Atherosclerosis exacerbates arrhythmia following myocardial infarction: Role of myocardial inflammation

Nicole M. De Jesus, Lianguo Wang, Anthony W. Herren, Jingjing Wang, Fatemah Shenasa, Donald M. Bers, Merry L. Lindsey, Crystal M. Ripplinger

Research output: Contribution to journalArticle

27 Citations (Scopus)

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). 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.

Original languageEnglish (US)
Pages (from-to)169-178
Number of pages10
JournalHeart Rhythm
Volume12
Issue number1
DOIs
StatePublished - Jan 1 2015

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Cardiac Arrhythmias
Atherosclerosis
Myocardial Infarction
Inflammation
Apolipoproteins E
Lipopolysaccharides
Connexin 43
Macrophages
Atherogenic Diet
Ventricular Remodeling
Ventricular Function
Electrophysiology
Interleukin-1
Fluorescent Dyes
Action Potentials

Keywords

  • Arrhythmia
  • Atherosclerosis
  • Inflammation
  • Myocardial infarction
  • Optical mapping

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

De Jesus, N. M., Wang, L., Herren, A. W., Wang, J., Shenasa, F., Bers, D. M., ... Ripplinger, C. M. (2015). Atherosclerosis exacerbates arrhythmia following myocardial infarction: Role of myocardial inflammation. Heart Rhythm, 12(1), 169-178. https://doi.org/10.1016/j.hrthm.2014.10.007

Atherosclerosis exacerbates arrhythmia following myocardial infarction : Role of myocardial inflammation. / De Jesus, Nicole M.; Wang, Lianguo; Herren, Anthony W.; Wang, Jingjing; Shenasa, Fatemah; Bers, Donald M.; Lindsey, Merry L.; Ripplinger, Crystal M.

In: Heart Rhythm, Vol. 12, No. 1, 01.01.2015, p. 169-178.

Research output: Contribution to journalArticle

De Jesus, NM, Wang, L, Herren, AW, Wang, J, Shenasa, F, Bers, DM, Lindsey, ML & Ripplinger, CM 2015, 'Atherosclerosis exacerbates arrhythmia following myocardial infarction: Role of myocardial inflammation', Heart Rhythm, vol. 12, no. 1, pp. 169-178. https://doi.org/10.1016/j.hrthm.2014.10.007
De Jesus, Nicole M. ; Wang, Lianguo ; Herren, Anthony W. ; Wang, Jingjing ; Shenasa, Fatemah ; Bers, Donald M. ; Lindsey, Merry L. ; Ripplinger, Crystal M. / Atherosclerosis exacerbates arrhythmia following myocardial infarction : Role of myocardial inflammation. In: Heart Rhythm. 2015 ; Vol. 12, No. 1. pp. 169-178.
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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). 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.",
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AU - Shenasa, Fatemah

AU - Bers, Donald M.

AU - Lindsey, Merry L.

AU - Ripplinger, Crystal M.

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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.

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