RESUMEN
BACKGROUND: Recent studies suggest that immune-mediated inflammation of perivascular adipose tissue of abdominal aortic aneurysms (AAAs) contributes to disease development and progression. Whether the perivascular adipose tissue of AAA is characterized by a specific adaptive immune signature remains unknown. METHODS AND RESULTS: To investigate this hypothesis, we sequenced the T-cell receptor ß-chain in the perivascular adipose tissue of patients with AAA and compared it with patients with aortic occlusive disease, who share the former anatomical site of the lesion and risk factors but differ in pathogenic mechanisms. Our results demonstrate that patients with AAA have a lower repertoire diversity than those with aortic occlusive disease and significant differences in variable/joining gene segment usage. Furthermore, we identified a set of 7 public T-cell receptor ß-chain clonotypes that distinguished AAA and aortic occlusive disease with very high accuracy. We also found that the T-cell receptor ß-chain repertoire differentially characterizes small and large AAAs (aortic diameter<55 mm and ≥55 mm, respectively). CONCLUSIONS: This work supports the hypothesis that T cell-mediated immunity is fundamental in AAA pathogenesis and opens up new clinical perspectives.
Asunto(s)
Aneurisma de la Aorta Abdominal , Humanos , Aneurisma de la Aorta Abdominal/inmunología , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/patología , Masculino , Anciano , Femenino , Linfocitos T/inmunología , Tejido Adiposo/patología , Tejido Adiposo/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Persona de Mediana Edad , Aorta Abdominal/patología , Aorta Abdominal/inmunologíaRESUMEN
PURPOSE: This study reports the outcomes from a Multicenter Registry on unibody stent-graft system for the treatment of spontaneous infrarenal acute aortic syndrome (MURUSSIAS registry). MATERIALS AND METHODS: The retrospective MURUSSIAS registry included spontaneous infrarenal acute aortic dissection (IAAS) managed with the unibody stent-graft system (AFX endovascular AAA system; Endologix Inc., Irvine, California) outside the current instruction for use. IAAS considered aortic dissection (AD), intramural hematoma (IMH), and penetrating aortic ulcer (PAU). Indications to IAAS treatment were symptoms, associated dilated abdominal aorta (>3 cm), rapidly-growing (>0.5 cm/6 months) aorta, IAAS disease progression. Measured results were technical success, early (within 30 days) and midterm outcomes (after 30 days), including mortality, complications, symptoms recurrence, type I/III endoleak occurrence, stent-graft patency, survival, and freedom from reintervention. The mean follow-up was 22.12 ± 17 months. RESULTS: The MURUSSIAS registry included 83 patients from 7 participating centers. IAAS indication to treatment were symptoms in 42 (51%). In 14 (17%) patients, the infrarenal aortic length was <80 mm, and in 28 (34%), the aortic bifurcation diameter was <16 mm. Technical success was 100%. Mortality occurred early in 1 (1%) and at the midterm in 3 (4%) patients. Complications occurred early in 10 (12%) patients (1 severe, 3 moderates, and 6 mild) and at midterm in 2 (2%) (2 moderate). No symptoms' recurrence or type I/III endoleaks were registered. The 36-month estimated survival and freedom from reinterventions were 89% and 92%, respectively. CONCLUSIONS: The MURUSSIAS registry is the largest collection of spontaneous IAAS managed endovascularly using the AFX endovascular AAA system. The IAAS peculiar anatomic features were fitted with the used technique with excellent results. This treatment strategy might be considered in IAAS unless specifically-designed endovascular solutions will be available also in the emergent setting. Further studies are required to assess the longer-term performances and the stability of the reported technique. CLINICAL IMPACT: The lack of specifically designed devices for infrarenal acute aortic syndrome (IAAS) disease remains an issue principally for its specific anatomic features. The MURUSSIAS registry retrospectively examined the outcomes of spontaneous IAAS treated using the unibody stent-graft system in a spontaneous national study; and reports the largest available data on this topic. The use of the unibody stent-graft system showed to fit the anatomic peculiarities of IAAS with excellent outcomes. This IAAS treatment strategy should be considered unless specifically designed endovascular solutions will be available.
RESUMEN
Background: A strong association between aortic valve sclerosis (AVSc), the earliest manifestation of calcific aortic valve disease, and atherosclerosis exists. The aim of the study was to evaluate the predictive capabilities of AVSc on long-term all-cause mortality, in patients requiring carotid endarterectomy (CEA). Methods and Results: 806 consecutive CEA patients were enrolled. Preoperative echocardiography was used to assess AVSc. Computed tomography angiography was applied for plaque characterization. Kaplan-Meier curves, Cox linear regression, and area under the receiving operator characteristic (AUC) curve analyses were used to evaluate the predictive capability of AVSc. Overall, 348 of 541 patients had AVSc (64%). Age, diabetes, and estimated glomerular filtration rate (eGFR) were associated with AVSc. In the 5-year follow-up, AVSc group had a mortality rate of 16.7% while in no-AVSc group was 7.8%. Independent predictors of all-cause mortality were age, sex, eGFR, left ventricular ejection fraction, and AVSc. After adjustments, AVSc was associated with a significant increase in all-cause mortality risk (hazard ratio, HR = 1.9; 95%CI: 1.04-3.54; p = 0.038). We stratify our cohort based on carotid atheromatous plaque-type: soft, calcified, and mixed-fibrotic. In patients with mixed-fibrotic plaques, the mortality rate of AVSc patients was 15.5% compared to 2.4% in no-AVSc patients. In this group, AVSc was associated with an increased long-term all-cause mortality risk with an adjusted HR of 12.8 (95%CI: 1.71-96.35; p = 0.013), and the AUC, combing eGFR and AVSc was 0.77 (p < 0.001). Conclusions: Our findings indicate that AVSc together with eGFR may be used to improve long-term risk stratification of patients undergoing CEA surgery.
RESUMEN
Perivascular adipose tissue (PVAT) helps regulate arterial homeostasis and plays a role in the pathogenesis of large vessel diseases. In this study, we investigated whether the PVAT of aortic occlusive lesions shows specific gene-expression patterns related to pathophysiology. By a genome-wide approach, we investigated the PVAT transcriptome in patients with aortoiliac occlusive disease. We compared the adipose layer surrounding the distal aorta (atherosclerotic lesion) with the proximal aorta (plaque-free segment), both within and between patients with complete aortoiliac occlusion (Oc) and low-grade aortic stenosis (St). We found that PVAT of the distal versus proximal aorta within both Oc- and St-patients lacks specific, locally restricted gene-expression patterns. Conversely, singular gene-expression profiles distinguished the PVAT between Oc- and St-patients. Functional enrichment analysis revealed that these signatures were associated with pathways related to metabolism of cholesterol, vessel tone regulation, and remodeling, including TGF-ß and SMAD signaling. We finally observed that gene-expression profiles in omental-visceral or subcutaneous fat differentiated between Oc- and St-patients, suggesting that the overall adipose component associates with a different atherosclerosis burden. Our work points out the role of PVAT and, likely, other adipose tissues play in the pathophysiological mechanisms underlying atherosclerotic disease, including the abdominal aortic occlusive forms.
Asunto(s)
Estenosis de la Válvula Aórtica/diagnóstico , Aterosclerosis/diagnóstico , Grasa Intraabdominal/patología , Placa Aterosclerótica/diagnóstico , Transcriptoma/genética , Anciano , Aorta Abdominal/patología , Aorta Abdominal/cirugía , Estenosis de la Válvula Aórtica/genética , Estenosis de la Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/cirugía , Aterosclerosis/genética , Aterosclerosis/patología , Aterosclerosis/cirugía , Diagnóstico Diferencial , Femenino , Arteria Femoral/cirugía , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Arteria Ilíaca/cirugía , Grasa Intraabdominal/irrigación sanguínea , Masculino , Persona de Mediana Edad , Epiplón/irrigación sanguínea , Epiplón/patología , Placa Aterosclerótica/patología , Placa Aterosclerótica/cirugíaRESUMEN
Rationale: Despite the preferred application of arterial conduits, the greater saphenous vein (SV) remains indispensable for coronary bypass grafting (CABG), especially in multi-vessel coronary artery disease (CAD). The objective of the present work was to address the role of mechanical forces in the activation of maladaptive vein bypass remodeling, a process determining progressive occlusion and recurrence of ischemic heart disease. Methods: We employed a custom bioreactor to mimic the coronary shear and wall mechanics in human SV vascular conduits and reproduce experimentally the biomechanical conditions of coronary grafting and analyzed vein remodeling process by histology, histochemistry and immunofluorescence. We also subjected vein-derived cells to cyclic uniaxial mechanical stimulation in culture, followed by phenotypic and molecular characterization using RNA and proteomic methods. We finally validated our results in vitro and using a model of SV carotid interposition in pigs. Results: Exposure to pulsatile flow determined a remodeling process of the vascular wall involving reduction in media thickness. Smooth muscle cells (SMCs) underwent conversion from contractile to synthetic phenotype. A time-dependent increase in proliferating cells expressing mesenchymal (CD44) and early SMC (SM22α) markers, apparently recruited from the SV adventitia, was observed especially in CABG-stimulated vessels. Mechanically stimulated SMCs underwent transition from contractile to synthetic phenotype. MALDI-TOF-based secretome analysis revealed a consistent release of Thrombospondin-1 (TSP-1), a matricellular protein involved in TGF-ß-dependent signaling. TSP-1 had a direct chemotactic effect on SV adventitia resident progenitors (SVPs); this effects was inhibited by blocking TSP-1 receptor CD47. The involvement of TSP-1 in adventitial progenitor cells differentiation and graft intima hyperplasia was finally contextualized in the TGF-ß-dependent pathway, and validated in a saphenous vein into carotid interposition pig model. Conclusions: Our results provide the evidence of a matricellular mechanism involved in the human vein arterialization process controlled by alterations in tissue mechanics, and open the way to novel potential strategies to block VGD progression based on targeting cell mechanosensing-related effectors.
Asunto(s)
Puente de Arteria Coronaria , Miocitos del Músculo Liso , Vena Safena , Trombospondina 1/fisiología , Remodelación Vascular , Adulto , Anciano , Animales , Proliferación Celular , Células Cultivadas , Femenino , Oclusión de Injerto Vascular/fisiopatología , Humanos , Masculino , Fenómenos Mecánicos , Persona de Mediana Edad , Miocitos del Músculo Liso/citología , Vena Safena/citología , PorcinosRESUMEN
Objective- Perivascular adipose tissue (PVAT) is thought to play a role in vascular homeostasis and in the pathogenesis of large vessel diseases, including abdominal aortic aneurysm (AAA). Herein, we tested the hypothesis that locally restricted transcriptional profiles characterize PVAT surrounding AAA, indicating specific dysfunctions associated with the disease. Approach and Results- Using a paired sample design to limit the effects of interindividual variation, we performed a microarray-based investigation of the PVAT transcriptome in 30 patients with AAA, comparing the adipose layer of the dilated abdominal aorta with that of the not-dilated aortic neck in each patient. Furthermore, we used a state-of-the-art data mining procedure to remove the effect of confounders produced by high-throughput gene expression techniques. We found substantial differences in PVAT gene expression clearly distinguishing the dilated from the not-dilated aorta, which increased in number and magnitude with increasing AAA diameter. Comparisons with other adipose depots (omental or subcutaneous fat) confirmed that gene expression changes are locally restricted. We dissected putative mechanisms associated with AAA PVAT dysfunction through a functional enrichment network analysis: both innate and adaptive immune-response genes along with genes related to cell-death pathways, metabolic processes of collagen, sphingolipids, aminoglycans, and extracellular matrix degradation were strongly overrepresented in PVAT of AAA compared with PVAT of the not-dilated aorta. Conclusions- Our results support a possible function of PVAT in AAA pathogenesis and suggest that AAA is an immunologic disease with an underlying autoimmune component. Interfering with these disease-specific pathways would clarify their precise role in AAA pathogenesis.
Asunto(s)
Tejido Adiposo/inmunología , Aneurisma de la Aorta Abdominal/etiología , Autoinmunidad , Transcriptoma , Tejido Adiposo/metabolismo , Anciano , Aneurisma de la Aorta Abdominal/inmunología , Aneurisma de la Aorta Abdominal/metabolismo , Humanos , Inmunidad Innata , Persona de Mediana Edad , Receptores Toll-Like/fisiologíaRESUMEN
Objective- Vascular calcification (VC) is age dependent and a risk factor for cardiovascular and all-cause mortality. VC involves the senescence-induced transdifferentiation of vascular smooth muscle cells (SMCs) toward an osteochondrogenic lineage resulting in arterial wall mineralization. miR-34a increases with age in aortas and induces vascular SMC senescence through the modulation of its target SIRT1 (sirtuin 1). In this study, we aimed to investigate whether miR-34a regulates VC. Approach and Results- We found that miR-34a and Runx2 (Runt-related transcription factor 2) expression correlates in young and old mice. Mir34a+/+ and Mir34a-/- mice were treated with vitamin D, and calcium quantification revealed that Mir34a deficiency reduces soft tissue and aorta medial calcification and the upregulation of the VC Sox9 (SRY [sex-determining region Y]-box 9) and Runx2 and the senescence p16 and p21 markers. In this model, miR-34a upregulation was transient and preceded aorta mineralization. Mir34a-/- SMCs were less prone to undergo senescence and under osteogenic conditions deposited less calcium compared with Mir34a+/+ cells. Furthermore, unlike in Mir34a+/+ SMC, the known VC inhibitors SIRT1 and Axl (AXL receptor tyrosine kinase) were only partially downregulated in calcifying Mir34a-/- SMC. Strikingly, constitutive miR-34a overexpression to senescence-like levels in human aortic SMCs increased calcium deposition and enhanced Axl and SIRT1 decrease during calcification. Notably, we also showed that miR-34a directly decreased Axl expression in human aortic SMC, and restoration of its levels partially rescued miR-34a-dependent growth arrest. Conclusions- miR-34a promotes VC via vascular SMC mineralization by inhibiting cell proliferation and inducing senescence through direct Axl and SIRT1 downregulation, respectively. This miRNA could be a good therapeutic target for the treatment of VC.
Asunto(s)
Senescencia Celular/fisiología , MicroARNs/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Sirtuina 1/metabolismo , Calcificación Vascular , Adulto , Envejecimiento/patología , Animales , Aorta/metabolismo , Proliferación Celular , Células Cultivadas , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Regulación hacia Abajo , Humanos , Masculino , Ratones , Ratones Noqueados , Músculo Liso Vascular/citología , Factor de Transcripción SOX9/metabolismo , Regulación hacia Arriba , Adulto Joven , Tirosina Quinasa del Receptor AxlRESUMEN
OBJECTIVES: Thoracic endovascular aneurysm repair (TEVAR) is an appealing alternative to the standard surgical approach, but requires rigorous radiological follow-up. The cumulative radiation exposure (RE) of patients undergoing TEVAR-including pre-operative workup, the procedure and subsequent follow-up computed tomography (CT) imaging-has not previously been investigated. METHODS: From August 2003 to February 2011, 48 patients underwent TEVAR at our institution. Mean age was 66 ± 11 years, with 10 patients (21%) aged <60 years. Forty-one (85%) patients were male; 7 (15%) had urgent/emergent operation; 21 (44%) had undergone previous aortic surgery. Mean aortic diameter was 7.3 ± 2.1 cm. Intra-operative screening time and RE were reviewed, and typical institutional thoracic CT scan RE was calculated (17.8 mSv). Life expectancy of an age- and sex-matched population was estimated to assess the cumulative RE from recurrent CT follow-up. RESULTS: The average screening time was 15.7 ± 11.4 min, with an RE of 11.3 ± 9 mSv. Obese patients had significantly higher RE during TEVAR (Pearson's coefficient = 0.388, P = 0.019). The RE dropped from 14.9 ± 9.4 mSv to 8.6 ± 7.9 mSv (P = 0.033) after a hybrid suite was established. Our institutional TEVAR protocol involves one pre-operative thoracoabdominal CT scan and three follow-up thoracic CT scans for the first year, with a yearly evaluation thereafter. The life expectancy of an age- and sex-matched population was 17 years. A patient adhering to our surveillance protocol would be subjected to an overall exposure of 89 mSv at 1 year and 161 mSv at 5 years, with a projected lifetime RE >350 mSv. CONCLUSIONS: A 2-year RE exceeding the threshold of 100 mSv with a life expectancy >15 years can be estimated to lead to a lifetime risk increase in radiation-induced leukaemia and solid-tumour cancer >2.7%. The risks of cumulative RE especially in younger and/or obese patients must be balanced with the expected morbidity and mortality reduction in TEVAR versus traditional open repair, and the anticipated benefits of recurrent radiographic imaging.
Asunto(s)
Aneurisma de la Aorta Torácica/cirugía , Procedimientos Endovasculares/efectos adversos , Tomografía Computarizada por Rayos X/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Aneurisma de la Aorta Torácica/diagnóstico por imagen , Aneurisma de la Aorta Torácica/mortalidad , Procedimientos Endovasculares/métodos , Procedimientos Endovasculares/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Cuidados Posoperatorios/efectos adversos , Cuidados Preoperatorios/efectos adversos , Dosis de Radiación , Tomografía Computarizada por Rayos X/métodos , Tomografía Computarizada por Rayos X/mortalidad , Adulto JovenRESUMEN
We report on a patient with a femoropopliteal bypass infected by Kytococcus sedentarius. Treatment consisted of resection of the infected prosthesis with homograft substitution and antibiotic therapy started postoperatively. At 6 months followup, the patient showed no signs of infection and results of laboratory findings were normal.
Asunto(s)
Prótesis Vascular/microbiología , Infecciones por Bacterias Grampositivas/cirugía , Micrococcus/aislamiento & purificación , Infecciones Relacionadas con Prótesis/cirugía , Anciano , Antibacterianos/uso terapéutico , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Humanos , Masculino , Arteria Poplítea/cirugía , Infecciones Relacionadas con Prótesis/tratamiento farmacológico , Resultado del TratamientoRESUMEN
In the last ten years the contribution of both vessel wall-derived tissue factor (TF) and platelets to atherosclerosis has been revisited. At the beginning of the 2000 a circulating blood-borne TF has been proposed to sustain coagulation activation and propagation on the edge of a growing thrombus. Concomitantly with the observation that platelets not only contribute to thrombus formation, but also take part to the onset of the atherosclerotic lesion, evidences have been provided that they express functionally active TF, making them able to trigger the coagulation cascade.