Hundreds of thousands of Americans with heart failure are sick enough to benefit from a transplant, yet only around 4,000 heart transplants are performed annually.
One reason for this gap is the time window during which a heart can survive outside the donor body before transplant hovers around four hours. And the longer it takes for the donor heart to be transported to the recipient, the more likely that heart will not work well once it's implanted.
Using a drug previously used to treat seizures, researchers have found a way to reprogram donor hearts to boost the production of a beneficial enzyme that both increases the amount of time they can be stored and transported, as well as improves their function after they are transplanted, a study published in Science Translational Medicine suggests.
"This technology that coaxes donor hearts to mount adaptive responses to existence outside the body could lead to a paradigm shift not only for extending the time a heart can be outside of the donor during transport but for improving heart function after transplant," said Paul C. Tang, M.D., Ph.D., senior author of the study and a heart transplant surgeon at University of Michigan Health. "Being able to extend the storage of hearts by figuring out the pathways that define and modulate preservation biology is the first step toward the ultimate goal of organ banking."
In around 10-20% of heart transplants, transplanted hearts cannot pump sufficient blood to supply to the rest of the body. The condition, known as primary graft dysfunction, is responsible for nearly 40% of early deaths after heart transplant and can still predictably occur despite newer machine heart perfusion technology.
Investigators in the study sought to reduce primary graft dysfunction by increasing the production of itaconate, an anti-inflammatory and antioxidant metabolite produced by the enzyme Irg1. Itaconate neutralizes the effects of succinate, a harmful molecule which accumulates while a heart is on ice and creates a flash of oxidative stress following blood reperfusion that causes the heart to malfunction.
"Current donor preservation techniques focus on cold storage and, more recently, technologies that keep the organs perfused during transport to minimize injury to the heart, but there are no targeted molecular therapies to improve heart preservation in a very precise fashion," said Ienglam Lei, Ph.D., first author of the study and a research investigator in the Department of Cardiac Surgery at U-M Medical School.
When an organ is in cold storage, succinate is free to build up in excess—more ammunition for stress against the soon-to-be-transplanted heart. To reprogram hearts to take on the heart-damaging succinate, researchers used valproic acid, a histone deacetylase inhibitor previously used as an anti-seizure medication. They found that it defused a significant amount of this cumulative stress in both human and pig hearts by instructing the donor heart to produce antioxidants and anti-inflammatory proteins while preserved on ice.
"Using a metabolomic screen, we found that valproic acid can reprogram the donor heart to produce beneficial itaconate during preservation," said Tang, who is also an assistant professor of cardiac surgery at U-M Medical School. "We showed previously that hearts are in fact biologically very active while stored on ice, which opens up the therapeutic opportunity to help it protect itself from metabolic stress during this time. Not only could this possibly double the time a heart could spend in cold storage, but it could reduce the risk of primary graft dysfunction to make transplant even safer."
Valproic acid is approved by the FDA to treat seizures, bipolar disorder and for the prevention of migraine headaches. For that reason, researchers believe the road to a clinical trial may be shorter.
"This discovery will buy time to allow a donor heart to reach patients in parts of the country not previously accessible—greatly impacting the landscape of organ transplant in America," said Y. Eugene Chen, M.D., Ph.D., co-author of the study and Frederick G. L. Huetwell Professor of Cardiovascular Medicine at U-M Medical School. "The overarching principles here can be expected to apply to preservation of other organs, such as lungs, livers and kidneys. I would also anticipate this treatment strategy to be relevant for other conditions where blood supply is disrupted, such as heart attack or stroke."
Additional authors include, Wei Huang, M.D.., Ph.D., Suyash Naik, B.S., Miriyam Ghali, B.S., Liu Liu, Ph.D., Pracis D. Pagani, M.D., Ph.D., Ashraf Abou el ela, M.D., Bertram Pitt, M.D., Jeffrey L. Platt, M.D., Marilia Cascalho, M.D., Ph.D., Zhong Wang, Ph.D., Richard M. Mortensen, M.D., Ph.D., all of University of Michigan, Pierre Emmanuel Noly, M.D., Ph.D., Université de Montréal, and Jordan S. Pober, M.D., Ph.D., Yale University.
More information: Ienglam Lei et al, Metabolic reprogramming by immune-responsive gene 1 upregulation improves donor heart preservation and function, Science Translational Medicine (2023). DOI: 10.1126/scitranslmed.ade3782. www.science.org/doi/10.1126/scitranslmed.ade3782
Citation: Donor hearts can be reprogrammed with medication for longer storage, improved transplant outcomes (2023, February 8) retrieved 8 February 2023 from https://medicalxpress.com/news/2023-02-donor-hearts-reprogrammed-medication-longer.html
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.
Zaidi ya watu elfu mia moja wana ugonjwa wa moyo ambao wanaweza kupewa upasuaji wa moyo, lakini ni karibu upasuaji wa moyo 4,000 tu unaofanywa kila mwaka. Sababu moja ya pengo hili ni dirisha la wakati ambapo moyo unaweza kuishi nje ya mwili wa wafadhili kabla ya kupandikizwa huzunguka saa nne. Kadiri moyo wa mtoaji unavyopita, ndivyo moyo unavyozidi kuharibika baada ya kupandikizwa. Kwa kutumia dawa iliyotumiwa hapo awali kutibu mshtuko wa moyo, watafiti wamepata njia ya kuhariri moyo wa wafadhili ili kuongeza uzalishaji wa enzyme muhimu ambayo huongeza muda ambao inaweza kuhifadhiwa na kusafirishwa, na pia kuboresha kazi yao baada ya kupandikizwa. "Teknolojia hii ambayo inawashawishi mioyo ya wafadhili kuanzisha majibu ya kukabiliana na kuwepo nje ya mwili inaweza kusababisha mabadiliko ya mfano, sio tu kwa kupanua muda ambao moyo unaweza kuwa nje ya wafadhili wakati wa usafirishaji, lakini kwa kuboresha kazi ya moyo baada ya kupandikiza, ""alisema Paul C. Tang, M.D., Ph.D., mwandishi mwandamizi wa utafiti na daktari wa upandikizaji wa moyo katika Chuo Kikuu cha Michigan." "Kufanikiwa kupanua kuhifadhi kwa moyo kwa kugundua njia ambazo hufafanua na kurekebisha biolojia ya kuhifadhi ni hatua ya kwanza kuelekea lengo la mwisho la benki ya viungo.""" Katika asilimia 10 hadi 20 ya maambukizi ya moyo, moyo unaopandikizwa hauwezi kusukuma damu ya kutosha kwa mwili wote. Ugonjwa huu unaojulikana kama primary graft dysfunction, unawaua karibu asilimia 40 ya watu wanaokufa mapema baada ya kupandikizwa moyo na bado unaweza kutokea licha ya teknolojia mpya ya kupandikiza moyo. Utafiti huo ulijaribu kupunguza dysfunction ya msingi ya graft kwa kuongeza uzalishaji wa itaconate, metabolite ya kupambana na uvimbe na antioxidant inayotokana na enzyme IrG1. Itaconate inazuia athari za succinate, molekuli mbaya ambayo hukusanyika wakati moyo uko kwenye barafu na huunda flash ya mkazo wa oxidative kufuatia reperfusion ya damu ambayo husababisha moyo kufanya kazi vibaya. "Utaratibu wa sasa wa kuhifadhi wafadhili unazingatia kuhifadhi baridi na, hivi karibuni, teknolojia ambazo zinaweka viungo vya mwili wakati wa usafirishaji ili kupunguza uharibifu wa moyo, lakini hakuna matibabu ya molekuli yaliyolenga kuboresha uhifadhi wa moyo kwa njia sahihi sana, ""alisema Ienglam Lei, PhD, mwandishi wa kwanza wa utafiti na mtafiti wa utafiti katika Idara ya Upasuaji wa Moyo katika UMS." Wakati chombo ni katika kuhifadhi baridi, succinate ni huru kujenga juu ya ziada - risasi zaidi kwa ajili ya mkazo dhidi ya moyo hivi karibuni-kwa-kuwa kupandikizwa. Ili kuharakisha moyo kuchukua suguinate, watafiti walitumia asidi ya valproic, kichocheo cha histone deacetylase ambacho hapo awali kilitumiwa kama dawa ya kuzuia mshtuko wa moyo. Utafiti huo ulionyesha kuwa moyo wa binadamu na wa nguruwe unafungiwa na mgonjwa kwa kuagiza moyo wa mtoaji utokeze protini za antioxidant na anti-inflammatory wakati wa kuhifadhiwa kwenye barafu. "Kwa kutumia skrini ya metabolomic, tuligundua kwamba asidi ya valproic inaweza kuunda upya moyo wa wafadhili ili kuzalisha itaconate ya manufaa wakati wa kuhifadhi, ""Tang alisema, ambaye pia ni profesa msaidizi wa upasuaji wa moyo katika Chuo Kikuu cha U.M. Medical." "Tumeonyesha hapo awali kwamba mioyo ni kweli hai sana wakati kuhifadhiwa juu ya barafu, ambayo inafungua fursa ya matibabu ya kusaidia kujilinda dhidi ya mkazo wa kimetaboliki wakati huu. """ "Hii inaweza kuongeza mara mbili ya muda moyo unaweza kutumia katika kuhifadhi baridi, lakini inaweza kupunguza hatari ya graft dysfunction ya msingi na kufanya kupandikiza hata salama zaidi. """ Asidi ya Valproic ni dawa ya kawaida inayotumiwa na wagonjwa wa ugonjwa wa kifafa, ugonjwa wa bipolar, na maumivu ya kichwa. Kwa sababu hiyo, watafiti wanaamini kwamba huenda njia ya kufika kwenye majaribio ya kliniki ikawa fupi zaidi. "Ugunduzi huu utapata wakati wa kuruhusu moyo wa mchangiaji kufikia wagonjwa katika sehemu za nchi ambazo hazikufikia hapo awali, na kuathiri sana mazingira ya upandikizaji wa viungo nchini Marekani, ""alisema Y. Eugene Chen, MD, PhD, mwandishi mwenza wa utafiti na Profesa wa Frederick G. L. Huetwell wa Tiba ya Cardiovascular katika Shule ya Tiba ya UM." "Kanuni kuu hapa zaweza kutarajiwa kutumika kwa kuhifadhi viungo vingine, kama vile mapafu, ini na figo. "Ninaamini pia kwamba mbinu hii ya matibabu inahusiana na hali nyingine ambapo usambazaji wa damu umevurugwa, kama vile mshtuko wa moyo au kiharusi. """ "Wanafunzi wa chuo hicho ni: Dr. W.A.S.H. (M.S.H.), Dr. A.M.S. (M.S.H.), Dr. A.M.S. (M.S.H.), Dr. A.M.S. (M.S.H.), Dr. A.M.S.H., Dr. A.M.S.H., Dr. A.M.S.H., Dr. A.S.S.H., Dr. A.S.H., Dr. A.S.H., Dr. A.S.H., Dr. A.S.H., Dr. A.S.H., Dr. A.S.H., Dr. A.S.H., Dr. A.S.H., Dr. A.S.H., Dr. A.S.H., Dr. A.S.H., Dr. A.S.H., Dr. A.S.H., Dr. A.S.H., Dr. A.S.H., Dr. A.S.H., Dr. A.S.H., Dr. A.A., Dr. "Ingram, Lei et al, ""Metabolic reprogramming by immune-responsive gene 1 upregulation improves donor heart preservation and function"" (Utaalamu wa Tiba ya Uhamisho wa Sayansi, 2023)." "Kama ilivyoelezwa katika taarifa ya ""SITANCE"" (SITANCE) ya 10116 (SITANCE) na ""SITANCE"" (SITANCE) ya 10126 (SITANCE) ya 10126 (SITANCE) na ""SITANCE"" ya 10126 (SITANCE) ya 10126 (SITANCE)." "Kama ilivyoelezwa katika makala ya ""Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti wa Utafiti." Isipokuwa kwa ajili ya utafiti wa kibinafsi au utafiti, hakuna sehemu yoyote inaweza kuzalishwa bila ruhusa ya maandishi. Yaliyomo hutolewa kwa madhumuni ya habari tu.