The Association of Donor Thyroid Hormone Supplementation on Heart Transplant Recipient Survival

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Introduction
Te majority of organs for transplantation are procured from brain dead donors and it is well documented that brain death is accompanied by hormonal alterations including marked drops in thyroid hormone blood levels, which have been shown to be responsive to supplementation [1].Hormonal supplementation with triiodothyronine (T3) or thyroxine (T4) has been promoted as a means to improve donor cardiac function and thus increase the yield of donor hearts available for transplantation [2][3][4].Despite these fndings, the use of thyroid hormone supplementation (THS) for donor optimization has not been standardized and remains an area of academic investigation and clinical interest [5,6].Te purpose of this study is to investigate the impact of THS in donors on post-transplant outcomes for heart recipients.

Methods
2.1.Design.Tis was a retrospective study of a large database.Since all information is deidentifed, the Cleveland Clinic Weston Florida IRB did not require patient consent to perform this study.

Setting Population.
Te United Network of Organ Sharing (UNOS) database was analyzed using adult donors (age greater than 15 years) and recipients (age ≥18 years) with inclusion dates beginning January 1, 2000 and ending June 30, 2022.

Data Collection.
Of those donors that received THS (N � 28,911), the vast majority (98%) were given T4 alone.One percent was given T3 alone and 1% was given both T3 and T4.For the present analysis, these three were combined into one binary variable, T3 or T4 (T3/T4).Explicitly stated, our primary comparison was between donors who received T3 and/or T4 prior to transplant procurement vs. those that received neither.

Data Analysis.
Summary statistics were compiled where appropriate and simple comparisons were made with t-tests or chi-squared tests.Logistic regression models were used to predict 30 day and 1 year survival, while accelerated failure time models with Weibull distributions were employed to analyze time-to-death and time-to-transplant rejection.Tese models were adjusted for donor age, sex, ethnicity, BMI, ischemic time, and steroid support as well as recipient age, sex, ethnicity, BMI, length of stay, UNOS region, ventricular assist devices (VAD), creatinine, and days on the waiting list.Donor and recipient sex was constructed as a four-category variable and this was interacted with THS usage to ascertain whether diferential efects between the donor/recipient sex pairs of the THS-survival relationships were observed.Appropriate linear combinations were constructed to examine comparisons of interest.THS usage across time was estimated tabulated and plotted with unadjusted percentages.All statistical analyses were done with Stata v17.0.

Results
Tere were 47,660 hearts transplanted during this inclusion time period.Of these, 1110 were excluded due to missing THS information and another 8 were excluded for being labeled as an inactive recipient status leaving 46,542 as the fnal cohort sample size.Mean donor age was 32.29 ± 11.31 years for the cohort (32.28 ± 11.30 no TSH vs 32.30 ± 11.32 years TSH; p � 0.877).Nonwhite donors comprised 35% of the overall cohort, 35% of the no TSH group, and 34% of the TSH group (0.055).Mean donor left ventricular ejection fraction was 61.59 ± 7.11 for the entire cohort (61.92 ± 7.17 no TSH vs. 61.39± 7.07% TSH; p < 0.001).
Of the 46,543 donors included, 28,911 (62%) received THS and 17,631 (38%) did not.Tere were small but statistically signifcant diferences between these two groups regarding recipient age, diabetes status, creatinine, and use of ventricular assist devices (VAD) (Table 1).Donors differed on ischemic time, diabetes status, left ventricular ejection fraction (LVEF), and steroid administration.Most absolute diferences in these variables between the two groups of interest were inconsequential (Table 2).Sex specifc donor-to-recipient percentages were consistent across groups, despite the low p value, with male-to-male transplants making up the vast majority of the cohort.
In adjusted models including all patients, donor THS showed a reduction of 12% in the odds of death within 30 days (OR � 0.88; p � 0.032); however, this relationship did not extend to one year mortality (OR � 1.00; p � 0.969).THS had a positive impact in both overall survival and posttransplant rejection, reducing the hazard of death and rejection by 6% and 4%, respectively (HR � 0.94; p < 0.001 and HR � 0.96; p � 0.013) (Table 3) (Figure 1).
We further evaluated if these efects were diferential across donor-recipient sex pairings.Tese results are also shown in Table 3/Figure 2. Te 30-day survival beneft was strongest in the male-to-male pairing (OR for death � 0.81; p � 0.006), but was not observed in other groups (all p > 0.310).Similarly, the overall survival and post-transplant rejection benefts were similar in the male-to-male group (HR � 0.93; p � 0.001 and HR � 0.96; p � 0.038) and were enhanced in the female-to-female group (HR � 0.88; p � 0.003 and HR � 0.90; p � 0.016).We did not observe any associated survival beneft with donor THS in the sex mismatched groups (all p > 0.319).
It was hypothesized that donor steroid administration would provide further survival benefts, but this was not observed in neither main efects of steroid administration (all p > 0.115) nor when steroid support was interacted with THS (all p > 0.431).
Rates of THS across the study period are shown in Figure 3. Te early 2000s saw a steady increase in usage, with a large increase beginning in 2005.THS usage peaked in 2009 with nearly 80% of heart donors having the therapy.Since the 2009 peak, usage has seen a steady decline with more recent years falling below 50%.

Discussion
Our results demonstrate that THS for brain dead heart donors ofers a modest survival beneft for heart transplant recipients, particularly within the frst 30 days.Tis relationship was strongest in the case of male donor hearts transplanted into male recipients.Overall survival benefts were observed for sex matched transplants but were not observed for sex mismatched transplant recipients.A conference abstract for this paper has previously been published [7].
Te role of hormone supplementation in general has been borne out through clinical studies which have demonstrated the impact of brain death on circulating hormone levels and the benefts of THS for donor heart optimization [1,3,8].While hormone supplementation protocols are not standardized, these prior fndings are refected in the relatively high rate of usage demonstrated in our results, even with the recent decrease in utilization.Novitzky et al. performed a similar analysis of the UNOS registry which included 63,593 donors from 2000 to 2009 for whom THS data were available [5].While this study was not specifcally looking at heart donors, they demonstrated that THS resulted in signifcantly increased heart procurement and 2 Journal of Cardiac Surgery a statistically signifcant improvement in survival at 30 days and 1 year.More recently, Peled et al. performed an analysis of the impact of THS using the registry of the International Society for Heart and Lung Transplantation (ISHLT) for a period from 2006 to 2016 [6].Tis analysis included 23,002 adult heart transplants of which 15,821 received THS and revealed THS to be associated with an increased risk of early graft loss and similar long-term survival with or without THS.Our study of a large, more contemporary, registry than these two studies support the evidence of a beneft from THS but one that is more pertinent to select heart transplant recipients.Te diference between the study by Peled et al. may be attributed to their use of early graft loss, which is defned as death or retransplant within 48 hours, as a primary end point.While this was associated with THS, our more long term based analysis is actually in accord with their fndings of decreased incidence of transplant vasculopathy and similar long term survival between groups.
In particular, the sex-based analysis of our study demonstrated an association with beneft and THS only in sex matched donor-recipient pairings, with no diference in survival observed with THS in sex mismatched groups.While the underlying etiology for such a relationship remains controversial, several previous studies have demonstrated a similar relationship for sex mismatched heart transplants [9,10].Khush et al. performed an analysis of the ISHLT thoracic transplant registry including 60,584 heart transplants from 1990 to 2008 to examine outcomes based on donor and recipient sex [11].Te demonstrated significantly worse outcomes for sex mismatched pairings compared to sex matched pairs.Similarly, Meiser et al. performed an analysis of the ISHLT registry from 1990 to   Journal of Cardiac Surgery 2009 which included 67,855 heart transplants and demonstrated decreased 1 year survival for female-to-male pairings and concluded that sex matched pairings would optimize clinical outcomes if feasible [12].It is possible that hormone supplementation further contributes to these diferences by maintaining a physiologic hormonal status and that hormone matching is a contributor to the beneft seen with sex matching; however, this would require further analysis.Our analysis did not demonstrate clinical beneft from steroid administration in addition to, or in the absence of, THS.Te study by Novitzky et al. included an analysis for corticosteroid administration which revealed a beneft but only in the cohort that did not receive THS [5].Other studies have been inconclusive or contradictory with some demonstrating increased rates of procurement after corticosteroid supplementation but that such supplementation exacerbates hyperglycemia which in turn worsens posttransplant outcomes [13,14].Some centers advocate a protocol of low dose corticosteroid administration to improve rates of organ procurement with improved

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Journal of Cardiac Surgery glycemic control [15].Tis is clearly an issue that warrants further investigation.

4.1.
Limitations.Limitations of this study include its retrospective nature and the inability to distinguish between T3 and T4 supplementation.In addition, the lack of standardized protocols for the administration of THS limits the ability to make broader generalization or recommendations about its use based on this analysis.

Conclusions
Donor THS is associated with improved 30-day posttransplant survival as well as overall survival after OHT in sex-matched donor-recipient pairs.Further study, particularly with a standardized protocol for THS supplementation in heart donors is warranted.

Figure 1 :Figure 2 :
Figure 1: Overall survival probability for donors receiving thyrsoid hormone supplementation vs. those not receiving thyroid hormone supplementation.

Table 2 :
Donor characteristics.ventricular ejection fraction.Means (standard deviations) are presented for continuous variables.Counts (%) are presented for categorical variables.

Table 3 :
Survival associations for various predictors across four models are adjusted for donor age, BMI, ethnicity, ischemic time, and steriod use, as well as recipient age, BMI, ethnicity, LOS, region, VAD, creatinine, and days on waiting list.