Cariporide (HOE-642) improves cardiac allograft preservation in a porcine model of orthotopic heart transplantation

Ryan, Jonathon B.; Hicks, Mark; Cropper, Jonathan R.; Garlick, Sarah; Kesteven, Scott; Wilson, Michael K.; Feneley, Michael P.; Macdonald, P.

doi:10.1097/01.tp.0000054619.13962.30

Cited by 19 publications

(4 citation statements)

References 27 publications

(34 reference statements)

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“…PCXD may occur due to xenotransplantation-specific factors, such as the use of young donor organs, the inflammatory effects of preformed non-Gal antibody, and incompatibility between porcine and primate plasma including known dysfunctions in thromboregulation and may be further effected by pig-specific factors, most notably the sensitivity of the pig heart to cardiopulmonary bypass and ischemia-reperfusion (I/R) injury (47, 48). If this is the case then a combination of pretransplant immunoabsorption, cardiac preconditioning (49) or pharmacological treatments to improve cardiac resistance to I/R injury (50, 51) may modulate PCXD.…”

Section: Orthotopic Cardiac Xenotransplantationmentioning

confidence: 99%

Cardiac xenotransplantation

Byrne¹,

McGregor²

2012

Current Opinion in Organ Transplantation

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Purpose of Review Cardiac xenotransplantation (CXTx) remains a promising approach to alleviate the chronic shortage of donor hearts. This review summarizes recent results of heterotopic and orthotopic CXTx, highlights the role of non-Gal antibody in xenograft rejection, and discusses challenges to clinical orthotopic CXTx. Recent Findings Pigs mutated in the α 1,3 galactosyltransferase gene (GTKO pigs) are devoid of the galactose α 1,3 galactose (αGal) carbohydrate antigen. This effectively eliminated any role for anti-Gal antibody in GTKO cardiac xenograft rejection. Survival of heterotopic GTKO cardiac xenografts in nonhuman primates continues to increase. GTKO graft rejection commonly involves vascular antibody deposition and variable complement deposition. Non-Gal antibody responses to porcine antigens associated with inflammation, complement, and hemostatic regulation and to new carbohydrate antigens have been identified. Their contribution to rejection remains under investigation. Orthotopic CXTx is limited by early perioperative cardiac xenograft dysfunction (PCXD). However, hearts affected by PCXD recover full cardiac function and orthotopic survival up to 2 months without rejection has been reported. Summary CXTx remains a promising technology for treating end-stage cardiac failure. Genetic modification of the donor and refinement of immunosuppressive regimens have extended heterotopic cardiac xenograft survival from minutes to in excess of 8 months.

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Section: Orthotopic Cardiac Xenotransplantationmentioning

confidence: 99%

Cardiac xenotransplantation

Byrne¹,

McGregor²

2012

Current Opinion in Organ Transplantation

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“…In the DCD context, however, intracellular acidosis develops concurrently with the depletion of ATP stores. The combined effect of increased NHE activity and inhibition of the sodium–potassium ATPase produces a pathological accumulation of intracellular sodium (Figure 4 A) ( 31 , 32 ). Subsequent reperfusion at the time of organ procurement rapidly normalizes the extracellular pH and creates a large hydrogen ion gradient across the plasma membrane that causes further sodium influx via the NHE ( 33 ).…”

Section: Dcd Heart Transplantationmentioning

confidence: 99%

“…The cardioprotective effects of NHE inhibition in IRI are well documented. Cariporide has been shown to limit myocardial IRI in clinical trials ( 65 – 67 ) and translational animal models of DCD heart transplantation ( 32 , 68 – 70 ). Zoniporide is a recently developed NHE inhibitor that possesses greater potency and selectivity toward the cardiac NHE ( 71 ), and has potent cardioprotective effects through activation of prosurvival kinase pathways and inhibition of apoptosis ( 72 ).…”

Section: Dcd Heart Transplantationmentioning

confidence: 99%

“…Dhital et al reported the first clinical adult DCD heart transplants in the modern era ( 22 ). These three transplants represented direct clinical translation of the groups’ research in pharmacologic post-conditioning in large animal models ( 32 , 53 , 64 , 72 , 96 , 97 , 140 ). Based on these studies, the authors considered Maastricht category III donors <40 years of age with a WIT <30 min ( 97 ).…”

Section: Dcd Heart Transplantationmentioning

confidence: 99%

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Transplantation of Hearts Donated after Circulatory Death

White

Messer

Large

et al. 2018

Front. Cardiovasc. Med.

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Cardiac transplantation has become limited by a critical shortage of suitable organs from brain-dead donors. Reports describing the successful clinical transplantation of hearts donated after circulatory death (DCD) have recently emerged. Hearts from DCD donors suffer significant ischemic injury prior to organ procurement; therefore, the traditional approach to the transplantation of hearts from brain-dead donors is not applicable to the DCD context. Advances in our understanding of ischemic post-conditioning have facilitated the development of DCD heart resuscitation strategies that can be used to minimize ischemia-reperfusion injury at the time of organ procurement. The availability of a clinically approved ex situ heart perfusion device now allows DCD heart preservation in a normothermic beating state and minimizes exposure to incremental cold ischemia. This technology also facilitates assessments of organ viability to be undertaken prior to transplantation, thereby minimizing the risk of primary graft dysfunction. The application of a tailored approach to DCD heart transplantation that focuses on organ resuscitation at the time of procurement, ex situ preservation, and pre-transplant assessments of organ viability has facilitated the successful clinical application of DCD heart transplantation. The transplantation of hearts from DCD donors is now a clinical reality. Investigating ways to optimize the resuscitation, preservation, evaluation, and long-term outcomes is vital to ensure a broader application of DCD heart transplantation in the future.

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