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Inflammation & Infection in Acute Coronary Syndromes

Enrique P. Gurfinkel, M.D., Ph.D.

Director, Coronary Unit, Fundación Favaloro
Buenos Aires- Argentina

The mechanisms responsible for the transition from a relatively stable to a clinically unstable situation, are still obscure.
It is accepted that activated macrophages and T lymphocytes through the release of cytokines, adhesive proteins and tissue factor modify the plaque stability
(1- 2- 3).
The fibrous layer becomes thinner and prone to rupture
(4).   The exposure of plaque components to the blood stream triggers the formation of an endoluminal thrombus and the onset of acute coronary events (5).
In fact, during the acute phase of coronary syndromes the coagulation cascade is extremely activated. This pathophisiological process justified the use of antithrombotic therapies

During the clinical practice, a substantial number of unstable angina patients have an adverse clinical outcome despite the use of aspirin and standard heparin during the acute phase (7). This loss of an initial benefit could be explained by the rebound activation of the coagulation system that follows the discontinuation of the heparin infusion (8- 9) and the continuing inflammatory process that remains up to 6 months from the onset of the coronary event (10). Then it is possible to understand that cyclic waves of thrombosis and lysis may occur preceding clot formation which becomes into ischemic complications.

A sizable proportion of patients with these acute coronary syndromes continue to have a severe adverse events outcomes despite the initial approach during the in-hospital stay. The incidence of the sum of death, and acute myocardial infarction at hospital discharge rose to 8% by two months and 14% by one year.

Then, other potential pathophisiological mechanism could be implicated in the instabiltity of the plaque.
Recently, there has been renewed interest in the possibility that coronary heart disease might be associated with infection and specifically with Chlamydia pneumoniae infection. This organism is now recognised as a common cause of respiratory tract infection. Several investigators have documented an association between coronary heart disease and the presence of high titres of antibodies to C. pneumoniae
(11-12-13). The organism has been detected in atherosclerotic plaques using a variety of techniques including electron microscopy, immunocytochemistry and the polymerase chain reaction (PCR) and viable C. pneumoniae have been cultured from atherosclerotic tissue (14-15). Furthermore, it has recently been found that C. pneumoniae might be involved both in atherogenesis and in the plaque instability (2-16).
In fact, other intracellular pathogens were implicated with atherosclerosis as Cytomegalovirus, Mycoplasma pneumoniae, Helicobacter pylori.
However, there are considerable problems in investigating potential associations between Helicobacter pylori and Coronary Heart Disease
The impact of Helicobacter pylori infection as an independet risk factor for Coronary Heart Disease seems to be minor
Patients with Coronary Heart Disease, especially those with two or three vessel diseases, are more often Helicobacter pylory seropositive than the non-diseased controls.
In addition, some studies demonstrated that Helicobacter pylori seropositive is associated with an increase of Acute Myocardial Infarction before statistical adjustment.
But unfortunately, after adjustment for these risk factors, its relation between Helicobacter pylori and Coronary Heart Disease is considerable weak.

Controversial exist as well since Helicobacter pylori seropositivity is inversely related to HDL cholesterol concentrations, but unrelated to other major cardiovascular risk factors (19)
Mycoplasma pneumoniae was also explored in the setting of the acute coronary syndromes but we were unable to find any strong correlation with this pathogen and symptomatic atherosclerosis (20).
Other organisms such as cytomegalovirus have been associated with coronary artery disease, although results have been equivocal and the correlation between these pthogens and coronary artery disease is not as well established as that with C. pneumoniae
Therefore, we investigated this infectious process associated with the Human Leukocyte antigens. The HLA system plays an important role in immune response to human diseases and to transplanted organs.
We analyzed the HLA phenotypes in an adequate proportion of patients suffering from unstable angina consecutively selected from Class I and Class II.
What we found was that among HLA DR locus, the B-4 was positively related in patients Chlamydia pneumoniae seropositive who developed major ischemic complications
Under this circunstances, Chlamydia pneumoniae could modify the adequate inmunological response in this subset of patients.

Then, we decided to test the hypothesis that treatment of patients with unstable angina with and antibiotic with antichlamydial activity, such as roxithromycin, in addition to conventional therapy, might reduce subsequent plaque instability and associated clinical events.
The Roxis Pilot Study
(25) was a double blind, randomized, prospective, multicenter, parallel group, placebo-controlled pilot study with a treatment phase of 30 days and a follow-up period of 6 months.
All patients with non-Q-wave MI and unstable angina that met criteria for type IIIb of Braunwald’s classification received conventional antithrombotic plus antiischemic therapy. When the therapy was started and informed consent was obtained, patients were randomly allocated to receive roxithromycin 150 mg b.i.d. PO or its placebo b.i.d. PO during 30 consecutive days.
The preliminary report showed a rate of recurrent ischemia of 5.4%, myocardial infarction 2.2%, and ischemic death 2.2% in the placebo group, and 1.1%, 0%, and 0% respectively in the roxithromycin group. A statistically significant reduction in the composite double and triple end point rates was observed in favor of the roxithromycin group: (p= 0.04, RR 0.96 [CI 0.92-1.0] and p= 0.009, RR 0.91 [CI 0.85-0.98] respectively). No significant drug related adverse effects were observed.
At 6 months the composite triple end point was 14.6% in the placebo group and 8.69% in the active arm (p value = 0.259)

The beneficial actions of antibiotics, independent of baseline antibody titres, suggest that IgG titres may not be an adequate marker for guiding treatment therapy (27). Given the relatively small number of events occurring during the study as well as the total sample size, one cannot evaluate if the ischeamic events observed were associated with an acute re-infection, which is common in C pneumoniae, or a chronic infection.
The ROXIS study is one of the first prospective analyses to investigate the prognostic value of c-RP. C-RP levels were not a predictor of primary clinical events, but elevated baseline levels were found in those patients who eventually required a revascularization procedure.

This is consistent with Maseri’s hypothesis (28) that proposes c-RP levels should be included in a patients risk profile. The predictive value, however, might be exaggerated in a low risk population (29), or as in the present study, if one analyses baseline levels during active ischaemia. The relationship between elevated levels of c-RP and the need for revascularization in patients presumably with more diffuse atherosclerotic disease is understandable given that inflammatory cells are found in all stages of chronic atherosclerosis with a potential pathological immune response (30). The immune system is capable of unleashing a powerful inflammatory reaction when stimulated by chlamydia-like bacterial proteins (31), lipopolysaccharides (32), as well as antigens such as heat shock proteins that trigger a humoral and cellular immune reaction (33 -34).
If indeed c-RP is a sensitive but non-specific marker of inflammation, then antibiotics apparently do have an influence in their level. C-RP levels decreased in both groups after the treatment period, although with a significantly greater decrease in the active treatment arm. A potential anti-inflammatory effect of macrolide antibiotics beyond their bactericidal action
(35) remains uncertain and may require different markers of inflammation to evaluate.



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Enrique P. Gurfinkel, M.D., Ph.D.
Director, Coronary Unit, Fundación Favaloro
Avenida Belgrano 1746 (1093)
Buenos Aires- Argentina
Telephone: 54 11 4378 13557- Fax: 54 11 4805 7225