I. M. Loftus

Prospective, randomized, double-blind trial investigating the effect of doxycycline on matrix metalloproteinase expression within atherosclerotic carotid plaques.

Background and Purpose— Elevated levels of matrix metalloproteinases (MMPs), particularly MMP-1 and MMP-9, have been implicated in plaque rupture. It has been suggested that inhibition of MMPs may stabilize vulnerable atherosclerotic plaques and improve clinical outcome. The aim of the study was to investigate the ability of doxycycline, a nonspecific MMP inhibitor, to reduce MMP concentration in carotid atheroma. Methods— The study design was a prospective, double-blind randomized trial. One hundred patients requiring carotid endarterectomy were randomized to receive 200 mg/d doxycycline or placebo for 2 to 8 weeks before surgery. During endarterectomy, carotid plaques were retrieved. The concentrations of MMPs and doxycycline were determined in the atherosclerotic tissue by enzyme-linked immunosorbent assay and high-performance liquid chromatography, respectively. Clinical events were recorded, as was the rate of preoperative embolization (transcranial Doppler). Results— Analysis of endarterectomized specimens demonstrated a mean doxycycline concentration of 6.0 &mgr;g/g wet weight in treated patients. Administration of doxycycline significantly reduced the concentration of MMP-1 in carotid plaques from a mean of 14.8 to 10.3 ng/100g wet weight (P =0.038). This difference was due to decreased MMP-1 transcript (P <0.001). There was no difference in any other MMP (MMP-2, -3, or -9) or tissue inhibitor of matrix metalloproteinases–1 or –2. Conclusions— Doxycycline penetrated atherosclerotic plaques with acceptable tissue levels. This resulted in a reduction in MMP-1 concentration because of decreased expression.

Quality control during endovascular aneurysm repair: monitoring aneurysmal sac pressure and superficial femoral artery flow velocity.

Purpose: To use intraoperative aneurysmal sac pressure measurement and flow monitoring of the superficial femoral artery (SFA) to ensure complete exclusion of the aneurysm from the circulation. Methods: A 5F catheter was positioned in the aneurysmal sac of 15 consecutive patients undergoing endovascular aortomonoiliac aneurysm repair between February and September 1997. The catheter was connected to an external pressure transducer allowing pressure monitoring throughout the operation and for 24 hours postprocedurally. Flow velocity was monitored in the contralateral SFA by insonation with a 2-MHz Doppler ultrasound probe. Results: No technical defect was observed in the deployment of 10 endografts, which demonstrated marked reduction in sac pressure and good flow in the lower limb. The mean aneurysm pressure dropped from 123 to 57 mmHg after graft insertion. In 5 cases, monitoring detected problems during the endograft procedure. In 3, incomplete stent deployment was detected by a failure of sac pressure to fall following stent inflation and by the presence of flow in the contralateral femoral artery. In the other 2 cases, a distal endoleak was detected by direct injection of contrast into the sac. Conclusions: Measuring aneurysm pressure in combination with SFA Doppler flow monitoring can detect complications of endovascular aneurysm repair.

Prevalence of true vein graft aneurysms: Implications for aneurysm pathogenesis

BACKGROUNDnCircumstantial evidence suggests that arterial aneurysms have a different cause than atherosclerosis and may form part of a generalized dilating diathesis. The aim of this study was to compare the rates of spontaneous aneurysm formation in vein grafts performed either for popliteal aneurysms or for occlusive disease. The hypothesis was that if arterial aneurysms form a part of a systemic process, then the rates of vein graft aneurysms should be higher for patients with popliteal aneurysms than for patients with lower limb ischemia caused by atherosclerosis.nnnMETHODSnInfrainguinal vein grafting procedures performed from 1990 to 1995 were entered into a prospective audit and graft surveillance program. Aneurysmal change was defined as a focal increase in the graft diameter of 1.5 cm or greater, excluding false aneurysms and dilatations after graft angioplasty.nnnRESULTSnDuring the study period, 221 grafting procedures were performed in 200 patients with occlusive disease and 24 grafting procedures were performed in 21 patients with popliteal aneurysms. Graft surveillance revealed spontaneous aneurysm formation in 10 of the 24 bypass grafts (42%) for popliteal aneurysms but in only 4 of the 221 grafting procedures (2%) that were performed for chronic lower limb ischemia.nnnCONCLUSIONnThis study provides further evidence that aneurysmal disease is a systemic process, and this finding has clinical implications for the treatment of popliteal aneurysms.

Carotid endarterectomy without angiography does not compromise operative outcome

OBJECTIVESnCarotid angiography is associated with a 2% risk of stroke and, since the advent of colour-duplex ultrasound, its role in the assessment of patients with carotid disease has been the subject of debate. The aim of this study was to evaluate a policy of adopting routine duplex supplemented by selective angiography on operative outcome over a 5-year period.nnnMETHODSnA prospective audit of the results of carotid endarterectomy without routine angiography from January 1992 to December 1996. Angiography was performed only if the ultrasonography was concerned about the distal or proximal extent of disease or to assess subocclusion.nnnRESULTSnDuring the study period, 494 carotid endarterectomies were performed but only 35 patients underwent carotid angiography. The indications for angiography were subocclusion/string sign in 22 patients, to assess the limits of proximal or distal disease in 12 and abnormal anatomy in one. During the 5-year study period the overall perioperative death and/or stroke rate was 4.2%. By 1997, the perioperative stroke rate had fallen to 1.3%. In no case in this series was the operation abandoned due to unexpected findings.nnnCONCLUSIONnAlthough concerns exist about the precise duplex criteria for diagnosing a severe stenosis, this study has shown that a policy of selective angiography does not compromise patient safety or operability and avoids the unnecessary mortality, morbidity and costs associated with routine angiography.

MMP Inhibition Reduces Intimal Hyperplasia in a Human Vein Graft Stenosis Model

More than 30% of vein bypass grafts develop stenoses in the first year after operation. 1 The underlying pathological process is intimal hyperplasia, characterized by the early migration and proliferation of smooth muscle cells. 2 This is dependent upon the degradation of the extracellular matrix by matrix metalloproteinases (MMPs), secreted predominantly by the smooth muscle cells. In particular, gelatinase A and B (MMP-2 and MMP-9) efficiently degrade type IV collagen, the major structural component of the basement membrane. Previous animal studies have shown that MMP inhibition prevents the migration and proliferation of smooth muscle cells. Although work using human tissue has been limited, we have shown, using a well-validated organ culture model of human intimal hyperplasia, 3,4 that increased production of MMP-9 occurs during neointima formation. 5 The hypothesis in this study was that raised levels of MMPs may play a significant role in intimal hyperplasia and that inhibition of these enzymes may prevent intimal hyperplasia and offer a potential therapeutic strategy for the prevention of vein graft stenoses. The aim was to investigate whether marimastat (a nonselective MMP inhibitor) or doxycycline (an antibiotic of the tetracycline family known to inhibit MMPs) reduce neointima formation in cultured long saphenous vein.

Amlodipine potentiates metalloproteinase activity and accelerates elastin degradation in a model of aneurysmal disease.

AIMSnAbdominal aortic aneurysms are characterised by changes in the extracellular matrix of the arterial media, in particular a reduction in elastin concentration. These changes are mediated by increased levels of endogenous matrix metalloproteinases (MMPs). Recently, calcium channel blockers have been shown to increase the proteolytic activity of MMP-2 secreted by vascular smooth muscle cells. It may therefore by hypothesised that calcium antagonists may potentiate the activity of MMPs in aneurysmal disease and thus accelerate AAA expansion. In this study, the ability of amlodipine--a calcium antagonist--to influence elastin degradation, was assessed in a previously described model of aneurysmal disease.nnnMETHODSnPorcine aortic segments (n = 8) were pre-incubated in exogenous pancreatic elastase for 24 h prior to culture in standard conditions for 6 days with 10 and 100 micrograms/l amlodipine. Control segments were cultured both with and without amlodipine and without elastase. At the termination of culture MMPs were extracted from the tissue and quantified by a combination of substrate gel enzymography and immunoblotting. The volume fractions of elastin and collagen were determined by stereological analysis of EVG stained sections.nnnRESULTSnGel enzymography demonstrated significantly increased MMP-9 activity in the amlodipine treated segments, median 4.218 vs. 2.809 arbitrary units (p < 0.01) and this elevated activity was reflected in a significant destruction of medial elastin 27.0 vs. 40.5% (p < 0.05).nnnCONCLUSIONnTherapeutic ranges of amlodipine significantly enhanced elastin degradation and potentiated MMP-9 activity within the aortic organ cultures.

Increased MMP‐9 Activity in Acute Carotid Plaques: Therapeutic Avenues to Prevent Stroke

It is now generally accepted that acute changes in atherosclerotic plaques are a prelude to the onset of clinical syndromes such as transient ischemic attacks, stroke, 1 angina, or myocardial infarction. 2 Each phase of the atherosclerotic process involves modification of the extracellular matrix, with the integrity of the plaque depending upon the relative degradation and synthesis of the individual matrix components. Unstable plaques, at risk of acute disruption and subsequent thrombosis, are characterized by an inflammatory infiltration and increased matrix degrading activity in their most vulnerable regions. 3 The major physiological regulators of the ECM are the matrix metalloproteinases (MMPs), and release of these enzymes, particularly by inflammatory cells, has been suggested as a mechanism for plaque disruption. 4

Therapeutic Options in Small Abdominal Aneurysms: The Role of in Vitro Studies

Abdominal aneurysms are characterized by increased expression and production of metalloproteinases (MMPs) within the arterial wall, degradation of the extracellular matrix—particularly elastin—and a diffuse inflammatory infiltrate. These changes have been described in a rodent model, which uses instillation of pancreatic elastase into an isolated aortic segment to initiate aneurysm formation. To further isolate cellular interactions during aneurysm formation, we have developed an in vitro model of aneurysmal disease, which uses aortic organ cultures exposed to a brief pulse of elastase to stimulate MMP production and elastin degradation.