TY - JOUR
T1 - Atherosclerosis exacerbates arrhythmia following myocardial infarction
T2 - Role of myocardial inflammation
AU - De Jesus, Nicole M.
AU - Wang, Lianguo
AU - Herren, Anthony W.
AU - Wang, Jingjing
AU - Shenasa, Fatemah
AU - Bers, Donald M.
AU - Lindsey, Merry L.
AU - Ripplinger, Crystal M.
N1 - Funding Information:
This work was funded by National Institutes of Health (NIH) T32 GM099608 to Ms. De Jesus, Mr. A. Herron, and Dr. Bers; Howard Hughes Medical Institute to Ms. De Jesus; China Scholarship Council and Natural Science Foundation of Shandong Province ZR2010HQ031 to Dr. Wang; NIH P01 HL080101 to Dr. Bers; the San Antonio Cardiovascular Proteomics Center to Dr. Lindsey (funded from NHLBI HHSN 268201000036C N01-HV-00244); NIH R01 HL075360 to Dr. Lindsey; the UC Davis Clinical and Translational Science Center to Dr. Ripplinger (funded from UL1 RR024146); NIH P30 HL101280 to Drs. Ripplinger and Bers; and NIH R01 HL111600 to Dr. Ripplinger.
Publisher Copyright:
© 2015 Heart Rhythm Society. All rights reserved.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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). Shamoperated (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. CONCLUSION: 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.
AB - 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). Shamoperated (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. CONCLUSION: 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.
KW - Arrhythmia
KW - Atherosclerosis
KW - Inflammation
KW - Myocardial infarction
KW - Optical mapping
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U2 - 10.1016/j.hrthm.2014.10.007
DO - 10.1016/j.hrthm.2014.10.007
M3 - Article
C2 - 25304682
AN - SCOPUS:84920668893
SN - 1547-5271
VL - 12
SP - 169
EP - 178
JO - Heart Rhythm
JF - Heart Rhythm
IS - 1
ER -