title: Atherosclerosis exacerbates arrhythmia following myocardial infarction: Role of myocardial inflammation.
abstract: BACKGROUND
  Atherosclerotic animal models show increased recruitment of inflammatory cells to the heart after myocardial infarction (MI), which impacts ventricular function and remodeling.
  
  
  OBJECTIVE
  The purpose of this study was to determine whether increased myocardial inflammation after MI also contributes to arrhythmias.
  
  
  METHODS
  MI was created in 3 mouse models: (1) atherosclerotic (apolipoprotein E deficient [ApoE(-/-)] on atherogenic diet, n = 12); (2) acute inflammation (wild-type [WT] given daily lipopolysaccharide [LPS] 10 μg/day, n = 7); and (3) WT (n = 14). Sham-operated (n = 4) mice also were studied. Four days post-MI, an inflammatory protease-activatable fluorescent probe (Prosense680) was injected intravenously to quantify myocardial inflammation on day 5. Optical mapping with voltage-sensitive dye was performed on day 5 to assess electrophysiology and arrhythmia susceptibility.
  
  
  RESULTS
  Inflammatory activity (Prosense680 fluorescence) was increased approximately 2-fold in ApoE+MI and LPS+MI hearts vs WT+MI (P<.05) and 3-fold vs sham (P<.05). ApoE+MI and LPS+MI hearts also had prolonged action potential duration, slowed conduction velocity, and increased susceptibility to pacing-induced arrhythmias (56% and 71% vs 13% for WT+MI and 0% for sham, respectively, P<.05, for ApoE+MI and LPS+MI groups vs both WT+MI and sham). Increased macrophage accumulation in ApoE+MI and LPS+MI hearts was confirmed by immunofluorescence. Macrophages were associated with areas of connexin43 (Cx43) degradation, and a 2-fold decrease in Cx43 expression was found in ApoE+MI vs WT+MI hearts (P<.05). ApoE+MI hearts also had a 3-fold increase in interleukin-1β expression, an inflammatory cytokine known to degrade Cx43.
  
  
  CONCLUSIONS
  Underlying atherosclerosis exacerbates post-MI electrophysiological remodeling and arrhythmias. LPS+MI hearts fully recapitulate the atherosclerotic phenotype, suggesting myocardial inflammation as a key contributor to post-MI arrhythmia.
authors.affiliation: Department of Pharmacology, University of California, Davis, School of Medicine, Davis, California; Department of Biomedical Engineering, University of California, Davis, School of Engineering, Davis, California.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: De Jesus
authors.affiliation: Department of Pharmacology, University of California, Davis, School of Medicine, Davis, California.
authors.forename: Lianguo
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, University of California, Davis, School of Medicine, Davis, California.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Herren
authors.affiliation: Department of Pathology and Pathophysiology, Shandong University School of Medicine, Shandong, P.R. China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, University of California, Davis, School of Medicine, Davis, California.
authors.forename: Fatemah
authors.initials: F
authors.lastname: Shenasa
authors.affiliation: Department of Pharmacology, University of California, Davis, School of Medicine, Davis, California.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.affiliation: Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center and Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, Mississippi.
authors.forename: Merry L
authors.initials: ML
authors.lastname: Lindsey
authors.affiliation: Department of Pharmacology, University of California, Davis, School of Medicine, Davis, California. Electronic address: cripplinger@ucdavis.edu.
authors.forename: Crystal M
authors.initials: CM
authors.lastname: Ripplinger
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology; D050197:Atherosclerosis / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004562:Electrocardiography; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D009205:Myocarditis / Q000150:complications* / Q000473:pathology / Q000503:physiopathology*
keywords: Arrhythmia; Atherosclerosis; Inflammation; Myocardial infarction; Optical mapping