Inflammatory Differences in Plaque Erosion and Rupture in Patients With ST-Segment Elevation Myocardial Infarction

Abstract

Background: Plaque erosion causes 30% of ST-segment elevation myocardial infarctions, but the underlying cause is unknown. Inflammatory infiltrates are less abundant in erosion compared with rupture in autopsy studies. We hypothesized that erosion and rupture are associated with significant differences in intracoronary cytokines in vivo.

Methods and results: Forty ST-segment elevation myocardial infarction patients with <6 hours of chest pain were classified as ruptured fibrous cap (RFC) or intact fibrous cap (IFC) using optical coherence tomography. Plasma samples from the infarct-related artery and a peripheral artery were analyzed for expression of 102 cytokines using arrays; results were confirmed with ELISA. Thrombectomy samples were analyzed for differential mRNA expression using quantitative real-time polymerase chain reaction. Twenty-three lesions were classified as RFC (58%), 15 as IFC (38%), and 2 were undefined (4%). In addition, 12% (12 of 102) of cytokines were differentially expressed in both coronary and peripheral plasma. I-TAC was preferentially expressed in RFC (significance analysis of microarrays adjusted P<0.001; ELISA IFC 10.2 versus RFC 10.8 log₂ pg/mL; P=0.042). IFC was associated with preferential expression of epidermal growth factor (significance analysis of microarrays adjusted P<0.001; ELISA IFC 7.42 versus RFC 6.63 log₂ pg/mL, P=0.036) and thrombospondin 1 (significance analysis of microarrays adjusted P=0.03; ELISA IFC 10.4 versus RFC 8.65 log₂ ng/mL, P=0.0041). Thrombectomy mRNA showed elevated I-TAC in RFC (P=0.0007) epidermal growth factor expression in IFC (P=0.0264) but no differences in expression of thrombospondin 1.

Conclusions: These results demonstrate differential intracoronary cytokine expression in RFC and IFC. Elevated thrombospondin 1 and epidermal growth factor may play an etiological role in erosion.

Keywords: coronary artery disease; erosion; inflammation; myocardial infarction; optical coherence tomography; thrombospondin 1.

Figure 1

Study enrollment. IFC indicates intact fibrous cap; OCT, optical coherence tomography; PPCI, primary percutaneous coronary intervention; RFC, ruptured fibrous cap; STEMI, ST‐segment elevation myocardial infarction.

Figure 2

Ruptured and intact fibrous cap appearance using optical coherence tomography. A, Ruptured fibrous cap. *Rupture cavity. >Wire artifact. B, Intact fibrous cap.*Thrombus. >Wire artifact.

Figure 3

Differential expression analysis of cytokines. A, Heat maps of the cytokines differentially expressed between the 2 plaque pathologies. The coronary samples are shown in the left heat map and peripheral samples on the right heat map. Samples (columns) are sorted from left to right in ascending order within the IFC (left‐hand panels) and RFC (right‐hand panels) groups. The cytokines (rows) are ordered from top to bottom by descending average fold change within the IFC‐assigned cytokine group (top panels), the RFC‐assigned group (middle panels), and discordantly assigned group (bottom panels). Heat map colors represent log₂ expression values standardized across the data set. A legend that maps color to standardized expression value is shown to the side of the heat maps. The golden bars on the side of each heat map indicate significant hits. B, Bar plots of concordance between preferential expression assignments for coronary samples and peripheral samples. For peripheral samples, cytokines are stratified by bar: IFC‐high cytokines in the left bar and RFC‐high cytokines in the right bar. For coronary samples, cytokines are stratified by color: IFC‐high cytokines in orange and RFC‐high cytokines in blue. Odds ratio, 95% CI, and P value are reported for Fisher exact test. C, Volcano plots of the log₂ fold change of expression for all cytokines against the significance analysis of microarrays differential expression score for the coronary (left plot) and peripheral (right plot) samples. Positive differential expression scores indicate an association to the group more highly expressed in RFC cases than in IFC cases, whereas negative D‐scores represent an association to the group more highly expressed in IFC cases. Cytokines that were significantly associated with either plaque type (adjusted P<0.05; significance analysis of microarrays) are colored in gold, whereas nonsignificant associations are in grey. BDNF indicates brain‐derived neurotrophic factor; EGF, epidermal growth factor; HGF, hepatocyte growth factor; IFC, intact fibrous cap; I‐TAC, interferon‐inducible T cell alpha chemoattractant; MIG, monokine induced by γ‐interferon; MIP‐3α, macrophage inflammatory protein 3α; MMP‐9, matrix metalloprotein 9; MPO, myeloperoxidase; RFC, ruptured fibrous cap; TNFα, tumor necrosis factor α; TSP‐1, thrombospondin 1.

Figure 4

Plasma ELISA analysis. Plasma titers according to plaque pathology and sample site. Horizontal lines indicate median log₂ values and interquartile ranges. EGF indicates epidermal growth factor; IFC, intact fibrous cap; I‐TAC, interferon‐inducible T cell alpha chemoattractant; MIG, monokine induced by γ‐interferon; TSP‐1, thrombospondin 1; RFC, ruptured fibrous cap.

Figure 5

Quantitative real‐time polymerase chain reaction analysis of thrombectomy specimens. Relative mRNA expression in coronary thrombectomy specimens. Lower ΔCt values indicate higher expression. EGF, epidermal growth factor; IFC, intact fibrous cap; I‐TAC, interferon‐inducible T cell alpha chemoattractant; TSP‐1, thrombospondin 1; RFC, ruptured fibrous cap.