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Circulation. 1995;91:1029-1035

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(Circulation. 1995;91:1029-1035.)
© 1995 American Heart Association, Inc.

Articles

Increased Early Mortality in Women Undergoing Cardiac Transplantation

Presented in part at the 65th Scientific Sessions of the American Heart Association, New Orleans, La, November 17, 1992.

Mindy E. Wechsler, MD; Elsa-Grace V. Giardina, MD; Robert R. Sciacca, ScD, Eng; Eric A. Rose, MD; Mark L. Barr, MD

From the Cardiovascular Clinical Pharmacology Laboratory and Center for Women's Health, Department of Medicine (M.E.W., E.-G.V.G., R.R.S.), and the Division of Cardiothoracic Surgery, Department of Surgery (E.A.R., M.L.B.), College of Physicians and Surgeons, Columbia University, New York, NY, and Health Care Consultation Center (M.L.B.), USC School of Medicine, Los Angeles, Calif.


*    Abstract
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 *Abstract
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Background To evaluate factors that explain sex differences affecting mortality after cardiac transplantation, a retrospective analysis of adult patients undergoing orthotopic cardiac transplantation was undertaken at the Columbia-Presbyterian Medical Center.

Methods and Results The study population consisted of 379 patients (75 women, 304 men) >=18 years of age who survived for >=48 hours after undergoing orthotopic cardiac transplantation between March 1985 and March 1992. The following were analyzed: incidence of death and treated rejection episodes, donor and recipient cytomegalovirus (CMV) matches, use of OKT3 induction therapy, and donor and recipient HLA mismatches. Women 49±12 years old and men 47±12 years old were characterized by differences in race and diagnosis. Women were more likely to be nonwhite (P<.01) and have idiopathic cardiomyopathy than were men (P<.01). A trend toward an increase in first-year rejection frequency was seen in women compared with men (P=.08). Overall actuarial survival was significantly reduced in women after transplantation (P<.05). At 36 months, female actuarial survival was 64±7% versus 76±3% for men (P<.05). The majority of patients in this study did not receive CMV prophylaxis. Univariate analysis revealed that only CMV(+) donor status and the use of OKT3 induction therapy affected survival in women. Multivariate analysis revealed a marked reduction in survival in female recipients of CMV(+) donors given OKT3 induction therapy. At 36 months, only 25% of women were still alive compared with 86% of women with neither risk factor (P<.001). Even without OKT3 induction there was markedly reduced survival in women with mismatched CMV status, ie, CMV(-) recipients of CMV(+) donors; 17% survival after 36 months versus 86% in women who were CMV(+) recipients (P<.05). Although at this institution during the study time period, CMV prophylaxis was not routinely employed and OKT3 induction was selectively used in higher-risk patients, conclusions regarding differences in outcome that are sex dependent are valid.

Conclusions (1) Women are at risk for reduced actuarial survival up to 3 years after cardiac transplantation. (2) Univariate analysis shows that women are selectively at risk for death when receiving hearts from CMV(+) donors and after receiving OKT3 induction therapy. (3) Multivariate analysis reveals that women are at even greater risk for death when receiving hearts from CMV(+) donors in conjunction with OKT3 induction therapy. (4) In the absence of OKT3 use, the greatest risk of death occurs in CMV(-) women transplanted with CMV(+) donor hearts. (5) When female to male survival curves are compared, factors that influenced survival in women did not appear to be problematic in men.


Key Words: risk factors • transplantation • clinical trials • rejection


*    Introduction
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While cardiac transplantation has become an accepted treatment available for end-stage cardiac disease, the number of women undergoing cardiac transplantation is significantly fewer than the number of men. From 1988 through 1992, women represented between 17% and 19% of the population of patients undergoing transplantation.1 2 A number of factors account for the relatively small number of women, including the different nature of heart disease affecting the sexes and the different time course the heart disease follows. Women are more likely to have cardiomyopathy and men to have coronary artery disease. Coronary artery disease is more likely to affect men at a younger age.

Due to the relatively small number of women undergoing cardiac transplantation, few studies have clearly examined the effect of gender on cardiac transplantation. Among reported studies, there are conflicting data on rejection and survival. Two small studies, of 21 and 27 women, respectively, concluded that women have a higher incidence of rejection after cardiac transplantation.3 4 In a larger population of 70 women, Zerbe and coinvestigators5 found that rejection in women is comparable to that found in men. Another report from Sharples and associates6 found that women are at increased risk of death from rejection. Although the International Heart Transplant Registry reported decreased actuarial survival in women compared with men in the 1988 report, it was not decreased in the 1989 report.1 7

The present study was undertaken to evaluate the risk factors for mortality and morbidity in women after cardiac transplantation. It is a retrospective analysis of survival and rejection after cardiac transplantation in 75 women and 304 men. The study seeks to examine factors that might explain sex-related differences after cardiac transplantation.


*    Methods
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 *Methods
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Study Design
A retrospective analysis was performed on all patients undergoing orthotopic primary cardiac transplantation at the Columbia-Presbyterian Medical Center between March 1985 and March 1992 who survived for >=48 hours and were >18 years old. Only patients surviving 48 hours were analyzed to exclude surgical mortality. Data were obtained by review of each patient's chart, as well as review of autopsy and pathology reports to verify rejection, survival, and cause of death. All patients were maintained on triple immunosuppressive therapy consisting of cyclosporine, azathioprine, and prednisone. Beginning in 1988, OKT3 induction, 5 mg/d for 7 to 14 days, was used for higher-risk patients requiring preoperative intravenous inotropic drugs or having an elevated serum creatinine (>1.5 to 1.8 mg/dL).8 Since 1988, 21 of 67 women and 103 of 294 men were treated with OKT3 induction. Death and rejection were the only end points for the study.

Risk Factors
Potential risk factors for mortality and rejection investigated included sex, age, race, cardiac diagnosis, cardiac classification before treatment by New York Heart Association (NYHA) criteria and cardiac classification by United Network for Organ Sharing (UNOS) criteria, cytomegalovirus (CMV) serology of the donor, CMV serology of the recipient, use of OKT3 induction therapy, ABO blood types, HLA types, comorbid disease, prior cardiac surgery, and parity.

Rejection
Rejection was diagnosed and graded by endomyocardial biopsy in combination with clinical criteria. All acute rejection episodes [International Society for Heart and Lung Transplantation (ISHLT) IIIa or greater] were treated and patients with infiltrates (ISHLT Ib or II) were treated on the basis of their clinical condition and the hemodynamic data at the time of catheterization. For the purposes of this study, rejection episodes are defined as those episodes that required intervention and were treated with at least augmented corticosteroids.

Cytomegalovirus Status
CMV serology of donor and recipient was screened before transplantation to determine the presence or absence of anti-CMV antibodies. CMV prophylaxis was begun in May 1989 for all newly transplanted patients receiving organs from CMV(+) donors. Prophylaxis consisted of Sandoglobulin (Sandoz) or Gammagard (Baxter) globulin preparations (eight doses over 12 weeks) and oral acyclovir. Ganciclovir was used only to treat documented CMV infections and was not part of the prophylactic regimen.

HLA Typing
HLA-A, HLA-B, and HLA-DR type was ascertained before transplantation in the recipient and after transplantation in the donor in the majority of patients. The total number of HLA-A, -B, and -DR mismatches found between donor and recipient were retrospectively determined.

Statistical Analysis
Data are reported as means and standard deviations for continuous variables and as percent prevalence for discrete variables. Group differences in continuous variables were assessed by a t test (comparison between two groups) or by ANOVA (comparisons among three or more groups). Differences in the prevalence of discrete variables were analyzed by Fisher's exact test or by {chi}2. Tests for group differences of nonnormally distributed continuous variables, ie, rejection frequency, were performed with the Kruskal-Wallis nonparametric procedure.9 Kaplan-Meier estimates of survival were computed, and univariate and multivariate tests of the significance of group differences were performed with the log-rank test.10


*    Results
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*Results
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Clinical Characteristics
Table 1Down shows that in the 7-year period, 379 adult patients, 75 women and 304 men, underwent primary orthotopic cardiac transplantation. Women and men were similar in age but differed in cardiac diagnoses. Women were diagnosed with idiopathic cardiomyopathy 1.4 times as frequently as men, and women were diagnosed with coronary artery disease only half as frequently as men (P<.01). Both women and men were predominantly white; however, there were more black and Hispanic women than men. Of the women, 69% were white, 19% black, and 12% Hispanic, while 87% of the men were white, 6% black, and 5% Hispanic (P<.01). There was no difference in age between women and men when they were stratified for type of heart disease.


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  		Table 1. Clinical Characteristics of Patients

Overall Survival and Rejection
Overall actuarial survival was significantly reduced in women after transplantation (P<.05). In this study, 26 of 75 women (35%) and 77 of 304 men (25%) died. At 6 months after transplantation, female actuarial survival was 75±5% versus 84±2% for men. At 36 months after transplantation, female survival was 64±7% versus 76±3% for men (P<.05) (Fig 1Down). Eighteen female deaths occurred within a 6-month period and 20 within the first year. Primary cause of death is listed in Table 2Down. No significant differences between primary cause of death between women and men were seen. In women and in men the number of HLA-A, HLA-B, and HLA-DR mismatches did not correlate with increased mortality. There was no significant difference in mortality between women and men with four to six HLA mismatches. However, women with four to six HLA mismatches had significantly increased first-year rejection frequency (0.26±0.41 episodes per patient month) compared with men with four to six HLA mismatches (0.15±0.27 episodes per patient month) (P<.05). In men, no significant difference in first-year rejection frequency was seen in those with zero to three HLA mismatches compared with men with four to six HLA mismatches.



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  		Figure 1. Graphs show Kaplan-Meier estimates of survival in adult patients up to 60 months after cardiac transplantation. Female actuarial survival was significantly reduced compared with male survival (P<.05).


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  		Table 2. Primary Causes of Death

Univariate Analysis of Factors Affecting Mortality
Univariate analysis of the following risk factors affecting survival in women and men was performed: age, diagnosis, race, NYHA classification, UNOS classification, CMV serologies of donor and recipient, use of OKT3 induction therapy, blood type, HLA mismatch, and, in women, parity. Only CMV donor status and the use of OKT3 induction therapy were found to affect survival in women. Therefore, further multivariate analy- sis was performed to determine the interaction of CMV donor status and the use of OKT3 induction therapy in women and men.

Multivariate Analysis of CMV, OKT3, and Sex on Survival
A marked reduction in survival was seen in female recipients of CMV(+) donors given OKT3 induction (n=11; Fig 2Down). At 36 months, only 25% of female recipients of CMV(+) donors given OKT3 induction were still alive versus 86% in women with neither risk factor (n=15) (P<.001). A reduction in survival was also noted in female recipients of CMV(+) donors not treated with OKT3 (n=24), 52% compared with 86% in those with neither risk factor; however, this was of borderline significance (P=.06). Survival in female recipients of CMV(-) donors who received OKT3 (n=10) was not different from those with neither risk factor, 80% versus 86% (P=NS).



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  		Figure 2. Graphs show Kaplan-Meier estimates of survival in women up to 42 months after cardiac transplantation according to CMV donor and OKT3 induction status. Actuarial survival in female recipients of CMV(+) donors who received concurrent OKT3 induction was significantly diminished compared with those with neither risk factor (P<.001).

Survival was slightly reduced in male recipients of CMV(+) donors given OKT3 induction (n=54), 65% compared with 85% in men with neither risk factor (n=76); however, this was of borderline significance (P=.09; Fig 3Down). No difference in survival was seen in male recipients of CMV(+) donors not given OKT3 (n=65) nor male recipients of CMV(-) donors who were given OKT3 (n=49) compared with male recipients of CMV(-) donors not treated with OKT3.



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  		Figure 3. Graphs show Kaplan-Meier estimates of survival in men up to 42 months after cardiac transplantation according to CMV donor and OKT3 induction status. Actuarial survival in male recipients of CMV(+) donors who received concurrent OKT3 induction was somewhat reduced compared with those with neither risk factor but was of borderline statistical significance (P<.09).

Effect of CMV Mismatching
In women not treated with OKT3 induction, additional subgroup analysis of CMV mismatching was performed. Markedly reduced survival was observed in female CMV(-) recipients of CMV(+) donors (n=8), 17% after 36 months compared with 86% survival in female CMV(+) recipients of CMV(+) donors (n=16) (P<.05). This analysis was precluded in those patients given OKT3 due to the limited number of patients in each of the subgroups.

In men not treated with OKT3 induction, there was no significant difference in survival between CMV(-) recipients of CMV(+) donors (n=18), 77% at 36 months, and CMV(+) recipients of CMV(+) donors (n=46), 76% at 36 months.

Multivariate Analysis of CMV, OKT3, and Sex on Rejection
Increased first-year rejection frequency was observed only in women transplanted with CMV(+) donors irrespective of OKT3 use (Table 3Down).


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  		Table 3. First-Year Rejection Frequency


*    Discussion
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*Discussion
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Effect of Gender on Rejection and Survival
Gender has been reported to affect rate of rejection and actuarial survival after cardiac transplantation.1 3 4 11 Several considerations regarding sex differences have been examined to account for the poorer outcome after cardiac transplantation in women. These include risk of multiple pregnancy,12 risk of male to female mismatch,4 13 and corticosteroid therapy after cardiac transplantation.3 13 Since the number of women undergoing transplantation has been small compared with the number of men, conclusions have been limited. The present study seeks to address these issues in a relatively large group of 75 women. Some studies suggest that while the incidence of rejection is increased in women undergoing cardiac transplantation, the actuarial survival rate is comparable with that of men.3 4 Others fail to show that women are at increased risk for rejection.5 We found that rejection frequency is increased somewhat compared with men but fails to reach statistical significance. Of greater interest, however, is the significant reduction in actuarial survival in women (P<.05). To determine the possible cause(s) of reduced survival in women, further analysis of risk factors was made. Of all variables examined, only CMV(+) status of the donor and OKT3 induction therapy affected survival.

CMV as a Risk Factor for Adverse Outcome
Clinically it has been recognized that mismatched CMV status is problematic for cardiac transplantation.14 15 Theoretically, with the advent of improved immunosuppression, prophylaxis, and treatment with antiviral agents, this problem is manageable. Reports on therapy, however, frequently discuss outcome in morbidity terms but do not report effects on survival.16 17 18 19 Even in renal transplantation, trials conducted with immunosuppressive and antiviral agents limit end points to morbidity.20 21 Conducted within a population treated with triple immunosuppressive therapy, the present study strongly suggests that mismatched CMV status in women places them at a significantly increased risk for a fatal outcome. Is mismatched CMV status for women (1) primarily a marker for rejection and decreased survival or is it (2) causally related to CMV infection and a subsequent adverse outcome? The association of CMV infection with a variety of infections, increased rejection, increased incidence of cardiac allograft atherosclerosis, and death after cardiac transplantation has been recognized.22 23 24 During transplantation both the allograft and blood products can transmit exogenous virus from infected donors to recipients. The mechanism(s) responsible for CMV infection at transplantation include (1) transmission by donor organ or via transfusion of CMV(+) blood to a CMV(-) recipient, (2) reactivation of latent CMV infection in an immunocompromised host, and (3) transmission of a different strain of CMV to an already seropositive CMV recipient.18 Matching donor and recipient with respect to CMV serology should minimize primary infection with CMV25 26 and should therefore improve survival. In 1988, the group at Papworth26 27 described CMV infection in a series of 33 heart-lung transplantation recipients. Of 8 patients who received grafts from CMV(+) donors, 5 developed severe CMV pneumonitis, and an additional patient developed gastrointestinal CMV. Death occurred in 3 of 5 patients with CMV pneumonitis, leading to the adoption of a policy of obligatory CMV donor-recipient matching. After implementation of the policy, morbidity and mortality from CMV infection declined. To date, review of sex in relation to CMV status and survival in heart transplant recipients has not been performed. The results of the present study show an increase in rejection episodes and an alarming and significant reduction in survival in female recipients of CMV(+) donors up to 36 months after heart transplantation. Since this was a retrospective study, we could neither evaluate CMV serology posttransplantation nor perform molecular studies to determine if CMV strains found in the donor were also found in the recipient. The possibility that primary CMV infection contributed to the poorer outcome of CMV(-) female recipients cannot be excluded. Primary CMV infection, particularly when transmitted by the donated organ, is associated with significantly higher morbidity than infection caused by secondary CMV infection or reactivation of latent virus.15 However, not all organs from CMV(+) donors contain latent virus, and some studies report that only 60% of CMV(+) donors transmit CMV even to seronegative recipients at risk for primary infection.27 The substantially better outcome for men compared with women receiving CMV(+) donor hearts raises the question as to the source of observed sex differences.

CMV and Coronary Artery Disease
Much speculation as to the potential mechanism(s) for interaction between CMV infection, rejection, and coronary artery disease after cardiac transplantation exists, though no causal relation has been proved. One possible direct mechanism related to accelerated atherosclerosis is via the induction of immunoglobulin Fc receptors on CMV-infected endothelial cells. These receptors may interact with granulocytes and lead to endothelial cell damage.29 30 Other indirect theories include viral attachments to the blood vessel surface, which then serve as haptens and activate the immune system. This leads to damage of the neighboring vascular structures and modification of blood vessel wall cell surface antigen markers.22 In addition, the first five peptides of the CMV show sequence homology and immunologic cross-reactivity with the HLA-DR ß chain.31 This may lead to increased rejection after transplantation in those infected with CMV by the cross-reactivity of virus-directed antibodies with graft HLA molecules.22 31 It is possible that the same mechanisms promoting accelerated atherosclerosis and rejection after primary or reactivated CMV may also contribute to graft loss and death after cardiac transplantation. In a recent study of 8331 patients, Opelz and Wujciak32 found that graft survival after cardiac transplantation is significantly influenced by the extent of HLA compatibility. Since their group studied a large population, a sizable number of patients, 128, received grafts with no or only one HLA-A, -B or -DR mismatch. In our study we did not find that HLA mismatching led to reduced survival after cardiac transplantation; however, most of our patients, women and men, had greater than three HLA mismatches.

OKT3 as a Risk Factor for Mortality
There are several reports in the literature discussing outcome after OKT3 induction on rejection,32 36 increased CMV infection,33 34 35 37 and survival33 38 in patients undergoing cardiac or renal transplantation. OKT3 has not been shown to significantly affect long-term rejection rates.8 33 34 Three reports, however, indicate that OKT3 is associated with increased CMV infection33 35 37 38 in small numbers of patients. The report by Johnson and associates33 in cardiac transplantation indicates there is no benefit on survival after OKT3 treatment. In this analysis, the findings indicate OKT3 induction is associated with decreased survival especially in recipients of organs from CMV(+) donors. There are several confounding factors in our population that require consideration in the analysis of the significance of OKT3 induction as a risk factor for mortality after transplantation in women. First, the population of women treated with OKT3 induction was small and consisted of a sicker cohort (33% of women given OKT3 induction therapy were UNOS status I versus 15% of women not given OKT3 induction therapy). Second, only beginning in 1989 was concurrent CMV prophylaxis with immunoglobulin therapy used with OKT3 induction therapy in female recipients of CMV(+) donors. Insufficient numbers precluded analysis of OKT3 as a risk factor after CMV prophylaxis. Given these limitations, it appears that OKT3 adversely affects survival in women receiving a CMV(+) heart.

Possible Causes of Adverse Outcome in Women
Why do women fare less well, reject more frequently, and die sooner and in greater numbers than men of the same age? One possible explanation could be related to differences in frequency of autoimmune-mediated diseases in women.3 Women are at higher risk for developing many autoimmune-mediated diseases including systemic lupus erythematosus, idiopathic thrombocytopenic purpura, primary biliary cirrhosis, rheumatoid arthritis, sarcoidosis, and Graves' disease. Because sequence homology exists between CMV and cardiac endothelium, an autoimmune mechanism whereby the body attacks itself may lead to a more vigorous reaction in women than in men. Some female patients carried the diagnosis of cardiomyopathy and may have had an underlying autoimmune mechanism mediating involvement of the native and transplanted heart. The issue of multiparity has also been raised in an effort to account for poorer outcome after cardiac transplantation via antibodies to foreign material.6 12 13 However, in the present group of female patients, the majority were multiparous, and no relation between number of pregnancies and outcome was found.

Another factor considered was the influence of race on outcome. Of women in this study, 31% were nonwhite compared with 11% nonwhite men. A recent study of racial differences in cadaveric renal allograft survival revealed that decreased long-term survival of allografts is related not only to poor HLA matching but also to unfavorable socioeconomic factors and reduced compliance in black subjects.39 It is unlikely, however, that racial differences adequately address the disparate survival rates between women and men since, when stratified according to donor CMV status, survival of female recipients of CMV(-) donors, regardless of race, paralleled that of male recipients of CMV(-) donors.

Limitations
This retrospective study identifies the risk factors for mortality up to 36 months after transplantation. It does not determine if CMV status is a marker or is causally related to outcome for rejection and survival nor does it answer if CMV prophylaxis removes the apparent increased risk for mortality in women treated with OKT3 induction. A prospective study with a longer follow-up period might clarify the role of CMV status in late mortality when accelerated coronary artery disease occurs and may also reveal other factors responsible for poorer outcome in women after transplantation. Although at this institution during the study time period, CMV prophylaxis was not routinely employed and OKT3 induction was selectively used in higher-risk patients, conclusions regarding differences in outcome that are sex dependent are valid.

Conclusions
CMV is a potential subfactor that identifies increased risk for mortality after cardiac transplantation. In summary: (1) Women are at risk for reduced actuarial survival up to 3 years after cardiac transplantation. (2) Univariate analysis shows that women are selectively at risk for death when receiving hearts from CMV(+) donors and after receiving OKT3 induction therapy. (3) Multivariate analysis reveals that women are at even greater risk for death when receiving hearts from CMV(+) donors in conjunction with OKT3 induction therapy. (4) In the absence of OKT3 use, the greatest risk of death occurs in CMV(-) women transplanted with CMV(+) donor hearts. (5) When survival curves of women and men were compared, factors that influenced survival in women did not appear to be problematic in men.


*    Acknowledgments
 
This study was supported in part by grant RR-00645 from the Research Resources Administration, Bethesda, Md.


*    Footnotes
 
Reprint requests to Elsa-Grace V. Giardina, MD, Division of Cardiology, Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 W 168th St, New York, NY 10032.

Received April 29, 1994; revision received August 5, 1999; accepted September 23, 1994.


*    References
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*References
 

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