Identifying the molecular and cellular signature of cardiac dilation following myocardial infarction.

Abstract

Establishing molecular and cellular indicators that reflect the extent of dilation of the left ventricle (LV) after myocardial infarction (MI) may improve diagnostic and prognostic capabilities. We queried the Mouse Heart Attack Research Tool (mHART) 1.0 for day 7 post-MI mice (age 3-9 months, untreated males and females) with serial echocardiographic data at days 0, 1, and 7 (n = 51). Mice were classified into two subgroups determined by a median fold change of 1.6 in end-diastolic dimensions (EDD) normalized to pre-MI values; n = 26 fell below (moderate; mean of 1.42 ± 0.01) and n = 25 fell above this cut-off (extreme; mean of 1.79 ± 0.01; p < 0.001 vs. moderate). Plasma proteomic profiling of 34 analytes measured at day 7 post-MI from male mice (n = 12 moderate and 12 extreme) were evaluated as the test dataset, and receiver operating curve (ROC) analysis was used to assess strength of biomarkers. Females (n = 6 moderate and 9 extreme) were used as the validation dataset. Both by t-test and characteristic (ROC) curve analysis, lower macrophage inflammatory protein-1 gamma (MIP-1γ), lymphotactin, and granulocyte chemotactic protein-2 (GCP-2) were identified as plasma indicators for dilation status (p < 0.05 for all). Macrophage numbers were decreased and complement C5, laminin 1, and Ccr8 gene levels were significantly higher in the LV infarcts of the extreme dilation group (p < 0.05 for all). A composite panel including plasma MIP-1γ, lymphotactin, and GCP-2, and LV infarct Ccr8 and macrophage numbers strongly mirrored LV dilation status (AUC = 0.92; p < 0.0001). Using the mHART 1.0 database, we determined that a failure to mount sufficient macrophage-mediated inflammation was indicative of exacerbated LV dilation.

• Authors: Merry L Lindsey, Yonggang Ma, Elizabeth R Flynn, Michael D Winniford, Michael E Hall, Kristine Y DeLeon-Pennell
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1865 Issue 7 Pg. 1845-1852 (07 01 2019) ISSN: 1879-260X [Electronic] Netherlands
• PMID: 31109452 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Published by Elsevier B.V.

Chemical References

• Ccl9 protein, mouse
• Chemokine CXCL6
• Chemokines, CC
• Lymphokines
• Macrophage Inflammatory Proteins
• Sialoglycoproteins
• lymphotactin

Topics

• Animals
• Cardiomyopathy, Dilated (blood, etiology, pathology)
• Chemokine CXCL6 (blood)
• Chemokines, CC (blood)
• Databases, Factual
• Female
• Heart Ventricles (pathology)
• Lymphokines (blood)
• Macrophage Inflammatory Proteins (blood)
• Macrophages (pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Myocardial Infarction (complications)
• Proteomics
• Sialoglycoproteins (blood)