Ranjit John

Multicenter review of preoperative risk factors for stroke after coronary artery bypass grafting.

BACKGROUNDnStroke complicates the postoperative course in 1% to 6% of patients undergoing coronary revascularization. There has been no large scale mandatory database reporting on the incidence of stroke after coronary revascularization.nnnMETHODSnA multicenter regional database from the Bureau of Health Care Research Information Services, New York State Department of Health, on 19,224 patients who underwent coronary revascularization in 31 hospitals within New York State during 1995 was analyzed to determine the risk factors for postoperative stroke.nnnRESULTSnThe incidence of postoperative stroke was 1.4% (n = 270). Hospital mortality for patients who had a stroke was 24.8%, compared with 2.0% for the rest of the patient population. Postoperative stroke increased the hospital length of stay threefold (27.9+/-1.9 versus 9.1+/-0.9 days, p<0.0001). Multivariable logistic regression identified the following variables to be significantly associated with a postoperative stroke: calcified aorta (p<0.0001; odds ratio [OR], 3.013), prior stroke (p = 0.0003; OR, 1.909), age (p<0.0001; OR, 1.522 per 10 years), carotid arterial disease (p = 0.002; OR, 1.590), duration of cardiopulmonary bypass (p = 0.0004; OR, 1.27 per 60 minutes), renal failure (p = 0.0062; OR, 2.032), peripheral vascular disease (p = 0.0157; OR, 1.62), cigarette smoking (p = 0.0197; OR, 1.621), and diabetes mellitus (p = 0.0158; OR, 1.373).nnnCONCLUSIONSnPostoperative stroke increases mortality and length of stay after coronary revascularization. Several risk factors can be identified, and some of these factors are potentially amenable to intervention, either before or during coronary revascularization, and should also influence patient selection.

Long-term outcomes after cardiac transplantation: an experience based on different eras of immunosuppressive therapy.

BACKGROUNDnConstantly changing practices in heart transplantation have improved posttransplant survival in patients with end-stage heart disease. The objective of this study was to evaluate long-term outcomes in different eras of immunosuppressive therapy after cardiac transplantation at a single center during a two-decade period.nnnMETHODSnA retrospective review of 1,086 consecutive cardiac allograft recipients who underwent transplantation between 1977 to 1999 was performed. Patients were divided into four eras based on type of immunosuppressive therapy: era 1 = steroids, azathioprine (n = 26, February 1977 to March 1983), era II = steroids, cyclosporine (n = 43, April 1983 to April 1985), era III = cyclosporine, steroids, azathioprine (n = 752, April 1985 to December 1995), era IV = cyclosporine, steroids, mycophenolate mofetil (n = 315, January 1996 to October 1999).nnnRESULTSnThe actuarial survival of the entire cohort of 1,086 patients undergoing cardiac transplantation was 79%, 66%, and 49% at 1, 5, and 10 years, respectively. There were significant trends in recipient age and gender distribution among the four eras with increasing proportion of older age (> 60 years) and female recipients in eras III and IV (p = 0.001 and 0.02). Early mortality and long-term survival improved significantly over all eras (p < 0.001). Rejection as a cause of death decreased over time (era I, 24%; era II, 21%; era III, 15%; era IV, 9%; p = 0.02), whereas the contribution of transplant coronary artery disease as a cause of death remained unchanged.nnnCONCLUSIONSnCardiac transplantation provides satisfactory long-term survival for patients with end-stage heart failure. The improving outcomes in survival correlate with improved immunosuppressive therapy in each era. Although the reasons for improvement in survival over time are multifactorial, we believe that changes in immunosuppressive therapy have had a major impact on survival as evidenced by the decreasing number of deaths due to rejection.

Interactions between the recipient immune system and the left ventricular assist device surface: immunological and clinical implications

The unquestionable clinical success of left ventricular assist device (LVAD) implantation has, nevertheless, been accompanied by complications arising from interactions between the implanted biomaterial and the host immune system. The aberrant state of monocyte and T-cell activation resulting from these host/device interactions is accompanied by two parallel processes: (1) selective loss of Th1 cytokine producing CD4 T-cells through activation-induced cell death; and (2) unopposed activation of Th2 cytokine producing CD4 T-cells resulting in B-cell hyperreactivity and dysregulated immunoglobulin synthesis through Th2 cytokines and heightened CD40 ligand-CD40 interactions. The net results of these events is that, on the one hand, the LVAD recipient develops progressive defects in cellular immunity and is at increased risk of serious infection, and, on the other hand, is more likely to develop allosensitization, posing a significant risk to successful transplant outcome. Intravenous immunoglobulin therapy is an effective and safe modality for sensitized LVAD recipients awaiting cardiac transplantation, reducing serum anti-human lymphoicyte antigen (HLA) alloreactivity and shortening the duration to transplantation. The therapeutic and safety profile of intravenous immunoglobulin would appear to be superior to plasmapheresis. Immunosuppression incorporating intravenous cyclophosphamide before and after transplantation is safe and highly effective in sensitized LVAD recipients of cardiac transplantation. When used after transplantation as part of triple immunosuppressive regimens, cyclophosphamide is superior to mycophenolate mofetil in reducing episodes of allograft rejection in these patients. Because these immune dysfunctions appear to be related to the effects of excessive biomaterial-associated T-cell activation, future efforts will need to be directed at either altering the physical properties of the materials interacting with the host circulation or pharmacological intervention aimed more selectively at inhibiting T-cell activation.

B-Cell activation and allosensitization after left ventricular assist device implantation is due to T-Cell activation and CD40 ligand expression

Left ventricular assist device (LVAD) implantation is frequently complicated by B-cell activation and allosensitization, posing a significant risk to successful transplant outcome. This study investigated whether B-cell hyperreactivity and alloantibody production in LVAD recipients involves T-cell dependent pathways. T-cell calcium flux and nuclear translocation of NFATc were used to determine states of T-cell activation. Flow cytometry was used to assess human T- and B-cell activation after culture with LVAD-derived biomaterial particles. Sera from LVAD recipients and controls were tested for the presence of anti-HLA antibodies, and for soluble CD40 ligand. LVAD-derived biomaterial induced rapid and sustained calcium flux into normal T cells, resulting in calcineurin-dependent nuclear translocation of NFATc. This resulted in increased T-cell expression of CD40 ligand and subsequent B-cell activation, which was reduced by inhibitors of T-cell activation (CsA or anti-CD25 mAb) or by anti-CD40 ligand mAb. LVAD recipients demonstrated higher frequencies of anti-HLA antibodies and serum levels of soluble CD40 ligand compared with heart failure controls. The results indicate that exposure of human mononuclear cells to LVAD-derived biomaterial leads to T-cell dependent B-cell activation via CD40--CD40 ligand interaction, and suggest that treatment with calcineurin inhibitors or monoclonal antibodies against either CD25 or CD40 ligand could be effective at preventing B-cell hyperreactivity and allosensitization after LVAD implantation.

Prolonged donor ischemic time does not adversely affect long-term survival in adult patients undergoing cardiac transplantation

OBJECTIVEnWith liberalization of donor eligibility criteria, organs are being harvested from remote locations, increasing donor ischemic times. Although several studies have evaluated the effects of prolonged donor ischemic times on short-term survival and graft function, few have addressed concerns regarding long-term survival.nnnMETHODSnOver the last 11 years, 819 consecutive adults underwent cardiac transplantation at Columbia Presbyterian Medical Center. Recipients were separated into the following 4 groups based on donor ischemic time: <150 minutes, 150 to 200 minutes, 200 to 250 minutes, and >250 minutes. Statistical analysis included Kaplan-Meier survival and Cox proportional hazard models to identify predictors of long-term survival.nnnRESULTSnDonor ischemic time was 120.1 +/- 21.1 minutes for group 1 (n = 321), 174.1 +/- 14.7 minutes for group 2 (n = 264), 221.7 +/- 14.6 minutes for group 3 (n = 154), and 295.5 +/- 37.1 minutes for group 4 (n = 80) (P <.001). There were no significant differences in recipient age, donor age, etiology of heart failure, United Network for Organ Sharing status, or history of previous cardiac surgery among the groups (P = NS). Prolonged donor ischemic time did not adversely affect long-term survival, with actuarial survival at 1, 5, and 10 years of 86.9%, 75.2%, and 56.4% for group 1; 86.2%, 76.9%, and 50.9% for group 2; 86.4%, 71.0%, and 43.7% for group 3; and 86.7%, 70.1%, and 50.9% for group 4 (P =.867). There was no significant difference in freedom from transplant coronary artery disease among the 4 groups (P =.474).nnnCONCLUSIONSnProlonged donor ischemic time is not a risk factor for decreased long-term survival. Procurement of hearts with prolonged donor ischemic time is justified in the setting of an increasing recipient pool with a fixed donor population.

Impact of current management practices on early and late death in more than 500 consecutive cardiac transplant recipients.

ObjectiveTo study risk factors for early and late death after heart transplantation in the current era. Summary Background DataThe current cardiac transplant population differs from earlier periods in that an increasing number of sicker patients, such as those with ventricular assist device (LVAD) support, prior cardiac allotransplantation, and pulmonary hypertension, are undergoing transplantation. In addition, sensitized patients constitute a greater proportion of the transplanted population. Emphasis has been placed on therapies to prevent early graft loss, such as the use of nitric oxide and improved immunosuppression, in addition to newer therapies. MethodsFive hundred thirty-six patients undergoing heart transplantation between 1993 and 1999 at a single center were evaluated (464 adults and 72 children; 109 had received prior LVAD support and 24 underwent retransplantation). The mean patient age at transplantation was 44.9 years. Logistic regression and Cox proportional hazard models were used to evaluate the following risk factors on survival: donor and recipient demographics, ischemic time, LVAD, retransplantation, pretransplant pulmonary vascular resistance, and immunologic variables (ABO, HLA matching, and pretransplant anti-HLA antibodies). ResultsThe rate of early death (less than 30 days) was 8.5% in adults and 8.8% in children. The actuarial survival rate of the 536 patients was 83%, 77%, and 71% at 1, 3, and 5 years, respectively, by Kaplan Meier analysis. Risk factors adversely affecting survival included the year of transplant, donor age, and donor-recipient gender mismatching. Neither early nor late death was influenced by elevated pulmonary vascular resistance, sensitization, prior LVAD support, or prior cardiac allotransplantation. ConclusionsPreviously identified risk factors did not adversely affect short- or long-term survival of heart transplant recipients in the current era. The steady improvement in survival during this period argues that advances in transplantation have offset the increasing acuity of transplant recipients.

Long-term results of cardiac transplantation in patients 65 years of age and older: a comparative analysis

BACKGROUNDnAdvanced age is viewed by some transplant centers as a contraindication for heart transplantation secondary to concerns regarding decreased survival.nnnMETHODSnBetween January 1992 and June 2002, 63 of 881 (7.2%) orthotopic heart transplants were performed in patients above 65 years. These patients were compared to 63 recipients below age 65 who were matched for sex, etiology of heart failure, United Network for Organ Sharing status, and immunosuppression therapy era.nnnRESULTSnMean age was 67.1 +/- 2.3 years (range, 65.0 to 74.8) for the older group and 48.1 +/- 14.5 years (range, 18.3 to 64.4) for the younger group (p < 0.001). There was no significant difference in the incidence of diabetes, hypertension, chronic obstructive pulmonary disease, or peripheral vascular disease between the groups (p = not significant) although there were more patients with prior myocardial infarctions in the older group (p < 0.001). There was no significant difference in overall survival between the groups, with 1-, 3-, 5-, and 10-year actuarial survival of 85.8%, 80.3%, 73.1%, and 49.9% for the older group; and 86.9%, 83.4%, 75.0%, and 57.0% for the younger group (p = 0.597). Postoperative intensive care unit stay and overall hospital stay were similar for the two groups (p = not significant). There was no significant difference between the groups in freedom from infection or rejection at 1, 3, or 5 years after transplant (p = not significant) although the incidence of transplant coronary artery disease was higher in the older group (p = 0.025).nnnCONCLUSIONSnThese data demonstrate similar short-term and long-term results for elderly and young recipients undergoing cardiac transplantation. This supports proceeding with transplantation in carefully selected elderly patients.

Induction of swine major histocompatibility complex class I molecules on porcine endothelium by tumor necrosis factor-α reduces lysis by human natural killer cells

BACKGROUNDnNatural killer (NK) cells have been implicated in a process of delayed xenograft rejection occurring in pig-to-primate organ transplants. As tumor necrosis factor-a (TNF-a) induces expression of both adhesion receptors and major histocompatibility complex class I molecules on porcine endothelium, we investigated the effects of TNF-alpha on human NK cell adherence to and cytotoxicity of porcine aortic endothelial cell (PAEC) monolayers.nnnMETHODSnAdherence of human NK cells was measured after PAEC treatment with increasing concentrations of TNF-alpha. Monoclonal antibodies (mAbs) against adhesion molecules on NK cells and PAEC were used in inhibition studies. Resting or TNF-alpha-treated PAEC were used as targets for NK lysis. Increasing titers of anti-swine leukocyte antigen (SLA) class I antibodies or pooled human immune globulin (IVIg) were used to reverse the effects of TNF-alpha on NK lysis.nnnRESULTSnNK cell adhesion to TNF-a-treated PAEC increased in a dose-dependent manner by a maximum of 44%, and was inhibited by mAbs against CD49d, CD11a, CD11b, CD18, and CD2, as well as porcine vascular cell adhesion molecules. In contrast, TNF-alpha treatment of PAEC reduced human NK lysis in a dose-dependent manner. Preincubation of TNF-a-treated PAEC with increasing concentrations of anti-SLA class I mAb increased NK lysis in a titer-dependent manner, and reversed the protective effect on human NK lysis by 77%. Treatment with IVIg, containing antibodies against an a-helical region of HLA class I molecules, had a similar effect.nnnCONCLUSIONSnThese results imply that SLA class I molecules can bind to inhibitory receptors on human NK cells, and that these interactions can be augmented by increasing the level of SLA class I molecule expression on porcine endothelium. Strategies that can increase porcine endothelial cell expression of either swine or human major histocompatibility complex class I molecules may reduce human NK activity against porcine xenografts.

Factors Affecting Long-Term Survival (.10 Years) After Cardiac Transplantation in the Cyclosporine Era

OBJECTIVESnThe aim of this study was to determine long-term survival (>10 years) after cardiac transplantation in the cyclosporine era and identify risk factors influencing long-term survival.nnnBACKGROUNDnDespite the availability of newer modalities for heart failure, cardiac transplantation remains the treatment of choice for end-stage heart disease.nnnMETHODSnBetween 1983 and 1988, 195 patients underwent heart transplantation at a single center for the treatment of end-stage heart disease. Multivariable logistic regression analysis of pretransplant risk factors affecting long-term survival after cardiac transplantation included various recipient and donor demographic, immunologic and peritransplant variables.nnnRESULTSnAmong the group of 195 cardiac transplant recipients, actuarial survival was 72%, 58% and 39% at 1, 5 and 10 years respectively. In the 65 patients who survived >10 years, mean cardiac index was 2.91/m2 and mean ejection fraction was 58%. Transplant-related coronary artery disease (TRCAD) was detected in only 14 of the 65 patients (22%). By multivariable analysis, the only risk factor found to adversely affect long-term survival was a pretransplant diagnosis of ischemic cardiomyopathy (p = 0.04).nnnCONCLUSIONSnLong-term survivors maintain normal hemodynamic function of their allografts with a low prevalence of TRCAD. It is possible that similar risk factors that lead to coronary artery disease in native vessels continue to operate in the post-transplant period, thereby contributing to adverse outcomes after cardiac transplantation. Aggressive preventive and therapeutic measures are essential to limit the risk factors for development of coronary atherosclerosis and enable long-term survival after cardiac transplantation.

Immunobiologic consequences of assist devices

The aberrant state of monocyte and T-cell activation resulting from these host-device interaction is accompanied by two parallel processes: (1) selective loss of Th1 cytokine-producing CD4 T cells through activation-induced cell death, and (2) unopposed activation of Th2 cytokine-producing CD4 T cells resulting in B-cell hyperreactivity and dysregulated immunoglobulin synthesis via Th2 cytokines and heightened CD40 ligand-CD40 interactions. The net result of these events is that on one hand the VAD recipient develops progressive defects in cellular immunity and is at increased risk of serious infection, and on the other hand the VAD recipient is more likely to develop allosensitization, posing a significant risk to successful transplant outcome.