The current standard of care for pediatric patients with unrepairable congenital valvular disease is a heart valve implant. However, current heart valve implants are unable to accommodate the somatic growth of the recipient, preventing long-term clinical success in these patients. Therefore, there is an urgent need for a growing heart valve implant for children. This article reviews recent studies investigating tissue-engineered heart valves and partial heart transplantation as potential growing heart valve implants in large animal and clinical translational research. In vitro and in situ designs of tissue engineered heart valves are discussed, as well as the barriers to clinical translation.
Unrepairable congenital heart valve disease is an unsolved problem in pediatric cardiac surgery because there are no growing heart valve implants. Partial heart transplantation is a new type of transplant that aims to solve this problem. In order to study the unique transplant biology of partial heart transplantation, animal models are necessary. This study aimed to assess the morbidity and mortality of heterotopic partial heart transplantation in rodent models. This study assessed two models. The first model involved transplanting heart valves from donor animals into the abdominal aortic position in the recipient animals. The second model involved transplanting heart valve leaflets into the renal subcapsular position of the recipient animals. A total of 33 animals underwent heterotopic partial heart transplantation in the abdominal aortic position. The results of this model found a 60.61% (n = 20/33) intraoperative mortality rate and a 39.39% (n = 13/33) perioperative mortality rate. Intraoperative mortality was due to vascular complications from the procedure, and perioperative mortality was due to graft thrombosis. A total of 33 animals underwent heterotopic partial heart transplantation in the renal subcapsular position. The results of this model found a 3.03% (n = 1/33) intraoperative mortality rate, and the remaining 96.97% survived (n = 32/33). We conclude that the renal subcapsular model has a lower mortality rate and is technically more accessible than the abdominal aortic model. While the heterotopic transplantation of valves into the abdominal aortic position had significant morbidity and mortality in the rodent model, the renal subcapsular model provided evidence for successful heterotopic transplantation.
Many young adults require heart valve replacements. Current options for valve replacement in adults include mechanical valves, bioprosthetic valves, or the Ross procedure. Of these, mechanical and bioprosthetic valves are the most common options, although mechanical valve usage predominates in younger adults due to durability, while bioprosthetic valve usage predominates in older adults. Partial heart transplantation is a new method of valvular replacement that can deliver durable and self-repairing valves and allow adult patients freedom from anticoagulation therapy. This procedure involves transplantation of donor heart valves only, permitting expanded utilization of donor hearts as compared with orthotopic heart transplantation. In this review, we discuss the potential benefits of this procedure in adults who elect against the anticoagulation regimen required of mechanical valve replacements, although it has not yet been clinically established. Partial heart transplantation is a promising new therapy for the treatment of pediatric valvular dysfunction. This is a novel technique in the adult population with potential utility for valve replacement in young patients for whom anticoagulation therapy is problematic, such as women who wish to become pregnant, patients with bleeding disorders, and patients with active lifestyles.
The phosphatidylinositol-3-kinase (PI3K) pathway is of significant interest due to its ability to regulate cell proliferation, growth, and migration in numerous contexts including in T cells. Furthermore, gain-of-function mutations in PI3K can lead to an upregulation of the pathway, resulting in tumorigenesis, autoimmunity, and leukemia. Specific furanosesquiterpenoids, such as wortmannin, have been known to inhibit the PI3K pathway in T cells. However, wortmannin has unfavorable characteristics as a chemotherapeutic or immunomodulatory drug due to its insolubility in neutral buffers, instability, and high toxicity in vivo. Hibiscone C, another furanosesquiterpenoid, lacks many of the functional groups as wortmannin, but contains the same diacyl furan ring that is critical for interacting with the ATP binding pocket of PI3K. Via analysis of phosphorylation of the downstream effector molecule Akt in activated T cells, we demonstrate that Hibiscone C also can irreversibly inhibit PI3K activity, however not as effectively as wortmannin. These results led us to test other derivatives of hibiscone C, to see if modifications to the molecule’s structure would affect potency of the molecule.
Cold preservation is a key component to organ procurement and transplantation. Cold preservation functions by slowing metabolic activity of procured organs and begins the period known as cold ischemic time (CIT). Reducing CIT and warm ischemic time (WIT) are paramount to minimizing donor organ damage from ischemia and the build-up of waste products and signals that drive reperfusion injury prior to transplantation into a matching recipient. Preventing damage from CIT and WIT and extending the amount of time that organs can tolerate has been a major goal of organ transplantation since donors and recipients are frequently not located within the same hospital, region, or state. Meanwhile, the amount of CIT that a transplant center is willing to accept differs based on the organ, the institution receiving the organ offer, and the doctor receiving the offer for that institution. With the introduction of a partial heart transplantation conducted last year at Duke University, it is important to discuss how much CIT transplant centers conducting a partial heart transplantation (pHT) are willing to accept. This article will review the physiology of WIT and CIT, associated organ damage, CIT variation among transplant centers and organ types, and provide a brief discussion of the future of pHT-accepted CIT and the need for research in this field.
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