PROMISE I: Early feasibility study of the LimFlow System for percutaneous deep vein arterialization in no-option chronic limb-threatening ischemia: 12-month results.

OBJECTIVE: We report the 6- and 12-month outcomes of the PROMISE I early feasibility study after treatment of no-option chronic limb-threatening ischemia (CLTI) with percutaneous deep vein arterialization (pDVA) using the LimFlow System. METHODS: Thirty-two patients with no-option CLTI, previously offered major amputation, were enrolled in this single-arm early feasibility study of the LimFlow pDVA System. No-option CLTI was defined as being ineligible for surgical or endovascular arterial revascularization. Patients were assessed for clinical status, pain, wound healing, and duplex ultrasound at 30 days, 6 months, and 12 months post-treatment. Primary endpoint analysis was amputation-free survival (AFS) at 30 days and 6 and 12 months. AFS was defined as freedom from above-ankle amputation of the index limb and freedom from all-cause mortality. Secondary endpoints evaluated included technical success of the procedure, and wound healing at 6 and 12 months. RESULTS: Of 32 enrolled patients, 31 (97%) were successfully treated with the LimFlow System at the time of the procedure, and two (6.3%) were lost to follow-up. The 30-day, 6-month, and 12-month AFS rates were 91%, 74%, and 70% respectively. The wound healing status of fully healed or healing was 67% at 6 months, and 75% at 12 months. Reintervention was performed in 16 patients (52%) with 14 (88%) of the maintenance reinterventions occurring within the first 3 months. The majority of reinterventions (n = 12; 75%), involved the arterial inflow tract proximal to the stented LimFlow circuit, and no in-stent stenoses were determined to have been the cause of reintervention. CONCLUSIONS: The LimFlow pDVA System was utilized in treating patients with no-option CLTI. A high technical success rate was observed, with a significant percentage of patients surviving free of major amputation at 12 months. These results suggest early safety and provide an initial assessment of the efficacy of the LimFlow pDVA System that supports the expansion of carefully executed studies to determine whether this is a viable option that can be used in this critically disadvantaged and growing patient population.

A knowledge-based, structural-aided discovery of a novel class of 2-phenylimidazo[1,2-a]pyridine-6-carboxamide H-PGDS inhibitors.

Through an internal virtual screen at GlaxoSmithKline a distinct class of 2-phenylimidazo[1,2-a]pyridine-6-carboxamide H-PGDS inhibitors were discovered. Careful evaluation of crystal structures and SAR led to a novel, potent, and orally active imidazopyridine inhibitor of H-PGDS, 20b. Herein, describes the identification of 2 classes of inhibitors, their syntheses, and their challenges.

The exploration of aza-quinolines as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors with low brain exposure.

GlaxoSmithKline and Astex Pharmaceuticals recently disclosed the discovery of the potent H-PGDS inhibitor GSK2894631A 1a (IC50 = 9.9 nM) as part of a fragment-based drug discovery collaboration with Astex Pharmaceuticals. This molecule exhibited good murine pharmacokinetics, allowing it to be utilized to explore H-PGDS pharmacology in vivo. Yet, with prolonged dosing at higher concentrations, 1a induced CNS toxicity. Looking to attenuate brain penetration in this series, aza-quinolines, were prepared with the intent of increasing polar surface area. Nitrogen substitutions at the 6- and 8-positions of the quinoline were discovered to be tolerated by the enzyme. Subsequent structure activity studies in these aza-quinoline scaffolds led to the identification of 1,8-naphthyridine 1y (IC50 = 9.4 nM) as a potent peripherally restricted H-PGDS inhibitor. Compound 1y is efficacious in four in vivo inflammatory models and exhibits no CNS toxicity.

Dissections After Infrainguinal Percutaneous Transluminal Angioplasty: A Systematic Review and Current State of Clinical Evidence.

Purpose: To systematically review the literature and extract information on the definitions, prevalence, implications, and treatment of dissections after infrainguinal balloon angioplasty, with a goal of summarizing current data and identifying gaps in knowledge to help direct future research. Materials and Methods: A systematic review was performed according to the PRISMA guidelines. Medline (PubMed), Scopus, and Cochrane CENTRAL databases were reviewed for prospective and retrospective studies reporting dissection identification, characterization, incidence, severity, and/or outcomes after infrainguinal balloon angioplasty up to January 30, 2019. The electronic search resulted in 288 studies. From these, 153 full-text articles were assessed, and 51 published from 1964 to 2018 were selected as relevant to this systematic review. Because of the significant between-study differences in lesion characteristics, reporting methods, and lack of core laboratory adjudication, the findings were summarized from each study, but the results were not pooled. Results: The mechanism of percutaneous transluminal angioplasty (PTA) consists of adventitial stretching, medial necrosis, and controlled dissection or plaque fracture. PTA-induced dissections can precipitate pathological high and low shear hemodynamic defects and have been implicated as a contributing factor in procedural complications as well as restenosis at the treatment site. The development of significant dissection after PTA often leads to the use of adjunctive therapies, including stent placement. Despite the ubiquitous nature of dissection after balloon angioplasty (incidence 7.4% to 84%), limited data are available to categorize dissections in the peripheral arteries and direct subsequent treatments to improve vessel patency. With the increased utilization of drug-coated balloon angioplasty, understanding the outcomes of postangioplasty dissection has become increasingly important, as the decision to treat dissections with additional strategies has therapeutic and economic implications. Conclusion: All post-PTA dissections in the femoropopliteal arteries may benefit from a treatment approach that ensures optimal hemodynamics with long-term durability in treated lesions. Further understanding the importance of postangioplasty dissections, along with the development of new technologies, will help optimize the patency of endovascular interventions.

The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors.

With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC50 = 220,000 nM, LE = 0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC50 = 3,100 nM, LE = 0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC50 = 9.9 nM, LE = 0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD2 production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.

2,4-Diamino-8-quinazoline carboxamides as novel, potent inhibitors of the NAD hydrolyzing enzyme CD38: Exploration of the 2-position structure-activity relationships.

Starting from 4-amino-8-quinoline carboxamide lead 1a and scaffold hopping to the chemically more tractable quinazoline, a systematic exploration of the 2-substituents of the quinazoline ring, utilizing structure activity relationships and conformational constraint, resulted in the identification of 39 novel CD38 inhibitors. Eight of these analogs were 10-100-fold more potent human CD38 inhibitors, including the single digit nanomolar inhibitor 1am. Several of these molecules also exhibited improved therapeutic indices relative to hERG activity. A representative analog 1r exhibited suitable pharmacokinetic parameters for in vivo animal studies, including moderate clearance and good oral bioavailability. These inhibitor compounds will aid in the exploration of the enzymatic functions of CD38, as well as furthering the study of the therapeutic implications of NAD enhancement in metabolic disease models.

Role of high shear rate in thrombosis.

Acute arterial occlusions occur in high shear rate hemodynamic conditions. Arterial thrombi are platelet-rich when examined histologically compared with red blood cells in venous thrombi. Prior studies of platelet biology were not capable of accounting for the rapid kinetics and bond strengths necessary to produce occlusive thrombus under these conditions where the stasis condition of the Virchow triad is so noticeably absent. Recent experiments elucidate the unique pathway and kinetics of platelet aggregation that produce arterial occlusion. Large thrombi form from local release and conformational changes in von Willebrand factor under very high shear rates. The effect of high shear hemodynamics on thrombus growth has profound implications for the understanding of all acute thrombotic cardiovascular events as well as for vascular reconstructive techniques and vascular device design, testing, and clinical performance.

The ROX coupler: creation of a fixed iliac arteriovenous anastomosis for the treatment of uncontrolled systemic arterial hypertension, exploiting the physical properties of the arterial vasculature.

OBJECTIVES: Uncontrolled hypertension, whether due to drug resistance or poor adherence and persistence, remains a problem in many patients. The ROX coupler is a novel technology designed to reduce arterial blood pressure consequent to the predicted physical effects of reducing vascular resistance and improving arterial compliance. This article describes the technical aspects of the device and implantation procedure, results from a preclinical study, patient selection criteria, and potential complications of this therapy for uncontrolled hypertension. BACKGROUND: The coupler is a self-expanding, stent-like device that exploits the mechanical effects of the creation of a low-resistance, high-compliance venous segment to the central arterial tree, and can be implanted in a standard catheterization laboratory under fluoroscopic guidance. METHODS: Preclinical studies were conducted in sheep with acute or chronic hypertension. The devices were implanted in the aorta for up to 12 months. The anastomoses were evaluated for patency, healing, conformation into the artery and vein, and complications. RESULTS: Deployment of the anastomotic device in ovine aortas for up to 12 months showed optimal anastomotic patency in all animals with proper healing and conformation of the device into the artery and the vein. There was no significant residual mural thrombus and minimal to moderate intimal thickening at the vein outflow, consistent with expected arterialization. CONCLUSIONS: A novel arteriovenous coupler for percutaneous placement in the iliac vasculature is under clinical investigation as a potential treatment modality for selected patients with uncontrolled hypertension. Initial results from patients with uncontrolled hypertension are expected in Autumn 2014.

Novel heterocyclic scaffolds of GW4064 as farnesoid X receptor agonists.

The farnesoid X receptor (FXR) may play a crucial role in a number of metabolic diseases and, as such, could potentially serve as a target for the development of therapeutics as a treatment for those diseases. Previous work has described GW4064 as an FXR agonist with an interesting activity profile. This manuscript will describe the synthesis of novel analogs of GW4064 and the activity profile of those analogs.

Outcome of the pivotal study of the Aptus endovascular abdominal aortic aneurysms repair system.

OBJECTIVE: Endovascular treatment of abdominal aortic aneurysm (AAA) is associated with benefits over open surgery, yet limitations remain with current endovascular devices. This study was performed to assess outcomes of AAA repair with the Aptus endograft and EndoAnchors (Aptus Endosystems, Sunnyvale, Calif). METHODS: This prospective, multicenter, single-arm investigational device exemption trial was conducted at 25 sites in the United States. A total of 155 patients were enrolled in the trial (mean age, 73 ± 8 years; male, 93.5%; mean AAA diameter, 53.6 ± 7.9 mm). The Aptus endograft is a two-component system: a multilumen, modular endograft with two docking limbs (Aptus Endograft System) and the Heli-FX Aortic Securement System comprising an electronically controlled applier (Heli-FX Applier) with helical EndoAnchors provided in a cassette and a deflectable sheath (Heli-FX Guide) designed for delivery of the applier to the target location for EndoAnchor implantation. The main eligibility criteria included proximal neck length of ≥12 mm, diameter of 19 to 29 mm, and infrarenal angulation of ≤60 degrees. The primary safety end point was freedom from major adverse events at 30 days, and the primary effectiveness end point was successful aneurysm treatment at 12 months. Thrombus-related events (TRE) were defined as limb occlusion or thromboembolism from the endograft. Subjects were observed for a median of 4.2 years, with imaging end points analyzed by a core laboratory and adverse events adjudicated by a clinical events committee. RESULTS: Among 155 enrolled subjects, 153 (98.7%) underwent successful implantation of the Aptus endograft and a median of five EndoAnchors; two subjects were converted to open surgical repair during the initial procedure. Overall, the primary safety and effectiveness end points were met in 98.1% and 97.4% of the subjects, respectively. Aneurysm-related mortality was 0.6%, with one postdischarge cardiac death 18 days after implantation. There were no AAA ruptures. There were no fractures of stents or EndoAnchors. There was one type I endoleak and one type III endoleak. Stent graft migration was noted in five subjects, none associated with sac enlargement, type I endoleak, or EndoAnchor dislocation from the endograft. AAA sac shrinkage of ≥5 mm at 1, 2, and 3 years was observed in 60.3%, 72.9%, and 81.7%, respectively. Sixty-one subjects (39.4%) experienced 113 TRE, associated with 80 reinterventions (in 58 subjects) unassociated with limb loss or death. A root cause analysis of TRE identified small, out-of-specification docking limbs with graft infolding and high local shear, resulting in thrombus formation within the endograft with subsequent distal embolization in some cases. CONCLUSIONS: Early results of the Aptus endograft trial met its safety and effectiveness end points; however, a high rate of TRE was observed because of manufacturing discrepancies. The findings confirm a low rate of type I and type III endoleaks, migration, and non-TRE reintervention with a high rate of aneurysm sac regression during midterm follow-up.

Arteriovenous fistula creation using the Optiflow vascular anastomosis device: a first in man pilot study.

Although arteriovenous fistulae are the preferred form of dialysis vascular access they continue to have significant problems with maturation failure. The Optiflow device is a sutureless anastomotic conduit which could potentially reduce surgical time and also standardize the surgical procedure. We report herein on the "First in Man" experience with the Optiflow device.

Helical EndoStaples enhance endograft fixation in an experimental model using human cadaveric aortas.

OBJECTIVE: This study evaluated the contribution of Aptus EndoStaples (Aptus Endosystems, Sunnyvale, Calif) in the proximal fixation of eight endografts used in the endovascular repair of abdominal aortic aneurysms (EVAR). METHODS: Nine human cadaveric aortas were exposed, left in situ, and transected to serve as fixation zones. The Zenith (Cook, Bloomington, Ind), Anaconda (Vascutek, Inchinnan, Scotland, UK), Endurant (Medtronic, Minneapolis, Minn), Excluder (W. L. Gore and Associates, Flagstaff, Ariz), Aptus (Aptus Endosystems), Aorfix (Lombard Medical, Didcot, UK), Talent (Medtronic), and AneuRx (Medtronic) stent grafts were proximally deployed and caudal displacement force (DF) was applied via a force gauge, recording the DF required to dislocate each device ≥20 mm from the infrarenal neck. Measurements were repeated after four and six EndoStaples were applied at the proximal fixation zone, as well as after a Dacron graft was sutured at the proximal neck in standard fashion. Finally, a silicone tube was used as a control fixation zone to test the DF of grafts with EndoStaples in a material that exceeded the integrity of a typical human cadaveric aorta and provided a consistent substrate to examine the differential effect of variable degrees of EndoStaple implantation using zero, two, four, and six EndoStaples. RESULTS: In the cadaveric model, the mean DF required to dislocate the endografts without the application of EndoStaples was 19.73 ± 12.52 N; this increased to 49.72 ± 12.53 N (P < .0001) when four EndoStaples where applied and to 79.77 ± 28.04 N when six EndoStaples were applied (P = .003). The DF necessary to separate the conventionally hand-sutured Dacron graft from the aorta was 56 N. In the silicone tube model, the Aptus endograft without EndoStaples withstood 3.2 N of DF. The DF increased to 39 ± 3 N when two EndoStaples were added, to 71 ± 6 N when four were added, and to 98 ± 5 N when six were added. In eight of the 13 cadaver experiments conducted with four and six EndoStaples, the displacement occurred as a result of complete aortic transection proximal to the fixation site, indicating that aortic tissue integrity was the limiting factor in these experiments. CONCLUSIONS: The fixation of eight different endografts was increased by a mean of 30 N with four Aptus EndoStaples and by a mean of 57 N with six EndoStaples in this model. Endostaples can increase endograft fixation to levels equivalent or superior to that of a hand-sewn anastomosis. The application of six EndoStaples results in aortic tissue failure above the fixation zone, demonstrating fixation strength that exceeds inherent aortic integrity in these cadavers.

Early outcomes following transatrial transcatheter mitral valve replacement in patients with severe mitral annular calcification.

OBJECTIVE: Implantation of a transcatheter valve-in-mitral annular calcification (ViMAC) has emerged as an alternative to traditional surgical mitral valve (MV) replacement. Previous studies evaluating ViMAC aggregated transseptal, transapical, and transatrial forms of the procedure, leaving uncertainty about each technique's advantages and disadvantages. Thus, we sought to evaluate clinical outcomes specifically for transatrial ViMAC from the largest multicenter registry to-date. METHODS: Patients with symptomatic MV dysfunction and severe MAC who underwent ViMAC were enrolled from 12 centers across the United States and Europe. Clinical characteristics, procedural details, and clinical outcomes were abstracted from the electronic record. The primary end point was all-cause mortality. RESULTS: We analyzed 126 patients who underwent ViMAC (median age 76 years [interquartile range {IQR}, 70-82 years], 28.6% female, median Society of Thoracic Surgeons score 6.8% [IQR, 4.0-11.4], and median follow-up 89 days [IQR, 16-383.5]). Sixty-one (48.4%) had isolated mitral stenosis, 25 (19.8%) had isolated mitral regurgitation (MR), and 40 (31.7%) had mixed MV disease. Technical success was achieved in 119 (94.4%) patients. Thirty (23.8%) patients underwent concurrent septal myectomy, and 8 (6.3%) patients experienced left ventricular outflow tract obstruction (7/8 did not undergo myectomy). Five (4.2%) patients of 118 with postprocedure echocardiograms had greater than mild paravalvular leak. Thirty-day and 1-year all-cause mortality occurred in 16 and 33 patients, respectively. In multivariable models, moderate or greater MR at baseline was associated with increased risk of 1-year mortality (hazard ratio, 2.31; 95% confidence interval, 1.07-4.99, P = .03). CONCLUSIONS: Transatrial ViMAC is safe and feasible in this selected, male-predominant cohort. Patients with significant MR may derive less benefit from ViMAC than patients with mitral stenosis only.

Conformationally constrained farnesoid X receptor (FXR) agonists: alternative replacements of the stilbene.

To further explore the optimum placement of the acid moiety in conformationally constrained analogs of GW 4064 1a, a series of stilbene replacements were prepared. The benzothiophene 1f and the indole 1g display the optimal orientation of the carboxylate for enhanced FXR agonist potency.

Conformationally constrained farnesoid X receptor (FXR) agonists: heteroaryl replacements of the naphthalene.

To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.

The phase I multicenter trial (STAPLE-1) of the Aptus endovascular repair system: results at 6 months and 1 year.

OBJECTIVE: This phase I IDE study (STAPLE-1) evaluated the primary endpoints of safety (major device-related adverse events at 30 days) and feasibility (successful deployment of all endograft components) of the Aptus Endovascular abdominal aortic aneurysm (AAA) Repair System (Aptus Endosystems, Inc, Sunnyvale, Calif) to treat AAAs. METHODS: A prospective, single arm Federal Drug Administration (FDA) Phase I IDE study was performed. The Aptus endograft is a three-piece modular device with a flexible unsupported main body and two fully supported limbs in a 5.3 mm outer diameter (OD) (16F) delivery system for all iliac limbs and two of three main body sizes. The largest main body (29 mm diameter) is in a 6 mm (18 F OD) delivery system. EndoStaples measuring 4 mm (length) by 3 mm (diameter) designed to provide transmural graft fixation to the adventitia are applied independent of the endograft delivery system. Inclusion criteria included a proximal aortic neck length of 12 mm and iliac landing zone of 10 mm. Secondary endpoints included freedom from endoleaks, rupture, migration, and device integrity. RESULTS: Twenty-one (21) patients were enrolled at five centers. All patients received the Aptus Endograft and EndoStaples. Ninety-six EndoStaples (range, 2-10; median, 4) were implanted. All patients (n = 21) completed 1-month and 6-month follow-up evaluation and 14 completed 1-year follow-up. Two proximal cuffs and one limb extension were used as adjunctive endograft components at implantation. Three secondary interventions were performed in 2 patients for limb thrombosis. There were no EndoStaple-related adverse events, device integrity failures, migrations, or conversions. CONCLUSION: These results of the STAPLE-1 trial document the acute safety and feasibility of the Aptus Endograft and EndoStaples. Early follow-up demonstrates excellent 6-month and 1-year results. A pivotal phase II trial is underway at 25 US centers.

Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064.

Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.

FXR agonist activity of conformationally constrained analogs of GW 4064.

Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.

Imaging in patients with severe mitral annular calcification: insights from a multicentre experience using transatrial balloon-expandable valve replacement.

AIMS: To investigate valve sizing and the haemodynamic relevance of the predicted left ventricular outflow tract (LVOT) in patients with mitral annular calcification (MAC) undergoing transatrial transcatheter valve implantation (THV). METHODS AND RESULTS: In total, 21 patients undergoing transatrial THV, multiplanar reconstruction (MPR), maximum intensity projection (MIP), and cubic spline interpolation (CSI) were compared for MA sizing during diastole. In addition, predicted neo-LVOT areas were measured in 18 patients and correlated with the post-procedural haemodynamic dimensions. The procedure was successful in all patients (100%). Concomitant aortic valve replacement was performed in eight patients (43%) (AVR group). Sizing using MPR and MIP yielded comparable results in terms of area, perimeter, and diameter, whereas the dimensions obtained with CSI were systematically smaller. The simulated mean systolic neo-LVOT area was 133.4 ± 64.2 mm2 with an anticipated relative LVOT area reduction (neo-LVOT area/LVOT area × 100) of 59.3 ± 14.7%. The systolic relative LVOT area reduction, but not the absolute neo-LVOT area, was found to predict the peak (r = 0.69; P = 0.002) and mean (r = 0.65; P = 0.004) post-operative aortic gradient in the overall population as well as separately in the AVR (peak: r = 0.91; P = 0.002/mean: r = 0.85; P = 0.002) and no-AVR (peak: r = 0.89; P = 0.003/mean: r = 0.72; P = 0.008) groups. CONCLUSION: In patients with severe MAC undergoing transatrial transcatheter valve implantation, MPR, and MIP yielded comparable annular dimensions, while values obtained with CSI tended to be systematically smaller. Mitral annular area and the average annular diameter appear to be reliable parameters for valve selection. Simulated relative LVOT reduction was found to predict the post-procedural aortic gradients.

Thiol-based angiotensin-converting enzyme 2 inhibitors: P1' modifications for the exploration of the S1' subsite.

Explorations of the S(1') subsite of ACE2 via modifications of the P(1') methylene biphenyl moiety of thiol-based metalloprotease inhibitors led to improvements in ACE2 selectivity versus ACE and NEP, while maintaining potent ACE2 inhibition.