With heart transplant advances, a quest for ‘holy grail’ of tolerance, improved outcomes
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Key takeaways:
- Advances like donation after circulatory death are increasing the rate of heart transplants in the U.S.
- Side effects from immunosuppressive regimens remain an issue after heart transplant.
Editor's Note: This is part 1 of a three-part Healio Exclusive series on developments and challenges in heart transplantation. Part 2 can be viewed here. Part 3 can be viewed here.
Heart transplantation is considered standard therapy for patients with end-stage HF, and survival and the availability of donor hearts have continued to improve over time.
In 2022, there were 4,111 heart transplants in the United States, an increase of 21.5% from 2021, according to the United Network for Organ Sharing (UNOS). The number of heart transplants in particular steeply increased from 2021 to 2022 compared with other solid organ transplants because of donation after brain death, which increased by 4.6%, as well as a new advance: donation after circulatory death, which increased by 68%.
Recent advancements, remaining challenges
Other advancements in the past 2 years have garnered significant media attention. In 2022, a man became the first in the world to receive a genetically modified pig’s heart at University of Maryland Medical Center. The man, aged 57 years, died 2 months after receiving a procedure that was nonetheless hailed as a milestone for xenotransplantation. Also in 2022, surgeons at Duke University successfully completed the first combination heart transplant and allogeneic processed thymus tissue implant in an infant with severe single-ventricle heart disease with thymic deficiency. The combination of procedures could lead to expanded viability for transplanted organs in the future.
Despite these advances, many patients listed for a heart transplant still do not receive one. Only about one-third of donor hearts are accepted for transplant, while many viable hearts go unused for a variety of reasons, according to Adam D. DeVore, MD, associate professor of medicine at Duke University School of Medicine and member in the Duke Clinical Research Institute.
Despite the improvements we are talking about, there are still way more people that need transplants than organs available,” DeVore told Healio. “Keeping people healthy and alive so they can thrive after the surgery also remains a challenge.”
Today, approximately half of heart transplant recipients now survive 13 years or more, despite being older and having more comorbidities at the time of transplant, compared with earlier transplant recipients, according to data from the Mayo Clinic. Yet, longer survival comes at a price — namely, risks from long-term exposure to immunosuppressive drugs to avoid organ rejection.
“The criteria for ‘success’ is 1-year survival; however, patients are living more than 1 year — they live for 10, 14 years or more, and then they are stymied by immunosuppressive side effects,” Healio | Cardiology Today Editorial Board Member Jon Kobashigawa, MD, director of the advanced heart disease division and of the heart transplant program at the Smidt Heart Institute at Cedars-Sinai, as well as associate director of the institute, said in an interview. “We want better immunosuppression. We want better quality of life and better survival.”
In a perspective published in the Annals of Cardiothoracic Surgery, Kobashigawa wrote that tolerance remains the “holy grail” of transplant.
“The future of heart transplantation is bright with the advent of newer immunosuppressive medications and strategies that may even result in tolerance,” Kobashigawa wrote. “Much of this progress in heart transplant medicine is predicated on a better understanding of acute and chronic rejection pathways through basic science studies. The future will also include personalized medicine where genomics and molecular science will dictate customized treatment for optimal outcomes.”
Improving immunosuppression
During the first year after heart transplant, the biggest risks for patients remain rejection and infection. In the long term, clinicians must manage the risks of lifelong immunosuppressive medications, including graft vasculopathy and malignancy, according to Healio | Cardiology Today Editorial Board Member Mary Norine Walsh, MD, MACC, medical director of heart failure and transplantation at St. Vincent Heart Center in Indianapolis and past president of the American College of Cardiology.
“Early detection of both rejection and various types of infection have been improving and noninvasive imaging has allowed for accurate and early detection of graft vasculopathy,” Walsh told Healio. “Long term, we worry about the effect immunosuppressive medications have on bone health, diabetes, hypertension, kidney disease and cancer. Over the years, we as a community have learned that adequate surveillance and appropriate modification of immunosuppression can improve outcomes.”
Heart transplant recipients typically require more aggressive immunosuppressive regimens than recipients of other solid organ transplants, and this is likely responsible for the increased incidence of malignancy and other adverse effects, according to Seth Hollander, MD, pediatrics cardiologist and medical director of heart transplantation at Stanford Medicine Children’s Health.
“Interestingly enough, the world’s first two adult heart transplant patients died not of rejections, but of infections, because they were overly immune suppressed,” Hollander told Healio. “Now that our immune suppression is better and our patients are living so much longer, the new issue is how do you allow them to thrive and have a good quality of life, and minimize the side effects of the medications we use?”
Most maintenance immunosuppressive protocols involve calcineurin inhibitors, antimetabolites and steroids. The regimens “are not the panacea of drugs we thought they were,” said Kobashigawa, who is also the DSL/Thomas D. Gordon Chair in Heart Transplantation Medicine at Cedars-Sinai and associate director of the Comprehensive Transplant Center at Cedars-Sinai.
“There are side effects, including infection, hypertension, nephropathy and cancer,” he said. “Cancer is becoming, if not already, the major cause of death among long-term heart transplant recipients, exceeding even chronic rejection. That is a big issue, and something all heart transplant programs face. How can we minimize that risk of malignancy but not have patients reject their donor hearts?”
Walsh said after transplant, clinicians must continue to scrutinize how much immunosuppression patients require. In select patients, single immunosuppressive agents like tacrolimus have been shown to be effective, she said.
“We have done a good job at trying to minimize that over time,” Walsh said. “Diligent follow-up is important, so we can identify hypertension early, protect the kidneys, minimize any risks and ensure patients receive routine cancer screenings.”
In pediatric heart transplant, there are currently no FDA-approved immunosuppression regimens to prevent rejection; any use of immunosuppressive therapy is considered off-label. Hollander and colleagues recently completed the first-ever clinical trial in pediatric heart transplant medicine that compared everolimus as an alternative to standard tacrolimus as the primary immunosuppressant to prevent rejection. The goal, Hollander said, is for one or both regimens to receive a pediatric indication from the FDA.
“In pediatric heart transplant, 1-year survival is close to 95%. More than half of patients are now living 20 years and beyond. We need to think about ways to keep the patient’s kidneys healthy, prevent opportunistic infections and other risks from taking over and helping patients cope with, adapt to and minimize the physical and emotional impacts of their heart transplant,” Hollander said. “We want heart transplant patients to grow up, finish school, be married or partnered, become parents, if that is what they want. We certainly do not want them to endure second organ transplants, particularly the kidney.”
Editor’s Note: Part 2 of this Healio Exclusive series will discuss equity issues in heart transplantation, including race and sex disparities in who gets listed for and receives a transplant.
We want to hear from you:
Healio wants to hear from you: What advances in heart transplant are most exciting to you and why? Share your thoughts with Healio by emailing rschaffer@healio.com or tweeting @CardiologyToday. We will contact you if we wish to publish any part of your story.
References:
- Koomalsingh K, et al. Ann Cardiothorac Surg. 2018;doi:10.21037/acs.2017.12.02.
- Madan S, et al. J Am Coll Cardiol. 2023;doi:10.1016/j.jacc.2023.04.022.
- Mohiuddin MM, et al. Lancet. 2023;doi:10.1016/S0140-6736(23)00775-4.
- Platt JL, et al. N Engl J Med. 2023;doi:10.1056/nejmE2207105.
- United Network for Organ Sharing. Another record year for heart transplants: Steep increases seen in DCD transplants in 2022. Available at: https://unos.org/news/in-focus/2022-heart-transplants-steep-increases-in-transplants-from-dcd-donors/. Accessed: July 5, 2023.
For more information:
Adam DeVore, MD, can be reached at adam.devore@duke.edu; Twitter: @_adevore.
Seth Hollander, MD, can be reached at sethh1@stanford.edu; Twitter: @sethhollander.
Jon Kobashigawa, MD, can be reached at jon.kobashigawa@cshs.org.
Mary Norine Walsh, MD, MACC, can be reached at macwalsh@iquest.net; Twitter: @minnowwalsh.
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