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. 2020 Sep 1;41(33):3156-3165.
doi: 10.1093/eurheartj/ehz893.

Low-grade endotoxaemia enhances artery thrombus growth via Toll-like receptor 4: implication for myocardial infarction

Roberto Carnevale  1   2 , Sebastiano Sciarretta  1   3 , Valentina Valenti  1 , Flavio di Nonno  3 , Camilla Calvieri  4 , Cristina Nocella  5 , Giacomo Frati  1   3 , Maurizio Forte  3 , Giulia d'Amati  6 , Maria G Pignataro  6 , Anna Severino  7 , Roberto Cangemi  5 , Alessio Arrivi  8 , Marcello Dominici  8 , Enrico Mangieri  5 , Carlo Gaudio  5 , Gaetano Tanzilli  5 , Francesco Violi  2   5
Affiliations

Low-grade endotoxaemia enhances artery thrombus growth via Toll-like receptor 4: implication for myocardial infarction

Roberto Carnevale et al. Eur Heart J. .

Abstract

Aims: Low-grade endotoxaemia is detectable in human circulation but its role in thrombosis is still unclear.

Methods and results: We measured serum lipopolysaccharide (LPS) concentration, soluble P-selectin (sP-selectin), a marker of platelet activation, and zonulin, a marker of gut permeability, in peripheral circulation, coronary thrombi, and intracoronary blood of patients with ST-elevation myocardial infarction (STEMI, n = 50) and stable angina (SA) (n = 50), respectively, and in controls (n = 50). Experimental study was carried out in mice to assess if Escherichia coli-LPS (E. coli-LPS) possess thrombotic property. Coronary thrombi from STEMI showed higher concentrations of LPS, sP-selectin vs. intracoronary blood of SA and peripheral blood of controls (P < 0.001). Zonulin was higher in STEMI compared to the other two groups [4.57 (3.34-5.22); 2.56 (0.41-4.36); 1.95 (1.22-2.65) ng/mL; P < 0.001] and correlated with LPS (Rs = 0.585; P < 0.001). Escherichia coli DNA was positive in 34% of STEMI vs. 12% of SA and 4% of controls (P < 0.001). In a subgroup of 12 STEMI, immunohistochemical analysis of coronary thrombi showed positivity for leucocyte Toll-like receptor 4 (TLR4), cathepsin G, and LPS from E. coli in 100%, 80%, and 25% of samples, respectively. E. coli-LPS injected in mice to reach LPS concentrations like those detected in coronary thrombi was associated with enhanced artery thrombosis and platelet activation, an effect blunted by TLR4 inhibitor co-administration. In vitro study demonstrated that LPS from E. coli enhanced platelet aggregation via TLR4-mediated leucocyte cathepsin G activation.

Conclusion: ST-elevation myocardial infarction patients disclose an enhanced gut permeability that results in LPS translocation in human circulation and eventually thrombus growth at site of artery lesion via leucocyte-platelet interaction.

Keywords: LPS; Myocardial infarction; Platelets; Thrombosis.

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