(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.
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.
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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
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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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.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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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
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
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Clinical Characteristics
Table 1
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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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
1). Eighteen female deaths occurred within a 6-month
period and 20 within the first year. Primary cause of death is listed
in Table 2. 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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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 2).
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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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 3). 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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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
3).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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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.
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Acknowledgments |
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This study was supported in part by grant RR-00645 from the Research Resources Administration, Bethesda, Md.
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Footnotes |
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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.
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References |
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TopAbstractIntroductionMethods Results Discussion References |
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1. Fragomeni LS, Kaye MP. The registry of the International Society for Heart Transplantation: fifth official report—1988. J Heart Transplant. 1988;7:249-253. [Medline] [Order article via Infotrieve]
2. Kaye MP. The registry of the International Society for Heart and Lung Transplantation: ninth official report—1992. J Heart Lung Transplant. 1992;12:599-606.
3. Crandall BG, Renlund DG, O'Connell JB, Burton NA, Jones KW, Gay WA, Doty DB, Karwande SV, Lee HR, Holland C et al. Increased cardiac allograft rejection in female heart transplant recipients. J Heart Transplant. 1988;7:419-423. [Medline] [Order article via Infotrieve]
4. Esmore D, Keogh A, Spratt P, Jones B, Chang V. Heart transplantation in females. J Heart Lung Transplant. 1991;10:335-341. [Medline] [Order article via Infotrieve]
5. Zerbe TR, Arena VC, Kormos RL, Griffith BP, Hardesty RL, Duquesnoy RJ. Histocompatibility and other risk factors for histological rejection of human cardiac allografts during the first three months following transplantation. Transplantation. 1991;52:485-490. [Medline] [Order article via Infotrieve]
6. Sharples LD, Caine N, Mullins P, Scott JP, Solis E, English TAH, Large SR, Schofield PM, Wallwork J. Risk factor analysis for the major hazards following heart transplantation—rejection, infection, and coronary occlusive disease. Transplantation. 1991;52:244-252. [Medline] [Order article via Infotrieve]
7. Heck CF, Shumway SJ, Kaye MP. The registry of the International Society for Heart Transplantation: sixth official report—1989. J Heart Transplant. 1989;8:271-276. [Medline] [Order article via Infotrieve]
8. Barr ML, Sanchez JA, Seche LA, Schulman LL, Smith CR, Rose EA. Anti CD3 monoclonal antibody induction therapy: immunological equivalency with triple drug therapy in heart transplantation. Circulation. 1990;82(suppl IV):IV-291-IV-294.
9. Kruskal WH, Wallis WA. Use of ranks in one-criterion analysis of variance. J Am Stat Assoc. 1952;47:583-621.
10. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, Peto J, Smith PG. I. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer. 1977;35:1-39. [Medline] [Order article via Infotrieve]
11. Cochrane A, Benson E, Williams T, Bergin P, Esmore D. Effect of HLA-DR matching on rejection after cardiac transplantation. Transplant Proc. 1992;24:169-170. [Medline] [Order article via Infotrieve]
12. Laufer G, Miholic J, Laczkovics A, Wollenek G, Holzinger C, Hajek-Rosenmeier A, Wuzl G, Schreiner W, Buxbaum P, Wolner E. Independent risk factors predicting acute graft rejection in cardiac transplant recipients treated by triple drug immunosuppression. J Thorac Cardiovasc Surg. 1989;98:1113-1121. [Abstract]
13. Keogh AM, Valantine HA, Hunt SA, Schroeder JS, Oyer PE. Increased rejection in gender-mismatched grafts: amelioration by triple therapy. J Heart Lung Transplant. 1991;10:106-110. [Medline] [Order article via Infotrieve]
14. Ho M. Observations from transplantation contributing to the understanding of pathogenesis of CMV infection. Transplant Proc. 1991;23:104-109.
15. Gorensek MJ, Stewart RW, Key TF, McHenry MC, Goormastic M. A multivariate analysis of the risk of cytomegalovirus infection in heart transplant recipients. J Infect Dis. 1988;157:515-522. [Medline] [Order article via Infotrieve]
16. Schafers HJ, Wahlers T, Jurmann M, Fieguth HG, Milbradt H, Flik J, Haverich A. Hyperimmuneglobulin for cytomegalovirus prophylaxis following heart transplantation. J Hosp Infect. 1988;12:61-65.
17.
Metsalaar HJ, Balk AHMM, Mochtar B, Rothbarth PH,
Weimar W. Cytomegalovirus seronegative heart transplant
recipients—prophylactic use of anti-CMV immunoglobulin.
Chest. 1990;97:396-399.
18. Laske A, Gallino A, Mohacsi P, Bauer EP, Carrel T, von Segesser LK, Turina MI. Prophylactic treatment with ganciclovir for cytomegalovirus infection in heart transplantation. Transplant Proc. 1991;23:1170-1173. [Medline] [Order article via Infotrieve]
19. Merigan TC, Renlund DG, Keay S, Bristow MR, Starnes V, O'Connell JB, Resta S, Dunn D, Gamberg P, Ratkovec RM et al. A controlled trial of ganciclovir to prevent cytomegalovirus disease after heart transplantation. N Engl J Med. 1992;326:1182-1186. [Abstract]
20. Snydman DR, Werner BG, Heinze-Lacey B, Bernardi VP, Tilney NL, Kirkman RL, et al. Use of cytomegalovirus immune globulin to prevent cytomegalovirus disease in renal transplant recipients. N Engl J Med. 1987;317:1049-1054. [Abstract]
21. Davis CL. The prevention of cytomegalovirus disease in renal transplantation. Am J Kidney Dis. 1990;16:175-188. [Medline] [Order article via Infotrieve]
22. Grattan MT, Moreno-Cabral CE, Starnes VA, Oyer PE, Stinson EB, Shumway NE. Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis. JAMA. 1989;261: 3561-3566.
23. McDonald K, Rector TS, Braunlin EA, Kubo SH, Olivari MT. Association of coronary artery disease in cardiac transplant recipients with cytomegalovirus infection. Am J Cardiol. 1989;64:359-362. [Medline] [Order article via Infotrieve]
24. Loebe M, Schuller S, Zais O, Warnecke H, Fleck E, Hetzer R. Role of cytomegalovirus infection in the development of coronary artery disease in the transplanted heart. J Heart Transplant. 1990;9:707-711. [Medline] [Order article via Infotrieve]
25. Hakim M, Wreghitt TG, English TAH, Stovin PGI, Cory-Pearce R, Wallwork J. Significance of donor transmitted disease in cardiac transplantation. J Heart Transplant. 1985;4:302-306. [Medline] [Order article via Infotrieve]
26.
Hutter JA, Scott J, Wreghitt T, Higenbottam T, Wallwork J. The
importance of cytomegalovirus in heart-lung transplant recipients.
Chest. 1989;95:627-631.
27.
Wreghitt TG, Hakim M, Gray JJ, Kucia S, Wallwork J, English
TAH. Cytomegalovirus infection in heart and heart and lung transplant
recipients. J Clin Pathol. 1988;41:660-667.
28. Farrugia E, Schwab T. Management and prevention of cytomegalovirus infection after renal transplantation. Mayo Clin Proc. 1992;67:879-890. [Medline] [Order article via Infotrieve]
29.
Keller R, Peitchel R, Goldman JN, Goldman M. An IgG-Fc
receptor induced in cytomegalovirus-infected human fibroblasts.
J Immunol. 1976;116:772-778.
30. Kendall TJ, Wilson JE, Radio SJ, Kandolf R, Gulizia JM, Winters GL, Costanzo-Nordin MR, Malcolm GT, Thieszen SL, Miller LW et al. Cytomegalovirus and other herpes viruses: do they have a role in the development of accelerated coronary arterial disease in human heart allografts? J Heart Lung Transplant. 1992;11:s15-s20.
31.
Fujinami RS, Nelson JA, Walker L, Oldstone MBA. Sequence
homology and immunologic cross-reactivity of human cytomegalovirus with
HLA-DR ß chain: a means for graft rejection and immunosuppression.
J Virol. 1988;62:100-105.
32. Opelz G, Wujciak T. The influence of HLA compatibility on graft survival after heart transplantation. N Engl J Med. 1994; 330:816-819.
33. Johnson MR, Mullen GM, O'Sullivan EJ, Liao Y, Heroux AL, Kao W, Pifarre R, Costanzo-Nordin MR. Risk/benefit ratio of perioperative OKT3 in cardiac transplantation. Transplant Proc. 1993;25:1149-1151. [Medline] [Order article via Infotrieve]
34. Kobashigawa JA, Stevenson LW, Brownfield E, Moriguchi JD, Kawata N, Hamilton M, Mindley R, Drinkwater D, Laks H. Does short-course induction with OKT3 improve outcome after heart transplantation? A randomized trial. Transplantation. 1993;12:250-258.
35. Morgan JD, Horsburgh Y, Simpson A, Donnelly PK, Veitch PS, Bell PRF. Cytomegalovirus infection during OKT3 treatment for renal allograft rejection. Transplant Proc. 1992;24:2634-2635.[Medline] [Order article via Infotrieve]
36. O'Connell JB, Bristow MR, Renlund DG. The use of OKT3 for induction therapy in cardiac transplantation. In: Burlingham WJ, ed. A Critical Analysis of Monoclonal Antibody Therapy in Transplantation. Ann Arbor, Mich: CRC Press; 1992.
37. Costanzo-Nordin MR, Swinnen LJ, Fisher SG, et al. Cytomegalovirus infections in heart transplant recipients: relationship to immunosuppression. J Heart Lung Transplant. 1992;11:837-846. [Medline] [Order article via Infotrieve]
38. Hibberd PL, Tolkoff-Rubin NE, Cosini AB, Schooley RT, Isaacson D, Doran M, Delvecchio A, Delmonico FL, Auchincloss H Jr, Rubin RH. Symptomatic cytomegalovirus disease in the cytomegalovirus antibody seropositive renal transplant recipient treated with OKT3. Transplantation. 1992;53:68-72. [Medline] [Order article via Infotrieve]
39. Butkus DE, Meyrech EF, Raju SS. Racial differences in survival of cadaveric renal allografts. N Engl J Med. 1992;327:840-845.[Abstract]
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