TY - JOUR
T1 - Identifying the molecular and cellular signature of cardiac dilation following myocardial infarction
AU - Lindsey, Merry L.
AU - Ma, Yonggang
AU - Flynn, Elizabeth R.
AU - Winniford, Michael D.
AU - Hall, Michael E.
AU - DeLeon-Pennell, Kristine Y.
N1 - Funding Information:
We acknowledge funding from the American Heart Association [15SDG22930009], from the National Institutes of Health [GM104357, GM114833, GM115428, HL051971, HL075360, HL105324, and HL129823], and from the Biomedical Laboratory Research and Development Service of the VA Office of Research and Development [5I01BX000505 and IK2BX003922]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the American Heart Association, the National Institutes of Health, or the Veterans Administration. All authors have reviewed and approved the article. All authors have read the journal authorship agreement and policy on disclosure of potential conflicts of interest and have nothing to disclose. None.
Funding Information:
We acknowledge funding from the American Heart Association [ 15SDG22930009 ], from the National Institutes of Health [ GM104357 , GM114833 , GM115428 , HL051971 , HL075360 , HL105324 , and HL129823 ], and from the Biomedical Laboratory Research and Development Service of the VA Office of Research and Development [ 5I01BX000505 and IK2BX003922 ]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the American Heart Association, the National Institutes of Health, or the Veterans Administration. All authors have reviewed and approved the article. All authors have read the journal authorship agreement and policy on disclosure of potential conflicts of interest and have nothing to disclose.
Publisher Copyright:
© 2018
PY - 2019/7/1
Y1 - 2019/7/1
N2 - 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.
AB - 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.
KW - Big data
KW - Cardiovascular disease
KW - Inflammation
KW - LV dilation
KW - Macrophage
KW - Myocardial infarction
KW - Proteomics
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U2 - 10.1016/j.bbadis.2018.09.023
DO - 10.1016/j.bbadis.2018.09.023
M3 - Article
C2 - 31109452
AN - SCOPUS:85054079920
SN - 0925-4439
VL - 1865
SP - 1845
EP - 1852
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 7
ER -