Jean-Marc Alsac

Porphyromonas gingivalis Participates in Pathogenesis of Human Abdominal Aortic Aneurysm by Neutrophil Activation. Proof of Concept in Rats

Background Abdominal Aortic Aneurysms (AAAs) represent a particular form of atherothrombosis where neutrophil proteolytic activity plays a major role. We postulated that neutrophil recruitment and activation participating in AAA growth may originate in part from repeated episodes of periodontal bacteremia. Methods and Findings Our results show that neutrophil activation in human AAA was associated with Neutrophil Extracellular Trap (NET) formation in the IntraLuminal Thrombus, leading to the release of cell-free DNA. Human AAA samples were shown to contain bacterial DNA with high frequency (11/16), and in particular that of Porphyromonas gingivalis (Pg), the most prevalent pathogen involved in chronic periodontitis, a common form of periodontal disease. Both DNA reflecting the presence of NETs and antibodies to Pg were found to be increased in plasma of patients with AAA. Using a rat model of AAA, we demonstrated that repeated injection of Pg fostered aneurysm development, associated with pathological characteristics similar to those observed in humans, such as the persistence of a neutrophil-rich luminal thrombus, not observed in saline-injected rats in which a healing process was observed. Conclusions Thus, the control of periodontal disease may represent a therapeutic target to limit human AAA progression.

Comparison of 18F-fluoro-deoxy-glucose, 18F-fluoro-methyl-choline, and 18F-DPA714 for positron-emission tomography imaging of leukocyte accumulation in the aortic wall of experimental abdominal aneurysms

OBJECTIVEnAbdominal aortic aneurysm (AAA) is a frequent form of atherothrombotic disease, whose natural history is to enlarge and rupture. Indicators other than AAA diameter would be useful for preventive surgery decision-making, including positron-emission tomography (PET) methods permitting visualization of aortic wall leukocyte activation relevant to prognostic AAA evaluation. In this study, we compare three PET tracers of activated leukocytes, 18F-fluoro-deoxy-glucose (FDG), 18F-fluoro-methyl-choline (FCH), and 18F-DPA714 (a peripheral benzodiazepine receptor antagonist) for in vivo PET quantification of aortic wall inflammation in rat experimental AAAs, in correlation with histopathological studies of lesions.nnnMETHODSnAAAs were induced by orthotopic implantation of decellularized guinea pig abdominal aorta in 46 Lewis rats. FDG-PET (n = 20), FCH-PET (n = 8), or both (n = 12) were performed 2 weeks to 4 months after the graft, 1 hour after tracer injection (30 MBq). Six rats (one of which had FDG-PET) underwent 18F-DPA714-PET. Rats were sacrificed after imaging; AAAs and normal thoracic aortas were cut into axial sections for quantitative autoradiography and histologic studies, including ED1 (macrophages) and CD8 T lymphocyte immunostaining. Ex vivo staining of AAAs and thoracic aortas with 18F-DPA714 and unlabeled competitors was performed.nnnRESULTSnAAAs developed in 35 out of 46 cases. FCH uptake in AAAs was lower than that of FDG in all cases on imaging, with lower AAA-to-background maximal standardized uptake value (SUV(max)) ratios (1.78 ± 0.40 vs 2.71 ± 0.54; P < .01 for SUV(max) ratios), and lower AAA-to-normal aorta activity ratios on autoradiography (3.52 ± 1.26 vs 8.55 ± 4.23; P < .005). FDG AAA-to-background SUV(max) ratios correlated with the intensity of CD8 + ED1 staining (r = .76; P < .03). FCH AAA-to-background SUV(max) ratios correlated with the intensity of ED1 staining (r = .80; P < .03). 18F-DPA714 uptake was similar in AAAs and in normal aortas, both in vivo and ex vivo.nnnCONCLUSIONSnIn rat experimental AAA, characterized by an important aortic wall leukocytes activity, FDG-PET showed higher sensitivity than FCH-PET and 18F-DPA714-PET to detect activated leukocytes. This enhances potential interest of this tracer for prognostic evaluation of AAA in patients.

Fucoidan interferes with Porphyromonas gingivalis-induced aneurysm enlargement by decreasing neutrophil activation

PURPOSEnNeutrophils have been shown to be involved in all stages of human and experimental abdominal aortic aneurysm (AAA) development. The initial processes of neutrophil rolling and trapping in the intraluminal thrombus (ILT) are mediated mainly by P-selectin expressed by activated platelets. In the present study, we propose to evaluate the beneficial effect of fucoidan, a competitive binding agent of P-selectin, on aneurysmal growth in a rat model of aortic aneurysm with neutrophil enrichment of the ILT induced by repeated episodes of weak bacteremia.nnnMETHODSnSixty Lewis rats with experimental AAAs, developed from decellularized aortic xenografts, were divided into four groups. Two groups were used as controls: group fucoidan control (FC) was treated with 200 mg of fucoidan (F) delivered by 2 mL, 4-week osmotic pumps placed intraperitoneally before closing the abdomen, and group C received saline instead of fucoidan. Two more groups were injected weekly with Porphyromonas gingivalis (P. gingivalis [Pg]): group F+Pg received 200 mg of intraperitoneal fucoidan and group Pg received saline. AAAs were harvested after 4 weeks and peripheral blood was sampled at that time. Cell-free DNA (cf-DNA) and myeloperoxydase (MPO) antigen concentrations were determined in plasma and in AAA-conditioned media. Histology and P-selectin immunostaining were performed on AAA tissue samples.nnnRESULTSnComparing rats injected with Pg, those receiving fucoidan presented reduced aneurysmal diameter. Histologic analysis of AAAs showed that fucoidan reduced the ILT thickness in Pg-injected rats, with fewer trapped neutrophils, and with signs of a healing process, as observed in control group C. Immunohistological analysis revealed a substantial decrease in P-selectin immunostaining at the luminal surface of aneurysms in fucoidan-treated rats compared to the other groups, suggesting an interaction between fucoidan and P-selectin. A significant decrease in MPO concentrations in both plasma and conditioned medium was induced by fucoidan treatment in Pg-injected rats, reflecting a pacification of the ILT biological activity. This effect was associated with a reduction in neutrophil activation and apoptosis, reflected by a significant decrease in cf-DNA concentration in both plasma and conditioned medium of fucoidan-treated rats.nnnCONCLUSIONSnOur results suggest that fucoidan has a beneficial effect on experimental aneurysmal degeneration by decreasing neutrophil activation in the ILT enhanced by weak pathogen contamination. This effect seems to be related to its interaction with P-selectin, which may decrease the trapping of neutrophils into the ILT. Fucoidan could represent a therapeutic option in AAAs to decrease the neutrophil activation involved in the degenerative process of aneurysmal expansion and rupture.

Deformable Surface Model for the Evaluation of Abdominal Aortic Aneurysms Treated with an Endovascular Sealing System

Rupture of abdominal aortic aneurysms (AAA) is responsible for 1–3% of all deaths among the elderly population in developed countries. A novel endograft proposes an endovascular aneurysm sealing (EVAS) system that isolates the aneurysm wall from blood flow using a polymer-filled endobag that surrounds two balloon-expandable stents. The volume of injected polymer is determined by monitoring the endobag pressure but the final AAA expansion remains unknown. We conceived and developed a fully deformable surface model for the comparison of pre-operative sac lumen size and final endobag size (measured using a follow-up scan) with the volume of injected polymer. Computed tomography images were acquired for eight patients. Aneurysms were manually and automatically segmented twice by the same observer. The injected polymer volume resulted 9% higher than the aneurysm pre-operative lumen size (pxa0<xa00.05), and 11% lower than the final follow-up endobag volume (pxa0<xa00.01). The automated method required minimal user interaction; it was fast and used a single set of parameters for all subjects. Intra-observer and manual vs. automated variability of measured volumes were 0.35xa0±xa02.11 and 0.07xa0±xa03.04xa0mL, respectively. Deformable surface models were used to quantify AAA size and showed that EVAS system devices tended to expand the sac lumen size.

Elastase inhibitor AZD9668 treatment prevented progression of experimental abdominal aortic aneurysms

OBJECTIVEnAbdominal aortic aneurysm (AAA) is a particular form of arterial disease characterized by the dilation of the aortic wall and the presence of an intraluminal thrombus linked to a high proteolytic activity. The aim of this study was to investigate the effect of an elastase inhibitor (AZD9668 from AstraZeneca) on aneurysm progression.nnnMETHODSnFor this purpose, we have used a rat model of elastase perfusion followed by repeated injection of Porphyromonas gingivalis (Pg), a weak periodontal pathogen recently reported to enhance AAA thrombus formation. Pg (1.10(7) colony-forming units) was injected through the jugular vein once a week for 4 weeks, and AZD9668, incorporated in the food, was delivered concomitantly.nnnRESULTSnOur results show a beneficial effect of AZD9668 treatment on AAA progression and composition. The increased AAA diameter induced by Pg was significantly reduced by AZD9668 treatment. Histologic analyses allowed us to observe the persistence of a neutrophil-rich luminal thrombus associated with calcifications in Pg-injected rats and the presence of a healing process in the Pg/AZD9668-treated group. The enhanced concentrations of markers of neutrophil activation, cell-free DNA, and myeloperoxidase and elastase activity in Pg-injected rats were significantly reduced both in the conditioned medium of AAA tissue samples and in plasma of rats injected with Pg and treated with AZD9668.nnnCONCLUSIONSnAZD9668 treatment could therefore constitute a new therapeutic tool for treatment of AAA.

Age-related changes of thoracic aorta geometry used to predict the risk for acute type B dissection.

AIMSnRisk models that use a single aortic diameter threshold have failed to successfully predict acute type B aortic dissection (TBAD). We sought to identify meaningful age-indexed anatomical variables to predict TBAD risk.nnnMETHODS AND RESULTSnA geometric deformable model, consisting of virtual elastic balloons that inflate inside a vessel lumen, was developed to quantify thoracic aorta geometry. In the presence of TBAD, true and total artery lumen morphology were assessed. A stepwise logistic model was built to predict TBAD risk. Initial covariates included age, gender, body mass index and all anatomic variables not directly related to the dissected segment. Patients with acute TBAD (n=34, 62±12years old, 57% male gender) were compared with subjects with symptoms of dissection, but with a subsequent negative diagnosis (n=51, 62±12years old, 76% male gender). Patient risk factors did not differ between groups. Most aortic anatomical variables were age-dependent. Aortic size was larger in every segment of the dissected with respect to non-dissected aortas (p<0.001). Variables entering the TBAD risk prediction model were aortic arch diameter, thoracic aorta length and age (predictability=0.9764, r=0.85), confirmed by a bootstrap internal validation. In dissected aortas, the true lumen volume was correlated to age (r=0.72).nnnCONCLUSIONSnTBAD probability increases with a larger aortic arch diameter and a longer thoracic aorta, whereas threshold values increase with age. The aortic morphology was age-dependent. After dissection, true lumen volume correlated to age. The use of threshold values indexed to age should be encouraged to better prevent and eventually treat TBAD.

Association Between Thoracic Aorta Calcium and Thoracic Aorta Geometry in a Cohort of Asymptomatic Participants at Increased Cardiovascular Risk

INTRODUCTION AND OBJECTIVESnThoracic aorta calcium detection is known to improve cardiovascular risk prediction for cardiac and noncardiac events beyond traditional risk factors. We investigated the influence of thoracic aorta morphometry on the presence and extent of aortic calcifications.nnnMETHODSnNonenhanced computed tomography heart scans were performed in 970 asymptomatic participants at increased cardiovascular risk. An automated algorithm estimated the geometry of the entire thoracic aorta and quantified the aortic calcium Agatston score. A nonparametric model was used to analyze the percentiles of calcium score by age. Logistic regression models were calculated to identify anatomical associations with calcium levels.nnnRESULTSnCalcifications were concentrated in the aortic arch and descending portions. Higher amounts of calcium were associated with an enlarged, unfolded, less tapered and more tortuous aorta. The size of the ascending aorta was not correlated with aortic calcium score, whereas enlargement of the descending aorta had the strongest association: the risk of having a global calcium score > 90th percentile was 3.62 times higher (confidence interval, 2.30-5.91; P < .001) for each 2.5-mm increase in descending aorta diameter. Vessel taper, tortuosity, unfolding and aortic arch and descending volumes were also correlated with higher amounts of calcium.nnnCONCLUSIONSnThoracic aorta calcium was predominantly found at the arch and descending aorta and was positively associated with the size of the descending aorta and the aortic arch, but not with the size of the ascending aorta. These findings suggest that aortic dilatation may have different mechanisms and may consequently require different preventive strategies according to the considered segments.

Mid-term Outcomes of Stent Assisted Balloon Induced Intimal Disruption and Relamination in Aortic Dissection Repair (STABILISE) in Acute Type B Aortic Dissection

OBJECTIVESnThis article reports mid-term results of 41 patients treated by the stent assisted balloon induced intimal disruption and relamination (STABILISE) technique for acute type B aortic dissection.nnnMETHODSnBetween November 2011 and November 2017, 41 patients (10 male; median age 50 years) underwent proximal descending aortic stent grafting plus stent assisted balloon induced intimal disruption of the thoraco-abdominal aorta for acute type B aortic dissection. Serial computed tomography angiography was used to assess aortic remodelling.nnnRESULTSnThere were no intra-procedural complications. Fifteen branch arteries supplied by the false lumen were stented (9% of the visceral branch arteries). The thirty day incidence of death, stroke, and paralysis/visceral ischaemia was 2% (nxa0=xa01), 0%, 5% (nxa0=xa02), and 2% (nxa0=xa01) respectively. During a median follow up of 12 months (range 1-168) eight patients (20%) required re-intervention. Primary visceral stent patency was 93% (nxa0=xa014). No aortic related deaths occurred. On the most recent computed tomography angiogram, complete false lumen obliteration and aortic remodelling was obtained in all patients at the thoraco-abdominal level, and in 39% (nxa0=xa016) at the unstented infrarenal aorto-iliac level. The maximum aortic diameter increased in only two patients (5%) at the unstented infrarenal level.nnnCONCLUSIONnTo obtain immediate and durable thoraco-abdominal aortic remodelling in acute type B dissections, the STABILISE technique is safe and reproducible while not compromising the patency of collateral branches.

Experimental Evaluation of Endovascular Fenestration Scissors in an Ovine Model of Aortic Dissection

OBJECTIVE/BACKGROUNDnTo evaluate the experimental feasibility of endovascular fenestration using specific endovascular scissor prototypes in an ovine model of acute aortic dissection (AD).nnnMETHODSnA previously described endovascular technique was used to create a model of acute type B AD in sheep. Endovascular fenestrations using either endovascular scissor prototypes or a long sheath were compared. Four prototypes of endovascular fenestration scissors were evaluated. Both validity of the experimental model of AD and technical success of endovascular fenestration were assessed by haemodynamic criteria, completion angiography, transesophageal echocardiography, and post-procedural analysis of harvested aortas.nnnRESULTSnExperimental acute AD was created by endovascular means in 17 sheep, with a technical success rate of 82%. Systolic blood pressure was lower in the false lumen than in the true lumen (58xa0±xa05 vs. 79xa0±xa03xa0mmHg, respectively; pxa0<xa0.001). Endovascular fenestration was performed in 11 models (endovascular scissors nxa0=xa08; long sheath nxa0=xa03). Controlled endovascular fenestration was obtained by the use of endovascular scissors (nxa0=xa05/8), resulting in a significant rise in false lumen systolic blood pressure after fenestration (60xa0±xa02 vs. 67xa0±xa09xa0mmHg before and after fenestration, respectively; pxa0<xa0.047). Long sheath fenestration resulted in an uncontrolled flap motion, leading to either pseudo-coarctation syndrome or aortic rupture (58xa0±xa06 vs. 40xa0±xa02xa0mmHg before and after fenestration, respectively; pxa0<xa0.001).nnnCONCLUSIONnIn this experimental study, a reproducible AD model has been developed in sheep using endovascular procedures exclusively to evaluate endovascular fenestration techniques. Endovascular fenestration using a long sheath appeared hazardous and risky inxa0vivo. Endovascular scissors constitute a dedicated and suitable tool to perform a safe controlled and effective endovascular fenestration in an ovine model.

Existing reporting guidelines for clinical trials are not completely relevant for implantable medical devices: a systematic review

OBJECTIVESnThe aim of this study was to determine relevant items for reporting clinical trials on implantable medical devices (IMDs) and to identify reporting guidelines which include these items.nnnSTUDY DESIGN AND SETTINGnA panel of experts identified the most relevant items for evaluating IMDs from an initial list based on reference papers. We then conducted a systematic review of articles indexed in MEDLINE. We retrieved reporting guidelines from the EQUATOR networks library for health research reporting. Finally, we screened these reporting guidelines to find those using our set of reporting items.nnnRESULTSnSeven relevant reporting items were selected that related to four topics: randomization, learning curve, surgical setting, and device information. A total of 348 reporting guidelines were identified, among which 26 met our inclusion criteria. However, none of the 26 reporting guidelines presented all seven items together. The most frequently reported item was timing of randomization (65%). On the contrary, device information and learning curve effects were poorly specified.nnnCONCLUSIONnTo our knowledge, this study is the first to identify specific items related to IMDs in reporting guidelines for clinical trials. We have shown that no existing reporting guideline is totally suitable for these devices.