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Decellularization Reduces Calcification While Improving Both Durability and One Year Functional Results of Pulmonary Homograft Valves in Juvenile Sheep
R. A. Hopkins1, A. Linthurst Jones2, L. Wolfinbarger2, M. A. Moore2, A. Bert1, G. K. Lofland1. 1Cardiovascular Surgery, Children's Mercy Hospitals and Clinics, Kansas City, MO, 2LifeNet Health, Virginia Beach, VA,
BACKGROUND:
Effective decellularization of homograft valves removes donor antigens and proinflammatory debris and thus offers promise for prolonging durability by reducing recipient inflammation, immune responses, fibrous scarring, and calcification as compared to standard cryopreserved valve implants. The juvenile sheep working valve chronic implant calcification model was used to compare classic cryopreserved homografts to two versions of decellularized pulmonary valved conduit RVOT functional implants to determine long-term calcification rates, functional performance and durability.
METHODS:
Fifteen juvenile sheep underwent RVOT implant and were assigned equally to one of three study Arms: 1) Cryopreserved ovine pulmonary valves (OPV); 2) Decellularized OPV, and 3) Decellularized, glycerol-preserved/-80°C stored OPVs (LifeNet Health technology). Animal growth, serial echocardiography (6 exams/animal) with assessment of valve performance, dimensions, and tissue-specific calcification were measured and compared with pre-explant angiography and RVOT pressure measurements, cardiac MRI, specimen X-ray, gross explant pathology, and histopathology. Data were analyzed by parametric and non-parametric statistical methods: P <0.05 = significant.
RESULTS:
Nondestructive calcium imaging procedures correlated highly with each other (P = 0.001) and with explant pathology findings. No conduit wall or leaflet calcification was observed in Arm 3, unlike valves in Arms 1 and 2 (P = 0.0005, 0.0072, respectively). As expected and consistent with clinical experience, cryopreserved valves developed the most calcium deposits at all time points (P = 0.00009, compared to Arms 2 and 3). Unlike Arms 1 and 2, no leaflets in Arm 3 stiffened by week 52 (P = 0.0095). Leaflet dysfunction typically caused regurgitation and was significantly less in Arm 3 as compared to Arms 1 and 2 (P = 0.0064). Logistic regression indicated positive association between echo identified leaflet calcium and the mean gradients for valves that developed stenosis gradients (P = 0.0443, R2= 0.1848). MRI results confirmed echo/angio assessment of normal valve function in the Arm 3 valves all of which were without calcification, stenosis, or regurgitation at 1 year (an implant duration roughly equivalent to 15 years in humans). Animal growth and heart function were similar among the three treatment groups. Peak and mean gradients, EOAI and EOA were not different among the Arms. Dimensions/age were comparable among the three Arms throughout the year. Laser confocal immunohisto-microscopy revealed leaflet and wall recellularization with phenotypically appropriate cells.
CONCLUSIONS:
The juvenile ovine cardiac valve preclinical chronic implant model is highly sensitive and robust for predicting structural valve deterioration in biologic valves intended for human use, so much so, that the potential for valve dysfunction and calcification are typically and accurately assessed at 20 weeks s/p implantation. These superior one-year results for the putative clinical protocol represented by Arm 3 for a decellularized extracellular matrix semilunar valve allograft conduit predict excellent results that are far better than those achieved with cryopreserved allograft valves in which variably viable donor cells are retained. Normal valve function and absent wall and leaflet calcium at 1 year in the Arm 3 clinically relevant decellularized glycerolized homograft pulmonary valve conduits predict prolonged durability and superior long-term valve performance.
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