Loss of SIRT1 in diabetes accelerates DNA damage-induced vascular calcification.

AIMS: Vascular calcification is a recognized predictor of cardiovascular risk in the diabetic patient, with DNA damage and accelerated senescence linked to oxidative stress-associated pathological calcification. Having previously shown that systemic SIRT1 is reduced in diabetes, the aim was to establish whether SIRT1 is protective against a DNA damage-induced senescent and calcified phenotype in diabetic vascular smooth muscle cells (vSMCs). METHODS AND RESULTS: Immunohistochemistry revealed decreased SIRT1 and increased DNA damage marker expression in diabetic calcified arteries compared to non-diabetic and non-calcified controls, strengthened by findings that vSMCs isolated from diabetic patients show elevated DNA damage and senescence, assessed by the Comet assay and telomere length. Hyperglycaemic conditions were used and induced DNA damage and enhanced senescence in vSMCs in vitro. Using H2O2 as a model of oxidative stress-induced DNA damage, pharmacological activation of SIRT1 reduced H2O2 DNA damage-induced calcification, prevented not only DNA damage, as shown by reduced comet tail length, but also decreased yH2AX foci formation, and attenuated calcification. While Ataxia Telanglectasia Mutated (ATM) expression was reduced following DNA damage, in contrast, SIRT1 activation significantly increased ATM expression, phosphorylating both MRE11 and NBS1, thus allowing formation of the MRN complex and increasing activation of the DNA repair pathway. CONCLUSION: DNA damage-induced calcification is accelerated within a diabetic environment and can be attenuated in vitro by SIRT1 activation. This occurs through enhancement of the MRN repair complex within vSMCs and has therapeutic potential within the diabetic patient.

Retained Functionality of Atherosclerotic Human Arteries Following Photoactivated Linking of the Extracellular Matrix by Natural Vascular Scaffolding Treatment.

In this study, we investigated natural vascular scaffolding (NVS) treatment on vascular functionality using freshly isolated human popliteal arteries in vitro. Arteries were exposed to intraluminal NVS treatment consisting of a compound (4 amino-1,8-naphthalimide) photoactivated by a 450-nm light-emitting light fiber placed inside the artery. This procedure results in covalent linking between the extracellular matrix proteins to achieve a larger vessel diameter post-angioplasty and minimizing elastic recoil. Immediately following NVS treatment, rings were cut from the treated arteries and mounted in organ baths for contractility testing in response to U46619 and sodium nitroprusside. We also investigated the effect of NVS treatment on IL-6 cytokine release from vascular rings following a 4-h organoculture post-NVS treatment. Based on our results, we conclude that exposure of the vessels to NVS treatment does not adversely affect the contractile responsiveness of the vascular smooth muscle and exerts no pro-inflammatory effect. Graphical abstract.

Acute mitochondrial antioxidant intake improves endothelial function, antioxidant enzyme activity, and exercise tolerance in patients with peripheral artery disease.

Peripheral artery disease (PAD) is a manifestation of atherosclerosis in the leg arteries, which causes claudication. This may be in part due to vascular mitochondrial dysfunction and excessive reactive oxygen species (ROS) production. A mitochondrial-targeted antioxidant (MitoQ) has been shown to improve vascular mitochondrial function that, in turn, led to improved vascular function in older adults and animal models. However, the roles of vascular mitochondria in vascular function including endothelial function and arterial stiffness in patients with PAD are unknown; therefore, with the use of acute MitoQ intake, this study examined the roles of vascular mitochondria in endothelial function, arterial stiffness, exercise tolerance, and skeletal muscle function in patients with PAD. Eleven patients with PAD received either MitoQ or placebo in a randomized crossover design. At each visit, blood samples, brachial and popliteal artery flow-mediated dilation (FMD), peripheral and central pulse-wave velocity (PWV), blood pressure (BP), maximal walking capacity, time to claudication (COT), and oxygen utility capacity were measured pre- and-post-MitoQ and placebo. There were significant group by time interactions (P < 0.05) for brachial and popliteal FMD that both increased by Δ2.6 and Δ3.3%, respectively, and increases superoxide dismutase (Δ0.03 U/mL), maximal walking time (Δ73.8 s), maximal walking distance (Δ49.3 m), and COT (Δ44.2 s). There were no changes in resting heart rate, BP, malondialdehyde, total antioxidant capacity, PWV, or oxygen utility capacity (P > 0.05). MitoQ intake may be an effective strategy for targeting the vascular mitochondrial environment, which may be useful for restoring endothelial function, leg pain, and walking time in patients with PAD.NEW & NOTEWORTHY The results of this study reveal for the first time that acute oral intake of mitochondrial-targeted antioxidant (MitoQ, 80 mg) is effective for improving vascular endothelial function and superoxide dismutase in patients with peripheral artery disease (PAD). Acute MitoQ intake is also effective for improving maximal walking capacity and delaying the onset of claudication in patients with PAD. These findings suggest that the acute oral intake of MitoQ-mediated improvements in vascular mitochondria play a pivotal role for improving endothelial function, the redox environment, and skeletal muscle performance in PAD.

Eight weeks of fish oil supplementation does not prevent sitting-induced leg endothelial dysfunction.

Prolonged sitting impairs leg endothelial function and this impairment is thought to be mediated by a sustained reduction in blood flow-induced shear stress. However, whether nutritional strategies can be used to prevent sitting-induced leg endothelial dysfunction remains unknown. Herein, we tested the hypothesis that 8 weeks of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation would prevent endothelial dysfunction associated with sitting. Nineteen healthy men were randomly assigned to a placebo group or EPA+DHA group in a double-blind fashion. The EPA+DHA group was administered EPA-rich fish oil, containing 600 mg EPA and 260 mg DHA per day for 8 weeks. The placebo group received matching capsules for the same duration of time. Popliteal artery flow-mediated dilation (FMD) was measured at baseline and before and after a 3-h sitting period. During sitting, blood pressure, popliteal artery diameter, and blood velocity were measured every hour. Throughout the sitting period, popliteal artery blood flow and shear rate were markedly and similarly reduced in both groups (P < 0.05). However, counter to the hypothesis, 3 h of sitting impaired popliteal artery FMD to the same extent in both groups (P < 0.05). In conclusion, daily EPA and DHA supplementation is not effective at preventing the detrimental effects of prolonged sitting on leg endothelial function. Novelty We provide evidence that sitting-induced leg endothelial dysfunction in young healthy subjects cannot be remediated by a nutritional strategy known to produce cardiovascular benefits. This could be partially due to the low total dose of EPA and DHA administered.

[Comparison of efficacy of rivaroxaban and warfarin after open operations on the infrainguinal segment]. / Sravnenie éffektivnosti rivaroksabana i varfarina posle otkrytykh operatsii na infraingvinal'nom segmente.

The authors analysed oral anticoagulant agents prescribed in the postoperative period to patients after endured reconstructive operative intervention on arteries of the femorotibial segment. The study included a total of 104 patients subjected to femoropopliteal or femorotibial bypass grafting using an autologous vein or a prosthesis. Depending on the prescribed anticoagulation agent, the patients were subdivided into two groups. Group One patients (n=43) in the postoperative period received rivaroxaban, and Group Two patients (n=61) took warfarin. Efficacy of therapy was evaluated by the frequency of haemorrhage and thromboses in the early and remote postoperative periods. The findings of the immediate postoperative period demonstrated comparable rates of haemorrhagic complications, early thromboses and redo interventions in both Groups (p=0.7). The duration of long-term postoperative period varied from 3 months to 5 years. No statistically significant differences in patency of the performed reconstructions were revealed between the groups. The 3-year primary assisted patency rate in the rivaroxaban group and warfarin group amounted to 89 and 80%, respectively. The incidence of haemorrhagic complications in the postoperative period was insignificant in the studied groups. Hence, rivaroxaban may be prescribed in the early and remote postoperative period to patients who underwent open reconstructive operative intervention on arteries of the infrainguinal zone.

Biologic Drug Effect and Particulate Embolization of Drug-Eluting Stents versus Drug-Coated Balloons in Healthy Swine Femoropopliteal Arteries.

PURPOSE: To compare the drug effect in treated vessels and downstream effects in distal skeletal muscle of drug-coated balloons (DCBs) and drug-eluting stents (DESs) in a healthy preclinical swine model. MATERIALS AND METHODS: Four groups of treated iliofemoral arteries (percutaneous transluminal angioplasty [PTA]+DES, DCB+DES, DCB+bare metal stent [BMS], and DCB alone) of 12 healthy swine were assessed, with euthanasia at 30 days. Biological drug effect was evaluated using smooth muscle cell (SMC) loss score according to both depth and circumference as well as a neointimal fibrin and medial proteoglycan scores which were compared between the 4 groups. Vascular and skeletal muscle changes in regions downstream from the treated site were also assessed histologically for evidence of emboli. RESULTS: DESs showed greater medial SMC loss in the treated arteries irrespective of preceding DCB or PTA treatment in terms of depth (DCB+DES vs PTA+DES vs DCB+BMS vs DCB alone; median, 4.0 mm vs 3.8 mm vs 3.0 mm vs 2.2 mm; P = .009) and circumference (4.0 mm vs 3.5 mm vs 2.0 mm vs 1.2 mm, respectively; P = .007). Sections of skeletal muscles downstream from the treated arteries showed arteriolar changes of fibrinoid necrosis consistent with paclitaxel effect exclusively in the DCB groups (DCB+BMS, 26.9% of sections; DCB+DES, 14.3%; DCB alone, 19.2%; PTA+DES, 0%; P = .02). CONCLUSIONS: In the treated arteries, irrespective of preceding DCB treatment or PTA, DES treatment showed maximum drug effects vs DCB alone or in combination with BMS placement, and there was no detrimental toxic effect in DCB-treated iliofemoral arteries before DES treatment compared with PTA before DES treatment. Downstream vascular changes were exclusively seen in groups treated with DCBs.

Sustained Effectiveness of Cilostazol After Endovascular Treatment of Femoropopliteal Lesions: Midterm Follow-up From the Sufficient Treatment of Peripheral Intervention by Cilostazol (STOP-IC) Study.

PURPOSE: To investigate the midterm safety and effectiveness of cilostazol treatment in claudicant patients undergoing endovascular therapy. METHODS: The Sufficient Treatment of Peripheral Intervention by Cilostazol (STOP-IC) study ( ClinicalTrials.gov identifier NCT00912756; University Hospital Medical Information Network identifier UMIN000002091) enrolled 200 patients (mean age 73 years; 131 men) treated for femoropopliteal disease from March 2009 to April 2011 at 13 cardiovascular centers in Japan. The participants were randomized 1:1 to receive oral aspirin with or without cilostazol. Of the 100 patients assigned to the 2 treatment groups, 7 patients in the cilostazol group and 2 patients in the no-cilostazol group were withdrawn from the study without undergoing endovascular treatment, leaving 93 patients in the cilostazol group and 98 patients in the no-cilostazol group for follow-up analysis. The primary outcome measure was primary patency; secondary outcome measures were freedom from clinically-driven target lesion revascularization (CD-TLR) and overall survival. Outcomes were analyzed on an intention-to-treat basis using the Kaplan-Meier method; estimates were compared with the log-rank test. RESULTS: The median follow-up was 38.1 months (interquartile range 25.1, 47.7). Among the 93 subjects in the cilostazol group, 7 died and 26 withdrew from administration 1 year after the endovascular procedure. Discontinuation of cilostazol was not a significant factor for restenosis. Primary patency was significantly higher in the cilostazol group than in the no-cilostazol group (69% vs 54%, p=0.026) at 3 years. The cilostazol group also had better 3-year freedom from CD-TLR (78% vs 63%, p=0.014), although overall survival estimates did not differ significantly (p=0.95). CONCLUSION: These results suggest that the safety and effectiveness of cilostazol treatment were sustained in patients with femoropopliteal disease undergoing endovascular treatment.

Adventitial Drug Delivery of Dexamethasone to Improve Primary Patency in the Treatment of Superficial Femoral and Popliteal Artery Disease: 12-Month Results From the DANCE Clinical Trial.

OBJECTIVES: This study was designed to evaluate outcomes of adventitial dexamethasone delivery adjunctive to standard endovascular revascularization in femoropopliteal peripheral artery disease. BACKGROUND: Drug-coated balloons and drug-eluting stents improve patency of endovascular interventions with passive diffusion of antiproliferative drugs. Adventitial dexamethasone delivery targets the initial triggers of the inflammatory reaction to injury, thus potentially providing a potent antirestenotic strategy. METHODS: The single-arm DANCE (Dexamethasone to the Adventitia to Enhance Clinical Efficacy After Femoropopliteal Revascularization) trial enrolled 262 subjects (283 limbs) with symptomatic peripheral artery disease (Rutherford category 2 to 4) receiving percutaneous transluminal angioplasty (PTA) (n = 124) or atherectomy (ATX) (n = 159) in femoropopliteal lesions ≤15 cm in length. A mixture of dexamethasone/contrast medium (80%/20%) was delivered to the adventitia and perivascular tissues surrounding target lesions in all subjects. Thirty-day assessments included major adverse limb events (MALE) and post-operative death. Twelve-month assessments included primary patency, freedom from clinically driven target lesion revascularization (CD-TLR), Rutherford scoring, and walking impairment questionnaire. RESULTS: At 12 months, primary patency rates in DANCE-ATX and -PTA per-protocol populations were 78.4% (74.8% intent-to-treat [ITT]) and 75.5% (74.3% ITT), respectively. Rates of CD-TLR in DANCE-ATX and -PTA subjects were 10.0% (13.1% ITT) and 11.0% (13.7% ITT), respectively. There were no 30-day MALE + post-operative death events nor 12-month device- or drug-related deaths or MALE. CONCLUSIONS: Direct adventitial delivery of dexamethasone appears to be an effective and safe therapy to prevent restenosis. Randomized studies are needed to further test this possibility. (Dexamethasone to the Adventitia to Enhance Clinical Efficacy After Femoropopliteal Revascularization [DANCE]; NCT01983449).

The association of statin therapy with the primary patency of femoral and popliteal artery stents.

OBJECTIVE: It has long been known that hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) broadly reduce cardiovascular events in patients with peripheral vascular disease. It was the goal of this study to determine whether there is an association between statin therapy and primary patency after stenting of superficial femoral and popliteal arteries. METHODS: The records of all patients undergoing primary nitinol stenting of the femoral and popliteal arteries at a single institution and by a single surgeon during a 10-year period were reviewed. Demographic characteristics of the patients and risk factors were identified. TransAtlantic Inter-Society Consensus (TASC II) classifications were determined for all stented lesions. Analysis was performed to determine whether the use of statins at the time of stent placement was associated with a change in rates of primary patency. Loss of primary patency was said to have occurred when an intrastent occlusion or a ≥70% stenosis was identified by arterial duplex ultrasound or angiography. Kaplan-Meier survival curves were plotted, and differences between groups were tested by log-rank method. RESULTS: Between 2004 and 2014, primary femoral or popliteal stenting was performed on 308 limbs in 250 patients. At the time of intervention, 52.4% of these patients were being treated with statin therapy; 137 interventions were done for claudication and 113 for critical limb ischemia. Of the lesions treated, 165 were TASC A or B and 85 were TASC C or D. Primary patency rates for all stented lesions were 75%, 54%, and 35% at 12, 24, and 36 months. The patency rates at 12, 24, and 36 months, respectively, were 80%, 55%, and 40% for those taking statins and 68%, 49%, and 28% for those not taking statins (P = .178). Statin therapy demonstrated a trend toward an association with improved primary patency rates in TASC A/B lesions but had no association in TASC C/D lesions (TASC A/B, P = .056; TASC C/D, P = .537). Statin compliance was found to be 87% at a mean follow-up of 24.1 months. CONCLUSIONS: Although the use of statins has been shown to reduce cardiovascular morbidity and mortality in patients with peripheral vascular disease, overall there is not an association of these drugs with improved primary patency after primary stenting of femoral and popliteal artery lesions. However, when limbs are stratified for severity, less severe (TASC A/B) lesions demonstrated a trend toward a significant association between statin use and improved primary patency. This finding was not seen in more severe (TASC C/D) disease.

Long-Term Results from the MAJESTIC Trial of the Eluvia Paclitaxel-Eluting Stent for Femoropopliteal Treatment: 3-Year Follow-up.

PURPOSE: To report the 3-year results of the MAJESTIC first-in-human study of the Eluvia Drug-Eluting Vascular Stent System for treating femoropopliteal artery lesions. METHODS: The prospective, single-arm, multicenter clinical trial enrolled 57 patients with symptomatic lower limb ischemia (Rutherford category 2, 3, or 4) and lesions in the superficial femoral artery or proximal popliteal artery. Mean lesion length was 70.8 ± 28.1 mm, and 46% of lesions were occluded. Efficacy measures at 2 years included primary patency, defined as duplex ultrasound peak systolic velocity ratio of ≤2.5 and the absence of target lesion revascularization (TLR) or bypass. Safety monitoring through 3 years included adverse events and TLR. RESULTS: Primary patency was estimated as 83.5% (Kaplan-Meier analysis) at 24 months, and 90.6% (48/53) of patients maintained an improvement in Rutherford class. At 36 months, the Kaplan-Meier estimate of freedom from TLR was 85.3%. No stent fractures were identified, and no major target limb amputations occurred. CONCLUSION: MAJESTIC results demonstrated long-term treatment durability among patients whose femoropopliteal arteries were treated with the paclitaxel-eluting Eluvia stent. LEVEL OF EVIDENCE: Level 2b, cohort study.

SAFE (Sarpogrelate Anplone in Femoro-popliteal artery intervention Efficacy) study: study protocol for a randomized controlled trial.

BACKGROUND: Sarpogrelate is expected to reduce restenosis by protecting blood vessels from oxidative stress and vascular endothelial dysfunction as well as by acting as an antiplatelet agent after endovascular treatment (EVT). This trial was designed to compare aspirin plus sustained-release (SR) sarpogrelate with aspirin plus clopidogrel for the prevention of restenosis in patients with femoro-popliteal (FP) peripheral artery disease (PAD) who underwent EVT. METHODS/DESIGN: This is an open label, multicenter, prospective randomized controlled clinical trial. Patients will be eligible for inclusion in this study if they require EVT for stenosis or occlusion of a de novo FP lesion. Patients in each group will receive aspirin 100 mg with clopidogrel 75 mg or aspirin 100 mg with SR sarpogrelate 300 mg (Anplone®) orally once a day for six months. The primary outcome of the study is the restenosis rate, defined as > 50% luminal reduction by computed tomography angiography or catheter angiography in the six-month follow-up period. Secondary outcomes include target lesion revascularization, major bleeding, ipsilateral major amputation, all-cause mortality, and all adverse events that take place in those six months. DISCUSSION: This study is a multicenter randomized controlled trial designed to show non-inferiority in terms of the re-stenosis rate of SR sarpogrelate compared to clopidogrel for EVT for PAD in FP lesion patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02959606 . Registered on 9 November 2016.

Impact of Cilostazol Administration on Femoropopliteal In-Stent Restenosis.

PURPOSE: To investigate whether administering cilostazol after treatment for femoropopliteal in-stent restenosis (ISR) can have a positive impact on recurrent ISR (Re-ISR). METHODS: The database of a multicenter, retrospective, observational registry was interrogated to identify 338 consecutive patients (mean age 72.3±8.8 years; 148 men) who underwent endovascular therapy for femoropopliteal ISR in 379 limbs from January 2010 to December 2014. Ninety-seven patients (103 limbs) who received cilostazol after the initial stent implantation procedure were excluded. This left 24 ISR patients (30 limbs) who received cilostazol initially after ISR treatment for comparison with 217 ISR patients (246 limbs) who did not receive the drug. The primary endpoint was 2-year Re-ISR after treatment. The secondary endpoints were recurrent target lesion revascularization (Re-TLR) and reocclusion at 2 years. Restenosis was determined by a peak systolic velocity ratio >2.4 on a duplex scan or >50% stenosis on angiography. RESULTS: The mean follow-up was 23.3±15.5 months. At 2 years, freedom from Re-ISR was significantly higher in the cilostazol group than in the no cilostazol group (48.6% vs 32.4%, p=0.047). However, freedom from Re-TLR and reocclusion between the 2 groups did not differ significantly [64.7% vs 53.8% (p=0.15) and 88.3% vs 73.9% (p=0.11), respectively]. After adjusting for prespecified risk factors, cilostazol administration was a negative predictor of Re-ISR. CONCLUSION: This small comparative study suggests that administering cilostazol for ISR lesions after femoropopliteal stenting reduces recurrent ISR.

Angiographic and Clinical Outcomes After Treatment of Femoro-Popliteal Lesions with a Novel Paclitaxel-Matrix-Coated Balloon Catheter.

OBJECTIVES: Based on a novel paclitaxel-resveratrol drug matrix, the safety and efficacy to inhibit intimal hyperplasia were studied in symptomatic claudicants with morphologically challenging lesions. BACKGROUND: The treatment of peripheral artery occlusive disease (PAOD) with percutaneous transluminal angioplasty is limited by occurrence of vessel recoil and neointimal hyperplasia. Drug-coated balloons (DCB) deliver drugs to the arterial wall to potentially reduce the restenosis rate. A number of paclitaxel-coated balloon technologies are available to treat peripheral lesions. METHODS: In this randomized controlled trial, a total of 153 patients with symptomatic PAOD in femoro-popliteal lesions were randomized either to DCB or plain old balloon angioplasty (POBA). RESULTS: The mean lesion length was 13.2 ± 10.4 cm with target lesion total occlusions in 26.1% of all patients (40/153). The primary endpoint of in-lesion late lumen loss (LLL) at 6 months was significantly reduced in the DCB group as compared to the POBA group (0.35 mm CI [0.19; 0.79 mm] vs. 0.72 mm CI [0.68; 1.22 mm], p = 0.006). At 12 months, the TLR rate in the DCB group was significantly lower as compared to the POBA group (17.8 vs. 37.7% p = 0.008). The censored walking distance increase suggests a benefit for patients who underwent DCB angioplasty as compared to the standard POBA treatment (12 months 165 ± 105 vs. 94 ± 136 m, p = 0.012). CONCLUSION: The use of paclitaxel-resveratrol-matrix-coated peripheral balloon angioplasty as compared to POBA was associated with significantly reduced in-lesion LLL and reduced TLR rates. ClinicalTrials.gov identifier NCT01970579.

Impact of Chronic Renal Failure on Safety and Effectiveness of Paclitaxel-Eluting Stents for Femoropopliteal Artery Disease: Subgroup Analysis from Zilver PTX Post-Market Surveillance Study in Japan.

PURPOSE: Favorable long-term outcomes of the Zilver PTX drug-eluting stent (DES) in femoropopliteal lesions have been demonstrated. Chronic renal failure (CRF) has been shown to be a risk factor for restenosis and decreased limb salvage. The results of the DES in patients with CRF have not previously been reported. This study compares the results with the DES in patients with CRF and those without CRF. METHODS: This retrospective analysis from the Zilver PTX Japan Post-Market Surveillance Study included 321 patients with CRF and 584 patients without CRF. Outcomes included freedom from target lesion revascularization (TLR) and patency. RESULTS: Of the patients included in this subgroup analysis, 2-year data were available for 209 patients in the CRF group and 453 patients in the non-CRF group. The two groups were similar in terms of lesion length and the frequency of in-stent restenosis. Critical limb ischemia, severe calcification, and diabetes were more common in patients with CRF, whereas total occlusion was more common in patients without CRF. Freedom from TLR rates were 81.4 versus 84.9% (p = 0.24), and patency rates were 70.7 versus 70.3% (p = 0.95) in patients with and without CRF at 2 years, respectively. CONCLUSION: This is the first comparative study of the DES in femoropopliteal artery lesions in patients with and without CRF. These results indicate that the DES placed in femoropopliteal artery lesions of CRF patients is safe and effective with similar patency and TLR rates to patients without CRF. LEVEL OF EVIDENCE: Level 3, Post-Market Surveillance Study.

Drug-eluting stenting for femoropopliteal lesions, followed by cilostazol treatment, reduces stent restenosis in patients with symptomatic peripheral artery disease.

BACKGROUND: Cilostazol improves clinical endovascular therapy outcomes for femoropopliteal (FP) lesions in patients with symptomatic peripheral arterial disease, but whether it also has clinical benefits for patients after drug-eluting stent implantation remains unclear. METHODS: This study is a subanalysis of the ZilvEr PTX for tHe Femoral ArterY and Proximal Popliteal ArteRy (ZEPHYR) study, a prospective multicenter study investigating FP lesions treated with the Zilver (Cook Medical, Bloomington, Ind) paclitaxel-eluting stent. The present study analyzed 475 lesions in 459 limbs of 399 patients who maintained therapy with aspirin and thienopyridine, with or without cilostazol, during the 1-year follow-up period. RESULTS: Restenosis rates at 1 year were assessed with duplex ultrasound imaging (peak systolic velocity ratio >2.4) or angiography (≥50% diameter stenosis) and compared in the groups with and without cilostazol. Propensity score matching was performed to minimize intergroup differences in baseline characteristics. The present study included 93 cilostazol-treated and 382 cilostazol-free cases. Among the patients, 71% had diabetes mellitus and 31% were on dialysis. Critical limb ischemia accounted for 29% of cases. The prevalence of de novo lesions was 76%, and in-stent restenosis was present in 15%. Propensity score matching was performed in 91 pairs. The 1-year restenosis rate was 33% (95% confidence interval [CI], 23%-43%) in the cilostazol-treated group and 51% (95% CI, 41%-62%) in the cilostazol-free group (P = .008). The odds ratio was 0.5 (95% CI, 0.3-0.8). CONCLUSIONS: The propensity score-matching analysis demonstrated that additional cilostazol administration was associated with a significantly lower restenosis incidence 1 year after drug-eluting stent implantation for FP lesions.

Vascular function and endothelin-1: tipping the balance between vasodilation and vasoconstriction.

Endothelin-1 (ET-1), a potent vasoconstrictor secreted by vascular endothelial cells, has been implicated in the pathophysiology of numerous cardiovascular diseases, yet the direct impact of ET-1 on vascular function remains unclear. Therefore, in seven young (23 ± 1 yr) healthy subjects, we investigated the effect of an intra-arterial infusion of ET-1 on reactive hyperemia (RH) and flow-mediated dilation (FMD) in the popliteal artery following 5 min of suprasystolic cuff occlusion. ET-1 infusion significantly attenuated basal leg blood flow (control: 62 ± 4 ml/min, ET-1: 47 ± 9 ml/min), RH [area-under-curve (AUC); control: 162 ± 15 ml, ET-1: 104 ± 16 ml], and peak RH (control: 572 ± 51 ml/min, ET-1: 412 ± 32 ml/min) (P < 0.05). Administration of ET-1 also reduced FMD (control: 2.4 ± 0.3%, ET-1: 0.5 ± 0.5%) and FMD normalized for shear rate (control: 10.5 × 10-4 ± 2.0 × 10-4%/s-1, ET-1: 0.9 × 10-4 ± 2.8 ×10-4%/s-1). These findings reveal that elevated levels of ET-1 have a significant impact on vascular function, indicating that studies employing RH and FMD as markers of microvascular function and nitric oxide bioavailability, respectively, should exercise caution, as ET-1 can impact these assessments by tipping the balance between vasodilation and vasoconstriction, in favor of the latter.NEW & NOTEWORTHY Endothelin-1 (ET-1) is recognized as the body's most potent endogenous vasoconstrictor, but the impact of this peptide on vascular function is not well understood. The present study revealed that the intra-arterial administration of ET-1 impaired both microvascular and conduit vessel function of the leg in young, healthy, humans. Studies employing vascular testing in patient cohorts that experience a disease-related increase in ET-1 should thus exercise caution, as ET-1 clearly impairs vascular function.

Local Ultrasound to Enhance Paclitaxel Delivery After Femoral-Popliteal Treatment in Critical Limb Ischemia: The PACUS Trial.

OBJECTIVES: The aim of this study was to evaluate the safety and efficacy of percutaneous catheter-delivered ultrasound energy to improve local paclitaxel delivery effects in patients with critical limb ischemia (CLI) treated for femoral-popliteal arterial disease. BACKGROUND: Treatment of patients with CLI continues to be the greatest challenge in peripheral artery disease; in particular, treatment of femoral-popliteal chronic total occlusion is characterized by poor primary patency. METHODS: This single-center, single-blind, randomized trial included 56 patients with CLI randomly assigned to treatment in 2 groups: 28 patients (the control group) were treated with drug-eluting balloons, and 28 patients (the study group) were treated with intravascular ultrasound using the CardioProlific Genesis System followed by local administration of a liquid mixture of iopromide 370 and paclitaxel 1.0 µg/mm3. In the study group, mean lesion length was 168.8 mm, and 21 patients had calcifications. In the control group, mean lesion length was 164 mm, and 23 patients had calcifications. RESULTS: No adverse procedural events were observed; all 56 patients tolerated the procedure well. At 6-month follow-up, no myocardial infarction, deaths, or amputations were observed in either group. In the study group, the rate of restenosis at 6 months was 3.6% (1 of 28), and the rate of target lesion revascularization (TLR) was 0% (0 of 28); at 12 months, the rate of TLR was 3.8% (1 of 26), and the rate of amputation was 0% (0 of 26). In the control group, the rate of restenosis at 6 months was 21.4% (6 of 28), and the rate of TLR was 10.7% (3 of 28); at 12 months, the rate of TLR was 36% (9 of 25), and the rate of amputation was 16% (4 of 25). CONCLUSIONS: This study demonstrates encouraging results at 6- and 12-month follow-up in patients treated with ultrasound and paclitaxel compared with drug-eluting balloons. Larger multicenter studies are required to validate this approach.

Drug-Coated Balloons for Complex Femoropopliteal Lesions: 2-Year Results of a Real-World Registry.

OBJECTIVES: The authors sought to investigate the efficacy of a drug-coated balloon (DCB) for treatment of complex femoropopliteal lesions. BACKGROUND: Superiority of DCBs compared with uncoated balloon angioplasty for femoropopliteal interventions has been demonstrated in randomized trials for short lesions. Their performance in complex lesions with higher restenosis rates is unclear. METHODS: Patency, target lesion revascularization (TLR) rate, clinical improvement, and safety endpoints of femoropopliteal lesions in 288 limbs (n = 260) treated with the In.Pact Pacific or Admiral DCB (Medtronic, Minneapolis, Minnesota) were retrospectively analyzed for up to 2 years of follow-up. Predictors of restenosis were identified by logistic regression. RESULTS: Lesions were de novo in 51.7%, restenosis in 11.1%, and in-stent restenosis in 37.2%. Mean lesion length was 24.0 ± 10.2 cm, and 65.3% were occluded. Stent implantation was performed in 23.3%. Kaplan Meier estimates of primary patency were 79.2% and 53.7% for all lesions at 1 and 2 years, respectively, whereas freedom from TLR was 85.4% and 68.6%. Primary patency for in-stent restenosis treatment was 76.6% and 48.6%, and freedom from TLR was 83.0% and 58.7% at 1 and 2 years, respectively. Rutherford category improved from a median 3.3 to 1.2 at 1 year, and to 1.1 at 2 years. Major amputation rate was 2.1% at 2 years. No adverse events were thought to be attributable to the coating of the balloon. CONCLUSIONS: These results suggest that DCB are safe and effective in delaying rather than preventing restenosis in long, complex lesions and restenosis of the femoropopliteal tract. Further studies are recommended to confirm these results.

Durable Clinical Effectiveness With Paclitaxel-Eluting Stents in the Femoropopliteal Artery: 5-Year Results of the Zilver PTX Randomized Trial.

BACKGROUND: This randomized controlled trial evaluated clinical durability of Zilver PTX, a paclitaxel-coated drug-eluting stent (DES), for femoropopliteal artery lesions. Outcomes compare primary DES versus percutaneous transluminal angioplasty (PTA), overall DES (primary and provisional) versus standard care (PTA and provisional Zilver bare metal stent [BMS]), and provisional DES versus provisional BMS. METHODS AND RESULTS: Patients with symptomatic femoropopliteal artery disease were randomly assigned to DES (n=236) or PTA (n=238). Approximately 91% had claudication; 9% had critical limb ischemia. Patients experiencing acute PTA failure underwent secondary randomization to provisional BMS (n=59) or DES (n=61). The 1-year primary end points of event-free survival and patency showed superiority of primary DES in comparison with PTA; these results were sustained through 5 years. Clinical benefit (freedom from persistent or worsening symptoms of ischemia; 79.8% versus 59.3%, P<0.01), patency (66.4% versus 43.4%, P<0.01), and freedom from reintervention (target lesion revascularization, 83.1% versus 67.6%, P<0.01) for the overall DES group were superior to standard care in nonrandomized comparisons. Similarly, clinical benefit (81.8% versus 63.8%, P=0.02), patency (72.4% versus 53.0%, P=0.03), and freedom from target lesion revascularization (84.9% versus 71.6%, P=0.06) with provisional DES were improved over provisional BMS. These results represent >40% relative risk reduction for restenosis and target lesion revascularization through 5 years for the overall DES in comparison with standard care and for provisional DES in comparison with provisional BMS. CONCLUSIONS: The 5-year results from this large study provide long-term information previously unavailable regarding endovascular treatment of femoropopliteal artery disease. The Zilver PTX DES provided sustained safety and clinical durability in comparison with standard endovascular treatments. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00120406.