Can we treat the Aortic Aneurysms medically?
Abdominal aortic aneurysms (AAA) continue to provide an intractable clinical problem. As a disease that affects nearly 10% of the elderly population and claims over 15,000 lives/yr (USA), it is remarkable that treatment of a ruptured AAA is still associated with high mortality rates (in excess of 80%). Many would argue that physicians remain largely incapable of altering the natural history of this disease, despite our growing understanding of the pathophysiology of the vascular lesion. Several promising therapies, including statins, β-blockers, and antibiotics, have all failed to conclusively improve outcomes in large clinical trials, and no medicine is currently approved to treat AAA formation. In clinical management of Aortic Aneurysms, doctors and patients are often faced with the important decision of whether to perform invasive repair or to manage the condition conservatively. The mortality rate associated with reparative surgery has been reported to be as high as 5.5%.Current guidelines recommend endovascular repair or surgery if the aortic diameter exceeds 5.5 cm and the performance of anatomic imaging every 3 to 6 months for aneurysms above 4 cm. If growth is observed to exceed 1 cm per year in smaller aneurysms, surgical repair is also recommended. However, individual risk is also influenced by gender, age, smoking, and co-morbidities, but its assessment is rarely easy because reliable data regarding how best to evaluate these variables are not readily available. This situation often leaves one with a difficult decision, and many patients are unnecessarily exposed to the risks of reparative surgery when their aneurysm might never have ruptured if left untreated.
Aneurysms are complex entities that differ physiologically from stenotic and atherosclerotic vascular lesions. Although atheromas are dominated by neointimal proliferation and foam cell generation, the AAA is defined by the progressive loss of extracellular matrix and medial degeneration. Macrophages are recruited to the involved vessel in both conditions, but have differing roles in each case. Unlike the subendothelial lipid-laden cells of the fatty streak, macrophages of the abdominal aneurysm accumulate in the medial layer where they present antigens to other leukocytes, secrete collagenases, and elaborate proinflammatory cytokines and chemoattractants. Ultimately, they play a role in progressive aneurysmal dilation and clinical presentation. Novel therapies that can reverse this pathological course are eagerly sought.
A number of studies in patients have suggested that doxycycline can inhibit MMPs in aneurysm tissue. Curci et al66 treated a series of patients with a 3-week course of doxycycline before open aneurysm repair. Tissue levels of MMP-9 were significantly reduced by doxycycline compared with untreated patients. Baxter et al showed in a small series of 36 patients on a 6-month course of doxycycline that plasma MMP-9 levels decreased significantly compared with baseline levels. This work has been followed by a small, prospective, randomized trial of doxycycline in which 32 patients were randomized, with 17 receiving doxycycline (150 mg/d) for 3 months. Patients were followed up for 18 months. C pneumoniae titers were assessed but found not to be affected by doxycycline treatment. The calculated growth rate at the end of the 18-month period of observation was 1.5 mm per year in the doxycycline-treated group versus 3.0 mm per year in the placebo-treated group. This difference did not achieve statistical significance, but the 6- and 12-month time periods did show a significant difference in favor of doxycycline treatment. Level B evidence (from small randomized trials) suggests that roxithromycin or doxycycline will decrease the rate of aneurysm expansion.
A small study by Lindholt et al suggested that serological evidence of a C pneumoniae infection was associated with an increased rate of aneurysm expansion. This led to a randomized clinical trial in which 43 patients received a 1-month course of roxithromycin, whereas 49 patients received placebo.60 Patients in the treatment arm had an expansion rate at the end of the study of 1.56 mm per year compared with a rate of 2.75 mm per year in the placebo-treated group. The inhibition was greater in the first year than the second year. The study did not clarify the mechanism of effect because there was no correlation between Chlamydia titers and roxithromycin ability to inhibit aneurysm expansion.
We need more medical therapies which can alter the natural course of the small aneurysms and prevent the rupture of these Aortic aneurysms which are diagnosed when they are small and note taken up for the interventions.
Aneurysms are complex entities that differ physiologically from stenotic and atherosclerotic vascular lesions. Although atheromas are dominated by neointimal proliferation and foam cell generation, the AAA is defined by the progressive loss of extracellular matrix and medial degeneration. Macrophages are recruited to the involved vessel in both conditions, but have differing roles in each case. Unlike the subendothelial lipid-laden cells of the fatty streak, macrophages of the abdominal aneurysm accumulate in the medial layer where they present antigens to other leukocytes, secrete collagenases, and elaborate proinflammatory cytokines and chemoattractants. Ultimately, they play a role in progressive aneurysmal dilation and clinical presentation. Novel therapies that can reverse this pathological course are eagerly sought.
A number of studies in patients have suggested that doxycycline can inhibit MMPs in aneurysm tissue. Curci et al66 treated a series of patients with a 3-week course of doxycycline before open aneurysm repair. Tissue levels of MMP-9 were significantly reduced by doxycycline compared with untreated patients. Baxter et al showed in a small series of 36 patients on a 6-month course of doxycycline that plasma MMP-9 levels decreased significantly compared with baseline levels. This work has been followed by a small, prospective, randomized trial of doxycycline in which 32 patients were randomized, with 17 receiving doxycycline (150 mg/d) for 3 months. Patients were followed up for 18 months. C pneumoniae titers were assessed but found not to be affected by doxycycline treatment. The calculated growth rate at the end of the 18-month period of observation was 1.5 mm per year in the doxycycline-treated group versus 3.0 mm per year in the placebo-treated group. This difference did not achieve statistical significance, but the 6- and 12-month time periods did show a significant difference in favor of doxycycline treatment. Level B evidence (from small randomized trials) suggests that roxithromycin or doxycycline will decrease the rate of aneurysm expansion.
A small study by Lindholt et al suggested that serological evidence of a C pneumoniae infection was associated with an increased rate of aneurysm expansion. This led to a randomized clinical trial in which 43 patients received a 1-month course of roxithromycin, whereas 49 patients received placebo.60 Patients in the treatment arm had an expansion rate at the end of the study of 1.56 mm per year compared with a rate of 2.75 mm per year in the placebo-treated group. The inhibition was greater in the first year than the second year. The study did not clarify the mechanism of effect because there was no correlation between Chlamydia titers and roxithromycin ability to inhibit aneurysm expansion.
We need more medical therapies which can alter the natural course of the small aneurysms and prevent the rupture of these Aortic aneurysms which are diagnosed when they are small and note taken up for the interventions.
