Orientation-Independent Catheter-Based Characterization of Myocardial Activation.

Cardiac electrogram (EGM) signals and electrophysiologic (EP) characteristics derived from them such as amplitude and timing are central to the diagnosis and therapeutic management of arrhythmias. Bipolar EGMs are often used but possess polarity and shape dependence on catheter orientation contributing to uncertainty. OBJECTIVE: We describe a novel method to map cardiac activation that resolves signals into meaningful directions and is insensitive to electrode directional effects. METHODS: Multielectrode catheters that span 2- and 3-D space are used to derive local electric field (E-field) signals. A traveling wave model of local EGM propagation motivates a new "omnipolar" reference frame in which to understand EGM E-field signals and provide bipolar component EGMs aligned with these anatomic and physiologic directions. We validate the basis of this technology and determine its accuracy using a saline tank in which we simulate physiologic propagation. RESULTS: Omnipole signals from healthy tissue are nearly free of catheter orientation effects and are constrained by biophysics to consistent morphologies and thus consistent measured amplitudes and timings. Using a 3-D EP mapping system, traveling wave treatment, and omnipolar technology (OT) E-field loops, we derived a new and nearly instantaneous means to determine conduction velocity and activation direction. CONCLUSION: We describe the basis of OT and validate it with ablation and mapping catheters in a saline tank. Finally, we illustrate OT with signals from live subjects. SIGNIFICANCE: OT's novel approach with signal processing and real-time visualization allows for a newly detailed characterization of myocardial activation that is insensitive to catheter orientation.

Resolving Myocardial Activation With Novel Omnipolar Electrograms.

BACKGROUND: With its inherent limitations, determining local activation times has been the basis of cardiac mapping for over a century. Here, we introduce omnipolar electrograms that originate from the natural direction of a travelling wave and from which instantaneous conduction velocity amplitude and direction can be computed at any single location without first determining activation times. We sought to validate omnipole-derived conduction velocities and explore potential application for localization of sources of arrhythmias. METHODS AND RESULTS: Electrograms from omnipolar mapping were derived and validated using 4 separate models and 2 independent signal acquisition methodologies. We used both electric signals and optical signals collected from monolayer cell preparations, 3-dimensional constructs built with cardiomyocytes derived from human embryonic stem cells, simultaneous optical and electric mapping of rabbit hearts, and in vivo pig electrophysiology studies. Conduction velocities calculated from omnipolar electrograms were compared with wavefront propagation from optical and electric-mapping studies with a traditional local activation time-based method. Bland-Altman analysis revealed that omnipolar measurements on optical data were in agreement with local activation time methods for wavefront direction and velocity within 25 cm/s and 30°, respectively. Similar agreement was also found on electric data. Furthermore, mathematical operations, such as curl and divergence, were applied to omnipole-derived velocity vector fields to locate rotational and focal sources, respectively. CONCLUSIONS: Electrode orientation-independent cardiac wavefront trajectory and speed at a single location for each cardiac activation can be determined accurately with omnipolar electrograms. Omnipole-derived vector fields, when combined with mathematical transforms may aid in real-time detection of cardiac activation sources.

Contribution of saccadic motion to intravitreal drug transport: theoretical analysis.

PURPOSE: The vitreous humor liquefies with age and readily sloshes during eye motion. The objective was to develop a computational model to determine the effect of sloshing on intravitreal drug transport for transscleral and intra-vitreal drug sources at various locations METHODS: A finite element model based on a telescopic implicit envelope tracking scheme was developed to model drug dispersion. Flow velocities due to saccadic oscillations were solved for and were used to simulate drug dispersion. RESULTS: Saccades induced a three-dimensional flow field that indicates intense drug dispersion in the vitreous. Model results showed that the time scale for transport decreased for the sloshing vitreous when compared to static vitreous. Macular concentrations for the sloshing vitreous were found be much higher than that for the static vitreous. For low viscosities the position of the intravitreal source did not have a big impact on drug distribution. CONCLUSION: Model results show that care should be taken when extrapolating animal data, which are mostly done on intact vitreous, to old patients whose vitreous might be a liquid. The decrease in drug transport time scales and changes in localized concentrations should be considered when deciding on treatment modalities and dosing strategies.

Computer modeling of drug delivery to the posterior eye: effect of active transport and loss to choroidal blood flow.

PURPOSE: The direct penetration route following transscleral drug administration presents several barrier and clearance mechanisms-including loss to choroidal blood flow, active transport by the retinal pigment epithelium (RPE), and loss to the conjunctival lymphatics and episcleral blood vessels. The objective of this research was to quantify the role of choroidal and episcleral losses. MATERIALS AND METHODS: A finite element model was created for drug distribution in the posterior human eye. The volumetric choroidal loss constant, active transport component and mass transfer from the scleral surface were unknown parameters in the model. The model was used to simulate drug distribution from a systemic source, and the results were compared to existing experimental results to obtain values for the parameters. RESULTS: The volumetric choroidal loss constant, mass transfer coefficient from the scleral surface and active transport component were evaluated to be (2.0 +/- 0.6) x 10(-5) s(-1), (2.0 +/- 0.35) x 10(-5) cm/s and 8.54 x 10(-6) cm/s respectively. CONCLUSION: Loss to the choroidal circulation was small compared to loss from the scleral surface. Active transport was predicted to induce periscleral movement of the drug, resulting in more rapid distribution and elevated drug concentrations in the choroid and sclera.

Sustained transscleral drug delivery.

Transscleral delivery is an emerging, high-potential method for delivering drugs to the posterior eye. If successful, it could offer non-invasiveness comparable to drops and delivery efficiency comparable to intravitreal injection. However, there are numerous challenges to be overcome before transscleral delivery will be a significant treatment option. The resistance of the sclera is extremely well understood, but the other tissues, especially the retinal pigment epithelium, clearly demand more attention and the effect of drug chemistry remains poorly understood. In this review, the major research on transscleral delivery with an emphasis on current understanding of these points and open questions for the field is summarized.