Clinical relevance of clonal hematopoiesis in persons aged ≥80 years.

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged ≥80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged ≥80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged ≥80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged ≥80 years, with the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged ≥80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged ≥80 years. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.

Cost-Effectiveness of Open Repair of Abdominal Aortic Aneurysms with a Novel Perioperative Protocol.

BACKGROUND: In 2015, a novel perioperative protocol (nPOP), comprising of 19 evidence-based interventions, was adopted as a standard practice for open repair of abdominal aortic aneurysms (AAA) at the Humanitas Clinical and Research Center (Milan, Italy). Its implementation translated into lower complication rates, faster ambulation and return of bowel function, better nausea/vomiting and pain control, and, consequently, a shorter length of hospital stay. Because value of a patient's care cycle can be defined as clinical outcomes relative to costs, we aimed to analyze the cost-effectiveness of nPOP compared to the previously implemented protocols. METHODS: Three groups were identified and retrospectively analyzed: (A) 66 patients (September 2007 to March 2009) treated according to the traditional protocol; (B) 225 patients (April 2009 to March 2015) treated in line with a transitional protocol, incorporating 5 perioperative interventions; and (C) 103 patients (April 2015 to February 2019) treated according to nPOP. For each group a monetary value of required clinical resources and the actual total cost per patient from admission to discharge were determined. The following were analyzed (including nurse and anesthesiologist time): diagnostic tests, medications, materials, operating time, surgical team time, blood transfusion, ward stay, and intensive care unit stay. Two indicators of effectiveness were determined based on the postoperative outcomes: complication-free incidents and relative shortening of hospitalization time. A cost (€) of an improvement in effectiveness (%) was calculated. RESULTS: Alongside enhancement of clinical outcomes, nPOP constituted the cheapest approach. It consumed the least human and material resources, resulting in the direct reduction in the overall clinical cost per patient. The length-of-stay variable provided the largest reduction in total costs. The actual total clinical cost per patient in Group C was 26% lower than in Group A (4,437€ vs. 6,005€) and 39% lower than in Group B (4,437€ vs. 7,305€). Every unit of enhancement of clinical outcomes was 2.43 times more expensive for the traditional protocol and 2.23 times more costly for the transitional protocol compared to nPOP, making it the most cost-effective. CONCLUSIONS: The nPOP for AAA open repair is not inferior to other perioperative protocols while allowing for efficient utilization of limited hospital resources, thus creating a high social value. The proposed methods for cost-effectiveness analysis are easily reproducible and therefore can be applied in future projects ranging from a micro- to a macro-economic scale.

The epigenetic enzyme DOT1L orchestrates vascular smooth muscle cell-monocyte crosstalk and protects against atherosclerosis via the NF-κB pathway.

AIMS: Histone H3 dimethylation at lysine 79 is a key epigenetic mark uniquely induced by methyltransferase disruptor of telomeric silencing 1-like (DOT1L). We aimed to determine whether DOT1L modulates vascular smooth muscle cell (VSMC) phenotype and how it might affect atherosclerosis in vitro and in vivo, unravelling the related mechanism. METHODS AND RESULTS: Gene expression screening of VSMCs stimulated with the BB isoform of platelet-derived growth factor led us to identify Dot1l as an early up-regulated epigenetic factor. Mouse and human atherosclerotic lesions were assessed for Dot1l expression, which resulted specifically localized in the VSMC compartment. The relevance of Dot1l to atherosclerosis pathogenesis was assessed through deletion of its gene in the VSMCs via an inducible, tissue-specific knock-out mouse model crossed with the ApoE-/- high-fat diet model of atherosclerosis. We found that the inactivation of Dot1l significantly reduced the progression of the disease. By combining RNA- and H3K79me2-chromatin immunoprecipitation-sequencing, we found that DOT1L and its induced H3K79me2 mark directly regulate the transcription of Nf-κB-1 and -2, master modulators of inflammation, which in turn induce the expression of CCL5 and CXCL10, cytokines fundamentally involved in atherosclerosis development. Finally, a correlation between coronary artery disease and genetic variations in the DOT1L gene was found because specific polymorphisms are associated with increased mRNA expression. CONCLUSION: DOT1L plays a key role in the epigenetic control of VSMC gene expression, leading to atherosclerosis development. Results identify DOT1L as a potential therapeutic target for vascular diseases.

Long term follow-up after balloon expandable covered stents implantation for management of transcatheter aortic valve replacement related vascular access complications.

OBJECTIVES: To report the experience of a high-volume center with balloon-expandable (BE) stents implantation to manage vascular complications after transcatheter aortic valve replacement (TAVR). BACKGROUND: Despite increased operator experience and better devices, vascular complications after TAVR are still a major issue and covered stent implantation is often required. METHODS: We retrospectively collected baseline and procedural data about 78 consecutive patients who underwent BE stent implantation to manage a vascular complication after transfemoral TAVR. Primary endpoints were technical success, incidence of new-onset claudication and need for vascular interventions during long-term follow-up. Secondary endpoints included length of hospitalization, in-hospital and 30-day mortality, and major postoperative complications. RESULTS: BE stents implantation to manage vascular complications after TAVR was successfully performed in 96.2% of the cases, with bailout surgery required in two cases. One patient suffered in-hospital death. Predischarge Doppler Ultrasound revealed no cases of in-stent occlusion or fracture. At a median follow-up of 429 days (interquartile range, 89-994 days), no cases of symptomatic leg ischemia were reported and only one patient experienced new-onset claudication. CONCLUSIONS: Our experience showed good periprocedural and long-term results of BE covered stent implantation to manage vascular complication after TAVR. Their great radial outward force may guarantee effective hemostasis without necessarily being associated with stent deformation/fracture resulting in restenosis or further interventions. More research is needed to define the role of BE covered stents in this setting.

miR-128-3p Is a Novel Regulator of Vascular Smooth Muscle Cell Phenotypic Switch and Vascular Diseases.

RATIONALE: MicroRNAs (miRNAs, miRs) are small noncoding RNAs that modulate gene expression by negatively regulating translation of target genes. Although the role of several miRNAs in vascular smooth muscle cells (VSMCs) has been extensively characterized, the function of miRNA-128-3p (miR-128) is still unknown. OBJECTIVE: To determine if miR-128 modulates VSMC phenotype and to define the underlying mechanisms. METHODS AND RESULTS: We screened for miRNAs whose expression is modulated by an altered DNA methylation status in VSMCs, and among the hits, we selected miR-128. We found that miR-128 was expressed in various tissues, primary murine cells, and pathological murine and human vascular specimens. Through gain- and loss-of-function approaches, we determined that miR-128 affects VSMC proliferation, migration, differentiation, and contractility. The alterations of those properties were dependent upon epigenetic regulation of key VSMC differentiation genes; notably, Kruppel-like factor 4 was found to be a direct target of miR-128 and able to modulate the methylation status of the pivotal VSMC gene myosin heavy chain 11 (Myh11). Finally, in vivo lentiviral delivery of miR-128 prevented intimal hyperplasia in a mouse model of carotid restenosis without modifying vital cardiovascular parameters. CONCLUSION: miR-128 is a critical modulator of VSMCs and is regulated by epigenetic modifications upon stress. Its modulation in the context of disease could be exploited for therapeutic purposes.

Implementation of a perioperative protocol to enhance open aortic repair.

BACKGROUND: Although appreciated for its long-term benefits, open repair of abdominal aortic aneurysms (AAA) is associated with a significant perioperative burden. Enhanced recovery and fast track protocols have improved surgical outcomes in many specialties, but remain scarcely applied in the vascular field. METHODS: Based on the applied perioperative protocol in a single-center experience, three consecutive study groups were identified among 394 consecutive patients undergoing elective AAA open repair in the last 12 years. Group A included 66 patients who underwent traditional surgery, group B comprised 225 patients treated according to a partially adopted perioperative protocol, and group C consisted of 103 patients, operated in line with a complete perioperative protocol. The aim of this study was to evaluate the impact of the perioperative protocol on recovery time by measuring complication rates, analgesic and antiemetic control, and return of bowel function and ambulation, as well as the length of hospitalization. RESULTS: The study groups had similar baseline characteristics. A significant improvement was noted in the complication rates (P = .019) and hospitalization time (P < .001) following a complete implementation of the perioperative protocol, where the median hospitalization time was 3 days. No mortality and no readmissions within 30 postoperative days were recorded in this group. There was an improvement in pain levels, as well as postoperative nausea and vomiting control (P < .001). CONCLUSIONS: Perioperative protocol implementation in AAA open repair is feasible; the clinical outcomes may be improved when strictly adhering to the protocol. All the applied perioperative management interventions seem to have a synergic effect on shortening the recovery time.

Circ_Lrp6, a Circular RNA Enriched in Vascular Smooth Muscle Cells, Acts as a Sponge Regulating miRNA-145 Function.

RATIONALE: microRNAs (miRNAs) modulate gene expression by repressing translation of targeted genes. Previous work has established a role for miRNAs in regulating vascular smooth muscle cell (VSMC) activity. Whether circular RNAs are involved in the modulation of miRNA activity in VSMCs is unknown. OBJECTIVE: We aimed to identify circular RNAs interacting with miRNAs enriched in VSMCs and modulating the cells' activity. METHODS AND RESULTS: RNA sequencing and bioinformatics identified several circular RNAs enriched in VSMCs; however, only one, possessing multiple putative binding sites for miR-145, was highly conserved between mouse and man. This circular RNA gemmed from alternative splicing of Lrp6 (lipoprotein receptor 6), a gene highly expressed in vessels and implicated in vascular pathologies and was thus named circ_Lrp6. Its role as a miR-145 sponge was confirmed by determining reciprocal interaction through RNA immunoprecipitation, stimulated emission depletion microscopy, and competitive luciferase assays; functional inhibition of miR-145 was assessed by measuring expression of the target genes ITGß8 (integrin-ß8), FASCIN (fascin actin-bundling protein 1), KLF4 (Kruppel-like factor 4), Yes1 (YES proto-oncogene 1), and Lox (lysyl oxidase). The interaction was preferentially localized to P-bodies, sites of mRNA degradation. Using loss- and gain-of-function approaches, we found that circ_Lrp6 hindered miR-145-mediated regulation of VSMC migration, proliferation, and differentiation. Differential expression of miR-145 and circ_Lrp6 in murine and human vascular diseases suggests that the ratio of circ_Lrp6 bound to miR-145 versus unbound could play a role in vascular pathogenesis. Viral delivery of circ_Lrp6 shRNA prevented intimal hyperplasia in mouse carotids. CONCLUSIONS: circ_Lrp6 is an intracellular modulator and a natural sponge for miR-145, counterbalancing the functions of the miRNA in VSMCs.

Clinical Diagnosis and Treatment of Internal Jugular Venous Aneurysms.

BACKGROUND: The aneurysms of internal jugular vein (IJV) are very rare and hence scarcely described in the literature. Owing to the lack of guidelines on the treatment paradigm of this condition, management strategies vary. METHODS: Six patients presenting in our institution with internal jugular venous aneurysms from September 2007 to August 2017 were retrospectively analyzed. RESULTS: IJV aneurysms were confirmed in all 6 patients. For 3 of them, a surgical treatment was deemed necessary. These were 2 patients with intravenous thrombosis and 1 patient with progressive aneurysmal enlargement during the initial monitoring period. The choice of surgical technique was based on aneurysm morphology: 2 patients with saccular aneurysms underwent tangential aneurysmectomy with lateral venorrhaphy, and a patient presenting a fusiform aneurysm underwent its total excision followed by IJV ligation. Three remaining patients were managed conservatively, with one of them fully regressing and the other 2 remaining asymptomatic. CONCLUSIONS: IJV aneurysms are very rare and usually of benign natural history. For asymptomatic patients, conservative treatment with close follow-up is generally recommended. If any accompanying signs or symptoms are present, such as pain, swelling, evidence of thrombosis, progressive enlargement, or severe psychological stress, timely and appropriate surgical intervention should ensue.

Unconventional Endovascular Access for Symptomatic Thoracic Aortic Ulcer with Infrarenal Aortic Occlusion-A Case Report.

BACKGROUND: A man in very poor general condition was admitted for acute thrombosis of the infrarenal aorta associated to a penetrating aortic ulcer (PAU) of the distal thoracic aorta. METHODS: We planned a two-stage procedure: an axillobifemoral revascularization to be followed by thoracic endovascular aortic repair (TEVAR) after rehabilitation. Before the second stage, the patient presented with acute respiratory failure secondary to an abrupt PAU evolution. RESULTS: A properly selected stent graft was successfully deployed in an antegrade manner through a left axillary artery access with the nose of the delivery system pushed over a guidewire deep into the aortic thrombosis. CONCLUSIONS: Inadequate access and paraplegia are the major challenges hampering clinical success of TEVAR. Off-the-shelf stent graft can be used outside its primary use in an unconventional setting. Careful planning, consideration of all comorbidities and vascular anatomy, as well as correct choice of the device are crucial for the successful treatment.

Paraplegia Due to Spinal Cord Ischemia after Endovascular Treatment of a Type II Endoleak.

Type II endoleaks are a common complication after endovascular abdominal aortic aneurysm repair, with transarterial embolization using synthetic surgical glue being an established treatment option. We report a case of paraplegia due to spinal cord ischemia after lumbar arteries embolization by Glubran-lipiodol glue for a type II endoleak. Special attention must be given by interventional specialists when applying surgical diluted glues for the treatment of type II endoleaks to avoid distal embolization and subsequent spinal cord ischemia.

Endovascular Treatment of Post-traumatic Superior Mesenteric Arteriovenous Fistula: A Case Report.

Superior mesenteric arteriovenous fistulae (SMAVFs) are extremely rare with no consensus about therapeutic indications and optimal approach. Here, we present a case of a symptomatic SMAVF found in a young patient a few years after a penetrating abdominal injury. Following a complex clinical management of the acute status, we successfully managed the fistula with 3 covered stents in 2 consecutive endovascular procedures. Technical details of the performed procedures, including the main pitfalls and chosen solutions, have been explored and discussed.

Transarterial Endoleak Closure After Endovascular Thoracoabdominal Aneurysm Repair: When the "Sandwich" Goes Wrong.

PURPOSE: To describe the use of vascular plugs to close a complex type Ib endoleak following the sandwich procedure used in conjunction with endovascular thoracoabdominal aortic aneurysm (TAAA) repair. CASE REPORT: A 59-year-old man with a 6.5-mm TAAA was treated with initial deployment proximally of 2 Zenith TX2 stent-grafts. In preparation for the sandwich technique to preserve flow to the celiac trunk, a 10×100-mm Viabahn covered stent was delivered from a brachial access into the celiac trunk unprotected by the sheath of the introducer. The trigger wire system became snagged on the struts of the distal aortic stent-graft; when the wire was pulled, the proximal end of the Viabahn migrated outside the aortic stent-graft, which migrated upward. The main body extension intended for the aortic component of the sandwich technique was deployed close to the distal end of the aneurysm sac, but a large type Ib endoleak formed in the gutter between the Viabahn, aortic extension, and sac wall. The leak perfused the celiac trunk, and the procedure was terminated. Increasing sac size on 3-month imaging prompted closure of the leak with 2 type II Amplatzer vascular plugs aiming to occlude the endoleak outflow into the Viabahn and the endoleak outflow at the site of the gutter. Imaging follow-up at 6 months demonstrated successful exclusion of the TAAA with no residual endoleak and excellent perfusion of the celiac trunk. CONCLUSION: Transarterial treatment of complex endoleaks is feasible when preceded by meticulous imaging and detailed preprocedural planning.

Use of a novel hybrid vascular graft for sutureless revascularization of the renal arteries during open thoracoabdominal aortic aneurysm repair.

OBJECTIVE: The aim of this study was to assess the safety and short-term effectiveness of a novel hybrid vascular graft used to address renal revascularization during open thoracoabdominal aortic aneurysm (TAAA) repair, performing a sutureless distal anastomosis. METHODS: Between 2012 and 2013, 25 patients (16 men; mean age, 66 ± 8 years) underwent revascularization of one (24 patients) or both (one patient) renal arteries with the Gore Hybrid Vascular Graft (GHVG; W. L. Gore and Associates, Flagstaff, Ariz) during open TAAA repair. Specific indications included remote location of the ostium of the renal artery, severe atherosclerotic wall degeneration, focal dissection, and stenosis. All surviving patients underwent computed tomography angiography and follow-up visit at 1 month. Preoperative characteristics, intraoperative data, and short-term results were compared with those of 49 concurrent TAAA patients operated on within the same period by standard renal revascularization (SRR) techniques. RESULTS: All GHVG target renal vessels (26 of 26) were successfully revascularized without technical concerns. No significant differences were found between GHVG and SRR groups in preoperative and intraoperative data, except for a relative prevalence of aortic dissection (28% vs 6%; P = .026) and renal artery stenosis (44% vs 12%; P = .003) in the GHVG group and for intraoperative renal bare stenting that was predominantly used in the SRR group (12% vs 28%; P = .036). The 30-day mortality was 4% in both groups. Postoperative acute renal failure (doubling of creatinine level and creatinine level >3.0 mg/dL) occurred in two GHVG patients (8%) and seven SRR patients (14%; P = NS). Perioperative peak decrease of estimated glomerular filtration rate was lower in the GHVG group (26 ± 18 mL/min/1.73 m(2) vs 37 ± 22 mL/min/1.73 m(2); P = .034). At 1-month computed tomography angiography, renal artery patency was 92% for the GHVG vessels, 91% for the contralateral to GHVG renal vessels, and 92% for the SRR group arteries. No GHVG-related complications requiring reintervention or cases of new-onset renal failure requiring dialysis were observed at follow-up. CONCLUSIONS: Renal revascularization during open TAAA repair by the GHVG with distal sutureless anastomosis is feasible, especially in cases of aortic dissection, remote location of the renal vessel, and severe atherosclerotic disease of the ostium. Short-term results are satisfactory, at least comparable to those of SRR. Larger series and longer follow-up are needed to assess clinical advantages and durability of this new device.

Role of Cine-Magnetic Resonance Imaging in the Assessment of Mediastinal Masses with Uncertain/Equivocal Findings from Pre-Operative Computed Tomography Scanning.

BACKGROUND: Malignant neoplasms originating from or involving the mediastinum represent a diagnostic and therapeutic challenge when they are in contact with nearby cardiovascular structures. We aimed to test the diagnostic accuracy of cine-magnetic resonance imaging (cine-MRI) in detecting the infiltration of cardiovascular structures in cases with uncertain or equivocal findings from contrast-enhanced Computed Tomography (CT) scanning. METHODS: Fifty patients affected by tumors with a suspected invasion of mediastinal cardiovascular structures at the pre-operative chest CT scan stage underwent cine-MRI before surgery at our Institution. Intraoperative findings and the histological post-surgical report were used as a reference standard to define infiltration. Inter- and intra-observer agreement for CT scans and cine-MRI were also computed over a homogenous sample of 14 patients. RESULTS: Cine-MRI had a higher negative predictive value (93% vs. 54%, p < 0.001) than CT scans, higher sensitivity (91% vs. 16%, p < 0.001), as well as greater accuracy (66% vs. 50%, p < 0.001) in detecting cardiovascular invasion. Cine-MRI also showed better inter- and intra-observer agreement for infiltration detection. CONCLUSIONS: Cine-MRI outperforms conventional contrast-enhanced chest CT scans in the preoperative assessment of cardiovascular infiltration by mediastinal or pulmonary tumors, making it a useful imaging modality in the preoperative staging and evaluation of patients with equivocal findings at the chest CT scan stage.