Project Grant R41HL169059

EVALUATION OF GROWTH POTENTIAL OF ICE-FREE VITRIFIED HEART VALVES IN A PEDIATRIC PORCINE MODEL. - ABSTRACT: HEART VALVE REPLACEMENT IN CHILDREN IS A SERIOUS PROBLEM BECAUSE THERE ARE NO HEART VALVE IMPLANTS THAT GROW WITH THE PATIENT. THE VALVES THAT ARE CURRENTLY EMPLOYED NEED TO BE CHANGED AS THE PATIENT GROWS WITH A VERY HIGH ASSOCIATED MORTALITY RATE (~40%). IN RESPONSE TO THIS CLINICAL NEED, WE ARE PIONEERING AN ENTIRELY NEW APPROACH TO DELIVER GROWING HEART VALVE IMPLANTS, WHICH WE ARE CALLING PARTIAL HEART TRANSPLANTATION (PHT). PHT DIFFERS FROM HEART TRANSPLANTATION BECAUSE ONLY THE PART OF THE HEART CONTAINING A VALVE IS TRANSPLANTED. BASED ON OUR PRELIMINARY DATA IN IMMUNOSUPPRESSED PIGLETS, WE RECENTLY PERFORMED THE WORLD'S FIRST HUMAN PARTIAL HEART TRANSPLANT ON 4/22/2022 WITH DEMONSTRATED VALVE GROWTH. HOWEVER, THE CHANCE OF A DONOR PARTIAL HEART TRANSPLANT BEING AVAILABLE AT JUST THE RIGHT TIME IS LOW. THEREFORE, WE PROPOSE DEVELOPMENT OF A NETWORK OF TISSUE BANKS WITH TECHNOLOGY LICENSES AT MAJOR PEDIATRIC CARDIOVASCULAR MEDICAL CENTERS NATIONWIDE IN PREPARATION FOR CLINICAL APPLICATION. OUR CENTRAL HYPOTHESIS IS THAT VITRIFIED AND NANOWARMED PHTS CAN FULFILL BOTH THEIR HEMODYNAMIC AND BIOLOGICAL FUNCTIONS AFTER ORTHOTOPIC TRANSPLANTATION IN GROWING CHILDREN. IN THIS PHASE I PROPOSAL THERE ARE THREE SPECIFIC AIMS: FIRST WE PROPOSE OPTIMIZATION OF SHORT-TERM PRESERVATION PROTOCOLS. OUR WORKING HYPOTHESIS FOR THIS AIM IS THAT PHTS WILL TOLERATE LONGER POST-MORTEM COLD ISCHEMIC TIMES THAN INTACT HEARTS. THE IMPACT OF PROCUREMENT AND REFRIGERATION ON PIGLET-DERIVED PHTS WILL BE EVALUATED BY ASSESSMENT OF VIABILITY IN VITRO. THIS WILL ESTABLISH THE ANTICIPATED GEOGRAPHIC RANGE FOR PHT PROCUREMENT AFTER DISSECTION BASED UPON ESTIMATED REFRIGERATED TRAVEL TIME. IN THE SECOND SPECIFIC AIM WE WILL OPTIMIZE VITRIFICATION PROTOCOLS FOR PHTS. OUR WORKING HYPOTHESIS FOR THIS AIM IS THAT ICE-FREE CRYO-PRESERVATION EMPLOYING TISSUE VITRIFICATION, RAPID NANOWARMING AND APOPTOSIS INHIBITION DEVELOPED FOR ADULT PORCINE PULMONARY HEART VALVES CAN BE FURTHER OPTIMIZED FOR SMALLER PHTS REQUIRED FOR PEDIATRIC CASES. DIFFERENT CRYOPROTECTANT LOADING TIMES, EXPOSURE CONDITIONS, AND APOPTOSIS INHIBITORS WILL BE EVALUATED BY ASSESSMENT OF VIABILITY IN VITRO. THIS WILL ESTABLISH THE OPTIMAL VITRIFICATION PROTOCOL FOR PEDIATRIC PHTS. IN THE FINAL AIM WE WILL EVALUATE POST- TRANSPLANT GROWTH, LEAFLET VIABILITY AND HEMODYNAMIC FUNCTION OF OPTIMALLY VITRIFIED AND NANOWARMED CRYOPRESERVED PHTS. OUR WORKING HYPOTHESIS FOR THIS AIM IS THAT OPTIMIZED PROTOCOLS WILL ALLOW VITRIFIED PHTS THAT WERE BANKED FOR ONE MONTH TO FUNCTION IN VIVO LIKE FRESH PHTS. THE OPTIMIZED PROTOCOLS DEVELOPED IN THE EARLIER AIMS WILL BE EVALUATED IN A SWINE LEUKOCYTE ANTIGEN MATCHED GROWING IMMUNOSUPPRESSED PIGLET PHT MODEL BY TRANSPLANTATION. THIS WILL ESTABLISH THE PHT VITRIFICATION, WARMING, AND BANKING METHODS FOR FUTURE CLINICAL APPLICATION.