Novel implantable device to detect cardiac allograft rejection.

BACKGROUND: Allograft rejection remains the nemesis of solid organ transplantation. Soul Mate is a novel implantable wireless data transmission system that analyzes 9 intramyocardial electrogram parameters recorded from 4 or 6 configurations of 2 or 3 epicardial leads to detect allograft rejection. This study determined the ability of the Soul Mate to detect early rejection of transplanted hearts. METHODS AND RESULTS: Five dogs underwent heterotopic cervical heart transplantation and simultaneous implantation of the Soul Mate's Cardiac Rejection Monitoring Device. Dogs were initially immunosuppressed, but subsequent drug discontinuation allowed allograft rejection to appear. Allograft biopsies were performed at regular intervals to determine rejection grade, which was compared to a calculated rejection score determined as percent change from baseline of values for each intramyocardial electrogram. There was significant correlation between the biopsy results and the evolution of 5 parameters. The strongest correlation (r=0.939; P<0.001) was obtained using the "general median" parameter from 4 configurations, assessed 1 day before the biopsy, with a sensitivity of 85.7% and a specificity of 100% compared to the myocardial biopsy results. CONCLUSIONS: The Soul Mate allograft rejection monitoring system accurately detected transplanted heart rejection in a canine model noninvasively with continuous sampling. This proof-of-concept study suggests that the Soul Mate could be used to more intensely and more frequently monitor cardiac allografts for rejection.

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.

Functional roles of 3'-terminal structures of template RNA during in vivo retrotransposition of non-LTR retrotransposon, R1Bm.

R1Bm is a non-LTR retrotransposon found specifically within 28S rRNA genes of the silkworm. Different from other non-LTR retrotransposons encoding two open reading frames (ORFs), R1Bm structurally lacks a poly (A) tract at its 3' end. To study how R1Bm initiates reverse transcription from the poly (A)-less template RNA, we established an in vivo retrotransposition system using recombinant baculovirus, and characterized retrotransposition activities of R1Bm. Target-primed reverse transcription (TPRT) of R1Bm occurred from the cleavage site generated by endonuclease (EN). The 147 bp of 3'-untranslated region (3'UTR) was essential for efficient retrotransposition of R1Bm. Even using the complete R1Bm element, however, reverse transcription started from various sites of the template RNA mostly with 5'-UG-3' or 5'-UGU-3' at their 3' ends, which are presumably base-paired with 3' end of the EN-digested 28S rDNA target sequence, 5'-AGTAGATAGGGACA-3'. When the downstream sequence of 28S rDNA target was added to the 3' end of R1 unit, reverse transcription started exactly from the 3' end of 3'UTR and retrotransposition efficiency increased. These results indicate that 3'-terminal structure of template RNA including read-through region interacts with its target rDNA sequences of R1Bm, which plays important roles in initial process of TPRT in vivo.

Large aneurysm in saphenous vein coronary artery graft with fistula: case report and review.

Aneurysms developing in a saphenous vein graft (SVG) after coronary artery bypass grafting (CABG) are an unusual complication and fistulae forming between an SVG aneurysm and a cardiac chamber are even rarer. A 71-year-old man had undergone a triple CABG with the left internal thoracic artery and double SVGs. Twenty years later, he was admitted with repeated congestive heart failure. A large true aneurysm (99 × 60 mm) developed in the mid portion of a saphenous vein graft to the right coronary artery together with a fistula with a diameter of 8 mm in the right atrium. The aneurysm was surgically resected and the fistula was closed.

Analysis of temporal patterns of GPCR-ß-arrestin interactions using split luciferase-fragment complementation.

We developed bioluminescence probes to detect quantitative interaction of GPCRs with arrestin isoforms ß-arrestin1 and ß-arrestin2 based on split luciferase complementation. Time-dependent GPCR-ß-arrestin interactions showed two-types of remarkable variations that were consistent with a classification of GPCR classes. Positive charge residues in serine clusters located at the C-terminal region of GPCRs were necessary for binding to ß-arrestin. This quantitative method enables elucidation of the mechanisms of different classes of GPCRs that regulate ß-arrestin isoforms.

Left atrial appendage occlusion: pilot study of a fourth-generation, minimally invasive device.

OBJECTIVE: Exclusion of the left atrial appendage is proposed to reduce the risk of stroke in patients with atrial fibrillation. The aim of this study was to evaluate the feasibility and efficacy of a fourth-generation atrial exclusion device developed for minimally invasive applications. METHODS: The novel atrial exclusion device consists of two polymer beams and two elastomeric bands that connect the two beams at either end. Fifteen mongrel dogs were implanted with the device at the base of the left atrial appendage through a median sternotomy and were evaluated at 30 (n = 7), 90 (n = 6), and 180 (n = 2) days after implantation by epicardial echocardiography, left atrial and coronary angiography, gross pathology, and histology. RESULTS: Left atrial appendage exclusion was completed without hemodynamic instability. Coronary angiography revealed that the left circumflex artery was patent in all cases. A new endothelial tissue layer developed, as expected, on the occluded orifice of the left atrium. CONCLUSIONS: This novel atrial exclusion device achieved easy, reliable, and safe exclusion of the left atrial appendage, with favorable histological results in a canine model for up to 6 months. Clinical application could provide a new therapeutic option for reducing the risk of stroke in patients with atrial fibrillation.

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.

A pilot study for inducing chronic heart failure in calves by means of oral monensin.

INTRODUCTION: Heart failure remains a major cause of mortality in the United States, despite advancing technologies, newer methods of treatment, and novel devices. To evaluate such novel devices, a large-animal model of chronic heart failure is critical in carrying out preclinical animal studies. METHODS: We evaluated the efficacy of oral monensin in inducing stable heart failure in five Jersey calves. Various doses of monensin were administered. Hemodynamics, pressure-volume loops, echocardiographic measurements, extent of tissue perfusion, and histopathologic data were recorded before and after induction of heart failure. RESULTS: Responses were variable in the animals. One experiment showed a significant decrease in cardiac output within one week, associated with simultaneous increases in left atrial pressure, central venous pressure, and mean pulmonary artery pressure. Left ventricular pressure-volume loops showed that the slope of the end-systolic pressure-volume relation decreased markedly between the baseline and terminal study, suggesting a decrease in contractility. Echocardiographic studies indicated a decrease in ejection fraction. Histopathologic analysis in cardiac tissue showed extensive fibrosis and necrosis. CONCLUSION: We demonstrated the feasibility of inducing and maintaining severe yet stable heart failure for up to 3 weeks in a calf model by administration of oral monensin.

Extensive total arch replacement via clamshell incision in a patient with aortic arch aneurysm and Stanford type B aortic dissection.

The utility of the clamshell approach, namely, a bilateral anterior thoracotomy incision for treating extensive thoracic aortic disease was described by Kouchoukos et al. in 2001 and by Doss et al. in 2003. We describe the utility of this approach for treating aortic arch aneurysm with Stanford type B aortic dissection.

Median sternotomy approach for chronic bovine experiments.

Lateral thoracotomy is the traditional surgical approach for preclinical animal testing of various ventricular assist devices. Median sternotomy, however, is regarded from a functional standpoint as the most appropriate approach for cardiac surgical procedures, particularly for device implantation. The purpose of this study was to evaluate the outcomes of performing a median sternotomy in chronic bovine studies. Three chronic studies using the sternotomy approach were performed. Surgical access was compared to the lateral thoracotomy approach used in three other animal experiments. Postoperative speed of recovery, pain management, sternotomy incision, and monitoring line exit site healing and infection were also evaluated. With sternotomy, better surgical access to all cardiac chambers and great vessels and more room for device placement were achieved. The recovery time was similar to that using the lateral thoracotomy approach, with no additional difficulties observed in standing or recumbency and no need for increased pain management. At the time of autopsy, the sternum was well healed without any sign of infection. In conclusion, these studies showed that a median sternotomy can be used successfully for chronic bovine studies. This approach will be used for our future biventricular assist device implantation surgeries.

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.

Implantation of a mechanical valve in a previously implanted mitral bioprosthetic orifice in a patient with mitral bioprosthetic failure.

Complete removal of a previously implanted dysfunctional mitral bioprosthesis could result in extensive damage. Therefore, a 66-year-old female patient with a deteriorated mitral bioprosthesis had leaflet excision, and a "new" mechanical valve was sewn onto the previously implanted bioprosthetic sewing cuff. On postoperative echocardiography, the implanted valve had good hemodynamic performance with no paravalvular leakage. The patient's clinical condition improved after surgery.

Feasibility study of a direct endo-aortic clamp balloon.

We have developed a new end-aortic clamp balloon catheter intended to be inserted directly into, thereby occluding, the ascending aorta. We examined the performance of this catheter in a canine model. We evaluated the extent of migration tolerance of the catheter under cardiopulmonary bypass perfusion in 12 mongrel dogs, weighing 20 kg, under general anesthesia. After institution of cardiopulmonary bypass, this catheter was inserted into the ascending aorta, and the balloon was inflated to occlude the ascending aorta. After the canine heart was arrested following the administration of cardioplegic solution, balloon migration was examined over a period of 3 hours, with hourly increases in perfusion pressure from 50 mm Hg to 80 mm Hg and finally to 100 mm Hg. After the migration test, ascending aortic wall sections, where the balloon was inflated, were examined microscopically. At internal balloon pressure of 300 to 400 mm Hg, migration occurred at perfusion pressure of > or =90 to 100 mm Hg. No histological differences were observed with use of the balloon catheter, compared with an extra-aortic clamp forceps. Based on these results, this device is safe, feasible, and can adequately occlude the ascending aorta during cardiopulmonary bypass. We conclude that this device is effective in patients weighing 20 kg.

Repeated transluminal endovascular Inoue stent graft placement for progressive dilatation of prosthetic graft that had been repaired with Inoue stent graft placement for dilatation 23 years after extraanatomical bypass.

A 76-year-old man had undergone aneurysm exclusion and ascending abdominal aortic extraanatomical bypass for a thoracoabdominal aortic aneurysm in 1978. In 1983 hemoptysis occurred, and resection and closure of the central stump of the aorta and a left lower lobectomy were performed. Dilatation (phi50 mm) of a prosthetic graft (Cooley Graft phi18 mm) used for extraanatomical bypass was noted in 2001 and was repaired by placement of an Inoue stent graft. However, the aneurysm diameter increased further (phi70 mm), although no endoleak was noted: Placement of an Inoue stent graft covering the whole length of the prosthetic graft was repeated in 2006. The postoperative course was smooth, no endoleak occurred, and the patient was discharged 2 weeks after surgery.

Crystal structure of the endonuclease domain encoded by the telomere-specific long interspersed nuclear element, TRAS1.

The telomere-specific long interspersed nuclear element, TRAS1, encodes an endonuclease domain, TRAS1-EN, which specifically cleaves the telomeric repeat targets (TTAGG)n of insects and (TTAGGG)n of vertebrates. To elucidate the sequence-specific recognition properties of TRAS1-EN, we determined the crystal structure at 2.4-A resolution. TRAS1-EN has a four-layered alpha/beta sandwich structure; its topology is similar to apurinic/apyrimidinic endonucleases, but the beta-hairpin (beta10-beta11) at the edge of the DNA-binding surface makes an extra loop that distinguishes TRAS1-EN from cellular apurinic/apyrimidinic endonucleases. A protein-DNA complex model suggests that the beta10-beta11 hairpin fits into the minor groove, enabling interaction with the telomeric repeats. Mutational studies of TRAS1-EN also indicated that the Asp-130 and beta10-beta11 hairpin structure are involved in specific recognition of telomeric repeats.