Motorized template for MRI-guided focal cryoablation of prostate cancer.

MR-guided focal cryoablation of prostate cancer has often been selected as a minimally-invasive treatment option. Placing multiple cryo-needles accurately to form an ablation volume that adequately covers the target volume is crucial for better oncological/functional outcomes. This paper presents an MRI-compatible system combining a motorized tilting grid template with insertion depth sensing capabilities, enabling the physician to precisely place the cryo-needles into the desired location. In vivo animal study in a swine model (3 animals) was performed to test the device performance including targeting accuracy and the procedure workflow. The study showed that the insertion depth feedback improved the 3D targeting accuracy when compared to the conventional insertion technique (7.4 mm vs. 11.2 mm, p=0.04). All three cases achieved full iceball coverage without repositioning the cryo-needles. The results demonstrate the advantages of the motorized tilting mechanism and real-time insertion depth feedback, as well as the feasibility of the proposed workflow for MRI-guided focal cryoablation of prostate cancer.

Transcranial focused ultrasound modulates cortical and thalamic motor activity in awake sheep.

Transcranial application of pulsed low-intensity focused ultrasound (FUS) modulates the excitability of region-specific brain areas, and anesthetic confounders on brain activity warrant the evaluation of the technique in awake animals. We examined the neuromodulatory effects of FUS in unanesthetized sheep by developing a custom-fit headgear capable of reproducibly placing an acoustic focus on the unilateral motor cortex (M1) and corresponding thalamic area. The efferent responses to sonication, based on the acoustic parameters previously identified in anesthetized sheep, were measured using electromyography (EMG) from both hind limbs across three experimental conditions: on-target sonication, off-target sonication, and without sonication. Excitatory sonication yielded greater amplitude of EMG signals obtained from the hind limb contralateral to sonication than that from the ipsilateral limb. Spurious appearance of motion-related EMG signals limited the amount of analyzed data (~ 10% selection of acquired data) during excitatory sonication, and the averaged EMG response rates elicited by the M1 and thalamic stimulations were 7.5 ± 1.4% and 6.7 ± 1.5%, respectively. Suppressive sonication, while sheep walked on the treadmill, temporarily reduced the EMG amplitude from the limb contralateral to sonication. No significant change was found in the EMG amplitudes during the off-target sonication. Behavioral observation throughout the study and histological analysis showed no sign of brain tissue damage caused by the acoustic stimulation. Marginal response rates observed during excitatory sonication call for technical refinement to reduce motion artifacts during EMG acquisitions as well as acoustic aberration correction schemes to improve spatial accuracy of sonication. Yet, our results indicate that low-intensity FUS modulated the excitability of regional brain tissues reversibly and safely in awake sheep, supporting its potential in theragnostic applications.

Effects of sonication parameters on transcranial focused ultrasound brain stimulation in an ovine model.

Low-intensity focused ultrasound (FUS) has significant potential as a non-invasive brain stimulation modality and novel technique for functional brain mapping, particularly with its advantage of greater spatial selectivity and depth penetration compared to existing non-invasive brain stimulation techniques. As previous studies, primarily carried out in small animals, have demonstrated that sonication parameters affect the stimulation efficiency, further investigation in large animals is necessary to translate this technique into clinical practice. In the present study, we examined the effects of sonication parameters on the transient modification of excitability of cortical and thalamic areas in an ovine model. Guided by anatomical and functional neuroimaging data specific to each animal, 250 kHz FUS was transcranially applied to the primary sensorimotor area associated with the right hind limb and its thalamic projection in sheep (n = 10) across multiple sessions using various combinations of sonication parameters. The degree of effect from FUS was assessed through electrophysiological responses, through analysis of electromyogram and electroencephalographic somatosensory evoked potentials for evaluation of excitatory and suppressive effects, respectively. We found that the modulatory effects were transient and reversible, with specific sonication parameters outperforming others in modulating regional brain activity. Magnetic resonance imaging and histological analysis conducted at different time points after the final sonication session, as well as behavioral observations, showed that repeated exposure to FUS did not damage the underlying brain tissue. Our results suggest that FUS-mediated, non-invasive, region-specific bimodal neuromodulation can be safely achieved in an ovine model, indicating its potential for translation into human studies.

Localized Blood-Brain Barrier Opening in Ovine Model Using Image-Guided Transcranial Focused Ultrasound.

Transcranial application of focused ultrasound (FUS) combined with vascular introduction of microbubble contrast agents (MBs) has emerged as a non-invasive technique that can temporarily create a localized opening in the blood-brain barrier (BBB). Under image-guidance, we administered FUS to sheep brain after intravenous injection of microbubbles. BBB opening was confirmed by performing dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to detect the extravasated gadolinium-based magnetic resonance contrast agents. Through pharmacokinetic analysis as well as independent component analysis of the DCE-MRI data, we observed localized enhancement in BBB permeability at the area that subjected to acoustic pressure of 0.48 MPa (mechanical index = 0.96). On the other hand, application of a higher pressure at 0.58 MPa resulted in localized, minor cerebral hemorrhage. No animals exhibited abnormal behavior during the post-FUS survival periods up to 2 mo. Our data suggest that monitoring for excessive BBB disruption is important for safe translation of the method to humans.

Impact of Lowering Irrigation Flow Rate on Atrial Lesion Formation in Thin Atrial Tissue: Preliminary Observations From Experimental and Clinical Studies.

OBJECTIVES: The authors sought to investigate the effect of low irrigation flow rate on lesion characteristics and ablation outcomes in a clinicopathological study. BACKGROUND: Irrigated ablation produces deeper lesions compared with nonirrigated ablation, which may not be desirable in the thin-walled posterior left atrium (LA), where collateral esophageal injury is possible. METHODS: Lesions were placed on the smooth posterior right atrium in 20 swine and posterior LA in 60 patients at a maximum power of 20 to 25 W with either: 1) power-controlled ablation at an irrigation flow rate of 17 ml/min (high-flow group 10 swine; n = 40) or 2) temperature-controlled ablation at an irrigation flow rate of 2 ml/min (low-flow group 10 swine; n = 20). Safety and efficacy was also compared in 326 patients undergoing AF ablation using high-flow (n = 160) or low-flow settings (n = 166) for posterior LA ablation. RESULTS: Low-flow, compared with high-flow, lesions in swine had a higher incidence of lesions with: impedance fall ≥10 Ω, loss of pace capture, electrograms characteristic of transmural lesions, and visible lesions on anatomic inspection (p < 0.05 for all). Low-flow lesions had a maximal diameter at the endocardial surface, whereas high-flow lesions had a maximal diameter at the epicardial surface. In humans, impedance, pace capture, and transmurality data also strongly favored low-flow lesions. There was no difference in acute pulmonary vein isolation, complications, or 12-month arrhythmia-free survival between the groups. CONCLUSIONS: Low-flow irrigated ablation provides favorable lesion characteristics for posterior LA ablation without increasing the risk of adverse events.

Image-Guided Focused Ultrasound-Mediated Regional Brain Stimulation in Sheep.

Non-invasive brain stimulation using focused ultrasound has largely been carried out in small animals. In the present study, we applied stimulatory focused ultrasound transcranially to the primary sensorimotor (SM1) and visual (V1) brain areas in sheep (Dorset, all female, n = 8), under the guidance of magnetic resonance imaging, and examined the electrophysiologic responses. By use of a 250-kHz focused ultrasound transducer, the area was sonicated in pulsed mode (tone-burst duration of 1 ms, duty cycle of 50%) for 300 ms. The acoustic intensity at the focal target was varied up to a spatial peak pulse-average intensity (Isppa) of 14.3 W/cm(2). Sonication of SM1 elicited electromyographic responses from the contralateral hind leg, whereas stimulation of V1 generated electroencephalographic potentials. These responses were detected only above a certain acoustic intensity, and the threshold intensity, as well as the degree of responses, varied among sheep. Post-sonication animal behavior was normal, but minor microhemorrhages were observed from the V1 areas exposed to highly repetitive sonication (every second for ≥500 times for electroencephalographic measurements, Isppa = 6.6-10.5 W/cm(2), mechanical index = 0.9-1.2). Our results suggest the potential translational utility of focused ultrasound as a new brain stimulation modality, yet also call for caution in the use of an excessive number of sonications.

Functional and diffusion tensor magnetic resonance imaging of the sheep brain.

BACKGROUND: An ovine model can cast great insight in translational neuroscientific research due to its large brain volume and distinct regional neuroanatomical structures. The present study examined the applicability of brain functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) to sheep using a clinical MR scanner (3 tesla) with a head coil. The blood-oxygenation-level-dependent (BOLD) fMRI was performed on anesthetized sheep during the block-based presentation of external tactile and visual stimuli using gradient echo-planar-imaging (EPI) sequence. RESULTS: The individual as well as group-based data processing subsequently showed activation in the eloquent sensorimotor and visual areas. DTI was acquired using 26 differential magnetic gradient directions to derive directional fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values from the brain. White matter tractography was also applied to reveal the macrostructure of the corticospinal tracts and optic radiations. CONCLUSIONS: Utilization of fMRI and DTI along with anatomical MRI in the sheep brain could shed light on a broader use of an ovine model in the field of translational neuroscientific research targeting the brain.

An optimized method for the estimation of the respiratory rate from electrocardiographic signals: implications for estimating minute ventilation.

It is well-known that respiratory activity influences electrocardiographic (ECG) morphology. In this article we present a new algorithm for the extraction of respiratory rate from either intracardiac or body surface electrograms. The algorithm optimizes selection of ECG leads for respiratory analysis, as validated in a swine model. The algorithm estimates the respiratory rate from any two ECG leads by finding the power spectral peak of the derived ratio of the estimated root-mean-squared amplitude of the QRS complexes on a beat-by-beat basis across a 32-beat window and automatically selects the lead combination with the highest power spectral signal-to-noise ratio. In 12 mechanically ventilated swine, we collected intracardiac electrograms from catheters in the right ventricle, coronary sinus, left ventricle, and epicardial surface, as well as body surface electrograms, while the ventilation rate was varied between 7 and 13 breaths/min at tidal volumes of 500 and 750 ml. We found excellent agreement between the estimated and true respiratory rate for right ventricular (R(2) = 0.97), coronary sinus (R(2) = 0.96), left ventricular (R(2) = 0.96), and epicardial (R(2) = 0.97) intracardiac leads referenced to surface lead ECGII. When applied to intracardiac right ventricular-coronary sinus bipolar leads, the algorithm exhibited an accuracy of 99.1% (R(2) = 0.97). When applied to 12-lead body surface ECGs collected in 4 swine, the algorithm exhibited an accuracy of 100% (R(2) = 0.93). In conclusion, the proposed algorithm provides an accurate estimation of the respiratory rate using either intracardiac or body surface signals without the need for additional hardware.

Loss of pace capture after radiofrequency application predicts the formation of uniform transmural lesions.

AIMS: Lesion transmurality is critical to procedural success in radiofrequency catheter ablation. We sought to determine whether loss of pace capture (PC) with high-output unipolar and/or bipolar pacing predicts the formation of uniform transmural lesions. METHODS AND RESULTS: Ten juvenile swine were anaesthetized and prepped under sterile conditions. Seventy-seven isolated radiofrequency applications (RFAs) using a 3.5 mm tip-irrigated catheter were available for analysis. Pace capture was assessed before and after RFA at 10 mA/2 ms and catheter stability verified with a three-dimensional mapping system. Pace capture was defined as 1 : 1 or intermittent local capture per paced beat. Myocardial contact and catheter orientation were assessed using intracardiac echo. Endocardial and epicardial lesion areas were measured after sacrifice using 2,3,5-triphenyltetrazolium chloride staining. A uniform transmural lesion was defined as an epicardial-to-endocardial surface ratio (epi/endo) ≥ 76%. Seventy-four per cent of lesions were transmural and 55.8% of lesions had an epi/endo ratio ≥ 76%. In all, 79.2% of lesions associated with loss of bipolar PC were uniform whereas 20.8% of lesions with loss of bipolar PC were non-uniform (P = 0.006). Loss of bipolar PC was associated with higher mean epicardial/endocardial ratio compared with lesions with persistent PC (P = 0.019). Echocardiographic evidence of optimal catheter contact during RFA improved the predictive accuracy of uniform lesion formation when loss of bipolar PC was noted after RFA. CONCLUSION: Loss of bipolar PC after RFA is associated with the formation of uniform lesions in atrial tissue. Optimal catheter contact further improves the predictive accuracy associated with loss of PC.

Effect of cardiac stem cells on left-ventricular remodeling in a canine model of chronic myocardial infarction.

BACKGROUND: Regenerative medicine, including cell therapy, is a promising strategy for recovery of the damaged myocardium. C-kit-positive cardiac stem cells (CSCs) have been shown to improve myocardial function after ischemic injury in animal models and in early clinical experience. We used a chronic large animal model of myocardial infarction with substantial reductions in left-ventricular (LV) ejection fraction and adverse remodeling to examine the effect of late autologous CSC intramyocardial injection on long-term cardiac structure and function. METHODS AND RESULTS: Thoracotomy and ligation of the proximal left anterior descending artery, additional diagonal branches, and atrial biopsy for CSC culture were performed in canines. Baseline cardiac MRI was performed at 6 weeks postinfarct followed by repeat thoracotomy for randomization to intramyocardial injection of CSCs (n=13) or vehicle alone (n=6). At 30 weeks postmyocardial infarction, repeat MRI was performed. Data were analyzed using nonparametric tests (Wilcoxon signed-rank and rank-sum tests). In control animals, LV end-systolic volume and end-diastolic volume increased from 6 to 30 weeks (median and interquartile range, 51.3 mL [43.3-57.4] to 76.1 mL [72.0-82.4]; P=0.03 and 78.5 mL [69.7-86.1] to 99.2 mL [97.1-100.4]; P=0.03). Left-ventricular ejection fraction declined further (35.2% [27.9-38.7] to 26.4% [22.0-31.0]; P=0.12). In the cell-treated animals, this late adverse LV remodeling was attenuated (LV end-systolic volume, 42.6 mL [38.5-50.5] to 56.1 mL [50.3-63.0]; P=0.01 versus control). There was a nonsignificant attenuation in the increase in LV end-diastolic volume (64.8 mL [60.7-71.3] to 83.5 mL [74.7-90.8]; P=0.14 versus control) and LV ejection fraction change over time differed (30.5% [28.4-33.4] to 32.9% [28.6-36.9]; P=0.04 versus control). CONCLUSIONS: Intramyocardial injection of autologous CSCs in a late phase model of chronic infarction resulted in less increase in LV end-systolic volume and preservation of LV ejection fraction.

A novel lead configuration for optimal spatio-temporal detection of intracardiac repolarization alternans.

BACKGROUND: Electric alternans is a pattern of variation in the shape of ECG waveform that occurs every other beat. In humans, alternation in ventricular repolarization, known as repolarization alternans (RA), has been associated with increased vulnerability to ventricular tachycardia/fibrillation and sudden cardiac death. METHODS AND RESULTS: This study investigates the spatio-temporal variability of intracardiac RA and its relationship to body surface RA in an acute myocardial ischemia model in swine. We developed a real-time multichannel repolarization signal acquisition, display, and analysis system to record ECG signals from catheters in the right ventricle, coronary sinus, left ventricle, and epicardial surface before and after circumflex coronary artery balloon occlusion. We found that RA is detectable within 4 minutes after the onset ischemia and is most prominently seen during the first half of the repolarization interval. Ischemia-induced RA was detectable on unipolar and bipolar leads (both in near- and far-field configurations) and on body surface leads. Far-field bipolar intracardiac leads were more sensitive for RA detection than body surface leads, with the probability of body surface RA detection increasing as the number of intracardiac leads detecting RA increased, approaching 100% when at least three intracardiac leads detected RA. We developed a novel, clinically applicable intracardiac lead system based on a triangular arrangement of leads spanning the right ventricular and coronary sinus catheters, which provided the highest sensitivity for intracardiac RA detection when compared with any other far-field bipolar sensing configurations. CONCLUSIONS: In conclusion, intracardiac alternans, a complex spatio-temporal phenomenon associated with arrhythmia susceptibility and sudden cardiac death, can be reliably detected through a novel triangular right ventricular-coronary sinus lead configuration.

Importance of catheter contact force during irrigated radiofrequency ablation: evaluation in a porcine ex vivo model using a force-sensing catheter.

INTRODUCTION: Ablation electrode-tissue contact has been shown to be an important determinant of lesion size and safety during nonirrigated ablation but little data are available during irrigated ablation. We aimed to determine the importance of contact force during irrigated-tip ablation. METHODS AND RESULTS: Freshly excised hearts from 11 male pigs were perfused and superfused using fresh, heparinized, oxygenated swine blood in an ex vivo model. One-minute ablations were placed using one of 3 different power control strategies (impedance control-15 Omega target impedance drop, and 20 W or 30 W fixed power) and 3 different contact forces (2 g, 20 g, and 60 g) to give a grid of 9 ablation groups. The force sensing catheter (Tacticath, Endosense SA) was irrigated at 17 mL/min for all of the ablations. Of a total 101 ablations, no thrombus formation was noted but popping was seen in 17 lesions. The lesion depth and incidence of pops was 5.0 +/- 1.3 mm /0%, 5.0 +/- 1.6 mm /10% and 6.7 +/- 2.5 mm /45% for the 15 Omega, 20 W, and 30 W groups (P < 0.01), respectively, and 4.4 +/- 1.8 mm /3%, 5.8 +/- 1.6 mm /17% and 6.6 +/- 2.0 mm /37% for the 2 g, 20 g, and 60 g groups, respectively (P < 0.01). The impedance drop in the first 5 seconds was significantly correlated to catheter contact force: 9.7 +/- 9.9 Omega, 22.3 +/- 11.0 Omega, and 41.7 +/- 22.1 Omega, respectively, for the 2 g, 20 g, and 60 g groups (Pearson's r = 0.65, P < 0.01). CONCLUSION: Catheter contact force has an important impact on both ablation lesion size and the incidence of pops.

Electroanatomic mapping and radiofrequency ablation of porcine left atria and atrioventricular nodes using magnetic resonance catheter tracking.

BACKGROUND: The MRI-compatible electrophysiology system previously used for MR-guided left ventricular electroanatomic mapping was enhanced with improved MR tracking, an MR-compatible radiofrequency ablation system and higher-resolution imaging sequences to enable mapping, ablation, and ablation monitoring in smaller cardiac structures. MR-tracked navigation was performed to the left atrium (LA) and atrioventricular (AV) node, followed by LA electroanatomic mapping and radiofrequency ablation of the pulmonary veins (PVs) and AV node. METHODS AND RESULTS: One ventricular ablation, 7 PV ablations, 3 LA mappings, and 3 AV node ablations were conducted. Three MRI-compatible devices (ablation/mapping catheter, torqueable sheath, stimulation/pacing catheter) were used, each with 4 to 5 tracking microcoils. Transseptal puncture was performed under x-ray, with all other procedural steps performed in the MRI. Preacquired MRI roadmaps served for real-time catheter navigation. Simultaneous tracking of 3 devices was performed at 13 frames per second. LA mapping and PV radiofrequency ablation were performed using tracked ablation catheters and sheaths. Ablation points were registered and verified after ablation using 3D myocardial delayed enhancement and postmortem gross tissue examination. Complete LA electroanatomic mapping was achieved in 3 of 3 pigs, Right inferior PV circumferential ablation was achieved in 3 of 7 pigs, with incomplete isolation caused by limited catheter deflection. During AV node ablation, ventricular pacing was performed, 3 devices were simultaneously tracked, and intracardiac ECGs were displayed. 3D myocardial delayed enhancement visualized node injury 2 minutes after ablation. AV node block succeeded in 2 of 3 pigs, with 1 temporary block. CONCLUSIONS: LA mapping, PV radiofrequency ablation, and AV node ablation were demonstrated under MRI guidance. Intraprocedural 3D myocardial delayed enhancement assessed lesion positional accuracy and dimensions.

Full-color direct visualization of the atrial septum to guide transseptal puncture.

INTRODUCTION: Transseptal puncture is required for many interventional procedures but has a serious complication rate of approximately 1%-primarily related to misidentification of the fossa ovalis resulting in inadvertent puncture of other cardiac structures. We investigated the utility of a full color visualization catheter to correctly position and guide transseptal puncture of the fossa ovalis. METHODS AND RESULTS: Transseptal puncture and left atrial cannulation were performed after visualization of the atrial septum and fossa ovalis with the visualization catheter (IRIS, Voyage Medical Inc.) on six swine. For each animal, the transseptal puncture was performed twice and the catheter was examined for clot after each puncture. The 12 transseptal punctures required 6.8 +/- 3.6 minutes procedural time and 300 +/- 94 mL of fluid administered per procedure (i.e., two punctures). IRIS visualization of the atrial septum correlated well with postmortem examination of the atrial septum. In the three animals in which a patent foramen ovale was present (as confirmed by pathological examination), it was also correctly identified by in vivo visualization using the IRIS catheter. CONCLUSION: The IRIS catheter allows direct in vivo visualization of the interatrial septum to guide transseptal puncture of previous punctures.

Temporary occlusion of the great cardiac vein and coronary sinus to facilitate radiofrequency catheter ablation of the mitral isthmus.

INTRODUCTION: Ablation of the mitral isthmus to achieve bidirectional conduction block is technically challenging, and incomplete block slows isthmus conduction and is often proarrhythmic. The presence of the blood pool in the coronary venous system may act as a heat-sink, thereby attenuating transmural RF lesion formation. This porcine study tested the hypothesis that elimination of this heat-sink effect by complete air occlusion of the coronary sinus (CS) would facilitate transmural endocardial ablation at the mitral isthmus. METHODS: This study was performed in nine pigs using a 30 mm-long prototype linear CS balloon catheter able to occlude and displace the blood within the CS (the balloon was inflated with approximately 5 cc of air). Using a 3.5 mm irrigated catheter (35 W, 30 cc/min, 1 minute lesions), two sets of mitral isthmus ablation lines were placed per animal: one with the balloon deflated (CS open) and one inflated (CS Occluded). After ablation, gross pathological analysis of the linear lesions was performed. RESULTS: A total of 17 ablation lines were placed: 7 with CS Occlusion, and 10 without occlusion. Despite similar biophysical characteristics of the individual lesions, lesion transmurality was consistently noted only when using the air-filled CS balloon. CONCLUSIONS: Temporary displacement of the venous blood pool using an air-filled CS balloon permits transmurality of mitral isthmus ablation; this may obviate the need for ablation within the CS to achieve bidirectional mitral isthmus conduction.

How good are the internal controls in your group practice? Ten questions to contemplate.

Internal controls are the methods and procedures used by any business to prevent or detect errors, safeguard assets (especially cash) from being misappropriated, and encourage staff adherence to prescribed managerial policies. Internal controls in a medical practice differ depending on the size and complexity of the practice. The key, however, is that they prevent or detect errors and efforts to circumvent the established policies and procedures of the organization. How good are the internal controls in your group practice? This article identifies ten questions you should use to evaluate your risk of asset misappropriation.