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Atherosclerosis exacerbates arrhythmia following myocardial infarction: Role of myocardial inflammation.

ABSTRACT: Atherosclerotic animal models show increased recruitment of inflammatory cells to the heart after myocardial infarction (MI), which impacts ventricular function and remodeling.The purpose of this study was to determine whether increased myocardial inflammation after MI also contributes to arrhythmias.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 ?g/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.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-1? expression, an inflammatory cytokine known to degrade Cx43.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.

SUBMITTER: De Jesus NM

PROVIDER: S-EPMC4277908 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Atherosclerosis exacerbates arrhythmia following myocardial infarction: Role of myocardial inflammation.

De Jesus Nicole M NM Wang Lianguo L Herren Anthony W AW Wang Jingjing J Shenasa Fatemah F Bers Donald M DM Lindsey Merry L ML Ripplinger Crystal M CM

Heart rhythm 20141007 1

<h4>Background</h4>Atherosclerotic animal models show increased recruitment of inflammatory cells to the heart after myocardial infarction (MI), which impacts ventricular function and remodeling.<h4>Objective</h4>The purpose of this study was to determine whether increased myocardial inflammation after MI also contributes to arrhythmias.<h4>Methods</h4>MI was created in 3 mouse models: (1) atherosclerotic (apolipoprotein E deficient [ApoE(-/-)] on atherogenic diet, n = 12); (2) acute inflammatio ...[more]

PMID: 25304682

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Project description:Preclinical data suggest that an acute inflammatory response following myocardial infarction (MI) accelerates systemic atherosclerosis. Using combined positron emission and computed tomography, we investigated whether this phenomenon occurs in humans.Overall, 40 patients with MI and 40 with stable angina underwent thoracic 18F-fluorodeoxyglucose combined positron emission and computed tomography scan. Radiotracer uptake was measured in aortic atheroma and nonvascular tissue (paraspinal muscle). In 1003 patients enrolled in the Global Registry of Acute Coronary Events, we assessed whether infarct size predicted early (?30 days) and late (>30 days) recurrent coronary events. Compared with patients with stable angina, patients with MI had higher aortic 18F-fluorodeoxyglucose uptake (tissue-to-background ratio 2.15±0.30 versus 1.84±0.18, P<0.0001) and plasma C-reactive protein concentrations (6.50 [2.00 to 12.75] versus 2.00 [0.50 to 4.00] mg/dL, P=0.0005) despite having similar aortic (P=0.12) and less coronary (P=0.006) atherosclerotic burden and similar paraspinal muscular 18F-fluorodeoxyglucose uptake (P=0.52). Patients with ST-segment elevation MI had larger infarcts (peak plasma troponin 32 300 [10 200 to >50 000] versus 3800 [1000 to 9200] ng/L, P<0.0001) and greater aortic 18F-fluorodeoxyglucose uptake (2.24±0.32 versus 2.02±0.21, P=0.03) than those with non-ST-segment elevation MI. Peak plasma troponin concentrations correlated with aortic 18F-fluorodeoxyglucose uptake (r=0.43, P=0.01) and, on multivariate analysis, independently predicted early (tertile 3 versus tertile 1: relative risk 4.40 [95% CI 1.90 to 10.19], P=0.001), but not late, recurrent MI.The presence and extent of MI is associated with increased aortic atherosclerotic inflammation and early recurrent MI. This finding supports the hypothesis that acute MI exacerbates systemic atherosclerotic inflammation and remote plaque destabilization: MI begets MI.URL: https://www.clinicaltrials.gov. Unique identifier: NCT01749254.

Project description:Rationale: Acute myocardial infarction (MI) triggers a systemic inflammatory response including crosstalk along the heart-kidney axis. We employed radionuclide-based inflammation-targeted whole-body molecular imaging to identify potential cardio-renal crosstalk after MI in a translational setup. Methods: Serial whole-body positron emission tomography (PET) with the specific CXCR4 ligand 68Ga-Pentixafor was performed after MI in mice. Tracer retention in kidneys and heart was compared to hematopoietic organs to evaluate systemic inflammation, validated by ex vivo analysis and correlated with progressive contractile dysfunction. Additionally, 96 patients underwent 68Ga-Pentixafor PET within the first week after MI, for systems-based image analysis and to determine prognostic value for adverse renal outcome. Results: In mice, transient myocardial CXCR4 upregulation occurred early after MI. Cardiac and renal PET signal directly correlated over the time course (r = 0.62, p < 0.0001), suggesting an inflammatory link between organs. Ex-vivo autoradiography (r = 0.9, p < 0.01) and CD68 immunostaining indicated signal localization to inflammatory cell content. Renal signal at 7d was inversely proportional to left ventricular ejection fraction at 6 weeks after MI (r = -0.79, p < 0.01). In patients, renal CXCR4 signal also correlated with signal from infarct (r = 0.25, p < 0.05) and remote myocardium (r = 0.39, p < 0.0001). Glomerular filtration rate (GFR) was available in 48/96 (50%) during follow-up. Worsening of renal function (GFR loss >5 mL/min/1.73m2), occurred a mean 80.5 days after MI in 16/48 (33.3%). Kaplan-Meier analysis revealed adverse renal outcome for patients with elevated remote myocardial CXCR4 signal (p < 0.05). Multivariate Cox analysis confirmed an independent predictive value (relative to baseline GFR, LVEF, infarct size; HR, 5.27). Conclusion: Systems-based CXCR4-targeted molecular imaging identifies inflammatory crosstalk along the cardio-renal axis early after MI.

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Atherosclerosis exacerbates arrhythmia following myocardial infarction: Role of myocardial inflammation.

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Atherosclerosis exacerbates arrhythmia following myocardial infarction: Role of myocardial inflammation.

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