*3.3.6 The vulnerable atherosclerotic plaque, plaque complications, and Chlamydia pneumoniae*

As we mentioned previously, the plaque vulnerability depends on plaque volume, both the collagen content and the macrophage population of the fibrous cap, and the cap fatigue caused by mechanical stresses on the plaque (flexion, shear, pressure alterations, etc.). The role of CP in atherosclerosis development through macrophages was demonstrated in previous studies. Cytokines produced by CP-infected macrophages (such as TNF-α, IL-1β, and IL-6) may aggravate inflammatory response resulting with fibrous cap degradation and increase necrotic core volume and thereby increase the plaque size. The activated T lymphocytes by the infected vascular cells (endothelial cells, smooth muscle cells, and macrophages) can aggravate inflammatory activation *via* the NF-κB pathway, resulting in enhanced VEGF-1 (vascular cell adhesion molecule−1) and the additional inflammatory cell recruitment. Also, these cytokines can promote thrombin generation resulting in a thrombophilic intravascular milieu [78]. All these alterations might be responsible mechanisms for the plaque vulnerability and resulting in acute events. The data are scarce regarding the association of the CP infection and the plaque vulnerability and acute events. In one study, the intimal presence of Chlamydial heat shock proteins (HSP) was demonstrated to be associated with major adverse cardiac events in 6 months following coronary intervention. Also in this study, the C reactive protein (CRP) levels as an indirect measure of the inflammation severity was demonstrated to be correlated with the major cardiac adverse events [79].

Serological studies in patients with acute coronary events demonstrated a possible association with CP infections and acute vascular events. However, this serological finding could be an indirect association and does not establish an exact causality. Moreover, this serological response may also be just a part of a nonspecific humoral response to inflammation. Further studies with using direct detection tools in the vulnerable lesions—if possible—might provide further information [80–82].

Protective effects of statins on acute cardiac events, stroke, and mortality were demonstrated in previous studies. Beyond cholesterol lowering, their effect on the modulation of the immune response was revealed by clinical studies. The reduction of the CRP (C-reactive protein) levels with statin treatment indicates their immunomodulatory actions. Either the future cardiovascular events or CRP levels—in other words the inflammation—decrease with the statin treatment. Moreover in a recent study, the reduction in major adverse cardiac events with rosuvastatin treatment and especially its efficacy in patients with increased high sensitive CRP (hs-CRP) levels were demonstrated. This study demonstrated that with statin treatment, the lower

#### *The Probable Role of* Chlamydia pneumoniae *Infection in Acute Stroke DOI: http://dx.doi.org/10.5772/intechopen.109582*

primary endpoint rate was achieved (acute coronary syndrome, stroke, confirmed cardiac death, etc.) in patients with high hs-CRP despite their low cholesterol levels. These all findings shifted the idea of preventing future vulnerable plaque-mediated events by reducing the cholesterol with statins, to the idea of prevention of these events by reducing the inflammation with statin treatment [83–86].

Statins inhibit cholesterol production by inhibition of mevalonate pathway. This inhibition also decreases the production of other downstream metabolites such as isoprenoids. Prenylation of certain proteins by certain isoprenoid compounds is essential for their function, such as post-translational modification of membrane GTPases the members of Ras, Rho, and Rab families. These GTPases are important in various cell signaling pathways, which regulate cell growth, proliferation, and inflammation. Disturbance of these prenylation pathways by statins exert the immune modulatory effect especially through the function of macrophages. Inflammatory responses of M1 macrophages are diminished by modulation of TLR (Toll-like receptors) signaling pathways *via* inhibition of NF-кB, and modulation of the IFN-γ receptor signaling system. Inhibition of M1 response results in decreased level of cytokine expression such as IL-1ß, IL-6, IL-12, TNFα [87–89].

*In vitro* studies demonstrated the modification of immune response by statins in CP-infected human macrophages and endothelial cells. The increased NF-кB expression in CP-infected cells was demonstrated to be inhibited with statins. Also, it was demonstrated that in the vascular smooth muscle cells infected with CP, the reactive oxygen species production, the activity of RhoA and Rac1, and the expression of NF-кB, MCP-1, and RANTES were reduced with cerivastatin [90, 91]. The interruption of the CP-activated signal transduction cascade by statins inhibits the inflammation response in the infected vascular cells. Thereby, inhibition of the inflammation by statins in the possibly CP infected atherosclerotic plaque results in plaque stability. Despite the absence of an direct evidence, these all findings could support the hypothesis that CP infection may have a role in atherosclerosis development and plaque vulnerability *via* aggravating the immune responses in the plaque.
