Lipopolysaccharide-binding protein (LBP) is associated with total and cardiovascular mortality in individuals with or without stable coronary artery disease – Results from the Ludwigshafen Risk and Cardiovascular Health Study (LURIC)

Abstract

Background

Atherosclerosis of coronary arteries is hallmarked by non-specific local inflammatory processes accompanied by a systemic response. Lipopolysaccharide-binding protein (LBP) has been suggested to be associated with coronary artery disease (CAD) in a previous study without follow-up.

Patients and methods

LBP plasma levels were measured in 2959 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort study referred to coronary angiography at baseline between 1997 and 2000. Median follow-up time was 8.0 years. Primary and secondary end points were cardiovascular and all-cause mortality, respectively. Multivariable adjusted logistic regression analyses were conducted to investigate the role of LBP.

Results

Serum LBP concentration was significantly increased in 2298 patients with angiographically confirmed CAD compared to 661 individuals without coronary atherosclerosis (6.78 μg/mL (5.46–8.84) vs. 6.13 μg/mL (5.05–7.74), respectively; p < 0.001). Moreover in multivariable logistic regression analyses, adjusted for established cardiovascular risk factors and markers of systemic inflammation, LBP was a significant and independent predictor of total and cardiovascular mortality (hazard ratio (HR) for all cause mortality: 1.43, 95% CI: 1.06–1.94, p = 0.024; HR for cardiovascular mortality in the 4th quartile of LBP: 1.55, 95% CI: 1.06–2.27, p = 0.025).

Conclusion

The present results add information on LBP in CAD. The data underscore the potential importance of innate immune mechanisms for atherosclerosis. Further studies are needed to clarify the pathways between innate immune system activation and atherosclerosis.

Introduction

Atherosclerosis can be regarded as a chronic inflammatory response limited to the vascular bed [1]. New insights into the pathogenesis of atherosclerosis clearly show, that apart from well established factors, such as hypertension, high plasma concentrations of low-density lipoprotein (LDL) cholesterol and diabetes mellitus, inflammatory processes strongly influence the development and progression of atherosclerosis [2]. Although the inflammatory nature of the disease is widely accepted, what initiates and maintains this inflammatory state remains unclear. Epidemiologic evidence has suggested a link between microbial infection and atherosclerosis [3], [4]. In particular, it is possible that danger or pathogen associated molecular patterns (DAMPs and PAMPs), e.g., lipopolysaccharide (LPS) and lipoteichoic acids (LTA), from bacteria such as Chlamydia pneumonia [5], [6], [7], Helicobacter pylori [8], [9], or Porphyromonas gingivalis [9], [10], but also endogenous substances may be triggering the inflammatory response that leads to atherogenesis. The question that remains is if and how DAMPs or PAMPs may trigger this inflammatory disease. The recent discovery of toll-like receptors (TLRs), which are the key microbial sensors of the innate immune system [11], in atherosclerotic lesions [12], [13] provides a mechanistic link between infection, innate immune recognition, inflammation, and atherosclerosis.

The detection of microbial infection and the initiation of the innate immune response rely on TLRs, which recognize DAMPs/PAMPs. Ligation of TLRs results in activation of nuclear factor κB and the production of proinflammatory cytokines. A link between TLRs and atherosclerosis has been suggested in studies where expression of TLR-1, -2, and -4 was found in atherosclerotic lesions [13], [14], [15] as well as in studies where loss of TLR-4 or MyD88 reduced disease severity in atherosclerosis [16], [17].

Thus it is emerging that triggering TLRs might lead to the initiation of events that lead to the recruitment of inflammatory cells into atherosclerotic lesions [9]. Lipopolysaccharide-binding protein (LBP) is a 50-kDa polypeptide mainly synthesized in the liver and is released as a 58- to 60-kDa glycoprotein into the bloodstream after glycosylation [18]. LBP is a secretory class 1 acute-phase protein whose gene is transcriptionally activated by the acute-phase response element/signal transducer and activator of transcription 3 (APRF/STAT3) and other cytokine-inducible nuclear proteins [19]. Various PAMPs binds to LBP, and these complexes are delivered to surface receptors [20], [21] which in turn interact with TLRs. The detection of PAMPs stimulates the synthesis of interleukins, growth factors, and cytokines with the potential to exert proinflammatory and proatherogenic activities [18], [22], [23].

Highly sensitive C-reactive protein (hsCRP) has been shown to be a valuable marker for the assessment of future cardiac events, even in apparently healthy persons [20], [24], [25], however modulation of its receptor [26] or genetic variations in the expression level of hsCRP [27] do not influence CAD risk. The JUPITER trial [20] cannot answer whether reduction in CRP per se reduces CAD risk. Thus CRP might not play a causal role in the initiation of CAD [28]. The signaling cascade of LBP/TLR/MyD88, however, has been shown to influence atherosclerosis pathogenesis mechanistically [16].

We recently showed an association between lipopolysaccharide-binding protein (LBP) and coronary artery disease (CAD) in men [29]. In order to further explore the role of LBP in CAD, we measured LBP in a large and well defined cohort of patients with a follow-up of 8.0 years.