Current Antibiotic Trials Test Role of Bacteria in Atherosclerosis
Several intervention trials with antibiotics will within the next 36 months possibly shed new light on the role of bacteria in atherosclerosis.
Such trials are based on studies over the past 10 years, which point to several novel risk factors for atherosclerosis, including inflammation and infections, points out Dr. Maija Leinonen and colleagues at the National Public Health Institute, Oulu, Finland.
If microbes cause persistent infection in the vessel wall, they could directly promote a proinflammatory, procoagulant, and proatherogenic environment, the clinicians point out.
Microbes could also have a remote effect, for example, in the presence of a chronic infection, bacterial heat shock proteins with high sequence homology with human counterpart could induce autoimmunity against vascular cells, and lead to an atherosclerotic process.
A paradox is that coronary heart disease (CHD) morbidity and mortality have been in steady decline in industrialized countries since the 1960s, the clinicians point out in their review of current and future trials. This decline has been attributed to changes in dietary habits, and to a decrease in incidence of conventional risk factors such as smoking and hypertension.
“An alternative explanation could be that the decline started when tetracyclines came on the market, and has continued after the introduction of macrolides and fluoroquinolones for the treatment of different types of infection,” Dr. Leinonen and colleagues suggest.
“These treatments might have influenced the course of C pneumoniae, H pylori, and dental infections in affected people. The first preliminary intervention trials with antibiotics in CHD patients gave positive results: azithromycin decreased cardiac events in patients with raised C pneumoniae antibodies, and roxithromycin did so in patients with unstable angina. In both studies, a reduction in inflammation markers was also seen.”
Several large-scale prospective antibiotic intervention trials with thousands of patients — such as WIZARD, ACES, and PROVE IT — will produce results in the next one to three years. Clinicians point out that the duration of treatment in these studies is rather long: azithromycin for three months in WIZARD and for one year in ACES, and gatifloxacin for one year in PROVE IT.
At the same time, the clinicians declare, such trials, “even if unsuccessful, will not disprove the C pneumoniae theory, because we do not know the right therapy or even how to find the patients who might benefit most from antimicrobial drugs. In addition, antibiotics, as well as statins, are potent anti-inflammatory drugs.”
Dr. Leinonen and colleagues postulate that infectious processes could begin in early childhood but are only manifested in old age.
“Immunological imbalance could develop gradually when the defense mechanisms begin to deteriorate due to increasing age and accompanying diseases,” they declare. “Thus, for instance, an acute infection could activate a latent infection in the plaque and cause an acute cardiac event such as [acute myocardial infarction] AMI, which is often seen after an acute respiratory infection.”
The researchers acknowledge that the microbial pathogenesis theory for atherosclerosis remains unproven.
They conclude, however, that since “several of the pathogens linked with atherosclerosis are amenable to treatment, and the development of vaccines is in progress, further studies to verify causality are urgently needed.”
Lancet Infectious Diseases 2002; 2: 11-17.
