Researchers headed by teams at Michigan Medicine and Mayo Clinic have discovered how a molecular process that occurs when donor hearts are preserved in cold storage contributes to failure after transplant. In the study, in both humans and animals, researchers found that a drug already used to treat heart conditions can prevent this damage.
The investigators suggest that their therapeutic solution may significantly improve the function of donor hearts and increase the distance that the organs can be transported in cold storage. They also believe that the mechanism that underpins the new therapy could be applied to other transplantable solid organs.
“When a donor heart is stored in the cold, physical changes occur in cardiac cells that cannot be seen by the naked eye,” said Paul Tang, MD, PhD, a heart transplant surgeon who conducted research with collaborators at both the University of Michigan Health Frankel Cardiovascular Center and the Mayo Clinic. “We observed special protein behaviors during cold preservation at the molecular level that accentuate harmful signaling and cause donor hearts to weaken following transplantation. Disrupting this process can greatly improve a donor heart’s resilience to ischemic injury and its function after transplantation.”
Tang is senior author of the team’s published paper in Nature Cardiovascular Research, titled “Mineralocorticoid receptor phase separation modulates cardiac preservation,” in which they concluded, “Our results reveal an understudied area of preservation biology that may be further exploited to improve the preservation of multiple solid organs.”
Heart transplantation is the gold standard treatment for patients with end-stage heart failure, but fewer than half of donor hearts are ultimately used, the authors stated. One major reason is the relatively short window for transplanting a donated heart into a patient, due to issues that come from leaving a heart in cold storage too long. “Inefficient use of this life-saving resource is contributed to by the 4-h time limit for cold static preservation during which the heart is mechanically arrested but still experiences ischemia,” the investigators explained.
Although cold storage slows metabolism and helps preserve tissue, prolonged exposure to cold can lead to molecular changes that compromise how well the heart performs after transplant. One complication is called primary graft dysfunction, in which the transplanted heart cannot pump effectively after surgery. This may affect up to 20% of recipients to varying degrees.
To investigate why damage to donor hearts occurs, Tang’s team examined the molecular responses to the cold storage process at the individual cell level. They identified a promising candidate in the mineralocorticoid receptor (MR), a protein responsible for carrying out the biological effects of hormones like aldosterone and cortisol. “It is generally accepted based on numerous clinical trials and translational science studies that MR is important for mediating myocardial dysfunction and heart failure,” the investigators stated. “However, little is known about its role in modulating donor heart function in transplantation.”
When a heart is placed in cold storage, its tissue lacks oxygen and cells experience stress. Both human and animal hearts respond to this stress by signaling through MR. Tang’s team found that during cold preservation, the receptor does not require hormones to activate. Instead, MR protein production greatly increases, and the proteins cluster together into liquid droplets, or condensates, within the cell nucleus, by a process known as liquid-liquid phase separation (LLPS). Investigators found that phase separation “autoactivates” the receptors and greatly increases the stress and harm for cardiac cells.
“The donor heart does not realize that we intend to transplant them into another person soon, so it is essentially turning on and supercharging the destructive cellular tools that would be better off left unused,” Tang said. “This damage increases progressively the longer the heart is preserved. Organ transplantation is a uniquely human activity that never occurred for millions of years in nature until modern times. There is no evolutionary adaptation for this highly unusual situation.”
The inflammation and oxidative stress that occur during phase separation weaken the heart and limit its ability to pump blood. The decline is known as primary graft dysfunction and is responsible for more than one-third of deaths after heart transplant.
To stop the cycle of inflammation from damaging the donor heart, the research team needed to interrupt the MR clustering. They accomplished this by injecting the cold preservation solution with canrenone, a water-soluble MR inhibitor that is best known as a diuretic but has important cardiac effects. Canrenone is commonly used in Europe to treat high blood pressure as well as chronic heart failure.
The researchers found that treating animal and human hearts using canrenone stopped the MRs from clustering and reduced cardiac cell death. It also significantly improved donor heart function after four hours of storage, a commonly accepted preservation time threshold. In human donor hearts stored beyond the typical timeframe, treatment with the drug nearly tripled their pumping strength compared to hearts stored without it. The hearts also showed better blood flow and fewer signs of cell injury. “In human hearts preserved for 10 h, canrenone also greatly improved ex vivo cardiac function … while accompanied by increased cardiac output, coronary blood flow and reduced circulating cTnI levels, suggesting greater cardiac viability,” the scientists commented. “Not only did we see improvement at a clinically acceptable threshold of four hours, but the use of canrenone displayed clinical potential of significantly extending cold preservation time beyond what we can currently achieve,” added co-author Francis Pagani, MD, PhD, the Otto Gago MD Endowed Professor in Cardiac Surgery at University of Michigan Medical School.
“As a cardiovascular surgeon, I’ve seen how every additional hour of preservation can impact the likelihood of whether a donor heart can return to normal function after transplantation,” Tang added. “This discovery may give us a new tool to preserve heart function for longer during storage, improve transplant outcomes and enhance patient access to lifesaving transplants.”
The study’s findings have the potential to improve the preservation of other transplantable organs. Similar protein clustering was observed in donor kidneys, lungs and livers during cold storage. “Perhaps unsurprisingly, LLPS is a shared theme during cold preservation of other organs including the liver, kidneys and lungs,” the team stated. This suggests that the same strategy may help expand transplant options across multiple organ systems. “We demonstrate that molecular LLPS with condensate formation is a widespread biophysical phenomenon in the preservation of many different solid organs and is expected to play a critical role in governing organ preservation quality,” they wrote.
Researchers say the similar findings between mouse, pig and human hearts will allow for accelerated investigation of biotechnologies to improve organ preservation. “Furthermore, examining phase separation of other proteins in various compartments may also shed light on mechanisms of organ impairment during preservation,” they suggested.
“It is critical that we can determine the ‘freshness’ and resilience of donor organs during preservation and transport,” said co-author Eugene Chen, MD, PhD, the Frederick G. L. Huetwell Professor of Cardiovascular Medicine at University of Michigan Medical School. “Any innovation to preserve the quality of donor organs must be vigorously pursued, and this method brings promise for the improvement of the lifesaving transplantation process.”
The post Donor Heart Damage from Cold Storage May Be Prevented by Diuretic appeared first on GEN - Genetic Engineering and Biotechnology News.
The investigators suggest that their therapeutic solution may significantly improve the function of donor hearts and increase the distance that the organs can be transported in cold storage. They also believe that the mechanism that underpins the new therapy could be applied to other transplantable solid organs.
“When a donor heart is stored in the cold, physical changes occur in cardiac cells that cannot be seen by the naked eye,” said Paul Tang, MD, PhD, a heart transplant surgeon who conducted research with collaborators at both the University of Michigan Health Frankel Cardiovascular Center and the Mayo Clinic. “We observed special protein behaviors during cold preservation at the molecular level that accentuate harmful signaling and cause donor hearts to weaken following transplantation. Disrupting this process can greatly improve a donor heart’s resilience to ischemic injury and its function after transplantation.”
Tang is senior author of the team’s published paper in Nature Cardiovascular Research, titled “Mineralocorticoid receptor phase separation modulates cardiac preservation,” in which they concluded, “Our results reveal an understudied area of preservation biology that may be further exploited to improve the preservation of multiple solid organs.”
Heart transplantation is the gold standard treatment for patients with end-stage heart failure, but fewer than half of donor hearts are ultimately used, the authors stated. One major reason is the relatively short window for transplanting a donated heart into a patient, due to issues that come from leaving a heart in cold storage too long. “Inefficient use of this life-saving resource is contributed to by the 4-h time limit for cold static preservation during which the heart is mechanically arrested but still experiences ischemia,” the investigators explained.
Although cold storage slows metabolism and helps preserve tissue, prolonged exposure to cold can lead to molecular changes that compromise how well the heart performs after transplant. One complication is called primary graft dysfunction, in which the transplanted heart cannot pump effectively after surgery. This may affect up to 20% of recipients to varying degrees.
To investigate why damage to donor hearts occurs, Tang’s team examined the molecular responses to the cold storage process at the individual cell level. They identified a promising candidate in the mineralocorticoid receptor (MR), a protein responsible for carrying out the biological effects of hormones like aldosterone and cortisol. “It is generally accepted based on numerous clinical trials and translational science studies that MR is important for mediating myocardial dysfunction and heart failure,” the investigators stated. “However, little is known about its role in modulating donor heart function in transplantation.”
When a heart is placed in cold storage, its tissue lacks oxygen and cells experience stress. Both human and animal hearts respond to this stress by signaling through MR. Tang’s team found that during cold preservation, the receptor does not require hormones to activate. Instead, MR protein production greatly increases, and the proteins cluster together into liquid droplets, or condensates, within the cell nucleus, by a process known as liquid-liquid phase separation (LLPS). Investigators found that phase separation “autoactivates” the receptors and greatly increases the stress and harm for cardiac cells.
“The donor heart does not realize that we intend to transplant them into another person soon, so it is essentially turning on and supercharging the destructive cellular tools that would be better off left unused,” Tang said. “This damage increases progressively the longer the heart is preserved. Organ transplantation is a uniquely human activity that never occurred for millions of years in nature until modern times. There is no evolutionary adaptation for this highly unusual situation.”
The inflammation and oxidative stress that occur during phase separation weaken the heart and limit its ability to pump blood. The decline is known as primary graft dysfunction and is responsible for more than one-third of deaths after heart transplant.
To stop the cycle of inflammation from damaging the donor heart, the research team needed to interrupt the MR clustering. They accomplished this by injecting the cold preservation solution with canrenone, a water-soluble MR inhibitor that is best known as a diuretic but has important cardiac effects. Canrenone is commonly used in Europe to treat high blood pressure as well as chronic heart failure.
The researchers found that treating animal and human hearts using canrenone stopped the MRs from clustering and reduced cardiac cell death. It also significantly improved donor heart function after four hours of storage, a commonly accepted preservation time threshold. In human donor hearts stored beyond the typical timeframe, treatment with the drug nearly tripled their pumping strength compared to hearts stored without it. The hearts also showed better blood flow and fewer signs of cell injury. “In human hearts preserved for 10 h, canrenone also greatly improved ex vivo cardiac function … while accompanied by increased cardiac output, coronary blood flow and reduced circulating cTnI levels, suggesting greater cardiac viability,” the scientists commented. “Not only did we see improvement at a clinically acceptable threshold of four hours, but the use of canrenone displayed clinical potential of significantly extending cold preservation time beyond what we can currently achieve,” added co-author Francis Pagani, MD, PhD, the Otto Gago MD Endowed Professor in Cardiac Surgery at University of Michigan Medical School.
“As a cardiovascular surgeon, I’ve seen how every additional hour of preservation can impact the likelihood of whether a donor heart can return to normal function after transplantation,” Tang added. “This discovery may give us a new tool to preserve heart function for longer during storage, improve transplant outcomes and enhance patient access to lifesaving transplants.”
The study’s findings have the potential to improve the preservation of other transplantable organs. Similar protein clustering was observed in donor kidneys, lungs and livers during cold storage. “Perhaps unsurprisingly, LLPS is a shared theme during cold preservation of other organs including the liver, kidneys and lungs,” the team stated. This suggests that the same strategy may help expand transplant options across multiple organ systems. “We demonstrate that molecular LLPS with condensate formation is a widespread biophysical phenomenon in the preservation of many different solid organs and is expected to play a critical role in governing organ preservation quality,” they wrote.
Researchers say the similar findings between mouse, pig and human hearts will allow for accelerated investigation of biotechnologies to improve organ preservation. “Furthermore, examining phase separation of other proteins in various compartments may also shed light on mechanisms of organ impairment during preservation,” they suggested.
“It is critical that we can determine the ‘freshness’ and resilience of donor organs during preservation and transport,” said co-author Eugene Chen, MD, PhD, the Frederick G. L. Huetwell Professor of Cardiovascular Medicine at University of Michigan Medical School. “Any innovation to preserve the quality of donor organs must be vigorously pursued, and this method brings promise for the improvement of the lifesaving transplantation process.”
The post Donor Heart Damage from Cold Storage May Be Prevented by Diuretic appeared first on GEN - Genetic Engineering and Biotechnology News.