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Inflammation and infection in acute coronary syndromes
Bermejo García José; Martínez Martínez Prudencio; Martín Rodríguez José Francisco; de la Torre Carpente María del Mar; Bustamante Bustamante Rosa; Guerrero Peral Ana Belén; Ortiz de Lejarazu Raul; Eiros Bouza José María; Blanco García Santiago; Fernández-Avilés Francisco.
Material and Methods
In recent years, several states or diseases related to coronary artery disease (CAD) have appeared and among them chronic infection is mentioned as a cause of local and systemic inflammation. Different infectious agents are associated with CAD such as cytomegalovirus (CMV) and Helicobacter pylori but Chlamydia pneumoniae is the most outstanding and the more frequently studied among them. The mechanism underlying infection in the development or complication of atherosclerotic lesions is uncertain. This link between infection and atherosclerosis is mainly based on serological and epidemiological data but some pathology reports contribute to this evidence too and some organisms have been identified in atheromatous lesions by different thecniques (recognizing DNA with amplification techniques, immunocitology or microscope). Whether the presence of this agents in the lesions is the cause or just a coincidence remains unsolved and this fact leaves their role in the genesis of atherosclerosis in question.
This study investigates whether CAD, including acute coronary syndrome (ACS), is related to infection due to C. pneumoniae, H. pylori or CMV assessed by serology and whether CAD is associated with inflammation detected by C-reactive protein (CRP) determinations.
Material and Methodss
From December to March, 140 patients classified in three groups were included. One group included 60 consecutive patients admitted in the Coronary Care Unit with ACS (acute myocardial infarction 40 and unstable angina or non-Q-wave myocardial infarction 18). Forty patients with stable CAD, without acute episodes in the previous six months, from the outpatient clinic formed the stable group. The control group included 40 healthy individuals, all of them more than 40 years old, selected from blood donors. In the ACS group two blood samples were obtained, the first one during the acute phase and one month later the second one. In the first sample CRP and serology against the aforementioned microorganisms were analyzed (serum IgM titres against C. pneumoniae and CMV and serum IgG titres against C. pneumoniae, CMV and H. pylori). In the second sample serum IgG titres and CRP were measured. In the control and stable groups, a single baseline blood sample was taken and serum IgG titres against the studied agents and CRP levels were determined. Serological response against C. pneumoniae was measured with microimmunofluorescence assay; serological response against CMV and H. pylori was assessed with enzimeimmunoassay (ELISA) (CMV Ig M and IgG VIDAS, BioMérieux, France and Pyloriset Ò EIA-G, Orion diagnosis, Finland respectively). CRP levels were determined by nephelometry (Neephelometer analyzer II, Dade Behring). The following criteria were considered for seropositivity: C. pneumoniae IgM, dilution ³ 1/12 and C. pneumoniae IgG ³ 1/128; CMV IgM ³ 0.90 Ua/ml and CMV IgG ³ 6 Ua/ml; H. pylori IgG ³ 300 UI/ml. CRP positive results were defined as > 0.5 mg/dl. The c 2 test was used to compare the prevalence of seropositivity and positive CRP among the groups. The median test was used to compare the CRP levels distribution among the groups while the evolution of CRP levels was analyzed by the signs test. Non-parametric tests were used because of the asymmetrical distribution of CRP values. Logarithmic transformation of the raw data was only used for graphic representation.
Table 1 shows the baseline characteristics of the patients. The control group tended to be younger whereas the stable group had a tendency to be older. The prevalence of seropositivity (defined following the aforementioned criteria) among the different study groups in addition to positive CRP prevalence are shown in table 2. There were neither acute infection nor reinfection due to C. pneumoniae or CMV (all patients had negative IgM and no IgG seroconversion was found). No differences were found regarding IgG seropositivity among the three studied groups with a high prevalence in all of them. However, there was a significant difference in the rate of positive CRP (ACS group 80%, SCAD group 25% and none in control group).
Figure 1 represents the distribution of CRP values in the groups. It can be noticed that ACS patients had the highest values (p<0.001).
Figure 2 shows CRP values according to the type of ACS. Patients with Q-wave infarction had a significant higher level of CRP than those suffering from unstable or non-Q-wave infarction.
Finally, we analyzed the behavior of elevated CRP as time went by and this is summarized in figure 3. This figure shows that CRP levels decreased with time and in the second measure carried out one month later the values of CRP were significantly lower (p<0.001), although these values remained above the normal range in 40% of the patients with positive CRP in the first determination made during the acute phase. We can conclude, therefore, that while the link between ACS and inflammation determined by CRP is apparently clear, the association between CAD and infection assesed by serology can not be assured due to the high prevalence of IgG seropositivity in all the groups. We can reasonably rule out acute infection or reinfection to be cause of ACS.
CRP is a marker of systemic inflammation that has been found above the normal range in patients with acute ischemia and of course, with myocardial infarction. CRP is a predictor of worse outcome because it foretells recurrent ischemic events in patients with stable or unstable angina. Inflammation is an accepted mechanism in the pathogenic development of CAD. This mechanism includes both local (macrophages and lymphocytes infiltration) and systemic inflammation which are well documented. Our study confirms the association between inflammation determined by CRP and CAD, mainly acute CAD although there are also 25% of patients with stable CAD who had positive PCR. It had been speculated that chronic infection could stimulate local and systemic inflammation and in this way it could play a role in the progression of atherosclerosis and in the vulnerability of the plaque. This association would originate possibilities for new treatments. Pilot interventional studies with some macrolide antibiotics following this line apparently indicated it. In this regard, there are ongoing studies. Our results failed to find that association due to the high prevalence of seropositivity in all the studied groups. The fact that in the control group there was not any patient with positive CRP whereas they had a high prevalence of seropositivity is against this association and these data oblige us to be cautious when relating chronic infection assessed by serology with inflammation and with CAD.
It can be concluded that: 1) Inflammation can be detected in most patients (albeit not all) with ACS; 2) We failed to find a direct link between ACS and acute infection due to C. pneumoniae or CMV; 3) The prevalence of seropositivity against the studied microorganisms was high in all the study groups.
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