Abdominal aortic aneurysms (AAA) are the 13th cause of death, and are currently responsible for more than 15.000 annual deaths in the US alone. For unknown reasons, the incidence of AAA is steadily rising, and a further increase is anticipated for the future (1). Current approach towards AAA is surveillance, and preventive surgical elimination ('repair') of AAA over 5.5 cm. Unfortunately, morbidity and mortality of conventional transabdominal AAA repair is significant. Although short-term results of endovascular repair are more favorable, long-term mortality is similar to that of open repair. Moreover, the required life-long follow-up, the high reintervention rate compromise the cost effectivity of endovascular repair (2,3), and concern about increasing late aneurysm-related mortality following EVAR compromise the effectivity of endovascular repair (4). Accordingly, pharmaceutical intervention inhibiting AAA progression, thus reducing or postponing the need for repair has major advances, both from patients' and from socio-economical perspective (5,6).
The tetracycline analogue doxycycline effectively inhibits AAA formation and progression in various animal models of the disease (7-10). Moreover, data from two preliminary clinical studies suggest that these observations may also apply to humans (11-12).
The mechanism(s) underlying the effect of doxycycline is still unclear. We studied the effect of short term (2 weeks) doxycycline therapy in patients scheduled for open AAA repair and found that treatment resulted in a profound but selective suppression of vascular inflammation as reflected by a resp. 72% and 95% reduction of the aortic wall neutrophil and cytotoxic T-cell content (13,14). Evaluation of inflammatory pathways underlying this effect showed that treatment specifically quenched AP-1 and C/EBP pro-inflammatory transcription pathways and reduced vascular IL-6, 8 and 13 and G-CSF levels.
Doxycycline has a well established safety record (15,16), is generally well tolerated, and is inexpensive; positing it an excellent lead-candidate for the medical stabilization of AAA as outlined in a recent comment (17). We now propose to evaluate the effects of doxycycline on AAA growth in a double blind placebo controlled multi-centre study in patients under surveillance for a small (3.5-5.0 cm)AAA and patients with an AAA of 5.0 cm or larger that refuse or are not eligible for AAA repair.