Novel Percutaneous Epicardial Autonomic Modulation in the Canine for Atrial Fibrillation: Results of an Efficacy and Safety Study.

BACKGROUND: Endocardial ablation of atrial ganglionated plexi (GP) has been described for treatment of atrial fibrillation (AF). Our objective in this study was to develop percutaneous epicardial GP ablation in a canine model using novel energy sources and catheters. METHODS: Phase 1: The efficacy of several modalities to ablate the GP was tested in an open chest canine model (n = 10). Phase 2: Percutaneous epicardial ablation of GP was done in six dogs using the most efficacious modality identified in phase 1 using two novel catheters. RESULTS: Phase 1: Direct current (DC) in varying doses (blocking [7-12 µA], electroporation [300-500 µA], ablation [3,000-7,500 µA]), radiofrequency ablation (25-50 W), ultrasound (1.5 MHz), and alcohol (2-5 mL) injection were successful at 0/8, 4/12, 5/7, 3/8, 1/5, and 5/7 GP sites. DC (500-5,000 µA) along with alcohol irrigation was tested in phase 2. Phase 2: Percutaneous epicardial ablation of the right atrium, oblique sinus, vein of Marshall, and transverse sinus GP was successful in 5/6 dogs. One dog died of ventricular fibrillation during DC ablation at 5,000 µA. Programmed stimulation induced AF in six dogs, preablation and no atrial arrhythmia in three, flutter in one, and AF in one postablation. Heart rate, blood pressure, effective atrial refractory period, and local atrial electrogram amplitude did not change significantly postablation. Microscopic examination showed elimination of GP, and minimal injury to atrial myocardium. CONCLUSION: Percutaneous epicardial ablation of GP using DC and novel catheters is safe and feasible and may be used as an adjunct to pulmonary vein isolation in the treatment of AF in order to minimize additional atrial myocardial ablation.

Direct Pulmonary Vein Ablation With Stenosis Prevention Therapy.

INTRODUCTION: The dominant location of electrical triggers for initiating atrial fibrillation (AF) originates from the muscle sleeves inside pulmonary veins (PVs). Currently, radiofrequency ablation (RFA) is performed outside of the PVs to isolate, rather than directly ablate these tissues, due to the risk of intraluminal PV stenosis. METHODS: In 4 chronic canine experiments, we performed direct PV muscle sleeve RFA ± postablation drug-coated balloon (DCB) treatment with paclitaxel/everolimus. Of the 4 PVs, 2 PVs were ablated and treated with DCB, 1 PV was ablated without DCB treatment (positive control), and 1 PV was left as a negative control. Local electrograms were assessed in PVs for near-field signals and were targeted for ablation. After 12-14 weeks survival, PVs were interrogated for absence of near-field PV potentials, and each PV was assessed for stenosis. RESULTS: All canines survived the study period without cardiorespiratory complications, and remained ambulatory. In all canines, PVs that were ablated and treated with DCB remained without any significant intraluminal stenosis. In contrast, PVs that were ablated and not treated with DCB showed near or complete intraluminal stenosis. At terminal study, PV potentials remained undetectable. A blinded, histologic analysis demonstrated that ablated PVs without DCB treatment had extensive thrombus, fibrin, mineralization, and elastin disruption. CONCLUSION: Our chronic canine data suggest that direct PV tissue ablation without subsequent stenosis is feasible with the use of postablation DCBs.

Noninvasive potassium determination using a mathematically processed ECG: proof of concept for a novel "blood-less, blood test".

OBJECTIVE: To determine if ECG repolarization measures can be used to detect small changes in serum potassium levels in hemodialysis patients. PATIENTS AND METHODS: Signal-averaged ECGs were obtained from standard ECG leads in 12 patients before, during, and after dialysis. Based on physiological considerations, five repolarization-related ECG measures were chosen and automatically extracted for analysis: the slope of the T wave downstroke (T right slope), the amplitude of the T wave (T amplitude), the center of gravity (COG) of the T wave (T COG), the ratio of the amplitude of the T wave to amplitude of the R wave (T/R amplitude), and the center of gravity of the last 25% of the area under the T wave curve (T4 COG) (Fig. 1). RESULTS: The correlations with potassium were statistically significant for T right slope (P<0.0001), T COG (P=0.007), T amplitude (P=0.0006) and T/R amplitude (P=0.03), but not T4 COG (P=0.13). Potassium changes as small as 0.2mmol/L were detectable. CONCLUSION: Small changes in blood potassium concentrations, within the normal range, resulted in quantifiable changes in the processed, signal-averaged ECG. This indicates that non-invasive, ECG-based potassium measurement is feasible and suggests that continuous or remote monitoring systems could be developed to detect early potassium deviations among high-risk patients, such as those with cardiovascular and renal diseases. The results of this feasibility study will need to be further confirmed in a larger cohort of patients.

Compatibility of electroanatomical mapping systems with a concurrent percutaneous axial flow ventricular assist device.

BACKGROUND: Hemodynamic instability hinders activation and entrainment mapping during ventricular tachycardia ablation. The Impella 2.5 microaxial flow device (MFD; Abiomed Inc., Danvers, MA, USA) is used to prevent hemodynamic instability during electrophysiologic study. However, electromagnetic interference (EMI) generated by this device can preclude accurate electroanatomic mapping. METHODS: Impella was placed in the left ventricle of 7 canines for circulatory support. Electroanatomic mapping during sinus rhythm, ventricular pacing, and ventricular fibrillation (VF) was performed using magnet- (CARTO3, Biosense Webster Inc., Diamond Bar, CA, USA) and impedance- (EnSite Velocity System/EnSite NavX, St. Jude Medical Inc., St. Paul, MN, USA) based systems. Distance from device to points with severe EMI precluding acquisition was compared to points with mild/no EMI. Two methods were used to reduce EMI: (1) titration of MFD performance, and (2) impedance-only mapping combined with manual annotation of activation. RESULTS: Severe EMI did not occur during impedance-based mapping. Severe EMI was observed using CARTO3 at 9.4% of all points attempted at maximum performance level (P8) of device. Severe EMI occurred at points closer to device (40.1 ± 16.8 mm) versus (55.5 ± 20.0 mm) for mild/no EMI, P < 0.0001. Severe EMI using CARTO3 was resolved by either (1) reduction of performance from P8 to P6 or (2) impedance-only mapping with manual annotation. CONCLUSION: Concurrent use of MFD caused EMI to prevent acquisition of points with magnet-based mapping. Predictors for EMI were distance from device and performance level. Temporary reductions to P6 or impedance-only mapping are 2 methods to resolve EMI.

Transvenous stimulation of the renal sympathetic nerves increases systemic blood pressure: a potential new treatment option for neurocardiogenic syncope.

BACKGROUND: Neurocardiogenic syncope (NCS) is a common and sometimes debilitating disorder, with no consistently effective treatment. NCS is due to a combination of bradycardia and vasodilation leading to syncope. Although pacemaker devices have been tried in treating the bradycardic aspect of NCS, no device-based therapy exists to treat the coexistent vasodilation that occurs. The renal sympathetic innervation has been the target of denervation to treat hypertension. We hypothesized that stimulation of the renal sympathetic nerves can increase blood pressure and counteract vasodilation in NCS. METHODS AND RESULTS: High-frequency stimulation (800-900 pps, 10 V, 30-200 seconds) was performed using a quadripolar catheter in the renal vein of 7 dogs and 1 baboon. A significant increase in blood pressure (BP; mean [SD] systolic BP 117 [±28] vs. 128 [±33], diastolic BP 75 [±19] vs. 87 [±29] mmHg) was noted during the stimulation, which returned to baseline after cessation of stimulation. The mean increase in systolic and diastolic BP was 13.0 (±3.3) (P = 0.006) and 10.2 (±4.6) (P = 0.08), respectively. CONCLUSION: We report the first ever study of feasibility and safety of high-frequency electrical stimulation of the renal sympathetic innervation to increase BP in animal models. This has potential applications in the treatment of hypotensive states such as NCS.

Use of the aortoatrial continuity as means of providing left ventricular assist support without entering the ventricle: a feasibility study.

BACKGROUND: Left ventricular assist devices (LVADs) are increasingly used to treat patients with refractory heart failure. Current-generation LVADs have major limitations, including the need for open chest surgery, limiting their widespread use. We hypothesized that the aortoatrial continuity could be used as a unique anatomic vantage point for entirely percutaneous LVAD placement. METHODS AND RESULTS: Forty human autopsied hearts were examined to ascertain the presence and define the dimensions of the continuity between the posterior aortic wall and the left atrium. In all cases, a "septum" between the aorta and left atrium was identified. In 3 animal experiments, a custom mechanical shunt was deployed in the wall between the left atrium and noncoronary cusp. With continuous intracardiac ultrasound imaging, and at necropsy, there was no evidence of device dislodgement, pericardial effusion, or aortic or coronary artery trauma noted. CONCLUSIONS: It is feasible to use the wall between the aorta and left atrium as an access route for a potentially entirely percutaneous LVAD. Such a system obviates the need for accessing the left ventricle, minimizing complications. In the future, such devices may allow widespread treatment of heart failure, malignant cardiac arrhythmia, and severe aortic and mitral valvular disease.

Electroporation ablation of bronchial smooth muscle cells: A novel non-thermal asthma therapy.

OBJECTIVE: Asthma is a common disease which places significant burden on the US healthcare system and which can be associated with significant patient morbidity and mortality. Current medical therapies are costly and not curative. A new approach for a more permanent asthma treatment is the use of radiofrequency ablation. However, this radiofrequency approach is thermal-based and can result in deleterious effects to the airways, such as stenosis or ulceration. We describe a novel, improved therapeutic approach for smooth muscle ablation using non-thermal DC electroporation ablation. METHODS: We developed and tested prototype electroporation ablation devices that access the airways both endoscopically and via a bronchoscope. We tested the feasibility of this approach and demonstrated proof-of-concept in 2 mongrel dogs. In order to assess for smooth muscle function, we performed functional studies pre and post ablation with methacholine challenge to assess for airway reversibility. We also evaluated bronchial lesions via direct vision with bronchoscopy. RESULTS: We developed novel electroporation catheters to delivery energy to the bronchial smooth muscle through an endoscopic approach. We tested these catheters in 2 acute canine studies and successfully demonstrated the ability to destroy smooth muscle tissue via novel prototypes and saline irrigation for widespread non-thermal electroporation ablation. Our functional studies demonstrate the efficacy of this approach. CONCLUSION: We report a novel method for non-thermal bronchial smooth muscle ablation using novel prototypes and electroporation with normal saline. These early findings require further evaluation in larger, chronic canine studies to assess for use as a potential curative therapy.

Novel Techniques in Epilepsy Management: Venous Pacing and Capture of Electrical Activity in the Primate Cortex.

OBJECTIVE: Pharmacotherapy for epilepsy is limited with 30% of patients refractory to this approach of suppressing seizures. Current surgical options are invasive and carry significant morbidities including infection, bleeding, and the potential for deleterious neurocognitive effects. As a result, there is a burgeoning need for innovation to develop safer and efficacious interventions. METHODS: Four distinct catheters (2 existing: Cardima catheter, Standard EPT Blazer catheter; 2 new prototypes: balloon catheter, basket catheters) were tested in 12 baboons (21-30 kg, 100% male). For each, we assessed whether or not the catheter was able to be maneuvered safely in various locations of the cerebral venous system, provide adequate cortical tissue contact to record signals, detect these signals as normal or abnormal, successfully stimulate the cortex, and capture the cortical tissue. Locations trialed included the petrosal sinus, straight sinus, vein of Galen, and occipital vein. Pacing cycle length and pacing thresholds varied among experiments. RESULTS: Successful mapping was conducted in all 12 baboons. The pacing cycle length varied from 75 ms to 650 ms depending on location of the cortex. Pacing threshold was recorded in 4/12 (33%) of the experiments; data is not available for the remaining 8/12 experiments. The threshold values ranged from 0.3 - 20 mAmps. Capture of cortical electrical activity was observed in 11/12 (91.7 %) experiments though the number of successful capture and stimulation attempts varied among experiments. The most reliable and consistent capture occurred with the use of our novel prototyped over-the-wire balloon catheter (9/12; 75%) and basket catheter (3/3; 100%). Necropsy and histology were performed post-experimentation, and only minimal complications were noted (Table 1). CONCLUSION: New electrode design can be maneuvered safely in the venous system, provide adequate cortical tissue contact to record signals, detect these signals as normal or abnormal, successfully stimulate the cortex, and capture cortical tissue. These novel devices merit further study in chronic baboons to establish long-term efficacy of continuous seizure recording.

Percutaneous ligation of the left atrial appendage results in atrial electrical substrate modification.

Debulking of electrically active atrial tissue may reduce the mass of fibrillating tissue during atrial fibrillation, eliminate triggers, and promote maintenance of normal sinus rhythm (NSR). We investigated whether left atrial appendage (LAA) ligation results in modification of atrial electrical substrate. Healthy male mongrel dogs (N = 20) underwent percutaneous epicardial LAA ligation. The ligation system grabber recorded LAA local electrograms (EGM) continuously before, during, and after closure. Successful ligation with a preloaded looped suture was confirmed intraprocedurally by LAA Doppler flow cessation on transesophageal echocardiography (TEE) and loss of LAA electrical activity, and after procedure by direct necropsic visualization. P-wave duration on surface electrocardiograms was measured immediately before and after LAA closure. Percent P-wave duration reduction was correlated with preclosure LAA internal dimensions measured by TEE and external dimensions measured on necropsy specimens to investigate associations of LAA geometry with the extent of electrical substrate modification. LAA ligation was successful in all dogs and accompanied by loss of LAA EGM. P-wave duration reduced immediately on ligation (mean 75 ms preligation to 63 ms postligation; mean difference ± standard error, 12 ± 1 ms; P < 0.0001). Percent P-wave reduction was associated with larger LAA longitudinal cross-sectional area (R(2) = 0.263, P = 0.04) and smaller external circumference (R(2) = 0.687, P = 0.04). All dogs were in sinus rhythm. Percutaneous LAA ligation results in its acute electrical isolation and atrial electrical substrate modification, the degree of which is associated with LAA geometry. These electrical changes raise the possibility that LAA ligation may promote NSR by removing LAA substrate and triggers.

Percutaneous Epicardial Pacing using a Novel Insulated Multi-electrode Lead.

INTRODUCTION: Epicardial cardiac resynchronization therapy (CRT) permits unrestricted electrode positioning. However, this requires surgical placement of device leads and the risk of unwanted phrenic nerve stimulation. We hypothesized that shielded electrodes can capture myocardium without extracardiac stimulation. METHODS: In 6 dog and 5 swine experiments, we used a percutaneous approach to access the epicardial surface of the heart, and deploy novel leads housing multiple electrodes with selective insulation. Bipolar pacing thresholds at prespecified sites were tested compare electrode threshold data both facing towards and away from the epicardial surface. RESULTS: In 151 paired electrode recordings (70 in 6 dogs; 81 in 5 swine), thresholds facing myocardium were lower than facing away (median [IQR] mA: dogs 0.9 [0.4-1.6] vs 4.6 [2.1 to >10], p<0.0001; swine 0.5 [0.2-1] vs 2.5 [0.5-6.8], p<0.0001). Myocardial capture was feasible without extracardiac stimulation at all tested sites, with mean ± SE threshold margin 3.6±0.7 mA at sites of high output extracardiac stimulation (p=0.004). CONCLUSION: Selective electrode insulation confers directional pacing to a multielectrode epicardial pacing lead. This device has the potential for a novel percutaneous epicardial resynchronization therapy that permits placement at an optimal pacing site, irrespective of the anatomy of the coronary veins or phrenic nerves.

Novel balloon catheter device with pacing, ablating, electroporation, and drug-eluting capabilities for atrial fibrillation treatment--preliminary efficacy and safety studies in a canine model.

Pulmonary vein isolation is an established therapeutic procedure for symptomatic atrial fibrillation (AF). This approach involves ablation of atrial tissue just outside the pulmonary veins. However, patient outcomes are limited because of a high rate of arrhythmia recurrence. Ablation of electrically active tissue inside the pulmonary vein may improve procedural success, but is currently avoided because of the complication of postablation stenosis. An innovative device that can ablate inside pulmonary veins and prevent stenosis is a viable strategy to increase long-term efficacy. We have developed a prototypical balloon catheter device capable of nonthermal pulmonary vein ablation along with elution of an antifibrotic agent intended to eliminate arrhythmogenic substrate without the risk of stenosis and have demonstrated its functionality in 4 acute canine experiments. Further optimization of this device may provide an innovative means to simultaneously ablate and prevent pulmonary vein stenosis for improved AF treatment in humans.

Advances in radiofrequency ablation of the cerebral cortex in primates using the venous system: Improvements for treating epilepsy with catheter ablation technology.

BACKGROUND: Pharmacology frequently fails for the treatment of epilepsy. Although surgical techniques are effective, these procedures are highly invasive. We describe feasibility and efficacy of minimally invasive mapping and ablation for the treatment of epilepsy. METHODS: Mapping and radiofrequency ablations were performed via the venous system in eleven baboons and three dogs. RESULTS: Mapping in deep cerebral areas was obtained in all animals. High-frequency pacing was able to induce seizure activity of local cerebral tissue in 72% of our attempts. Cerebral activity could be seen during mapping. Ablative lesions were deployed at deep brain sites without steam pops or sudden impedance rise. Histologic analysis showed necrosis at the sites of ablation in all primates. CONCLUSION: Navigation through the cerebral venous system to map seizure activity is feasible. Radiofrequency energy can be delivered transvenously or transcortically to successfully ablate cortical tissue in this animal model using this innovative approach.