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Eur Heart J. 2020 Jan 3. pii: ehz893. doi: 10.1093/eurheartj/ehz893. [Epub ahead of print]

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

Author information

1
Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, Latina 04100, Italy.
2
Mediterranea Cardiocentro, via Orazio 2, Napoli 80122, Italy.
3
IRCCS NeuroMed, via Atinense 18, Pozzilli 86077, Italy.
4
Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences, Sapienza University of Rome, Viale del Policlinico 155, Rome 00161, Italy.
5
Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, Rome 00161, Italy.
6
Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Viale del Policlinico 155, Rome 00161, Italy.
7
Institute of Cardiology, Catholic University of the Sacred Heart, Largo Francesco Vito 1, Rome 00168, Italy.
8
Interventional Cardiology Unit, Santa Maria Hospital, Viale Tristano di Joannuccio, Terni 05100, Italy.

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

PMID:
31898723
DOI:
10.1093/eurheartj/ehz893

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