Malek G. Massad

Factors Influencing HLA Sensitization in Implantable LVAD Recipients

BACKGROUNDnPatients bridged to transplantation (TX) with the implantable left ventricular assist device (LVAD) may be at increased risk for the development of panel-reactive antibodies (PRA) during support.nnnMETHODSnTo investigate that, we evaluated 60 patients who received the HeartMate LVAD at our institution, of whom 53 had PRA results available for analysis. T lymphocyte PRA levels were examined before LVAD, at the peak PRA level during LVAD support (PEAK), and just before TX. A PRA level more than 10% was considered indicative of sensitization against HLA antigens.nnnRESULTSnThe only factor that had a significant effect on PRA levels before LVAD was patients sex (1.3% for men versus 7.4% for women; p = 0.005). During LVAD support, peak PRA levels increased significantly and the sex-associated differences were no longer evident (33.3% men, 34.3% women; not significant). At the time of TX, PRAs decreased to 10.9% (men) and 7.0% (women) (not significant). We examined the influence of blood products received before TX on PRA levels. Patients who received less than the median number of total units (median). When examined by the type of blood product, only the number of platelet transfusions significantly increased the peak PRA (median: 46.9%; p = 0.03). Patients who received blood that was leukocyte-depleted tended to have lower TX PRA levels (2.9%) compared with those who did not (13.9%, p = 0.18). Forty-two patients were successfully bridged to TX, with three early and two late deaths after TX. Whereas 39 patients received transplants without intervention, 3 were treated by plasmapheresis with a 77% reduction in their HLA antibody levels at TX as measured by flow cytometry.nnnCONCLUSIONSnPatients with the implantable LVAD are at significant risk for the development of anti-HLA antibodies during support. Although this sensitization is often transient, intervention using plasmapheresis may be useful for some patients.

Risk Factors for Death After Heart Transplantation: Does a Single-Center Experience Correlate With Multicenter Registries?

BACKGROUNDnRisk factors for death after heart transplantation (Tx) are frequently documented from multicenter registries. Although this information is helpful, it reflects a whole range of experiences and results, and may not translate to a particular center. This study was performed to (1) evaluate pre-Tx factors affecting mortality in a single-center experience, and (2) compare these factors with risk factors obtained from multicenter registry reports.nnnMETHODSnReview of our transplant database between January 1984 and December 1995 identified 405 adults who received a primary heart Tx. Multiple factors were analyzed, including demographics, Tx era, cytomegalovirus status, United Network for Organ Sharing status of recipient, presence of pulmonary hypertension, previous cardiac operations, mechanical ventilation or circulatory support, ischemia time, number of rejection episodes, and preoperative flow cytometry crossmatching.nnnRESULTSnOne- and 5-year survival rates were 87.8% and 73.4%, respectively (Kaplan-Meier). Contrary to multicenter registry reports, our data indicate that reoperative procedures, left ventricular assist device support, increasing donor and recipient age, and ischemia time up to 4.2 hours are not risk factors for death after Tx. Likewise, mode of donor death is not a risk factor affecting outcome. Significant risk factors for mortality identified by multivariate analysis included early transplant era (1984 to 1989; p = 0.002), female donor (p = 0.042), cytomegalovirus-seropositive donor (p = 0.048), high pulmonary vascular resistance (p = 0.018), and intraaortic balloon pump support (p = 0.03). It also identified a positive B-cell flow cytometry crossmatch (p = 0.015) to be a risk factor with univariate analysis.nnnCONCLUSIONSnOur data identify a group of recipients, reportedly at high risk in multicenter registries, who are not at increased risk of death after Tx. This information supports the growing experience with older donors and recipients and with bridged transplants, and has allowed us to expand our donor pool. These prognostic factors at evaluation allow more liberal selection of patients and donors for transplantation.

Does successful bridging with the implantable left ventricular assist device affect cardiac transplantation outcome

OBJECTIVESnWe sought to determine whether cardiac transplant recipients who required a bridge to transplantation with an implantable left ventricular assist device had a different outcome than patients who underwent transplantation without such a bridge.nnnMETHODSnA retrospective study of 256 cardiac transplants from 1992 to 1996 included 53 patients who received the HeartMate left ventricular assist device and 203 patients who had no left ventricular assist device support.nnnRESULTSnLeft ventricular assist device transplants increased from 8% of all transplants in 1992 (n = 63) to 32% in 1995 (n = 65) and 43% in 1996 (n = 14 year to date). Patients with and without left ventricular assist device had similar age and sex distributions. Left ventricular assist device recipients were larger (body surface area 1.96 vs 1.86 m2, p = 0.004). They were more likely to have ischemic cardiomyopathy (70% vs 45%, p = 0.001) and type O blood group (51% vs 34%, p = 0.06). All patients with left ventricular assist device and 42% of those without had undergone previous cardiac operations by the time of transplantation (mean number per patient 1.5 vs 0.3, p < 0.001). More patients in the left ventricular assist device group had anti-HLA antibodies before transplantation (T-cell panel reactive antibody level > 10% in 66% of left ventricular assist device group vs 15% of control group, p < 0.0001). Waiting time was longer for the left ventricular assist device than for patients in status I without a left ventricular assist device (median 88 vs 37 days, p = 0.002). There was no difference in length of posttransplantation hospital stay (median 15 days for each) or operative mortality (3.8% vs 4.4%). Mean follow-up averaged 22 months. No significant difference was found in Kaplan-Meier survival estimates. One-year survival was 94% in the left ventricular assist device group and 88% in the control group (difference not significant). Comparison of posttransplantation events showed no significant difference in actuarial rates of cytomegalovirus infection (20% vs 17%) or vascular rejection (15% vs 12%) at 1 year of follow-up. Similar percentages of patients were free from cellular rejection at 1 year of follow-up (12% vs 22%, p = 0.36).nnnCONCLUSIONSnLeft ventricular assist device support intensified the donor shortage by including recipients who otherwise would not have survived to transplantation. Bridging affected transplant demographics, favoring patients who are larger, have ischemic cardiomyopathy, have had multiple blood transfusions and complex cardiac operations, and are HLA sensitized. Successfully bridged patients wait longer for a transplant than do UNOS status I patients without such a bridge, but they have similar posttransplantation hospital stay, operative mortality, and survival to those of patients not requiring left ventricular assist device support.

Pulmonary hypertension is not a risk factor for RVAD use and death after left ventricular assist system support

Unlike transplantation candidates, patients with pulmonary hypertension (PHTN) and a high transpulmonary gradient do not appear to be at increased risk for right ventricular dysfunction after left ventricular assist system implant. To verify this observation, we reviewed 63 patients supported with the HeartMate (Thermo Cardiosystems, Inc, Woburn, MA) left ventricular assist system. Patients were divided into two groups: patients with PHTN (47 patients) had mean pulmonary artery pressure > 30 mm Hg and/or pulmonary vascular resistance > 4 Wood units, and the remainder of patients did not have PHTN (16 patients). Both groups were similar in age (mean, 51 years), gender distribution (% men, 83% vs 94%, not significant), and number of patients with ischemic cardiomyopathy (72% vs 69%, not significant). More patients in the group without PHTN required extracorporeal membrane oxygenation support (38% vs 12%, p = .06). Right ventricular assist device support was instituted in five (11%) patients with PHTN and four (25%) patients without PHTN. A significantly larger number of patients without PHTN died while on support (14% vs 44%, p = .01). Survival after transplantation in both groups was > 90%. Patients with PHTN have higher transpulmonary gradient, show a significant decrease in pulmonary pressure after left ventricular assist system implantation, and have a higher transplantation rate compared to patients without PHTN. A larger patient cohort is needed to determine if the absence of PHTN is a risk factor for RVAD need and poor outcome after LVAS support.

Vascular rejection post heart transplantation is associated with positive flow cytometric cross-matching

OBJECTIVEnUse of flow cytometry cross-matching for measurement of donor-specific alloreactivity and monitoring anti-donor antibodies is well established. This study was performed to determine (1) its accuracy as a marker of vascular rejection, (2) its correlation with post-transplant outcome and (3) its ability to monitor highly sensitized patients requiring antibody removal with plasma exchange.nnnMETHODSnSerial serum samples from 99 heart transplant recipients were examined for the presence of anti-donor antibodies of the IgG class that were reactive with T and/or B cryopreserved donor lymphocytes. A sub-group of 20 HLA sensitized patients required plasma exchange to remove the anti-HLA antibodies and were monitored with flow cytometry cross-matching to assess the degree of antibody removal.nnnRESULTSnPositive T-cell reactions were observed in 26 patients and positive B-cell reactions in 54. Twenty patients had vascular rejection. A significantly larger number of patients with a positive flow cytometry cross-match had vascular rejection (42% versus 12% for T-cell reactions, and 32% versus 7% for B-cell reactions; P = 0.002 each). Of the patients who had vascular rejection, 11 had a positive T-cell reaction (flow cytometry cross-match sensitivity of 55%), and 17 had a positive B-cell reaction (sensitivity of 85%). Of the 79 patients who did not develop vascular rejection, 64 had a negative T-cell reaction (specificity of 81%), and 42 had a negative B-cell reaction (specificity of 53%). The actuarial 2-year survival estimates were significantly higher in patients with negative T-cell reactions (90% versus 75%; P = 0.04), and B-cell reactions (95% versus 78%; P = 0.02). In the highly sensitized subgroup (n = 20) the effectiveness of plasma exchange to decrease anti-HLA antibody reactivity was a strong predictor of outcome. For patients in whom plasma exchange (PE) reduced anti-donor reactivity, 1-year survival was 87% compared to 25% in those whom PE did not reduce the level of antibody binding as assessed with flow cytometry cross-matching (P < 0.0001).nnnCONCLUSIONSnFlow cytometry cross-matching provides a valuable marker for the detection of vascular rejection after cardiac transplantation. Quantitative measurements may allow evaluation of the efficacy of treatment modalities employed in the management of vascular rejection in an attempt to improve outcome.

Bench repair of donor mitral valve before heart transplantation

Bench repair of the donor mitral valve was performed before orthotopic heart transplantation in a 57-year-old status I recepient. Mitral regurgitation in the structurally normal mitral valve was due to annular dilatation at the attachment of the posterior leaflet and was corrected with posterior annuloplasty. The patient is clinically well 18 months after transplantation.

Will permanent LVADs be better than heart transplantation

Current interest in permanent mechanical support systems has been renewed as a result of the present shortage of human heart donors, and in view of the satisfactory results obtained with their use as a bridge-to-transplant. As the number of donors is unlikely to increase dramatically in the near future, there is an urgent need to develop mechanical alternatives to transplantation. Preliminary data on the use of the implantable electric LVAD as a bridge-to-transplant indicate that the adverse clinical and mechanical events in outpatients are few and do not preclude use of the device on a permanent basis. Except for infections, transplant issues relating to need for endomyocardial biopsies, rejection, malignancies, and graft arteriosclerosis do not apply to LVAD recipients who face important issues relating to device durability, cost, and potential need for concomitant right heart support. This lack of data on long-term durability contrasts with a yearly mortality rate of about 5% after the first year of transplant. With the initiation of clinical trials on the permanent use of the electric LVAD, several design modifications and upgrading of the currently available devices are expected. Completely sealed systems with steadily improving durability will hopefully appear. Inductive coupling techniques under investigation and development appear to be able to transmit energy without damage across the skin. It is anticipated that with more reliable electronic microprocessors, the future generation of implantable LVADs will be smaller, more reliable and longer lasting.

Age related outcome after implantable left ventricular assist system support

To examine the relationship between age and outcome after implantable left ventricular assist system support, the authors investigated the results of 223 patients from 17 centers who were supported with a HeartMate (Thermo Cardiosystems, Inc., Woburn, MA) pneumatic left ventricular assist system between 1986 and 1994. In addition, the authors examined a single centers experience with 67 patients between 1992 and 1996. Ages are separated by decile and ranged from 10 to 69 years. Men dominated all age groups, averaging 82% of the total (range, 64-91%). Viral, idiopathic, and post partum cardiomyopathies were the indication for support in 88% of the patients younger than 39 years of age. Ischemic cardiomyopathy was the cause of myocardial failure in the majority of patients older than 40 years of age (40-49 years, 54%; 50-59 years, 57%; and 60-69 years, 67%). Patients aged 40-59 accounted for 64% of the patients supported, and had the best outcomes both on support and after transplantation. Survival to transplantation was not significantly different among the groups, although the patients older than 60 and younger than 69 years of age had higher mortalities on support, most commonly from cardiac failure. At the Cleveland Clinic Foundation, the survival to transplantation and survival to discharge were indistinguishable between age groups. Age does not appear to be significant risk factor for outcome after implantable left ventricular assist system support. These results predict acceptable mortality for patients supported who are older than the age of 60.