Research and development of an implantable, axial-flow left ventricular assist device: the Jarvik 2000 Heart.

Advances in technology and increased clinical need have led to the development of a new type of blood pump. The Jarvik 2000 Heart is an electrically powered, axial-flow left ventricular assist device that has been developed during the past 13 years. Unlike first-generation left ventricular assist devices, which were developed in the 1970s and were designed to totally capture the cardiac output, the Jarvik 2000 is designed to normalize the cardiac output by augmenting the function of the chronically failed heart for extended periods. Design iterations have been tested in 67 animals, and clinical trials have recently begun. Three patients have received the Jarvik 2000 as a bridge to transplantation, and 1 patient is being supported permanently outside the hospital. All 4 patients have improved from New York Heart Association functional class IV to class I, and 2 of them have been discharged from the hospital after heart transplantation. The experimental and clinical results indicate that the Jarvik 2000 can provide physiologic support with minimal complications and is reliable, biocompatible, and easy to implant.

Infection and thrombosis in total artificial heart technology: past and future challenges--a historical review.

On the basis of animal testing and a single clinical implant during the 1960s, development of the total artificial heart (TAH) began in earnest in the 1970s. The goal was to produce a pump that could treat biventricular heart failure or any other condition that necessitated removal of the patient's native heart. The early TAHs were pneumatically powered, with externalized drivelines. After undergoing in vivo evaluation in hundreds of sheep and calves at several centers (mainly the Utah Heart Institute), these pumps were implanted in humans, initially for permanent cardiac replacement and later for bridging to transplantation. In both the in vivo experimental setting and the clinical setting, infection and thrombosis were problematic, infection being encountered much more frequently than thrombosis in clinical cases. To minimize these problems, four research groups, funded by NIH, began in 1988 to develop permanent, transcutaneously powered, totally implantable, electromechanical TAHs. For the first time, TAH technology was able to minimize infection and thrombosis, as confirmed by current in vivo studies. These new TAHs will undergo preclinical, pre-IDE studies this year and clinical trials in the near future. This article briefly reviews the evolution of TAH technology, with an emphasis on the prevention and management of infection and thrombosis.

Effects of myocardial contractility on microemboli production by mechanical heart valves in a bovine model.

Microemboli caused by mechanical heart valves have the potential to cause cerebrovascular events. We investigated the effects of myocardial contractility and heart rate on microemboli production in association with conventional and experimental mechanical heart valves implanted in the mitral position in a bovine model. In 10 calves, the mitral valves were replaced with mechanical valves. Doppler recordings were analyzed for high-intensity transient signals, which are ultrasound reflections from circulating microemboli. The animals were studied at rest, during pacing at 160 bpm, after dobutamine infusion, and after esmolol infusion. The incidence of high intensity transient signals was expressed as signal frequency (signals per hour) and as signal rate (signals per 100 heart cycles). With a 68% increase in the heart rate, signal frequency increased by 135%, but signal rate increased by only 41 %. With a 144% increase in myocardial contractility, signal rate increased by 264 %. With a 31 % decrease in contractility, signal rate decreased by 62 %. We conclude that microemboli production by mechanical heart valves varies with myocardial contractility and heart rate. The fact that contractility affects the incidence of high-intensity transient signals suggests that the microemboli are gaseous in nature, that their production is pressure driven, and that cavitation is a possible cause. It is likely that mechanical heart valve design is responsible for the quantity of microemboli production.

A bovine model for detecting high intensity transient signals originating from mechanical heart valves.

In patients with mechanical heart valves (MHVs), transcranial Doppler methods commonly detect high intensity transient signals (HITS) representing microemboli. These microemboli, which are presumably gaseous, may cause stroke and cognitive deterioration. A bovine model was therefore developed for studying the relationship between mitral MHV induced HITS and potential etiogenic factors. We placed an 18 mm, 4 MHz Doppler probe in the brachiocephalic artery to detect MHV induced microbubbles at baseline (rest) and under 9 other conditions. To elucidate the gas composition (CO2 or N2) of the microbubbles, we administered 1%, 3%, and 5% CO2, and 100% O2. To determine effect of the heart rate, we paced the heart at 120, 160, and 180 bpm. To alter the myocardial contractility, we gave dobutamine and esmolol. Two independent, blinded observers counted the HITS from recorded doppler spectra. HITS were defined by an initial unidirectional spectral deviation, a signal power of >8 dB relative to the background power, and lack of a cyclic appearance. The electrocardiogram, aortic and LV pressures, and LV dP/dt were obtained telemetrically. The calves were studied 4 to 6, 8 to 10, and 12 to 14 weeks postoperatively, after which the animals were sacrificed at an approximate 4 month study duration, and a postmortem evaluation of the heart and the main viscera was performed. In all, 27 HITS recordings were made in 10 calves. Myocardial contractility was the only factor to significantly affect HITS frequency; the heart rate and blood gas concentrations had minimal effect on HITS frequency. Our bovine model will be useful for assessing valve designs, as well as the mechanism of HITS, the composition of the microemboli, and their possible pathophysiologic effects on the kidneys and brain.

Intraoperative arrhythmias and tissue damage during transmyocardial laser revascularization.

BACKGROUND: Transmyocardial laser revascularization creates transmural channels to improve myocardial perfusion. Different laser sources and ablation modalities have been proposed for transmyocardial laser revascularization. We investigated the incidence of cardiac arrhythmias and laser-tissue interactions during transmyocardial laser revascularization of normal porcine myocardium with three different lasers. METHODS: We used a continuous-wave, chopped CO2 laser (20 J/pulse, 15 ms/pulse) synchronized with the R wave; a holmium:yttrium aluminum garnet (Ho:YAG) laser (2 J/pulse, 250 micros/pulse, 5 Hz); and a xenon-chloride (excimer, Xe:Cl) laser (35 mJ/pulse, 20 ns/pulse, 30 Hz). Each laser was used 30 times as the sole modality in four consecutive pigs, yielding 120 channels. RESULTS: The average number of pulses needed to create a channel was 1, 11 +/- 4, and 37 +/- 8 for the CO2, Ho:YAG, and Xe:Cl lasers, respectively. All Ho:YAG and Xe:Cl channels had premature ventricular contractions. Ventricular tachycardia occurred in 70% of the Xe:Cl and 60% of the Ho:YAG channels. Only 36% of the CO2 channels had premature ventricular contractions, and only 3% of the CO2 channels had ventricular tachycardia (p < 0.001 versus Ho:YAG and Xe:Cl). Ho:YAG channels were highly irregular: each had a 0.6-mm-wide central zone surrounded by a ring of coagulation necrosis (diameter, 1.84 +/- 0.67 mm) with effaced cellular architecture in a thin hemorrhagic zone. The Xe:Cl sections exhibited the same patterns on a smaller scale (diameter, 0.74 +/- 0.18 mm). The CO2 channels were straight and well demarcated. The zone of structural and thermal damage extended over half the channel's diameter, measuring 0.52 +/- 0.25 mm. CONCLUSIONS: During transmyocardial laser revascularization, the CO2 laser synchronized with the R wave is significantly less arrhythmogenic than the Ho:YAG and Xe:Cl lasers not synchronized with the R wave. In addition, the interaction of the CO2 laser with porcine cardiac tissue is significantly less traumatic than that of the Ho:YAG and the Xe:Cl lasers.

Progress in the development of a transcutaneously powered axial flow blood pump ventricular assist system.

Development of the Jarvik 2000 intraventricular assist system for long-term support is ongoing. The system integrates the Jarvik 2000 axial flow blood pump with a microprocessor based automatic motor controller to provide response to physiologic demands. Nine devices have been evaluated in vivo (six completed, three ongoing) with durations in excess of 26 weeks. Instrumented experiments include implanted transit-time ultrasonic flow probes and dual micromanometer LV/AoP catheters. Treadmill exercise and heart pacing studies are performed to evaluate control system response to increased heart rates. Pharmacologically induced cardiac dysfunction studies are performed in awake and anesthetized calves to demonstrate control response to simulated heart failure conditions. No deleterious effects or events were encountered during any physiologic studies. No hematologic, renal, hepatic, or pulmonary complications have been encountered in any study. Plasma free hemoglobin levels of 7.0 +/- 5.1 mg/dl demonstrate no device related hemolysis throughout the duration of all studies. Pathologic analysis at explant showed no evidence of thromboembolic events. All pump surfaces were free of thrombus except for a minimal ring of fibrin, (approximately 1 mm) on the inflow bearing. Future developments for permanent implantation will include implanted physiologic control systems, implanted batteries, and transcutaneous energy and data transmission systems.

Long- and short-term effects of transmyocardial laser revascularization in acute myocardial ischemia.

BACKGROUND AND OBJECTIVE: This study examined the effect of transmyocardial laser revascularization (TMLR) on infarct size and global and regional left ventricular (LV) function. STUDY DESIGN/MATERIALS AND METHODS: Acute ischemia was induced in 24 dogs by ligating the left anterior descending artery. TMLR was done through a left thoracotomy in 12 dogs. The 12 control dogs had ligation only. Global and regional LV function were measured before ligation, then at 6 hours or 3 months after ligation. We calculated the volumetric ratio of damaged myocardium to myocardium at risk (Vd/Vr). RESULTS: At 6 hours, global compensation despite regional dyskinesia was universal; Vd/Vr was the same in control and TMLR dogs. At 3 months, global function during stress was significantly higher in TMLR dogs than in control dogs (P < .05); regional contractions were synergic only in TMLR dogs; mean Vd/Vr was significantly lower in TMLR dogs. CONCLUSION: TMLR limits infarct expansion and improves long-term global and regional function after acute ischemia.

PTCA in angulated segments: effects of balloon material, balloon length, and inflation sequence on straightening forces in an in vitro model.

We sought to determine the effect of balloon material, balloon length, and inflation sequence on the straightening forces generated during percutaneous transluminal coronary angioplasty (PTCA) in angulated segments. Using an in vitro model consisting of a curved channel (3/4" radius) with a displaceable pressure sensor, we examined four different balloon materials: compliant (POC), semicompliant (PE600 and Duralyn), and noncompliant (PET), two balloon lengths (20 mm and 40 mm), and two inflation sequences (rapid and slow) with continuous recording of straightening force during each balloon inflation. Three balloons were tested for each combination of materials, length, and inflation sequence. Long balloons exerted significantly lower straightening forces. There were significantly higher straightening forces with noncompliant, particularly short, balloons. Varying the inflation sequence had no significant effect. For PTCA in angulated segments: (1) long balloons produce lower straightening force, (2) noncompliant balloons produce higher straightening force, particularly with short balloons, and (3) varying the inflation sequence has no significant effect on straightening force.

Myocardial revascularization with laser. Preliminary findings.

BACKGROUND: We assessed the transmyocardial laser revascularization (TMLR) as sole therapy in patients with symptomatic coronary artery disease refractory to interventional or medical treatment. METHODS AND RESULTS: Thirty-one patients were evaluated with positron emission tomography (PET), dobutamine echocardiography, 201Tl single-photon emission computed tomography (201Tl-SPECT), and multigated acquisition radionuclide ventriculography (MUGA). TMLR was performed in 21 patients who had demonstrable ischemia in viable myocardium. The mean Canadian Cardiovascular Society (CCS) angina class was 3.70 +/- 0.7 (4 patients with unstable angina). Untreated septal segments were used as controls. At 3 months, (n = 15 patients), the mean CCS angina class was to 2.43 +/- 0.9 (P < .05). On dobutamine echocardiography, the mean resting wall motion score index was improved by 16% in lased segments (P < .03 vs control), and mean LVEF at peak stress increased by 19% (P = NS vs baseline). On 201Tl-SPECT, perfusion of lased and nonlased segments did not change. On PET, the mean ratio of subendocardial to subepicardial perfusion (SEn/SEp) increased 14% over baseline (P < .001 vs control). At 6 months (n = 15 patients), the mean CCS angina class was 1.7 +/- 0.8 (P < .05). The mean resting wall motion score index was up by 13% in lased segments (P < .05 vs control). Resting LVEF was unchanged. Stress LVEF increased 21% (P = NS vs baseline). Myocardial perfusion remained unchanged by 201Tl-SPECT. On PET, 36% of the lased segments were better, and 25% were worse compared with baseline. The resting SEn/SEp by PET was up 21% (P < .001 vs control). All deaths (two perioperative and three late) occurred in patients with preoperative congestive heart failure. Two patients required repeat revascularization of new coronary lesions. CONCLUSIONS: These results suggest that TMLR improves anginal status, relative endocardial perfusion, and cardiac function in patients who do not have preoperative congestive heart failure.

Five month survival in a calf supported with an intraventricular axial flow blood pump.

We are studying in vivo an intraventricular axial flow blood pump (Jarvik 2000) designed for long-term left ventricular support. The small (25 cc, 85 g) valveless pump has been placed intraventricularly in seven calves; pumps have functioned for as long as 5 months. In the four most recent long-term studies completed, calves have survived for 70, 120, 155, and 162 days (in that order); weight gain has averaged 0.56 kg/day. One study is ongoing at more than 30 days. Under resting physiologic conditions in the normal calf, the continuous flow pump produces flows of 5-6 L/min with a decreased arterial pulse contour. The device has caused no physiologic complications. Calves in the completed studies had mean free plasma hemoglobin levels of 11.4, 7.1, 6.5, and 4.3 mg/dl, respectively. We have modified the inflow structures of the device, and these results suggest that a thrombus free design with no pannus at or around the inlet of the pump can be achieved. Histopathologic analyses of the heart and kidneys in studies of as long as 5 months show no deleterious effects of this device. These studies demonstrate the feasibility of a small implanted intraventricular blood pump for long-term use. Future developments for permanent implantation will include implanted physiologic control systems, transcutaneous energy transmission systems, and implanted batteries.

In vivo evaluation of a trileaflet mechanical heart valve.

Design goals for a mechanical heart valve include duplicating the hemodynamic performance of the natural valve, eliminating the need for anticoagulants, and maintaining safety. The Lapeyre-Dassault (Dassault-Aviation, Paris, France) prosthetic valve, undergoing development, addresses these goals. The unique trileaflet design consists of a solid titanium ring and three leaflets. Prototypes of the valve fabricated with Delrin leaflets were implanted in the mitral position in six calves (70-90 kg). Four calves (Studies 1, 2, 3, 5) had long-term survival of 165, 158, 219, and 281 days, respectively. Two calves were killed, one on Day 37 and one on Day 39, after complications unrelated to the valve developed. In all calves heparin was given intravenously to maintain partial thromboplastin time at 1.5 to 2.0 x baseline for approximately 1 week. In Studies 1 and 2 full anticoagulation and antiplatelet therapy was given (orally administered sodium warfarin to maintain prothrombin time at 1.5 to 2.0 x baseline, along with aspirin (1 g/day) and dipyridamole 400 mg/day). In Study 3, all anticoagulation and antiplatelet therapy was discontinued at 1 month after implant. In Study 5, no anticoagulation therapy was given after the initial week of intravenous heparin; however, antiplatelet therapy was started on the fifth postoperative month and maintained until the study's end at 9 months. At 1, 2, 3, and 5 months, the mean plasma free hemoglobin level in the four long-term animals was 5.0 +/- 2.16, 6.0 +/- 3.83, 8.5 +/- 4.93, and 11.3 +/- 6.74 mg/dl, respectively. Hemolysis was not a problem. Valve performance during normal activity was excellent in all the calves, as evidenced by echocardiography and the overall appearance of good health. In the four completed long-term studies, left heart catheterization showed a mean valve pressure gradient of 11.57 +/- 1.26 mmHg and no apparent valvular regurgitation. Histopathologic examination of major organs showed no evidence of thromboembolic events. This study shows that the innovative design of this trileaflet valve performed well in initial in vivo testing, justifying further development.

Simultaneous evaluation of cardiac wall motion and myocardial ischemic injury by measurement of electrical impedance.

The authors devised a new method to simultaneously evaluate cardiac wall motion and myocardial ischemic injury by measurement of myocardial electrical impedance. This method is based on the principle that electrical properties of the myocardium are affected by intra- or extracellular structure. Impedance was assessed by measuring voltage while a constant alternating current (0.4 mA, 50 kHz) was being applied to the myocardium by way of an electrode that had two parallel 6 mm long needles. In five dogs, an electrode was placed in the left ventricular wall, adjacent to a pair of ultrasonic crystals that were used to estimate regional wall thickness. To change regional contractility and to induce ischemic injury, the left anterior descending coronary artery was ligated. The impedance waveforms were observed to be synchronized with cardiac contraction, and changes in impedence correlated well with changes in wall thickness. Dyskinetic movements in the ischemic myocardium could also be detected through assessment of the impedance waveform. During the first 2 hr, the average value of impedance increased significantly, from 254 +/- 38 omega-cm to 329 +/- 13 omega-cm (P < 0.005), and then decreased, indicating a correlation with the progression and irreversibility of ischemic injury. This simple technique may eventually allow us to simultaneously assess cardiac wall motion and myocardial ischemia in humans.

Peripheral organ perfusion augmentation during left ventricular failure. A controlled bovine comparison between the intraaortic balloon pump and the Hemopump.

Despite the use of inotropic therapy and the intraaortic balloon pump (IABP), inadequate peripheral organ perfusion and subsequent multiorgan failure from left ventricular dysfunction is a major cause of death following cardiac surgery. To compare the end-organ perfusion provided by the IABP with that of the recently developed Hemopump Cardiac Assist System, blood flow from visceral organs was measured by ultrasonic flow probes during separate periods of support with each of these pumps. Ten calves underwent coronary artery ligations with beta-receptor blockade; hemodynamic parameters were recorded before the induction of failure, during unsupported cardiac failure, and during Hemopump and IABP support. Improvement in mean cardiac output, mixed venous oxygen saturation, and pulmonary artery wedge pressure was significantly greater (p < 0.05) during Hemopump support than during IABP support. Renal artery flow was significantly greater during Hemopump support (276 +/- 74.2 cc/min) than during IABP support (164 +/- 79.6 cc/min). Hepatic artery flow was significantly greater during Hemopump support (34.7 +/- 25.7 cc/min) than during IABP support (24.4 +/- 18.9 cc/min), and portal vein flow was significantly greater during Hemopump support (1588 +/- 315 cc/min) than IABP support (1259 +/- 310 cc/min). There were no significant differences, however, between carotid artery flow during Hemopump support (292 +/- 171 cc/min) and that during IABP support (317 +/- 204 cc/min). We conclude that renal, hepatic, and mesenteric perfusion provided by the nonpulsatile Hemopump is superior to that of the IABP in this bovine model of left ventricular failure. Therefore, the Hemopump may be more effective in preventing multiorgan failure during recovery of ventricular function.

An ex vivo model for the reperfusion of explanted human hearts.

A model of an ex vivo-reperfused human heart was developed by using a modified Langendorff coronary perfusion circuit. The technical and physiologic aspects of reestablishing myocardial contractility are described. Preliminary studies were conducted in animals. In the present study, we obtained 12 human hearts that had been arrested with cardioplegic solution and excised from cardiac transplant recipients. The perfusate contained type-specific human donor red blood cells in a lactated Ringer's solution containing 5% dextrose. Myocardial contractility was successfully reestablished in 11 hearts and sustained for an average of 98 minutes (range, 79 to 180 minutes) at a coronary perfusion pressure of 80 mmHg. Left ventricular contraction pressures reached 40 mmHg (against intraventricular balloons at an internal pressure of 50 to 75 mmHg). Partial oxygen pressure (PO2) dropped significantly across the empty beating myocardium (from 498 +/- 40 mmHg to 219 +/- 53 mmHg [mean +/- SD]), but no significant change in hemoglobin saturation was observed. Myocardial failure generally stemmed from edematous changes leading to progressive impairment of myocardial relaxation. The intracoronary insertion of over-the-wire catheters did not adversely affect myocardial function. In conclusion, an ex vivo-supported human heart model has been developed that may have a number of applications, including the preclinical evaluation of new interventional diagnostic and therapeutic techniques aimed at the coronary circulation, and the investigation of myocardial mechanics, preservation, and metabolism.

Preliminary results of intraoperative excimer laser angioplasty: phase 1: an adjunct to coronary artery bypass surgery.

The excimer laser underwent phase I clinical trials at three centers to determine its safety for intraoperative coronary laser angioplasty as an adjunct to coronary artery bypass grafting. A 308-nm Xenon-Chloride, pulsed-wave excimer laser was used to perform angioplasty in 30 patients undergoing coronary artery bypass surgery. Forty vessels (30 patients) were treated, in which the extent of occlusion ranged from 30% to 100%, with complete occlusion in 40% of all vessels. Improvement in vessel luminal caliber was achieved in 33 (79%) vessels, with perforations occurring in 4 (12%) vessels, 2 of which required surgical repair. The lumens of the remaining 8 (19%) vessels were not enlarged, and 2 (5%) of these vessels were perforated. Luminal enlargement was most often achieved in totalled occluded vessels in which 16/17 (94%) were recanalized. No patients died within 30 days postoperatively. Five patients demonstrated biochemical and electrocardiographic evidence of myocardial injury 48 hr postoperatively, and one patient died of cardiac arrest 139 days postoperatively. On the basis of these results, we believe that excimer laser angioplasty can be performed safely to improve coronary luminal patency, even in totally occluded vessels, in an operative setting. The long-term value of this procedure remains to be elucidated.

The development of a clinically relevant canine model of postperfusion syndrome.

Investigation into the complex etiology of the postperfusion syndrome (PPS) has been limited by access to only retrospective human case studies, and performance of animal studies that examine biochemical predictors of injury rather than the PPS itself. To determine whether a reproducible canine model of the clinical syndrome was possible, seven dogs underwent cardiopulmonary bypass (CPB) with a bubble oxygenator for 0 (n = 1, sham), 2 (n = 1), 4 (n = 1), and 6 (n = 4) hours. Arterial oxygenation, chest radiographs, serum creatinine, and total leukocyte and platelet counts continued to change through the second postoperative day, illustrating the need for prolonged follow-up (48 hours) to accurately detect postperfusion organ dysfunction. The dogs that did not undergo CPB for 6 hours (n = 3) did not develop important pulmonary dysfunction postoperatively, but three of the four dogs undergoing 6 hours of CPB developed profound, persistent, arterial hypoxemia associated with radiographic, histologic, and hemodynamic evidence of severe PPS. Early evidence of renal dysfunction was also apparent within 84 hours of 6 hour CPB. It is concluded that the canine long duration (6 hour) CPB model, with prolonged (48 hour) postoperative monitoring, generates a reproducible, clinically relevant model of human PPS.