Clinical outcome of drug-coated balloons in patients with femoropopliteal chronic total occlusive lesions: results from the multicenter EAGLE study.

BACKGROUND: Several studies have reported the efficacy of drug-coated balloons (DCB) for simple femoropopliteal (FP) lesions. However, the effectiveness of DCB for FP chronic total occlusive lesions (CTO) is controversial. The present study investigated the clinical outcomes of DCB for FP-CTO. MATERIALS AND METHODS: We retrospectively analyzed 359 limbs of 318 patients who underwent endovascular therapy with DCB for FP-CTO between July 2017 and February 2021 at seven cardiovascular centers. The primary endpoint was 12-month primary patency. The secondary endpoints were the 12-month rates of freedom from: (1) clinically-driven target lesion revascularization (CD-TLR), and (2) re-occlusion. The association of baseline characteristics with the 12-month restenosis risk was investigated using the Cox proportional hazards regression model. RESULTS: The 12-month rate of primary patency was 79.8% (95% confidence interval [95%CI], 75.1% to 84.8%), whereas the corresponding rates of freedom from CD-TLR and re-occlusion were 86.4% (95%CI: 82.6% to 90.4%) and 88.5% (95%CI: 84.7% to 92.4%), respectively. The bailout stent rate was 8.9%. Independent risk factors for restenosis were hemodialysis (adjusted hazard ratio, 2.18 [1.39 to 3.45]; P = 0.001), chronic limb-threatening ischemia (CLTI) (2.02 [1.33 to 3.07]; P = 0.001), and restenosis lesion (2.02 [1.32 to 3.08]; P = 0.001). Use of dual antiplatelet therapy (DAPT) was identified as a protective factor for restenosis (0.54 [0.35 to 0.82]; P = 0.003). CONCLUSIONS: Despite the low rate of bailout stent, DCB treatment for FP-CTO was effective in real-world clinical practice. Hemodialysis, CLTI, and restenosis lesion were independent risk factors for 12-month restenosis, and the use of DAPT significantly attenuated the risk of 12-month restenosis.

Combining transradial access and sheathless femoral access for complex iliac artery chronic total occlusions.

BACKGROUND: The transradial approach (TRA) is associated with fewer serious access site-related complications compared with the transfemoral or transbrachial approach. However, TRA has associated problems in complex aortoiliac (AI) lesions, including the procedural difficulty. A bidirectional approach was used combining TRA with a sheathless technique for femoral artery (FA) puncture to treat complex AI lesions, as a minimally-invasive approach. This report describes a representative cases with AI chronic total occlusion in which the combination of TRA and a sheathless technique for FA puncture was useful for guidewire crossing. CASE PRESENTATION: Case 1 was a 71-year-old man with intermittent claudication (IC). Control angiography showed total occlusion of the left common iliac artery (CIA) ostium to the distal external iliac artery (EIA). Guidewire externalization was achieved by combining TRA using a 6Fr guiding sheath and a sheathless technique for the left FA. Two nitinol stents were deployed in the CIA to EIA. Case 2 was a 63-year-old man with IC. Control angiography revealed total occlusion of the right CIA ostium to the common femoral artery (CFA) with severe calcification. The antegrade wire could not pass through the CTO lesion because of the calcified CFA occlusion. A 21-G metal needle was used to penetrate the CFA calcification through the distal true lumen of the CFA, and the wire was inserted into the EIA for wire externalization. Three nitinol stents were deployed in the CIA to EIA, and a drug-coated balloon was dilated in the CFA with hemostasis of the distal puncture site. In both cases, the retrograde puncture site was hemostatic during the procedure and postoperative bed rest was not required. CONCLUSIONS: TRA combined with a sheathless technique from the FA has the potential to treat AI complex lesions in a less invasive manner.

Optimal Intraluminal Drug-Coated Balloon Versus Drug-Eluting Stent in Patients With Chronic Total Occlusion of the Superficial Femoral Artery: A Retrospective Analysis.

BACKGROUND: Paclitaxel-eluting technologies improve the clinical outcome of femoropopliteal (FP) occlusive disease. Several studies reported efficacy of the high-dose (nominal paclitaxel density of 3.5 µg/mm2) drug-coated balloon (DCB) for complex FP lesions. However, previous studies of DCB have shown a high rate of bailout stents, and few studies have compared the high-dose DCB with successful lesion pre-dilation without bailout stent and drug-eluting stent (DES) in chronic total occlusion (CTO) of the superficial femoral artery (SFA). This study aimed to compare the clinical outcome of high-dose DCB with successful lesion preparation and DES in CTO of the SFA. METHODS: This was a single-center, retrospective study. From June 2018 to November 2020, we compared 41 patients (43 lesions) treated with high-dose DCB and 36 patients (37 lesions) treated with DES. The study period was defined as the period after DCB and DES became available simultaneously at our hospital, when all surviving patients had at least 1 year of follow-up. The primary endpoint was 12-month primary patency. The secondary endpoints were 12-month freedom from: (1) clinically driven target lesion revascularization (CD-TLR), and (2) re-occlusion. RESULTS: Baseline clinical data were comparable between the two groups. Reference vessel diameter was smaller in the DCB group. The mean lesion and occlusion lengths were about the same in both groups. The subintimal angioplasty and bailout stent rate was 0% in the DCB group. The Kaplan-Meier estimate for 12-month primary patency was 92.0% in the DCB group and 87.2% in the DES group (p = 0.47). Freedom from CD-TLR also did not differ significantly between the two groups. The 12-month freedom from re-occlusion rate tended to be higher in the DCB group than in the DES group. CONCLUSIONS: High-dose DCB with successful lesion preparation showed 12-month clinical outcomes comparable with DES for CTO of the SFA, even without bailout stents.

Efficacy of navigating through the intraplaque route using AnteOwl WR intravascular ultrasound in femoropopliteal chronic total occlusion.

BACKGROUND: There is no consensus on the optimal guidewire passage route for femoropopliteal (FP) chronic total occlusion (CTO). If intraplaque wiring can be performed, a stent-less strategy using a drug-coated balloon can be realized even with FP CTO, and there is a high possibility that good expansion can be obtained even when stent deployment is performed. AnteOwl WR (AnteOwl) is a novel intravascular ultrasound (IVUS) device useful for navigating the second guidewire into the intraplaque route under IVUS observation from the subintimal space. Here, we describe representative cases of FP CTO in which CTO-specific IVUS was extremely useful. CASE PRESENTATION: Case 1 involved a 79-year-old man with total occlusion of the left superficial femoral artery (SFA). We used a contralateral antegrade approach, but the guidewire was advanced into the subintimal space. We advanced AnteOwl into the CTO. By utilizing the asymmetric structure of the transducer and the IVUS wire, we were able to reflect the positional relationship among the IVUS transducer, IVUS wire, and target plaque onto the angiographic image. By aiming the wiring in that direction, we succeeded in traversing the center of the plaque and finally succeeded in obtaining good expansion using the drug-coated balloon. Case 2 involved a 76-year-old woman with total occlusion from the SFA to the popliteal artery. We used an ipsilateral antegrade approach. When AnteOwl was placed on the wire and advanced to the popliteal artery, the subintimal space in the middle of the SFA could be visualized. We employed an IVUS-guided parallel wiring technique and succeeded in passing through all intraplaque routes. Although the CTO was long, we could easily advance through the intraplaque route by reflecting the information obtained from AnteOwl in angiography. CONCLUSIONS: AnteOwl is an effective IVUS for FP CTO and facilitates a complex IVUS-guided procedure.

FUS interacts with nuclear matrix-associated protein SAFB1 as well as Matrin3 to regulate splicing and ligand-mediated transcription.

FUS (Fused-in-Sarcoma) is a multifunctional DNA/RNA binding protein linked to familial amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). Since FUS is localized mainly in the nucleus with nucleo-cytoplasmic shuttling, it is critical to understand physiological functions in the nucleus to clarify pathogenesis. Here we report a yeast two-hybrid screening identified FUS interaction with nuclear matrix-associated protein SAFB1 (scaffold attachment factor B1). FUS and SAFB1, abundant in chromatin-bound fraction, interact in a DNA-dependent manner. N-terminal SAP domain of SAFB1, a DNA-binding motif, was required for its localization to chromatin-bound fraction and splicing regulation. In addition, depletion of SAFB1 reduced FUS's localization to chromatin-bound fraction and splicing activity, suggesting SAFB1 could tether FUS to chromatin compartment thorough N-terminal DNA-binding motif. FUS and SAFB1 also interact with Androgen Receptor (AR) regulating ligand-dependent transcription. Moreover, FUS interacts with another nuclear matrix-associated protein Matrin3, which is muted in a subset of familial ALS cases and reportedly interacts with TDP-43. Interestingly, ectopic ALS-linked FUS mutant sequestered endogenous Matrin3 and SAFB1 in the cytoplasmic aggregates. These findings indicate SAFB1 could be a FUS's functional platform in chromatin compartment to regulate RNA splicing and ligand-dependent transcription and shed light on the etiological significance of nuclear matrix-associated proteins in ALS pathogenesis.

Treatment with a Global Methyltransferase Inhibitor Induces the Intranuclear Aggregation of ALS-Linked FUS Mutant In Vitro.

FUS/TLS (fused in sarcoma/translocated in liposarcoma) encodes a multifunctional DNA/RNA binding protein with non-classical carboxy (C)-terminal nuclear localization signal (NLS). A variety of ALS-linked mutations are clustered in the C-terminal NLS, resulting in the cytoplasmic mislocalization and aggregation. Since the arginine methylations are implicated in the nuclear-cytoplasmic shuttling of FUS, a methylation inhibitor could be one of therapeutic targets for FUS-linked ALS. We here examined effects of methylation inhibitors on the cytoplasmic mislocalization and aggregates of ALS-linked C-terminal FUS mutant in a cell culture system. Treatment with adenosine dialdehyde (AdOx), a representative global methyltransferase inhibitor, remarkably mitigated the cytoplasmic mislocalization and aggregation of FUS mutant, which is consistent with previous reports. However, AdOx treatment of higher concentration and longer time period evoked the intranuclear aggregation of the ectopic expressed FUS protein. The pull down assay and the morphological analysis indicated the binding between FUS and Transportin could be potentiated by AdOx treatment through modulating methylation status in RGG domains of FUS. These findings indicated the treatment with a methylation inhibitor at the appropriate levels could alleviate the cytoplasmic mislocalization but in excess this could cause the intranuclear aggregation of FUS C-terminal mutant.

Aggregation of ALS-linked FUS mutant sequesters RNA binding proteins and impairs RNA granules formation.

Protein aggregate/inclusion is one of hallmarks for neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). FUS/TLS, one of causative genes for familial ALS, encodes a multifunctional DNA/RNA binding protein predominantly localized in the nucleus. C-terminal mutations in FUS/TLS cause the retention and the inclusion of FUS/TLS mutants in the cytoplasm. In the present study, we examined the effects of ALS-linked FUS mutants on ALS-associated RNA binding proteins and RNA granules. FUS C-terminal mutants were diffusely mislocalized in the cytoplasm as small granules in transiently transfected SH-SY5Y cells, whereas large aggregates were spontaneously formed in ∼10% of those cells. hnRNP A1, hnRNP A2, and SMN1 as well as FUS wild type were assembled into stress granules under stress conditions, and these were also recruited to FUS mutant-derived spontaneous aggregates in the cytoplasm. These aggregates stalled poly(A) mRNAs and sequestered SMN1 in the detergent insoluble fraction, which also reduced the number of nuclear oligo(dT)-positive foci (speckles) in FISH (fluorescence in situ hybridization) assay. In addition, the number of P-bodies was decreased in cells harboring cytoplasmic granules of FUS P525L. These findings raise the possibility that ALS-linked C-terminal FUS mutants could sequester a variety of RNA binding proteins and mRNAs in the cytoplasmic aggregates, which could disrupt various aspects of RNA equilibrium and biogenesis.