Cardiac preservation for transplantation disrupts normal vascular homeostatic mechanisms. Hypoxia and reoxygenation increase endothelial cell permeability, induce procoagulant activity, and alter endothelial cell/leukocyte interactions, with a parallel reduction in endothelial cAMP and nitric oxide levels. Because hypoxia/reoxygenation simulates a significant component of the global ischemia/reperfusion of cardiac transplantation, we hypothesized that preservation failure may be related to these perturbations. This work focuses on repleting the intercellular/intracellular second messengers nitric oxide/cGMP and cAMP in the donor heart to enhance cardiac preservation for transplantation.Methods and Results.
A heterotopic rat heart transplant model was used to compare lactated Ringer's (LR) and University of Wisconsin (UW) solutions to a novel storage solution (Columbia University solution, CU), which contains a cAMP analogue (dibutyryl cAMP) and nitroglycerin (to enhance nitric oxide-related mechanisms). By 24 to 28 hours of preservation, no LR hearts survived (n=9), 35% of UW hearts survived (n=20), and 88% of CU-preserved hearts survived (n=8;P<.05 versus LR or UW). The viability of preserved hearts was explored by determining whether CU preservation enabled myocytes to maintain resting membrane potentials and preserve their ability to generate an action potential in response to a field stimulus. Of 24 sites explored with a microelectrode in UW-preserved hearts, only 4% were able to generate an action potential, compared with 75% of 36 sites in CU-preserved hearts (P<.001), with corresponding preservation of resting membrane potential in the CU-preserved hearts (-13 mV for UW versus -54 mV for CU,P<.001). Orthotopic baboon cardiac transplantation performed after 24-hour simple hypothermic preservation demonstrated that no UW-preserved heart (n=4) survived the perioperative period; in contrast, four of five hearts stored for 24 hours in CU solution sustained the recipient with minimal inotropic support, and two animals survived long-term.Conclusions.
Sustaining higher levels of intercellular/intracellular second messengers cAMP and nitric oxide/cGMP provides a new approach to enhancing cardiac preservation. (Circulation.1993;88[part 2]: 291–297.)