Determination of lethal electric field threshold for pulsed field ablation in ex vivo perfused porcine and human hearts.

Introduction: Pulsed field ablation is an emerging modality for catheter-based cardiac ablation. The main mechanism of action is irreversible electroporation (IRE), a threshold-based phenomenon in which cells die after exposure to intense pulsed electric fields. Lethal electric field threshold for IRE is a tissue property that determines treatment feasibility and enables the development of new devices and therapeutic applications, but it is greatly dependent on the number of pulses and their duration. Methods: In the study, lesions were generated by applying IRE in porcine and human left ventricles using a pair of parallel needle electrodes at different voltages (500-1500 V) and two different pulse waveforms: a proprietary biphasic waveform (Medtronic) and monophasic 48 × 100 µs pulses. The lethal electric field threshold, anisotropy ratio, and conductivity increase by electroporation were determined by numerical modeling, comparing the model outputs with segmented lesion images. Results: The median threshold was 535 V/cm in porcine ((N = 51 lesions in n = 6 hearts) and 416 V/cm in the human donor hearts ((N = 21 lesions in n = 3 hearts) for the biphasic waveform. The median threshold value was 368 V/cm in porcine hearts ((N = 35 lesions in n = 9 hearts) cm for 48 × 100 µs pulses. Discussion: The values obtained are compared with an extensive literature review of published lethal electric field thresholds in other tissues and were found to be lower than most other tissues, except for skeletal muscle. These findings, albeit preliminary, from a limited number of hearts suggest that treatments in humans with parameters optimized in pigs should result in equal or greater lesions.

Reversible and Irreversible Effects of Electroporation on Contractility and Calcium Homeostasis in Isolated Cardiac Ventricular Myocytes.

BACKGROUND: Irreversible electroporation is an energy form utilizing high-voltage pulsed electric field, leading to cellular homeostasis disruption and cell death. Recently, irreversible electroporation has shown promising results for the treatment of cardiac arrhythmias. However, reversible and irreversible effects of pulsed electric field on cardiac myocytes remain poorly understood. Here, we evaluated the influence of a monophasic single electric pulse (EP) on the contractility, Ca2+ homeostasis and recovery of cardiac myocytes. METHODS: Isolated rat left ventricular myocytes were electroporated using single monophasic EP of different durations and voltages. Sarcomere length and intracellular Ca2+ were simultaneously monitored for up to 20 minutes after EP application in Fura-2 loaded left ventricular myocytes. Lethal voltage thresholds were determined using 100 µs and 10 ms pulses and by discriminating cell orientation with respect to the electric field. RESULTS: Electroporation led to an immediate increase in intracellular Ca2+ which was dependent upon the voltage delivered to the cell. Intermediate-voltage EP (140 V, 100 µs) increased sarcomere shortening, Ca2+ transient amplitude, and diastolic Ca2+ level measured 1 minute post-EP. Although sarcomere shortening returned to pre-EP level within 5 minutes, Ca2+ transient amplitude decreased further below pre-EP level and diastolic Ca2+ level remained elevated within 20 minutes post-EP. Spontaneous contractions were observed after sublethal EP application but their frequency decreased progressively within 20 minutes. Lethal EP voltage threshold was lower in myocytes oriented perpendicular than parallel to the electric field using 100 µs pulses while an opposite effect was found using 10 ms pulses. CONCLUSIONS: Sublethal EP affected rat left ventricular myocytes contractility and disrupted Ca2+ homeostasis as a function of the EP voltage. Moreover, EP-induced lethality was preceded by a large increase in intracellular Ca2+ and was dependent upon the EP duration, amplitude and left ventricular myocytes orientation with respect to the electric field. These findings provide new insights into the effect of pulsed electric field on cardiac myocytes.

Effects of Electrode-Tissue Proximity on Cardiac Lesion Formation Using Pulsed Field Ablation.

BACKGROUND: Pulsed field ablation (PFA) is a novel energy modality for treatment of cardiac arrhythmias. The impact of electrode-tissue proximity on lesion formation by PFA has not been conclusively assessed. The objective of this investigation was to evaluate the effects of electrode-tissue proximity on cardiac lesion formation with a biphasic, bipolar PFA system. METHODS: PFA was delivered on the ventricular epicardial surface in an isolated porcine heart model (n=8) via a 4-electrode prototype catheter. An offset tool was designed to control the distance between electrodes and target tissue; deliveries were placed 0 mm (0 mm offset), 2 mm (2 mm offset), and 4 mm away from the tissue (4 mm offset). Lesions were assessed using tetrazolium chloride staining. Numerical models for the experimental setup with and without the offset tool validated and supported results. RESULTS: Cardiac lesion dimensions decreased proportional to the distance between epicardial surface and electrodes. Lesion depth averaged 4.3±0.4 mm, 2.7±0.4 mm, and 1.3±0.4 mm for the 0, 2, and 4 mm and lesion width averaged 9.4±1.1 mm, 7.5±0.8 mm and 5.8±1.4 mm for the 0, 2, and 4 mm offset distances, respectively. Numerical modeling matched ex vivo results well and predicted lesion creation with and without the offset tool. CONCLUSIONS: Using a biphasic, bipolar PFA system resulted in cardiac lesions even in the 0 mm offset distance case. The relationship between lesion depth and offset distance was linear, and the deepest lesions were created with 0 mm offset distance, that is, with electrodes in contact with tissue. Therefore, close electrode-tissue proximity increases the likelihood of achieving transmural lesions by maximizing the electric field penetration into the target tissue.

Characterization of Phrenic Nerve Response to Pulsed Field Ablation.

BACKGROUND: Phrenic nerve palsy is a well-known complication of cardiac ablation, resulting from the application of direct thermal energy. Emerging pulsed field ablation (PFA) may reduce the risk of phrenic nerve injury but has not been well characterized. METHODS: Accelerometers and continuous pacing were used during PFA deliveries in a porcine model. Acute dose response was established in a first experimental phase with ascending PFA intensity delivered to the phrenic nerve (n=12). In a second phase, nerves were targeted with a single ablation level to observe the effect of repetitive ablations on nerve function (n=4). A third chronic phase characterized assessed histopathology of nerves adjacent to ablated cardiac tissue (n=6). RESULTS: Acutely, we observed a dose-dependent response in phrenic nerve function including reversible stunning (R2=0.965, P<0.001). Furthermore, acute results demonstrated that phrenic nerve function responded to varying levels of PFA and catheter proximity placements, resulting in either: no effect, effect, or stunning. In the chronic study phase, successful isolation of superior vena cava at a dose not predicted to cause phrenic nerve dysfunction was associated with normal phrenic nerve function and normal phrenic nerve histopathology at 4 weeks. CONCLUSIONS: Proximity of the catheter to the phrenic nerve and the PFA dose level were critical for phrenic nerve response. Gross and histopathologic evaluation of phrenic nerves and diaphragms at a chronic time point yielded no injury. These results provide a basis for understanding the susceptibility and recovery of phrenic nerves in response to PFA and a need for appropriate caution in moving beyond animal models.

Safety and chronic lesion characterization of pulsed field ablation in a Porcine model.

BACKGROUND: Pulsed field ablation (PFA) has been identified as an alternative to thermal-based ablation systems for treatment of atrial fibrillation patients. The objective of this Good Laboratory Practice (GLP) study was to characterize the chronic effects and safety of overlapping lesions created by a PFA system at intracardiac locations in a porcine model. METHODS: A circular catheter with nine gold electrodes was used for overlapping low- or high-dose PFA deliveries in the superior vena cava (SVC), right atrial appendage (RAA), and right superior pulmonary vein (RSPV) in six pigs. Electrical isolation was evaluated acutely and chronic lesions were assessed via necropsy and histopathology after 4-week survival. Acute and chronic safety data were recorded peri- and post-procedurally. RESULTS: No animal experienced ventricular arrhythmia during PFA delivery, and there was no evidence of periprocedural PFA-related adverse events. Lesions created in all anatomies resulted in electrical isolation postprocedure. Lesions were circumferential, contiguous, and transmural, with all converting into consistent lines of chronic replacement fibrosis, regardless of trabeculated or smooth endocardial surface structure. Ablations were non-thermally generated with only minimal post-delivery temperature rises recorded at the electrodes. There was no evidence of extracardiac damage, stenosis, aneurysms, endocardial disruption, or thrombus. CONCLUSION: PFA deliveries to the SVC, RAA, and RSPV resulted in complete circumferential replacement fibrosis at 4-week postablation with an excellent chronic myocardial and collateral tissue safety profile. This GLP study evaluated the safety and efficacy of a dosage range in preparation for a clinical trial and characterized the non-thermal nature of PFA.

Reduction in Pulmonary Vein Stenosis and Collateral Damage With Pulsed Field Ablation Compared With Radiofrequency Ablation in a Canine Model.

BACKGROUND: Pulmonary vein (PV) stenosis is a highly morbid condition that can result after catheter ablation for PV isolation. We hypothesized that pulsed field ablation (PFA) would reduce PV stenosis risk and collateral injury compared with irrigated radiofrequency ablation (IRF). METHODS: IRF and PFA deliveries were randomized in 8 dogs with 2 superior PVs ablated using one technology and 2 inferior PVs ablated using the other technology. IRF energy (25-30 W) or PFA was delivered (16 pulse trains) at each PV in a proximal and in a distal site. Contrast computed tomography scans were collected at 0, 2, 4, 8, and 12-week (termination) time points to monitor PV cross-sectional area at each PV ablation site. RESULTS: Maximum average change in normalized cross-sectional area at 4-weeks was -46.1±45.1% post-IRF compared with -5.5±20.5% for PFA (P≤0.001). PFA-treated targets showed significantly fewer vessel restrictions compared with IRF (P≤0.023). Necropsy showed expansive PFA lesions without stenosis in the proximal PV sites, compared with more confined and often incomplete lesions after IRF. At the distal PV sites, only IRF ablations were grossly identified based on focal fibrosis. Mild chronic parenchymal hemorrhage was noted in 3 left superior PV lobes after IRF. Damage to vagus nerves as well as evidence of esophagus dilation occurred at sites associated with IRF. In contrast, no lung, vagal nerve, or esophageal injury was observed at PFA sites. CONCLUSIONS: PFA significantly reduced risk of PV stenosis compared with IRF postprocedure in a canine model. IRF also caused vagus nerve, esophageal, and lung injury while PFA did not.

Intracardiac pulsed field ablation: Proof of feasibility in a chronic porcine model.

BACKGROUND: Radiofrequency (RF) has become an accepted energy source for myocardial ablation but may result in discontinuous lesions and nontargeted tissue injury. We examined the feasibility and safety of lesion formation using high-amplitude, bipolar pulsed electric fields delivered from a multielectrode array catheter. OBJECTIVE: The purpose of this study was to compare duty-cycled radiofrequency ablation (RFA) to pulsed field ablation (PFA) in terms of acute electrical effects, 2-week lesion formation, and injury to nontargeted tissues. METHODS: Intracardiac ablations were performed in 6 pigs using a circular pulmonary vein ablation catheter. The energy source for ablation delivery was randomized to deliver either PFA or RFA to 3 atrial endocardial sites. Bipolar pace capture and electrogram amplitude measurements were recorded at each site. Histopathology and necropsies were performed after 2 weeks. RESULTS: The circular pulmonary vein ablation catheter was used to deliver pulsed electric fields to produce cardiac lesions without skeletal muscle stimulation. Evaluating all ablations in each site, electrogram amplitudes were reduced to <0.5 mV in 67.5% of PFA vs 27.0% of RFA deliveries (P <.001). Bipolar cardiac capture was lost after 100% vs 92.0% of PFA vs RFA (P = .005). At 2 weeks, PFA resulted in consistent transmural and homogeneous replacement fibrosis devoid of lingering myocyte "sequesters." RFA lesions showed a stronger inflammatory response extending to the epicardial fat, arterial injury, and thrombosis. Neither PFA nor RFA lesions showed endocardial thrombus. CONCLUSION: Intracardiac PFA can be feasibly delivered from a circular catheter to create fibrotic lesions that have acute electrical effects, without injury to nontargeted tissue.

Predictability of lesion durability for AF ablation using phased radiofrequency: Power, temperature, and duration impact creation of transmural lesions.

BACKGROUND: Long-term clinical outcomes for atrial fibrillation ablation depend on the creation of durable transmural lesions during pulmonary vein isolation and on substrate modification. Focal conventional radiofrequency (RF) ablation studies have demonstrated that tissue temperature and power are important factors for lesion formation. However, the impact and predictability of temperature and power on contiguous, transmural lesion formation with a phased RF system has not been described. OBJECTIVE: The purpose of this study was to determine the sensitivity, specificity, and predictability of power and temperature to create contiguous, transmural lesions with the temperature-controlled, multielectrode phased RF PVAC GOLD catheter. METHODS: Single ablations with the PVAC GOLD catheter were performed in the superior vena cava of 22 pigs. Ablations from 198 PVAC GOLD electrodes were evaluated by gross examination and histopathology for lesion transmurality and contiguity. Lesions were compared to temperature and power data from the phased RF GENius generator. Effective contact was defined as electrodes with a temperature of ≥50°C and a power of ≥3 W. RESULTS: Eighty-five percent (168 of 198) of the lesions were transmural and 79% (106 of 134) were contiguous. Electrode analysis showed that >30 seconds of effective contact identified transmural lesions with 85% sensitivity (95% confidence interval [CI] 78%-89%), 93% specificity (95% CI 76%-99%), and 99% positive predictive value (95% CI 94%-100%). Sensitivity for lesion contiguity was 95% (95% CI 89%-98%), with 62% specificity (95% CI 42%-78%) and 90% positive predictive value (95% CI 83%-95%). No char or coagulum was observed on the catheter or tissue. CONCLUSION: PVAC GOLD safely, effectively, and predictably creates transmural and contiguous lesions.

Do you see what I hear? Vantage point preference and visual dominance in a time-space synaesthete.

Time-space synaesthetes "see" time units organized in a spatial form. While the structure might be invariant for most synaesthetes, the perspective by which some view their calendar is somewhat flexible. One well-studied synaesthete L adopts different viewpoints for months seen vs. heard. Interestingly, L claims to prefer her auditory perspective, even though the month names are represented visually upside down. To verify this, we used a spatial-cueing task that included audiovisual month cues. These cues were either congruent with L's preferred "auditory" viewpoint (auditory-only and auditory + month inverted) or incongruent (upright visual-only and auditory + month upright). Our prediction was that L would show enhanced cueing effects (larger response time difference between valid and invalid targets) following the audiovisual congruent cues since both elicit the "preferred" auditory perspective. Also, when faced with conflicting cues, we predicted L would choose the preferred auditory perspective over the visual perspective. As we expected, L did show enhanced cueing effects following the audiovisual congruent cues that corresponded with her preferred auditory perspective, but that the visual perspective dominated when L was faced with both viewpoints simultaneously. The results are discussed with relation to the reification hypothesis of sequence space synaesthesia (Eagleman, 2009).

Microembolism and catheter ablation I: a comparison of irrigated radiofrequency and multielectrode-phased radiofrequency catheter ablation of pulmonary vein ostia.

BACKGROUND: Cerebral diffusion-weighted MRI lesions have been observed after catheter ablation of atrial fibrillation. We hypothesized that conditions predisposing to microembolization could be identified using a porcine model of pulmonary vein ablation and an extracorporeal circulation loop. METHODS AND RESULTS: Ablations of the pulmonary veins were performed in 18 swine with echo monitoring. The femoral artery and vein were cannulated and an extracorporeal circulation loop with 2 ultrasonic bubble detectors and a 73-µm filter were placed in series. Microemboli and microbubbles were compared between ablation with an irrigated radiofrequency system (Biosense-Webster) and a phased radiofrequency multielectrode system (pulmonary vein ablation catheter [PVAC], Medtronic, Inc, Carlsbad, CA) in unipolar and 3 blended unipolar/bipolar modes. Animal pathology was examined. The size and number of microbubbles observed during ablation ranged from 30 to 180 µm and 0 to 3253 bubbles per ablation. Microbubble volumes with PVAC (29.1 nL) were greater than with irrigated radiofrequency (0.4 nL; P=0.045), and greatest with type II or III microbubbles on transesophageal echocardiography. Ablation with the PVAC showed fewest microbubbles in the unipolar mode (P=0.012 versus bipolar). The most occurred during bipolar energy delivery with overlap of proximal and distal electrodes (median microbubble volume, 1744 nL; interquartile range, 737-4082 nL; maximum, 19 516 nL). No cerebral MRI lesions were seen, but 2 animals had renal embolization. CONCLUSIONS: Left atrial ablation with irrigated radiofrequency and PVAC catheters in swine is associated with microbubble and microembolus production. Avoiding overlap of electrodes 1 and 10 on PVAC should reduce the microembolic burden associated with this procedure.

Microembolism and catheter ablation II: effects of cerebral microemboli injection in a canine model.

BACKGROUND: Asymptomatic cerebral lesions have been observed on diffusion weighted MRI (DWI) scans shortly after catheter ablation of atrial fibrillation, but the pathogenesis of these lesions is incompletely understood. METHODS AND RESULTS: Twelve dogs underwent selective catheterization of the internal carotid or vertebral arteries. Either a microbubbled mixture of air (1.0-4.0 mL), blood, contrast, and saline (n=5), or heat-dried pulverized blood (particle size <600 µm) mixed with saline and contrast (n=6) was injected. One sham control experiment was performed. MRI scans were performed preinjection, and at 1, 2, and 4 days postinjection. Neurological tests were performed daily. Gross pathology and histopathology were performed on the brains after being euthanized on day 4. Three animals died <24 hours after injection. Hyperintense lesions were observed on DWI (median maximum diameter 3.1 mm) in 2 of 4 animals after air embolism and in 3 of 5 animals after particulate embolism. No DWI lesions were detected in the remaining 5 animals (including the sham control). Lesions seen on DWI and confirmed on the fluid attenuating inversion recovery sequence correlated well with anatomic lesions on histopathology. CONCLUSIONS: Cerebral embolization of air microbubbles or microparticulate debris that approximate the embolic sources from catheter ablation can create hyperintense DWI punctate lesions in a canine model. The location and size of the DWI/fluid attenuating inversion recovery lesions correlate with pathological findings.

A power function method for estimating base flow.

Analytical base flow separation techniques are often used to determine the base flow contribution to total stream flow. Most analytical methods derive base flow from discharge records alone without using basin-specific variables other than basin area. This paper derives a power function for estimating base flow, the form being aQ(b) + cQ, an analytical method calibrated against an integrated basin variable, specific conductance, relating base flow to total discharge, and is consistent with observed mathematical behavior of dissolved solids in stream flow with varying discharge. Advantages of the method are being uncomplicated, reproducible, and applicable to hydrograph separation in basins with limited specific conductance data. The power function relationship between base flow and discharge holds over a wide range of basin areas. It better replicates base flow determined by mass balance methods than analytical methods such as filters or smoothing routines that are not calibrated to natural tracers or empirical basin and gauge-specific variables. Also, it can be used with discharge during periods without specific conductance values, including separating base flow from quick flow for single events. However, it may overestimate base flow during very high flow events. Application of geochemical mass balance and power function base flow separation methods to stream flow and specific conductance records from multiple gauges in the same basin suggests that analytical base flow separation methods must be calibrated at each gauge. Using average values of coefficients introduces a potentially significant and unknown error in base flow as compared with mass balance methods.

Evaluation of the MODFLOW-2005 Conduit Flow Process.

The recent development of the Conduit Flow Process (CFP) by the U.S. Geological Survey (USGS) provides hydrogeologic modelers with a new tool that incorporates the non-Darcian, multiporosity components of flow characteristic of karst aquifers. CFP introduces new parameters extending beyond those of traditional Darcian groundwater flow codes. We characterize a karst aquifer to collect data useful for evaluating this new tool at a test site in west-central Florida, where the spatial distribution and cross-sectional area of the conduit network are available. Specifically, we characterize: (1) the potential for Darcian/non-Darcian flow using estimates of specific discharge vs. observed hydraulic gradients, and (2) the temporal variation for the direction and magnitude of fluid exchange between the matrix and conduit network during extreme hydrologic events. We evaluate the performance of CFP Mode 1 using a site-scale dual-porosity model and compare its performance with a comparable laminar equivalent continuum model (ECM) using MODFLOW-2005. Based on our preliminary analyses, hydraulic conductivity coupled with conduit wall conductance improved the match between observed and simulated discharges by 12% to 40% over turbulent flow alone (less than 1%).

Cardiac ablation via electroporation.

Thermal-based ablation for the treatment of arrhythmias is known to cause issues (e.g. heat loss due to blood perfusion, mechanical damage of the tissue from excessive heat, etc.) that hamper the success of the treatment. A novel technique termed "electroporation" is a process that leads to pore formation in cell membranes. These pores may cause cellular death without inducing negative thermal effects. We successfully developed a system, tools, and methodology to operate this new ablation technique. Preliminary in vivo acute animal studies (ovine) suggest distinct lesion morphology. High transmurality success rates also suggest the possibility of applying this new ablation modality to cardiac ablation. A long term study confirming lesion durability is necessary to warrant the successful adoption of this technique.

Exit vs. entrance block testing for cardiac lesion assessment.

Cardiac lesions are created to act as barriers which prohibit the transmission of cardiac myocyte contractile activity from one side of the lesion to the other. Testing for conduction block is the main way to acutely confirm the effectiveness of this therapy. There are two general methods used to test for conduction block. These methods are called: 1) "exit block testing" and 2) "entrance block testing." In this study, two different devices were used on n = 5 swine to determine if the method of lesion assessment (exit vs. entrance block testing) affected the ability to correctly identify if acute conduction block was achieved. No significant difference was found between conclusions drawn from either method of lesion assessment. However, the most robust lesion assessment will occur when both methods are employed so that the physician has the most information available for analysis.

A different outlook on time: visual and auditory month names elicit different mental vantage points for a time-space synaesthete.

Synaesthesia is a fascinating condition whereby individuals report extraordinary experiences when presented with ordinary stimuli. Here we examined an individual (L) who experiences time units (i.e., months of the year and hours of the day) as occupying specific spatial locations (January is 30 degrees to the left of midline). This form of time-space synaesthesia has been recently investigated by Smilek et al. (2007) who demonstrated that synaesthetic time-space associations are highly consistent, occur regardless of intention, and can direct spatial attention. We extended this work by showing that for the synaesthete L, her time-space vantage point changes depending on whether the time units are seen or heard. For example, when L sees the word JANUARY, she reports experiencing January on her left side, however when she hears the word "January" she experiences the month on her right side. L's subjective reports were validated using a spatial cueing paradigm. The names of months were centrally presented followed by targets on the left or right. L was faster at detecting targets in validly cued locations relative to invalidly cued locations both for visually presented cues (January orients attention to the left) and for aurally presented cues (January orients attention to the right). We replicated this difference in visual and aural cueing effects using hour of the day. Our findings support previous research showing that time-space synaesthesia can bias visual spatial attention, and further suggest that for this synaesthete, time-space associations differ depending on whether they are visually or aurally induced.

Studying reliability using identical handheld lactate analyzers.

Accusport analyzers were used to generate lactate performance curves in an investigative laboratory activity emphasizing the importance of reliable instrumentation. Both the calibration and testing phases of the exercise provided students with a hands-on opportunity to use laboratory-grade instrumentation while allowing for meaningful connections to be made between data collection and analysis. Pairs of student teams tested individual aerobically trained participants exercising to voluntary exhaustion on a cycle ergometer. The analysis of four volunteers' postexercise blood samples revealed lactate data that, although highly correlated, showed small but statistically significant differences between devices. This laboratory activity provides a useful platform for introducing students to the reliability of instrumentation, in particular noting its relevance to designs employing repeated measures.

Comprehending spoken metaphoric reference: a real-time analysis.

Speakers and writers often use metaphor to describe someone or something in a referential fashion (e.g., The creampuff didn't show up for the fight to refer to a cowardly boxer). Research has demonstrated that readers do not comprehend metaphoric reference as easily as they do literal reference (Gibbs, 1990; Onishi & Murphy, 1993). In two experiments, we used a naming version of the cross-modal lexical priming (CMLP) paradigm to monitor the time-course of comprehending spoken metaphoric reference. In Experiment 1, listeners responded to visual probe words of either a figurative or literal nature that were presented at offset or 1000 ms after a critical prime word. Significant facilitatory priming was observed at prime offset to probes consistent with the metaphorical interpretation of the figuratively referring description, yet no priming was found for either probe type at the downstream location. In Experiment 2, we partially replicated Experiment 1 results at prime offset and found no priming at a probe point placed 1000 ms upstream from prime onset. Taken together, the data from these two experiments indicate that listeners are able to comprehend metaphoric reference faster than literal reference. Moreover, the effect appears to be strongest at prime offset, suggesting that activation of the nonliteral interpretation is closely tied to the relationship between the figuratively referring description and the intended referent. Implications for theories of metaphor comprehension, as well as for research in spoken metaphor, are discussed.