a-porcine-heterotopic-heart-transplantation-protocol-for-delivery

A Porcine Heterotopic Heart Transplantation Protocol for Delivery of Therapeutics to a Cardiac Allograft

Cardiac transplantation is the gold standard treatment for end-stage heart failure. However, it remains limited by the number of available donor hearts ...

a-high-fidelity-porcine-model-orthotopic-heart-transplantation

A High-Fidelity Porcine Model of Orthotopic Heart Transplantation Following Donation after Circulatory Death

The number of advanced heart failure patients who can receive a heart transplant is limited by a shortage of suitable organ donors. In efforts to expand ...

Duke University

Duke University Medical Center

Early iterations of the Norwood procedure used aortic cross-clamping, myocardial arrest, and, sometimes, deep hypothermic circulatory arrest. The resulting hypothermia and prolonged ischemia caused frequent cardiac, neurologic, renal, and other end-organ dysfunctions. Our group describes a novel technique, sustained total all-region (STAR) perfusion, which circumvents these issues by providing continuous perfusion to the head, heart, and coronaries at temperatures of 32-34°C. A single DLP straight venous cannula (Medtronic, Minneapolis, MN) is placed in the right atrium, and a DLP pediatric arterial cannula, with a high-flow stopcock attached, is placed in the ascending aorta or innominate artery to provide flow to the head. A cardioplegia needle with walrus tubing is connected to the stopcock to provide flow to the coronary arteries. For lower body perfusion, an olive tip cannula is placed into the descending aorta lumen and attached to the 1/8″ line from the cardioplegia system which provides warm arterial blood flow. STAR perfusion allows the Norwood procedure to be completed with mild hypothermia and continuous perfusion to all vascular beds with reduced cardiopulmonary bypass as well as total operative times. This technique is successfully achieved with minimal changes to circuitry, minor modifications to heart-lung machine servoregulation and few additional cannulation disposables.

Sustained Total All-Region (STAR) Perfusion: An Optimized Perfusion Strategy for Norwood Reconstruction.

Transplantation, the gold standard intervention for organ failure, is a clinical field that is ripe for applications of gene therapy. One of the major challenges in applying gene therapy to this field is the need for a method that achieves consistent and robust gene delivery to allografts. Normothermic  perfusion is a growing organ preservation method and a device for cardiac preservation was recently approved by the Food and Drug Administration (FDA) (Organ Care System, OCS™; TransMedics, Inc., Andover, MA); this device maintains donor hearts in a near physiologic state while they are transported from the donor to the recipient. This study describes the administration of recombinant adeno-associated viral vectors (rAAVs) during  normothermic perfusion for the delivery of transgenes to porcine cardiac allografts. We utilized a myocardial-enhanced AAV3b variant, SASTG, assessing its transduction efficiency in the OCS perfusate relative to other AAV serotypes. We describe the use of normothermic  perfusion to deliver SASTG carrying the Firefly Luciferase transgene to porcine donor hearts in four heterotopic transplant procedures. Durable and dose-dependent transgene expression was achieved in the allografts in 30 days, with no evidence of off-target transgene expression. This study demonstrates the feasibility and efficiency of delivering genes to a large animal allograft utilizing AAV vectors during  perfusion. These findings support the idea of gene therapy interventions to enhance transplantation outcomes.

 Gene Delivery to Porcine Cardiac Allografts Using a Myocardial-Enhanced Adeno-Associated Viral Vector.

Congenital tuberculosis is a rare infectious disease with less than 500 cases documented worldwide. Mortality is significant, ranging from 34 to 53%, and death without treatment is inevitable. Patients exhibit nonspecific symptoms such as fever, cough, respiratory distress, feeding intolerance, and irritability which can make appropriate diagnosis challenging in Peng et al. (2011) Pediatr Pulmonol 46(12), 1215-1224. Tuberculosis prevalence is particularly high in developing countries where access to resources can be limited in World Health Organization (2019) Global tuberculosis report 2019, Geneva. We present a 2.4-kg premature male infant with acute respiratory distress syndrome secondary to congenital tuberculosis caused by Mycobacterium bovis and tuberculosis-immune reconstitution inflammatory syndrome who was successfully supported with veno-arterial extracorporeal membrane oxygenation.

Case Report: Congenital tuberculosis in a premature infant requiring extracorporeal membrane oxygenation.

Reliable biomarkers for assessing the viability of the donor hearts undergoing  perfusion remain elusive. A unique feature of normothermic  perfusion on the TransMedics® Organ Care System (OCS™) is that the donor heart is maintained in a beating state throughout the preservation period. We applied a video algorithm for an  assessment of cardiac kinematics, video kinematic evaluation (Vi.Ki.E.), to the donor hearts undergoing  perfusion on the OCS™ to assess the feasibility of applying this algorithm in this setting.

Video analysis of  beating hearts during preservation on the TransMedics® organ care system.

Partial heart transplantation (PHT) is a novel surgical approach that involves transplantation of only the part of the heart containing a valve. The rationale for this approach is to deliver growing heart valve implants that reduce the need for future re-operations in children. However, prior to clinical application of this approach, it was important to assess it in a preclinical model. To investigate PHT short-term outcomes and safety, we performed PHT in a piglet model. Yorkshire piglets (n = 14) were used for PHT of the pulmonary valve. Donor and recipient pairs were matched based on blood types. The piglets underwent PHT at an average age of 44 days (range 34-53). Post-operatively, the piglets were monitored for a period of two months. Of the 7 recipient piglets, one mortality occurred secondary to anesthesia complications while undergoing a routine echocardiogram on post-operative day 19. All piglets had appropriate weight gain and laboratory findings throughout the post-operative period indicating a general state of good health and rehabilitation after undergoing PHT. We conclude that PHT has good short-term survival in the swine model. PHT appears to be safe for clinical application.

ArticleTotal : 2	Year
Publication title Cited by 11	2022
Publication title Cited by 2	2025

Article	Year
Sustained Total All-Region (STAR) Perfusion: An Optimized Perfusion Strategy for Norwood Reconstruction. The journal of extra-corporeal technology\| PubMed ID: 33343037	2020
Gene Delivery to Porcine Cardiac Allografts Using a Myocardial-Enhanced Adeno-Associated Viral Vector. Human gene therapy\| PubMed ID: 36927038	2023
Case Report: Congenital tuberculosis in a premature infant requiring extracorporeal membrane oxygenation. The journal of extra-corporeal technology\| PubMed ID: 37378441	2023
Video analysis of beating hearts during preservation on the TransMedics® organ care system. Frontiers in cardiovascular medicine\| PubMed ID: 37408655	2023
Survival after partial heart transplantation in a piglet model. Scientific reports\| PubMed ID: 38811656	2024

Amy Evans

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