Mårten Falkenberg

Plasminogen activators and inhibitors in peritoneal tissue

Serosal trauma elicits an inflammatory response which leads to the deposition of fibrin at injured sites, the residuals of which appear to be essential in excessive tissue repair and formation of intraabdominal adhesions. Local plasminogen activity may modulate this early phase of tissue repair. The present study was undertaken to investigate the distribution and cellular expression of plasminogen activators and their inhibitors in human peritoneal normal and inflamed tissue. Tissue‐type plasminogen activator (t‐PA) was expressed in subserosal capillary walls, and in normal mesothelium, but not in inflammation. Immunoreactivity for the plasminogen activator inhibitor type 1 (PAI‐1) was present in normal mesothelium, and substantially increased in inflammation, where, in addition, immunoreactivity was found throughout the submesothelial tissue. This PAI‐1 was partly co‐localized with macrophages, as was the urokinase plasminogen activator (u‐PA), suggesting an involvement of these cells in peritoneal tissue fibrinolysis. Inflammation or abrasion of the mesothelium during surgery is likely to cause a depletion of the local t‐PA source and expose the potentially PAI‐1‐containing submesothelial tissue, thus promoting persistence of fibrin and formation of adhesions.

Endovascular Treatment of Type B Thoracic Aortic Dissections

Abstract  Purpose: To evaluate the initial experience of endovascular repair of aortic dissections from a single center. Materials and Methods: From June 1999 to March 2002, endovascular stent grafting was performed in 20 high‐risk patients (16 to 80 years). Eighteen patients had a type B dissection (14 acute and 4 chronic). Two patients had chronic type A dissection. Preoperative work‐up included CT and MRI to evaluate the extent of the dissection, the relation to the left subclavian artery, the size of false and true lumen, and branch complications. Results: Stent‐graft deployment was technically successful in all cases. None was converted to open repair. Three patients died within 30 days, i.e., a 15% mortality rate. Four patients (20%) had a perioperative stroke. Paraplegia was observed in one case. No migration of the stent grafts or endoleaks was observed during the mean follow‐up period of 13 months. In all but two patient thrombosis of the false lumen was noted. Conclusions: Endovascular treatment of thoracic dissections is feasible. Early results are encouraging. While endovascular repair with stent‐grafts is progressing rapidly as a viable strategy for aortic dissections in selected patients careful investigations must continue to focus on its safety. Randomized controlled trials are urgently needed. (J Card Surg 2003;18:539‐544)

Air bubbles are released by thoracic endograft deployment: An in vitro experimental study

Purpose: Embolic stroke is a dreaded complication of thoracic endovascular aortic repair. The prevailing theory about its cause is that particulate debris from atherosclerotic lesions in the aortic wall are dislodged by endovascular instruments and embolize to the brain. An alternative source of embolism might be air trapped in the endograft delivery system. The aim of this experimental study was to determine whether air is released during deployment of a thoracic endograft. Methods: In an experimental benchtop study, eight thoracic endografts (five Medtronic Valiant Thoracic and three Gore TAG) were deployed in a water-filled transparent container drained from air. Endografts were prepared and deployed according to their instructions for use. Deployment was filmed and the volume of air released was collected and measured in a calibrated syringe. Results: Air was released from all the endografts examined. Air volumes ranged from 0.1 to 0.3 mL for Medtronic Valiant Thoracic and from <0.025 to 0.04 mL for Gore TAG. The largest bubbles had a diameter of approximately 3 mm and came from the proximal end of the Medtronic Valiant device. Conclusion: Air bubbles are released from thoracic endografts during deployment. Air embolism may be an alternative cause of stroke during thoracic endovascular aortic repair.

Ethylene vinyl alcohol copolymer (Onyx) to seal type 1 endoleak. A new technique

The aim of this study was to investigate whether the liquid embolic agent Onyx, an ethylene vinyl alcohol copolymer, can be used to seal type 1 endoleaks during endovascular aortic repair (EVAR). Six patients with large aortic aneurysms and remaining type 1 endoleaks during or after EVAR were treated with Onyx embolization through a microcatheter placed in the proximal neck in five cases and in the distal neck in one case. Four of the patients were treated using the chimney technique. The type 1 endoleak was primarily sealed by Onyx in all six patients. There was no distal embolization. Two patients had complications during follow-up. One patient had occlusions of chimney grafts to the renal arteries and to one leg extension. These occlusions were not anatomically related to Onyx embolization. One patient had late stentgraft migration of the Onyx-treated distal neck with aneurysm rupture 18 months after treatment. Early experience of Onyx embolization as a bailout solution of type 1 endoleaks after complicated EVAR is promising. However, effective seal with Onyx does not prevent late stentgraft migration. More reported patients and longer follow-up are necessary to evaluate this new technique.

Construct Validity and Reliability of Structured Assessment of endoVascular Expertise in a Simulated Setting

OBJECTIVES To study the construct validity and reliability of a novel endovascular global rating scale, Structured Assessment of endoVascular Expertise (SAVE). DESIGN A Clinical, experimental study. MATERIALS Twenty physicians with endovascular experiences ranging from complete novices to highly experienced operators performed a video-recorded simulated contra-lateral iliac-artery-stenting procedure. The virtual-patient case was a novel technically challenging procedure presenting the distal arteries below the knee. METHODS Three experts assessed the performances blinded to operator identity. Validity was analysed by correlating experience with performance results. Reliability was analysed according to generalisability theory. RESULTS The mean score on the 29 items of the SAVE scale correlated well with clinical experience (R = 0.84, P < 0.01) and was found discriminative even among the more experienced participants having performed up to 500 endovascular procedures in total. Only the most experienced participants (>5000 procedures) obtained maximum scores. The inter-rater reliability was high (G = 0.94 and G = 0.95). The procedure time (median 69 min, range 32-86) correlated moderately with clinical experience (R = -0.53, P < 0.05), whereas the fluoroscopy time and amount of contrast fluid did not correlate. CONCLUSIONS The construct validity and reliability of assessment with the SAVE scale was high when applied to performances in a simulation setting with advanced realism. No ceiling effect was present in the assessment situation.

EVAR Guided by 3D Image Fusion and CO2 DSA: A New Imaging Combination for Patients With Renal Insufficiency.

Purpose: To present a new combination of imaging techniques that helps reduce the use of iodinated contrast during endovascular aneurysm repair (EVAR) procedures in patients with renal insufficiency. Technique: Relevant anatomical structures are marked in the preprocedure computed tomography (CT) angiogram. A 3D-3D image fusion between the preprocedure CT and an intraprocedure cone-beam CT is performed in order to overlay anatomical information on live fluoroscopy. Verification of the correct overlay matching (or adjustment if necessary) is based on carbon dioxide (CO2) digital subtraction angiograms (DSA) instead of iodine DSA. The stent-graft is placed and deployed based on the overlaid information. Correct device placement is finally verified with conventional contrast angiography. Conclusion: The combination of 3D image fusion of a preoperative CT with live fluoroscopy and CO2 DSA verification is feasible and sufficient for guidance of abdominal EVAR. This method minimizes the use of iodinated contrast media, protecting residual function in the setting of preexisting renal insufficiency.

Cardiovascular outcomes in patients with peripheral arterial disease as an initial or subsequent manifestation of atherosclerotic disease: Results from a Swedish nationwide study

Objective: Long‐term progression of peripheral arterial disease (PAD) as initial manifestation of atherosclerotic arterial disease is not well described. Cardiovascular (CV) risk was examined in different PAD populations diagnosed in a hospital setting in Sweden. Methods: Data for this retrospective cohort study were retrieved by linking data on morbidity, medication use, and mortality from Swedish national registries. Primary CV outcome was a composite of myocardial infarction, ischemic stroke (IS), and CV death. Kaplan‐Meier analysis and Cox proportional hazards modeling was used for describing risk and relative risk. Results: Of 66,189 patients with an incident PAD diagnosis (2006‐2013), 40,136 had primary PAD, 16,786 had PAD + coronary heart disease (CHD), 5803 had PAD + IS, and 3464 had PAD + IS + CHD. One‐year cumulative incidence rates of major CV events for the groups were 12%, 21%, 29%, and 34%, respectively. Corresponding numbers for 1‐year all‐cause death were 16%, 22%, 33%, and 35%. Compared with the primary PAD population, the relative risk increase for CV events was highest in patients with PAD + IS + CHD (hazard ratio [HR], 2.01), followed by PAD + IS (HR, 1.87) and PAD + CHD (HR, 1.42). Despite being younger, the primary PAD population was less intensively treated with secondary preventive drug therapy. Conclusions: PAD as initial manifestation of atherosclerotic disease diagnosed in a hospital‐based setting conferred a high risk: one in eight patients experienced a major CV event and one in six patients died within 1 year. Despite younger age and substantial risk of future major CV events, patients with primary PAD received less intensive secondary preventive drug therapy.

Displacement Forces in Iliac Landing Zones and Stent Graft Interconnections in Endovascular Aortic Repair: An Experimental Study

OBJECTIVES Stent graft migration influences the long-term durability of endovascular aortic repair. Flow-induced displacement forces acting on the attachment zones may contribute to migration. Proximal fixation of aortic stent grafts has been improved by using hooks, while distal fixation and stent graft interconnections depend on self-expansion forces only. We hypothesized that flow-induced displacement forces would be significant at the distal end, and would correlate with graft movements. METHODS As part of an experimental study, an iliac limb stent graft was inserted in a pulsatile flow model similar to aortic in vivo conditions, and fixed-mounted at its proximal and distal ends to strain gauge load cells. Peak displacement forces at both ends and pulsatile graft movement were recorded at different graft angulations (0-90°), perfusion pressures (145/80, 170/90, or 195/100 mmHg), and stroke frequencies (60-100 b.p.m.). RESULTS Flow-induced forces were of the same magnitude at the proximal and distal end of the stent graft (peak 1.8 N). Both the forces and graft movement increased with angulation and perfusion pressure, but not with stroke rate. Graft movement reached a maximum of 0.29 ± 0.01 mm per stroke despite fixed ends. There were strong correlations between proximal and distal displacement forces (r = 0.97, p < .001), and between displacement forces and graft movement (r = 0.98, p < .001). CONCLUSIONS Pulsatile flow through a tubular untapered stent graft causes forces of similar magnitude at both ends and induces pulsatile graft movements in its unsupported mid-section. Peak forces are close to those previously reported to be required to extract a stent graft. The forces and movements increase with increasing graft angulation and perfusion pressure. Improved anchoring of the distal end of stent grafts may be considered.

Abnormal levels of urokinase plasminogen activator protein and tissue plasminogen activator activity in human aortic aneurysms.

OBJECTIVE To measure the concentrations and activities of plasminogen activators and plasminogen activator inhibitors in human abdominal aneurysms. DESIGN Laboratory study. SETTING University hospital, Sweden. MATERIAL Biopsy specimens from 12 abdominal aortic aneurysms and 8 normal aortas (controls). INTRERVENTIONS: Tissues were homogenised and eluted. The supernatants were assayed for antigens of tissue and urokinase plasminogen activator and plasminogen activator inhibitor 1 and 2. The activities of tissue plasminogen activator and plasminogen activator inhibitor-1 were assayed by ELISA. Frozen sections were immunostained for tissue and urokinase plasminogen activators and for plasminogen activator inhibitor-1. MAIN OUTCOME MEASURES Concentrations and activities of these activators and inhibitors. RESULTS The concentration of urokinase plasminogen activator antigen was higher in aneurysmal walls than in normal aortas; it was detected immunohistochemically in aneurysmal but not in normal aortas. The concentration (and the detection immunohistochemically) of tissue plasminogen activator was equal in aneurysmal and normal aortas, but its activity was reduced in the aneurysmal wall. Plasminogen activator inhibitor-1 did not differ significantly between the groups. CONCLUSIONS Urokinase plasminogen activator may be responsible for the digestion of the media of the aorta and the development of an aneurysm. Reduced activity of tissue plasminogen activator may be responsible for thrombosis in the aneurysm.

Urokinase Plasminogen Activator Colocalizes with CD25+ Cells in Atherosclerotic Vessels

Proteolytic activity in vascular tissue is necessary for cellular migration, remodelling of extracellular matrix and the development of atherosclerotic lesions. Inflammatory cells, mainly macrophages, are numerous in atherosclerotic plaques and may synthesize and secrete proteolytic enzymes. The principal activator of plasminogen in tissues is urokinase plasminogen activator (u-PA). To determine if an activated phenotype of inflammatory cells colocalizes with local expression of u-PA in atherosclerotic vessels, vascular biopsies from 15 patients with peripheral atherosclerotic disease were analyzed by immunohistochemistry on consecutive sections. Anti-CD68 antibodies were used as markers for macrophages and were positive in 14/15 specimens. Anti-CD25 (interleukin-2 receptor-α) antibodies were used to identify inflammatory cells with an activated phenotype and were positive in 9/14 CD68+ specimens. The same 9 specimens were positive for u-PA. A positive reaction for u-PA was found only in specimens with CD25+ cells. Specimens with positive reactions for all three antibodies were further analyzed with computer-assisted image analysis. The colocalization with u-PA was higher for CD25 compared to CD68 in all specimens. Mean percentage of the u-PA-positive area in regions positive for cellular markers was 52% (SEM 6%) for CD25 and 19% (SEM 5%) for CD68 (p < 0.01). The results indicated that the activation of macrophages in atherosclerotic vessels may modulate local proteolysis and be of importance in plaque development and stability.