Understanding Why Donor Hearts Fail During Cold Storage and How to Prevent It

Researchers have uncovered a critical molecular mechanism responsible for the failure of donor hearts preserved in cold storage, a common step in organ transplantation. This discovery, based on studies involving both humans and animals, has highlighted a potential therapeutic approach to improve organ preservation.

A collaborative effort between Michigan Medicine and Mayo Clinic revealed that during cold storage, cardiac cells exhibit harmful protein behaviors at the molecular level. Central to this process is the mineralocorticoid receptor (MR), a protein that normally reacts to hormones like aldosterone and cortisol. When a donor heart is cooled, the tissue lacks oxygen and experiences cellular stress. Interestingly, MR becomes highly produced and begins to cluster into liquid droplets within the cell nucleus through phase separation—a process that activates the receptor uncontrollably.

This inappropriate activation exacerbates cellular stress, leading to inflammation and oxidative damage, which weaken the heart’s ability to pump effectively after transplantation. This damage, known as primary graft dysfunction, accounts for more than one-third of post-transplant deaths.

To combat this, the researchers tested an MR inhibitor called canrenone, commonly prescribed for high blood pressure and heart failure. By adding canrenone to the preservation solution, they observed a significant reduction in MR clustering, decreased cellular death, and improved heart function after four hours of cold storage. This suggests that treatment with MR inhibitors could extend the safe preservation time for donor hearts, potentially improving transplant outcomes.

The implications of these findings extend beyond the heart, as similar mechanisms of MR phase separation could be involved in preserving other organs such as the liver, kidneys, and lungs. The ongoing research aims to accelerate the development of biotechnologies that enhance organ resilience during transport.

In summary, disrupting the harmful molecular process involving MR phase separation offers a promising strategy to minimize donor heart failure caused by cold storage, ultimately enhancing the success rate of heart transplants and saving more lives. The study has been published in Nature Cardiovascular Research and highlights a significant step forward in transplant medicine.