Heart Transplant Recipients Fare Poorer When Stroke Is Cause of Death for Younger Donors

For heart transplant patients, both mortality and allograft failure are higher when the organ they receive comes from a younger donor whose brain death was due to stroke rather than other causes, according to new data. But stroke as the cause of death isn’t linked to additional risk when the donor is older.

Yet researchers emphasize their findings should not affect decision-making when accepting possible hearts for transplant.

“We are not trying to say that young donors who died of stroke should be avoided,” co-author Shinobu Itagaki, MD (Mount Sinai Medical Center, New York, NY), told TCTMD. “Young donors are still very valuable resources for the transplant community. But still, I think what we are trying to suggest is that this study may provide some opportunities for future studies to improve overall transplant outcomes.”

Similarly, in an accompanying editorial, Sunit-Preet Chaudhry, MD (St. Vincent Medical Group, Indianapolis, IN), and colleagues warn against misinterpreting the results.

The findings, they write, “should in no way dissuade us from accepting and implanting these donor hearts,” as overall survival at 1 year was over 90%. “Instead, these findings highlight the importance of evaluating in more detail the mechanisms that underlie the differences in clinical outcomes so interventions (eg, right ventricular protective strategies) can be developed that would hopefully attenuate the adverse outcomes of stroke in younger donors and lead to further improvement in outcomes.”

Worse Outcomes With Stroke in Younger Donors

Today, organs for heart transplant are generally harvested from brain-dead donors, but there has been some controversy as to whether stroke as the cause death in the donor would affect the long-term outcomes of the recipient. Having a heart from a younger patient, though, has been considered beneficial for the recipient, because the organ would have had less potential exposure to comorbidities.

For the study, published in the March 22, 2022, issue of the Journal of the American College of Cardiology, Takahisa Mikami, MD (Tufts University School of Medicine, Boston, MA), and colleagues analyzed long-term mortality of 3,761 allograft recipients from donors with stroke as the cause of brain death and 14,677 with nonstroke causes from the United Network for Organ Sharing (UNOS) registry who underwent transplant between 2005 and 2018. The researchers used inverse probability weighting for risk adjustment.

I think your heart is somehow connected to your brain, even after it goes to somebody else. Shinobu Itagaki

Over a median follow-up period of 4 years, there was no change in the rate of donors with stroke as the cause of brain death. There was a relationship between the cause of brain death and donor age (P for interaction = 0.008). When donors were 40 years old or younger and stroke was the cause of brain death, the risk of recipient mortality at 5 years increased (23% vs 19%; HR 1.17; 95% CI 1.02-1.35) as did allograft failure (HR 1.30; 95% CI 1.04-1.63). Landmark analyses showed these increased hazards were most likely within the first 60 days. However, the cause of brain death was not associated with outcomes when donors were older than 40 years.

Hemodynamics were similar for younger donors who died of stroke or other causes. But the median time from admission to brain death was significantly longer in younger donors with stroke compared with nonstroke (3.4 vs 2.8 days), and similarly when the time from brain death to aortic clamping was included (5.0 vs 4.3 days; P < 0.001 for both).

Mikami and colleagues suggest several possible explanations for the age-dependent effect they observed. First, younger patients are more likely to have hemorrhagic compared with ischemic stroke, with the former causing “a more abrupt increase in intracranial pressure, which could lead to more frequent and severe myocardial injury and permanent or transient impairment in the allografts,” they write.

Also, stroke at an early age, “especially when not associated with traditional risk factors such as uncontrolled hypertension, may be a surrogate marker of inherent underlying vasculopathy,” the authors say. “This predisposition may be correlated with allograft coronary vasculopathy.”

Lastly, there’s the fact that younger patients typically have a larger gap than older patients between presentation to the hospital and brain death. Over this protracted time, the allograft may be exposed to “detrimental physiological insults,” Mikami et al write.

“We made a lot of assumptions about the results we got, but we don't really know what is actually explain the findings we found,” Itagaki said, adding that further work into the mechanisms at play here is warranted. Other factors like donor age and ejection fraction have been linked with recipient outcomes, but the association between stroke is “not very intuitive,” he said. Ultimately, Itagaki concluded, “I think your heart is somehow connected to your brain, even after it goes to somebody else.”

Heart Brain Connection

Nosheen Reza, MD (Hospital of the University of Pennsylvania and Perelman School of Medicine at the University of Pennsylvania, Philadelphia), who commented on the study for TCTMD, agrees with the authors that there are differences in the types of stroke occurring in younger and older patients. “Perhaps there's just a difference in the physiologic impact of these types of intracranial events when a stroke is hemorrhagic versus ischemic,” said Reza.

However, she pointed out that cause of death can be difficult to ascertain. “And even though there is certainly an approximate cause of death, might there be anything else underlying that we're just not aware of?” she said.

Like Itagaki and the editorialists, Reza does not think the findings should affect the potential of using a heart for transplant from a younger stroke donor. “I do think that this consideration, though, and future investigation into some of these points that the authors raise as possible explanatory hypotheses, offer us an opportunity to think more about how to personalize transplant,” she said.

These data offer an opportunity to alter the “broad set of rules and best practices” that have been applied to all comers in heart transplant for many years regardless of underlying characteristics, Reza said. “This may represent something another checklist item that we go through when, say, we encounter the opportunity of a gift from a young donor who had an intracranial event.”

Specifically, she imagines prospectively better phenotyping young donors who die from intracranial events as well as differentiating ischemic versus hemorrhagic strokes, and then being extra careful to monitor for any signs of primary graft dysfunction in the early posttransplant period.

While a variety of donor characteristics are known to the recipient’s care team, Reza said, “I don't know that I can say durably that on day 50 posttransplant that I'm still thinking about this donor's cause of death as an impact to me right now [when] taking care of this patient in front of me.”

But perhaps physicians should be paying more attention to that, she suggested. “Maybe stroke as a cause of death is not the only domain that we're going see associations like this.”