Relationship of MMP-14 and TIMP-3 Expression with Macrophage Activation and Human Atherosclerotic Plaque Vulnerability

Matrix metalloproteinase-14 (MMP-14) promotes vulnerable plaque morphology in mice, whereas tissue inhibitor of metalloproteinases-3 (TIMP-3) overexpression is protective. MMP-14hi  TIMP-3lo rabbit foam cells are more invasive and more prone to apoptosis than MMP-14lo  TIMP-3hi cells. We investigated the implications of these findings for human atherosclerosis. In vitro generated macrophages and foam-cell macrophages, together with atherosclerotic plaques characterised as unstable or stable, were examined for expression of MMP-14, TIMP-3, and inflammatory markers. Proinflammatory stimuli increased MMP-14 and decreased TIMP-3 mRNA and protein expression in human macrophages. However, conversion to foam-cells with oxidized LDL increased MMP-14 and decreased TIMP-3 protein, independently of inflammatory mediators and partly through posttranscriptional mechanisms. Within atherosclerotic plaques, MMP-14 was prominent in foam-cells with either pro- or anti-inflammatory macrophage markers, whereas TIMP-3 was present in less foamy macrophages and colocalised with CD206. MMP-14 positive macrophages were more abundant whereas TIMP-3 positive macrophages were less abundant in plaques histologically designated as rupture prone. We conclude that foam-cells characterised by high MMP-14 and low TIMP-3 expression are prevalent in rupture-prone atherosclerotic plaques, independent of pro- or anti-inflammatory activation. Therefore reducing MMP-14 activity and increasing that of TIMP-3 could be valid therapeutic approaches to reduce plaque rupture and myocardial infarction

Carotid atherosclerotic plaque matrix metalloproteinase-12-positive macrophage subpopulation predicts adverse outcome after endarterectomy

BACKGROUND: Matrix metalloproteinase-12 (MMP-12) promotes atherosclerosis in animal models. MMP-12 is expressed in only a subset of foam-cell macrophages (FCMs) in human plaques. We investigated whether the prevalence of this MMP-12–expressing subpopulation is a prognostic indicator of adverse outcome in patients after carotid endarterectomy (CEA). METHODS AND RESULTS: Serial sections of culprit lesions from 236 patients who underwent CEA and had undergone 3 years of clinical follow-up were stained immunocytochemically for MMP-12 and for CD68, and the MMP-12/CD68 ratio was used to quantify the MMP-12–expressing subpopulation. A high MMP-12/CD68 ratio correlated with a high content of lipid and total macrophages and a low content of vascular smooth muscle cells, as well as with MMP-8 (R=0.211, P=0.001), MMP-9 (R=0.251, P<0.001), and cleaved caspase-3 (R=0.142, P=0.036) activity measured in a neighboring segment. Dual immunohistochemical examination confirmed the location of MMP-12 in a subpopulation of MMP-8– and MMP-9–positive FCMs, whereas all apoptotic FCMs were MMP-12 positive. Patients who yielded plaques within the highest quartile compared with the lowest quartile of MMP-12/CD68 ratio had a 2.4-fold (hazard ratio, 2.4; 95% CI, 1.1- to 5.1-fold; adjusted P=0.027) increased risk of major adverse cardiovascular event and a 3.4-fold (3.4; 1.2- to 9.6-fold, P=0.024) increased risk for stroke. CONCLUSIONS: The prevalence of an MMP-12–positive subset of FCMs is a prognostic marker for adverse clinical outcome after CEA

Secretion of Hepatitis C Virus Envelope Glycoproteins Depends on Assembly of Apolipoprotein B Positive Lipoproteins

The density of circulating hepatitis C virus (HCV) particles in the blood of chronically infected patients is very heterogeneous. The very low density of some particles has been attributed to an association of the virus with apolipoprotein B (apoB) positive and triglyceride rich lipoproteins (TRL) likely resulting in hybrid lipoproteins known as lipo-viro-particles (LVP) containing the viral envelope glycoproteins E1 and E2, capsid and viral RNA. The specific infectivity of these particles has been shown to be higher than the infectivity of particles of higher density. The nature of the association of HCV particles with lipoproteins remains elusive and the role of apolipoproteins in the synthesis and assembly of the viral particles is unknown. The human intestinal Caco-2 cell line differentiates in vitro into polarized and apoB secreting cells during asymmetric culture on porous filters. By using this cell culture system, cells stably expressing E1 and E2 secreted the glycoproteins into the basal culture medium after one week of differentiation concomitantly with TRL secretion. Secreted glycoproteins were only detected in apoB containing density fractions. The E1–E2 and apoB containing particles were unique complexes bearing the envelope glycoproteins at their surface since apoB could be co-immunoprecipitated with E2-specific antibodies. Envelope protein secretion was reduced by inhibiting the lipidation of apoB with an inhibitor of the microsomal triglyceride transfer protein. HCV glycoproteins were similarly secreted in association with TRL from the human liver cell line HepG2 but not by Huh-7 and Huh-7.5 hepatoma cells that proved deficient for lipoprotein assembly. These data indicate that HCV envelope glycoproteins have the intrinsic capacity to utilize apoB synthesis and lipoprotein assembly machinery even in the absence of the other HCV proteins. A model for LVP assembly is proposed

Endovascular Treatment of Aortic Stump Rupture After Extra-anatomic Aortoduodenal Fistula Repair is not a Definitive Treatment: A Case Report and Literature Review

Introduction: Endovascular treatment of an aortic stump rupture is technically feasible. Whether this is a definitive treatment or a bridge to further surgery is unknown. Report: Previously a Case of an aortic stump rupture following extra-anatomic repair of a recurrent aortoduodenal fistula (ADF), which was successfully treated endovascularly by placement of an Amplatzer® Vascular Plug was described. The patient survived this acute procedure, but four years later was admitted with fever and back pain. Imaging revealed progressive enlargement of the aortic stump. A re-exploration was performed with removal of the infected aortic stump including the Amplatzer plug. A new aortic stump was created together with resection of an adherent part of the duodenum. The patient was discharged after five months and was able to survive for two more years without any recurring vascular complications. Discussion: This Case demonstrates that after four years, endovascular treatment was not a definitive treatment for aortic stump rupture. Endovascular treatment should be followed by definitive treatment when the patient is fit for surgery, especially in cases of ADF. If the patient is unfit for surgery, conservative treatment with culture based antibiotics is a reasonable alternative. Positive obstinacy lengthened the survival of this patient with eight years of reasonably good quality life

Capnocytophaga canimorsus Mycotic Aortic Aneurysm After a Dog Bite

Introduction: Mycotic aortic aneurysm is defined as dilatation of the aortic wall due to infection caused by a variety of microorganisms and is associated with high mortality rates. This case report describes a patient with a rapid growing mycotic infrarenal aneurysm caused by Capnocytophaga canimorsus following a dog bite. Report: A 61 year old male professional dog handler presented with a history of progressive abdominal pain and constitutional symptoms. He had been bitten by a Pit Bull Terrier dog that was attacking a young girl three weeks prior to the onset of complaints. Investigations revealed a mycotic infrarenal aortic aneurysm that grew 0.5 cm in only three days. Open surgical repair consisting of an infrarenal aorto-aortic bypass with a 21 mm × 15 cm bovine bioprosthesis was performed successfully. All cultures and biopsies were negative and the subsequent 16S–23S rRNA intergenic spacer region based polymerase chain reaction (IS-pro) technique revealed C. canimorsus, a Gram negative bacterial pathogen that lives as a commensal in the gingival flora of dogs and cats that can cause a variety of severe infections, as the causative agent. Identification made it possible to treat the patient with eight weeks of intravenous followed by four weeks of oral antibiotics. At the last follow up over a year after surgery, the patient was symptom free, without infection and on ultrasound examination there were no signs of complications or aneurysm formation. Discussion: This case highlights C. canimorsus as a rare cause of a rapid growing mycotic aortic aneurysm following a dog bite. 16S–23S rRNA profiling (IS-pro) led to the identification of the bacterial pathogen. The use of biological grafts should be considered in the management of mycotic aortic aneurysms

Capnocytophaga canimorsus Mycotic Aortic Aneurysm After a Dog Bite

Introduction: Mycotic aortic aneurysm is defined as dilatation of the aortic wall due to infection caused by a variety of microorganisms and is associated with high mortality rates. This case report describes a patient with a rapid growing mycotic infrarenal aneurysm caused by Capnocytophaga canimorsus following a dog bite. Report: A 61 year old male professional dog handler presented with a history of progressive abdominal pain and constitutional symptoms. He had been bitten by a Pit Bull Terrier dog that was attacking a young girl three weeks prior to the onset of complaints. Investigations revealed a mycotic infrarenal aortic aneurysm that grew 0.5 cm in only three days. Open surgical repair consisting of an infrarenal aorto-aortic bypass with a 21 mm x 15 cm bovine bioprosthesis was performed successfully. All cultures and biopsies were negative and the subsequent 16S-23S rRNA intergenic spacer region based polymerase chain reaction (IS-pro) technique revealed C. canimorsus, a Gram negative bacterial pathogen that lives as a commensal in the gingival flora of dogs and cats that can cause a variety of severe infections, as the causative agent. Identification made it possible to treat the patient with eight weeks of intravenous followed by four weeks of oral antibiotics. At the last follow up over a year after surgery, the patient was symptom free, without infection and on ultrasound examination there were no signs of complications or aneurysm formation. Discussion: This case highlights C. canimorsus as a rare cause of a rapid growing mycotic aortic aneurysm following a dog bite. 16S-23S rRNA profiling (IS-pro) led to the identification of the bacterial pathogen. The use of biological grafts should be considered in the management of mycotic aortic aneurysms. (C) 2022 The Author(s). Published by Elsevier Ltd on behalf of European Society for Vascular Surgery

Carotid Atherosclerotic Plaque Matrix Metalloproteinase‐12–Positive Macrophage Subpopulation Predicts Adverse Outcome After Endarterectomy

BACKGROUND: Matrix metalloproteinase-12 (MMP-12) promotes atherosclerosis in animal models. MMP-12 is expressed in only a subset of foam-cell macrophages (FCMs) in human plaques. We investigated whether the prevalence of this MMP-12–expressing subpopulation is a prognostic indicator of adverse outcome in patients after carotid endarterectomy (CEA). METHODS AND RESULTS: Serial sections of culprit lesions from 236 patients who underwent CEA and had undergone 3 years of clinical follow-up were stained immunocytochemically for MMP-12 and for CD68, and the MMP-12/CD68 ratio was used to quantify the MMP-12–expressing subpopulation. A high MMP-12/CD68 ratio correlated with a high content of lipid and total macrophages and a low content of vascular smooth muscle cells, as well as with MMP-8 (R=0.211, P=0.001), MMP-9 (R=0.251, P<0.001), and cleaved caspase-3 (R=0.142, P=0.036) activity measured in a neighboring segment. Dual immunohistochemical examination confirmed the location of MMP-12 in a subpopulation of MMP-8– and MMP-9–positive FCMs, whereas all apoptotic FCMs were MMP-12 positive. Patients who yielded plaques within the highest quartile compared with the lowest quartile of MMP-12/CD68 ratio had a 2.4-fold (hazard ratio, 2.4; 95% CI, 1.1- to 5.1-fold; adjusted P=0.027) increased risk of major adverse cardiovascular event and a 3.4-fold (3.4; 1.2- to 9.6-fold, P=0.024) increased risk for stroke. CONCLUSIONS: The prevalence of an MMP-12–positive subset of FCMs is a prognostic marker for adverse clinical outcome after CEA

Type 2 diabetes is not associated with an altered plaque phenotype among patients undergoing carotid revascularization. A histological analysis of 1455 carotid plaques

Aims: Diabetes accelerates progression of atherosclerotic disease, but data on associations between diabetes and advanced atherosclerotic plaque composition are scarce. Methods and results: We used one of the largest biobanks, the Athero-Express study (n = 1455) at carotid endarterectomy (CEA). All plaques were subjected to histological analysis to assess lipid core size, collagen, macrophages, smooth muscle cells, micro-vessel density and calcifications. In addition, within a subset of patients cytokines and chemokines were assessed. The 295 patients (20%) with type-2 diabetes showed a higher proportion of previous cardiovascular interventions and more stringent treatment for hypertension and hypercholesterolaemia compared with patients without type-2 diabetes. Surprisingly, no associations between diabetes and histological plaque characteristics were observed. In addition, no differences were observed in the expression of inflammatory chemokines, cytokines or advanced glycation end products in plaques of diabetic and non-diabetic patients. Conclusion: In patients suffering from significant carotid artery disease, diabetes does not appear to be associated with specific atherosclerotic plaque characteristics