Female Donor Ups the Risk For Male Heart Transplantation Patients

SAN DIEGO – For men undergoing heart transplantation, the sex of their donor may mean the difference between life and death, according to a pair of large retrospective cohort studies

The studies, which were reported at the annual meeting of the International Society for Heart and Lung Transplantation (ISHLT), each analyzed data from more than 60,000 recipients over periods spanning several decades.

Their conclusion: Men were more likely to die if they received a heart from a female donor vs. a male donor, with the elevation in risk largely resulting from excess deaths in the first year. Overall mortality was 13% higher for these men after potential confounders were taken into account.

In contrast, women undergoing heart transplantation had a similar risk of death regardless of whether their donor was male or female.

A possible explanation for the higher risk of death in men with female donors, according to Dr. Ingo Kaczmarek, a cardiac surgeon at the Transplantation Center Munich of Ludwig-Maximilians University of Munich and the lead investigator of one of the studies, is that women’s hearts are smaller than men’s, even given the same body height and weight (J. Am. Coll. Cardiol. 2002;39:1055-60).

Additionally, medication nonadherence may play a part. "In our population ... I can tell you that females take their medication and males don’t," he said. "And that might be a big confounder that you can’t measure."

Although her study took donor characteristics into account, it is still possible that the smaller size of female hearts played a role, agreed Dr. Kiran K. Khush, lead investigator of the other study. "But I think there are probably also some immunological processes involved and sex differences that we don’t completely understand," she added.

This new information helps explain why some patients fare better than others after heart transplantation, but it would not necessarily alter her practice, said Dr. Khush, a cardiologist and instructor in cardiovascular medicine at Stanford (Calif.) University.

"I would worry about it clinically, but I’m not sure that would preclude me from accepting a female graft for a male recipient, because – as we all know – when you have a very sick recipient who is in imminent danger of dying, you just want to have a heart for that patient," she commented.

However, she added, perhaps given a situation wherein several highest-priority patients on the waiting list were otherwise similar, sex matching might be something to consider.

Dr. Khush and her colleagues analyzed data from the ISHLT database, the largest repository of heart transplant outcomes, for the years 1990-2008, restricting analyses to 60,584 adult recipients having at least 2 years of follow-up post transplantation.

"The ISHLT database pulls data from a lot of different transplant centers worldwide," she noted, including ones in North America, Europe, Australia, and New Zealand, among others. "So this really represents a truly international experience."

Fully 79% of the heart transplant recipients were men. On average, the men were 52 years old and the women were 49 years old at the time of transplantation.

Men’s odds of acute rejection within 2 years of transplantation were higher if their donor was female vs. male before adjustment for more than a dozen potential confounders (odds ratio, 1.22), although not afterward. Women’s odds of this outcome did not differ by the sex of their donor.

The donor’s sex did not affect the likelihood of cardiac allograft vasculopathy for either group before adjustment. But afterward, men actually had a lower risk of this outcome if their donor was female (OR, 0.77).

Here, Dr. Khush sounded a note of caution about the variability in assessing and defining vasculopathy across centers. "Some use angiography, some use IVUS [intravascular ultrasound], maybe some use clinical suspicion," she explained, and disease extent is often not documented. "So I think this is a really hard end point to interpret because the definition is so vague."

But there is no gray area when it comes to defining death, she noted, and results showed that men were more likely to die after transplantation if their donor was female vs. male, both before statistical adjustment (hazard ratio, 1.18) and afterward (HR, 1.13). The donor’s sex had no influence on this outcome among women.

Temporal patterns, assessed with follow-up out to 20 years, suggested that the poorer survival of men who were given a female heart was largely because of increased mortality in the first year post transplantation.

Men also had a higher risk of graft failure resulting in death or retransplantation (after censoring for death from other causes) if their donor was female (HR, 1.17).

A study caveat was that the numbers of patients were limited for several of the outcomes because of missing data, acknowledged Dr. Khush. "It is very difficult to account for center-specific differences – for example, differences in patient populations and management practices," she further noted. And unknown confounders could have influenced the findings.

Dr. Kaczmarek and his coinvestigators similarly analyzed data from the ISHLT database, but for a wider range of years (1980-2009). Their analyses were based on 67,833 heart transplant recipients.

Overall, 80% were men. On average, the men were 53 years old and the women were 51 years old. One-quarter of men received a female donor heart, and slightly fewer than one-half of women received a male donor heart.

The 15-year survival rate was best for women who were given a female heart and worst for men who were given a female heart. "The curves divide in the first year," Dr. Kaczmarek pointed out. "In the long run, they seem to be parallel, but women with female hearts do a bit better."

The 1-year rate of survival ranged from a low of 78% among men who were given a female heart to a high of 84% among men who were given a male heart. "This [latter] effect lasts for a few years, and then the better combination is female donor, female recipient," he said.

When patients who died in the first year post transplantation were excluded, the survival curves diverged gradually over time, but still arrived at the same final pattern, with long-term survival best for women who were given a female heart and worst for men who were given a female heart.

"We have seen that acute rejection contributes to that effect," Dr. Kaczmarek commented. "Acute rejection [rates] are a bit higher in male recipients who receive female donor hearts."

Results were similar when the investigators focused just on the subgroup of patients from their own institution in Munich.

"I want to carefully conclude that the combination of male recipient, female donor carries a higher risk for early mortality, whereas other gender constellations yield similar outcomes," said Dr. Kaczmarek.

"In the long-term follow-up, female recipients reveal superior results, especially the combination of female recipient and female donor," he concluded.

Dr. Khush reported having no conflicts of interest related to the research. Dr. Kaczmarek reported receiving travel or research grants from Novartis, Astellas, Roche, Orion Pharma, and Berlin Heart.

SAN DIEGO – For men undergoing heart transplantation, the sex of their donor may mean the difference between life and death, according to a pair of large retrospective cohort studies

The studies, which were reported at the annual meeting of the International Society for Heart and Lung Transplantation (ISHLT), each analyzed data from more than 60,000 recipients over periods spanning several decades.

Their conclusion: Men were more likely to die if they received a heart from a female donor vs. a male donor, with the elevation in risk largely resulting from excess deaths in the first year. Overall mortality was 13% higher for these men after potential confounders were taken into account.

In contrast, women undergoing heart transplantation had a similar risk of death regardless of whether their donor was male or female.

A possible explanation for the higher risk of death in men with female donors, according to Dr. Ingo Kaczmarek, a cardiac surgeon at the Transplantation Center Munich of Ludwig-Maximilians University of Munich and the lead investigator of one of the studies, is that women’s hearts are smaller than men’s, even given the same body height and weight (J. Am. Coll. Cardiol. 2002;39:1055-60).

Additionally, medication nonadherence may play a part. "In our population ... I can tell you that females take their medication and males don’t," he said. "And that might be a big confounder that you can’t measure."

Although her study took donor characteristics into account, it is still possible that the smaller size of female hearts played a role, agreed Dr. Kiran K. Khush, lead investigator of the other study. "But I think there are probably also some immunological processes involved and sex differences that we don’t completely understand," she added.

This new information helps explain why some patients fare better than others after heart transplantation, but it would not necessarily alter her practice, said Dr. Khush, a cardiologist and instructor in cardiovascular medicine at Stanford (Calif.) University.

"I would worry about it clinically, but I’m not sure that would preclude me from accepting a female graft for a male recipient, because – as we all know – when you have a very sick recipient who is in imminent danger of dying, you just want to have a heart for that patient," she commented.

However, she added, perhaps given a situation wherein several highest-priority patients on the waiting list were otherwise similar, sex matching might be something to consider.

Dr. Khush and her colleagues analyzed data from the ISHLT database, the largest repository of heart transplant outcomes, for the years 1990-2008, restricting analyses to 60,584 adult recipients having at least 2 years of follow-up post transplantation.

"The ISHLT database pulls data from a lot of different transplant centers worldwide," she noted, including ones in North America, Europe, Australia, and New Zealand, among others. "So this really represents a truly international experience."

Fully 79% of the heart transplant recipients were men. On average, the men were 52 years old and the women were 49 years old at the time of transplantation.

Men’s odds of acute rejection within 2 years of transplantation were higher if their donor was female vs. male before adjustment for more than a dozen potential confounders (odds ratio, 1.22), although not afterward. Women’s odds of this outcome did not differ by the sex of their donor.

The donor’s sex did not affect the likelihood of cardiac allograft vasculopathy for either group before adjustment. But afterward, men actually had a lower risk of this outcome if their donor was female (OR, 0.77).

Here, Dr. Khush sounded a note of caution about the variability in assessing and defining vasculopathy across centers. "Some use angiography, some use IVUS [intravascular ultrasound], maybe some use clinical suspicion," she explained, and disease extent is often not documented. "So I think this is a really hard end point to interpret because the definition is so vague."

But there is no gray area when it comes to defining death, she noted, and results showed that men were more likely to die after transplantation if their donor was female vs. male, both before statistical adjustment (hazard ratio, 1.18) and afterward (HR, 1.13). The donor’s sex had no influence on this outcome among women.

Temporal patterns, assessed with follow-up out to 20 years, suggested that the poorer survival of men who were given a female heart was largely because of increased mortality in the first year post transplantation.

Men also had a higher risk of graft failure resulting in death or retransplantation (after censoring for death from other causes) if their donor was female (HR, 1.17).

A study caveat was that the numbers of patients were limited for several of the outcomes because of missing data, acknowledged Dr. Khush. "It is very difficult to account for center-specific differences – for example, differences in patient populations and management practices," she further noted. And unknown confounders could have influenced the findings.

Dr. Kaczmarek and his coinvestigators similarly analyzed data from the ISHLT database, but for a wider range of years (1980-2009). Their analyses were based on 67,833 heart transplant recipients.

Overall, 80% were men. On average, the men were 53 years old and the women were 51 years old. One-quarter of men received a female donor heart, and slightly fewer than one-half of women received a male donor heart.

The 15-year survival rate was best for women who were given a female heart and worst for men who were given a female heart. "The curves divide in the first year," Dr. Kaczmarek pointed out. "In the long run, they seem to be parallel, but women with female hearts do a bit better."

The 1-year rate of survival ranged from a low of 78% among men who were given a female heart to a high of 84% among men who were given a male heart. "This [latter] effect lasts for a few years, and then the better combination is female donor, female recipient," he said.

When patients who died in the first year post transplantation were excluded, the survival curves diverged gradually over time, but still arrived at the same final pattern, with long-term survival best for women who were given a female heart and worst for men who were given a female heart.

"We have seen that acute rejection contributes to that effect," Dr. Kaczmarek commented. "Acute rejection [rates] are a bit higher in male recipients who receive female donor hearts."

Results were similar when the investigators focused just on the subgroup of patients from their own institution in Munich.

"I want to carefully conclude that the combination of male recipient, female donor carries a higher risk for early mortality, whereas other gender constellations yield similar outcomes," said Dr. Kaczmarek.

"In the long-term follow-up, female recipients reveal superior results, especially the combination of female recipient and female donor," he concluded.

Dr. Khush reported having no conflicts of interest related to the research. Dr. Kaczmarek reported receiving travel or research grants from Novartis, Astellas, Roche, Orion Pharma, and Berlin Heart.

SAN DIEGO – For men undergoing heart transplantation, the sex of their donor may mean the difference between life and death, according to a pair of large retrospective cohort studies

The studies, which were reported at the annual meeting of the International Society for Heart and Lung Transplantation (ISHLT), each analyzed data from more than 60,000 recipients over periods spanning several decades.

Their conclusion: Men were more likely to die if they received a heart from a female donor vs. a male donor, with the elevation in risk largely resulting from excess deaths in the first year. Overall mortality was 13% higher for these men after potential confounders were taken into account.

In contrast, women undergoing heart transplantation had a similar risk of death regardless of whether their donor was male or female.

A possible explanation for the higher risk of death in men with female donors, according to Dr. Ingo Kaczmarek, a cardiac surgeon at the Transplantation Center Munich of Ludwig-Maximilians University of Munich and the lead investigator of one of the studies, is that women’s hearts are smaller than men’s, even given the same body height and weight (J. Am. Coll. Cardiol. 2002;39:1055-60).

Additionally, medication nonadherence may play a part. "In our population ... I can tell you that females take their medication and males don’t," he said. "And that might be a big confounder that you can’t measure."

Although her study took donor characteristics into account, it is still possible that the smaller size of female hearts played a role, agreed Dr. Kiran K. Khush, lead investigator of the other study. "But I think there are probably also some immunological processes involved and sex differences that we don’t completely understand," she added.

This new information helps explain why some patients fare better than others after heart transplantation, but it would not necessarily alter her practice, said Dr. Khush, a cardiologist and instructor in cardiovascular medicine at Stanford (Calif.) University.

"I would worry about it clinically, but I’m not sure that would preclude me from accepting a female graft for a male recipient, because – as we all know – when you have a very sick recipient who is in imminent danger of dying, you just want to have a heart for that patient," she commented.

However, she added, perhaps given a situation wherein several highest-priority patients on the waiting list were otherwise similar, sex matching might be something to consider.

Dr. Khush and her colleagues analyzed data from the ISHLT database, the largest repository of heart transplant outcomes, for the years 1990-2008, restricting analyses to 60,584 adult recipients having at least 2 years of follow-up post transplantation.

"The ISHLT database pulls data from a lot of different transplant centers worldwide," she noted, including ones in North America, Europe, Australia, and New Zealand, among others. "So this really represents a truly international experience."

Fully 79% of the heart transplant recipients were men. On average, the men were 52 years old and the women were 49 years old at the time of transplantation.

Men’s odds of acute rejection within 2 years of transplantation were higher if their donor was female vs. male before adjustment for more than a dozen potential confounders (odds ratio, 1.22), although not afterward. Women’s odds of this outcome did not differ by the sex of their donor.

The donor’s sex did not affect the likelihood of cardiac allograft vasculopathy for either group before adjustment. But afterward, men actually had a lower risk of this outcome if their donor was female (OR, 0.77).

Here, Dr. Khush sounded a note of caution about the variability in assessing and defining vasculopathy across centers. "Some use angiography, some use IVUS [intravascular ultrasound], maybe some use clinical suspicion," she explained, and disease extent is often not documented. "So I think this is a really hard end point to interpret because the definition is so vague."

But there is no gray area when it comes to defining death, she noted, and results showed that men were more likely to die after transplantation if their donor was female vs. male, both before statistical adjustment (hazard ratio, 1.18) and afterward (HR, 1.13). The donor’s sex had no influence on this outcome among women.

Temporal patterns, assessed with follow-up out to 20 years, suggested that the poorer survival of men who were given a female heart was largely because of increased mortality in the first year post transplantation.

Men also had a higher risk of graft failure resulting in death or retransplantation (after censoring for death from other causes) if their donor was female (HR, 1.17).

A study caveat was that the numbers of patients were limited for several of the outcomes because of missing data, acknowledged Dr. Khush. "It is very difficult to account for center-specific differences – for example, differences in patient populations and management practices," she further noted. And unknown confounders could have influenced the findings.

Dr. Kaczmarek and his coinvestigators similarly analyzed data from the ISHLT database, but for a wider range of years (1980-2009). Their analyses were based on 67,833 heart transplant recipients.

Overall, 80% were men. On average, the men were 53 years old and the women were 51 years old. One-quarter of men received a female donor heart, and slightly fewer than one-half of women received a male donor heart.

The 15-year survival rate was best for women who were given a female heart and worst for men who were given a female heart. "The curves divide in the first year," Dr. Kaczmarek pointed out. "In the long run, they seem to be parallel, but women with female hearts do a bit better."

The 1-year rate of survival ranged from a low of 78% among men who were given a female heart to a high of 84% among men who were given a male heart. "This [latter] effect lasts for a few years, and then the better combination is female donor, female recipient," he said.

When patients who died in the first year post transplantation were excluded, the survival curves diverged gradually over time, but still arrived at the same final pattern, with long-term survival best for women who were given a female heart and worst for men who were given a female heart.

"We have seen that acute rejection contributes to that effect," Dr. Kaczmarek commented. "Acute rejection [rates] are a bit higher in male recipients who receive female donor hearts."

Results were similar when the investigators focused just on the subgroup of patients from their own institution in Munich.

"I want to carefully conclude that the combination of male recipient, female donor carries a higher risk for early mortality, whereas other gender constellations yield similar outcomes," said Dr. Kaczmarek.

"In the long-term follow-up, female recipients reveal superior results, especially the combination of female recipient and female donor," he concluded.

Dr. Khush reported having no conflicts of interest related to the research. Dr. Kaczmarek reported receiving travel or research grants from Novartis, Astellas, Roche, Orion Pharma, and Berlin Heart.