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C4d Fixing, Luminex Binding Antibodies—A New Tool for Prediction of Graft Failure After Heart Transplantation

The standard method to detect pretransplant antibodies has been the complement dependent cytotoxicity (CDC) test of donor leukocytes. Solid phase assays to detect HLA antibodies in pretransplant serum reveal a greater number of sensitized patients, but their clinical impact is less certain. Here we have developed a method of detecting C4d fixing HLA antibodies on Luminex beads. Pretransplant serum from 565 cardiac transplant patients was retrospectively tested for the presence of HLA antibodies using CDC, HLA coated Luminex beads and C4d deposition on Luminex beads, and the results correlated with graft survival. Whereas 5/565 patients had CDC positive donor specific antibodies (DSA) before their transplant, this number was increased by 19 using Luminex beads. The 1‐year survival of CDC –ve/Luminex +ve patients with DSA (n = 19) was 42% compared with 77% for CDC –ve/Luminex +ve without DSA (n = 39, p = 0.0039). Fixation of C4d (22/67 Luminex positive sera) had a negative effect on graft outcome; 1‐year graft survival was, C4d +ve/DSA +ve (n = 11) 20%, C4d +ve/DSA –ve (n = 11) 91%, C4d –ve DSA +ve (n = 13) 54%, C4d –ve DSA –ve (n = 32) 75%, compared with 75% for antibody‐negative patients (p = 0.0002). In conclusion, detection of Luminex +ve DSA in pretransplant serum provides a powerful negative predictor of graft survival, especially if they bind C4d.

Lack of Effect of MICA Antibodies on Graft Survival Following Heart Transplantation

Little is known about the effect of MICA antibodies (Abs) on cardiac allograft function and survival. Pretransplant and posttransplant serum from 491 and 196 adult cardiac allograft recipients, respectively, has been investigated for MICA Abs, donor specificity and the effect of MICA Abs on graft survival, acute rejection episodes (AR) and cardiac allograft vasculopathy (CAV). Patients with HLA Abs (11.6%) were excluded from the analysis. A total of 11.8% of patients had MICA Abs, without HLA Abs, before their transplant. Actuarial graft survival demonstrated slightly better survival of patients with donor‐specific MICA Abs at 1 and 5 years (88.9% and 83.3%) than patients negative for MICA Abs (72% and 63.7%, p = 0.051). After transplantation, 15.8% of patients produced MICA Abs, and in 17 patients these were produced de novo. There was no effect of pretransplant or posttransplant production of MICA Abs on numbers of AR episodes in year 1, or CAV assessed at years 3 and 5. Immunocytochemistry of cardiac biopsies from 11 patients did not demonstrate a presence of MICA. Sera from only 4/69 patients with MICA Abs fixed complement prior to transplantation and from 7/38 patients following transplantation. In conclusion, this study suggests that MICA Abs do not adversely affect the outcome of cardiac transplantation.

Determinants of outcome after heterotopic heart transplantation

BACKGROUNDnDonor availability is currently the major factor limiting the use of heart transplantation as a treatment for severe heart failure. Heterotopic heart transplantation may address this issue by allowing the use of smaller donor organs, which otherwise may not be used.nnnMETHODSnWe analyzed the outcome of 42 consecutive, adult heterotopic transplantations performed between 1993 and 1999 at our center and compared them with the 303 consecutive orthotopic transplants performed in adult patients during the same period.nnnMETHODSnUnivariate analysis showed a relative risk for death of 1.8 at 1 year after transplantation for the heterotopic group compared with the orthotopic transplantation group (p = 0.04). Multiple regression analysis using a proportional hazards model showed that donor-recipient size-mismatch, i.e., donor body surface area < or =75% of recipient body surface area (p = 0.0001), donor age (p = 0.0001), and use of a female donor (p = 0.04) were significant risk factors but heterotopic transplantation per se was not. A Kaplan-Meier survival analysis of heterotopic vs orthotopic transplantation showed that 30-day survival was 76% vs 87%. By 1 year, this was 59% vs 74%. At 3 years, the comparison was 56% vs 69%. Repeating this analysis after sub-dividing the heterotopic group into those size-matched vs size-mismatched, the 1-year survival was 81% vs 45%, respectively (p = 0.02).nnnCONCLUSIONSnHeterotopic transplantation using a size-matched graft resulted in similar survival to that seen after orthotopic transplantation during the same period. Heterotopic transplantation with an undersized graft resulted in significantly decreased survival.

Relationship of immunosuppression and serum lipids to the development of coronary arterial disease in the transplanted heart.

Coronary arterial disease in the cardiac allograft has emerged as the most serious long term complication of cardiac transplantation. The influence of patient-related and other potential risk factors on the development of coronary arterial disease at 1 year subsequent to cardiac transplantation was examined in 207 recipients. The mean age of donors in patients with coronary arterial disease was 28.5 +/- 9.5 years, compared to 22.6 +/- 7.9 years in patients without coronary arterial disease (P less than 0.01). Eight of the 35 patients who received immunosuppression by means of prednisone and azathioprine developed coronary arterial disease compared to 5 of the 172 patients who were treated with cyclosporin and azathioprine without routine oral prednisone (P less than 0.01). The relationship of levels of serum lipids to the subsequent development of coronary arterial disease was investigated in 95 patients with angiographically normal coronary arteries one year after cardiac transplantation. The cumulative probability of coronary arterial disease in those with total cholesterol greater than 5.8 mmol/l was 9.3% at 2 years (n = 40), 24.4% at 4 years (n = 21) and 45% at 4 years (n = 9) compared with 4.3% at 2 years (n = 45), 7.4% at 3 years (n = 32) and 14% at 4 years (n = 14) in those with a total cholesterol less than 5.8 mmol/l (P less than 0.05). Similarly, the incidence of coronary arterial disease was increased in patients with serum triglyceride greater than 1.4 mmol/l (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Heterotopic Heart Transplantation and Recipient Heart Operation in Ischemic Heart Disease

The role of heterotopic heart transplantation in coronary heart disease has not been defined. Between 1983 and 1988, 28 patients with end-stage ischemic heart disease were managed by heterotopic heart transplantation and adjunctive operation on the recipient heart: coronary artery bypass grafts and aneurysmectomy, 20; coronary artery bypass grafts, 5; and aneurysmectomy, 3. Indications were feasibility of operative procedures to the recipient heart and small donor size (61% of the donors were less than 15 years). The 1-year and 5-year actuarial survival was 79% and 63%. Of the 22 patients who survived to 2-year follow-up, all of whom had been severely limited (New York Heart Association grade III/IV) preoperatively, 20 were in grades I or II at 2-year follow-up (p less than 0.001). In 14 of 22 patients (64%), the recipient heart augmented the donor cardiac output substantially, and in 4 the recipient heart supported the patient when the donor heart failed to eject. In conclusion, this series demonstrates the efficacy of heterotopic transplantation combined with operation to the recipient heart in the management of patients with end-stage ischemic heart disease.

Intrathoracic organ transplantation from donors with meningitis: a single-center 20-year experience.

BACKGROUNDnAvailability of cadaveric organs continues to be the key factor limiting the number of transplants performed. Donor with bacterial meningitis is often considered to be controversial for organ retrieval. The purpose of this retrospective study was to review the long-term outcome of orthotopic heart and lung transplantation at our institution, from donors who died as a result of meningitis.nnnMETHODSnBetween July 1986 and July 2006, 39 adult patients who underwent heart and lung transplantation performed with organs from cadaveric donors with bacterial meningitis were retrospectively studied. Donors and recipients were identified by a prospectively kept database. Bacterial meningitis was identified either with positive blood or cerebrospinal fluid culture and positive signs and symptoms. All patients had one or more of these criteria. There were 15 heart, 12 lung (4 bilateral), and 12 heart-lung transplants.nnnRESULTSnAll donors had identified pathogens: Neisseria meningitidis (n = 21; 53.8%), Streptococcus pneumoniae (n = 16; 41%), and Haemophilus influenzae (n = 2; 5.2%). Adequate antimicrobial therapy before organ retrieval and after transplant was administered. The hospital mortality was 10.2% (n = 4). There were no infectious complications caused by meningeal pathogens. Other causes of hospital mortality were rejection (n = 2), intracranial bleeding (n = 1), and staphylococcus sepsis (n = 1). The mean posttransplant follow-up was 5.35 +/- 5.54 years (range, 1 month to 18.9 years).nnnCONCLUSIONSnIntrathoracic organ transplantation using donors with bacterial meningitis is an acceptable strategy. No organism (Neisseria meningitides, Streptococcus pneumoniae, and Haemophilus influenzae) could be identified as contraindication because no recipient died of infectious-related diseases.

Left ventricular function during support with an asynchronous pulsatile left ventricular assist device.

BACKGROUNDnLeft ventricular assist devices (LVADs) are frequently used to maintain patients with severe heart failure until heart transplantation becomes possible. Some patients may experience recovery of LV function during such support. Therefore, it is essential to be able to monitor changes in LV function in this setting.nnnMETHODSnWe studied LV function in 10 patients (median age 34 years, 9 male) who had LVADs implanted because of severe heart failure due to dilated cardiomyopathy a median of 4 months previously. Median pre-implant ejection fraction was 27% and all patients had been on maximal medical therapy, including intravenous inotropic support, prior to insertion of the LVAD.nnnRESULTSnDuring LVAD support there were cyclical variations in LV dimensions, fractional shortening (FS) and transmitral flow, related to changes in the phase relationship of the LV and the LVAD. The best FS occurred when LV systole coincided with device filling and the worst FS when LV systole coincided with device ejection. Median FS with the pump switched off was 18% (10% to 32%). Pump-off FS was significantly greater than the worst FS with the pump on (5%, p = 0.002), and similar to the best pump-on FS (19%, p = NS).nnnCONCLUSIONSnLV function could be studied echocardiographically during LV support and brief periods of interruption in support. Function varied according to the phase relationship of the LV and LVAD. The best FS measured during LVAD support was more closely related to the FS with the device switched off than the worst pump on FS. The best pump-on LV function is therefore most representative of intrinsic LV performance and can be used as a guide to recovery and the potential need for pump-off studies.

Evidence of clinical efficacy of counterpulsation therapy methods

Although heart transplantation remains the ultimate treatment for end-stage heart failure, its epidemiological impact is limited by donor organ availability. Surgical and device-based approaches have been introduced with the aim of increasing systemic perfusion and in some circumstances promoting left ventricular recovery by inducing reverse remodelling. Innovative counterpulsation devices based on the established principle of the intra-aortic balloon pump have been developed, and of these, the CardioVad and the C-Pulse System have been introduced in clinical practice with convincing evidence of haemodynamic efficacy. The evolution from pulsatile to continuous-flow left ventricular assist devices has been associated with improved survival rates during the first 2xa0years of support with the potential of matching heart transplantation outcomes. However, blood contact with the device remains a significant challenge despite the highly sophisticated technology currently available. Innovative extra-vascular counterpulsation devices have been shown to overcome the limitations of the intra-aortic balloon pump and rend the device suitable for prolonged support. Monitoring of the performance of these novel devices is essential, and carotid Doppler ultrasonography is of utility in assessing the haemodynamic performance of the devices in a clinical setting. Computational modelling has played a role in the simulation of these devices and should continue to assist with their optimisation and implementation in clinical practice.

Medium-term outcome of an ABO incompatible lung transplant.

In 2004, our department reported on a 24-year-old woman with cystic fibrosis who underwent bilateral sequential single lung transplantation and unintentionally received an ABO incompatible graft (donor type A1, recipient type O) (1). Her initial anti-A IgG antibody titer had been high (256). Emergency treatment with plasmapharesis, mycophenolate, rabbit thymocyte globulin and polyspecific intravenous immunoglobulin, and subsequently with immunoadsorption and rituximab, resulted in a good short-term outcome.

iNOS and peroxynitrite formation during acute rejection after human heart transplantation

endomyocardial biopsy (EMB) beyond 2 years post-transplant remains uncertain. We performed a retrospective analysis reflecting our singleinstitution experience with 4041 biopsies (188 patients) from 1986-2001. Late ISHLT grade 3A rejection ocurring beyond 2 years posttransplant was detected in 24% of cardiac transplant recipients (33 of 139 patients) up to 10 years post-transplant. Late rejection could not be attributed to subtherapeutic levels of immunosuppression or other established parameters. Late rejection was only marginally correlated with the incidence of moderate rejection within the first 2 posttransplant years (p 0.09). Unlike the incidence of moderate rejection in the first post-transplant year showing a steady decline toward more recent years (2.1430.13), the incidence of late rejection appeared not to be influenced by transplant era (mean 0.11 0.056) over a 10 year observation period (1989-1999). Spontaneous resolution of moderate rejection beyond 2 years post-transplant occurred in all 17 patients in whom specific anti-rejection therapy had been electively withheld. Mortality beyond 2 years post-transplant was slightly lower (p 0.033) in the late rejecting group (n 33) than in the control group (n 106), no difference was found in the prevalence of transplant vasculopathy diagnosed by coronary angiography. EMB continues to detect episodes of moderate rejection even very late after heart transplantation without a close correlation with the rejection frequency in the early posttransplant period. Late rejection may represent a distinct biological entity as evidenced by its spontaneous resolution, lack of an era effect as is found for early rejection and no negative impact on survival. The future role of late EMB will depend on its predictive value for diagnosis and risk stratification of chronic graft dysfunction.