A randomized trial to evaluate the effect of azithromycin in patients with unstable angina or non-Q-wave MI

Coronary artery disease is one of the largest causes of morbidity and mortality worldwide. It has been estimated to account for 1.5 million hospital admissions and 900,000 deaths annually in the United States alone. There are several well-known risk factors for coronary artery disease that are modifiable by changes in behavior or medication, including tobacco use, hypertension, hypercholesterolemia, and diabetes mellitus. Others, such as age, male gender and family history of premature coronary artery disease, are unmodifiable. These multiple risk factors do not account for all coronary artery disease, however; they are absent in up to 30% of patients with myocardial infarction. It is not known what predisposes patients without these classical risk factors to develop ischemic heart disease. Some studies have shown that infection with certain common organisms may contribute to coronary disease, the most well studied of which is Chlamydia pneumoniae. Chlamydia pneumoniae is an intracellular bacterium found throughout the world, and is a common cause of respiratory infections. The most common illnesses associated with this organism are pharyngitis, sinusitis, bronchitis and atypical pneumonias, although symptoms can be quite mild, and only about 10% of infections with Chlamydia pneumoniae may lead to a clinical diagnosis. In spite of this low rate of recognized disease, large numbers of people are infected by this organism one or more times during their lifetime: prevalence studies of antibody to Chlamydia pneumoniae have shown that half of the population has had an infection with this organism by the age of 20, and two-thirds by the age of 50. There is insufficient data to state at this time that Chlamydia pneumoniae definitively causes coronary artery disease or acute myocardial infarcts, but many studies have suggested an association between them. The majority of these studies have been of two types: seroepidemiologic studies measuring antibody levels to Chlamydia pneumoniae in different populations, and pathologic studies examining tissue for the presence of the organism. The initial study linking Chlamydia pneumoniae with coronary artery disease was a seroepidemiologic study from Finland, in which a case-control study showed that 68% of patients after acute myocardial infarction had a significant antibody response to Chlamydia pneumoniae, but only 3% of people in the control group (without MI) had antibodies. Later retrospective studies showed that patients with current MI were more likely to have had elevated antibody titers in the three to six months prior to the event, a finding more temporally consistent with a causative relationship. Numerous pathologic studies have also shown evidence for Chlamydia pneumoniae localization to atherosclerotic plaques. These studies have used as specimens cardiovascular plaques from both animals and humans, obtained by endarterectomy, coronary atherectomy, heart transplants and autopsies; they have used a variety of techniques, including immunostaining, electron microscopy, polymerase chain reaction (PCR) and culture of viable organisms from the plaque. These have provided more direct evidence for the possible role of Chlamydia pneumoniae in atherosclerotic disease. It is not clear how Chlamydia pneumoniae might be involved in the development of atherosclerotic disease – some researchers argue that it may just be an “innocent bystander”, that the organism may be present in atherosclerotic plaques but may not be harmful. However, it is known that other Chlamydia species are involved in low-grade chronic infections. It is thus thought by some researchers that infection with Chlamydia pneumoniae may induce a chronic immune activation mediated by cytokines; this may lead to the progression of atherosclerotic lesions by direct chronic endothelial damage, and/or by an enhanced procoagulant state with an increased risk of local or distant thrombosis. Recent animal and clinical studies have investigated the role of antibiotics in altering the risk for cardiac events. In one study, rabbits were fed high-cholesterol diets, with one group being inoculated with