The aim of the study was to use the ovine model to evaluate the hemocompatibility and end-organ effects of a newly developed magnetic suspension centrifugal left ventricular assist device (LVAD) by CH Biomedical Inc., Jiangsu, China. The LVADs were implanted in 6 healthy sheep, where inflow was inserted into the left ventricular apex and outflow was anastomosed to the descending aorta. All sheep received anticoagulation and antiaggregation therapy during the study. Hematologic and biochemical tests were performed to evaluate anemia, hepatorenal function, and the extent of hemolysis. The experiments lasted for up to 30 days on the beating hearts. All sheep were humanely killed at the termination of the experiments, and the end-organs were examined macroscopically and histopathologically. Autopsy was performed in all animals and there was no thrombus formation observed inside the pump. The pump’s inflow and outflow conduits were also free of thrombus. Hematologic and biochemical test results were within normal limits during the study period. Postmortem examination of the explanted organs revealed no evidence of ischemia or infarction. Based on the in vivo study, this LVAD is suitable for implantation and can provide efficient support with good biocompatibility. The encouraging results in this study suggest that it is feasible to evaluate the device’s long-term durability and stability.
The heart failure epidemic is a largely unabated problem, with more than 26 million people affected worldwide [
Few LVADs are clinically used in China partly because of high prices. Development of a less expensive pump for clinic use in China is urgently needed. We designed and manufactured a magnetic suspension third-generation implantable LVAD and conducted experiments to evaluate the hemocompatibility and end-organ effects of the device.
Six healthy adult sheep (weighing
The LVAD is a small, wearless, ultracompact centrifugal blood pump (Figure
The LVAD.
Comparison between of the LVAD and a table tennis ball.
Pressure-volumetric flow rate curve of the LVAD.
We followed a standard institutional anesthesia protocol that has previously been described in detail [
Each sheep was placed in the right lateral decubitus position for a left thoracotomy, while its electrocardiography was monitored. An arterial pressure line was then introduced in the left carotid artery for intraoperative and postoperative blood pressure monitoring. A lidocaine drip (2 mg/min) was initiated to prevent arrhythmias, and intravenous injection of vecuronium bromide (5 mg) was administered to maintain muscle relaxation. A left subcostal thoracotomy was performed at the 4th intercostal space. The pump was filled with saline and restarted to work at least for 5 minutes in order to ensure normal working conditions. The driveline was tunneled to exit near left paraspinal area at the 8th intercostal space and was connected to the external controller. The pericardium was incised after fully exposing the left ventricular apex. The descending thoracic aorta was dissected for outflow graft anastomosis. Heparin (1.5 mg/kg) was given intravenously to keep whole blood activated clotting time (ACT) above 480 s. Sodium nitroprusside (0.5 mg/kg/min) was injected intravenously to control the blood pressure. The descending thoracic aorta was clamped with a side biting clamp (Geister, Inc., Germany) and the 10 mm artificial blood vessels graft (Vascutek-Terumo), which was cut to proper length, was anastomosed with continuous 4-0 Prolene (Ethicon, Inc. USA) suture. The apex was elevated and a sewing ring was sutured circumferentially, to the apex with 10 to 12 interrupted 2-0 Ethibond pledgeted (Johnson, Inc., USA) sutures. Using a scalpel, a cruciform incision was made in the apex on the beating heart. Then the LV core was removed by a conical coring knife through the ventricular sewing ring, and the inflow cannula was inserted into the left ventricular cavity quickly and secured. The LVAD was activated and the pump was deaired through a small-diameter needle inserted into the outflow graft with a pump speed of about 1900 rpm; then the motor speed was initially adjusted to achieve maximum heart unloading. Figure
The process of the pump implantation: (a) outflow graft anastomosis; (b) suturing the sewing ring; (c) removing the LV core; and (d) implanted position of the pump.
During the surgery, penicillin (4.8 million units) was injected intravenously to prevent infection. Protamine was then administered to reverse the effects of heparin. One chest tube was inserted into the pleural cavity, which was closed in accordance with standard technique.
After extubation, the sheep was transferred into a specially designed cage in the observing room for continuous monitoring of heart rate, aortic pressure, and pump flow. Heparin was continuously infused to maintain the activated clotting time (ACT) within 150
During the study, blood samples were taken routinely from the carotid artery for hematologic and biochemical tests. These tests were repeated daily for 10 days and then every 5 days until the end of the study. The pump operating parameters, such as pump flow, pump speed, and power consumption, were recorded continuously by the control software. In addition, the body surface temperature was also measured daily throughout the study.
Heparin (3 mg/kg) was administered just before the sheep were humanely killed in order to prevent postmortem clot formation in the pump. In each case, the LVAD was explanted, opened, and photographed. Any infarcts or focal lesions in any tissue were noted during gross evaluation. The pump housing and impeller were carefully inspected for fibrin formation or thrombus. The inflow and outflow grafts, the aorta, and the ventricle at each cannulation site were also evaluated and photographed.
Routine histologic examination was performed on the heart, lungs, liver, kidneys, and spleen. Blocks of tissue were immersion-fixed in 10% neutral-buffered formalin with a tissue-to-volume fixative ratio of 1 : 10. After 72 hours of fixation, an illustration of the sectioning site was made for each device. Cross sections of the soft-tissue interface with the device were processed with standard paraffin. Two 5-micron-thick sections from each of the sampled regions were stained with hematoxylin-eosin stain.
All six sheep successfully underwent LVAD implantation in 3 hours without CPB and recovered from anesthesia without complications within the first 2 hours. All physiological indexes, including heart rate, respiratory rate, and body temperature, remained within normal ranges during the study period. None of the sheep developed anorexia, respiratory disorders, or neurological disorders.
No notable device-related problems occurred during the whole experiments. Average pump data values ± SD included an average speed of
Values at baseline and at postoperative days 1, 5, 10, 20, and 30 were shown in Table
Mean preoperative and postoperative hematologic and biochemical data.
Preoperative | Day 1 | Day 5 | Day 10 | Day 20 | Day 30 | |
---|---|---|---|---|---|---|
Hematologic data (mean ± SD) | ||||||
White blood cells ×109/L | 10.3 ± 1.6 | 29.9 ± 11.3 | 22.3 ± 8.7 | 15.6 ± 4.6 | 10.3 ± 1.6 | 9.6 ± 1.3 |
Red blood cells ×1012/L | 7.9 ± 1.6 | 5.7 ± 1.1 | 6.2 ± 0.8 | 7.1 ± 0.7 | 7.7 ± 1.1 | 8.1 ± 0.3 |
Hemoglobin, g/L | 107 ± 12.6 | 96 ± 7.7 | 91 ± 6.8 | 68 ± 5.0 | 91 ± 9.3 | 97 ± 8.2 |
Hematocrit, % | 31.14 ± 1.05 | 25.56 ± 2.03 | 25.34 ± 2.17 | 22.97 ± 1.45 | 21.86 ± 1.12 | 21.5 ± 2.13 |
Prothrombin time, sec | 13.2 ± 0.7 | 15.4 ± 1.1 | 20.6 ± 5.12 | 17.2 ± 3.14 | 14.6 ± 1.45 | 14.7 ± 1.12 |
International normalized ratio | 1.22 ± 0.08 | 2.3 ± 1.34 | 3.14 ± 0.89 | 1.46 ± 0.52 | 1.23 ± 0.37 | 1.24 ± 0.18 |
Partial thromboplastin time, sec | 32.35 ± 5.12 | 47.44 ± 4.23 | 57.21 ± 5.18 | 50.3 ± 4.65 | 44.92 ± 3.36 | 39.55 ± 4.63 |
Fibrinogen, mg/dL | 410.1 ± 52.2 | 407.5 ± 45.3 | 387.1 ± 38.9 | 313.7 ± 45.2 | 279.7 ± 36.7 | 222.7 ± 39.8 |
FHB, g/L | 0.039 ± 0.021 | 0.055 ± 0.014 | 0.093 ± 0.035 | 0.066 ± 0.024 | 0.065 ± 0.018 | 0.068 ± 0.026 |
Biochemical data (mean ± SD) | ||||||
SGOT (ALT), U/L | 16.3 ± 2.1 | 40.9 ± 5.2 | 28.5 ± 3.3 | 17 ± 2.9 | 14 ± 1.8 | 15.7 ± 2.3 |
Total bilirubin, Umol/L | 2.1 ± 0.3 | 2.4 ± 0.7 | 3.9 ± 1.1 | 2.7 ± 0.8 | 2.4 ± 0.6 | 2.1 ± 0.8 |
Albumin, g/dL | 2.6 ± 0.2 | 2.1 ± 0.9 | 2.2 ± 0.4 | 2.0 ± 0.5 | 2.3 ± 0.6 | 2.4 ± 0.3 |
AST, U/L | 124.8 ± 89.6 | 259.4 ± 91.2 | 170.8 ± 75.6 | 106.1 ± 57.6 | 103.5 ± 45.9 | 102.3 ± 46.8 |
Glutamyl endopeptidase, U/L | 81.3 ± 35.7 | 65.7 ± 33.6 | 54.3 ± 22.5 | 60.7 ± 17.9 | 64.4 ± 22.1 | 61.1 ± 24.5 |
Serum urea nitrogen, mmol/L | 5.42 ± 1.32 | 10.64 ± 2.89 | 7.36 ± 1.25 | 6.41 ± 1.10 | 5.72 ± 0.89 | 5.33 ± 0.75 |
Creatinine, Umol/L | 76.6 ± 9.32 | 67.4 ± 10.23 | 69.1 ± 11.32 | 70.6 ± 12.69 | 73.2 ± 11.85 | 66.6 ± 13.10 |
Glucose, Umol/L | 3.16 ± 0.28 | 3.65 ± 0.54 | 3.80 ± 0.32 | 3.45 ± 0.49 | 2.54 ± 0.36 | 3.59 ± 0.41 |
SGOT (ALT): serum glutamic-oxaloacetic transaminase (alanine aminotransferase); AST: aspartate aminotransferase.
Gross examination of the pump inflow conduits, the pump interiors, and the impeller surfaces from all sheep showed no remarkable thromboembolic fragments. Necropsy of the main organs of all sheep revealed no lesions. Figure
Pump, blood flow channels: (a) pump body; (b) the outflow graft; and (c) the arterial anastomotic stoma.
The left lung close to the outflow graft protective sleeve parts had lobular pneumonia in all sheep. Histologic examination (Figure
The histopathologic results of the diseased lungs (HE, 200x).
The histopathologic results of case 5 (HE, 100x): (a) liver; (b) spleen; (c) brain; (d) lung; (e) kidney; and (f) myocardium.
The LVAD demonstrated appropriate blood-handling characteristics and reliability in the ovine model for 30 days. The extent of hemolysis was demonstrated to be qualitatively negative throughout the experiments. There was no observation of anemia or hyperbilirubinemia. Therefore, the extent of hemolysis was considered to be within a tolerable range. In contrast to the HeartWare VAD (HeartWare Inc., USA), which utilizes the passive magnetic and hydrodynamic thrust bearings as the hybrid suspension system to drive the impeller, our blood pump utilizes a fully electromagnetic suspended system to create a contact-free rotation of impeller. Moreover, the device here is lighter than the HeartWare VAD. Miniaturization may enable less invasive surgical techniques, treatment of patients with nonstandard cardiac anatomy, right and left ventricular support, and support for a less ill cohort of patients [
Hemorrhagic complication is one of the major events observed during LVAD support [
Most LVADs require partial or total cardiopulmonary bypass support for LV apex cannulation, which increases the surgical time and risk and can further compromise ventricular function in patients who have acute heart failure [
The Thoratec HeartMate II (Thoratec Inc., USA) and the HeartWare HVAD (HeartWare Inc., USA) are currently the 2 most commonly implanted LVADs worldwide [
The authors declare that there is no conflict of interests regarding the publication of this paper.
This work was sponsored by the National High Technology Research and Development Program of China (2012AA041605) and the Capital Health Development Research Fund, Beijing, China (2011-1005-02).