P. Brenner

Early experience with robotic technology for coronary artery surgery

BACKGROUND To achieve an endoscopic coronary bypass anastomoses we performed a study with endoscopic robotic instrumentation and camera guidance using three-dimensional (3-D) visualization. METHODS The surgical robotic system ZEUS (Computer Motion Inc, Goleta, CA) consists of three interactive robotic arms and a control unit allowing the surgeon to move the instrument arms in a scaled down mode. The third arm (AESOP, Computer Motion Inc, Goleta, CA) positions the endoscope via voice control. The study had three phases. Phase I: In a phantom model, end-to-side anastomoses between vein grafts and the left anterior descending coronary artery (LAD) of 109 pig hearts were performed. Phase II: In 6 dogs (FBI, 20-25 kg) the left internal mammary artery (LIMA) was harvested endoscopically. During Port-Access (Heartport Inc, Redwood City, CA) cardiopulmonary bypass (CPB), LIMA and LAD were then anastomosed endoscopically with the help of telemetric ZEUS instruments (Computer Motion Inc). Phase III: A total of seven patients were operated on with help of the ZEUS system (Computer Motion Inc). After endoscopic LIMA harvesting and CPB using the Port-Access (Heartport Inc) system, the bypass graft (LIMA to LAD) was anastomosed endoscopically through three thoracic ports in 2 patients. Another 3 patients were operated on off-pump with regional stabilization and 2 patients with sternotomy and routine CPB. RESULTS The practice with the phantom model and the subsequent animal experiments allowed the surgeons to gain sufficient experience for the clinical setting. In the clinical cases, times for anastomoses ranged from 20 to 42 minutes. Median internal mammary artery flow rate was 74 mL per minute (range 36-110 mL per minute). One patient in the off-pump group was converted to CPB and routine anastomosis. All patients had an uneventful angiographic control and postoperative course. CONCLUSIONS Using telemetic technology, a completely endoscopic anastomosis of LIMA to LAD is possible on the arrested heart, as well as on the beating heart.

Reduction of systemic and cardiac adhesion molecule expression after off-pump versus conventional coronary artery bypass grafting.

ABSTRACT Cardiopulmonary bypass (CPB) and operative trauma are associated with increased expression of pro‐ inflammatory mediators. We determined the relative contribution of CPB on activation of cytokines and adhesion molecules in patients undergoing coronary revascularization by comparing them with patients receiving off‐pump coronary artery bypass grafting (OPCAB). Twenty‐six patients were assigned to either the OPCAB procedure using a suction device and regular sternotomy (n = 13), or were treated conventionally using extracorporeal circulation, blood cardioplegia, and hypothermic arrest (29°C‐31°C; n = 13). Systemic levels of TNF‐&agr; and the soluble adhesion molecules P‐selectin and intracellular adhesion molecule 1 (ICAM‐1) were assayed. Immunohistochemistry was used to account for cardiac‐specific expression of adhesion molecules in interventricular endomyocardial sections. Both systemic and endomyocardial expres‐ sion of adhesion molecules were lower in the OPCAB group. Coronary revascularization with CPB resulted in a significant higher expression of TNF‐&agr;, which was associated with P‐selectin and ICAM‐1 expression. This was accompanied with higher catecholamine requirement in the CPB group in the early postoperative period. Despite comparable surgical trauma, the OPCAB procedure without the use of CPB and cardioplegic arrest significantly reduces systemic and cardiac adhesion molecule expression and catecholamine requirement. Since the clinical course in the early postoperative period was comparable, larger trials are required to select the appropria te patient who benefits most from one or the other treatment regime.

First experience with heterotopic thoracic pig-to-baboon cardiac xenotransplantation

Bauer A, Postrach J, Thormann M, Blanck S, Faber C, Wintersperger B, Michel S, Abicht J‐M, Christ F, Schmitz C, Schmoeckel M, Reichart B, Brenner P. First experience with heterotopic thoracic pig‐to‐baboon cardiac xenotransplantation.
Xenotransplantation 2010; 17: 243–249.

Administration of GAS914 in an orthotopic pig‐to‐baboon heart transplantation model

Abstract:  Background:  Long‐term survival of transgenic cardiac xenografts is currently limited by a form of humoral rejection named acute vascular rejection. Preformed and elicited cytotoxic antibodies against Galα(1,3)Gal terminating carbohydrate chains, known as the primary cause of hyperacute rejection, are crucial for this process. We investigated whether GAS914, a soluble, polymeric form of a Galα(1,3)Gal trisaccharide would sufficiently minimize xenograft rejection of hDAF‐transgenic pig hearts orthotopically transplanted into baboons.

Detection of coronary artery bypass graft patency by contrast enhanced magnetic resonance angiography

OBJECTIVE The subject and purpose of the prospective study was to delineate coronary artery bypass graft (CABG) course and to determine patency of aortocoronary venous bypass grafts (ACVB) compared with internal mammary artery bypass grafts (IMA) in the early postoperative follow-up, by contrast enhanced magnetic resonance angiography (MRA). For control, patients were examined with X-ray angiography and spiral-computed tomography (CT). METHODS Eighty-five patients (74 male/11 female) with a mean age of 63.7 years underwent MRA examination, applying contrast enhanced gradient-echo sequence after an average distance of 7 days from CABG surgery. A 1.5 Tesla magnetom vision (Siemens, Erlangen, Germany) with phased array coil technology was used. Overall, 247 bypass grafts (160 ACVB/87 IMA) were studied with a 3D (three dimensional) ultrashort TE gradient-echo sequence (TR/TE/a:5 ms/2 ms/40 degrees) with 512*512 matrix and 500 mm FoV in single breath-hold technique after Gd-DTPA bolus injection. CABGs were judged in three different parts, including the course of CABG and both anastomoses. CABGs were controlled by angiography and spiral-CT to examine sensitivity, specificity and efficiency of MRA examination. Additional measurement of bypass graft flow velocity of arterial and venous grafts was performed with 2D phase contrast technique in breath-hold technique with ECG triggering. RESULTS One hundred and thirty-nine of 160 (86.9%) ACVB grafts and 83 of 87 (95.4%) IMA grafts could be visualized. Suspected occlusions of 10 CABGs were confirmed in 80% with a second modality. Five CABGs were false positive in MRA. MRA proved a high specificity (93.8%), sensitivity (89.9%) and efficiency (1.73), especially in detection of IMA to LAD and ACVB to LAD and RCA (Table 1). 3D maximum intensity projection (MIP) reconstruction was helpful in delineating CABG course and in several cases in detecting stenosis of coronary arteries. Results of flow velocity showed a significant higher mean systolic velocity in arterial bypasses than in venous grafts with a higher maximum velocity in systole than in diastole in both grafts. Bypass stenosis in distal anastomosis could not be verified with MRA and flow method. CONCLUSION Contrast enhanced 3D ultrashort TE gradient-echo magnetic resonance angiography has the potential for being a reliable method for CABG visualization and CABG patency determination in the early postoperative period. MR flow measurement was not qualified for detection of a bypass stenosis.

IG-therasorb immunoapheresis in orthotopic xenotransplantation of baboons with landrace pig hearts.

BACKGROUND The major problem of xenotransplantation is, that hyperacute xenograft rejection (HXR) causes graft failure within minutes or a few hours because of natural antibodies and activation of the complement system. As a preclinical model we transplanted pig hearts orthotopically into baboons. To prevent HXR after orthotopic xenotransplantation (oXHTx), the immunoglobulins (Ig) and natural antibodies were adsorbed to reusable Ig-Therasorb immunoadsorption (IA) columns. METHODS We performed three oXHTx of landrace pig hearts into baboons (19+/-6.8 kg), using extracorporeal circulation (ECC) connected to the IA unit. After separating the recipients blood into plasma and cellular fraction by a plasma filter, plasma flow was directed to the Ig-Therasorb column coated with polyclonal sheep-antibodies against human IgG, IgM, and IgA. Intraoperative treatment consisted of 4 cycles of IA. For a control, we transplanted one pig heart into a baboon (16.9 kg) without applying IA. Perioperatively, serum concentrations of Ig, anti-pig-antibodies, complement and cardiac enzymes were determined. Tissue samples of myocardium were collected at the end of the study for immunohistochemical examinations, light microscopic examination (LM) and electron microscopic examination (EM). For cardiac monitoring after oXHTx, we used ECG, echocardiography, and invasive measurement of cardiac output. To prevent a mismatch of donor and recipient heart size, the donor pig had a 30-40% lower body weight than the recipient baboon. RESULTS Four cycles of IA removed >80% of IgG, IgM, and IgA from plasma. The graft of the control animal failed after 29 min. The first oXHTx with IA was intentionally terminated after 100 min, the second oXHTx after 11 hr and the third oXHTx after 21 hr. All xenografts showed no histological signs of HXR. After weaning off ECC, these donor hearts worked in sinus rhythm without electrocardiographic ST-segment elevation. An excellent cardiac output was measured by echocardiography and thermodilution (2 L/min). Serological parameters indicating cardiac damage were significantly lower after IA if compared with the control experiment. Macroscopically, the xenograft of the control animal showed massive hemorrhage in comparison with the almost inconspicuous grafts after IA. The myocardium of the IA group demonstrated fewer deposits of Ig and complement components compared with the control animal. CONCLUSION Baboons do not hyperacutely reject a porcine xenograft after antibody depletion by the Ig-Therasorb column. In our experiment only 4 cycles of immunoapheresis effectively prevented HXR after oXHTx of baboons. The Ig-Therasorb column is a reusable device, which can be handled easily in combination with the ECC. IA must be tested in oXHTx longterm survival experiments, especially in combination with transgenic pig organs, which could be a reliable preclinical approach for future clinical xenotransplantation.

Extracorporeal membrane oxygenation in 108 patients with low cardiac output – a single-center experience

Background For short-term ventricular and pulmonary support the extracorporeal membrane oxygenation (ECMO) system using the Bio-Medicus centrifugal pump (Medtronic®, Minneapolis, MN, USA) was applied in 108 patients with cardiac low-output. Methods From December 1996 to July 2006 the ECMO was implanted in 108 patients (73 adult, mean age: 49.3±18.0 yrs and 35 children, mean age: 1.3 ± 2.7 yrs) with mostly postcardiotomy cardiac low output. The surgical procedures included congenital heart surgery (n=35), heart transplantation (HTx) (n=21), coronary artery bypass operation (CABG) and/or valvular operation (n=33), other operations (n=6) and 13 patients with ECMO support for bridge to recovery. Results The mean supporting time was 5.1±5.6 days. Overall, 30-day-survival was 40.2%. Best survival rates were seen after congenital heart surgery (24/35, 65.7%) and after HTx (9/21, 42.9%); the worst rates were in the group of CABG and/or valvular operations (5/33, 15.2%), only ECMO support (3/13, 23.1%) and other operations (1/6, 16.7%). Fifty-four patients died while supported by ECMO, 15 were weaned from ECMO but died in hospital, 39 patients were weaned and survived. Causes of death were multi-organ failure (40.6%), bleeding (23.2%), persistent cardiac low output (21.7%), thrombembolic events (8.7%), and graft failure (5.8%). Markers for adverse outcome were identified as older age, high body weight, increased AST/GOT levels, and lower thrombocyte count in adults; and as higher levels of serum creatinine in pediatric patients. Conclusions ECMO support showed best results in pediatric patients after congenital heart surgery and in patients after HTx in contrast to multimorbid, older patients with often irreversible myocardial damage.

The influence of antibody and complement removal with a Ig-Therasorb column in a xenogeneic working heart model

OBJECTIVE Organ transplantation is limited by the number of brain-dead human donors. Xenotransplantation could be an alternative to guarantee a constant supply of organs. A major problem of xenotransplantation are xenogeneic natural antibodies (XNAb) directed against species-specific antigens of a discordant donor species (e.g. pig). They trigger the hyperacute xenograft rejection (HXR). Re-usable immunoapheresis (LA)-columns Ig-Therasorb (Therasorb, Baxter) were used to adsorb these XNAb. The effect of immunoapheresis of the perfusing human blood was investigated in ex vivo working pig hearts. METHODS Hearts of 12 landrace pigs (body weight 14-31 kg) were explanted after inducing cardiac arrest with 4 degrees C Celsior solution. Human blood (500 ml, heparinized) was obtained from healthy volunteers. In group 1 (G1, n = 6), blood as perfusate remained untreated. In group 2 (G2, n = 6), native blood was separated by plasmapheresis into cellular components and plasma. The latter passed through the Ig-Therasorb column for removal of immunoglobulins (so-called immunoadsorption or immunoapheresis). After back-table preparation the hearts were mounted to the working heart model. After 20 min of reperfusion in Langendorff mode, the working heart mode was established. Blood samples were taken isochronously for measurement of: CK(-MB), LDH, ASAT, troponin, immunoglobulins, complement activity, anti-pig antibodies and others. After cessation of the heart, atrial and ventricular tissue samples were taken for histological examinations (light/electron microscopy and immunohistochemistry). RESULTS Two cycles of immunoapheresis reduced the levels of IgG by 84%, IgM by 83.3% and IgA by 76%. In G2, the antibody immunoadsorption of blood prolonged the duration of the working heart mode significantly to 335+/-37.5 min. In contrast, hearts of group 1 (control) failed after 125+/-31.3 min. Heart rate was significantly different between both groups (G1, 77.3+/-6.1 beats/min; G2, 86.5+/-5.5 beats/min). In G2 cardiac output was 118% and mean coronary flow was 154.6% higher than in G1. CK, LDH and ASAT showed no differences in the two groups. Heart weight increased significantly more in group 1 than in G2. Histological examination indicated specific signs of HXR in G1 after 1.5 h, whereas in G2 only slight unspecific damages were found after 6 h. CONCLUSION Antibody removal by means of immunoapheresis results in a significantly improved xenogeneic cardiac function. Immunoapheresis may, therefore, become an important adjunct in future pig-to-man clinical xenotransplantation.

Prevention of hyperacute xenograft rejection in orthotopic xenotransplantation of pig hearts into baboons using immunoadsorption of antibodies and complement factors

Abstract To prevent hyperacute xenograft rejection (HXR) caused by preformed natural antibodies (XNAb) after orthotopic heart xenotransplantation (oXHTx) of landrace pig hearts into baboons, we used immunoadsorption of immunoglobulins IgG, IgM and IgA and complement with the reusable Ig‐Therasorb column. In addition to functional data, tissue was sampled for histological, immunohistochemical and electron microscopical analysis. We performed three oXHTx of landrace pig hearts to baboons using extracorporeal circulation (ECC) connected to the immunoadsorption unit. Intraoperative treatment consisted of four cycles of immunoabsorption (IA). One oXHTx of a baboon without IA served as a control. A mismatch of donor and recipient heart size was prevented by selecting a 30‐40% lower body weight of donor pigs than recipients. Four cycles of IA removed more than 80% of IgG, IgM and IgA, 86% of anti‐pig antibodies and 66% of complement factors C3 and C4 from plasma. The graft of the control animal failed after 29 min. Orthotopic xenotransplantation with IA was selectively terminated after 100 min, 11 h and 21 h, respectively without any histological signs of HXR in light and electron microscopy. After weaning off from ECC these donor xenografts showed sufficient function with normal ECG and excellent cardiac output in echocardiography and invasive measurement (1.93 ± 0.035 l/min). The myocardium of the control xenograft demonstrated more deposits of Ig and complement components (C3, C4) than in the IA group. Baboons survive HXR after orthotopic pig heart xenotransplantation due to antibody depletion by reusable Ig‐Therasorb column treatment. Long‐term survival in an orthotopic baboon xenotransplantation model after IA, especially in combination with transgenic pig organs, could be a reliable preclinical trial for future clinical xenotransplantation programs.

Pre‐clinical heterotopic intrathoracic heart xenotransplantation: a possibly useful clinical technique

As a step towards clinical cardiac xenotransplantation, our experimental heterotopic intrathoracic xenotransplantation model offers a beating and ejecting donor heart while retaining the recipient′s native organ as a backup in case of graft failure. Clinically applicable immunosuppressive regimens (IS) were investigated first, then treatments known to be effective in hypersensitized patients or those with recalcitrant rejection reactions.