Identification of uterine pacemaker regions at the myometrial-placental interface in the rat.

KEY POINTS: Coordinated contraction of the uterine smooth muscle is essential to parturition. Histologically and physiologically defined pacemaker structures have not been identified in uterine smooth muscle. Here we report combined electrophysiological and histological evidence of zones associated with pacemaker activity in the rat myometrium. Our method relies crucially on the integration of histological and electrophysiological data in an in silico three-dimensional reconstruction of the rat myometrium at 10 µm resolution. We find that myometrial/placental pacemaking zones are closely related with placental sites and the area of disruptive myometrial remodelling surrounding such sites. If analogues of the myometrial/placental pacemaking zone are present in the human, defining their histology and physiology will be important steps towards treatment of pre-term birth, pre-eclampsia, and postpartum haemorrhage. ABSTRACT: Coordinated uterine contractions are essential for delivering viable offspring in mammals. In contrast to other visceral smooth muscles, it is not known where excitation within the uterus is initiated, and no defined pacemaking region has hitherto been identified. Using multi-electrode array recordings and high-resolution computational reconstruction of the three-dimensional micro-structure of late pregnant rat uterus, we demonstrate that electrical potentials are initiated in distinct structures within the placental bed of individual implantation sites. These previously unidentified structures represent modified smooth muscle bundles that are derived from bridges between the longitudinal and circular layers. Coordinated implantation and encapsulation by invading trophoblast give rise to isolated placental/myometrial interface bundles that directly connect to the overlying longitudinal smooth muscle layer. Taken together, these observations imply that the anatomical structure of the uterus, combined with site-specific implantation, gives rise to emergent patterns of electrical activity that drive effective contractility during parturition.

The location of pacemakers in the uteri of pregnant guinea pigs and rats.

The pregnant uterus is a smooth muscle organ whose pattern of contraction is dictated by the propagation of electrical impulses. Such electrical activity may originate from one or more pacemakers, but the location of these sites has not yet been determined. To detect the location of the pacemaker in the gravid uterus, two approaches were used: 1) determine the site from where the contraction started using isolated uteri from the pregnant guinea pig, and videotape their contractions; and 2) record, in isolated uteri from pregnant term rats, with 240 extracellular electrodes simultaneously, and determine where the electrical bursts started. In both the contractile and electrophysiological experiments, there was not a single, specific pacemaker area. However, most contractions (guinea pig 87%) and bursts (rat 76%) started close to the mesometrial border (mean 2.7 ± 4.0 mm SD in guinea pigs and 1.3 ± 1.4 mm in rats). In addition, in the rat, most sites of initiations were located closer to the ovarial end of the horn (mean distance from the ovarial end 6.0 ± 6.2 mm SD), whereas such an orientation was not seen in the guinea pig. In both guinea pig and rat uteri at term, there is not one specific pacemaker area. Rather, contractile and electrical activity may arise from any site, with the majority starting close to the mesometrial border. Furthermore, in the rat, most activities started at the ovarial end of the horn. This may suggest a slightly different pattern of contraction in both species.

Effect of Ethanol Exposure on Slow Wave Activity and Smooth Muscle Contraction in the Rat Small Intestine.

BACKGROUND: Ethanol ingestion causes a variety of gastrointestinal disturbances including motility alterations. Slow wave propagation coordinates gastrointestinal motility, and abnormal slow wave activity is thought to contribute to motility disorders. To date, however, little is known about the effect of acute ethanol on motility disturbances associated with slow wave activity. AIM: To investigate the effect of ethanol on small intestine slow wave activity. METHODS: Segments (3-5 cm long) were isolated from the rat duodenum, jejunum, and ileum and mounted in an organ bath superfused with a normal Tyrode solution or with 1, 3, or 5% ethanol containing Tyrode. The electrical activities were recorded using an array of 121 extracellular electrodes, and motility recordings were performed using a digital video camera. RESULTS: The frequency and amplitude of slow wave activity were not altered at 1, 3, or 5% ethanol concentrations, but a significant drop in velocity was found at 3 and 5% ethanol. Furthermore, inexcitable areas appeared in a dose-dependent manner. Slow wave was sometimes also seen to propagate in a circular fashion, thereby describing a reentrant loop. Finally, in all duodenal, jejunal, and ileal segments, ethanol inhibited contractions and became fully quiescent at 3-5%. CONCLUSIONS: These studies for the first time demonstrate that ethanol significantly inhibits slow wave and spike activity in a dose-dependent manner and could also initiate reentrant activities. Intestinal contractions were also inhibited in a dose-dependent manner. In conclusion, ethanol inhibits both slow wave activity and motor activity to cause ethanol-induced intestinal disturbances.

Recent progress in gastric arrhythmia: pathophysiology, clinical significance and future horizons.

Gastric arrhythmia continues to be of uncertain diagnostic and therapeutic significance. However, recent progress has been substantial, with technical advances, theoretical insights and experimental discoveries offering new translational opportunities. The discoveries that interstitial cells of Cajal (ICC) generate slow waves and that ICC defects are associated with dysmotility have reinvigorated gastric arrhythmia research. Increasing evidence now suggests that ICC depletion and damage, network disruption and channelopathies may lead to aberrant slow wave initiation and conduction. Histological and high-resolution (HR) electrical mapping studies have now redefined the human 'gastric conduction system', providing an improved baseline for arrhythmia research. The application of HR mapping to arrhythmia has also generated important new insights into the spatiotemporal dynamics of arrhythmia onset and maintenance, resulting in the emergence of new provisional classification schemes. Meanwhile, the strong associations between gastric functional disorders and electrogastrography (EGG) abnormalities (e.g. in gastroparesis, unexplained nausea and vomiting and functional dyspepsia) continue to motivate deeper inquiries into the nature and causes of gastrointestinal arrhythmias. In future, technical progress in EGG methods, new HR mapping devices and software, wireless slow wave acquisition systems and improved gastric pacing devices may achieve validated applications in clinical practice. Neurohormonal factors in arrhythmogenesis also continue to be elucidated and a deepening understanding of these mechanisms may open opportunities for drug design for treating arrhythmias. However, for all translational goals, it remains to be seen whether arrhythmia can be corrected in a way that meaningfully improves organ function and symptoms in patients.

Performance of a single-use gastroscope for esophagogastroduodenoscopy: Prospective evaluation.

Background and study aims Reprocessing reusable endoscopes is challenging due to their non-sterilizable nature. Disinfection has been shown to have a significant risk of failure with serious consequences. Single-use endoscopes can eliminate contamination risk and reduce workflow delays caused by reprocessing. This study evaluated the clinical performance of single-use gastroscopes in patients undergoing esophagogastroduodenoscopy (EGD). Patients and methods In this case series, 60 patients underwent EGD using single-use gastroscopes, with 34 procedures in the endoscopy department and 26 in the intensive care unit. The primary outcome was successful completion of the intended EGD objective. Furthermore, certified endoscopists assessed device performance on a five-point Likert scale (ranging from 1-"much worse" to 5-"much better"), considering their experience with a reusable gastroscope. Results Successful completion of EGDs using only the single-use gastroscope was achieved in 58 of 60 cases (96.7%). In two cases, crossover to an ultra-slim endoscope was necessary to either reach the esophageal stenosis or to transverse the stenosis. Overall satisfaction was rated as comparable to reusable scopes in 51 of 56 cases (91.1%) and inferior in five cases (8.9%). The lower weight of the single-use gastroscope was rated as superior in 42 of 60 cases (70.0%). Drawbacks included reduced image quality (23 of 45 cases; 51.1%). Feedback included the absence of a freeze button, lens cleaning issues, and small image size. Conclusions Single-use gastroscopes exhibited a high EGD completion rate and effectiveness for various indications. Further research should focus on evaluating the implementation of single-use gastroscopes in a comprehensive context, considering clinical effectiveness, costs, and environmental impact.

Diagnostic criteria and long-term outcomes in AIH-PBC variant syndrome under combination therapy.

Background & Aims: Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) can co-exist in AIH-PBC, requiring combined treatment with immunosuppression and ursodeoxycholic acid (UDCA). The Paris criteria are commonly used to identify these patients; however, the optimal diagnostic criteria are unknown. We aimed to evaluate the use and clinical relevance of both Paris and Zhang criteria. Methods: Eighty-three patients with a clinical suspicion of AIH-PBC who were treated with combination therapy were included. Histology was re-evaluated. Characteristics and long-term outcomes were retrospectively compared to patients with AIH and PBC. Results: Seventeen (24%) patients treated with combination therapy fulfilled the Paris criteria. Fifty-two patients (70%) fulfilled the Zhang criteria. Patients who met Paris and Zhang criteria more often had inflammation and fibrosis on histology compared to patients only meeting the Zhang criteria. Ten-year liver transplant (LT)-free survival was 87.3% (95% CI 78.9-95.7%) in patients with AIH-PBC. This did not differ in patients in or outside the Paris or Zhang criteria (p = 0.46 and p = 0.40, respectively) or from AIH (p = 0.086). LT-free survival was significantly lower in patients with PBC and severe hepatic inflammation - not receiving immunosuppression - compared to those with AIH-PBC (65%; 95% CI 52.2-77.8% vs. 87%; 95% CI 83.2-90.8%; hazard ratio 0.52; p = 0.043). Conclusions: In this study, patients with AIH-PBC outside Paris or Zhang criteria were frequently labeled as having AIH-PBC and were successfully treated with combination therapy with similar outcomes. LT-free survival was worse in patients with PBC and hepatic inflammation than in those treated as having AIH-PBC. More patients may benefit from combination therapy. Impact and implications: This study demonstrated that patients with AIH-PBC variant syndrome treated with combined therapy consisting of immunosuppressants and ursodeoxycholic acid often do not fulfill the Paris criteria. They do however have comparable response to therapy and long-term outcomes as patients who do fulfill the diagnostic criteria. Additionally, patients with PBC and additional signs of hepatic inflammation have poorer long-term outcomes compared to patients treated as having AIH-PBC. These results implicate that a larger group of patients with features of both AIH and PBC may benefit from combined treatment. With our results, we call for improved consensus among experts in the field on the diagnosis and management of AIH-PBC variant syndrome.

Abnormal initiation and conduction of slow-wave activity in gastroparesis, defined by high-resolution electrical mapping.

BACKGROUND & AIMS: Interstitial cells of Cajal (ICC) generate slow waves. Disrupted ICC networks and gastric dysrhythmias are each associated with gastroparesis. However, there are no data on the initiation and propagation of slow waves in gastroparesis because research tools have lacked spatial resolution. We applied high-resolution electrical mapping to quantify and classify gastroparesis slow-wave abnormalities in spatiotemporal detail. METHODS: Serosal high-resolution mapping was performed using flexible arrays (256 electrodes; 36 cm(2)) at stimulator implantation in 12 patients with diabetic or idiopathic gastroparesis. Data were analyzed by isochronal mapping, velocity and amplitude field mapping, and propagation animation. ICC numbers were determined from gastric biopsy specimens. RESULTS: Mean ICC counts were reduced in patients with gastroparesis (2.3 vs 5.4 bodies/field; P < .001). Slow-wave abnormalities were detected by high-resolution mapping in 11 of 12 patients. Several new patterns were observed and classified as abnormal initiation (10/12; stable ectopic pacemakers or diffuse focal events; median, 3.3 cycles/min; range, 2.1-5.7 cycles/min) or abnormal conduction (7/10; reduced velocities or conduction blocks; median, 2.9 cycles/min; range, 2.1-3.6 cycles/min). Circumferential conduction emerged during aberrant initiation or incomplete block and was associated with velocity elevation (7.3 vs 2.9 mm s(-1); P = .002) and increased amplitudes beyond a low base value (415 vs 170 µV; P = .002). CONCLUSIONS: High-resolution mapping revealed new categories of abnormal human slow-wave activity. Abnormalities of slow-wave initiation and conduction occur in gastroparesis, often at normal frequency, which could be missed by tests that lack spatial resolution. Irregular initiation, aberrant conduction, and low amplitude activity could contribute to the pathogenesis of gastroparesis.

Functional reentry and circus movement arrhythmias in the small intestine of normal and diabetic rats.

In a few recent studies, the presence of arrhythmias based on reentry and circus movement of the slow wave have been shown to occur in normal and diseased stomachs. To date, however, reentry has not been demonstrated before in any other part of the gastrointestinal system. No animals had to be killed for this study. Use was made of materials obtained during the course of another study in which 11 rats were treated with streptozotocin and housed with age-matched controls. After 3 and 7 mo, segments of duodenum, jejunum, and ileum were isolated and positioned in a tissue bath. Slow wave propagation was recorded with 121 extracellular electrodes. After the experiment, the propagation of the slow waves was reconstructed. In 10 of a total of 66 intestinal segments (15%), a circus movement of the slow wave was detected. These reentries were seen in control (n = 2) as well as in 3-mo (n = 2) and 7-mo (n = 6) diabetic rats. Local conduction velocities and beat-to-beat intervals during the reentries were measured (0.42 ± 0.15 and 3.03 ± 0.67 cm/s, respectively) leading to a wavelength of 1.3 ± 0.5 cm and a circuit diameter of 4.1 ± 1.5 mm. This is the first demonstration of a reentrant arrhythmia in the small intestine of control and diabetic rats. Calculations of the size of the circuits indicate that they are small enough to fit inside the intestinal wall. Extrapolation based on measured velocities and rates indicate that reentrant arrhythmias are also possible in the distal small intestine of larger animals including humans.

Altered sinoatrial node function and intra-atrial conduction in murine gain-of-function Scn5a+/ΔKPQ hearts suggest an overlap syndrome.

Mutations in SCN5A, the gene encoding the pore-forming subunit of cardiac Na(+) channels, cause a spectrum of arrhythmic syndromes. Of these, sinoatrial node (SAN) dysfunction occurs in patients with both loss- and gain-of-function SCN5A mutations. We explored for corresponding alterations in SAN function and intracardiac conduction and clarified possible mechanisms underlying these in an established mouse long QT syndrome type 3 model carrying a mutation equivalent to human SCN5A-ΔKPQ. Electrophysiological characterizations of SAN function in living animals and in vitro sinoatrial preparations were compared with cellular SAN and two-dimensional tissue models exploring the consequences of Scn5a+/ΔKPQ mutations. Scn5a+/ΔKPQ mice showed prolonged electrocardiographic QT and corrected QT intervals confirming long QT phenotypes. They showed frequent episodes of sinus bradycardia, sinus pause/arrest, and significantly longer sinus node recovery times, suggesting compromised pacemaker activity compared with wild-type mice. Electrocardiographic waveforms suggested depressed intra-atrial, atrioventricular node, and intraventricular conduction in Scn5a+/ΔKPQ mice. Isolated Scn5a+/ΔKPQ sinoatrial preparations similarly showed lower mean intrinsic heart rates and overall slower conduction through the SAN to the surrounding atrium than did wild-type preparations. Computer simulations of both single SAN cells as well as two-dimensional SAN-atrial models could reproduce the experimental observations of impaired pacemaker and sinoatrial conduction in terms of changes produced by both augmented tail and reduced total Na(+) currents, respectively. In conclusion, the gain-of-function long QT syndrome type 3 murine Scn5a+/ΔKPQ cardiac system, in overlap with corresponding features reported in loss-of-function Na(+) channel mutations, shows compromised SAN pacemaker and conduction function explicable in modeling studies through a combination of augmented tail and reduced peak Na(+) currents.

Propagation of the electrical impulse in reversible unilateral ureteral obstruction as determined at high electrophysiological resolution.

PURPOSE: We investigated the propagation of electrical impulses in a reversible, complete or partial unilateral ureteral obstruction model in vivo. MATERIALS AND METHODS: In Wistar rats the left mid ureter was completely (8) or partially (7) occluded and released after 24 hours. We recorded electrical activity of the left and right ureter before, during and after obstruction at different stages up to 2 weeks after obstruction using a high resolution, 64 extracellular electrode probe. RESULTS: Complete obstruction in the left proximal ureter caused an immediate increase in frequency from a mean ± SEM of 14.8 ± 1.3 to 18.6 ± 1.7 per minute (p <0.05), followed by a 1.4 ± 0.9 per minute decrease (p <0.001). Within the first 2 days after reversal velocity gradually decreased from 1.82 ± 0.12 to 0.79 ± 0.17 cm per second (p <0.001). Release of obstruction gradually restored frequency and velocity, which returned to baseline at 2 weeks. Generally the alterations in rats with complete and partial obstruction were similar but they were less marked in those with partial obstruction. Distal to the obstruction site the impulses disappeared (38%) or propagated retrograde (43%) at some stage in the post-obstruction period. These abnormal impulse propagations also gradually disappeared in the post-obstruction stage. CONCLUSIONS: After complete or partial ureteral obstruction there were immediate, significant changes in the propagation of electrical impulses in the proximal and distal left ureter, which were generally less marked after partial than after complete obstruction. Reversal of obstruction resulted in the gradual disappearance of this abnormality in 2 weeks.

Slow wave propagation and plasticity of interstitial cells of Cajal in the small intestine of diabetic rats.

The number of myenteric interstitial cells of Cajal (ICC-MY), responsible for the generation and propagation of the slow wave in the small intestine, has been shown to decrease in diabetes, suggesting impairment of slow-wave (SW) propagation and related motility. To date, however, this expected decrease in SW propagation has neither been recorded nor analysed. Eleven rats were treated with streptozotocin and housed in pairs with 11 age-matched control animals. After 3 or 7 months, segments of duodenum, jejunum and ileum were isolated and divided into two parts. One part was processed for immediate freezing, cryosectioning and immunoprobing using anti-c-Kit antibody to quantify ICC-MY. The second part was superfused in a tissue bath, and SW propagation was recorded with 121 extracellular electrodes. In addition, a cellular automaton was developed to study the effects of increasing the number of inactive cells on overall propagation. The number of ICC-MY was significantly reduced after 3 months of diabetes, but rebounded to control levels after 7 months of diabetes. Slow-wave frequencies, velocities and extracellular amplitudes were unchanged at any stage of diabetes. The cellular automaton showed that SW velocity was not linearly related to the number of inactive cells. The depletion of ICC-MY is not as severe as is often assumed and in fact may rebound after some time. In addition, at least in the streptozotocin model, the initial reduction in ICC-MY is not enough to affect SW propagation. Diabetic intestinal dysfunction may therefore be more affected by impairments of other systems, such as the enteric system or the muscle cells.

Propagation characteristics of the electrical impulse in the normal and obstructed ureter as determined at high electrophysiological resolution.

OBJECTIVE: To investigate the propagation of the electrical impulses in a unilateral ureteric obstruction model using a high-resolution technique in vivo. MATERIALS AND METHODS: In Wistar rats (n= 15), the left mid-ureter was occluded and the electrical activity was recorded from the proximal and distal part of the obstructed ureter and from the right ureter at different times up to 2 weeks post-obstruction using 64 extracellular electrodes. RESULTS: In the left ureter, impulses propagated in an antegrade direction at a frequency of 15.5 ± 1.3/min and a velocity of 1.6 ± 0.1 cm/s. Immediately post-obstruction, the proximal part showed an increase in frequency (19.1 ± 2.5/min; P < 0.05) followed by a gradual decrease (at 2 weeks: 2.5 ± 1.2/min; P < 0.001). The velocity of these impulses decreased gradually (at 2 weeks: 0.5 ± 0.1 cm/s; P < 0.05). Distally, the antegrade propagations gradually disappeared and, at 1 week, 33% of ureters showed retrograde impulses and 67% displayed no electrical activity. The frequency of both antegrade and retrograde impulses distal to the obstruction dropped immediately after obstruction so that, at 1 day, it was 1.0 ± 0.3 and 1.5 ± 0.2/min, respectively (P < 0.01 for both). The velocity of these antegrade and retrograde impulses showed a significant rise throughout the post-obstruction period. The right ureter showed only a transient increase in frequency from 18.7 ± 2.7 to 30.3 ± 6.1/min (P < 0.05). CONCLUSIONS: Using this high-resolution technique, it is concluded that, after ureteric obstruction, there were immediate and significant changes in the propagation of electrical impulses in the proximal and distal left ureter and in the right ureter, all of which behaved differently. This data may provide a better insight into the electrophysiological function of the normal and obstructed ureter.

Origin and propagation of human gastric slow-wave activity defined by high-resolution mapping.

Slow waves coordinate gastric motility, and abnormal slow-wave activity is thought to contribute to motility disorders. The current understanding of normal human gastric slow-wave activity is based on extrapolation from data derived from sparse electrode recordings and is therefore potentially incomplete. This study employed high-resolution (HR) mapping to reevaluate human gastric slow-wave activity. HR mapping was performed in 12 patients with normal stomachs undergoing upper abdominal surgery, using flexible printed circuit board (PCB) arrays (interelectrode distance 7.6 mm). Up to six PCBs (192 electrodes; 93 cm(2)) were used simultaneously. Slow-wave activity was characterized by spatiotemporal mapping, and regional frequencies, amplitudes, and velocities were defined and compared. Slow-wave activity in the pacemaker region (mid to upper corpus, greater curvature) was of greater amplitude (mean 0.57 mV) and higher velocity (8.0 mm/s) than the corpus (0.25 mV, 3.0 mm/s) (P < 0.001) and displayed isotropic propagation. A marked transition to higher amplitude and velocity activity occurred in the antrum (0.52 mV, 5.9 mm/s) (P < 0.001). Multiple (3-4) wavefronts were found to propagate simultaneously in the organoaxial direction. Frequencies were consistent between regions (2.83 +/- 0.35 cycles per min). HR mapping has provided a more complete understanding of normal human gastric slow-wave activity. The pacemaker region is associated with high-amplitude, high-velocity activity, and multiple wavefronts propagate simultaneously. These data provide a baseline for future HR mapping studies in disease states and will inform noninvasive diagnostic strategies.

High-resolution entrainment mapping of gastric pacing: a new analytical tool.

Gastric pacing has been investigated as a potential treatment for gastroparesis. New pacing protocols are required to improve symptom and motility outcomes; however, research progress has been constrained by a limited understanding of the effects of electrical stimulation on slow-wave activity. This study introduces high-resolution (HR) "entrainment mapping" for the analysis of gastric pacing and presents four demonstrations. Gastric pacing was initiated in a porcine model (typical amplitude 4 mA, pulse width 400 ms, period 17 s). Entrainment mapping was performed using flexible multielectrode arrays (

Focal activities and re-entrant propagations as mechanisms of gastric tachyarrhythmias.

BACKGROUND & AIMS: Gastric arrhythmias occur in humans and experimental animals either spontaneously or induced by drugs or diseases. However, there is no information regarding the origin or the propagation patterns of the slow waves that underlie such arrhythmias. METHODS: To elucidate this, simultaneous recordings were made on the antrum and the distal corpus during tachygastrias in open abdominal anesthetized dogs using a 240 extracellular electrode assembly. After the recordings, the signals were analyzed, and the origin and path of slow wave propagations were reconstructed. RESULTS: Several types of arrhythmias could be distinguished, including (1) premature slow waves (25% of the arrhythmias), (2) single aberrant slow waves (4%), (3) bursts (18%), (4) regular tachygastria (11%), and (5) irregular tachygastria (10%). During regular tachygastria, rapid, regular slow waves emerged from the distal antrum or the greater curvature, whereas, during irregular tachygastria, numerous variations occurred in the direction of propagation, conduction blocks, focal activity, and re-entry. In 12 cases, the arrhythmia was initiated in the recorded area. In each case, after a normal propagating slow wave, a local premature slow wave occurred in the antrum. These premature slow waves propagated in various directions, often describing a single or a double loop that re-entered several times, thereby initiating additional slow waves. CONCLUSIONS: Gastric arrhythmias resemble those in the heart and share many common features such as focal origin, re-entry, circular propagation, conduction blocks, and fibrillation-like behavior.

Sinus node dysfunction in ATX-II-induced in-vitro murine model of long QT3 syndrome and rescue effect of ranolazine.

The aim of this study was to characterize the role of the late Na+ current (I(Na,L)) as a mechanism for induction of both tachy and bradyarrhythmias in murine heart and sino-atrial node tissue. The sea anemone toxin ATX-II and ranolazine were used to increase and inhibit, respectively, I(Na,L). In sixteen hearts studied, exposure to 1-10nM ATX-II caused a slowing of intrinsic heart rate and prolongations of the P-R and QT intervals, the duration of the monophasic action potential, and the sinus node recovery time, accompanied by frequent occurrences of early after depolarisations, delayed after depolarisations and rapid, repetitive ventricular tachy and sino-atrial bradyarrhythmias. ATX-II also slowed sinus node pacemaking, and induced bradycardic arrhythmias in isolated sino-atrial preparations (n=5). The ATX-II-induced alteration of electrophysiological properties and occurrence of arrhythmic events were significantly attenuated by 10 microM ranolazine in intact hearts (n=11) and isolated sino-atrial preparations (n=5). In conclusion, the I(Na,L) enhancer ATX-II causes both tachy and bradyarrhythmias in the murine heart, and these arrhythmias are markedly attenuated by the I(Na,L) blocker, ranolazine (10 microM). The results suggest that I(Na,L) blockade may be the mechanism underlying the reductions of both brady and tachyarrhythmias by ranolazine that were observed during the MERLIN-TIMI clinical outcomes trial.

A novel laparoscopic device for measuring gastrointestinal slow-wave activity.

BACKGROUND: A periodic electrical activity, termed "slow waves", coordinates gastrointestinal contractions. Slow-wave dysrhythmias are thought to contribute to dysmotility syndromes such as postoperative gastroparesis, but the clinical significance of these dysrhythmias remains poorly defined. Electrogastrography (EGG) has been unable to characterize dsyrhythmic activity reliably, and the most accurate method for evaluating slow waves is to record directly from the surface of the target organ. This study presents a novel laparoscopic device for recording serosal slow-wave activity, together with its validation. METHODS: The novel device consists of a shaft (diameter, 4 mm; length, 300 mm) and a flexible connecting cable. It contains four individual electrodes and is fully shielded. Validation was performed by comparing slow-wave recordings from the laparoscopic device with those from a standard electrode platform in an open-abdomen porcine model. An intraoperative human trial of the device also was performed by recording activity from the gastric antrum of a patient undergoing a laparoscopic cholecystectomy. RESULTS: Slow-wave amplitudes were similar between the laparoscopic device and the standard recording platform (mean 0.38 ± 0.03 mV vs range 0.36-0.38 ± 0.03 mV) (p = 0.94). The signal-to-noise ratio (SNR) also was similar between the two types of electrodes (13.7 dB vs 12.6 dB). High-quality antral slow-wave recordings were achieved in the intraoperative human trial (amplitude, 0.41 ± 0.04 mV; SNR, 12.6 dB), and an activation map was constructed showing normal aboral slow-wave propagation at a velocity of 6.3 ± 0.9 mm/s. CONCLUSIONS: The novel laparoscopic device achieves high-quality serosal slow-wave recordings. It is easily deployable and atraumatic. It is anticipated that this device will aid in the clinical investigation of normal and dsyrhythmic slow-wave activity. In particular, it offers new potential for investigating the effect of surgical procedures on slow-wave activity.

Simulation and analysis of spatio-temporal maps of gastrointestinal motility.

BACKGROUND: Spatio-temporal (ST) maps provide a method for visualizing a temporally evolving and spatially varying field, which can also be used in the analysis of gastrointestinal motility. However, it is not always clear what the underlying contractions are that are represented in ST maps and whether some types of contractions are poorly represented or possibly not at all. METHODS: To analyze the translation from stationary or propagating rhythmic contractions of the intestine to ST maps, a simulation program was used to represent different patterns of intestinal contraction and to construct their corresponding ST maps. A number of different types of contractions were simulated and their ST maps analyzed. RESULTS: Circular strong contractions were well represented in ST maps as well as their frequency and velocity. Longitudinal contractions were not detected at all. Combinations of circular and longitudinal contractions were, to a limited extent detectable at a point in space and time. The method also enabled the construction of specific ST-patterns to mimic real-life ST maps and the analysis of the corresponding contraction patterns. CONCLUSION: Spatio-temporal simulations provide a method to understand, teach and analyze ST maps. This approach could be useful to determine characteristics of contractions under a variety of circumstances.