitored. On day 30, both pumps were evaluated at different speeds, under various hemodynamic conditions. By gradually occluding the pulmonary artery proximally or distally, we simulated varying degrees of high pulmonary vascular resistance, right ventricular hypertension, global heart failure, or ventricular fibrillation. The two VADs maintained biventricular support even during pulmonary artery occlusion and ventricular fibrillation, yielding a cardiac output of 3-11 L/min, left ventricular end-diastolic pressure of 11-24 mm Hg, and central venous pressure of 9-25 mm Hg. End-organ function was unimpaired, and no major adverse events occurred. The dual VADs offered safe, effective biventricular assistance in the calf. Additional studies are needed to assess the effects of lowered pulse pressure upon the pulmonary circulation and to develop a single pump speed controller.

Thrombogenicity of mechanical aortic valves in an animal model: site specific testing is crucial.

We evaluated a new trileaflet prosthesis and a control bileaflet prosthesis in the mitral and aortic positions in 27 calves. The prototype trileaflet valve (TV1) functioned satisfactorily in the mitral position (TV1m, n = 7) but later yielded thrombogenic complications in the aortic position (TV1a, n = 4). The valve was redesigned (TV2) and retested in the mitral (TV2m n = 4) and aortic (TV2a, n = 5) positions, along with control valves (Cm, n = 4; Ca, n = 3). At necropsy, the valves were graded on a scale of 0 (no visible thrombi) to 4 (thrombi greater than 5 mm and/or obstructed leaflets). The TV1m, TV2m, and Cm animals, respectively, had implant durations of 215+/-112, 140+/-63, and 159+/-89 days and thrombus grades of 0.71+/-0.76, 0.33+/-0.58, and 1.50+/-0.58. The TV1a, TV2a, and Ca animals had implant durations of 18+/-12, 159+/-61, and 108+/-62 days and thrombus grades of 2.75+/-1.00, 0.50+/-0.58, and 0.67+/-0.58 (p < .005; TV2a vs. TV1a). Three TV1a calves died early of valve related complications. A design irregularity, undetected in the mitral position but revealed in the aortic position, caused a high early mortality in the TV1a animals. Redesigning the prosthesis eliminated valve related mortality and significantly reduced the thrombus grade. Because satisfactory performance in the mitral position does not guarantee safety or efficacy in the aortic position, site specific preclinical testing is crucial for mechanical heart valves.

Baseline hemodynamic and echocardiographic indices in anesthetized calves.

The experimental calf model is used to assess mechanical circulatory support devices and prosthetic heart valves. Baseline indices of cardiac function have been established for the normal awake calf but not for the anesthetized calf. Therefore, we gathered hemodynamic and echocardiographic data from 16 healthy anesthetized calves (mean age, 189.0 +/- 87.0 days; mean body weight, 106.9 +/- 32.3 kg) by cardiac catheterization and noninvasive echocardiography, respectively. Baseline hemodynamic data included heart rate (65 +/- 12 beats per minute), mean aortic pressure (113.5 +/- 17.4 mm Hg), left ventricular end-diastolic pressure (16.3 +/- 38.9 mm Hg), and mean pulmonary artery pressure (21.7 +/- 8.3 mm Hg). Baseline two-dimensional echocardiographic data included left ventricular systolic dimension (3.5 +/- 0.7 cm), left ventricular diastolic dimension (5.6 +/- 0.8 cm), end-systolic intraventricular septal thickness (1.7 +/- 0.2 cm), end-diastolic intraventricular septal thickness (1.2 +/- 0.2 cm), ejection fraction (63 +/- 10%), and fractional shortening (37 +/- 10%). Doppler echocardiography revealed a maximum aortic valve velocity of 0.9 +/- 0.5 m/s and a cardiac index of 3.7 +/- 1.1 L/minute/m2. The collected baseline data will be useful in assessing prosthetic heart valves, cardiac assist pumps, new cannulation techniques, and robotics applications in the anesthetized calf model and in developing calf models of various cardiovascular diseases.

Preclinical hemodynamic assessment of a new trileaflet mechanical valve in the aortic position in a bovine model.

BACKGROUND AND AIM OF THE STUDY: The hemodynamic characteristics of a new trileaflet mechanical heart valve (TTV) (TriFlo Inc., Costa Mesa, CA, USA) in the aortic position were evaluated in a bovine model. The TTV was designed to combine the durability of mechanical heart valves with the central flow characteristics of a bioprosthesis. METHODS: Using nine calves, the native aortic valve was replaced with a 21-mm TTV (n = 6) or a St. Jude Medical (SJM) valve (n = 3). Hemodynamic values were assessed with echocardiography at implantation and with catheterization at explantation. All calves underwent a necropsy, followed by gross pathology and light microscopy studies. RESULTS: The mean implant duration was 159 +/- 55 days for the TTV and 102 +/- 67 days for the SJM valve. Immediately before euthanasia, the peak and mean pressure gradients were respectively 35 +/- 14 and 24 +/- 9 mmHg for the TTV, and 100 +/- 72 and 59 +/- 38 mmHg for the SJM valve (p = 0.03). Two of the SJM-valve animals were electively sacrificed after showing symptoms of aortic stenosis. At necropsy, all nine valves were free from thrombi, pannus, occlusive tissue, or mechanical impairment of leaflet motion. The prematurely sacrificed SJM-valve animals had concentric myocardial hypertrophy consistent with severe functional aortic stenosis. CONCLUSION: The significantly higher gradients and left ventricular hypertrophy in the SJM-valve animals were related to a smaller effective orifice area, which precluded adaptation to increasing transvalvular volumes in the growing animal. This problem was not seen with the TTV, which performed hemodynamically as well as the SJM valve. The high transvalvular gradients seen with the SJM valve at study end may suggest that the hemodynamic characteristics of the TTV may be superior, though additional studies are needed to confirm this.

Myocardial hemodynamics, physiology, and perfusion with an axial flow left ventricular assist device in the calf.

The Jarvik 2000 axial flow left ventricular assist device (LVAD) is used clinically as a bridge to transplantation or as destination therapy in end-stage heart disease. The effect of the pump's continuous flow output on myocardial and end-organ blood flow has not been studied experimentally. To address this, the Jarvik 2000 pump was implanted in eight calves and then operated at speeds ranging from 8,000 to 12,000 rpm. Micromanometry, echocardiography, and blood oxygenation measurements were used to assess changes in hemodynamics, cardiac dimensions, and myocardial metabolism, respectively, at different speeds as compared with baseline (pump off, 0 rpm) in this experimental model. Microsphere studies were performed to assess the effects on heart, kidney, and brain perfusion at different speeds. The Jarvik 2000 pump unloaded the left ventricle and reduced end-diastolic pressures and left ventricular dimensions, particularly at higher pump speeds. The ratio of myocardial oxygen consumption to coronary blood flow and the ratio of subendocardial to subepicardial blood flow remained constant. Optimal adjustment of pump speed and volume status allowed opening of the aortic valve and contribution of the native left ventricle to cardiac output, even at the maximum pump speed. Neither brain nor kidney microcirculation was adversely affected at any pump speed. We conclude that the Jarvik 2000 pump adequately unloads the left ventricle without compromising myocardial metabolism or end-organ perfusion.

Preclinical assessment of a trileaflet mechanical valve in the mitral position in a calf model.

BACKGROUND: The bileaflet valve is currently the mechanical replacement valve of choice. Though durable, it does not closely mimic native valve hemodynamics and remains potentially thrombogenic. METHODS: Prototype trileaflet valves (T1 and T2) were implanted in the mitral position in calves. Group I calves received either a T1 valve (n = 12) or a control bileaflet valve (n = 5); Group II, either a T2 valve (n = 7) or a control bileaflet valve (n = 5). Valve function, perivalvular leakage, and transvalvular pressure gradients were evaluated. Also, long-term prototype leaflet wear was evaluated in vivo in one Group I calf (502 days) and two Group II calves (385 and 366 days). Calves were euthanized and necropsied at study termination, and major organs weighed and examined. RESULTS: Valve function was excellent and hematologic parameters remained normal in all calves that survived to study termination. Mean peak transvalvular pressure gradients were 10 +/- 7 mm Hg for T1 valves, 6 +/- 3 mm Hg for T2 valves, and 12 +/- 4 mm Hg for bileaflet control valves. Clinically insignificant valvular regurgitation was observed in both prototypes. Explanted valves showed no thrombus-impaired leaflet motion, except in two T1-fitted calves and one T2-fitted calf. Major organs showed no evidence of clinically significant thromboembolic events. There were no other significant differences between the results of experimental and control groups. CONCLUSIONS: Prototype trileaflet valves performed safely and effectively in the mitral position in calves, even without long-term anticoagulation. This warrants their evaluation as an equivalent alternative to bileaflet valves.

Evaluation of a new cardiac recovery system in a bovine model of volume overload heart failure.

We evaluated the short-term hemodynamic efficacy of the Cancion cardiac recovery system (CRS) in a bovine model of volume overload heart failure. We created severe mitral regurgitation (MR) by disrupting the mitral chordae tendineae of two calves, which were allowed to survive for 13 and 11 months. Four hours before we killed the calves, we introduced the CRS, which maintained flows of 1.2 L/min. Hemodynamic data were recorded before and after MR creation and CRS initiation. Left ventriculography was performed at those same intervals and 4 hours after CRS initiation. After chordal disruption, the left ventricular end-diastolic pressure (LVEDP) increased from 14 to 23 mm Hg in calf 1 and 15 to 27 mm Hg in calf 2. After 4 hours of CRS support, the LVEDP decreased from 23 to 8 mm Hg (calf 1) and 27 to 14 mm Hg (calf 2); dP/dt increased from 1,373 to 2,900 mm Hg/s (calf 1) and 1,068 to 2,384 mm Hg/s (calf 2). MR decreased from 3+ to 1 in calf 2 but could not be determined in calf 1. In this bovine model of volume overload heart failure, the CRS unloaded the left ventricle and reduced the afterload. Future trials will determine the pump's ability to treat congestive heart failure.