Preservation with Custodiol Solution Containing Alpha-1-Antitrypsin Improves Graft Function after Prolonged Cold Ischemic Storage in a Rat Model of Heart Transplantation

Objectives: Heart transplantation (HTX) is the standard treatment in end-stage heart failure. Alpha-1-antitrypsin (AAT), a potent inhibitor of the serine proteases, is clinically used for the treatment of AAT deficiency in patients with emphysema. Evidence demonstrates anti-inflammatory and cytoprotective effects of AAT. We assessed the hypothesis that AAT, when added to a preservation solution, attenuates left ventricular (LV) graft dysfunction after prolonged cold ischemic storage in a rat model of HTX.

Methods: The hearts from Lewis donor rats were arrested using Custodiol solution, explanted and stored either for 1 or 5 hours in cold preservation solution (Custodiol) supplemented with 1 mg/mL human albumin vehicle (1 hour ischemia, n = 7 or 5 hours ischemia, n = 7 groups) or with 1 mg/mL AAT (1 hour ischemia + AAT, n = 7 or 5 hours ischemia + AAT, n = 9 groups). Then, they were heterotopically transplanted. Posttransplant graft function was assessed in vivo 1.5 hours after HTX via a Millar catheter. Additionally, the myocardial expression of 88 genes was profiled using PCR array and immunohistological detection of myeloperoxidase (MPO), a marker of neutrophil infiltration, was performed.

Result: After HTX, LV systolic function (maximal slope of the systolic pressure increment dP/dtmax 1-hour ischemia 3,123 ± 110 vs. 1-hour ischemia + AAT 4,197 ± 256; 5-hour ischemia 1,843 ± 104 vs. 5-hour ischemia + AAT 2,858 ± 154 mm Hg/s at an intraventricular volume of 90 µL; p < 0.05) and diastolic function (maximal slope of the diastolic pressure decrement dP/dtmin 5-hour ischemia 1,095 ± 67 vs. 5-hour ischemia + AAT 1,516 ± 68 mm Hg/s at an intraventricular volume of 90 µL; p < 0.05) were significantly improved in the AAT groups compared with the corresponding vehicle groups. Furthermore, the rate pressure product, used to determine the myocardial workload (1-hour ischemia 26 ± 1 vs. 1-hour ischemia + AAT 53 ± 4; 5-hour ischemia 21 ± 1 vs. 5-hour ischemia + AAT 37 ± 3 mm Hg * beats/min at an intraventricular volume of 90 µl; p < 0.05), was significantly increased in the AAT groups compared with the corresponding vehicle groups. Additionally, MPO-positive cell infiltration was significantly decreased in the 5-hour ischemia + AAT compared with the 5-hour ischemia group. Among the tested genes, prolonged ischemia altered the expression of six genes (ccl2, Fos, Icam1, Txnrd1, Hspa1a, and Tlr4), whereas AAT modified two genes (ccl11, Vcam) in this setup.

Conclusion: AAT added to a preservation solution Custodiol protects grafts from prolonged cold ischemia during HTX in rats.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
19 February 2021