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Principal Investigator: Joshua Anthony Keefe
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $49,244
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY/ABSTRACT
There is a fundamental gap in the understanding of the molecular drivers of postoperative atrial fibrillation (poAF),
which is self-limited atrial fibrillation (AF) 2-4 days after surgery. The recurrence rate of AF is eight-fold greater
and mortality risk two-fold greater in poAF patients compared to those that remain in sinus rhythm after surgery.
Thus, it is apparent that current poAF treatments such as beta-blockers, while effective in reducing acute
arrhythmia-related symptoms, do not adequately target the underlying molecular drivers of poAF. As can be
expected after surgery, there is systemic inflammation secondary to tissue damage, and studies show that the
degree of systemic inflammation positively correlates with poAF risk. Current anti-inflammatory agents such as
non-steroidal anti-inflammatory drugs target a broad spectrum of inflammatory mediators and have unwanted
side effects such as acute kidney injury and immunosuppression. Therefore, the rationale for this project is that
targeting a precise molecular pathway within specific cell types has the potential of decreasing poAF and, more
importantly, recurrent AF risk without the unwanted side effects of current anti-inflammatory agents. To this end,
our lab has recently developed and published a novel poAF mouse model consisting of atrial pericardiectomy
and transient aortic clamping. We and others have shown that interleukin (IL)-6 is reproducibly and robustly
elevated in the atria of mice with poAF. In addition, we have found that atrial macrophages mediate atrial IL-6
signaling through production of the IL-6 receptor alpha (IL-6R), which activates Ca2+/calmodulin-dependent
protein kinase II (CaMKII) in nearby atrial cardiomyocytes (ACMs) and leads to arrhythmogenic ryanodine
receptor-2 (RyR2) Ca2+ leak. The overall objective of this proposal is to identify whether inhibiting atrial IL-6
signaling at multiple levels can abrogate arrhythmogenic RyR2 Ca2+ leak and poAF. We hypothesize that
macrophages, which infiltrate the atria 48-72 hours after cardiac surgery, promote IL-6 trans-signaling to ACMs
through release of IL-6R, resulting in STAT3-mediated CaMKII transcriptional upregulation and RyR2
phosphorylation at Ser2814 and Ca2+ leak. We will test this hypothesis with the following two aims. Aim 1 will
assess whether atrial IL-6 signaling mediated by macrophages is necessary for poAF. Aim 2 will test whether
STAT3 activation is required for RyR2 Ca2+ leak. This project will constitute a significant advancement in the
identification of a targeted treatment for poAF via the IL-6 signaling axis, which has broad impacts on other types
of arrhythmias as well as cardiovascular diseases such as heart failure and atherosclerosis that are also driven
by IL-6-mediated systemic inflammation.
Terms: <Accessory Sinuses><Acute><Acute Renal Failure with Renal Papillary Necrosis><Address><Adrenergic beta-Antagonists><Adrenergic beta-Blockers><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Aorta><Apoplexy><Arrhythmia><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Atrial><Atrial Fibrillation><Auricular Fibrillation><Automobile Driving><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Binding><Blood leukocyte><Blood monocyte><Body Tissues><Brain Vascular Accident><Ca Release Channel-Ryanodine Receptor><CaM KII><CaM PK II><CaM kinase II><CaMKII><Calcium><Calcium-Ryanodine Receptor Complex><Cardiac Arrhythmia><Cardiac Atrium><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac Surgery><Cardiac Surgery procedures><Cardiocyte><Cardiovascular Diseases><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Chronic><Clampings><Closure by clamp><Data><Dichloromethylene Diphosphonate><Disease><Disorder><Drug Targeting><Exhibits><FDA approved><Future><GP130><Gene Transcription><Generations><Genetic Transcription><Goals><HPGF><Health><Heart Arrhythmias><Heart Atrium><Heart Muscle Cells><Heart Surgical Procedures><Heart failure><Heart myocyte><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Hepatocyte-Stimulating Factor><Hour><Human><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-6><IL-6Rα><IL6 Protein><IL6ST><IL6ST gene><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Incidence><Individual><Infiltration><Inflammasome><Inflammation><Inflammation Mediators><Interleukin 6 Signal Transducer><Interleukin-6><Interleukins><Intracellular Communication and Signaling><Ischemic Stroke><KO mice><Knock-out Mice><Knockout Mice><Leukocytes><Leukocytes Reticuloendothelial System><Liposomal><Liposomes><Liver Cells><Lymphatic cell><Lymphocyte><Lymphocytic><MGI-2><Macrophage><Marrow leukocyte><Marrow monocyte><Mediating><Membrane><Methods><Mice><Mice Mammals><Mission><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Myeloid Differentiation-Inducing Protein><Mφ><NHLBI><NSAIDs><Nasal Sinuses><Nasal cavity/Paranasal><Nasal cavity/Paranasal sinuses><National Heart, Lung, and Blood Institute><Non-Steroidal Anti-Inflammatory Agents><Null Mouse><ORFs><Open Reading Frames><Operative Procedures><Operative Surgical Procedures><Paranasal Sinuses><Pathway interactions><Patients><Pericardectomy><Pericardiectomy><Perioperative><Phosphorylation><Plasmacytoma Growth Factor><Post-Operative><Postoperative><Postoperative Period><Prevention><Production><Prophylactic treatment><Prophylaxis><Protein Coding Region><Protein Phosphorylation><Proteins><Publishing><RNA Expression><Recurrence><Recurrent><Reproducibility><Research><Risk><Risk Reduction><Ryanodine Receptor><Ryanodine Receptor Calcium Release Channel><STAT3><STAT3 gene><Secondary to><Signal Transduction><Signal Transduction Systems><Signaling><Sinus><Stroke><Surgical><Surgical Interventions><Surgical Procedure><Symptoms><Technology><Testing><Tissues><Transactivation><Transcription><Transgenic Mice><United States><Up-Regulation><Upregulation><White Blood Cells><White Cell><Work><acute kidney injury><atheromatosis><atherosclerotic disease><atherosclerotic vascular disease><atrium><beta blocker><beta-Adrenergic Blocking Agents><beta-Adrenergic Receptor Blockaders><biological signal transduction><brain attack><calcium-dependent CaM kinase II><calmodulin-dependent protein kinase II><cardiac failure><cardiomyocyte><cardiovascular disorder><cell type><cerebral vascular accident><cerebrovascular accident><clodronate><conditional knock-out><conditional knockout><death risk><driving><experiment><experimental research><experimental study><experiments><gp130 Transducer Chain><gp80 IL-6R alpha><heart surgery><immune suppression><immune suppressive activity><immune suppressive function><immunosuppressive activity><immunosuppressive function><immunosuppressive response><inflammatory mediator><inhibitor><interferon beta 2><interleukin-6 receptor alpha><interleukin-6 receptor α><interleukin-6R alpha><lymph cell><membrane structure><mimetics><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><monocyte><mortality risk><mouse model><murine model><non-steroidal anti-inflammatory drugs><novel><pathway><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><risk for stroke><risk of stroke><risk-reducing><side effect><stroke risk><stroked><strokes><surgery><systemic inflammation><systemic inflammatory response><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><trans-activation><white blood cell><white blood corpuscle>