HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Satoshi Furukawa Valluvan Jeevanandam Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Prendergast, T. W. Articles by Jeevanandam, V. Search for Related Content PubMed PubMed Citation Articles by Prendergast, T. W. Articles by Jeevanandam, V.

Ann Thorac Surg 1998;65:88-94
© 1998 The Society of Thoracic Surgeons

---

Original Articles: Cardiovascular

The Role of Gender in Heart Transplantation

Section of Cardiac and Thoracic Surgery, Temple University Health Sciences Center, Philadelphia, Pennsylvania, USA
Division of Cardiothoracic Surgery, Kansas University Medical Center, Kansas City, Kansas, USA

Accepted for publication June 30, 1997.

Dr Prendergast, Division of Cardiothoracic Surgery, Kansas University Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160.

Presented at the Sixteenth Annual Meeting of the International Society for Heart and Lung Transplantation, New York, NY, March 15–18, 1996.

	Abstract

Top Abstract Introduction Material and Methods Results Comment References

 
Background. The effect of donor and recipient gender on the outcome of heart transplantation (HT) remains uncertain.

Methods. One hundred seventy-four patients who underwent HT were divided into four groups according to donor and recipient gender. Group A consisted of 81 men who received male donor hearts, group B of 18 women who received female donor hearts, group C of 21 women who received male donor hearts, and group D of 54 men who received female donor hearts. All patients were treated by the same group of surgeons according to standard HT protocols. Comparisons were made between groups with regard to short- and long-term outcomes.

Results. Donor gender and recipient gender did not affect outcomes significantly. Overall, donor-recipient gender mismatching significantly increased the number of rejection episodes and reduced creatinine clearance, survival, and censored survival in the first year after HT (p < 0.05). More specifically, among female recipients, donor-recipient gender mismatching significantly increased the number of rejection episodes and decreased creatinine clearance in the first year after HT (p < 0.05); among male recipients, donor-recipient gender mismatching significantly reduced 1-year survival and censored survival to date after HT (p < 0.05).

Conclusions. Donor-recipient gender matching plays a significant role in determining HT outcomes.

	Introduction

Top Abstract Introduction Material and Methods Results Comment References

 
The discrepancy between the number of potential heart transplant (HT) recipients and the number of available organ donors necessitates that maximal donor-recipient matching be used. Many aspects of donor-recipient matching have been well studied. Large donor-to-recipient size differences, prolonged graft ischemia times, and high donor-specific antibody levels in the recipient all are known to be poor prognostic indicators after HT [1]. However, the effect of donor gender, recipient gender, and donor-recipient gender matching on HT outcomes has not been established definitely.

The demographics of HT in the United States underscore the importance of understanding donor-recipient gender mismatch. In the Delaware Valley Transplant Program, for example, whereas 47% of HT donors are female, only 18% of HT recipients are female. Thus, donor-recipient gender mismatch is necessary and frequent. Indeed, these demographics, which are typical for transplantation centers throughout the United States, dictate that donor-recipient gender mismatch occur to maximize donor utilization. Therefore, the present study was done to elucidate the impact of gender on HT outcomes.

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment References

 
Study Protocol
To examine the effect of gender on HT outcomes, we retrospectively reviewed 174 consecutive patients who underwent HT at our institution between 1992 and 1994. The patients were divided into four groups. Group A consisted of 81 men who received male donor hearts. Group B consisted of 18 women who received female donor hearts. Group C consisted of 21 women who received male donor hearts, and group D consisted of 54 men who received female donor hearts. All recipients underwent transplantation by the same group of surgeons using similar operative techniques. The atrial anastomotic technique [2] was used initially during the study period and the bicaval technique [3] was favored later.

Patients received standard triple-drug immunosuppression with methylprednisolone, azathioprine, and cyclosporin A. Methylprednisolone administration was initiated at a dosage of 125 mg intravenously every 8 hours for 3 days, followed by a steroid taper. Azathioprine administration was initiated at a dosage of 2 mg · kg^-1 · day^-1 and adjusted to keep the white blood cell count between 4 x 10³ and 10 x 10³. Administration of cyclosporine was begun at a dosage of 2.5 mg/kg twice per day and adjusted to achieve blood levels of 300 ng/dL as measured by a whole blood radioimmunoassay. Early in the series, patients who were in renal failure received OKT3 or antithymocyte gamma globulin induction for 2 to 5 days. Later in the series, this induction was omitted.

Patients were followed up after discharge from the hospital with endomyocardial biopsies performed weekly for 1 month, then every 2 weeks for 2 months, then every month for 9 months. After 1 year, patients were followed up with endomyocardial biopsies every 3 months. This biopsy schedule was adjusted as dictated by the patients’ clinical needs.

Data Collection
Preoperative data, including age, weight, body surface area, and United Network of Organ Sharing status, were collected for each patient. To evaluate early postoperative outcomes, hemodynamic parameters for each patient were reported at 1 week after HT. These included mean arterial blood pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, cardiac index, pulmonary vascular resistance, and mixed venous oxygen saturation.

In addition, the incidence of primary donor heart failure was examined. Primary donor heart failure encompassed right ventricular failure, left ventricular failure, and biventricular failure. Right ventricular failure was defined by a central venous pressure of greater than 20 mm Hg, a right ventricular end-diastolic pressure of greater than 15 mm Hg, a pulmonary capillary wedge pressure of less than 15 mm Hg, a mean pulmonary artery pressure of greater than 20 mm Hg, and a cardiac index of less than 1.5 L · min^-1 · m^-2. Left ventricular failure was defined by a pulmonary capillary wedge pressure of 25 mm Hg or greater and a cardiac index of 1.5 L · min^-1 · m^-2 or less. Primary donor heart failure was deemed to be present only when these parameters were observed despite the use of high-dose inotropic support (ie, dopamine, 10 µg · kg^-1 · min^-1; dobutamine, 10 µg · kg^-1 · min^-1; epinephrine, 8 µg/min; and milrinone 0.7 µg · kg^-1 · min^-1) and mechanical support (intraaortic balloon counterpulsation) in the immediate postoperative period.

Long-term outcomes were assessed 1 year after HT. At that time, hemodynamic parameters, creatinine levels, and creatinine clearance were examined. The number of rejection episodes in the first year after HT and the mortality rate associated with rejection were examined to evaluate the contribution of rejection to long-term patient outcomes. The percentage of patients who had undergone repeated HT and the long-term survival of patients also were reported.

Statistical Analysis
Continuous data were compared using analysis of variance. When differences between groups were recognized, Fisher’s test was performed to identify specifically the differences between individual groups. Censored survival was derived from Kaplan-Meier curves. Survival-to-date data were analyzed using an unpaired Student’s t test. A p value of less than 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Material and Methods Results Comment References

 
Recipient and Donor Data
Recipients in all groups were similar with regard to age, United Network of Organ Sharing status, creatinine level, creatinine clearance, blood pressure, pulmonary hemodynamics, pulmonary vascular resistance, cardiac function, and cause of cardiac failure (Table 1). The height, weight, and body surface area of male recipients were significantly greater than those of their female counterparts. The percent reactive antibody levels of female recipients were significantly higher than those of male recipients.

	Comment

Top Abstract Introduction Material and Methods Results Comment References

Donor and Recipient Gender
Statistically, male donor hearts did not appear to be superior to female donor hearts (Table 5). Nonetheless, there may be instances in which male donor hearts provide better HT outcomes. For example, most investigators suggest that male donor hearts improve results for recipients who undergo HT in the face of pulmonary hypertension. This may be due to the greater right ventricular mass in larger male hearts as compared with smaller female hearts [7]. Indeed, the effect of a male donor heart implanted into a recipient with pulmonary hypertension was not stratified in this report because we generally attempt to use exclusively male donors in recipients with this condition when possible. Thus, although our data demonstrate no influence of donor gender alone on outcomes in a large group of HT recipients, there may be specific groups of recipients for whom donor gender is an important consideration.

Similarly, recipient gender alone also did not significantly affect HT outcomes in our study patients (Table 6). These results agree with the work of Fabbri and co-workers [6] and suggest that the advantage demonstrated in male recipients in animal models [4] may not translate to human subjects. Another issue in which recipient gender has been believed to play a role is that of organ rejection. Esmore and colleagues [8] suggested that female recipients are at increased risk for rejection during the first year after HT and that donor-recipient gender mismatching further increases this risk. Our results agree with those of Esmore and colleagues only in part. Despite the fact that preoperative percent reactive antibody levels were significantly higher in female HT recipients (groups B and C) than in their male counterparts, the female recipients did not experience a higher number of rejection episodes during the first year after HT than did the male recipients. However, we did note an increased frequency of first-year rejection episodes among women who received male donor hearts compared with those who received female donor hearts. This discrepancy suggests that the frequency of rejection episodes among female recipients is more a function of donor-recipient gender mismatch than of recipient gender alone.

Interestingly, when male recipients were analyzed, gender matching did not significantly affect the incidence of rejection in the first year after transplantation. These results suggest that recipient gender alone does not influence the incidence of rejection in HT recipients. However, female recipients may be more susceptible than male recipients to rejection in the face of donor-recipient gender mismatch. Larger studies are needed to clarify this issue further.

Donor-Recipient Gender Matching
Our study demonstrates that the effect of donor-recipient gender matching on HT outcomes is profound. Patients who undergo donor-recipient gender-matched HT have improved outcomes compared with those who undergo gender-mismatched HT, in terms of creatinine clearance 1 year after HT, number of rejection episodes in the first year after HT, 1-year survival, and censored survival to date. The advantages of gender matching in HT are demonstrated best by examining female and male transplant recipients separately.

The most striking difference between female recipients who receive female donor hearts (group B) and those who receive male donor hearts (group C) is the increased number of rejection episodes experienced by the gender-mismatched recipients (Table 7). The cause of this increased incidence of rejection is not clear. Female recipients do have significantly higher preoperative percent reactive antibody levels than do male recipients (Table 1). This suggests that women have a heightened immune response and may be more susceptible to rejection than are men. However, the percent reactive antibody levels of women who received gender-mismatched hearts were not significantly different than those of women who received gender-matched hearts. Therefore, it is difficult to understand the increased incidence of rejection that occurs in women who undergo gender-mismatched HT.

It also is interesting that the increased rejection rates among gender-mismatched female HT recipients did not translate into decreased survival to date or censored survival for group C compared with group B. A possible explanation for the lack of correlation between the number of rejection episodes during the first year and survival rates is suggested by Esmore and associates [8] and by Keogh and co-workers [9]. Both these groups reported that although the incidence of rejection is higher in female HT recipients, this rejection can be ameliorated by increasing dosages of triple-drug immunosuppression. Our study did not address specifically whether female recipients receive a higher net state of immunosuppression than male recipients, but cyclosporine levels and white blood cell counts were maintained at similar values.

The second difference between female recipients who receive female hearts and those who receive male hearts is the lower creatinine clearance seen 1 year after transplantation in gender-mismatched recipients (Table 8). The decreased creatinine clearance in gender-mismatched women may reflect decreased end-organ perfusion in this group as a result of compromised cardiac function. However, hemodynamic parameters 1 year after HT were not significantly different in group C compared with group B (Table 4). Alternatively, it is possible that the elevated creatinine clearance in group C was secondary to increased levels of the nephrotoxic immunosuppressive agents used to treat rejection in this group.

Donor-recipient gender mismatching leads to particularly poor outcomes in male transplant recipients. In the immediate postoperative period, male recipients who have received female donor hearts are at risk for primary donor heart failure (Table 9). In addition, we observed that additional inotropic support was necessary when female hearts were transplanted into male recipients.

One year after they underwent HT, male recipients of female donor hearts (group D) were noted to have significantly higher pulmonary wedge pressures than male recipients of male donor hearts (group A) (Table 4). Other hemodynamic parameters were equivalent between these two groups of patients. The elevated pulmonary wedge pressure, however, suggests that cardiac function is compromised in male HT recipients who receive female organs. In these patients, higher filling pressures are required to produce equivalent levels of cardiac output. In light of the decreased cardiac function in this group of patients, it may seem surprising that end-organ perfusion, as reflected by creatinine clearance, was not different in group D compared with group A (Table 9). This finding may be explained by the fact that 1-year survival was significantly lower in group D. The reported creatinine clearance reflects only those men who survived 1 year after HT, and therefore it may be elevated falsely in this group of patients.

The effect of donor-recipient gender mismatching among male HT recipients was most dramatic in terms of survival. One-year survival and censored survival to date were significantly worse in male HT recipients when gender mismatch occurred. These poor outcomes do not appear to be secondary to rejection. Neither the number of rejection episodes during the first posttransplantation year nor the rejection-associated mortality rate were significantly different in male recipients who received male versus female hearts (Table 9).

Another possible explanation for the decreased survival in group D is donor-recipient size mismatch. The ratio of donor to recipient body surface area was significantly lower in group D than in the other groups, and one may speculate that female hearts simply are unable to support the circulation of male recipients because of their small size or poor ventricular function. However, we previously reported that substantially undersized donor hearts (donor-to-recipient ratio, <0.7) are not associated with worse long-term cardiac function or worse long-term survival [10][11]. Thus, there must be a factor other than size alone that makes female donor hearts poorly suited for transplantation into male recipients. Whatever this factor is, our results suggest that for men awaiting HT, women should be considered marginal donors. Although it certainly is appropriate to transplant female hearts into male recipients who are so critically ill that prolonging transplantation may result in death, it may be prudent to avoid this type of gender mismatch for recipients who are able to wait safely for a male donor heart.

Summary
Our study demonstrates the following effects of gender on HT outcomes: (1) Donor gender does not significantly affect HT outcomes. (2) Recipient gender does not significantly affect HT outcomes. (3) Overall, donor-recipient gender mismatching significantly worsens creatinine clearance 1 year after HT, the number of rejection episodes in the first year after HT, 1-year survival after HT, and censored survival after HT. (4) Among female HT recipients, donor-recipient gender mismatching significantly decreases creatinine clearance 1 year after HT and significantly increases the number of rejection episodes in the first year after HT. (5) Among male HT recipients, donor-recipient gender mismatching significantly reduces 1-year survival and censored survival to date after HT.

	References

Top Abstract Introduction Material and Methods Results Comment References

 

1. Hauptman PJ, Kartashov AI, Couper GS, et al. Changing patterns in donor and recipient risk: a 10 year evolution in one heart transplant center. J Heart Lung Transplant 1995;14:654-658.[Medline]
2. Lower RR, Stofer RC, Shumway NE Homovital transplantation of the heart. J Thorac Cardiovasc Surg 1961;41:196-202.
3. Sievers HH, Weyland M, Kraatz EG, Bernhard A An alternative technique for orthotopic cardiac transplantation with preservation of the normal anatomy of the right atrium. Thorac Cardiovasc Surg 1991;39:70-72.[Medline]
4. Takami H, Backer CL, Zales VR, et al. The influence of gender on allograft rejection in a rat heart transplant model. J Heart Lung Transplant 1995;14:529-536.[Medline]
5. Reed E, Cohen DJ, Barr ML, et al. Effect of recipient gender and race on heart and kidney allograft survival. Transplant Proc 1992;24:2670-2671.[Medline]
6. Fabbri A, Bryan AJ, Sharples LD, et al. Influence of recipient and donor gender on outcome after heart transplantation. J Heart Lung Transplant 1992;11:701-707.[Medline]
7. Hutchinson PL, Cureton KJ, Outz H, Wilson G Relationship of cardiac size to maximal oxygen uptake and body size in men and women. Int J Sports Med 1991;12:369-373.[Medline]
8. Esmore D, Keogh A, Spratt P, et al. Heart transplantation in females. J Heart Lung Transplant 1991;10:335-341.[Medline]
9. Keogh AM, Valantine HA, Hunt SA, et al. Increased rejection in gender mismatched grafts: amelioration by triple therapy. J Heart Lung Transplant 1991;10:106-110.[Medline]
10. Mather PJ, Jeevanandam V, Eisen HJ, et al. Functional and morphologic adaptation of undersized donor hearts after transplantation. J Am Coll Cardiol 1995;3:737-742.
11. Jeevanandam V, Furukawa S, Prendergast TW, Todd BA, Eisen HJ, McClurken JB Standard criteria for an acceptable donor heart are restricting heart transplantation. Ann Thorac Surg 1996;62:1268-1275.[Abstract/Free Full Text]

This article has been cited by other articles:

				J. C. Matthews and K. D. Aaronson Sex Matters, But to What Clinical Avail? Circ Heart Fail, September 1, 2009; 2(5): 389 - 392. [Full Text] [PDF]

				E. S. Weiss, J. G. Allen, N. D. Patel, S. D. Russell, W. A. Baumgartner, A. S. Shah, and J. V. Conte The Impact of Donor-Recipient Sex Matching on Survival After Orthotopic Heart Transplantation: Analysis of 18 000 Transplants in the Modern Era Circ Heart Fail, September 1, 2009; 2(5): 401 - 408. [Abstract] [Full Text] [PDF]

				S. J. Kim and J. S. Gill H-Y Incompatibility Predicts Short-Term Outcomes for Kidney Transplant Recipients J. Am. Soc. Nephrol., September 1, 2009; 20(9): 2025 - 2033. [Abstract] [Full Text] [PDF]

				A. A. Fox and N. A. Nussmeier Does Gender Influence the Likelihood or Types of Complications Following Cardiac Surgery? Seminars in Cardiothoracic and Vascular Anesthesia, December 1, 2004; 8(4): 283 - 295. [Abstract] [PDF]

				J. M. Chen, R. R. Davies, S. R. Mital, M. L. Mercando, L. J. Addonizio, S. P. Pinney, D. T. Hsu, J. M. Lamour, J. M. Quaegebeur, and R. S. Mosca Trends and Outcomes in Transplantation for Complex Congenital Heart Disease: 1984 to 2004 Ann. Thorac. Surg., October 1, 2004; 78(4): 1352 - 1361. [Abstract] [Full Text] [PDF]

				M. B. Marshall and L. J. Kohman Gender and lung transplantation: Size matters, does sex? J. Thorac. Cardiovasc. Surg., September 1, 2004; 128(3): 352 - 353. [Full Text] [PDF]

				N. A. Herity, S. Lo, D. P. Lee, M. R. Ward, S. D. Filardo, P. G. Yock, P. J. Fitzgerald, S. A. Hunt, and A. C. Yeung Effect of a change in gender on coronary arterial size: A longitudinal intravascular ultrasound study in transplanted hearts J. Am. Coll. Cardiol., May 7, 2003; 41(9): 1539 - 1546. [Abstract] [Full Text] [PDF]

				M. Zeier, B. Dohler, G. Opelz, and E. Ritz The Effect of Donor Gender on Graft Survival J. Am. Soc. Nephrol., October 1, 2002; 13(10): 2570 - 2576. [Abstract] [Full Text] [PDF]

				K. Lietz, R. John, A. Kocher, M. Schuster, D. M. Mancini, N. M. Edwards, and S. Itescu Increased Prevalence of Autoimmune Phenomena and Greater Risk for Alloreactivity in Female Heart Transplant Recipients Circulation, September 18, 2001; 104 (2009): I-177 - I-183. [Abstract] [Full Text] [PDF]

				R. John, H. A. Rajasinghe, J. M. Chen, A. D. Weinberg, P. Sinha, D. M. Mancini, Y. Naka, M. C. Oz, C. R. Smith, E. A. Rose, et al. Long-term outcomes after cardiac transplantation: an experience based on different eras of immunosuppressive therapy Ann. Thorac. Surg., August 1, 2001; 72(2): 440 - 449. [Abstract] [Full Text] [PDF]

				V M Miller Gender and vascular reactivity Lupus, June 1, 1999; 8(5): 409 - 415. [Abstract] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Satoshi Furukawa Valluvan Jeevanandam Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Prendergast, T. W. Articles by Jeevanandam, V. Search for Related Content PubMed PubMed Citation Articles by Prendergast, T. W. Articles by Jeevanandam, V.