Long-Term Follow-Up of Mechanical Circulatory Support in Peripartum Cardiomyopathy (PPCM) Refractory to Medical Management: A Multicenter Study.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is a rare, life-threatening form of heart disease, frequently associated with gene alterations and, in some cases, presenting with advanced heart failure. Little is known about ventricular assist device (VAD) implantation in severe PPCM cases. We describe long-term follow-up of PPCM patients who were resistant to medical therapy and received mechanical circulatory support or heart transplant. METHODS AND RESULTS: A total of 13 patients were included with mean follow-up of eight years. Mean age of PPCM onset was 33.7 ± 7.7 years. All patients were initially treated with angiotensin-converting enzyme inhibitors and beta-blockers, and four received bromocriptine. Overall, five patients received VADs (three biventricular, two isolated left ventricular) at median 27 days (range: 3 to 150) following childbirth. Two patients developed drive line infection. Due to the short support time, none of those patients had a stroke or VAD thrombosis. In total, five patients underwent heart transplantation, of which four previously had implanted VADs. Median time to transplantation from PPCM onset was 140 days (range: 43 to 776), and time to transplantation from VAD implantation were 7, 40, 132, and 735 days, respectively. All patients survived until most recent follow up, with the exception of one patient who died following unrelated abdominal surgery two years after PPCM recovery. CONCLUSIONS: In patients with severe, life-threatening PPCM refractory to medical management, mechanical circulatory support with or without heart transplantation is a safe therapeutic option.

Cold non-ischemic heart preservation with continuous perfusion prevents early graft failure in orthotopic pig-to-baboon xenotransplantation.

BACKGROUND: Successful preclinical transplantations of porcine hearts into baboon recipients are required before commencing clinical trials. Despite years of research, over half of the orthotopic cardiac xenografts were lost during the first 48 hours after transplantation, primarily caused by perioperative cardiac xenograft dysfunction (PCXD). To decrease the rate of PCXD, we adopted a preservation technique of cold non-ischemic perfusion for our ongoing pig-to-baboon cardiac xenotransplantation project. METHODS: Fourteen orthotopic cardiac xenotransplantation experiments were carried out with genetically modified juvenile pigs (GGTA1- KO/hCD46/hTBM) as donors and captive-bred baboons as recipients. Organ preservation was compared according to the two techniques applied: cold static ischemic cardioplegia (IC; n = 5) and cold non-ischemic continuous perfusion (CP; n = 9) with an oxygenated albumin-containing hyperoncotic cardioplegic solution containing nutrients, erythrocytes and hormones. Prior to surgery, we measured serum levels of preformed anti-non-Gal-antibodies. During surgery, hemodynamic parameters were monitored with transpulmonary thermodilution. Central venous blood gas analyses were taken at regular intervals to estimate oxygen extraction, as well as lactate production. After surgery, we measured troponine T and serum parameters of the recipient's kidney, liver and coagulation functions. RESULTS: In porcine grafts preserved with IC, we found significantly depressed systolic cardiac function after transplantation which did not recover despite increasing inotropic support. Postoperative oxygen extraction and lactate production were significantly increased. Troponin T, creatinine, aspartate aminotransferase levels were pathologically high, whereas prothrombin ratios were abnormally low. In three of five IC experiments, PCXD developed within 24 hours. By contrast, all nine hearts preserved with CP retained fully preserved systolic function, none showed any signs of PCXD. Oxygen extraction was within normal ranges; serum lactate as well as parameters of organ functions were only mildly elevated. Preformed anti-non-Gal-antibodies were similar in recipients receiving grafts from either IC or CP preservation. CONCLUSIONS: While standard ischemic cardioplegia solutions have been used with great success in human allotransplantation over many years, our data indicate that they are insufficient for preservation of porcine hearts transplanted into baboons: Ischemic storage caused severe impairment of cardiac function and decreased tissue oxygen supply, leading to multi-organ failure in more than half of the xenotransplantation experiments. In contrast, cold non-ischemic heart preservation with continuous perfusion reliably prevented early graft failure. Consistent survival in the perioperative phase is a prerequisite for preclinical long-term results after cardiac xenotransplantation.

Impact of porcine cytomegalovirus on long-term orthotopic cardiac xenotransplant survival.

Xenotransplantation using pig organs has achieved survival times up to 195 days in pig orthotopic heart transplantation into baboons. Here we demonstrate that in addition to an improved immunosuppressive regimen, non-ischaemic preservation with continuous perfusion and control of post-transplantation growth of the transplant, prevention of transmission of the porcine cytomegalovirus (PCMV) plays an important role in achieving long survival times. For the first time we demonstrate that PCMV transmission in orthotopic pig heart xenotransplantation was associated with a reduced survival time of the transplant and increased levels of IL-6 and TNFα were found in the transplanted baboon. Furthermore, high levels of tPA-PAI-1 complexes were found, suggesting a complete loss of the pro-fibrinolytic properties of the endothelial cells. These data show that PCMV has an important impact on transplant survival and call for elimination of PCMV from donor pigs.

Hemodynamic evaluation of anesthetized baboons and piglets by transpulmonary thermodilution: Normal values and interspecies differences with respect to xenotransplantation.

BACKGROUND: Transpulmonary thermodilution is well established as a tool for in-depth hemodynamic monitoring of critically ill patients during surgical procedures and intensive care. It permits easy assessment of graft function following cardiac transplantation and guides post-operative volume and catecholamine therapy. Since no pulmonary catheter is needed, transpulmonary thermodilution could be useful in experimental cardiac pig-to-baboon xenotransplantation. However, normal values for healthy animals have not yet been reported. Here, we present data from piglets and baboons before xenotransplantation experiments and highlight differences between the two species and human reference values. METHODS: Transpulmonary thermodilution from baboons (body weight 10-34 kg) and piglets (body weight 10-38kg) were analyzed. Measurements were taken in steady state after induction of general anesthesia before surgical procedures commenced. Cardiac index (CI), mean arterial pressure (MAP), systemic vascular resistance index (SVRI), parameters quantifying cardiac filling (global end-diastolic volume index, GEDI), and pulmonary edema (extravascular lung water, ELWI) were assessed. RESULTS: Preload, afterload, and contractility parameters clearly correlated with total body weight or body surface area. Baboons had lower CI values than weight-matched piglets (4.2 ± 0.9l/min/m2 vs 5.3 ± 1.0/min/m2 , P < .01). MAP and SVRI were higher in baboons than piglets (MAP: 99 ± 22 mm Hg vs 62 ± 11 mm Hg, P < .01; SVRI: 1823 ± 581 dyn*s/cm5 *m2 vs 827 ± 204 dyn*s/cm5 *m2 , P < .01). GEDI and ELWI did differ significantly between both species, but measurements were within similar ranges (GEDI: 523 ± 103 mL/m2 vs 433 ± 78 mL/m2 , P < .01; ELWI: 10 ± 3 mL/kg vs 11 ± 2 mL/kg, P < .01). Regarding adult human reference values, CI was similar to both baboons and piglets, but all other parameters were different. CONCLUSIONS: Parameters of preload, afterload, and contractility differ between baboons and piglets. In particular, baboons have a much higher afterload than piglets, which might be instrumental in causing perioperative xenograft dysfunction and post-operative myocardial hypertrophy after orthotopic pig-to-baboon cardiac xenotransplantation. Most transpulmonary thermodilution-derived parameters obtained from healthy piglets and baboons lie outside the reference ranges for humans, so human normal values should not be used to guide treatment in those animals. Our data provide reference values as a basis for developing algorithms for perioperative hemodynamic management in pig-to-baboon cardiac xenotransplantation.

Risk Factors and Outcome of Post Fallot Repair Junctional Ectopic Tachycardia (JET).

BACKGROUND: Junctional ectopic tachycardia (JET) is a common arrhythmia causing hemodynamic impairment following corrective cardiac surgery such as tetralogy of Fallot (TOF) repair. METHODS: We report our experience with postoperative JET following surgical repair of TOF. The retrospective study was done from 2003 to 2012 with a total of 105 patients who underwent TOF repair. These patients' clinical and electrocardiographic data (pre-, intra-, and postoperative) were monitored to identify risk factors for the occurrence of JET and to evaluate the outcome of the affected patients. RESULTS: Incidence-Fourteen patients developed JET, with only four patients going directly from sinus rhythm to JET. In all others, either a transient atrioventricular (AV) block or a junctional rhythm preceded JET, mostly intraoperatively, showing a significant relation ( P = .010). Age-Patients with JET were of younger age ( P = .025) and had longer cardiopulmonary bypass ( P = .044) and aortic cross-clamping times ( P = .038). Increased cost and care-The occurrence of JET was associated with a longer stay in the intensive care unit (ICU) and a prolonged need for inotropic support and mechanical ventilation. Time to rate control correlated with length of ICU and hospital stay. MORTALITY: All JET patients converted into sinus rhythm, one of them died shortly after cessation of JET and two patients subsequently developed a first-degree AV block. CONCLUSION: The occurrence of JET remains an important complication during the initial postoperative period by increasing mechanical ventilation time, the need for inotropic support, and prolonging the length of ICU and hospital stay. Risk factors are younger age, longer aortic cross-clamping/bypass times, and intraoperative arrhythmias.

Perioperative Telemetric Monitoring in Pig-to-Baboon Heterotopic Thoracic Cardiac Xenotransplantation.

BACKGROUND Perioperative monitoring and hemodynamic management after heterotopic thoracic cardiac xenotransplantation is challenging due to 2 independently beating hearts. Telemetry allows continuous monitoring of hemodynamic parameters of both the donor and recipient hearts. We describe our experience and report on the validity of a telemetric system during and after surgery. MATERIAL AND METHODS Wireless telemetry transmitters were implanted in 3 baboons receiving porcine donor hearts. Left ventricular pressure and ECG were assessed from the donor heart, whereas aortic pressure and temperature were assessed from the recipient. Telemetric data were validated with invasive blood pressure measurements. RESULTS Telemetric blood pressure was lower than invasive blood pressure. Intraoperatively, the probe in the graft's left ventricle measured negative end-diastolic pressures. Telemetry allowed simple discrimination between donor's and recipient's heart rates. Body temperature was underestimated by telemetry. Telemetric monitoring facilitates recognition of graft arrhythmias and volume demand. CONCLUSIONS In heterotopic thoracic cardiac xenotransplantation, telemetric implants are useful tools to continuously monitor the animals' hemodynamic parameters and to discriminate donor and recipient organs. Accuracy is sufficient for systemic pressure measurement, but perioperative use of left ventricular end-diastolic pressure as a surrogate parameter for graft function is not advisable. Temperature measurements by telemetry do not reflect body core temperature.

Long-term outcomes after resection of Stage IV cavoatrial tumour extension using deep hypothermic circulatory arrest.

OBJECTIVES: Renal neoplasms frequently expand into renal veins and inferior vena cava from the early stages of the disease. In this study, we set out to define the long-term outcomes of patients with Stage IV tumorous cavoatrial extension, undergoing radical nephrectomy with excision of cavoatrial extension in deep hypothermic circulatory arrest (DHCA). METHODS: Thirty-five patients with Stage IV cavoatrial extension of renal cell carcinoma underwent radical nephrectomy combined with en bloc excision of cavoatrial tumour-thrombus extension, performed in DHCA. The preoperative staging of the tumour and assessment of the intravascular position of the tumour were performed using standard imaging techniques, including computed tomography angiography, magnetic resonance imaging and echocardiography. Patient data were collected in the patient data bank and analysed retrospectively. RESULTS: In this study cohort, we demonstrate acceptable long-term results (the mean overall survival of 4.9 ± 1.0 years and the 5-year survival rate of 40%) and outline several clear predictors for postoperative long-term survival of the patients. Preoperative evidence of remote tumour metastases and tumourous lymph node involvement conversely predicts inferior postoperative survival. However, a high local postoperative tumour recurrence rate does not limit patient survival in this group. CONCLUSIONS: The data provide evidence for perioperative safety and acceptable long-term results of radical nephrectomy with excision of cavoatrial extension in DHCA in patients with Stage IV cavoatrial extension of renal neoplasm. Thus, this radical surgical procedure can provide effective long-term palliation in the absence of evident metastatic disease.

First Biventricular Jarvik 2000 Implants (Retroauricular Version) Via a Median Sternotomy.

OBJECTIVES: Organ shortages and increased numbers of nontransplant older patients have necessitated a search for alternatives to heart transplants. The Jarvik 2000 assist device (Jarvik Heart, Inc., Manhattan, NY, USA), as a small long-term axial flow pump, offers many advantages, such as retroauricular power supply, which minimizes driveline infection risks. When implanted biventricularly, the device may offer support for patients with biventricular heart failure, especially for nontransplant patients as a destination therapy. MATERIALS AND METHODS: We implanted biventricular Jarvik 2000 systems into 3 men (aged, 65.3 ± 5.0 y; ejection fraction, 24.7% ± 1.5% for left ventricle and 17.7% ± 5.0% for right ventricle). These were the first patients worldwide to receive a biventricular Jarvik 2000 device with retroauricular power supply via a median sternotomy and with additional cardiac surgical procedures. RESULTS: No technical problems were noted during biventricular assist device implant. Mean support time on the device was 224 ± 198 days. All 3 patients showed sufficient cardiac support; 2 patients died from noncardiac complications. Patient 1 died on day 3 as a result of postoperative hepatic failure after preoperative reanimation, and patient 3 died as a result of an ileus and colon perforation after 50 days. Patient 2 died of ventricular fibrillation (after 1.5 y), which occurred 1 year after right ventricular pump shutdown, although significant improvement of right ventricle function was shown (ejection fraction increased by 48%). CONCLUSIONS: Our 3 patients were old, had multiple comorbidities, and needed further cardiac surgery. None of the patients died as a result of technical failure of the device but because of complications accompanying their morbidities. If complication rates can be reduced, a biventricular assist device implant could and should be considered as a potential alternative for nontransplant patients.

Pre-clinical heterotopic intrathoracic heart xenotransplantation: a possibly useful clinical technique.

BACKGROUND: 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. METHODS: Consecutive experiments were carried out between 2009 and 2013. Twenty-one genetically modified pigs (GGTA1-knockout/hCD46/± thrombomodulin, in one case HLA-E instead) were used as donors. In all experiments, two cycles of immunoabsorption reduced preformed antibodies. Recipient baboons were divided into two groups according to IS regimen: In group one (n = 10), pre-treatment started either one (anti-CD20) or four weeks (anti-CD20 plus the proteasome inhibitor bortezomib) prior to transplantation. The extended conventional (as for allotransplantation) immunosuppressive maintenance regimen included anti-thymocyte globuline, tacrolimus, mycophenolate mofetil, methylprednisolone and weekly anti-CD20. In group two (n = 11), myeloablative pre-treatment as in multiple myeloma patients (long and short regimens) was added to extended conventional IS; postoperative total thoracic and abdominal lymphoid irradiation (TLI; single dose of 600 cGY) was used to further reduce antibody-producing cells. RESULTS: In the perioperative course, the surgical technique was safely applied: 19 baboons were weaned off extracorporeal circulation and 17 extubated. Nine animals were lost in the early postoperative course due to causes unrelated to surgical technique or IS regimen. Excluding these early failures, median graft survival times of group 1 and 2 were 18.5 (12-50) days and 16 (7-35) days. Necropsy examination of group 1 donor organs revealed hypertrophy of the left ventricular wall in the six longer-lasting grafts; myocardial histology confirmed pre-clinical suspicion of humoral rejection, which was not inhibited by the extended conventional IS including intensified treatments, and signs of thrombotic microangiopathy. Grafts of group 2 presented with only mild-to-moderate features of humoral rejection and thrombotic microangiopathy, except in one case of delayed rejection on day 17. The other experiments in this group were terminated because of untreatable pulmonary oedema, recurring ventricular fibrillation, Aspergillus sepsis, as well as a combination of a large donor organ and late toxic side effects due to TLI. CONCLUSIONS: Longer-term results were difficult to achieve in this model due to the IS regimens used. However, we conclude that heterotopic intrathoracic heart transplantation may be an option for clinical xenotransplantation.

Long-term self-management of anticoagulation therapy after mechanical heart valve replacement in outside trial conditions.

In this investigation, we hypothesize that quality of oral anticoagulation (OA) and long-term outcome after mechanical heart valve (MHV) replacement with self-management (Self-M) of OA is superior to conventional anticoagulation treatment (Conv-T), even in outside trial conditions. One hundred sixty patients (78.8% aortic valve replacements) were trained in international normalized ratio Self-M and 260 patients (86.2% aortic valve replacements) preferred Conv-T. Mean follow-up was 8.6 ± 2.1 years, representing 3612 patient-years. During follow-up, 37.2% bleedings and 10.6% thromboembolic events were recorded in the Self-M group versus 39.6% bleedings (P = 0.213) and 15.4% thromboembolic events (P = 0.064) in the Conv-T group. Serious adverse events were significantly lower in the Self-M group [grade III bleeding events causing disability or death: 0 versus 4.6% (P = 0.03); grade III thromboembolic events: 0.6 versus 5.0% (P = 0.011)]. Patients with Self-M were significantly more satisfied with their OA management and their quality of life (P < 0.001). Actuarial survival after 1, 5 and 10 years was 100, 99 and 97 with Self-M and 100, 95 and 81% with Conv-T, respectively (P < 0.001). Univariate risk factors for mortality were age (P = 0.008), type of operation (P = 0.021) and conventional OA (P < 0.001). In multivariate analysis, only conventional OA reached significance (P < 0.001). We conclude that in a routine setting under outside trial conditions Self-M of OA improves long-term outcome and treatment quality.

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.

Influence of hypothermia and cardioplegic solutions on expression of alpha-Gal epitope on porcine aortic endothelial cells.

OBJECTIVES: The Galalpha1-3Galbeta1-4GlcNAc-R is the major antigen on pig tissue bound by human xenoreactive natural antibodies in xenotransplant. We have investigated in vitro the influence of hypothermic storage with cardioplegic solutions on expression of Galalpha1-3Galbeta1-4GlcNAc-Rs and hyperacute xenograft rejection. MATERIALS AND METHODS: To analyze effects of hypothermia on the Galalpha1-3Galbeta1-4GlcNAc-Rs, cultured porcine aortic endothelial cells were exposed to a temperature of 4 degrees C for 1 hour, 4 hours, and 6 hours. Cell cultures of the control groups were incubated at the same time at 38 degrees C. To investigate the influence of cardioplegic solutions on the Galalpha1- 3Galbeta1-4GlcNAc-Rs, porcine aortic endothelial cells were exposed to 4 degrees C for 4 hours in the presence of University of Wisconsin solution or histidinetryptophan- ketoglutarate solution. Cells of the control groups were cooled at 4 degrees C for 4 hours without cardioplegic solution. After treatment, porcine aortic endothelial cells were submitted to fluorescence-activated cell sorter. RESULTS: Hypothermia of 4 degrees C showed no significant effect on the quantity of Galalpha1-3Galbeta1-4GlcNAc-Rs. However, the treatment of porcine aortic endothelial cells with University of Wisconsin solution resulted in a highly significant reduction of Galalpha1-3Galbeta1- 4GlcNAc-Rs by 50% (P = .006). Treatment of porcine aortic endothelial cells with histidine-tryptophanketoglutarate solution decreased Alpha-Gal quantity significantly by 32% (P = .011). CONCLUSIONS: Our data offer new perspectives in the prevention of hyperacute, humoral xenograft rejection by reducing the Galalpha1-3Galbeta1-4GlcNAc-Rs after exposure to different cardioplegic solutions.

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

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 Galalpha(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 Galalpha(1,3)Gal trisaccharide would sufficiently minimize xenograft rejection of hDAF-transgenic pig hearts orthotopically transplanted into baboons. METHODS: Orthotopic heart transplantations were performed using hDAF transgenic piglets as donors and four non-splenectomized baboons as recipients. Baseline immunosuppression consisted of tacrolimus, sirolimus, ATG, steroids. In addition two animals received low-dose GAS914, and two animals high-dose GAS914. One of these baboons received high dose GAS914 and cyclophosphamide induction therapy. Serum levels of anti-Galalpha(1,3)Gal IgM and IgG antibodies, and anti-pig antibodies were controlled daily by anti-Galalpha(1,3)Gal enzyme-linked immunosorbant assay and anti-pig hemolytic assays. Histomorphological (hematoxylin and eosin, elastic van Gieson) and immunohistochemical (IgM, IgG) evaluations were performed on tissue specimens. RESULTS: Following low-dose GAS914 therapy survival time was 1 and 9 days, respectively. In baboons treated with high dosages of GAS914 a survival of 30 h and 25 days could be obtained. GAS914 caused an immediate and significant reduction of both anti-Galalpha(1,3)Gal IgM and IgG antibodies. However, sufficient antibody reduction was independent of dosage and form of application of GAS914. A pre-transplant GAS914 treatment was not necessary to effectively reduce antibody levels and prevent hyperacute rejection. In the early postoperative period preformed anti-pig antibodies corresponded predominantly to anti-Galalpha(1,3)Gal antibodies making them susceptible to GAS914. Subsequently, while anti-Galalpha(1,3)Gal antibodies remained low, anti-pig antibodies increased despite of GAS914 application. Corresponding to increased anti-pig antibody titers depositions of IgM and IgG immunoglobulins were detected, which were possibly non-Galalpha(1,3)Gal-specific. CONCLUSIONS: Following orthotopic transplantation of hDAF-transgenic pig hearts into baboons, GAS914 is able to maintain a sufficient reduction of Galalpha(1,3)Gal-specific cytotoxicity to the graft. GAS914 therefore is able to prevent not only hyperacute rejection, but also acute vascular rejection at its beginning, when serum cytotoxicity to the pig heart appears to be predominantly Galalpha(1,3)Gal-specific. A sustained prevention of acute vascular rejection, however, still requires the identification of antibody specificities other than to Galalpha(1,3)Gal.