We have leveraged the advantages provided by the ISHLT Registry, the largest existing data repository of heart transplant outcomes worldwide, to examine differences in post-transplant survival based on donor and recipient sex. We then explored the survival differences identified by examining differences in AR and CAV in sex-matched versus mismatched transplants, although these analyses were limited by missing data and inconsistent data quality. In doing so, we have built upon previous studies in which these endpoints were studied individually.
We first examined differences in survival between our four donor: recipient sex strata, and demonstrated that patients who undergo sex-matched heart transplantation have improved survival compared to those with sex-mismatched allografts. This observation is especially profound for male recipients of female allografts, who consistently demonstrate the lowest survival in the short- and long-term. To specifically examine the relationship between sex-differences and allograft loss after heart transplantation, we studied the endpoint of death-censored allograft failure, which includes allograft loss leading to death or retransplantation, and excludes deaths due to causes other than allograft failure, such as infection and malignancy. As with overall survival, this analysis also showed inferior outcomes in sex-mismatched transplants, with the poorest outcomes for male recipients of female allografts.
Previous studies have demonstrated inferior survival after heart transplantation in male recipients of female allografts. These range from single-center studies of 174(7) to 869(5) heart transplants, to multi-center registry studies including 18,000(9) to 25,000(8) heart transplant procedures. By utilizing the ISHLT Registry, we were able to confirm these previous findings with survival data on close to 60,000 heart transplant recipients worldwide.
Several theories have been proposed to explain the increased mortality seen after sex-mismatched heart transplants. By examining differences in development of AR and CAV in this large patient population, we were able to examine major post-transplant complications that may have impacted survival. We did not detect significant differences in AR or CAV between male and female heart transplant recipients, when comparing sex-matched versus mismatched transplants, suggesting that these complications did not account for the survival differences observed. However, our analyses had limitations. In the case of AR, transplant centers have varying practices with respect to endomyocardial biopsies and other routine screening techniques. Furthermore, voluntary reporting of this post-transplant complication to the Registry was low (14%). In the case of CAV, it is worth noting that the Registry does not have a uniform definition or grading system, such that some centers may have diagnosed CAV based on angiography and others by intravascular ultrasound. Furthermore, data on CAV severity was not available.
While keeping these limitations in mind, we found significantly lower odds of CAV development in recipients of female donor organs. This finding contrasts with prior single-center studies showing a higher incidence of CAV in recipients of female donor hearts.(11
) The reason behind this discrepancy is unclear, but we suspect that our findings may reflect a higher prevalence of coronary atherosclerosis in male donor organs. Previous studies have shown that the presence of donor atherosclerosis is associated with the development of angiographic CAV after heart transplantation.(19
) Furthermore, “baseline” coronary angiography with intravascular ultrasound imaging at one month post-transplant has demonstrated greater coronary artery maximal intimal thickness in male allografts.(20
) Thus, recipients of female allografts may have less CAV due to less pre-existing donor disease. On the other hand, it is certainly possible that post-transplant factors may result in less coronary artery endothelial injury in female allografts. Regardless, we did not detect any difference in CAV development when comparing male and female recipients’ experience in receiving a sex-matched versus mismatched allograft.
Other theories for differences in mortality between donor: recipient sex strata refer to genetic, hormonal,(21
) and immunologic(22
) factors. Furthermore, sex differences in susceptibility to ischemia-reperfusion injury have also been proposed.(8
) All of these theories, however, remain speculative and require further investigation. Nevertheless, this study provides further evidence for a significant survival advantage for recipients of sex-matched heart transplants. This data lends support to sex matching, when feasible, bearing in mind the complex nature of the matching process that must account for recipient acuity (waitlist status), donor and recipient blood type, and the presence of pre-formed anti-HLA antibodies in the transplant recipient. This survival advantage persisted after adjusting for donor: recipient weight differences and may therefore support liberalization of our current strategy for size matching.
This study is limited by its retrospective nature, as we do not have control over the data quality. Reporting to the ISHLT registry is voluntary and there is a large amount of incomplete follow-up and missing data. This limited our ability to include potential confounders in the multivariable models, as doing so would have significantly reduced the sample size and power of our analyses. Variable definitions and inconsistencies in reporting also affected data quality. Furthermore, uniform definitions were lacking for many variables, including the study endpoints. We now recognize differences between acute cellular and antibody-mediated rejection based on histologic appearance; however, AR in this data set likely encompasses both processes. In addition, there was no standard definition for diagnosis of CAV, as mentioned previously. This, combined with a lack of data on CAV severity, limits our ability to further explore these outcomes. We also acknowledge that center-specific differences may affect heart transplant outcomes—the very large and international experience represented in this database hopefully mitigates that effect.