Nicola Sandler1, Elzbieta Kaczmarek2, Kiyoshi Itagaki3, Yi Zheng4, Leo Otterbein3, Kamal Khabbaz5, David Liu5, Venkatachalam Senthilnathan5, Russell L Gruen6, Carl J Hauser7. 1. Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA; National Trauma Research Institute, The Alfred Hospital, Monash University, Melbourne, Vic, Australia. 2. Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA; Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 3. Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 4. R&AA - Morphology Core, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 5. Department of Cardiac Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 6. National Trauma Research Institute, The Alfred Hospital, Monash University, Melbourne, Vic, Australia. 7. Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: cjhauser@bidmc.harvard.edu.
Abstract
BACKGROUND: Atrial fibrillation (AF) is the most frequent complication of surgery performed on cardiopulmonary bypass (CPB) and recent work associates CPB with postoperative inflammation. We have shown that all tissue injury releases mitochondrial damage associated molecular patterns (mtDAMPs) including mitochondrial DNA (mtDNA). This can act as a direct, early activator of neutrophils (PMN), eliciting a systemic inflammatory response syndrome (SIRS) while suppressing PMN function. Neutrophil Extracellular Traps (NETs) are crucial to host defence. They carry out NETosis wherein webs of granule proteins and chromatin trap and kill bacteria. We hypothesised that surgery performed on CPB releases mtDAMPs into the circulation. Molecular patterns thus mobilised during CPB might then participate in the pathogenesis of SIRS and predict postoperative complications like AF [1]. METHODS: We prospectively studied 16 patients undergoing elective operations on CPB. Blood was sampled preoperatively, at the end of CPB and on days 1-2 postoperatively. Plasma samples were analysed for mtDNA. Neutrophil IL-6 gene expression was studied to assess induction of SIRS. Neutrophils were also assayed for the presence of neutrophil extracellular traps (NETs/NETosis). These biologic findings were then correlated to clinical data and compared in patients with and without postoperative AF (POAF). RESULTS: Mitochondrial DNA was significantly elevated following CPB (six-fold increase post-CPB, p=0.008 and five-fold increase days 1-2, p=0.02). Patients with POAF showed greater increases in mtDNA post-CPB than those without. Postoperative AF was seen in all patients with a ≥2-fold increase of mtDNA (p=0.037 vs. <2-fold). Neutrophil IL-6 gene transcription increased postoperatively demonstrating SIRS that was greatest days 1-2 (p=0.039). Neutrophil extracellular trap (NET) formation was markedly suppressed in the post-CPB state. CONCLUSION: Mitochondrial DNA is released by CPB surgery and is associated with POAF. IL-6 gene expression increases after CPB, demonstrating the evolution of postoperative SIRS. Lastly, cardiac surgery on CPB also suppressed PMN NETosis. Taken together, our data suggest that mtDNA released during surgery on CPB, may be involved in the pathogenesis of SIRS and related postoperative inflammatory events like POAF and infections. Mitochondrial DNA may therefore prove to be an early biomarker for postoperative complications with the degree of association to be determined in appropriately sized studies. If mtDNA is directly involved in cardiac inflammation, mtDNA-induced toll-like receptor-9 (TLR9) signalling could also be targeted therapeutically.
BACKGROUND:Atrial fibrillation (AF) is the most frequent complication of surgery performed on cardiopulmonary bypass (CPB) and recent work associates CPB with postoperative inflammation. We have shown that all tissue injury releases mitochondrial damage associated molecular patterns (mtDAMPs) including mitochondrial DNA (mtDNA). This can act as a direct, early activator of neutrophils (PMN), eliciting a systemic inflammatory response syndrome (SIRS) while suppressing PMN function. Neutrophil Extracellular Traps (NETs) are crucial to host defence. They carry out NETosis wherein webs of granule proteins and chromatin trap and kill bacteria. We hypothesised that surgery performed on CPB releases mtDAMPs into the circulation. Molecular patterns thus mobilised during CPB might then participate in the pathogenesis of SIRS and predict postoperative complications like AF [1]. METHODS: We prospectively studied 16 patients undergoing elective operations on CPB. Blood was sampled preoperatively, at the end of CPB and on days 1-2 postoperatively. Plasma samples were analysed for mtDNA. Neutrophil IL-6 gene expression was studied to assess induction of SIRS. Neutrophils were also assayed for the presence of neutrophil extracellular traps (NETs/NETosis). These biologic findings were then correlated to clinical data and compared in patients with and without postoperative AF (POAF). RESULTS: Mitochondrial DNA was significantly elevated following CPB (six-fold increase post-CPB, p=0.008 and five-fold increase days 1-2, p=0.02). Patients with POAF showed greater increases in mtDNA post-CPB than those without. Postoperative AF was seen in all patients with a ≥2-fold increase of mtDNA (p=0.037 vs. <2-fold). Neutrophil IL-6 gene transcription increased postoperatively demonstrating SIRS that was greatest days 1-2 (p=0.039). Neutrophil extracellular trap (NET) formation was markedly suppressed in the post-CPB state. CONCLUSION: Mitochondrial DNA is released by CPB surgery and is associated with POAF. IL-6 gene expression increases after CPB, demonstrating the evolution of postoperative SIRS. Lastly, cardiac surgery on CPB also suppressed PMN NETosis. Taken together, our data suggest that mtDNA released during surgery on CPB, may be involved in the pathogenesis of SIRS and related postoperative inflammatory events like POAF and infections. Mitochondrial DNA may therefore prove to be an early biomarker for postoperative complications with the degree of association to be determined in appropriately sized studies. If mtDNA is directly involved in cardiac inflammation, mtDNA-induced toll-like receptor-9 (TLR9) signalling could also be targeted therapeutically.
Authors: John H Rosenberg; John H Werner; Gilman D Plitt; Victoria V Noble; Jordan T Spring; Brooke A Stephens; Aleem Siddique; Helenmari L Merritt-Genore; Michael J Moulton; Devendra K Agrawal Journal: Expert Rev Cardiovasc Ther Date: 2018-12-29
Authors: Michael Robich; Sergey Ryzhov; Doreen Kacer; Monica Palmeri; Sarah M Peterson; Reed D Quinn; Damien Carter; Forest Sheppard; Timothy Hayes; Douglas B Sawyer; Joseph Rappold; Igor Prudovsky; Robert S Kramer Journal: J Surg Res Date: 2020-04-30 Impact factor: 2.192
Authors: Joshua L Manghelli; Meghan O Kelly; Daniel I Carter; Jason M Gauthier; Davide Scozzi; Timothy S Lancaster; Robert M MacGregor; Ali J Khiabani; Richard B Schuessler; Andrew E Gelman; Ralph J Damiano; Spencer J Melby Journal: Ann Thorac Surg Date: 2020-09-16 Impact factor: 4.330