Short- and long-term effects of brain death on post-transplant graft function in a rodent model.

Abstract

Heart transplantation has become the most effective treatment for end-stage heart failure. Donors after brain death (BD) are currently the only reliable source for cardiac transplants. However, haemodynamic instability and cardiac dysfunction have been demonstrated in brain-dead donors and this could therefore also affect post-transplant graft function. We studied the effects of BD on cardiac function and its short-term (1 h) or long-term (5 h) impacts on graft function. In Lewis rats, BD was induced by inflation of a subdurally placed balloon catheter (n = 7). Sham-operated rats served as controls (n = 9). We continuously assessed cardiac function by left ventricular (LV) pressure-volume analysis. Then, 1 or 5 h after BD or sham operation, hearts were perfused with a cold preservation solution (Custodiol), then explanted, stored at 4°C in Custodiol and heterotopically transplanted. We evaluated graft function 1.5 h after transplantation. BD was associated with decreased left ventricular contractility (ejection fraction: 37 ± 6 vs 57 ± 5%; maximum rate of rise of LV pressure dP/dtmax: 4770 ± 197 vs 7604 ± 348 mmHg/s; dP/dtmax-end-diastolic volume: 60 ± 7 vs 74 ± 2 mmHg/s; slope Emax of the end-systolic pressure-volume relationship: 2.4 ± 0.1 vs 4.4 ± 0.3 mmHg/µl; preload recruitable stroke work: 47 ± 9 vs 78 ± 3 mmHg; P <0.05) and relaxation (maximum rate of fall of left ventricular pressure dP/dtmin: -6638 ± 722 vs -11 285 ± 539 mmHg/s; time constant of left ventricular pressure decay Tau: 12.6 ± 0.7 vs 10.5 ± 0.4 ms; end-diastolic pressure-volume relationship: 0.22 ± 0.05 vs 0.09 ± 0.03 mmHg/µl, P <0.05) 45 min after its initiation and for the rest of 5 h compared with controls. Moreover, after transplantation, graft systolic and diastolic functions were impaired in the 5-h brain-dead group, while they were identical in the 1-h brain-dead group compared with the corresponding controls. We established a well-characterized in vivo rat model to examine the influence of BD on cardiac function using a miniaturized technology for pressure-volume analysis. These results demonstrate that impaired donor cardiac function after short-term BD is reversible after transplantation and long-term BD renders hearts more susceptible to ischaemia/reperfusion injury.