doi: 10.1161/hc37t1.094704
(Circulation. 2001;104:I-177.)
© 2001 American Heart Association, Inc.
Thoracic Transplantation and Ventricular Assist Devices |
Increased Prevalence of Autoimmune Phenomena and Greater Risk for Alloreactivity in Female Heart Transplant Recipients
From the Divisions of Cardiothoracic Surgery (K.L., R.J., A.K., M.S., N.M.E., S.I.) and Cardiology (D.M.M.), Columbia Presbyterian Medical Center, Columbia University, New York, NY.
Correspondence to Silviu Itescu, MD, Division of Cardiothoracic Surgery, Columbia Presbyterian Medical Center, 630 W 168th St, P&S 14-402, New York, NY 10032. E-mail si5{at}columbia.edu
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Abstract |
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Background— The influence of sex on alloreactivity and graft outcome after heart transplantation was evaluated.
Methods and Results— A retrospective review of 520 consecutive recipients of a primary cardiac allograft between 1992 and 2000 at a single center was performed. The influence of sex on alloreactivity, acute rejection, transplant-related coronary artery disease, and survival was determined. Statistical methods included logistic regression analysis and Kaplan-Meier actuarial survival analysis. Female recipients had an increased prevalence before transplant of idiopathic cardiomyopathy, antinuclear antibodies, and HLA-B8, DR3 haplotypes. After transplant, female sex predicted shorter duration to a first rejection, higher cumulative rejection frequency, and earlier posttransplant production of anti-HLA antibodies. Female recipients had higher early mortality rates (<6 months) that were due to infection. Fatal infections correlated with 2-fold higher cyclosporine levels in female recipients. However, the incidence of transplant-related coronary artery disease developing beyond 1 year after transplant was lower in female than in male recipients.
Conclusions— Females undergoing cardiac transplantation are more likely to manifest features of an underlying autoimmune state. This may predispose to a higher posttransplant risk of allograft rejection and requirement for increased immunosuppression. Earlier diagnosis and management of alloreactivity in female recipients before development of acute rejection and the use of more focused and less globally immunosuppressive agents during established rejections may have a significant effect on the clinical outcome of female cardiac allograft recipients.
Key Words: transplantation • immune system • immunology
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Introduction |
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Despite many available modalities for the treatment of end-stage heart disease, cardiac transplantation remains the gold standard.1 Female recipients of cardiac transplantation have been reported to have increased mortality compared with male recipients.2–4 Although there is a relative paucity of information regarding differences in immunologic parameters between male and female patients undergoing cardiac transplantation, it is possible that differences in sex hormones may influence immunologic reactivity. Various immunologically related conditions, such as systemic lupus erythematosus, idiopathic thrombocytopenic purpura, and rheumatoid arthritis, are found in increased prevalence among women, and there is experimental evidence to suggest that fundamental immune responses, such as antibody production and rejection of allogeneic grafts, are potentiated in females.5 It has been suggested that these increased immune responses in females may be attributed to the distribution of androgens and estrogens, which have been shown to have opposing effects on the development and responsiveness of antigen presenting cells and lymphocytes within lymphoid organs.5,6
In the present study, we investigated the role of sex in alloreactivity and clinical outcome after cardiac transplantation. We retrospectively evaluated a cohort of >500 consecutive adult patients undergoing heart transplantation to study differences in the pretransplant and posttransplant immunologic and clinical profiles of male and female heart transplant recipients. A better understanding of the mechanisms by which sex influences cardiac allograft outcome may have important implications for management, including alterations in immunosuppression and changes in immunologic monitoring and surveillance in women after organ transplantation.
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Methods |
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Patients
Between January 1992 and January 2000, 520 primary transplants were consecutively performed in adult recipients at the New York Presbyterian Hospital-Columbia Medical Center. The patients were predominantly male (79%) and white (81%), with a mean age of 50.8±12.4 years. Mean ischemic time was 173±52 minutes. Pretransplant diagnosis was ischemic cardiomyopathy in 306 patients (59%), idiopathic cardiomyopathy in 131 (25%), congenital heart disease in 23 (4%), and other in 60 (12%). Mean follow-up time was 33.6±27.7 months (range 0 to 92 months).
Operative Techniques
Donor hearts were harvested from beating-heart, brain-dead individuals. Graft procurement and preservation used cold cardioplegic arrest with University of Wisconsin solution and topical hypothermia. From 1992 to 1996, orthotopic cardiac transplantation was performed by the biatrial technique described by Lower and Shumway.7 Since 1996, we have performed almost all transplants with the bicaval anastomosis technique.
Immunosuppressive Regimen
All patients received triple immunosuppression, consisting of cyclosporine, steroids, and azathioprine or mycophenolic acid. Azathioprine was given at an initial preoperative dose of 4 mg · kg-1 · d-1, followed by a daily intravenous dose of 2 mg/kg until the patient could tolerate oral medication. Since 1996, azathioprine has been replaced by mycophenolate mofetil at an initial dose of 1000 mg twice daily. Cyclosporine was given at the initial dose of 1 to 2 mg · kg-1 · d-1, which was adjusted to maintain trough whole-blood levels between 300 and 350 ng/dL. Between 3 and 6 months after transplantation, cyclosporine dosage was adjusted to maintain blood cyclosporine levels between 150 and 250 ng/dL, and after 6 months between 100 and 150 ng/dL. Intravenous methylprednisolone (500 mg) was administered during the operation and in the postoperative period at a dose of 125 mg every 8 hours over 24 hours. Prednisone was given in tapering doses of 1 mg · kg-1 · d-1 immediately postoperatively to 0.1 mg · kg-1 · d-1 by the fourth month. Rejection episodes (International Society for Heart and Lung Transplant [ISHLT] grade 3A or higher) were treated with oral or intravenous pulses of steroid 100 mg/d for 3 days followed by a taper over 1 week to the baseline dose. Nonresponders were treated with cytolytic therapy (OKT3 or ATGAM).
Clinical Data
The following pretransplant data variables were analyzed: recipient age, sex, ethnicity, pretransplant diagnosis, ventricular assist device use, weight, height, body mass index, pretransplant cytomegalovirus infection, and presence or absence of diabetes, as well as donor age, sex, race, weight, height, and body mass index, along with information on HLA-A, -B, and -DR mismatches. After transplantation, data on acute rejection (severity and time to first high-grade rejection), transplant-related coronary artery disease (TCAD), and 1-, 2-, and 5-year survival were obtained.
Acute Rejection
The diagnosis of acute rejection was based on clinical symptoms and confirmed by endomyocardial biopsy performed weekly for the first 3 weeks, every second week for the next 3 biopsies, every 3 weeks for the next 3 biopsies, monthly for the remainder of the first year, and every other month thereafter. Biopsy fragments were graded according to ISHLT criteria.8 High-grade cellular allograft rejection was defined pathologically as grade 3A or 3B.
Angiography/Diagnosis of TCAD
Patients underwent annual coronary angiography. The diagnosis of TCAD was based on the following: (1) discrete lesions resulting in >50% obstruction of the proximal or mid portions of major graft vessels or (2) diffuse, concentric narrowing of the whole vessels, including their branches. If TCAD was identified, the frequency of angiography was increased to a biannual regimen. Patients were not given routine vasodilators before coronary injections. All angiograms were reviewed by a cardiologist and compared with the previous year’s films to detect the presence of luminal irregularities, discrete stenoses, loss of third-order branches, or pruning of vessels. Explanted hearts and autopsy specimens were examined for evidence of vessel occlusion and irregularities, ischemic damage, and presence of acute cardiac rejection.
HLA Typing
Serological typing of HLA-A and HLA-B loci was performed by standard microcytotoxicity techniques. HLA-DR typing was performed by serological analysis.
Detection of Anti-HLA Antibodies
Sera were obtained from all patients on the day of transplantation and screened for the presence of lymphocytotoxic antibodies against separated T lymphocytes and B lymphocytes obtained from a panel of 70 individuals representative of all HLA class I and II antigens found in the North American population.
Determination of Anti-HLA Antibody Specificity for Major Histocompatibility Complex Class I or Class II Antigens
Working definitions for IgG antibodies against HLA class I molecules (IgG anti-I) or class II molecules (IgG anti-II) were established in our laboratory. For reference, we used sera from 28 heart transplant recipients with panel reactive antibody values >10% and with anti-HLA class I and II specificities defined by standard tail analysis, as described previously.9
Statistical Analysis
Differences between groups were examined by 
2 or Fisher exact test. Continuous variables were compared with the Student t test if normally distributed; if not, a Wilcoxon rank sum test was used. Survival estimates were based on the Kaplan-Meier method, and curves were compared with a log-rank test.10 Univariate and multivariate analyses were performed to determine the impact of pretransplant body mass index on incidence of acute rejection, TCAD, and posttransplant survival. The covariates, which correlated with end points on univariate analysis (P<0.15), were entered in the multivariate Cox proportional hazards model by stepwise selection. The cumulative rejection frequency used the method of Wei et al11 to produce tests and partial likelihood estimates for repeated events. Results were considered significant at P<0.05. Values are reported as mean±SD. Data were analyzed with SAS System software version 6.14 (SAS Institute, Inc).
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Results |
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Recipient Demographics
The differences between male and female recipients are represented in Table 1. The mean age of female recipients was significantly lower than that of male recipients (47.5±12.05 versus 51.7±12 years, P=0.001). Furthermore, 32 (29%) of 109 female recipients were younger than 40 years compared with 67 (16%) of 411 male recipients (P=0.002). There was an increased frequency of nonwhite ethnicity in female recipients (26% versus 17% for male recipients, P=0.03).
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Increased Features of Autoimmune Phenomena Before Transplantation in Female Recipients of Cardiac Allografts
In our patient population, idiopathic cardiomyopathy was found to be the leading cause of end-stage heart failure in female recipients (32%) but not in male recipients (23%, P=0.04), in whom the major cause of end-stage heart disease was ischemic cardiomyopathy (63%). Moreover, female recipients in the present study demonstrated an increased incidence of antinuclear antibodies before transplantation (32% versus 19% in male recipients, P=0.02) and an increased frequency of HLA-B8, DR3 haplotypes (11% versus 6% in males, P=0.06; Table 1).
Increased Risk of Anti-HLA Antibody Production After Transplantation in Female Recipients of Cardiac Allografts
Although there was no difference in the frequency of pretransplant sensitization (presence of preformed IgG anti-HLA class I or II antibodies) between female and male recipients (Table 1; P=0.1), female recipients were more likely than males to develop anti-HLA antibodies after transplantation (Table 2). At the end of the first posttransplant year, 39% of previously unsensitized females developed IgG anti-HLA antibodies compared with 28% of males (P=0.06). This was exclusively accounted for by production of IgG antibodies directed against HLA class II molecules.
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Female Cardiac Allograft Recipients Demonstrate a Shorter Time to First High-Grade Rejection and Increased Cumulative Rejection Frequency
We next investigated whether the increased prevalence of autoimmune phenomena and heightened alloreactivity among female cardiac allograft recipients had an effect on allograft outcome. As shown in Figure 1, female recipients demonstrated a shorter time to first high-grade rejection than male recipients (mean of 1.4 versus 2.6 weeks, P=0.01) and a 1.5-fold greater risk for rejection during the first posttransplant year (CI 1.047 to 2.052, P=0.02). At the end of the first year after transplant, 45% of female recipients had at least 1 high-grade rejection compared with 37% of males (P=0.025). Overall, the cumulative rejection frequency was significantly higher in female than in male recipients (0.98 versus 0.68 high-grade rejections per year, P=0.03; Table 3).
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Pretransplant Diagnosis of Idiopathic Cardiomyopathy Predicts Increased Risk for Cardiac Allograft Rejection in Female Recipients.
To investigate whether the increased risk for allograft rejection observed in female recipients was associated with the higher pretransplant prevalence of idiopathic cardiomyopathy in females, rejection frequency was reanalyzed after female recipients were stratified on the basis of pretransplant diagnosis. As shown in Figure 2, female recipients found to be at greatest risk for rejection were those with a pretransplant diagnosis of idiopathic cardiomyopathy. These findings were confirmed by multivariate analysis as shown in Table 4. As expected, other significant risk factors that influenced time to first high-grade rejection included a complete mismatch at the HLA-DR locus (RR 1.4, P=0.04).
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Female Recipients of Cardiac Allografts Have Greater Short-Term Mortality as a Result of Infection Than Male Recipients
Because we showed that female recipients had a higher incidence of allograft rejection after transplant, we next investigated whether mortality was also greater in female recipients. As shown in Figure 3, female recipients had significantly higher early mortality rates (within the first 6 months) after heart transplantation than male recipients. Actuarial survival by Kaplan-Meier analysis in females at 6 months after heart transplantation was 81% compared with 89% in males (P=0.03; Figure 3). Beyond this time period, both groups demonstrated similar actuarial survival rates (P=0.28). By multivariate analysis, female sex was found to be a significant risk factor for early (<6 month) mortality but not late mortality (Tables 5, 6, and 7). Additional risk factors for early mortality included prolonged ischemia and a preoperative diagnosis of congenital heart disease.
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We next examined the causes of early and late mortality in female transplant recipients. As shown in Table 8, female recipients had an increased frequency of fatal infections in the early posttransplant period (<6 months) compared with males (relative risk 1.5, P=0.08). The development of fatal infections within the first 6 months after transplantation was found to correlate with mean blood levels of cyclosporine in the first 2 weeks after transplantation, with mean trough levels at 2 weeks that were 2-fold higher in female than in male recipients (P=0.001). No significant differences between females and males were observed in the causes of deaths beyond 6 months. However, the incidence of TCAD developing beyond 1 year after transplant was lower in female than in male recipients (43% versus 62% at 3 years, P=0.027; Figure 4).
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Discussion |
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The influence of sex on patient outcomes after transplantation is a complex issue, as evidenced by conflicting reports in the literature.12,13 As has been reported for recipients of other solid organ transplants, in the present study we show that female cardiac allograft recipients demonstrate an increased development of alloreactivity compared with male recipients, as defined by early development of anti-HLA class II antibodies and allograft rejection.14–17 The increased risk for alloreactivity was especially evident in the subgroup of female recipients with idiopathic cardiomyopathy and may be a result of the presence of an undifferentiated autoimmune state in this group of patients, as supported by the observed increase in prevalence of antinuclear antibodies and HLA-B8, DR3 haplotypes in these patients, a genotype associated with a variety of autoimmune diseases including systemic lupus erythematosus and celiac disease.18,19
Despite the increased incidence of early and repeated episodes of acute rejection in female recipients, rejection was not directly implicated causally in the increased mortality seen early (at <6 months after transplantation) in this group. However, because the principal cause of the early mortality was infection and this directly correlated with blood levels of cyclosporine, which were found to be 2-fold higher in female than in male recipients, we conclude that the increase in early mortality was predominantly due to the requirement for excessive immunosuppression in females with acute rejection. These data suggest that earlier diagnosis and management of alloreactivity in female recipients before development of acute rejection and the use of more focused and less globally immunosuppressive agents during established rejections may have a significant effect on the clinical outcome of female cardiac allograft recipients.
There is a large body of clinical and experimental evidence that demonstrates that sex has a profound effect on the host immune system, including humoral or cellular immunity and autoimmune phenomena.20–23 Immunoglobulin levels vary between the sexes, and IgM in particular is consistently higher in females than in males. Familial studies that compare IgM levels among parents and offspring support the hypothesis that the X chromosome carries quantitative genes for IgM production.6 Furthermore, the observation of a higher IgM level in younger women and the increase in IgM levels in women taking oral contraceptives add credibility to the hypothesis that immunoglobulin levels may be dependent on estrogen. The mechanism by which estrogens influence the host antibody response is not well understood.
Androgens, which are believed to be immunosuppressive, are also a possible cause of enhanced graft acceptance in male recipients.24,25 Experimental studies have shown accelerated graft rejection in orchiectomized rats. Castro26 reported that castration is associated with an accelerated rejection of skin allografts, which could be prevented by androgen administration. Graff et al27 showed that the testis, rather than the ovary and the adrenal gland, was responsible for the sex difference in skin graft survival time between a congenic mouse strain pair that were only different at a minor histocompatibility (H-12) locus. One of the possible mechanisms that have been postulated to cause increased graft rejection in females is H-Y incompatibility. This process is believed to occur when male grafts are transplanted into female recipients (sex mismatch), in which antigenicity coded for by the Y chromosome in male grafts provokes an immune response to reject the graft in the female recipient.28,29
Although female recipients demonstrated increased early mortality in association with increased rejection rates, alloreactivity, and fatal infections, they had a significantly lower incidence of TCAD. Because enhanced alloreactivity in female recipients has also been described by other investigators,14,15 and development of alloreactivity and acute rejection have been shown to be major predictors of subsequent TCAD,30,31 this paradox requires further understanding. A protective role of estrogens could be responsible for the decreased incidence of TCAD in female patients.32,33 Moreover, nonimmunologic risk factors for TCAD, such as hypertension and hyperlipidemia, which occur more often in male recipients, may also be involved.34
Conclusions
Female recipients have a greater prevalence of autoimmune phenomena before transplantation and increased alloreactivity, resulting in an increased risk of posttransplant rejection compared with male recipients. The increase in rejection risk in female recipients results in greater use of immunosuppression and an increase in early (<6 month) mortality due to infection. Further studies are required to understand the relationship between autoimmune phenomena, female sex, and risk for alloreactivity after transplantation. Together, our data suggest that earlier diagnosis and management of alloreactivity in female recipients before development of acute rejection and the use of more focused and less globally immunosuppressive agents during established rejections may have a significant effect on the clinical outcome of female cardiac allograft recipients.
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