Mohammed Quader1, Eleonora Mezzaroma2, Kristine Kenning3, Stefano Toldo4. 1. Cardiovascular Surgery, Virginia Commonwealth University, Richmond, Virginia; Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia. Electronic address: mohammed.quader@vcuhealth.org. 2. Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia; School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia. 3. Cardiovascular Surgery, Virginia Commonwealth University, Richmond, Virginia. 4. Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia; Division of Cardiology, Virginia Commonwealth University, Richmond, Virginia.
Abstract
BACKGROUND: Donation after circulatory death donors (DCD) can expand the donor pool for heart transplantation, which primarily depends on brain death donors. Ischemia and reperfusion injury are inherent to the DCD process. We hypothesize that pharmacologic inhibition of interleukin-1 (IL-1) and/or IL-18 is protective to DCD hearts. MATERIALS AND METHODS: Following clinical protocol, in-situ ischemia time in control beating-heart donor (CBD) and DCD groups was less than 5 and 40 min, respectively. Wild type (WT) C57Bl6/j, IL-1 receptor type I knockout (IL-1RI-KO), and IL-18 KO mice were used. Hearts were reanimated for 90 min on a Langendorff system with Krebs-Henseleit buffer at 37°C, to assess physiologic parameters. Recombinant IL-1 receptor antagonist (IL-1Ra) and/or IL-18 binding protein (IL-18BP) were added to the Krebs-Henseleit buffer to inhibit IL-1 and/or the IL-18 signaling, respectively. RESULTS: Developed pressure and ± dP/dt were significantly impaired in the DCD-WT group compared to CBD-WT (P ≤ 0.05). Troponin release was higher in DCD-WT groups. Functional parameters were preserved, and troponin release was significantly less in the DCD knockout groups. Heart function was improved in DCD groups treated with IL-1Ra or IL-18BP compared to the DCD-WT group. CONCLUSIONS: Heart function was significantly impaired in the DCD-WT group compared to CBD-WT. Genetic deletion or pharmacologic blockade of IL-1 or IL-18 was protective to DCD hearts.
BACKGROUND: Donation after circulatory death donors (DCD) can expand the donor pool for heart transplantation, which primarily depends on brain death donors. Ischemia and reperfusion injury are inherent to the DCD process. We hypothesize that pharmacologic inhibition of interleukin-1 (IL-1) and/or IL-18 is protective to DCD hearts. MATERIALS AND METHODS: Following clinical protocol, in-situ ischemia time in control beating-heart donor (CBD) and DCD groups was less than 5 and 40 min, respectively. Wild type (WT) C57Bl6/j, IL-1 receptor type I knockout (IL-1RI-KO), and IL-18 KO mice were used. Hearts were reanimated for 90 min on a Langendorff system with Krebs-Henseleit buffer at 37°C, to assess physiologic parameters. Recombinant IL-1 receptor antagonist (IL-1Ra) and/or IL-18 binding protein (IL-18BP) were added to the Krebs-Henseleit buffer to inhibit IL-1 and/or the IL-18 signaling, respectively. RESULTS: Developed pressure and ± dP/dt were significantly impaired in the DCD-WT group compared to CBD-WT (P ≤ 0.05). Troponin release was higher in DCD-WT groups. Functional parameters were preserved, and troponin release was significantly less in the DCD knockout groups. Heart function was improved in DCD groups treated with IL-1Ra or IL-18BP compared to the DCD-WT group. CONCLUSIONS: Heart function was significantly impaired in the DCD-WT group compared to CBD-WT. Genetic deletion or pharmacologic blockade of IL-1 or IL-18 was protective to DCD hearts.
Authors: S H Kim; M Eisenstein; L Reznikov; G Fantuzzi; D Novick; M Rubinstein; C A Dinarello Journal: Proc Natl Acad Sci U S A Date: 2000-02-01 Impact factor: 11.205
Authors: Benjamin W Van Tassell; Ignacio M Seropian; Stefano Toldo; Eleonora Mezzaroma; Antonio Abbate Journal: Inflamm Res Date: 2013-05-07 Impact factor: 4.575
Authors: Stefano Toldo; Eleonora Mezzaroma; Leo F Buckley; Nicola Potere; Marcello Di Nisio; Giuseppe Biondi-Zoccai; Benjamin W Van Tassell; Antonio Abbate Journal: Pharmacol Ther Date: 2021-12-11 Impact factor: 13.400