Deficiency of lncRNA MERRICAL abrogates macrophage chemotaxis and diabetes-associated atherosclerosis.

Diabetes-associated atherosclerosis involves excessive immune cell recruitment and plaque formation. However, the mechanisms remain poorly understood. Transcriptomic analysis of the aortic intima in Ldlr-/- mice on a high-fat, high-sucrose-containing (HFSC) diet identifies a macrophage-enriched nuclear long noncoding RNA (lncRNA), MERRICAL (macrophage-enriched lncRNA regulates inflammation, chemotaxis, and atherosclerosis). MERRICAL expression increases by 249% in intimal lesions during progression. lncRNA-mRNA pair genomic mapping reveals that MERRICAL positively correlates with the chemokines Ccl3 and Ccl4. MERRICAL-deficient macrophages exhibit lower Ccl3 and Ccl4 expression, chemotaxis, and inflammatory responses. Mechanistically, MERRICAL guides the WDR5-MLL1 complex to activate CCL3 and CCL4 transcription via H3K4me3 modification. MERRICAL deficiency in HFSC diet-fed Ldlr-/- mice reduces lesion formation by 74% in the aortic sinus and 86% in the descending aorta by inhibiting leukocyte recruitment into the aortic wall and pro-inflammatory responses. These findings unveil a regulatory mechanism whereby a macrophage-enriched lncRNA potently inhibits chemotactic responses, alleviating lesion progression in diabetes.

Discrepancies in clavicle-to-carotid bifurcation length measurements for transcarotid artery revascularization using different imaging modalities.

OBJECTIVE: Transcarotid artery revascularization (TCAR) has emerged as an effective method for carotid artery stenting. However, anatomic eligibility for TCAR is most often limited by an inadequate clavicle-to-carotid bifurcation length of <5 cm. Preoperative clavicle-to-carotid bifurcation distances may be underestimated when using conventional straight-line measurements on computed tomographic angiography (CTA) imaging. We therefore compared clavicle-to-carotid bifurcation lengths as measured by straight-line CTA, center-line CTA, and intraoperative duplex ultrasound (US), to assess potential differences. METHODS: We conducted a single-center, retrospective review of consecutive TCAR procedures performed between 2016 and 2019 for atherosclerotic carotid disease. For each patient, we compared clavicle-to-carotid bifurcation lengths measured by straight-line CTA, center-line CTA using TeraRecon image reconstruction, and intraoperative duplex US with neck extension and rotation. We further assessed patient and imaging characteristics in individuals with a ≥0.5 cm difference among the measurement methods. In particular, common carotid artery (CCA) tortuosity, defined as the inability to visualize the entire CCA from clavicle to carotid bifurcation on both a single coronal and sagittal imaging cut, was examined as a contributing factor for these discrepancies. RESULTS: Of the 70 TCAR procedures identified, 46 had all three imaging modalities available for review. The median clavicle-to-carotid bifurcation length was found to be 6.4 cm (interquartile range [IQR], 5.4-6.7 cm) on straight-line CTA, 7.0 cm (IQR, 6.0-7.5 cm) on intraoperative duplex US, and 7.2 cm (IQR, 6.5-7.5 cm) on center-line CTA (P < .001). Patients with a ≥0.5 cm difference between their straight-line CTA and either their intraoperative duplex US or center-line CTA measurements were more likely to have tortuous CCAs (60.0% vs 19.1%; P = .01; 51.4% vs 0.0%; P = .01). There were no notable differences in age, gender, prior neck/cervical spine surgery, or neck immobility among these individuals. In patients with tortuous CCAs, duplex US and center-line CTA measurements added 1.0 cm (IQR, 0.6-1.5 cm) and 1.1 cm (IQR, 0.9-1.6 cm) more in length than straight-line CTA measurements, respectively. There was a strong linear correlation between the additional lengths provided by duplex US measurements and those provided by center-line CTA measurements for each individual within the tortuous CCA group (r = 0.83). CONCLUSIONS: The use of straight-line CTA during preoperative planning can underestimate the clavicle-to-carotid bifurcation lengths in patients undergoing carotid revascularization, particularly in those with tortuous CCAs. Both duplex US performed with extended-neck surgical positioning and center-line CTA provide similar and longer carotid length measurements, and should be utilized in patients with tortuous carotid vessels to better determine TCAR anatomic eligibility.

Thoracic endovascular aortic repair of metachronous thoracic aortic aneurysms following prior infrarenal abdominal aortic aneurysm repair.

OBJECTIVE: Thoracic endovascular aortic repair (TEVAR) of metachronous thoracic aortic aneurysms (M-TAAs) following previous infrarenal abdominal aortic aneurysm (AAA) repair has been associated with higher spinal cord ischemia (SCI) risk compared with TEVAR of primary thoracic aortic aneurysms (TAAs). However, data on the impact of the type of prior infrarenal aortic repair on outcomes are scarce. In this study, we examined perioperative outcomes and long-term mortality following TEVAR M-TAA compared with primary TEVAR of TAA. METHODS: We identified all Vascular Quality Initiative (VQI) patients who underwent TEVAR of TAA in the descending thoracic aorta from 2013 to 2022. Only patients undergoing primary TEVAR or TEVAR following infrarenal open (OAR) or endovascular (EVAR) repair were included. We performed univariate analyses to identify differences in baseline and procedural characteristics, and multivariable analyses for perioperative outcomes and 5-year mortality using logistic and Cox regression, respectively. RESULTS: We included 1493 patients who underwent primary TEVAR (81%) or TEVAR following prior OAR (9.0%) or prior EVAR (9.7%). Compared with primary TEVAR, patients undergoing TEVAR M-TAA were older, more commonly male, white, and had higher rates of hypertension, smoking, and renal dysfunction. Patients with M-TAA were more likely to be asymptomatic and have larger diameters at presentation but were exposed to greater contrast volume and procedural times relative to primary TEVAR patients. Following risk-adjustment, compared with primary TEVAR, TEVAR after prior EVAR was associated with higher perioperative mortality (9.7% vs 3.9%; odds ratio [OR], 5.3; 95% confidence interval [CI], 2.3-12; P < .001) and 5-year mortality (40% vs 24%; hazard ratio [HR], 2.1; 95% CI, 1.4-3.1; P = .001). Specifically, among octogenarians (n = 375; 25%), the perioperative and 5-year mortality differences were even more pronounced (perioperative mortality: 17% vs 8.4%; OR, 6.7; 95% CI, 2.2-21; P = .001; 5-year mortality: 50% vs 27%; HR, 3.0; 95% CI, 1.5-5.7; P = .010). However, in-hospital complications, including SCI (2.6% vs 2.8%; OR, 1.2; 95% CI, 0.33-3.3; P = .77), were not notably different. In contrast, TEVAR after previous OAR was associated with comparable perioperative mortality (4.4% vs 3.9%; OR, 1.2; 95% CI, 0.32-3.8; P = .73), 5-year mortality (28% vs 24%; HR, 1.3; 95% CI, 0.80-2.1; P = .54), and in-hospital complications, including SCI (2.6% vs 0.7%; OR, 0.21; 95% CI, 0.01-1.1; P = .16). CONCLUSIONS: Patients undergoing TEVAR of M-TAAs after prior EVAR, particularly octogenarians, have higher perioperative and 5-year mortality and therefore, represent a high-risk group. Future efforts should strive to discern the underlying factors leading to these poorer outcomes; meanwhile, these findings emphasize the need for careful patient selection and appropriate preoperative counseling in these high-risk individuals.

Impaired angiogenesis in diabetic critical limb ischemia is mediated by a miR-130b/INHBA signaling axis.

Patients with peripheral artery disease (PAD) and diabetes compose a high-risk population for development of critical limb ischemia (CLI) and amputation, although the underlying mechanisms remain poorly understood. Comparison of dysregulated microRNAs from diabetic patients with PAD and diabetic mice with limb ischemia revealed the conserved microRNA, miR-130b-3p. In vitro angiogenic assays demonstrated that miR-130b rapidly promoted proliferation, migration, and sprouting in endothelial cells (ECs), whereas miR-130b inhibition exerted antiangiogenic effects. Local delivery of miR-130b mimics into ischemic muscles of diabetic mice (db/db) following femoral artery ligation (FAL) promoted revascularization by increasing angiogenesis and markedly improved limb necrosis and amputation. RNA-Seq and gene set enrichment analysis from miR-130b-overexpressing ECs revealed the BMP/TGF-ß signaling pathway as one of the top dysregulated pathways. Accordingly, overlapping downregulated transcripts from RNA-Seq and miRNA prediction algorithms identified that miR-130b directly targeted and repressed the TGF-ß superfamily member inhibin-ß-A (INHBA). miR-130b overexpression or siRNA-mediated knockdown of INHBA induced IL-8 expression, a potent angiogenic chemokine. Lastly, ectopic delivery of silencer RNAs (siRNA) targeting Inhba in db/db ischemic muscles following FAL improved revascularization and limb necrosis, recapitulating the phenotype of miR-130b delivery. Taken together, a miR-130b/INHBA signaling axis may provide therapeutic targets for patients with PAD and diabetes at risk of developing CLI.

Staged autogenous to prosthetic hemodialysis access creation strategy to maximize forearm options.

OBJECTIVE: When an adequate cephalic vein is not available for fistula construction, surgeons often turn to basilic vein or prosthetic constructions. Single-stage forearm prosthetic hemodialysis accesses are associated with poor durability, and upper arm non-autogenous access options are often limited by axillary outflow failure, which inevitably drives transition to the contralateral arm or lower extremity. We hypothesized that initial creation of a modest flow proximal forearm arterial-venous anastomosis to dilate ("develop") inflow and outflow vessels, followed by a planned second-stage procedure to create a cannulation zone with a prosthetic graft in the forearm, would result in reliable and durable hemodialysis access in patients with limited options. METHODS: We performed an institutional cohort study from 2017 to 2021 using a prospectively maintained database supplemented with adjudicated chart review. Patients without traditional autogenous hemodialysis access options in the forearm underwent an initial non-wrist arterial-venous anastomosis creation in the forearm as a first stage, followed by a second-stage interposition graft sewn to the existing inflow and venous outflow segments to create a useable cannulation zone in the forearm while leveraging vascular development. Outcomes included time from second-stage access creation to loss of primary and secondary patency, frequency of subsequent interventions, and perioperative complications. RESULTS: The cohort included 23 patients; first-stage radial artery-based (74%) configurations were more common than brachial artery-based (26%). Mean age was 63 years (standard deviation, 14 years), and 65% were female. Median follow-up was 340 days (interquartile range [IQR], 169-701 days). Median time to cannulation from second-stage procedure was 28 days (IQR, 18-53 days). Primary, primary assisted, and secondary patency at 1 year was 16.7% (95% confidence interval [CI], 5.3%-45.8%), 34.6% (95% CI, 15.2%-66.2%), and 95.7% (95% CI, 81.3%-99.7%), respectively. Subsequent interventions occurred at a rate of 3.02 (IQR, 1.0-4.97) per person-year, with endovascular thrombectomy with or without angioplasty/stenting (70.9%) being the most common. There were no cases of steal syndrome. Infection occurred in two cases and were managed with antibiotics alone. CONCLUSIONS: For patients without adequate distal autogenous access options, staged prosthetic graft placement in the forearm offers few short-term complications and excellent durability with active surveillance while strategically preserving the upper arm for future constructions.

Impact of neighborhood social disadvantage on carotid artery disease presentation, management, and discharge outcomes.

OBJECTIVE: Recent studies have highlighted that race and socioeconomic status serve as important determinants of disease presentation and perioperative outcomes in carotid artery disease. However, these investigations only focus on individual factors of social disadvantage, and fail to account for community factors that may drive disparities. Area Deprivation Index (ADI) is a validated measure of neighborhood adversity that offers a more comprehensive assessment of social disadvantage. We examined the impact of ADI ranking on carotid artery disease severity, management, and postoperative outcomes. METHODS: We identified patients who underwent carotid endarterectomy (CEA), transfemoral carotid artery stenting (tfCAS), and transcarotid artery revascularization (TCAR) in the Vascular Quality Initiative registry between 2016 and 2020. Patients were assigned ADI scores of 1 to 100 based on zip codes and grouped into quintiles, with higher quintiles reflecting increasing adversity. Outcomes assessed included disease presentation, intervention type, and discharge patterns. Logistic regression was used to evaluate independent associations between ADI quintiles and these outcomes. RESULTS: Among 91,904 patients undergoing carotid revascularization, 9811 (10.7%) were in the lowest ADI quintile (Q1), 18,905 (20.6%) in Q2, 25,442 (27.7%) in Q3, 26,099 (28.4%) in Q4, and 11,647 (12.7%) in Q5. With increasing ADI quintiles, patients were more likely to present with symptomatic disease (Q5, 52.1% vs Q1, 46.6%; P < .001), and stroke vs transient ischemic attack (Q5, 63.1% vs Q1, 53.5%; P < .001); they also more frequently underwent CAS vs CEA (Q5, 46.4% vs Q1, 33.9%; P < .001), and specifically tfCAS vs TCAR (Q5, 54.2% vs Q1, 33.9%; P < .001). In adjusted analyses, higher ADI quintiles remained as independent risk factors for presenting with symptomatic disease and stroke and undergoing CAS and tfCAS. Across ADI quintiles, patients were more likely to experience death (Q5, 0.8% vs Q1, 0.4%; P < .001), stroke/death (Q5, 2.1% vs Q1, 1.6%; P = .001), failure to discharge home (Q5, 11.5% vs Q1, 8.0%; P < .001) and length of stay >2 days (Q5, 33.3% vs Q1, 26.3%; P < .001) following revascularization. CONCLUSIONS: Among carotid revascularization patients, those with greater neighborhood social disadvantage had greater disease severity and more frequently underwent tfCAS. These patients also had higher rates of death and stroke/death, were less frequently discharged home, and had prolonged hospital stays. Greater efforts are needed to ensure that patients in higher ADI quintiles undergo better carotid surveillance and are treated appropriately for their carotid artery disease.

A miRNA/CXCR4 signaling axis impairs monopoiesis and angiogenesis in diabetic critical limb ischemia.

Patients with peripheral artery disease (PAD) and diabetes have the highest risk of critical limb ischemia (CLI) and amputation, yet the underlying mechanisms remain incompletely understood. MicroRNA (miRNA) sequencing of plasma from diabetic patients with or without CLI was compared to diabetic mice with acute or subacute limb ischemia to identify conserved miRNAs. miRNA-KO mice on high-fat diet were generated to explore the impact on CLI. Comparison of dysregulated miRNAs from diabetic individuals with PAD and diabetic mice with limb ischemia revealed conserved miR-181 family members. High-fat-fed, diabetic Mir181a2b2-KO mice had impaired revascularization in limbs due to abrogation of circulating Ly6Chi monocytes, with reduced accumulation in ischemic skeletal muscles. M2-like KO macrophages under diabetic conditions failed to produce proangiogenic cytokines. Single-cell transcriptomics of the bone marrow niche revealed that the reduced monocytosis in diabetic KO mice was a result of impaired hematopoiesis, with increased CXCR4 signaling in bone marrow Lineage-Sca1+Kit+ (LSK) cells. Exogenous Ly6Chi monocytes from nondiabetic KO mice rescued the impaired revascularization in ischemic limbs of diabetic KO mice. Increased Cxcr4 expression was mediated by the miR-181 target, Plac8. Taken together, our results show that MiR-181a/b is a putative mediator of diabetic CLI and contributes to changes in hematopoiesis, monocytosis, and macrophage polarization.

Evaluating the Impact of ACGME Resident Duty Hour Restrictions on Patient Outcomes for Bilateral Breast Reductions.

The Accreditation Council for Graduate Medical Education (ACGME) implemented duty-hour restrictions limiting residents to 80 hours per week in 2003 and further extended restrictions in 2011 to improve resident and patient well-being. Numerous studies have examined the effects of these restrictions on patient outcomes with inconclusive results. Few efforts have been made to examine the impact of this reform on the safety of common plastic surgery procedures. This study seeks to assess the influence of ACGME duty-hour restrictions on patient outcomes, using bilateral breast reduction mammoplasty as a marker for resident involvement and operative autonomy. Methods: Bilateral breast reductions performed in the 3 years before and after each reform were collected from the National Inpatient Sample database: pre-duty hours (2000-2002), duty hours (2006-2008), and extended duty hours (2012-2014). Multivariable logistic regression models were constructed to investigate the association between ACGME duty hour restrictions on medical and surgical complications. Results: Overall, 19,423 bilateral breast reductions were identified. Medical and surgical complication rates in these patients increased with each successive iteration of duty hour restrictions (P < 0.001). The 2003 duty-hour restriction independently associated with increased surgical (OR = 1.51, P < 0.001) and medical complications (OR = 1.85, P < 0.001). The 2011 extended duty-hour restriction was independently associated with increased surgical complications (OR = 1.39, P < 0.001). Conclusions: ACGME duty-hour restrictions do not seem associated with better patient outcomes for bilateral breast reduction although there are multiple factors involved. These considerations and consequences should be considered in decisions that affect resident quality of life, education, and patient safety.

MiR-409-3p targets a MAP4K3-ZEB1-PLGF signaling axis and controls brown adipose tissue angiogenesis and insulin resistance.

Endothelial cells (ECs) within the microvasculature of brown adipose tissue (BAT) are important in regulating the plasticity of adipocytes in response to increased metabolic demand by modulating the angiogenic response. However, the mechanism of EC-adipocyte crosstalk during this process is not completely understood. We used RNA sequencing to profile microRNAs derived from BAT ECs of obese mice and identified an anti-angiogenic microRNA, miR-409-3p. MiR-409-3p overexpression inhibited EC angiogenic properties; whereas, its inhibition had the opposite effects. Mechanistic studies revealed that miR-409-3p targets ZEB1 and MAP4K3. Knockdown of ZEB1/MAP4K3 phenocopied the angiogenic effects of miR-409-3p. Adipocytes co-cultured with conditioned media from ECs deficient in miR-409-3p showed increased expression of BAT markers, UCP1 and CIDEA. We identified a pro-angiogenic growth factor, placental growth factor (PLGF), released from ECs in response to miR-409-3p inhibition. Deficiency of ZEB1 or MAP4K3 blocked the release of PLGF from ECs and PLGF stimulation of 3T3-L1 adipocytes increased UCP1 expression in a miR-409-3p dependent manner. MiR-409-3p neutralization improved BAT angiogenesis, glucose and insulin tolerance, and energy expenditure in mice with diet-induced obesity. These findings establish miR-409-3p as a critical regulator of EC-BAT crosstalk by modulating a ZEB1-MAP4K3-PLGF signaling axis, providing new insights for therapeutic intervention in obesity.

Endovascular Snare Facilitates Difficult Transfemoral Target Vessel Cannulation During Fenestrated and Branched Endovascular Aortic Aneurysm Repair.

We developed a novel technique using an endovascular snare system to stabilize target vessel cannulation via transfemoral access during fenestrated and branched endovascular aortic aneurysm repair (FBEVAR) in patients with challenging target vessel anatomy. This technique uses a snare, an outer sheath, and an inner delivery sheath to facilitate target vessel cannulation and stenting during FBEVAR. With the outer sheath positioned in the lower end of the partially deployed aortic graft and the delivery sheath within, a large snare is advanced through the outer sheath and over the outside of the delivery sheath until it reaches the curved portion of the delivery sheath at the level of the target vessel. The snare is then tightened to provide stability and maintain proper curvature and alignment of the delivery sheath while the target vessel is selected and stented. Following successful passage, the snare is loosened and removed from the body via the outer sheath. This snare technique is a simple, effective, and inexpensive tool that can be used for difficult target vessel cannulation during FBEVAR.

Surgical treatment patterns and clinical outcomes of patients treated for expanding aneurysm sacs with type II endoleaks after endovascular aneurysm repair.

OBJECTIVE: Persistent type II endoleaks (T2ELs) after endovascular aneurysm repair (EVAR) with sac growth have been associated with adverse events, including rupture. Whereas intervention in the presence of aneurysm growth has become an accepted treatment paradigm for T2ELs, the efficacy and clinical success of such interventions remain unclear. Therefore, we examined the treatment patterns and clinical outcomes of patients undergoing T2EL interventions after EVAR. METHODS: We performed a retrospective review of all patients treated for expanding aneurysm sacs with T2ELs after EVAR at an academic medical center between 2006 and 2017. The primary outcomes assessed were need for repeated intervention; intervention types; and achievement of clinical success, defined as stable aneurysm sac size on computed tomography angiography after treatment. RESULTS: Fifty-six patients underwent 119 interventions, of which 107 (90%) were technically successful. The median time from EVAR to index T2EL procedure was 37 months (interquartile range, 17-56 months), and the median follow-up time from first T2EL procedure was 27 months (interquartile range, 10-51 months). The most common index procedure was transarterial lumbar embolization (64%), followed by transarterial inferior mesenteric artery (20%), transcaval (14%), and translumbar embolization (1.8%). Thirty-three (59%) patients required further procedures for persistent aneurysm sac expansion. For subsequent T2EL interventions, the most common endovascular procedure was transarterial lumbar embolization (21%), followed by transcaval (21%), translumbar (11%), and transarterial inferior mesenteric artery embolization (8.6%). Twelve patients (21%) were found to have loss of proximal or distal seal on subsequent imaging and required graft extensions to stabilize aneurysm sac size. Ten patients (18%) ultimately underwent graft explantation or sacotomy with oversewing of the endoleak source. Freedom from any endoleak-related reintervention was 57% at 1 year and 36% at 3 years. Freedom from open treatment was 93% at 1 year and 82% at 3 years. Of the 44 patients with ≥6-month follow-up, 39 (89%) achieved clinical success. However, only 11 patients (25%) achieved clinical success without any further reintervention, and 29 patients (66%) achieved clinical success without open treatment. CONCLUSIONS: Despite high technical success, endoleak recurrence after T2EL treatment is common, and multiple interventions are often needed to stabilize aneurysm sac size in patients diagnosed with T2EL-associated sac growth. Notably, one in five patients treated for T2ELs was discovered, on further evaluation, to have proximal or distal seal zone loss that necessitated repair to achieve sac stability. Thus, thorough assessment of all endoleak types should be performed in patients with T2ELs associated with sac growth before T2EL treatment to ensure appropriate care and to minimize ineffective interventions.

Trib1 regulates T cell differentiation during chronic infection by restraining the effector program.

In chronic infections, the immune response fails to control virus, leading to persistent antigen stimulation and the progressive development of T cell exhaustion. T cell effector differentiation is poorly understood in the context of exhaustion, but targeting effector programs may provide new strategies for reinvigorating T cell function. We identified Tribbles pseudokinase 1 (Trib1) as a central regulator of antiviral T cell immunity, where loss of Trib1 led to a sustained enrichment of effector-like KLRG1+ T cells, enhanced function, and improved viral control. Single-cell profiling revealed that Trib1 restrains a population of KLRG1+ effector CD8 T cells that is transcriptionally distinct from exhausted cells. Mechanistically, we identified an interaction between Trib1 and the T cell receptor (TCR) signaling activator, MALT1, which disrupted MALT1 signaling complexes. These data identify Trib1 as a negative regulator of TCR signaling and downstream function, and reveal a link between Trib1 and effector versus exhausted T cell differentiation that can be targeted to improve antiviral immunity.

Anterior nutcracker syndrome in the setting of a duplicated inferior vena cava.

Nutcracker syndrome is a rare vascular disorder that involves compression of the left renal vein (LRV), most often at the level of the aortomesenteric angle. In some cases, this compression syndrome arises in the setting of unusual vascular anatomic variants. We describe the case of a 43-year-old woman with a duplicated inferior vena cava who was found to have LRV compression on magnetic resonance angiography and venography with intravascular ultrasound. The patient was successfully treated with concurrent transposition of the LRV and left-sided inferior vena cava, with complete resolution of symptoms.

MiR-4674 regulates angiogenesis in tissue injury by targeting p38K signaling in endothelial cells.

Neoangiogenesis is critical for tissue repair in response to injury such as myocardial ischemia or dermal wound healing. MicroRNAs are small noncoding RNAs and important regulators of angiogenesis under physiological and pathological disease states. Therefore, identification of microRNAs that may restore impaired angiogenesis in response to tissue injury may provide new targets for therapy. Using a microRNA microarray profiling approach, we identified a human-specific microRNA, miR-4674, that was significantly decreased in patients after myocardial tissue injury and had an endothelial cell (EC)-enriched expression pattern. Functionally, overexpression of miR-4674 markedly attenuated EC proliferation, migration, network tube formation, and spheroid sprouting, whereas blockade of miR-4674 had the opposite effects. Transcriptomic profiling, gene set enrichment analyses, bioinformatics, 3'-untranslated region (3'-UTR) reporter and microribonucleoprotein immunoprecipitation (miRNP-IP) assays, and small interfering RNA dependency studies revealed that miR-4674 regulates VEGF stimulated-p38 mitogen-activated protein kinase (MAPK) signaling and targets interleukin 1 receptor-associated kinase 1 (Irak1) and BICD cargo adaptor 2 (Bicd2) in ECs. Furthermore, Irak1 and Bicd2 were necessary for miR-4674-driven EC proliferation and migration. Finally, neutralization of miR-4674 increased angiogenesis, Irak1 and Bicd2 expression, and p38 phosphorylation in human skin organoids as a model of tissue injury. Collectively, targeting miR-4674 may provide a novel therapeutic target for tissue repair in pathological disease states associated with impaired angiogenesis.

Coronary Artery Disease Association With Arterial Calcifications on Routine Hand Radiographs.

PURPOSE: Arterial calcifications in the lower extremity, chest, and cardiac vessels have been linked to coronary artery disease (CAD). However, the relation between arterial calcifications observed on routine hand and upper-extremity radiographs and atherosclerosis has not been determined. This study examined whether arterial calcifications found on hand radiographs are associated with CAD. METHODS: A record review from a single institution identified 345 patients with both hand radiographs and CAD screening with cardiac stress testing or coronary angiography. Patients with chronic kidney disease, end-stage renal disease, or incomplete hand films were excluded. We reviewed x-rays for findings of arterial calcifications. Cardiac testing results were used to establish a baseline diagnosis of CAD. We made group comparisons and employed multivariable logistic regression to evaluate the association between upper-extremity calcification and CAD. RESULTS: A total of 210 patients met inclusion criteria: 155 with CAD and 55 without it. Mean age was 72 years, body mass index was 28.8, and 54% were male. Patients had comorbidities of hypertension (91%), hyperlipidemia (87%), diabetes (39%), cerebrovascular accident (9%), and a history of tobacco use (53%). Of 155 CAD patients, 67 had arterial calcifications on hand radiographs (43%), compared with 6 of 55 without it (11%). In a multivariable model controlling for sex, hyperlipidemia, and diabetes, the presence of arterial calcifications on hand plain films indicated a 6.2-fold increased odds of CAD. CONCLUSIONS: The current data demonstrate that arterial calcifications on hand radiographs are independently associated with CAD. This may represent an opportunity to the treating physician as a point of referral or investigation for underlying or occult CAD. TYPE OF STUDY/LEVEL OF EVIDENCE: Prevalence III.

MicroRNA-615-5p Regulates Angiogenesis and Tissue Repair by Targeting AKT/eNOS (Protein Kinase B/Endothelial Nitric Oxide Synthase) Signaling in Endothelial Cells.

Objective- In response to tissue injury, the appropriate progression of events in angiogenesis is controlled by a careful balance between pro and antiangiogenic factors. We aimed to identify and characterize microRNAs that regulate angiogenesis in response to tissue injury. Approach and Results- We show that in response to tissue injury, microRNA-615-5p (miR-615-5p) is rapidly induced and serves as an antiangiogenic microRNA by targeting endothelial cell VEGF (vascular endothelial growth factor)-AKT (protein kinase B)/eNOS (endothelial nitric oxide synthase) signaling in vitro and in vivo. MiR-615-5p expression is increased in wounds of diabetic db/db mice, in plasma of human subjects with acute coronary syndromes, and in plasma and skin of human subjects with diabetes mellitus. Ectopic expression of miR-615-5p markedly inhibited endothelial cell proliferation, migration, network tube formation in Matrigel, and the release of nitric oxide, whereas miR-615-5p neutralization had the opposite effects. Mechanistic studies using transcriptomic profiling, bioinformatics, 3' untranslated region reporter and microribonucleoprotein immunoprecipitation assays, and small interfering RNA dependency studies demonstrate that miR-615-5p inhibits the VEGF-AKT/eNOS signaling pathway in endothelial cells by targeting IGF2 (insulin-like growth factor 2) and RASSF2 (Ras-associating domain family member 2). Local delivery of miR-615-5p inhibitors, markedly increased angiogenesis, granulation tissue thickness, and wound closure rates in db/db mice, whereas miR-615-5p mimics impaired these effects. Systemic miR-615-5p neutralization improved skeletal muscle perfusion and angiogenesis after hindlimb ischemia in db/db mice. Finally, modulation of miR-615-5p expression dynamically regulated VEGF-induced AKT signaling and angiogenesis in human skin organoids as a model of tissue injury. Conclusions- These findings establish miR-615-5p as an inhibitor of VEGF-AKT/eNOS-mediated endothelial cell angiogenic responses and that manipulating miR-615-5p expression could provide a new target for angiogenic therapy in response to tissue injury. Visual Overview- An online visual overview is available for this article.

Socioeconomic Disparities in Brachial Plexus Surgery: A National Database Analysis.

BACKGROUND: Brachial plexus injuries have devastating effects on upper extremity function, with significant pain, psychosocial stress, and reduced quality of life. The aim of this study is to identify socioeconomic disparities in the receipt of brachial plexus repair in the emergent versus elective setting, and in the use of supported services on discharge. METHODS: Analysis of the Healthcare Cost and Utilization Project National Inpatient Sample Database was performed for the years 2009-2014. Adults with brachial plexus injury with or without nerve repair were identified; patient and hospital specific factors were analyzed. RESULTS: Overall, 6,618 cases of emergent brachial plexus injury were retrieved. Six hundred sixty cases of brachial plexus repair were identified in the emergency and elective settings over the study period. Of the 6,618 injured, 153 (2.3%) underwent nerve surgery during the admission. Patients undergoing repair in the elective setting were more likely to be white males with private insurance. Patients treated in the emergency setting were more likely to be African American and in the lowest income quartile. Significant differences were also seen in supported discharge: more likely males (P < 0.001), >55 years of age (P < 0.001), white (P < 0.001), with government-based insurance (P < 0.001). CONCLUSIONS: There are significant disparities in the timing of brachial plexus surgery. These relate to timing rather than receipt of nerve repair; socioeconomically advantaged individuals with private insurance in the higher income quartiles are more likely to undergo surgery in the elective setting and have a supported discharge.