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Epicardial adipose tissue microbial colonization and inflammasome activation in acute coronary syndrome

https://doi.org/10.1016/j.ijcard.2017.02.040Get rights and content

Highlights

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    Epicardial adipose tissue has a close relationship with epicardial coronary arteries.

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    Bacterial DNA has been isolated directly from epicardial adipose tissue.

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    NALP3/inflammasome pathway is activated in epicardial adipose tissue.

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    These findings add new elements to the pathogenesis of acute coronary syndromes.

Abstract

Background

Epicardial adipose tissue (EAT) has a close functional and anatomic relationship with epicardial coronary arteries. Accumulating evidence suggests that host microbiome alterations may play a role in several inflammatory/immune disorders, triggering a robust proinflammatory response also involving interleukin-1β (IL-1β) and the NALP3 inflammasome. In the current study, we explore the hypothesis that in patients with non-ST elevation acute coronary syndrome (ACS), EAT contains potentially pro-atherosclerotic bacteria that might elicit inflammasome activation.

Methods

EAT samples were obtained during coronary artery bypass grafting from ACS (n = 18) and effort stable angina (SA; n = 16) patients, and as controls, from patients with angiographically normal coronary arteries undergoing surgery for mitral insufficiency (MVD; n = 13). In all patients, NALP3 and proIL-1β mRNA expressions were evaluated with qRT-PCR. In 3 patients from each group, EAT microbiota composition was determined using next-generation sequencing technologies.

Results

In EAT, mRNA expression of both NALP3 and pro-IL1β was significantly higher in ACS than in SA and MVD (P = 0.028 and P = 0.005, respectively). A broad range of bacterial species (n = 76) was identified in both ACS and SA, with different predominant species. In contrast, microbial DNA was barely observed in MVD.

Conclusions

Our study demonstrated the presence of bacterial DNA directly into EAT, surrounding diseased coronary arteries, of patients with ACS. Furthermore, ACS is associated with NALP3/inflammasome pathway activation in EAT. Our data suggest that the EAT environment is susceptible to microbial colonization that might stimulate a proinflammatory response. These findings add new elements to the pathogenesis of ACS and suggest novel therapeutic targets.

Introduction

Inflammation plays a crucial role in the pathogenesis of acute coronary syndrome (ACS), and both innate immunity and adaptive immunity are involved in atherosclerosis onset and progression [1]. Several studies have demonstrated that NOD-like receptor protein 3 (NLRP3)-inflammasome is one of the innate immunity mediators involved in the development of atherosclerosis. This cytosolic receptor regulates the activation of caspase-1 and induces inflammation in response to infectious microbes and molecules derived from host proteins, through the release of pro-inflammatory cytokines, such as IL-1β and IL-18 [2]. NLRP3 expression in subcutaneous adipose tissue (SAT) is associated with the severity of coronary atherosclerosis [3] and systemic NLRP3 concentration is significantly higher in ACS patients, with a positive correlation with the extent of coronary atherosclerosis [4]. In the past decades, the relation between microbial infections and atherosclerosis has been widely studied and bacteria are known to represent a potential trigger for NLRP3 activation [5], [6], [7]. Epicardial adipose tissue (EAT) is a mediastinal fat depot with a close functional and anatomic relationship with epicardial coronary arteries. It has been demonstrated that human EAT represents a source of inflammatory mediators involved in the amplification of vascular inflammation and plaque instability [8]. Aim of the present study was to explore the hypothesis that, in patients with non-ST elevation ACS (NSTE-ACS), EAT contains potentially pro-atherosclerotic bacteria that might stimulate inflammasome activation and a negative loop finally causing plaque instability.

Section snippets

Methods

We obtained EAT samples from 34 patients undergoing coronary artery bypass grafting admitted to our Coronary Care Unit for NSTE-ACS (n = 18) or effort stable angina (SA, n = 16), with evidence of inducible ischemia at stress-ECG, myocardial perfusion imaging and/or stress-echocardiography. As controls, we enrolled patients with angiographically normal coronary arteries undergoing surgery for mitral valve regurgitation (MVD, n = 13). Exclusion criteria were: age > 80 years; inflammatory/infectious

Results

NLRP3 mRNA expression in EAT was higher in patients with ACS (42.8 ± 8.2) than in SA (24.9 ± 2.8) and MVD (21.3 ± 3.4) (P for trend = 0.028), with a significant difference between ACS and MVD (P = 0.043) (Fig. 1, Panel A). Also, the expression of pro-IL1β mRNA in EAT was higher in ACS (87.5 ± 11.02) as compared with SA (63.3 ± 11.24) and MVD (33.8 ± 9.4) (P for trend = 0.005), with a significant difference between ACS and MVD (P = 0.001) (Fig. 1, Panel B). Caspase-1 and mature IL-1β protein expression were

Discussion

Our study investigates for the first time the microbial environment of EAT, showing that there are significant differences both in number and in species of microbial agents between stable and unstable patients. Whether and how these microbes act in the pathogenesis of atherosclerotic disease and of plaque instability is still unknown and further studies are needed to clarify their role. On top of that, our results confirm the hypothesis that EAT plays a significant role in the inflammatory

Study limitations

Our study has some limitations. It is an observational prospective analysis, including a limited number of patients. No power calculation could be performed because of the lack of previous studies in this setting; thus, the enrollment of patients in each group was arbitrary. ACS, SA and MVD patients were matched for age and sex, but not for risk factors; however, no significant differences were observed to this regard between ACS and SA patients. Whether the changes in EAT of ACS patients

Conclusion

In conclusion, our data suggest that the EAT environment is probably susceptible to microbial colonization that might stimulate a proinflammatory response. These findings add new elements to the pathogenesis of ACS and suggest novel therapeutic targets.

Conflict of interest

The authors report no relationships that could be construed as a conflict of interest.

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1

These authors (DP, AS, SU) have contributed equally.

2

This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

3

These authors (FC and GL) have contributed equally.

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