Prolonged Inflammation Associates With Greater Infarct Size and Poor Outcome After ST-Segment Elevation Myocardial Infarction

Figures

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  Figure 1. Blood Leukocyte Kinetics Secondary to STEMI (A) Leukocyte counts at admission and during hospitalization over the course of 5 days in ST-segment elevation myocardial infarction (STEMI) patients in the total study population (N = 1,781). Leukocyte subset numbers derived from a subcohort of 345 patients, including (B) neutrophils, (C) monocytes, and (D) lymphocytes. (E) Transitioning between leukocyte tertiles at admission (Tad) to tertiles at day 3 (T3d) post-STEMI visualized using a Sankey diagram in a subcohort of 1,450 patients with leukocyte counts available at both admission and day 3. T1ad indicates low leukocyte levels, T2ad indicates intermediate leukocyte levels, and T3ad indicates high leukocyte levels. T13d indicates low leukocyte levels, T23d indicates intermediate leukocyte levels, and T33d indicates high leukocyte levels. Data are presented as median with 25th to 75th percentiles (boxes), 10th to 90th percentiles (bars), and values outside the given percentiles (dots).

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  Figure 2. Infarct Size and Left Ventricular Function in STEMI Patients Based on Leukocyte Counts on Day 3 (Tertile-Based Analysis) (A) Peak blood creatine kinase-myocardial band (CK-MB) values (U/L) and (B) peak troponin T values (ng/L) in patients with serial leukocyte measurement (n = 1,450). (C) Final infarct size assessed by scintigraphic imaging 7 to 14 days after primary percutaneous coronary intervention (% of the left ventricle [LV]) (n = 976 of 1,450). Left ventricular ejection fraction (LVEF) at (D) baseline, (E) 6 months after acute STEMI, and (F) comparison between baseline and 6 months (subgroup analysis of patients with scintigraphic data [n = 927 of 976]). Data are presented as median with 25th to 75th percentiles (boxes), 10th to 90th percentiles (bars), and values outside the given percentiles (dots). T13d indicates low leukocyte levels, T23d indicates intermediate leukocyte levels, and T33d indicates high leukocyte levels. ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001. Abbreviations as in Figure 1.

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  Figure 3. Leukocyte Dynamics and Survival Outcomes in STEMI Patients With Serial Leukocyte Measurements (A) Kaplan-Meier survival curves for patients with high leukocyte levels at admission (T3ad). The blue curve represents patients with persistently high leukocyte levels from admission to day 3 (T3ad to T33d). The orange curve represents patients with resolving inflammation, indicated by a decline in leukocyte levels (T3ad to T23d or T13d). (B) Kaplan-Meier survival curves for patients with intermediate leukocyte levels at admission (T2ad). The blue curve represents patients with stable leukocyte levels from admission to day 3 (T2ad to T23d). The orange curve represents patients with resolving inflammation (T2ad to T13d), while the green curve represents those with increasing inflammation (T2ad to T33d). Abbreviations as in Figure 1.

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  Figure 4. Association of Leukocyte Count on Day 3 With Survival Outcomes in STEMI Patients Kaplan-Meier curves of (A) 1-year and (B) 5-year all-cause mortality according to leukocyte counts on day 3 (tertile-based analysis, T3d) in STEMI patients with serial leukocyte measurements (n = 1,450). T13d indicates low leukocyte levels, T23d indicates intermediate leukocyte levels, and T33d indicates high leukocyte levels. Abbreviations as in Figure 1.

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  Figure 5. Qualitative Alteration of Inflammatory Blood Monocytes Secondary to Acute ST-Segment Elevation Myocardial Infarction (A to C) Volcano plot displaying differentially expressed genes (|log2 fold change [FC]| ≥1.0 and adjusted P < 0.05) from inflammatory (CD14+) blood monocytes isolated from stable coronary artery disease (CAD) patients and from patients 12 and 72 hours post–ST-segment elevation myocardial infarction (N = 20 per group, LIMMA (linear models for microarray data) t statistic approach with Benjamini-Hochberg multiple testing correction) as assessed by RNA sequencing. (D to I) Gene set enrichment analyses revealed overrepresentation of down- and up-regulated genes in distinct pathways. The percentage of down- and up-regulated genes per respective pathway and P values as assessed by Benjamini-Hochberg correction are shown for significant pathways.

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  Figure 6. Leukocyte Kinetics in the Heart and Blood Following Experimental MI in Mice (A) Experimental design. (B) Representative flow cytometry gating strategy (numbers next to gates indicate frequencies [%]) and quantification of (C) blood leukocyte subsets before and at different time points after myocardial infarction (MI). (D) Representative flow cytometry gating strategy and quantification of (E) cardiac leukocyte subsets pre- and post-MI (n = 7-12 mice per group, Kruskal-Wallis test followed by Dunn’s multiple comparisons test). Data are presented as mean ± SD. ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001. FSC-A = forward scatter area; LAD = left anterior descending coronary artery; SSC-A = side scatter area.