Fluorescence lifetime imaging in retinal artery occlusion.

PURPOSE Fluorescence lifetime imaging ophthalmoscopy is a technique to measure decay times of endogenous retinal fluorophores. The purpose of this study was to investigate fluorescence lifetimes in eyes with central and branch retinal artery occlusion. METHODS Twenty-four patients with central or branch retinal artery occlusion were included in this study. The contralateral unaffected fellow eye was used as control. Measurements were performed using a fluorescence lifetime imaging ophthalmoscope based on a HRA Spectralis system. Fluorescence excitation wavelength was 473 nm, and mean lifetimes were measured in a short (498-560 nm) and in a long (560-720 nm) spectral channel. Fluorescence lifetimes in the area of retinal artery occlusion were measured and compared to corresponding areas in contralateral unaffected eyes. Additionally, findings were correlated to optical coherence tomography measurements. RESULTS Retinal lifetime images of 24 patients with retinal artery occlusion were analyzed. Mean retinal fluorescence lifetimes were prolonged by 50% in the short and 20% in the long spectral channel in ischemic retinal areas up to 3 days after retinal artery occlusion compared to the contralateral unaffected eyes. In the postacute disease stage there was no difference between the lifetimes of affected areas and unaffected fellow eyes. CONCLUSIONS Retinal artery occlusion leads to significantly longer fluorescence lifetimes of the retina in the acute phase and may serve as a useful indicator for acute ischemic retinal damage.

High-flow venous pouch aneurysm in the rabbit carotid artery: A model for large aneurysms.

BACKGROUND AND PURPOSE Currently one of the most widely used models for the development of endovascular techniques and coiling devices for treatment of aneurysm is the elastase-induced aneurysm model in the rabbit carotid artery. Microsurgical techniques for creating an aneurysm with a venous pouch have also been established, although both techniques usually result in aneurysms less than 1 cm in diameter. We investigated whether an increase in blood flow toward the neck would produce larger aneurysms in a microsurgical venous pouch model. MATERIALS AND METHODS Microsurgical operations were performed on 11 New Zealand white rabbits. Both carotid arteries and the right jugular vein were dissected, and the right carotid artery was temporarily clipped followed by an arteriotomy. The left carotid artery was also clipped proximally, ligated distally, and sutured onto the proximal half of the arteriotomy in the right carotid artery. The venous graft was sutured onto the distal half of the arteriotomy. Digital subtraction angiography was also performed. RESULTS Angiography showed patent anastomosed vessels and aneurysms in the seven surviving rabbits. Mean aneurysm measurements among surviving rabbits with patent vessels were: 13.9 mm length, 9.3 mm width, and neck diameter 4.7 mm. The resulting mean aspect ratio was 3.35 and the mean bottleneck ratio was 3.05. CONCLUSION A large venous graft and increased blood flow toward the base of the aneurysm seem to be key factors in the creation of large venous pouch aneurysms. These large aneurysms allow testing of endovascular devices designed for large and giant aneurysms.

Finite element analysis predicts experimental failure patterns in vertebral bodies loaded via intervertebral discs up to large deformation

Vertebral compression fracture is a common medical problem in osteoporotic individuals. The quantitative computed tomography (QCT)-based finite element (FE) method may be used to predict vertebral strength in vivo, but needs to be validated with experimental tests. The aim of this study was to validate a nonlinear anatomy specific QCT-based FE model by using a novel testing setup. Thirty-seven human thoracolumbar vertebral bone slices were prepared by removing cortical endplates and posterior elements. The slices were scanned with QCT and the volumetric bone mineral density (vBMD) was computed with the standard clinical approach. A novel experimental setup was designed to induce a realistic failure in the vertebral slices in vitro. Rotation of the loading plate was allowed by means of a ball joint. To minimize device compliance, the specimen deformation was measured directly on the loading plate with three sensors. A nonlinear FE model was generated from the calibrated QCT images and computed vertebral stiffness and strength were compared to those measured during the experiments. In agreement with clinical observations, most of the vertebrae underwent an anterior wedge-shape fracture. As expected, the FE method predicted both stiffness and strength better than vBMD (R2 improved from 0.27 to 0.49 and from 0.34 to 0.79, respectively). Despite the lack of fitting parameters, the linear regression of the FE prediction for strength was close to the 1:1 relation (slope and intercept close to one (0.86 kN) and to zero (0.72 kN), respectively). In conclusion, a nonlinear FE model was successfully validated through a novel experimental technique for generating wedge-shape fractures in human thoracolumbar vertebrae.

A review of antithrombotic therapy and the rationale and design of the randomized edoxaban in patients with peripheral artery disease (ePAD) trial adding edoxaban or clopidogrel to aspirin after femoropopliteal endovascular intervention.

Compared with the coronary setting, knowledge about antithrombotic therapies after endovascular treatment (EVT) is inadequate in patients with peripheral artery disease (PAD). Based on a review of trials and guidelines, which is summarized in this article, there is scant evidence that antithrombotic drugs improve outcome after peripheral EVT. To address this knowledge gap, the randomized, open-label, multinational edoxaban in patients with Peripheral Artery Disease (ePAD) study (ClinicalTrials.gov identifier NCT01802775) was designed to explore the safety and efficacy of a combined regimen of antiplatelet therapy with clopidogrel and anticoagulation with edoxaban, a selective and direct factor Xa inhibitor, both combined with aspirin. As of July 2014, 203 patients (144 men; mean age 67 years) from 7 countries have been enrolled. These patients have been allocated to once-daily edoxaban [60 mg for 3 months (or 30 mg in the presence of factors associated with increased exposure)] or clopidogrel (75 mg/d for 3 months). All patients received aspirin (100 mg/d) for the 6-month duration of the study. The primary safety endpoint is major or clinically relevant nonmajor bleeding; the primary efficacy endpoint is restenosis or reocclusion at the treated segment(s) measured at 1, 3, and 6 months using duplex ultrasound scanning. All outcomes will be assessed and adjudicated centrally in a masked fashion. The ePAD study is the first of its kind to investigate a combined regimen of antiplatelet therapy and anticoagulation through factor Xa inhibition with edoxaban.

Stent placement vs. balloon angioplasty for popliteal artery treatment: two-year results of a prospective, multicenter, randomized trial.

PURPOSE To investigate the 2-year technical and clinical results of primary nitinol stent placement in comparison with percutaneous transluminal angioplasty (PTA) in the treatment of de novo lesions of the popliteal artery. METHODS The ETAP study (Endovascular Treatment of Atherosclerotic Popliteal Artery Lesions: balloon angioplasty vs. primary stenting; www.ClinicalTrials.gov identifier NCT00712309) is a prospective, randomized trial that enrolled 246 patients (158 men; mean age 72 years) who were randomly assigned to receive a nitinol stent (n=119) or PTA (n=127) for lesions averaging 42.3 mm in length. The results of the primary study endpoint were published. Secondary outcome measures and endpoints included primary patency (freedom from duplex-detected target lesion restenosis), target lesion revascularization (TLR), secondary patency, changes in ankle-brachial index and Rutherford class, and event-free survival (freedom from target limb amputation, TLR, myocardial infarction, and death). RESULTS In total, 183 patients (89 stent and 94 PTA) were available for the 2-year analysis. The primary patency rate was significantly higher in the stent group (64.2%) than in the PTA group (31.3%, p=0.0001). TLR rates were 22.4% and 59.5%, respectively (p=0.0001). When provisional stent placement in the PTA arm was not considered as TLR and loss in patency, the differences prevailed between the study groups but were not significant (64.2% vs. 56.1% for primary patency, respectively; p=0.44). A significant improvement in ABI and Rutherford category was observed at 2 years in both groups. CONCLUSION In treatment of obstructive popliteal artery lesions, provisional stenting reveals equivalent patency in comparison to primary stenting. However, the 2-year results of this trial suggest the possibility of a shift toward higher patency rates in favor of primary stenting.

First report of the Global SYMPLICITY Registry on the effect of renal artery denervation in patients with uncontrolled hypertension.

UNLABELLED This study aimed to assess the safety and effectiveness of renal denervation using the Symplicity system in real-world patients with uncontrolled hypertension (NCT01534299). The Global SYMPLICITY Registry is a prospective, open-label, multicenter registry. Office and 24-hour ambulatory blood pressures (BPs) were measured. Change from baseline to 6 months was analyzed for all patients and for subgroups based on baseline office systolic BP, diabetic status, and renal function; a cohort with severe hypertension (office systolic pressure, ≥160 mm Hg; 24-hour systolic pressure, ≥135 mm Hg; and ≥3 antihypertensive medication classes) was also included. The analysis included protocol-defined safety events. Six-month outcomes for 998 patients, including 323 in the severe hypertension cohort, are reported. Mean baseline office systolic BP was 163.5±24.0 mm Hg for all patients and 179.3±16.5 mm Hg for the severe cohort; the corresponding baseline 24-hour mean systolic BPs were 151.5±17.0 and 159.0±15.6 mm Hg. At 6 months, the changes in office and 24-hour systolic BPs were -11.6±25.3 and -6.6±18.0 mm Hg for all patients (P<0.001 for both) and -20.3±22.8 and -8.9±16.9 mm Hg for those with severe hypertension (P<0.001 for both). Renal denervation was associated with low rates of adverse events. After the procedure through 6 months, there was 1 new renal artery stenosis >70% and 5 cases of hospitalization for a hypertensive emergency. In clinical practice, renal denervation resulted in significant reductions in office and 24-hour BPs with a favorable safety profile. Greater BP-lowering effects occurred in patients with higher baseline pressures. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov. Unique identifier: NCT01534299.

The Initial Slope of the Variogram, Foundation of the Trabecular Bone Score, Is Not or Poorly Associated With Vertebral Strength

Trabecular bone score (TBS) rests on the textural analysis of DXA to reflect the decay in trabecular structure characterising osteoporosis. Yet, its discriminative power in fracture studies remains incomprehensible as prior biomechanical tests found no correlation with vertebral strength. To verify this result possibly due to an unrealistic set-up and to cover a wide range of loading scenarios, the data from three previous biomechanical studies using different experimental settings was used. They involved the compressive failure of 62 human lumbar vertebrae loaded 1) via intervertebral discs to mimic the in vivo situation (“full vertebra”), 2) via the classical endplate embedding (“vertebral body”) or 3) via a ball joint to induce anterior wedge failure (“vertebral section”). HR-pQCT scans acquired prior testing were used to simulate anterior-posterior DXA from which areal bone mineral density (aBMD) and the initial slope of the variogram (ISV), the early definition of TBS, were evaluated. Finally, the relation of aBMD and ISV with failure load (Fexp) and apparent failure stress (σexp) was assessed and their relative contribution to a multi-linear model was quantified via ANOVA. We found that, unlike aBMD, ISV did not significantly correlate with Fexp and σexp, except for the “vertebral body” case (r2 = 0.396, p = 0.028). Aside from the “vertebra section” set-up where it explained only 6.4% of σexp (p = 0.037), it brought no significant improvement to aBMD. These results indicate that ISV, a replica of TBS, is a poor surrogate for vertebral strength no matter the testing set-up, which supports the prior observations and raises a fortiori the question of the deterministic factors underlying the statistical relationship between TBS and vertebral fracture risk.

Impact of cardiovascular risk factors on severity of peripheral artery disease

OBJECTIVE The development of peripheral artery disease is affected by the presence of cardiovascular risk factors. It is unclear, whether particular risk factors are leading to different clinical stages of peripheral artery disease. The aim of this retrospective cross-sectional study was to assess the association of cardiovascular risk factors with the presence of critical limb ischaemia. METHODS The study cohort was derived from a consecutive registry of patients undergoing endovascular therapy in a tertiary referral centre between January 2000 and April 2014. Patients undergoing first-time endovascular intervention for chronic peripheral artery disease of the lower extremities were included. Univariate and multivariate logistic regression models were used to assess the association of age, sex, diabetes mellitus, hypertension, dyslipidaemia, smoking, and renal insufficiency with critical limb ischaemia vs. intermittent claudication. RESULTS A total of 3406 patients were included in the study (mean age 71.7 ± 11.8 years, 2075 [61%] male). There was a significant association of age (OR 1.67, 95%-CI 1.53-1.82, p < 0.001), male gender (OR 1.23, 95%-CI 1.04-1.47, p = 0.016), diabetes (OR 1.99, 95%-CI 1.68-2.36, p < 0.001) and renal insufficiency (OR 1.62, 95%-CI 1.35-1.96, p < 0.001) with the likelihood of critical limb ischaemia. Smoking was associated with intermittent claudication rather than critical limb ischaemia (OR 0.78, 95%-CI 0.65-0.94, p = 0.010), while hypertension and dyslipidaemia did not show an association with critical limb ischaemia. CONCLUSIONS In peripheral artery disease patients undergoing first-time endovascular treatment, age, male gender, diabetes, and renal insufficiency were the strongest predictors for the presence of critical limb ischaemia.

Dynamic changes of intramural hematoma in patients with acute spontaneous internal carotid artery dissection.

BACKGROUND We prospectively investigated temporal and spatial evolution of intramural hematomas in patients with acute spontaneous internal carotid artery dissection using repeated magnetic resonance imaging over six-months. AIM The aim of the present study was to assess dynamic changes of intramural hematoma in patients with acute spontaneous internal carotid artery dissection at multiple follow-up time-points with T1w, PD/T2w, and magnetic resonance angiography. METHODS We performed serial multiparametric magnetic resonance imaging in 10 patients with spontaneous internal carotid artery dissection on admission, at days 1, 3, 7-14 and at months 1·5, 3, and 6. We calculated the volume and extension of the hyperintense intramural hematoma using T1w and PD/T2w fat suppressed sequences and assessed the degree of stenosis due to the hematoma using magnetic resonance angiography. RESULTS Mean interval from symptom onset to first magnetic resonance imaging was two-days (SD 2·7). Two patients presented with ischemic stroke, three with transient ischemic attacks, and five with pain and local symptoms only. Nine patients had a transient increase of the intramural hematoma volume, mainly up to day 10 after symptom onset. Fifty percent had a transient increase in the degree of the internal carotid artery stenosis on MRA, one resulting in a temporary occlusion. Lesions older than one-week were predominantly characterized by a shift from iso- to hyperintese signal on T2w images. At three-month follow-up, intramural hematoma was no longer detectable in 80% of patients and had completely resolved in all patients after six-months. CONCLUSIONS Spatial and temporal dynamics of intramural hematomas after spontaneous internal carotid artery dissection showed an early volume increase with concomitant progression of the internal carotid artery stenosis in 5 of 10 patients. Although spontaneous internal carotid artery dissection overall carries a good prognosis with spontaneous hematoma resorption in all our patients, early follow-up imaging may be considered, especially in case of new clinical symptoms.

Determination of vertebral range of motion using inertial measurement units in 27 Franches-Montagnes stallions and comparison between conditions and with a mixed population

REASONS FOR PERFORMING STUDY: The diagnosis of equine back disorders is challenging. Objectively determining movement of the vertebral column may therefore be of value in a clinical setting. OBJECTIVES: To establish whether surface-mounted inertial measurement units (IMUs) can be used to establish normal values for range of motion (ROM) of the vertebral column in a uniform population of horses trotting under different conditions. STUDY DESIGN: Vertebral ROM was established in Franches-Montagnes stallions and a general population of horses and the variability in measurements compared between the two groups. Repeatability and the influence of specific exercise condition (on ROM) were assessed. Finally, attempts were made to explain the findings of the study through the evaluation of factors that might influence ROM. METHODS: Dorsoventral (DV) and mediolateral (ML) vertebral ROM was measured at a trot under different exercise conditions in 27 Franches-Montagnes stallions and six general population horses using IMUs distributed over the vertebral column. RESULTS: Variability in the ROM measurements was significantly higher for general population horses than for Franches-Montagnes stallions (both DV and ML ROM). Repeatability was strong to very strong for DV measurements and moderate for ML measurements. Trotting under saddle significantly reduced the ROM, with sitting trot resulting in a significantly lower ROM than rising trot. Age is unlikely to explain the low variability in vertebral ROM recorded in the Franches-Montagnes horses, while this may be associated with conformational factors. CONCLUSIONS: It was possible to establish a normal vertebral ROM for a group of Franches-Montagnes stallions. While within-breed variation was low in this population, further studies are necessary to determine variation in vertebral ROM for other breeds and to assess their utility for diagnosis of equine back disorders.

Comparison of proximal femur and vertebral body strength improvements in the FREEDOM trial using an alternative finite element methodology

Denosumab reduced the incidence of new fractures in postmenopausal women with osteoporosis by 68% at the spine and 40% at the hip over 36 months compared with placebo in the FREEDOM study. This efficacy was supported by improvements from baseline in vertebral (18.2%) strength in axial compression and femoral (8.6%) strength in sideways fall configuration at 36 months, estimated in Newtons by an established voxel-based finite element (FE) methodology. Since FE analyses rely on the choice of meshes, material properties, and boundary conditions, the aim of this study was to independently confirm and compare the effects of denosumab on vertebral and femoral strength during the FREEDOM trial using an alternative smooth FE methodology. Unlike the previous FE study, effects on femoral strength in physiological stance configuration were also examined. QCT data for the proximal femur and two lumbar vertebrae were analyzed by smooth FE methodology at baseline, 12, 24, and 36 months for 51 treated (denosumab) and 47 control (placebo) subjects. QCT images were segmented and converted into smooth FE models to compute bone strength. L1 and L2 vertebral bodies were virtually loaded in axial compression and the proximal femora in both fall and stance configurations. Denosumab increased vertebral body strength by 10.8%, 14.0%, and 17.4% from baseline at 12, 24, and 36 months, respectively (p < 0.0001). Denosumab also increased femoral strength in the fall configuration by 4.3%, 5.1%, and 7.2% from baseline at 12, 24, and 36 months, respectively (p < 0.0001). Similar improvements were observed in the stance configuration with increases of 4.2%, 5.2%, and 5.2% from baseline (p ≤ 0.0007). Differences between the increasing strengths with denosumab and the decreasing strengths with placebo were significant starting at 12 months (vertebral and femoral fall) or 24 months (femoral stance). Using an alternative smooth FE methodology, we confirmed the significant improvements in vertebral body and proximal femur strength previously observed with denosumab. Estimated increases in strength with denosumab and decreases with placebo were highly consistent between both FE techniques.

Time window for recanalization in basilar artery occlusion: Speculative synthesis.

Basilar artery occlusion (BAO) is one of the most devastating forms of stroke and few patients have good outcomes without recanalization. Most centers apply recanalization therapies for BAO up to 12-24 hours after symptom onset, which is a substantially longer time window than the 4.5 hours used in anterior circulation stroke. In this speculative synthesis, we discuss recent advances in BAO treatment in order to understand why and under which circumstances longer symptom duration might not necrotize the brainstem and turn therapeutic attempts futile. We raise the possibility that distinct features of the posterior circulation, e.g., highly developed, persistent collateral arterial network, reverse filling of the distal basilar artery, and delicate plasma flow siding the clot, might sustain brittle patency of brainstem perforators in the face of stepwise growth of the thrombus. Meanwhile, the tissue clock characterizing the rapid necrosis of a typical anterior circulation penumbra will not start. During this perilous time period, recanalization at any point would salvage the brainstem from eventual necrosis caused by imminent reinforcement and further building up of the clot.

Occlusion Location of Middle Cerebral Artery Stroke and Outcome after Endovascular Treatment.

BACKGROUND The aim of this study was to analyze the influence of the location of middle cerebral artery (MCA) occlusion on recanalization, complications and outcome after endovascular therapy. METHODS Four-hundred sixty-four patients with acute MCA occlusions were treated with endovascular therapy. RESULTS Two-hundred ninety-three patients had M1 occlusions, 116 had M2, and 55 had M3/4 occlusions. Partial or complete recanalization was more frequently achieved in M1 (76.8%) than in M2 (59.1%) or M3/4 (47.3%, p < 0.001) occlusions, but favorable outcome (modified Rankin Scale 0-2) was less frequent in M1 (50.9%) than M2 (63.7%) or M3/4 (72.7%, p = 0.018) occlusions. Symptomatic intracerebral hemorrhage (ICH) did not differ between occlusion sites, but asymptomatic ICH was more common in M1 (22.6%) than in M2 occlusions (8.6%, p = 0.003). Recanalization was associated with favorable outcome in M1 (p < 0.001) and proximal M2 (p = 0.003) but not in distal M2 or M3/4 occlusions. CONCLUSIONS Recanalization with endovascular therapy was more frequently achieved in patients with proximal than distal MCA occlusions, but recanalization was associated with favorable outcome only in M1 and proximal M2 occlusions. Outcome was better with distal than proximal occlusions. This study shows that recanalization can be used as a surrogate marker for clinical outcome only in patients with proximal occlusions.