RESUMEN
Background After a type A aortic dissection repair, a patent false lumen in the descending aorta is the most common situation encountered, and is a well-known risk factor for aortic growth, reinterventions and mortality. The aim of this study was to analyze the long-term results of residual aortic dissection (RAD) at a high-volume aortic center with prospective follow-up. Methods In this prospective single-center study, all patients operated for type A aortic dissection between January 2017 and December 2022 were included. Patients without postoperative computed tomography scans or during follow-up at our center, and patients without RAD were excluded. The primary endpoint was all-cause mortality during follow-up for patients with RAD. The secondary endpoints were perioperative mortality, rate of distal aneurysmal evolution, location of distal aneurysmal evolution, rate of distal reinterventions, outcomes of distal reinterventions, and aortic-related death during follow-up. Results In total, 200 survivors of RAD comprised the study group. After a mean follow-up of 27.2 months (1-66), eight patients (4.0%) died and 107 (53.5%) had an aneurysmal progression. The rate of distal reintervention was 19.5% (39/200), for malperfusion syndrome in seven cases (3.5%) and aneurysmal evolution in 32 cases (16.0%). Most reinterventions occurred during the first 2 years (82.1%). Twenty-seven patients were treated for an aneurysmal evolution of RAD including aortic arch with hybrid repair in 21 cases and branched aortic arch endoprosthesis in six cases. In the hybrid repair group, there was no death, and the rate of morbidity was 28.6% (6/21) (one minor stroke, one pulmonary complication, one recurrent paralysis with complete recovery and three major bleeding events). In the branched endograft group, there was no death, no stroke, and no paraplegia. There was one case (16.7%) of carotid dissection. Complete aortic remodeling or complete FL thrombosis on the thoracic aorta was found in 18 cases (85.7%) and in five cases (83.3%) in the hybrid and branched endograft groups, respectively. Conclusions: Despite a critical course in most cases of RAD, with a high rate of aneurysmal evolution and reintervention, the long-term mortality rate remains low with a close follow-up and a multidisciplinary management in an expert center.
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A 35-year-old man, with a deep pectus excavatum due to a Marfan syndrome treated 9 years before for an acute type A dissection involving only the aortic arch, by a Bentall surgery, was admitted for acute chest pain. Computed tomography (CT) scan showed an acute type non-A non-B dissection extending to the iliac. After 5 days with strict arterial blood pressure management, the patient had recurrent refractory chest pain and a hybrid technique associating full supra-aortic vessels debranching and STABILISE technique during the same procedure was performed. The patient had an uneventful recovery with CT scan showing complete aortic arch aneurysm exclusion.
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Aneurisma de la Aorta Torácica/cirugía , Disección Aórtica/cirugía , Implantación de Prótesis Vascular , Procedimientos Endovasculares , Síndrome de Marfan/complicaciones , Adulto , Disección Aórtica/diagnóstico por imagen , Disección Aórtica/etiología , Aneurisma de la Aorta Torácica/diagnóstico por imagen , Aneurisma de la Aorta Torácica/etiología , Prótesis Vascular , Implantación de Prótesis Vascular/instrumentación , Procedimientos Endovasculares/instrumentación , Humanos , Masculino , Síndrome de Marfan/diagnóstico , Stents , Resultado del TratamientoRESUMEN
OBJECTIVE: The objective of this study was to compare surgical risk and early and late mortality of patients treated for anatomically classified juxtarenal aortic aneurysms (JRAs) by fenestrated endovascular aneurysm repair (F-EVAR) or open surgical repair (OSR) during a period when the two treatments were available and to validate an institutional algorithm for JRA repair. METHODS: We retrospectively included all patients treated electively in our center between January 2005 and December 2015 for JRAs classified into three anatomic categories, excluding suprarenal aneurysms. Lee score and American Society of Anesthesiologists (ASA) class evaluated preoperative surgical risk. We compared clinical and radiologic parameters between the patients treated by F-EVAR and those treated by OSR. The primary study end point was 30-day mortality. We also compared 5-year survival. RESULTS: From 2005 to 2015, there were 191 patients separated into two groups, one treated by OSR (n = 134; mean age, 69 years) and the other treated by F-EVAR (n = 57; mean age, 74 years). Patients of the F-EVAR group were significantly older (P = .001). Intensive care unit length of stay was significantly higher in the OSR group (3.4 days vs 1.5 days; P = .01). Surgical risk was significantly higher in the F-EVAR group as measured by Lee score ≥2 (OSR, 8.9 %; F-EVAR, 21%; P = .02) and ASA class 3 and class 4 (OSR, 32.8%; F-EVAR, 73.6%; P = .001), whereas 30-day postoperative mortality was not significantly different (OSR, 1.5%; F-EVAR, 0%; P = .394). The 5-year survival was not significantly different in the two groups (OSR, 82.1%; F-EVAR, 69.2%). CONCLUSIONS: In this study, despite a higher surgical risk by Lee score and higher ASA class in the group of patients treated by F-EVAR, postoperative mortality was not significantly different between these groups. In our opinion, F-EVAR and OSR of JRA are complementary.
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Aneurisma de la Aorta Abdominal/cirugía , Implantación de Prótesis Vascular , Procedimientos Endovasculares , Anciano , Aneurisma de la Aorta Abdominal/diagnóstico por imagen , Prótesis Vascular , Implantación de Prótesis Vascular/efectos adversos , Implantación de Prótesis Vascular/instrumentación , Implantación de Prótesis Vascular/mortalidad , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/instrumentación , Procedimientos Endovasculares/mortalidad , Femenino , Humanos , Masculino , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/terapia , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Management of visceral ischemia due to non-A, non-B dissection is extremely challenging due to the position of the primary entry tear at the level of the brachiocephalic vessels. We report on a patient who was admitted for a complicated non-A, non-B-type dissection with visceral and leg ischemia. A covered stent graft was implanted below the primary entry tear to redirect the flow in the true lumen, associated with stents implantation in the visceral arteries, to treat the dissection's static component. The patient did well, without need for bowel resection visceral or late stent restenosis. Stent-graft implantation below the primary entry tear in cases of visceral ischemia due to non-A, non-B dissection seems feasible.
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Aneurisma de la Aorta/cirugía , Disección Aórtica/cirugía , Implantación de Prótesis Vascular/métodos , Procedimientos Endovasculares/métodos , Isquemia/cirugía , Vísceras/irrigación sanguínea , Anciano , Disección Aórtica/complicaciones , Disección Aórtica/diagnóstico por imagen , Disección Aórtica/fisiopatología , Aneurisma de la Aorta/complicaciones , Aneurisma de la Aorta/diagnóstico por imagen , Aneurisma de la Aorta/fisiopatología , Aortografía/métodos , Prótesis Vascular , Implantación de Prótesis Vascular/instrumentación , Angiografía por Tomografía Computarizada , Procedimientos Endovasculares/instrumentación , Humanos , Isquemia/diagnóstico por imagen , Isquemia/etiología , Isquemia/fisiopatología , Masculino , Flujo Sanguíneo Regional , Stents , Resultado del TratamientoAsunto(s)
Aneurisma , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Arteria Carótida Interna , Displasia Fibromuscular/diagnóstico por imagen , Aneurisma/diagnóstico por imagen , Aneurisma/cirugía , Enfermedades de las Arterias Carótidas/cirugía , Arteria Carótida Interna/diagnóstico por imagen , Arteria Carótida Interna/cirugía , Femenino , Displasia Fibromuscular/cirugía , Humanos , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The aim of this study was to determine the predictive factors of reduction in diameter ≥10 mm of the aneurysm sac after endovascular treatment and analyze evolution in these patients. METHODS: Between December 1997 and December 2008, all patients electively treated at our center for an infrarenal abdominal aortic aneurysm (AAA) were included in a prospective registry. We did a retrospective study between patients whose aneurysm was reduced by at least 10 mm in diameter on computed tomography scan during follow-up (Group 1) and the other patients who did not (Group 2). A univariate and multivariate statistical analysis was performed. RESULTS: The files of 197 patients (mean age 74.8 years) with a mean follow-up of 54.8 months were reviewed. One hundred two patients (51.8%) had a reduction of ≥10 mm of AAA diameter (Group 1); this reduction was achieved after an average follow-up of 23.6 months. The delay to obtain at least a 10-mm diameter reduction was not influenced by any preoperative characteristics of patients or characteristics of the AAA. Patients in Group 1 were younger (74 vs. 76 years, P = 0.039), with a longer (31 vs. 27.7 mm, P = 0.038) and narrower upper neck (23.1 vs. 24.0 mm, P = 0.02) compared with Group 2. After multivariate analysis, these 3 variables were independently predictive of reduction in AAA diameter. In Group 1, secondary procedures were performed in 13 patients after a diameter reduction of ≥10 mm, including 3 type 1 endoleaks treated after 36 months (1 case) and after 123 months (2 cases) and 1 type 3 endoleak treated after 78 months. In Group 2, secondary procedures were performed in 28 patients, including 9 type 1 endoleaks treated after a median time of 26 months and no type 3 endoleak. Secondary procedures were significantly more frequent in Group 2 than in Group 1 (29.4% vs. 12.7%, respectively; P = 0.005). Freedom from secondary procedure at 5 years was 87.9% in Group 1 and 65.4% in Group 2 (P = 0.003). Freedom from AAA rupture at 8 years was significantly superior in Group 1 than in Group 2 (100% vs. 83.5%, P = 0.008). CONCLUSIONS: Sac shrinkage after endovascular aortic aneurysm repair is more likely observed in younger patients with long and small proximal neck anatomy and is associated with better long-term outcomes. However, late failures do occur even in those with significant sac shrinkage; therefore, follow-up should continue lifelong.
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Aneurisma de la Aorta Abdominal/cirugía , Implantación de Prótesis Vascular , Procedimientos Endovasculares , Factores de Edad , Anciano , Anciano de 80 o más Años , Aneurisma de la Aorta Abdominal/diagnóstico por imagen , Rotura de la Aorta/etiología , Aortografía/métodos , Implantación de Prótesis Vascular/efectos adversos , Distribución de Chi-Cuadrado , Procedimientos Quirúrgicos Electivos , Endofuga/etiología , Procedimientos Endovasculares/efectos adversos , Femenino , Francia , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Análisis Multivariante , Oportunidad Relativa , Modelos de Riesgos Proporcionales , Sistema de Registros , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
OBJECTIVE: The aim of this study was to analyze the pelvic ischemic complications and their impact on quality of life after interventional occlusion of the hypogastric artery (IOHA) in patients undergoing endovascular aortic aneurysm repair (EVAR). METHODS: Between January 2004 and April 2012, 638 consecutive patients with aortoiliac aneurysm treated by EVAR were prospectively registered in two teaching hospitals. We identified all EVAR patients who underwent IOHA. Demographic, clinical, and radiologic data were extracted from electronic databases and patient records as requested. All patients who survived the postoperative period took part in a quality of life survey, the Walking Impairment Questionnaire (WIQ), which included four items: pain, distance, walking speed, and stair climbing. Outcome measures included the 30-day rate of pelvic ischemic complications, the buttock claudication (BC) rate at 30 days and during follow-up, and the comparative WIQ scores between patients with persistent BC, those with regressive BC, and those who never had BC after the IOHA procedure. RESULTS: A total of 71 patients (97% men; mean age, 76 years ± 7.69) required 75 IOHA procedures. These were deemed proximal in 44 cases and distal in 31, with use of coil embolization in 64%, Amplatzer plug in 24%, or a combination of coils and plugs in 12%. The technical success rate was 100%. Two patients (2.8%) experienced fatal acute pelvic ischemic complications in the postoperative period after EVAR. Another patient died of iliac rupture during EVAR, leading to an operative mortality rate of 4.3%. Eighteen patients (25.3%) suffered BC, among whom 11 cases resolved at a median follow-up of 42 months. Young age (odds ratio, 0.92; 95% confidence interval, 0.85-0.99; P = .03) and distal IOHA (odds ratio, 3.5; 95% confidence interval, 1.01-11.51; P = .04) were independent predictors of BC occurrence. The actuarial rate of persistent BC was 85% at 18 months. The WIQ scores were lower for patients with persistent BC (median score, 35.04; interquartile range, 16.36; P = .001) compared with patients with regressive BC (median score, 76.5; interquartile range, 36.66; P = .02) or those who never experienced BC after the IOHA procedure (median score, 65.34; interquartile range, 10.94; P < .0003). CONCLUSIONS: Pelvic ischemia associated with IOHA may be severe and lead to fatality after EVAR. Our data show that BC may lead to severe quality of life impairment when it does not regress during follow-up.
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Angioplastia/efectos adversos , Aneurisma de la Aorta/cirugía , Aneurisma Ilíaco/cirugía , Claudicación Intermitente/etiología , Isquemia/etiología , Calidad de Vida , Factores de Edad , Anciano , Anciano de 80 o más Años , Nalgas/irrigación sanguínea , Enfermedad Crónica , Embolización Terapéutica/efectos adversos , Femenino , Humanos , Masculino , Limitación de la Movilidad , Músculo Esquelético/irrigación sanguínea , Pelvis/irrigación sanguínea , Complicaciones Posoperatorias/mortalidadRESUMEN
OBJECTIVES: This study sought to analyze whether the plasmatic level of leukocyte-derived microparticles (LMP) is associated with unstable plaques in patients with high-grade carotid stenosis. BACKGROUND: Preventive carotid surgery in asymptomatic patients is currently debated given the improvement of medical therapy. Therefore, noninvasive biomarkers that can predict plaque instability are needed. The LMPs, originating from activated or apoptotic leukocytes, are the major microparticle (MP) subset in human carotid plaque extracts. METHODS: Forty-two patients with >70% carotid stenosis were enrolled. Using a new standardized high-sensitivity flow cytometry assay, LMPs were measured before thromboendarterectomy. The removed plaques were characterized as stable or unstable using histological analysis according to the American Heart Association criteria. The LMP levels were analyzed according to the plaque morphology. RESULTS: The median LMP levels were significantly higher in patients with unstable plaque (n = 28; CD11bCD66b+ MP/µl 240 [25th to 75th percentile: 147 to 394], and CD15+ MP/µl 147 [60 to 335]) compared to patients with stable plaque (16 [0 to 234] and 55 [36 to 157]; p < 0.001 and p < 0.01, respectively). The increase in LMP levels was also significant when considering only the group of asymptomatic patients with unstable plaque (n = 10; CD11bCD66b+ MP/µl 199 [153 to 410] and CD15+ MP/µl 78 [56 to 258] compared with patients with stable plaque (n = 14; 20 [0 to 251] and 55 [34 to 102]; p < 0.05 and p < 0.05, respectively). After logistic regression, the neurologic symptoms (odds ratio: 48.7, 95% confidence interval: 3.0 to 788, p < 0.01) and the level of CD11bCD66b+ MPs (odds ratio: 24.4, 95% confidence interval: 2.4 to 245, p < 0.01) independently predicted plaque instability. CONCLUSIONS: LMP constitute a promising biomarker associated with plaque vulnerability in patients with high-grade carotid stenosis. These data provide clues for identifying asymptomatic subjects that are most at risk of neurologic events.
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Estenosis Carotídea/sangre , Micropartículas Derivadas de Células/metabolismo , Endarterectomía Carotidea/métodos , Leucocitos/metabolismo , Enfermedades del Sistema Nervioso/prevención & control , Anciano , Enfermedades Asintomáticas , Biomarcadores/metabolismo , Arterias Carótidas/patología , Arterias Carótidas/cirugía , Estenosis Carotídea/complicaciones , Estenosis Carotídea/fisiopatología , Estenosis Carotídea/cirugía , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/etiología , Placa Aterosclerótica/patología , Placa Aterosclerótica/fisiopatología , Valor Predictivo de las Pruebas , Cuidados Preoperatorios/métodos , Medición de Riesgo/métodos , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: The purpose of this study was to evaluate short-term results of endovascular treatment of common iliac artery (CIA) aneurysms without a distal neck by using iliac branch devices (IBDs), which enable maintenance of antegrade perfusion to the internal iliac artery (IIA). METHODS: Our investigation was done in a prospective, multicenter, nonrandomized manner. IBD were implanted to exclude CIA aneurysms with a diameter >25 mm in patients unfit for open repair. The stent grafts were designed based on preoperative angio-CT findings. A covered stent implantation between the IBD and the target IIA was performed during the same surgical procedure. Angio-CT was performed within the 30 days after the procedure. From January 2009 to April 2010, 39 patients were included in our study (38 men and 1 woman, mean age 73 years). RESULTS: The CIA aneurysm (mean diameter 32.3 mm) was isolated in 15 patients and associated with an abdominal aorta aneurysm (mean diameter 66 mm) in 24 patients. The IBD was systematically connected to a bifurcated aortobiiliac stent graft. The bifurcated stent graft was implanted during the same procedure in all patients, except for two who had a bifurcated stent graft history. Median surgery time, fluoroscopy time, and volume of contrast product were 192 (range 90-360) minutes, 32 (10-120) minutes, and 150 (60-352) mL, respectively. In 37 patients (95%), the internal iliac branch was patent at the end of the surgery. In two patients (5%), it was occluded, entailing a subischemic colic episode and buttock claudication in one of them. To treat a type I endoleak, a proximal extension partially covering a renal artery was implanted during the same surgery. A type III endoleak was diagnosed on the postoperative angio-CT. In three patients, a cross-over femorofemoral bypass was performed for an external iliac leg thrombosis (and for an internal iliac branch thrombosis in one case). In all, at 30 days, no death was reported and the success rate was 90% (three leg stenoses and a type III endoleak). CONCLUSIONS: IBD implantation to maintain an antegrade internal iliac perfusion is possible and has shown promising early success. Our results can be compared with those in the published literature. A learning curve will be needed to improve the technical success rate.
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Implantación de Prótesis Vascular/instrumentación , Prótesis Vascular , Procedimientos Endovasculares/instrumentación , Aneurisma Ilíaco/cirugía , Arteria Ilíaca/cirugía , Stents , Anciano , Anciano de 80 o más Años , Implantación de Prótesis Vascular/efectos adversos , Procedimientos Endovasculares/efectos adversos , Femenino , Francia , Humanos , Aneurisma Ilíaco/diagnóstico por imagen , Aneurisma Ilíaco/fisiopatología , Arteria Ilíaca/diagnóstico por imagen , Arteria Ilíaca/fisiopatología , Masculino , Persona de Mediana Edad , Periodo Perioperatorio , Complicaciones Posoperatorias/cirugía , Estudios Prospectivos , Diseño de Prótesis , Reoperación , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
BACKGROUND: To study the incidence, the types, and the results of secondary procedures performed after endovascular treatment of infrarenal abdominal aortic aneurysm (AAA). To compare the population of patients who underwent secondary procedure (P2) with the population of those who did not require it. MATERIAL AND METHODS: Between 1998 and 2008, this study included all the patients electively treated for AAA with stentgrafts that were still available on the market on January 1, 2009. Data were prospectively collected and retrospectively analyzed. The postoperative follow-up included at least a systematic computed tomography scan at 6, 12, 18, and 24 months and then every year. P2 were defined as any additionnal procedures performed to treat aneurysm related complications after initial stentgraft implantation. RESULTS: We studied 162 patients with a mean 40 ± 31 months' follow-up. In 32 patients (19.7%), there were 46 P2, 3 of them were surgical conversion and 1 with endovascular conversion. Thirty-nine P2 were scheduled, and seven were performed in emergency. Nine patients underwent more than one P2. P2 was indicated for type II endoleak in 17 cases, 13 of them with a diameter increase; for type I endoleak in 10 cases; for AAA rupture in 3 cases; for occlusion or stentgraft stenosis in 13 cases; and for 1 type III endoleak, 1 endotension, and 1 femoro-femoral crossover bypass infection. Two ruptures occurred in patients who had undergone P2. The immediate technical success was 89.1%. At 30 days, morbidity was 10.9%, and there was no mortality. Survival rates at 3 and 5 years were respectively 85.2% and 71.9% in patients with secondary procedure and 70.6% and 47.5% in the others (p = 0.046). CONCLUSIONS: In patients treated for AAA with second generation stentgrafts, in the long term, secondary procedure rate was 19.7%. Survival rate for patients who underwent a secondary procedure was better, which was probably related to the fact that they were younger at the time of stentgraft implantation. Large AAA diameter was a secondary-procedure risk factor.
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Aneurisma de la Aorta Abdominal/cirugía , Rotura de la Aorta/cirugía , Implantación de Prótesis Vascular/instrumentación , Prótesis Vascular , Endofuga/cirugía , Procedimientos Endovasculares/instrumentación , Falla de Prótesis , Infecciones Relacionadas con Prótesis/cirugía , Stents , Anciano , Aneurisma de la Aorta Abdominal/diagnóstico por imagen , Aneurisma de la Aorta Abdominal/mortalidad , Rotura de la Aorta/diagnóstico por imagen , Rotura de la Aorta/etiología , Aortografía/métodos , Implantación de Prótesis Vascular/efectos adversos , Implantación de Prótesis Vascular/mortalidad , Distribución de Chi-Cuadrado , Endofuga/diagnóstico por imagen , Endofuga/etiología , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/mortalidad , Femenino , Francia , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Diseño de Prótesis , Infecciones Relacionadas con Prótesis/diagnóstico por imagen , Infecciones Relacionadas con Prótesis/etiología , Reoperación , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
We report the case of a false aneurysm at the origin of the anterior tibial artery complicating upper tibial osteotomy. The proximally located lesion compressed the posterior tibial nerve, and despite successful decompression, the patient suffers from probably irreversible neurologic after-effects. Even though it is rare, this complication must be considered when faced with leg pain consecutive to upper tibial osteotomy without deep venous thrombosis.
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Aneurisma Falso/etiología , Osteotomía/efectos adversos , Arterias Tibiales , Aneurisma Falso/diagnóstico por imagen , Aneurisma Falso/cirugía , Descompresión Quirúrgica , Humanos , Masculino , Persona de Mediana Edad , Síndromes de Compresión Nerviosa/etiología , Dolor/etiología , Vena Safena/trasplante , Arterias Tibiales/diagnóstico por imagen , Arterias Tibiales/cirugía , Neuropatía Tibial/etiología , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
We report our endovascular management of a highly kinked aortomonoiliac stent graft. This complication is unusual because kinks generally occur in bifurcated stent grafts and they are managed with extra-anatomic bypass. We will then expose the possible reasons for such complication. With long term follow-up severe kink might be reported more often.
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Aneurisma de la Aorta Abdominal/cirugía , Implantación de Prótesis Vascular/efectos adversos , Oclusión de Injerto Vascular/cirugía , Anciano de 80 o más Años , Aneurisma de la Aorta Abdominal/diagnóstico por imagen , Aortografía , Oclusión de Injerto Vascular/diagnóstico por imagen , Humanos , Arteria Ilíaca/diagnóstico por imagen , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , StentsRESUMEN
Dipeptidyl peptidase I (DPPI) is a lysosomal cysteine protease critical for the activation of granule-associated serine proteases, including neutrophil elastase, cathepsin G, and proteinase 3. DPPI and granule-associated serine proteases have been shown to play a key role in regulating neutrophil recruitment at sites of inflammation. It has recently been suggested that neutrophils and neutrophil-associated proteases may also be important in the development and progression of abdominal aortic aneurysms (AAAs), a common vascular disease associated with chronic inflammation and destructive remodeling of aortic wall connective tissue. Here we show that mice with a loss-of-function mutation in DPPI are resistant to the development of elastase-induced experimental AAAs. This is in part because of diminished recruitment of neutrophils to the elastase-injured aortic wall and impaired local production of CXC-chemokine ligand (CXCL) 2. Furthermore, adoptive transfer of wild-type neutrophils is sufficient to restore susceptibility to AAAs in DPPI-deficient mice, as well as aortic wall expression of CXCL2. In addition, in vivo blockade of CXCL2 by using neutralizing antibodies directed against its cognate receptor leads to a significant reduction in aortic dilatation. These findings suggest that DPPI and/or granule-associated serine proteases are necessary for neutrophil recruitment into the diseased aorta and that these proteases act to amplify vascular wall inflammation that leads to AAAs.
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Aneurisma de la Aorta Abdominal/enzimología , Catepsina C/metabolismo , Infiltración Neutrófila/inmunología , Traslado Adoptivo , Animales , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/patología , Catepsina C/deficiencia , Quimiocinas CXC/biosíntesis , Regulación de la Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Neutrófilos/citología , Neutrófilos/enzimología , Elastasa Pancreática , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Treatment with doxycycline suppresses the development of abdominal aortic aneurysms (AAAs) in experimental animal models, but its use in humans can be accompanied by dose-related side effects. We sought to determine if localized administration of doxycycline can achieve inhibition of AAAs equivalent to that achieved by systemic treatment. C57BL/6 mice underwent transient elastase perfusion of the abdominal aorta to induce the development of AAAs. After 14 days, the mean increase in aortic diameter was reduced from 167.2+/-7.8% in untreated mice to only 129.7+/-13.8% in mice treated with 100 mg/kg/day oral doxycycline (p<0.05). Using osmotic minipumps to provide continuous periaortic infusion of doxycycline, localized infusion at rates of 0.75 to 1.0 mg/kg/day suppressed AAAs to an equivalent or even greater extent than systemic treatment [mean increase in aortic diameter 131.5+/-14.4% at 0.75 mg/kg/day, p<0.05; 103.2+/-13.5% at 1.0 mg/kg/day, p<0.01). Mean plasma doxycycline levels reached 332+/- 62 ng/mL during oral administration, but the drug was undetectable in the circulation during localized infusion. The doxycycline concentration in aortic tissue extracts was 22+/- 6 ng/mL during systemic treatment compared to only 5.6+/- 2.2 ng/mL [at 0.75 mg/kg/day] and 7.8+/- 4.0 ng/mL [at 1.0 mg/kg/day] during localized infusion (p<0.05). Localized administration of doxycycline can effectively suppress experimental AAAs with undetectable plasma drug levels, even at doses 100-fold lower than those used during oral drug administration. Localized delivery of doxycycline holds promise as a novel strategy to inhibit the progressive expansion of aortic aneurysms, perhaps as a pharmacological adjunct to endovascular (stent graft) treatment.
Asunto(s)
Antibacterianos/uso terapéutico , Aorta Abdominal/efectos de los fármacos , Aneurisma de la Aorta Abdominal/prevención & control , Doxiciclina/uso terapéutico , Administración Oral , Animales , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Aorta Abdominal/metabolismo , Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/patología , Dilatación Patológica , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Doxiciclina/administración & dosificación , Doxiciclina/farmacocinética , Bombas de Infusión Implantables , Masculino , Ratones , Ratones Endogámicos C57BL , Elastasa PancreáticaRESUMEN
OBJECTIVE: Proinflammatory cytokines and matrix metalloproteinases (MMPs) are prominent mediators of the connective tissue destruction that characterizes abdominal aortic aneurysms (AAAs), and nuclear factor (NF)-kappaB is a cytokine-responsive transcription factor that promotes macrophage MMP expression. The purpose of this study was to determine whether aneurysmal degeneration is influenced by pyrrolidine dithiocarbamate (PDTC), a pharmacologic inhibitor of NF-kappaB. METHODS: Adult male C57BL/6 mice underwent transient elastase perfusion of the abdominal aorta to induce the development of AAAs. Animals were treated every 48 hours by intraperitoneal injection with either saline (n = 34) or PDTC 20 mg/kg (n = 49). Aortic diameter (AD) measurements were used to determine the extent of aortic dilatation before and immediately after elastase perfusion and again at day 14. RESULTS: All saline-treated mice developed AAAs associated with mononuclear inflammation and destruction of medial elastin (overall increase in AD, mean +/- SEM, 169.1% +/- 7.5%). In contrast, the incidence of AAAs was only 63% in PDTC-treated mice, with a reduction in the overall increase in AD to 109.8% +/- 4.2% ( P < .0001 vs saline), decreased inflammation, and structural preservation of aortic wall connective tissue. Although aneurysm development in saline-treated mice was associated with a marked increase in aortic tissue NF-kappaB and activator protein 1 DNA-binding activities, both activities were substantially reduced in PDTC-treated animals. PDTC-treated mice also exhibited significantly lower serum and aortic wall concentrations of interleukin 1beta and interleukin 6, as well as lower amounts of aortic wall MMP-9, as compared with saline-treated controls. CONCLUSIONS: Treatment with PDTC inhibits elastase-induced experimental AAAs in the mouse, along with suppression of aortic wall NF-kappaB and activator protein 1 transcription factor activities, reduced expression of proinflammatory cytokines, and suppression of MMP-9. NF-kappaB is therefore a potentially important therapeutic target for the suppression of aneurysmal degeneration. CLINICAL RELEVANCE: Development and progression of human AAAs is associated with inflammation and enzymatic degradation of connective tissue proteins. MMP-9 is one of the enzymes involved in aneurysm disease, and its production may be induced in part by activation of the transcription factor NF-kappaB. In this mouse model, treatment with pyrrolidine dithiocarbamate (a pharmacologic inhibitor of NF-kappaB) acted to suppress MMP-9 and aneurysm development. It is hoped that treatment strategies that target NF-kappaB may eventually be shown to suppress the growth of small aortic aneurysms in patients.