Pre-Clinical Investigation of Keratose as an Excipient of Drug Coated Balloons.

BACKGROUND: Drug-coated balloons (DCBs), which deliver anti-proliferative drugs with the aid of excipients, have emerged as a new endovascular therapy for the treatment of peripheral arterial disease. In this study, we evaluated the use of keratose (KOS) as a novel DCB-coating excipient to deliver and retain paclitaxel. METHODS: A custom coating method was developed to deposit KOS and paclitaxel on uncoated angioplasty balloons. The retention of the KOS-paclitaxel coating, in comparison to a commercially available DCB, was evaluated using a novel vascular-motion simulating ex vivo flow model at 1 h and 3 days. Additionally, the locoregional biological response of the KOS-paclitaxel coating was evaluated in a rabbit ilio-femoral injury model at 14 days. RESULTS: The KOS coating exhibited greater retention of the paclitaxel at 3 days under pulsatile conditions with vascular motion as compared to the commercially available DCB (14.89 ± 4.12 ng/mg vs. 0.60 ± 0.26 ng/mg, p = 0.018). Histological analysis of the KOS-paclitaxel-treated arteries demonstrated a significant reduction in neointimal thickness as compared to the uncoated balloons, KOS-only balloon and paclitaxel-only balloon. CONCLUSIONS: The ability to enhance drug delivery and retention in targeted arterial segments can ultimately improve clinical peripheral endovascular outcomes.

Vascular access for hemodialysis: A perpetual challenge.

Vascular access for hemodialysis has a long and rich history. This article highlights major innovations and milestones in the history of angioaccess for hemodialysis. Advances in achievement of lasting hemodialysis access, swift access transition, immediate and sustaining access to vascular space built the momentum at different turning points of access history and shaped the current practice of vascular access strategy. In the present era, absent of large-scale clinical trials to validate practice, the ever-changing demographic and comorbidity makeup of the dialysis population pushes against stereotypical angioaccess goals. The future of hemodialysis vascular access would benefit from proper randomized clinical trials and acclimatization to clinical contexts.

Loss of the hyaluronan receptor RHAMM prevents constrictive artery wall remodeling.

OBJECTIVE: Constrictive extracellular matrix (ECM) remodeling contributes significantly to restenosis after arterial reconstruction, but its molecular regulation is poorly defined. Hyaluronan (HA) accumulates within ECM at sites of injury where it is thought to facilitate smooth muscle cell (SMC) trafficking and collagen remodeling analogous to its role in cutaneous wound healing. SMC receptors for HA include receptor for hyaluronan-mediated motility (RHAMM), which mediates HA-induced migration. We hypothesized RHAMM would also mediate SMC-matrix interactions to alter the extent of constrictive remodeling. METHODS: We studied the role of RHAMM in SMC attachment to collagen, migration, and contraction of collagen gels using blocking antibodies and SMC from RHAMM -/- knockout mice. We then determined the role of RHAMM in constrictive artery wall remodeling by comparing changes in wall geometry in RHAMM -/- vs wild-type (WT) RHAMM +/+ controls 1 month after carotid ligation. RESULTS: HA increased SMC attachment to collagen-coated plates, but blocking RHAMM reduced adhesion (P = .025). RHAMM -/- SMC also demonstrated reduced adhesion (% adherent: 36.1 ± 2.2 vs 76.3 ± 1.9; P < .05). SMC contraction of collagen gels was enhanced by HA and further increased by RHAMM blockade (P < .01) or knockout (gel diameter, mm: RHAMM -/-, 6.7 ± 0.1 vs WT 9.8 ± 0.1; P < .01). RHAMM promoted constrictive remodeling in vivo as carotid artery size was significantly larger in knockout mice 1 month after ligation. Neointimal thickening, however, was not affected in RHAMM -/- (P = NS vs WT), but lumen size was significantly larger (lumen area, µm(2): 52.4 ± 1.4 × 10(3) vs 10.4 ± 1.8 × 10(3); P = .01) because artery size constricted less (external elastic lamina area, µm(2): RHAMM -/-, 92.4 ± 4.7 × 10(3) vs WT, 51.3 ± 5.9 × 10(3); P = .015). Adventitial thickening and collagen deposition were also more extensive in ligated RHAMM -/- carotids (adventitial thickness, µm: 218 ± 12.2 vs 109 ± 7.9; P = .01). CONCLUSIONS: HA activation of RHAMM significantly impacts SMC-ECM adhesive interactions and contributes to constrictive artery wall remodeling in mice. Strategies to block RHAMM at sites of vessel injury may prove useful in the prevention of clinical restenosis.

Setting high-impact clinical research priorities for the Society for Vascular Surgery.

With the overall goal of enhancing the effectiveness and efficiency of vascular care, the Society for Vascular Surgery (SVS) recently completed a process by which it identified its top clinical research priorities to address critical gaps in knowledge guiding practitioners in prevention and treatment of vascular disease. After a survey of the SVS membership, a panel of SVS committee members and opinion leaders considered 53 distinct research questions through a structured process that resulted in identification of nine clinical issues that were felt to merit immediate attention by vascular investigators and external funding agencies. These are, in order of priority: (1) define optimal management of asymptomatic carotid stenosis, (2) compare the effectiveness of medical vs invasive treatment (open or endovascular) of vasculogenic claudication, (3) compare effectiveness of open vs endovascular infrainguinal revascularization as initial treatment of critical limb ischemia, (4) develop and compare the effectiveness of clinical strategies to reduce cardiovascular and other perioperative complications (eg, wound) after vascular intervention, (5) compare the effectiveness of strategies to enhance arteriovenous fistula maturation and durability, (6) develop best practices for management of chronic venous ulcer, (7) define optimal adjunctive medical therapy to enhance the success of lower extremity revascularization, (8) identify and evaluate medical therapy to prevent abdominal aortic aneurysm growth, and (9) evaluate ultrasound vs computed tomographic angiography surveillance after endovascular aneurysm repair.

Excellent results seen with both transaxillary and infraclavicular approaches to first rib resection in patients with subclavian vein thrombosis.

BACKGROUND: Venous thoracic outlet syndrome (VTOS) is a debilitating condition with several well-documented treatment paradigms. We reviewed the outcomes from a large academic institution of patients who had undergone transaxillary first rib resection with delayed venography (TA) or infraclavicular first rib and subclavius muscle resection with concomitant venography (ICV) for VTOS with subclavian vein thrombosis. METHODS: We performed a retrospective review of the medical records of all patients who had undergone first rib resection and scalenectomy for VTOS with subclavian vein thrombosis at a single academic institution. The demographics, presentation, operative records, and outcomes were collected. Descriptive statistics were used to compare the two groups. RESULTS: A total of 73 patients had undergone first rib resection for VTOS during the study period. Of the 73 patients, 36 (49%) had presented with thrombosis of the subclavian vein and were included in the present review. Of the 36 patients, 26 (72%) had undergone TA and 10 (28%) had undergone ICV. No significant differences were seen between the two groups in female gender (54% vs 50%; P = 1.00) or age (28.7 years vs 29.5 years; P = .88). A higher percentage of the ICV group had undergone preoperative thrombolysis (70% vs 27%; P = .02). All the patients in the ICV group had undergone intraoperative balloon venoplasty at resection. The mean time from thrombosis to resection was 2.3 months. All of the TA group had undergone venography at 2 weeks postoperatively. Venography had revealed 15 stenotic veins requiring venoplasty, 8 widely patent veins, 1 acutely thrombosed vein, and 3 chronically occluded veins. The time from initial thrombosis to surgical intervention was 10 months for the patent group, 6 months for the stenotic group, and 4 months for the occluded group. In the TA group, 19% of the patients had required chest tube placement intraoperatively for pneumothorax. In the ICV group, complications included postoperative hematoma (n = 1), wound infection (n = 1), and hemothorax (n = 1). The mean length of stay was 1.04 days for the TA group and 2.00 days for the ICV group (P < .0001). The mean follow-up was 10.4 months and 15.8 months for the TA and ICV groups, respectively. No mortalities were reported. No differences in the vein patency rates were seen between the two groups at follow-up (TA, 93%; vs ICV, 100%; P = 1.00). All the patients were asymptomatic at follow-up. CONCLUSIONS: The outcomes for the patients who had undergone TA or ICV for subclavian vein thrombosis were excellent with no mortality and few complications. The subclavian vein patency rates were high, and all the patients were asymptomatic at follow-up.

Boney abnormalities cause arterial, venous, and/or neurogenic thoracic outlet syndrome.

Background: Thoracic outlet syndrome (TOS) is a rare condition caused by compression of the neurovascular structures within the thoracic outlet. Different classifications of TOS exist depending on the neurovascular structure being compressed: neurogenic, venous, or arterial. Any of these forms can present independently or coexist with one other. TOS symptoms are sometimes precipitated by the presence of boney abnormalities that often require surgical intervention for ultimate resolution. This retrospective review will examine the presentations and outcomes of patients with TOS whose cause was a boney abnormality. Methods: A total of 73 patients who underwent thoracic outlet surgery between 2016 and 2021 were retrospectively reviewed via electronic medical records. Twelve (16%) patients demonstrated boney abnormalities on presentation causing their symptoms. The patients with boney abnormalities were analyzed based on venous, arterial, or neurogenic TOS diagnosis. Results: Of the 12 patients with boney abnormalities, 5 were classified as venous TOS, 6 patients as neurogenic TOS, and 1 as arterial TOS. The boney abnormalities were as follows: venous TOS: three clavicular fractures, one nonfused congenital clavicle, and one residual rib; neurogenic TOS: three fractured first ribs, one fractured clavicle, and two cervical ribs; and arterial TOS: fused first and second rib with bilateral cervical ribs and arterial compression. Postoperatively, there were no artery, vein, or nerve injuries. Five patients had a pneumothorax treated over night with a chest tube, and one patient had a superficial wound infection. The median hospital stay was 1 day. All patients completed physical therapy after surgery. All patients have symptom resolution at follow-up. Conclusions: Patients with boney abnormalities constitute about one-fifth of patients who can present with all three forms of TOS: neurogenic, arterial, and venous, and some will have more than one of these presentations. Results in patients undergoing surgery with boney abnormalities causing thoracic outlet syndrome are excellent with symptom resolution and without substantial complications.

Bioengineered vascular access maintains structural integrity in response to arteriovenous flow and repeated needle puncture.

OBJECTIVE: Tissue-engineered blood vessels (TEBV) have been proposed as an alternative to prosthetic grafts for dialysis access. However, arteriovenous (AV) grafts must withstand extreme flow rates and frequent needle trauma. In a proof-of-concept study, we sought to determine whether scaffold-based TEBV could withstand the hemodynamic and mechanical challenges of chronic dialysis access. METHODS: TEBV were constructed using decellularized arterial scaffolds seeded with autologous ovine endothelial cells (EC) derived from circulating endothelial progenitor cells (EPC) using a novel high-affinity capture approach. Seeded scaffolds were preconditioned to arterial pressure and flow in a bioreactor for 2 weeks prior to implantation to create carotid artery to jugular vein AV grafts in each animal. TEBV were healed for 1 month before initiating percutaneous needle puncture 3 days/week. TEBV wall geometry and patency were monitored using duplex imaging and were either explanted for histologic analysis at 2 months (n = 5) or followed for up to 6 months until venous outflow stenosis threatened AV graft patency (n = 6). RESULTS: Despite high flow, TEBV maintained stable geometry with only modest wall dilation (under 6%) by 4 months after implantation. Needle access was well tolerated with a single puncture site complication, a small pseudoaneurysm, occurring in the late group. Time-to-hemostasis at puncture sites averaged 4 ± 2 minutes. Histologic analysis at 2 months demonstrated repopulation of the outer TEBV wall by host cells and healing of needle punctures by cellular ingrowth and new matrix deposition along the tract. TEBV followed beyond 2 months showed stable wall geometry but, consistent with the primary mode of clinical AV graft failure, all TEBV eventually developed venous anastomotic stenosis (mean, 4.4 ± 0.9 months; range, 3.3-5.6 months postimplantation; n = 6). CONCLUSIONS: This pilot study supports the concept of creating dialysis access from scaffold-based autologous TEBV. Engineered AV grafts were created within a clinically relevant time frame and demonstrated stable wall geometry despite high flow and repeated puncture. Cellular ingrowth and puncture site healing may improve wall durability, but venous outflow stenosis remains the primary mode of TEBV graft failure in the ovine model.

Vascular smooth muscle enhances functionality of tissue-engineered blood vessels in vivo.

OBJECTIVES: There is significant room for improvement in the development of tissue-engineered blood vessels (TEBVs) for vascular reconstruction. Most commonly, TEBVs are seeded with endothelial cells (ECs) only. This provides an antithrombogenic surface but suboptimal physiologic characteristics compared with native arteries, due to lack of smooth muscle cells (SMCs) in the vessel media. Although SMCs are critical in vessel architecture and function throughout the vascular tree, few studies have incorporated SMCs in TEBVs implanted in vivo. As such, the goal of the present study was to evaluate the effect of SMC coseeding with ECs on TEBV maturation, structure, and function after prolonged in vivo maturation. METHODS: Dual-seeded TEBVs (dsTEBVs) were created by coseeding autologous ECs derived from circulating progenitor cells and SMCs from artery explants onto the lumen and outer surface of extracellular matrix scaffolds, respectively. Control vessels were seeded with ECs alone (ecTEBV). All vessels were preconditioned to pulsatile flow for 10 to 14 days in a bioreactor, implanted as arterial interposition grafts in sheep, and allowed to heal and adapt in vivo for 4 months before ex vivo physiologic testing and histologic analysis. RESULTS: All implants were patent at 4 months. There were no structural failures, aneurysms, or infectious complications. The dsTEBVs exhibited a greater degree of wall maturation, characterized by higher medial cellularity (P = .01) and greater percentage of α-actin (P = .005) and SMC-specific muscle myosin heavy chain (P = .005) staining compared with ecTEBVs. Contractile responses to phenylephrine and serotonin were significantly greater in isolated rings of dsTEBVs than those observed in ecTEBVs (P = .01). CONCLUSIONS: To our knowledge, this is the first study that demonstrates enhanced in vivo wall maturation and contractile function of TEBVs coseeded with autologous SMCs and ECs compared with EC seeding alone. These data suggest a coseeding strategy can be accomplished in a clinically relevant timeframe (typically 6 weeks) and may provide advantages for arterial reconstruction compared with vessels engineered only with endothelium.

Arteriovenous Fistula Versus Graft Access Strategy in Older Adults Receiving Hemodialysis: A Pilot Randomized Trial.

BACKGROUND: It is unclear whether surgical placement of an arteriovenous (AV) fistula (AVF) confers substantial clinical benefits over an AV graft (AVG) in older adults with end-stage kidney disease (ESKD). We report vascular access outcomes of a pilot clinical trial. STUDY DESIGN: Pilot randomized parallel-group open-label trial. SETTING & PARTICIPANTS: Patients 65 years and older with ESKD and no prior AV access receiving maintenance hemodialysis through a tunneled central venous catheter referred for AV access placement by their treating nephrologist. INTERVENTION: Participants were randomly assigned in a 1:1 ratio to surgical placement of an AVG or AVF. OUTCOMES: Index AV access primary failure, successful cannulation, adjuvant interventions and infections. RESULTS: Of 122 older adults receiving hemodialysis and no prior AV access surgery, 24% died before (n = 18) or were too sick for (n = 11) referral for a permanent AV access. Of 46 eligible patients, 36 (78%) consented and were randomly assigned to AVG (n = 18) and AVF (n = 18) placement, of whom 13 (72%) and 16 (89%) underwent index AV access surgical placement, respectively. At a median follow-up of 321.0 days, primary AV access failure was noted in 31% in each group. The proportion of patients with successful cannulation was 62% (8 of 13) in the AVG and 50% (8 of 16) in the AVF group; median times to successful cannulation were 75.0 and 113.5 days, respectively. Endovascular procedures were recorded in 38% and 44%, and surgical reinterventions, in 23% and 25%, respectively. AV access infection was seen in 3 (23%) and 2 (13%) patients, respectively. LIMITATIONS: Small sample size precludes statistical inference. CONCLUSIONS: Almost one-quarter of older adults with incident ESKD and a central venous catheter as primary access were not referred for AV access placement due to medical reasons. Based on these limited results, there is little reason to favor either an AVF or AVG in this population until results from a larger randomized clinical trial become available. FUNDING: Government funding to an author (Dr Murea is supported by National Institutes of Health∖National Institute on Aging grant 1R03 AG060178-01). TRIAL REGISTRATION: NCT03545113.

Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL.

HDL lowers the risk for atherosclerotic cardiovascular disease by promoting cholesterol efflux from macrophage foam cells. However, other antiatherosclerotic properties of HDL are poorly understood. To test the hypothesis that the lipoprotein carries proteins that might have novel cardioprotective activities, we used shotgun proteomics to investigate the composition of HDL isolated from healthy subjects and subjects with coronary artery disease (CAD). Unexpectedly, our analytical strategy identified multiple complement-regulatory proteins and a diverse array of distinct serpins with serine-type endopeptidase inhibitor activity. Many acute-phase response proteins were also detected, supporting the proposal that HDL is of central importance in inflammation. Mass spectrometry and biochemical analyses demonstrated that HDL3 from subjects with CAD was selectively enriched in apoE, raising the possibility that HDL carries a unique cargo of proteins in humans with clinically significant cardiovascular disease. Collectively, our observations suggest that HDL plays previously unsuspected roles in regulating the complement system and protecting tissue from proteolysis and that the protein cargo of HDL contributes to its antiinflammatory and antiatherogenic properties.

The fate of an endothelium layer after preconditioning.

BACKGROUND: A strategy in minimizing thrombotic events of vascular constructs is to seed the luminal surface with autologous endothelial cells (ECs). The task of seeding ECs can be achieved via bioreactors, which induce mechanical forces (shear stress, strain, pressure) onto the ECs. Although bioreactors can achieve a confluent layer of ECs in vitro, their acute response to blood remains unclear. Moreover, the necessary mechanical conditions that will increase EC adhesion and function remain unclear. We hypothesize that preconditioning seeded endothelium under physiological flow will enhance their retention and function. OBJECTIVE: To determine the role of varying preconditioning protocols on seeded ECs in vitro and in vivo. METHODS: Scaffolds derived from decelluarized arteries seeded with autologous ECs were preconditioned for 9 days. Three specific protocols, low steady shear stress (SS), high SS, and cyclic SS were investigated. After preconditioning, the seeded grafts were exposed to 15 minutes of blood via an ex vivo arteriovenous shunt model or alternately an in vivo arteriovenous bypass graft model. RESULTS: The shunt model demonstrated ECs remained intact for all conditions. In the arteriovenous bypass model, only the cyclic preconditioned grafts remained intact, maintained morphology, and resisted the attachment of circulating blood elements such as platelets, red blood cells, and leukocytes. Western blotting analysis demonstrated an increase in the protein expression of eNOS and prostaglandin I synthase for the cyclic high shear stress-conditioned cells relative to cells conditioned with high shear stress alone. CONCLUSION: Cyclic preconditioning has been shown here to increase the ECs ability to resist blood flow-induced shear stress and the attachment of circulating blood elements, key attributes in minimizing thrombotic events. These studies may ultimately establish protocols for the formation of a more durable endothelial monolayer that may be useful in the context of small vessel arterial reconstruction.

Antibody-Conjugated Electrospun Vascular Scaffolds to Enhance In Situ Endothelialization.

Tissue-engineered vascular grafts (TEVGs) are promising alternatives to small-diameter prosthetic grafts. Previous methods of seeding tubular scaffolds with autologous vascular cells have been successful; however, these methods require significant preparation time. Endothelial cell (EC) growth on the luminal surface of vascular scaffolds may be critical for the integration of a TEVG to the host environment. An alternative approach for TEVGs includes the in situ endothelialization of acellular scaffolds by capturing circulating endothelial progenitor cells (EPCs) and ECs from the bloodstream through the biofunctionalization of the vascular scaffolds. In this study, fibrous scaffolds were electrospun with a 1:1 poly(ε-caprolactone) (PCL)/collagen blend solution. The electrospun fibrous scaffolds were surface-modified by immobilizing EC-specific antibodies: CD31, vascular endothelial cadherin (VE-CAD), vascular endothelial growth factor receptor 2 (VEGFR2), and von Willebrand factor (vWF). Antibodies most efficacious at capturing ECs were then paired to examine their potential synergistic cell-capturing capabilities. The study demonstrated that vascular scaffolds bioconjugated with dual antibodies demonstrated synergistic capture efficacy compared to bioconjugation with a single antibody. The capture of circulating EPCs and ECs can be optimized with bioconjugation of one or more antibodies on the luminal surface of TEVGs.

A randomized pilot study to evaluate graft versus fistula vascular access strategy in older patients with advanced kidney disease: results of a feasibility study.

BACKGROUND: Although older adults encompass almost half of patients with advanced chronic kidney disease, it remains unclear which long-term hemodialysis vascular access type, arteriovenous fistula or arteriovenous graft, is optimal with respect to effectiveness and patient satisfaction. Clinical outcomes based on the initial AV access type have not been evaluated in randomized controlled trials. This pilot study tested the feasibility of randomizing older adults with advanced kidney disease to initial arteriovenous fistula versus graft vascular access surgery. METHODS: Patients 65 years or older with pre-dialysis chronic kidney disease or incident end-stage kidney disease and no prior arteriovenous vascular access intervention were randomized in a 1:1 ratio to undergo surgical placement of a fistula or a graft after providing informed consent. Trial feasibility was evaluated as (i) recruitment of ≥ 70% of eligible participants, (ii) ≥ 50 to 70% of participants undergo placement of index arteriovenous access within 90 to 180 days of enrollment, respectively, (iii) ≥ 80% adherence to study-related assessments, and (iv) ≥ 70% of participants who underwent index arteriovenous access placement will have a follow-up duration of ≥ 12 months after index surgery date. RESULTS: Between September 2018 and October 2019, 81% (44/54) of eligible participants consented and were enrolled in the study; 11 had pre-dialysis chronic kidney disease, and 33 had incident or prevalent end-stage kidney disease. After randomization, 100% (21/21) assigned to arteriovenous fistula surgery and 78% (18/23) assigned to arteriovenous graft surgery underwent index arteriovenous access placement within a median (1st, 3rd quartile) of 5.0 (1.0, 14.0) days and 13.0 (5.0, 44.3) days, respectively, after referral to vascular surgery. The completion rates for study-specific assessments ranged between 40.0 and 88.6%. At median follow-up of 215.0 days, 5 participants expired, 7 completed 12 months of follow-up, and 29 are actively being followed. Assessments of grip strength, functional independence, and vascular access satisfaction were completed by > 85% of patients who reached pre-specified post-operative assessment time point. CONCLUSIONS: Results from this study reveal it is feasible to enroll and randomize older adults with advanced kidney disease to one of two different arteriovenous vascular access placement surgeries. The study can progress with minor protocol adjustments to a multisite clinical trial. TRIAL REGISTRATION: Clinical Trials ID, NCT03545113.

Restenosis after renal artery angioplasty and stenting: incidence and risk factors.

BACKGROUND: Management of renal artery stenosis (RAS) with primary renal artery percutaneous angioplasty and stenting (RA-PTAS) is associated with a low risk of periprocedural death and major complications; however, restenosis develops in a subset of patients and repeat intervention may be required. We examined the incidence of restenosis after RA-PTAS and associations with clinical factors. METHODS: Consecutive patients undergoing RA-PTAS for hemodynamically significant atherosclerotic RAS associated with hypertension or ischemic nephropathy, or both, between October 2003 and September 2007 were identified from a registry. Restenosis was defined using duplex ultrasound (DUS) imaging as a renal artery postintervention peak systolic velocity (PSV) >or=180 cm/s. The incidence and temporal distribution of restenosis was analyzed using survival analysis based on treated kidneys. Associations between clinical factors and recurrent stenosis were examined using proportional hazards regression. RESULTS: RA-PTAS was performed on 112 kidneys for atherosclerotic RAS during the study period. Initial postintervention renal artery DUS imaging confirming PSV <180 cm/s in 101 kidneys, which formed the basis of this analysis. Estimated restenosis-free survival was 50% at 12 months and 40% at 18 months. Decreased risk of restenosis was associated with preoperative statin use (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.16-0.74; P = .006) and increased preoperative diastolic blood pressure (DBP; HR, 0.70 per 10-mm Hg increase in preoperative DBP; 95% CI, 0.49-0.99; P = .049). No other factors assessed were associated with restenosis. CONCLUSION: Restenosis occurs in a substantial number of patients treated with RA-PTAS. Preoperative statin medication use and increased preoperative DBP are associated with reduced risk of restenosis. In the absence of contraindications, statins should be considered standard therapy for patients with atherosclerotic renal artery stenosis.

Pharmacomechanical Catheter-Directed Thrombolysis in Acute Femoral-Popliteal Deep Vein Thrombosis: Analysis from a Stratified Randomized Trial.

BACKGROUND AND OBJECTIVES: The Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) trial reported that pharmacomechanical catheter-directed thrombolysis (PCDT) did not reduce post-thrombotic syndrome (PTS), but reduced moderate-to-severe PTS and the severity of PTS symptoms. In this analysis, we examine the effect of PCDT in patients with femoral-popliteal deep vein thrombosis (DVT) (without involvement of more proximal veins). PATIENTS AND METHODS: Within the ATTRACT trial, 300 patients had DVT involving the femoral vein without involvement of the common femoral or iliac veins and were randomized to receive PCDT with anticoagulation or anticoagulation alone (no PCDT). Patients were followed for 24 months. RESULTS: From 6 to 24 months, between the PCDT versus no PCDT arms, there was: no difference in any PTS (Villalta scale ≥ 5: risk ratio [RR] = 0.97; 95% confidence interval [CI], 0.75-1.24); moderate-or-severe PTS (Villalta scale ≥ 10: RR = 0.93; 95% CI, 0.57-1.52); severity of PTS scores; or general or disease-specific quality of life (p > 0.5 for all comparisons). From baseline to both 10 and 30 days, there was no difference in improvement of leg pain or swelling between treatment arms. From baseline to 10 days, major bleeding occurred in three versus none (p = 0.06) and any bleeding occurred in eight versus two (p = 0.032) PCDT versus no PCDT patients. Over 24 months, recurrent venous thromboembolism occurred in 16 PCDT and 12 no PCDT patients (p = 0.24). CONCLUSION: In patients with femoral-popliteal DVT, PCDT did not improve short- or long-term efficacy outcomes, but it increased bleeding. Therefore, PCDT should not be used as initial treatment of femoral-popliteal DVT. (NCT00790335).

A randomized pilot study comparing graft-first to fistula-first strategies in older patients with incident end-stage kidney disease: Clinical rationale and study design.

Timely placement of an arteriovenous (AV) vascular access (native AV fistula [AVF] or prosthetic AV graft [AVG]) is necessary to limit the use of tunneled central venous catheters (TCVC) in patients with end-stage kidney disease (ESKD) treated with hemodialysis (HD). National guidelines recommend placement of AVF as the AV access of first choice in all patients to improve patient survival. The benefits of AVF over AVG are less certain in the older adults, as age-related biological changes independently modulate patient outcomes. This manuscript describes the rationale, study design and protocol for a randomized controlled pilot study of the feasibility and effects of AVG-first access placement in older adults with no prior AV access surgery. Fifty patients age ≥65 years, with incident ESKD on HD via TCVC or advanced kidney disease facing imminent HD initiation, and suitable upper extremity vasculature for initial placement of an AVF or AVG, will be randomly assigned to receive either an upper extremity AVG-first (intervention) or AVF-first (comparator) access. The study will establish feasibility of randomizing older adults to the two types of AV access surgery, evaluate relationships between measurements of preoperative physical function and vascular access development, compare vascular access outcomes between groups, and gather longitudinal assessments of upper extremity muscle strength, gait speed, performance of activities of daily living, and patient satisfaction with their vascular access and quality of life. Results will assist with the planning of a larger, multicenter trial assessing patient-centered outcomes.

RGS5, RGS4, and RGS2 expression and aortic contractibility are dynamically co-regulated during aortic banding-induced hypertrophy.

Overexpression of regulator of G protein signaling 5 (RGS5) in arteries over veins is the most striking difference observed using microarray analysis. The obvious question is what arterial function might require RGS5. Based on functions of homologous proteins in regulating cardiac mass and G-protein-coupled receptor (GPCR) signaling, we proposed that RGS5 and vascular expressed RGS2 and RGS4 could participate in regulating arterial hypertrophy. We used the suprarenal abdominal aorta banding model to induce hypertension and hypertrophy. All 3 RGS messages were expressed in unmanipulated aorta with RGS5 predominating. After 2 days, thoracic aorta lost expression of RGS5, 4, and 2. At 1 week, all three returned to normal, and at 28 days, they increased many fold above normal. Valsartan blockade of angiotensin II (angII)/angII type 1 receptor signaling prevented upregulation of RGS messages but only delayed mass increases, implying wall mass regulation involves both angII-dependent and angII-independent pathways. The abdominal aorta showed less dramatic expression changes in RGS5 and 4, but not 2. Again, those changes were delayed by valsartan treatment with no mass changes. Thoracic aorta contraction to GPCR agonists was examined in aortic explant rings to identify vessel wall physiological changes. In 2-day aorta, the response to Galphaq/i agonists increased above normal, while 28-day aorta had attenuated induced contraction via Galphaq/i agonist, implicating a connection between RGS message levels and changes in GPCR-induced contraction. In vitro overexpression studies showed RGS5 inhibits angII-induced signaling in smooth muscle cells. This study is the first experimental evidence that changes in RGS expression and function correlate with vascular remodeling.

Expression profiling identifies smooth muscle cell diversity within human intima and plaque fibrous cap: loss of RGS5 distinguishes the cap.

BACKGROUND: The fibrous cap of the atherosclerotic lesion is believed to be critical to stability because disruption of the cap is the final event leading to plaque rupture. We have, therefore, used expression arrays to define the phenotype of the cap and other plaque components. METHODS AND RESULTS: To identify unique expression programs able to distinguish the smooth muscle of the cap from other plaque smooth muscle cells, RNA profiles were determined in human carotid artery media, nonatherosclerotic adjacent intima, fibrous cap of advanced atherosclerotic plaques, and whole advanced plaque with cDNA arrays covering 21,000 or 26,000 Unigene clusters. The molecular signature of each tissue was dominated by a core gene-set with differential expression of <1% of clusters assayed. CONCLUSIONS: Both intima and cap expressed novel genes not previously associated with SMC pathology. If the cap is derived from a unique subpopulation, this pattern is the signature of that particular set of cells. The loss of RGS5 in the fibrous cap is of particular interest because of its role in vessel development and physiology.

Loss of expression of tropomyosin-1, a novel class II tumor suppressor that induces anoikis, in primary breast tumors.

Suppression of tropomyosins (TMs), a family of actin-binding, microfilament-associated proteins, is a prominent feature of many transformed cells. Yet it is unclear whether downregulation of TMs occur in human tumors. We have investigated the expression of tropomyosin-1 (TM1) in human breast carcinoma tissues by in situ hybridization and immunofluorescence. TM1 mRNA and protein are readily detectable in normal mammary tissue. In contrast, TM1 expression is abolished in the primary human breast tumors. Expression of other TM isoforms, however, is variable among the tumors. The consistent and profound downregulation of TM1 suggests that TM1 may be a novel and useful biomarker of mammary neoplasms. These data also support the hypothesis that suppression of TM1 expression during the malignant conversion of mammary epithelium as a contributing factor of breast cancer. In support of this hypothesis, we show that the ability to suppress malignant growth properties of breast cancer cells is specific to TM1 isoform. Investigations into the mechanisms of TM1-induced tumor suppression reveal that TM1 induces anoikis (detachment induced apoptosis) in breast cancer cells. Downregulation of TM1 in breast tumors may destabilize microfilament architecture and confer resistance to anoikis, which facilitates survival of neoplastic cells outside the normal microenvironment and promote malignant growth.

Expression profiling identifies 147 genes contributing to a unique primate neointimal smooth muscle cell phenotype.

OBJECTIVE: This study represents the first in an effort to systematically characterize different intimas by using expression array analysis. METHODS AND RESULTS: We compared smooth muscle cells (SMCs) of the neointima formed 4 weeks after aortic grafting with those from normal aorta and vena cava from cynomolgus monkeys. Hybridization to cDNA arrays identified subsets of 147 and 45 genes differentially expressed in the neointima versus the aorta and vena cava, respectively. The expression pattern differentiating neointima from aortic SMCs was characterized largely by suppression. Only 13 genes were induced in the neointima: 7 encoded matrix proteins (6 collagens and 1 versican) and 2 encoded inducers of matrix synthesis (osteoblast-specific factor-2/Cbfa1 and connective tissue growth factor). The genes suppressed most in the neointima included the regulator of G-protein signaling-5, SPARClike-1/hevin, and nonmuscle myosin heavy chain-B. A smaller gene set differentiated the neointima from the vena cava. Most were induced (39 of 45 genes), and overlap with the neointima-aorta set was significant (10 of 13 genes). Array results were validated with Northern analysis, in situ hybridization, or immunohistochemistry. CONCLUSIONS: These data underscore the importance of matrix synthesis in neointimal maturation, and novel genes, newly associated with neointimal SMCs (regulator of G-protein signaling-5 and osteoblast-specific factor-2/Cbfa1), have raised new hypotheses regarding the pathogenesis of intimal hyperplasia.