Predictors of bleeding complications during catHeter-dirEcted thrombolysis for peripheral arterial occlusions (POCHET)

Introduction The risk of major bleeding complications in catheter directed thrombolysis (CDT) for acute limb ischemia (ALI) remains high, with reported major bleeding complication rates in up to 1 in every 10 treated patients. Fibrinogen was the only predictive marker used for bleeding complications in CDT, despite the lack of high quality evidence to support this. Therefore, recent international guidelines recommend against the use of fibrinogen during CDT. However, no alternative biomarkers exist to effectively predict CDT-related bleeding complications. The aim of the POCHET biobank is to prospectively assess the rate and etiology of bleeding complications during CDT and to provide a biobank of blood samples to investigate potential novel biomarkers to predict bleeding complications during CDT. Methods The POCHET biobank is a multicentre prospective biobank. After informed consent, all consecutive patients with lower extremity ALI eligible for CDT are included. All patients are treated according to a predefined standard operating procedure which is aligned in all participating centres. Baseline and follow-up data are collected. Prior to CDT and subsequently every six hours, venous blood samples are obtained and stored in the biobank for future analyses. The primary outcome is the occurrence of non-access related major bleeding complications, which is assessed by an independent adjudication committee. Secondary outcomes are non-major bleeding complications and other CDT related complications. Proposed biomarkers to be investigated include fibrinogen, to end the debate on its usefulness, anti-plasmin and D-Dimer. Discussion and conclusion The POCHET biobank provides contemporary data and outcomes of patients during CDT for ALI, coupled with their blood samples taken prior and during CDT. Thereby, the POCHET biobank is a real world monitor on biomarkers during CDT, supporting a broad spectrum of future research for the identification of patients at high risk for bleeding complications during CDT and to identify new biomarkers to enhance safety in CDT treatment

Thalamic neuromodulation and its implications for executive networks

The thalamus is a key structure that controls the routing of information in the brain. Understanding modulation at the thalamic level is critical to understanding the flow of information to brain regions involved in cognitive functions, such as the neocortex, the hippocampus, and the basal ganglia. Modulators contribute the majority of synapses that thalamic cells receive, and the highest fraction of modulator synapses is found in thalamic nuclei interconnected with higher order cortical regions. In addition, disruption of modulators often translates into disabling disorders of executive behavior. However, modulation in thalamic nuclei such as the midline and intralaminar groups, which are interconnected with forebrain executive regions, has received little attention compared to sensory nuclei. Thalamic modulators are heterogeneous in regards to their origin, the neurotransmitter they use, and the effect on thalamic cells. Modulators also share some features, such as having small terminal boutons and activating metabotropic receptors on the cells they contact. I will review anatomical and physiological data on thalamic modulators with these goals: first, determine to what extent the evidence supports similar modulator functions across thalamic nuclei; and second, discuss the current evidence on modulation in the midline and intralaminar nuclei in relation to their role in executive function

Clinical validation of 2D perfusion angiography using Syngo iFlow software during peripheral arterial interventions

Objective: Endovascular surgery is an important treatment modality in peripheral arterial disease. Digital subtraction angiography is the standard post revascularisation diagnostic tool to locate lesions and to evaluate the effect of an intervention. However, interpretation of digital subtraction angiography images is subjective and it is difficult to determine whether revascularisation has been sufficient for clinical improvement. A new technique is 2D perfusion angiography, which creates a 2D colour map and time density curve from the digital subtraction angiography scan for an objective evaluation of the results. However, its clinical relevance is unknown. The aim is to evaluate the association between 2D perfusion angiography parameters and clinical outcome after peripheral arterial interventions. Methods: In this retrospective study, post revascularisation angiographic data and clinical data were reviewed of patients who underwent treatment of femoral-popliteal or femoral-tibial arteries. The outcome was assessed at three time points using three classification systems for peripheral arterial disease: Fontaine classification, American Medical Association whole person impairment classification (AMA) and average wound, ischemia, foot infection score. Post revascularisation angiographic data consisted of time density curves of the foot and lower leg which were extracted from the Syngo iFlow system (Siemens Healthineers). For each time density curve, five descriptive parameters were calculated: time of arrival, time to peak, mean transit time, wash-in rate and area under the curve. The association between the time density curve parameters and peripheral arterial disease classification systems was assessed using a regression analysis. Results: Between July 2016 and December 2018, 103 patients underwent peripheral endovascular interventions in the hybrid operating room; 39 patients were suitable for analysis, of which 28 patients underwent digital subtraction angiography of the lower leg, 3 patients underwent digital subtraction angiography of the foot and 8 patients underwent digital subtraction angiography of both regions. Limited significant relations were found for time of arrival with Fontainde classification (B = 0.806, p = 0.043) and area under the curve with AMA classification (B = −0.027, p = 0.047). Conclusion: In this retrospective study, time density curve parameters (time of arrival and area under the curve), measured in the lower leg, showed a limited significant association with two classification systems for peripheral arterial disease. Future prospective studies to determine the clinical relevance of this 2D perfusion angiography method should focus on standardisation of angiography protocols and comparison of pre- and post-intervention parameters

Vascular endothelial growth factor overexpression in ischemic skeletal muscle enhances myoglobin expression in vivo

Therapeutic angiogenesis using vascular endothelial growth factor ( VEGF) is considered a promising new therapy for patients with arterial obstructive disease. Clinical improvements observed consist of improved muscle function and regression of rest pain or angina. However, direct evidence for improved vascularization, as evaluated by angiography, is weak. In this study, we report an angiogenesis-independent effect of VEGF on ischemic skeletal muscle, ie, upregulation of myoglobin after VEGF treatment. Mice received intramuscular injection with adenoviral VEGF-A or either adenoviral LacZ or PBS as control, followed by surgical induction of acute hindlimb ischemia at day 3. At day 6, capillary density was increased in calf muscle of Ad.VEGF-treated versus control mice (P <0.01). However, angiographic score of collateral arteries was unchanged between Ad.VEGF-treated and control mice. More interestingly, an increase in myoglobin was observed in Ad. VEGF-treated mice. Active myoglobin was 1.5-fold increased in calf muscle of Ad. VEGF-treated mice (P&LE;0.01). In addition, the number of myoglobin-stained myofibers was 2.6-fold increased in Ad.VEGF-treated mice (P = 0.001). Furthermore, in ischemic muscle of 15 limb amputation patients, VEGF and myoglobin were coexpressed. Finally, in cultured C2C12 myotubes treated with rhVEGF, myoglobin mRNA was 2.8-fold raised as compared with PBS-treated cells (P=0.02). This effect could be blocked with the VEGF receptor tyrosine kinase inhibitor SU5416. In conclusion, we show that VEGF upregulates myoglobin in ischemic muscle both in vitro and in vivo. Increased myoglobin expression in VEGF-treated muscle implies an improved muscle oxygenation, which may, at least partly, explain observed clinical improvements in VEGF-treated patients, in the absence of improved vascularizatio

Expression of vascular endothelial growth factor, stromal cell-derived factor-1, and CXCR4 in human limb muscle with acute and chronic ischemia

OBJECTIVE: Vascular endothelial growth factor (VEGF)-induced stromal cell-derived factor-1 (SDF-1) has been implicated in angiogenesis in ischemic tissues by recruitment of CXCR4-positive bone marrow-derived circulating cells with paracrine functions in preclinical models. Here, evidence for this is provided in patients with peripheral artery disease. METHODS AND RESULTS: Expression patterns of VEGF, SDF-1, and CXCR4 were studied in amputated limbs of 16 patients. VEGF-A was expressed in vascular structures and myofibers. SDF-1 was expressed in endothelial and subendothelial cells, whereas CXCR4 was expressed in proximity to capillaries. VEGF-A, SDF-1, and CXCR4 expressions were generally decreased in ischemic muscle as compared with nonischemic muscle in patients with chronic ischemia (0.41-fold, 0.97-fold, and 0.54-fold induction [medians], respectively), whereas substantially increased in 2 patients with acute-on-chronic ischemia (3.5- to 65.8-fold, 3.9- to 19.0-fold, and 4.1- to 30.6-fold induction, respectively). Furthermore, these gene expressions strongly correlated with capillary area. Only acute ischemic tissue displayed a high percentage of hypoxia-inducible factor-1alpha-positive nuclei. CONCLUSIONS: These data suggest that VEGF and SDF-1 function as pro-angiogenic factors in patients with ischemic disease by perivascular retention of CXCR4-positive cells. Furthermore, these genes are downregulated in chronic ischemia as opposed to upregulated in more acute ischemia. The VEGF-SDF-1-CXCR4 pathway is a promising target to treat chronic ischemic diseas