First in Human Clinical Feasibility Study of Endovascular Navigation with Fiber Optic RealShape (FORS) Technology.

OBJECTIVE: Endovascular procedures are conventionally conducted using two dimensional fluoroscopy. A new technology platform, Fiber Optic RealShape (FORS), has recently been introduced allowing real time, three dimensional visualisation of endovascular devices using fiberoptic technology. It functions as an add on to conventional fluoroscopy and may facilitate endovascular procedures. This first in human study assessed the feasibility of FORS in clinical practice. METHODS: A prospective cohort feasibility study was performed between July and December 2018. Patients undergoing (regular or complex) endovascular aortic repair (EVAR) or endovascular peripheral lesion repair (EVPLR) were recruited. FORS guidance was used exclusively during navigational tasks such as target vessel catheterisation or crossing of stenotic lesions. Three types of FORS enabled devices were available: a flexible guidewire, a Cobra-2 catheter, and a Berenstein catheter. Devices were chosen at the physician's discretion and could comprise any combination of FORS and non-FORS devices. The primary study endpoint was technical success of the navigational tasks using FORS enabled devices. Secondary study endpoints were user experience and fluoroscopy time. RESULTS: The study enrolled 22 patients: 14 EVAR and eight EVPLR patients. Owing to a technical issue during start up, the FORS system could not be used in one EVAR. The remaining 21 procedures proceeded without device or technology related complications and involved 66 navigational tasks. In 60 tasks (90.9%), technical success was achieved using at least one FORS enabled device. Users rated FORS based image guidance "better than standard guidance" in 16 of 21 and "equal to standard guidance" in five of 21 procedures. Fluoroscopy time ranged from 0.0 to 52.2 min. Several tasks were completed without or with only minimal X-ray use. CONCLUSION: Real time navigation using FORS technology is safe and feasible in abdominal and peripheral endovascular procedures. FORS has the potential to improve intra-operative image guidance. Comparative studies are needed to assess these benefits and potential radiation reduction.

Dynamic coronary roadmapping during percutaneous coronary intervention: a feasibility study.

BACKGROUND: A novel software ("Dynamic Coronary Roadmap") was developed, which offers a real-time, dynamic overlay of the coronary tree on fluoroscopy. Once the roadmap has been automatically generated during angiography it can be used for navigation during percutaneous coronary interventions (PCI). As a feasibility study, we aimed to investigate the feasibility of real-time dynamic coronary roadmapping and consecutive coronary overlay during elective PCI. METHODS AND RESULTS: We studied 936 overlay runs, created following the same amount of angiographies, which were generated during 36 PCIs. Feasibility of dynamic coronary roadmapping was analyzed using a dedicated software tool. Roadmap quality (correct dynamic imaging of the vessels without relevant artefacts or missing parts) was distinguished from overlay quality (congruence of dynamic coronary roadmapping and coronary anatomy). Additionally, we assessed procedural success and the occurrence of major cardiac and cerebrovascular events (MACCE). Roadmap quality was defined as "fit for use" in 99.5%. In 97.4% of runs overlay quality was deemed "fit for use". Overall, we observed low inter and intra observer variability (ICC R = 0.84 for roadmap quality and R = 0.75 for overlay quality). Procedural success rate was 100%. MACCE occurred in two (5.6%) patients during post-interventional in-hospital stay and were not software-related. CONCLUSIONS: Dynamic coronary roadmapping provides in > 98% of cases sufficient roadmap quality with an anatomically correct overlay of the coronary vessels with good inter and intra observer variability. Future randomized studies are warranted to test possible advantages like procedure time reduction and less consumption of contrast medium.

Novel System for Real-Time Integration of 3-D Echocardiography and Fluoroscopy for Image-Guided Cardiac Interventions: Preclinical Validation and Clinical Feasibility Evaluation.

Real-time imaging is required to guide minimally invasive catheter-based cardiac interventions. While transesophageal echocardiography allows for high-quality visualization of cardiac anatomy, X-ray fluoroscopy provides excellent visualization of devices. We have developed a novel image fusion system that allows real-time integration of 3-D echocardiography and the X-ray fluoroscopy. The system was validated in the following two stages: 1) preclinical to determine function and validate accuracy; and 2) in the clinical setting to assess clinical workflow feasibility and determine overall system accuracy. In the preclinical phase, the system was assessed using both phantom and porcine experimental studies. Median 2-D projection errors of 4.5 and 3.3 mm were found for the phantom and porcine studies, respectively. The clinical phase focused on extending the use of the system to interventions in patients undergoing either atrial fibrillation catheter ablation (CA) or transcatheter aortic valve implantation (TAVI). Eleven patients were studied with nine in the CA group and two in the TAVI group. Successful real-time view synchronization was achieved in all cases with a calculated median distance error of 2.2 mm in the CA group and 3.4 mm in the TAVI group. A standard clinical workflow was established using the image fusion system. These pilot data confirm the technical feasibility of accurate real-time echo-fluoroscopic image overlay in clinical practice, which may be a useful adjunct for real-time guidance during interventional cardiac procedures.

New image processing and noise reduction technology allows reduction of radiation exposure in complex electrophysiologic interventions while maintaining optimal image quality: a randomized clinical trial.

BACKGROUND: Despite their carcinogenic potential, X-rays remain indispensable for electrophysiologic (EP) procedures. OBJECTIVE: The purpose of this study was to evaluate the dose reduction and image quality of a novel X-ray technology using advanced image processing and dose reduction technology in an EP laboratory. METHODS: In this single-center, randomized, unblinded, parallel controlled trial, consecutive patients undergoing catheter ablation for complex arrhythmias were eligible. The Philips Allura FD20 system allows switching between the reference (Allura Xper) and the novel X-ray imaging technology (Allura Clarity). Primary end-point was overall procedural patient dose, expressed in dose area product (DAP) and air kerma (AK). Operator dose, procedural success, and necessity to switch to higher dose settings were secondary end-points. RESULTS: A total of 136 patients were randomly assigned to the novel imaging group (n = 68) or the reference group (n = 68). Baseline characteristics were similar, except patients in the novel imaging group were younger (58 vs 65 years, P < .01). Median DAP and AK were 43% and 40% lower in the novel imaging group, respectively (P < .0001). A 50% operator dose reduction was achieved in the novel imaging group (P < .001). Fluoroscopy time, number of exposure frames, and procedure duration were equivalent between the two groups, indicating that the image quality was similarly adequate in both groups. Procedural success was achieved in 91% of patients in both groups; one pericardial tamponade occurred in the novel imaging group. CONCLUSION: The novel imaging technology, Allura Clarity, significantly reduces patient and operator dose in complex EP procedures while maintaining image quality.

Extended-field-of-view three-dimensional transesophageal echocardiography using image-based X-ray probe tracking.

The use of ultrasound imaging for guidance of cardiac interventional procedures is limited by the small field of view of the ultrasound volume. A larger view can be created by image-based registration of several partially overlapping volumes, but automatic registration is likely to fail unless the registration is initialized close to the volumes' correct alignment. In this article, we use X-ray images to track a transesophageal ultrasound probe and thereby provide initial position information for the registration of the ultrasound volumes. The tracking is possible using multiple X-rays or just a single X-ray for each probe position. We test the method in a phantom experiment and find that with at least 50% overlap, 88% of volume pairs are correctly registered when tracked using three X-rays and 86% when using single X-rays. Excluding failed registrations with errors greater than 10 mm, the average registration accuracy is 2.92 mm between ultrasound volumes and 4.75 mm for locating an ultrasound volume in X-ray space. We conclude that the accuracy and robustness of the registrations are sufficient to provide useful images for interventional guidance.

An integrated platform for image-guided cardiac resynchronization therapy.

Cardiac resynchronization therapy (CRT) is an effective procedure for patients with heart failure but 30% of patients do not respond. This may be due to sub-optimal placement of the left ventricular (LV) lead. It is hypothesized that the use of cardiac anatomy, myocardial scar distribution and dyssynchrony information, derived from cardiac magnetic resonance imaging (MRI), may improve outcome by guiding the physician for optimal LV lead positioning. Whole heart MR data can be processed to yield detailed anatomical models including the coronary veins. Cine MR data can be used to measure the motion of the LV to determine which regions are late-activating. Finally, delayed Gadolinium enhancement imaging can be used to detect regions of scarring. This paper presents a complete platform for the guidance of CRT using pre-procedural MR data combined with live x-ray fluoroscopy. The platform was used for 21 patients undergoing CRT in a standard catheterization laboratory. The patients underwent cardiac MRI prior to their procedure. For each patient, a MRI-derived cardiac model, showing the LV lead targets, was registered to x-ray fluoroscopy using multiple views of a catheter looped in the right atrium. Registration was maintained throughout the procedure by a combination of C-arm/x-ray table tracking and respiratory motion compensation. Validation of the registration between the three-dimensional (3D) roadmap and the 2D x-ray images was performed using balloon occlusion coronary venograms. A 2D registration error of 1.2 ± 0.7 mm was achieved. In addition, a novel navigation technique was developed, called Cardiac Unfold, where an entire cardiac chamber is unfolded from 3D to 2D along with all relevant anatomical and functional information and coupled to real-time device detection. This allowed more intuitive navigation as the entire 3D scene was displayed simultaneously on a 2D plot. The accuracy of the unfold navigation was assessed off-line using 13 patient data sets by computing the registration error of the LV pacing lead electrodes which was found to be 2.2 ± 0.9 mm. Furthermore, the use of Unfold Navigation was demonstrated in real-time for four clinical cases.

Limited angle C-arm tomography and segmentation for guidance of atrial fibrillation ablation procedures.

Angiographic projections of the left atrium (LA) and the pulmonary veins (PV) acquired with a rotational C-arm system are used for 3D image reconstruction and subsequent automatic segmentation of the LA and PV to be used as roadmap in fluoroscopy guided LA ablation procedures. Acquisition of projections at high oblique angulations may be problematic due to increased collision danger of the detector with the right shoulder of the patient. We investigate the accuracy of image reconstruction and model based roadmap segmentation using limited angle C-arm tomography. The reduction of the angular range from 200 degrees to 150 degrees leads only to a moderate increase of the segmentation error from 1.5 mm to 2.0 mm if matched conditions are used in the segmentation, i.e., the model based segmentation is trained on images reconstructed with the same angular range as the test images. The minor decrease in accuracy may be outweighed by clinical workflow improvement, gained when large C-arm angulations can be avoided.

Cardiac resynchronization therapy with individualized placement of two left ventricular leads at the sites of latest mechanical left ventricular contraction: guided by 3D-echocardiography and coronary sinus rotation angiography.

A 78-year-old woman with dilated cardiomyopathy was admitted for advanced dyspnoea and recurrent cardiac decompensation despite optimal medical therapy. Implantation of a cardiac resynchronization therapy (CRT) device was indicated according to current guidelines. The day before CRT implantation, three-dimensional echocardiography was performed together with coronary sinus (CS) rotation angiography, which identified two sites of latest mechanical left ventricular (LV) contraction with adjacently available target veins. This case presents the first description of CRT target vein selection using a combination of functional information on LV contraction with anatomical information on the CS venous tree. In this specific patient, the approach eventually necessitated placement of two LV leads.

Three-dimensional CT overlay in comparison to CartoMerge for pulmonary vein antrum isolation.

INTRODUCTION: Three-dimensional (3D) navigation systems are widely used for pulmonary vein antrum isolation (PVAI). To circumvent left atrial (LA) mapping, 3D CT reconstructions of the LA can be superimposed directly (CT overlay) on the fluoroscopy image to guide ablation catheters and to mark ablation sites. METHODS AND RESULTS: Sixty-eight patients (pts) with symptomatic AF refractory to medical therapy were randomly assigned to CT overlay (group 1, n = 38) or CartoMerge (group 2, n = 30). In group 1 registration of the CT image was performed with contrast injections in 2 orthogonal projections. In group 2, visualization of all pulmonary vein (PV) ostia was done by PV angiography, followed by merging of the CT image and the Carto shell. We compared procedural success, procedure time, fluoroscopy time and radiation burden, measured as dose area product (DAP). Baseline characteristics were comparable in both groups. Procedural success, defined as disappearance of PV potentials in all PVs, was achieved in 37/38 (97%) of group 1 patients and 27/30 (90%) patients in group 2 (P = NS). Total procedure time was significantly shorter in group 1 compared to group 2 (129 +/- 34 vs 181 +/- 30 min, P < 0.0001). Although fluoroscopy time tended to be longer in the CT overlay group (47 +/- 16 vs 40 +/- 13 min, P = 0.06), proper use of diaphragmation resulted in comparable radiation values for both groups (DAP 53 +/- 27 vs 56 +/- 35 Gy cm(2), P = 0.76). CONCLUSIONS: CT overlay for PV isolation is feasible and may, in comparison to conventional LA navigation systems, shorten procedural time without increases in radiation burden.

Concanavalin A inhibits pathophysiological effects of anti-ganglioside GQ1b antibodies at the mouse neuromuscular synapse.

Anti-GQ1b antibodies are present in the Miller Fisher syndrome (MFS), a monophasic neuropathy characterized by ataxia, areflexia, ophthalmoplegia, and sometimes cranial muscle weakness. We have previously shown, at the mouse neuromuscular junction (NMJ) ex vivo, that anti-GQ1b antibodies, through complement classic pathway activation, block synaptic transmission in a way that resembles the effect of the pore-forming alpha-latrotoxin (alphaLTx). In order to clarify the mechanism of these alphaLTx-like effects, including possible involvement of the alternative and mannose-binding protein complement pathways, we studied the effects of concanavalin A (ConA), a lectin known to block the action of alphaLTx, immunoglobulins, and early complement components. With electrophysiological, immunohistological, and bioassay experiments, we showed that the alphaLTx-like effects of anti-GQ1b antibody and complement were inhibited by pre- and coincubation with ConA. However, ConA was not able to inhibit evolution of alphaLTx-like effects when coincubated upon addition of complement at NMJs that had already bound anti-GQ1b antibody. Our data suggest that the mannose-binding protein pathway is not involved in the alphaLTx-like effect and that the inhibiting effect of ConA principally arises through interference with presynaptic binding of anti-GQ1b antibody. In control experiments, ConA prevented the neuroexocytotic effects of alphaLTx, indicating that alphaLTx receptors were inhibited under these conditions. We conclude that, although the physiological effects at the NMJ of anti-GQ1b antibody and alphaLTx are very similar, the activity of anti-GQ1b antibody is not mediated through activation of alphaLTx receptors, but rather is caused by direct presynaptic membrane damage through classic complement pathway activation.

Calpain inhibitors protect against axonal degeneration in a model of anti-ganglioside antibody-mediated motor nerve terminal injury.

Miller Fisher syndrome-associated anti-GQ1b ganglioside antibodies produce an acute complement-dependent neuroexocytic effect at the mouse neuromuscular junction (NMJ) that closely resembles the effect of alpha-latrotoxin (LTx). This pathophysiological effect is accompanied by morphological disruption of the nerve terminal involving the loss of major cytoskeletal components, including neurofilament. Both LTx and the membrane attack complex of complement form membrane pores that allow free ionic movement and we have previously hypothesized that Ca2+ ingress and the subsequent activation of Ca2+-dependent proteases, calpains, may lead to substrate degradation resulting in structural disorganization of the terminal. Here, we treated mouse NMJs in hemidiaphragm preparations with anti-GQ1b antibodies and complement, or with LTx in the presence and absence of extracellular Ca2+, and studied possible neuroprotective effects of the calpain inhibitors calpeptin and calpain inhibitor V. Both Ca2+ depletion and calpain inhibition protected the cytoskeleton from degradation, as assessed by immunohistological and ultrastructural analysis. Calpain inhibitors may therefore be useful therapeutically in limiting nerve terminal and axonal injury in autoimmune peripheral neuropathy and in human latrodectism.

Immunoglobulins inhibit pathophysiological effects of anti-GQ1b-positive sera at motor nerve terminals through inhibition of antibody binding.

High-dose intravenous immunoglobulin (IVIg) is an effective treatment for many antibody-mediated neuromuscular diseases, suggesting that IVIg directly interferes with the pathways through which the pathogenic antibodies exert their effects. However, the precise mechanisms of action are unclear. Serum anti-GQ1b antibodies are strongly associated with ophthalmoplegia in patients with Miller Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS). They induce complement-mediated alpha-latrotoxin-like effects on mouse neuromuscular junctions (NMJs) ex vivo, comprising transient muscle fibre twitching, due to a dramatic increase in the frequency of miniature end-plate potentials (spontaneous quantal acetylcholine release), followed by transmission block. To clarify the mechanisms by which IVIg may act in MFS and GBS, we investigated its effects on the interaction of anti-GQ1b antibodies with GQ1b in vitro and on anti-GQ1b antibody-mediated NMJ injury ex vivo, using anti-GQ1b-positive serum samples from MFS/GBS patients. We show that IVIg inhibits the binding of anti-GQ1b antibodies to GQ1b, thereby preventing complement activation and subsequent pathophysiological effects in our ex vivo mouse NMJ model. These results provide further support for the hypothesis that anti-ganglioside antibodies are the pathogenic factors in MFS/GBS and show that this NMJ model provides a suitable system for investigating the therapeutic effects of IVIg in antibody-mediated neuromuscular diseases.

Complex gangliosides as autoantibody targets at the neuromuscular junction in Miller Fisher syndrome: a current perspective.

Glycosphingolipid biology has increasingly interfaced with the field of human autoimmune neuropathy over the last two decades. There are currently over 20 distinct glycolipids that have been identified as autoantibody targets in a wide range of clinical neuropathy syndromes. This review sets out the clinical and experimental background to one interesting example of anti-glycolipid antibody-associated neuropathy termed Miller Fisher syndrome. This syndrome, comprising the triad of ataxia, areflexia, and ophthalmoplegia, correlates highly with the presence of serum anti-GQ1b antibodies, arising through molecular mimicry with microbial oligosaccharides. Anti-GQ1b antibodies mediate neural injury through binding to GQ1b-enriched sites in the peripheral nervous system, including extraocular nerves. Animal experimental evidence, along with a hypothetical background, indicates the motor nerve terminal may be a key site for anti-GQ1b antibody binding with consequent defects in synaptic transmission, as occurs in botulism and other toxinopathies. Our work in recent years on this hypothesis is summarized.

Complex gangliosides at the neuromuscular junction are membrane receptors for autoantibodies and botulinum neurotoxin but redundant for normal synaptic function.

One specialization of vertebrate presynaptic neuronal membranes is their multifold enrichment in complex gangliosides, suggesting that these sialoglycolipids may play a major functional role in synaptic transmission. We tested this hypothesis directly by studying neuromuscular synapses of mice lacking complex gangliosides attributable to deletion of the gene coding for beta1,4 GalNAc-transferase (GM2/GD2 synthase), which catalyzes an early step in ganglioside synthesis. Our studies show that complex gangliosides are surprisingly redundant for regulated neurotransmitter release under normal physiological conditions. In contrast, we show that they are membrane receptors for both the paralytic botulinum neurotoxin type-A and human neuropathy-associated anti-ganglioside autoantibodies that arise through molecular mimicry with microbial structures. These data prove the critical importance of complex gangliosides in mediating pathophysiological events at the neuromuscular synapse.

Detection and prevalence of alpha-latrotoxin-like effects of serum from patients with Guillain-Barré syndrome.

Anti-GQ1b antibodies are associated with the Miller Fisher syndrome (MFS), a variant of the Guillain-Barré syndrome (GBS). In the ex vivo mouse diaphragm, anti-GQ1b-positive MFS serum induces muscle fiber twitching, a temporary dramatic increase of spontaneous quantal acetylcholine release, and transmission blockade at neuromuscular junctions (NMJs). These effects resemble those of alpha-latrotoxin (alpha-LTx) and are induced by antibody-mediated activation of complement. We developed an assay for detection of the alpha-LTx-like effect, using muscle fiber twitching as indicator. We tested 89 serum samples from GBS, MFS, and control subjects, and studied correlations with clinical signs, anti-ganglioside antibodies, micro-electrode physiology, and complement deposition at NMJs. Twitching was observed with 76% of the MFS and 10% of the GBS samples. It was associated with ophthalmoplegia and anti-GQ1b antibodies in patients, and with increased spontaneous acetylcholine release and C3c-deposition at mouse NMJs. This study strongly suggests that antibodies to GQ1b (with cross-reactivity to related gangliosides) are responsible for the alpha-LTx-like activity. The twitching assay is an efficient test for detection of this effect, and allows for screening of large numbers of samples and modifying drugs.