title: Splenic metabolic activity predicts risk of future cardiovascular events: demonstration of a cardiosplenic axis in humans.
abstract: OBJECTIVE
  This study sought to determine whether splenic activation after acute coronary syndrome (ACS) is linked to leukocyte proinflammatory remodeling and whether splenic activity independently predicts the risk of cardiovascular disease (CVD) events.
  
  
  BACKGROUND
  Pre-clinical data suggest the existence of a cardiosplenic axis, wherein activation of hematopoietic tissues (notably in the spleen) results in liberation of proinflammatory leukocytes and accelerated atherosclerotic inflammation. However, it is presently unknown whether a cardiosplenic axis exists in humans and whether splenic activation relates to CVD risk.
  
  
  METHODS
  (18)F-fluorodeoxyglucose ((18)FDG)-positron emission tomography (PET) imaging was performed in 508 individuals across 2 studies. In the first study, we performed FDG-PET imaging in 22 patients with recent ACS and 22 control subjects. FDG uptake was measured in spleen and arterial wall, whereas proinflammatory gene expression of circulating leukocytes was assessed by quantitative real-time polymerase chain reaction. In a second study, we examined the relationship between splenic tissue FDG uptake with subsequent CVD events during follow-up (median 4 years) in 464 patients who previously had undergone FDG-PET imaging.
  
  
  RESULTS
  Splenic activity increased after ACS and was significantly associated with multiple indices of inflammation: 1) up-regulated gene expression of proinflammatory leukocytes; 2) increased C-reactive protein; and 3) increased arterial wall inflammation (FDG uptake). Moreover, in the second study, splenic activity (greater than or equal to the median) was associated with an increased risk of CVD events (hazard ratio [HR]: 3.3; 95% confidence interval [CI]: 1.5 to 7.3; p = 0.003), which remained significant after adjustment for CVD risk factors (HR: 2.26; 95% CI: 1.01 to 5.06; p = 0.04) and for arterial FDG uptake (HR: 2.68; 95% CI: 1.5 to 7.4; p = 0.02).
  
  
  CONCLUSIONS
  Our findings demonstrate increased splenic metabolic activity after ACS and its association with proinflammatory remodeling of circulating leukocytes. Moreover, we observed that metabolic activity of the spleen independently predicted risk of subsequent CVD events. Collectively, these findings provide evidence of a cardiosplenic axis in humans similar to that shown in pre-clinical studies.
authors.affiliation: Cardiac MR PET CT Program, Division of Cardiac Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Hamed
authors.initials: H
authors.lastname: Emami
authors.affiliation: Cardiac MR PET CT Program, Division of Cardiac Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Parmanand
authors.initials: P
authors.lastname: Singh
authors.affiliation: Cardiac MR PET CT Program, Division of Cardiac Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Megan
authors.initials: M
authors.lastname: MacNabb
authors.affiliation: Cardiac MR PET CT Program, Division of Cardiac Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Esad
authors.initials: E
authors.lastname: Vucic
authors.affiliation: Cardiac MR PET CT Program, Division of Cardiac Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Lavender
authors.affiliation: Division of Cardiovascular Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: James H F
authors.initials: JH
authors.lastname: Rudd
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Zahi A
authors.initials: ZA
authors.lastname: Fayad
authors.affiliation: Genentech, San Francisco, California.
authors.forename: Joshua
authors.initials: J
authors.lastname: Lehrer-Graiwer
authors.affiliation: BioInvent International AB, Lund, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Korsgren
authors.affiliation: Cardiac MR PET CT Program, Division of Cardiac Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Amparo L
authors.initials: AL
authors.lastname: Figueroa
authors.affiliation: Genentech, San Francisco, California.
authors.forename: Jill
authors.initials: J
authors.lastname: Fredrickson
authors.affiliation: Division of Vascular Surgery, Peter Munk Cardiac Centre, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Barry
authors.initials: B
authors.lastname: Rubin
authors.affiliation: Cardiac MR PET CT Program, Division of Cardiac Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Udo
authors.initials: U
authors.lastname: Hoffmann
authors.affiliation: Cardiac MR PET CT Program, Division of Cardiac Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Quynh A
authors.initials: QA
authors.lastname: Truong
authors.affiliation: Departments of Radiology and Medicine, Weill Cornell Medical College and the New York-Presbyterian Hospital, New York, New York.
authors.forename: James K
authors.initials: JK
authors.lastname: Min
authors.affiliation: Genentech, San Francisco, California.
authors.forename: Amos
authors.initials: A
authors.lastname: Baruch
authors.affiliation: Baptist Health South Florida, Miami, Florida.
authors.forename: Khurram
authors.initials: K
authors.lastname: Nasir
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
authors.affiliation: Cardiac MR PET CT Program, Division of Cardiac Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: atawakol@partners.org.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Tawakol
mesh_terms: D000328:Adult; D000368:Aged; D001167:Arteritis / Q000000981:diagnostic imaging; D002097:C-Reactive Protein / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D019788:Fluorodeoxyglucose F18; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D064847:Multimodal Imaging / Q000379:methods*; D049268:Positron-Emission Tomography / Q000379:methods; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D019275:Radiopharmaceuticals; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors; D013154:Spleen / Q000378:metabolism*; D013997:Time Factors; D061205:Vascular Calcification / Q000000981:diagnostic imaging
chemical_list: D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D002097:C-Reactive Protein
keywords: FDG; acute coronary syndrome; atherosclerosis; events; inflammation; spleen