A novel pulsed field ablation system using linear and spiral ablation catheters can create large and durable endocardial and epicardial ventricular lesions in vivo.

BACKGROUND: We investigated the preclinical safety and efficacy of ventricular pulsed field ablation (PFA) using a family of novel, 6-/8-Fr, linear, and spiral PFA/mapping catheters (CRC EP, Inc). METHODS: QRS-gated, bipolar PFA (>2.0 kV) was performed in 10 healthy swine. Altogether, 20 endocardial and epicardial right and left ventricular applications were delivered. The catheters were inserted through an 8.5-Fr steerable introducer. The intensity of skeletal muscle activation was quantified using an accelerometer. Lesions were assessed by pre- versus post-PFA electrogram analysis, pacing threshold, 3D voltage mapping, necropsy, and histology. The swine rete mirabile, liver and kidneys were examined for embolic events. RESULTS: All applications were single-shot (56 ± 18 s) without catheter repositioning. Minimal microbubbling was observed without significant skeletal muscle stimulation (mean acceleration 0.05 m/s2) or ventricular tachyarrhythmias. There was significant reduction in post- versus pre-PFA electrogram amplitude (0.5 ± 0.2 mV versus 3.2 ± 0.9 mV, P < 0.001) with a marked increase in pacing threshold (>20 mA versus 7.5 ± 2.9 mA, P < 0.001). All lesions were large and durable up to 28 days, measuring 32 ± 5 mm (length), 27 ± 8 mm (width), and 8 ± 3 mm (depth) using the spiral catheters and 43 ± 1 mm (length), 7 ± 1 mm (width), and 8 ± 1 mm (depth) using the linear catheters. Despite higher waveform voltages and prolonged applications, no thermal effects were detected at necropsy/histology. Moreover, gross and microscopic examinations revealed no evidence of thromboembolism, vascular or collateral injury. CONCLUSIONS: A novel, QRS-gated PFA system using linear and spiral PFA catheters is capable of creating large and durable ventricular lesions in vivo without significant microbubbling, ventricular arrhythmias or thromboembolism.

Preclinical evaluation of a novel single-shot pulsed field ablation system for pulmonary vein and atrial ablation.

INTRODUCTION: Pulsed field ablation (PFA) is a nonthermal ablative strategy that achieves cell death via electroporation. Herein, we investigated the preclinical safety and efficacy of PFA using two novel 8-French, 16-electrode spiral PFA/mapping catheters (ElePulse; CRC EP, Inc.). METHODS: Bipolar PFA (>1.8 kV) was performed using 30 s, single-shot, QRS-gated applications. Altogether, 94 atrial structures were ablated in 23 swine, one canine, and one ovine, including right and left atria and atrial appendages, pulmonary veins, and superior and inferior (IVC) vena cavae. We also examined the impact of PFA on the phrenic nerve (14 swine) and on a deviated esophagus after delivery of PFA from inside the IVC (five swine). RESULTS: All applications were single-shot without catheter repositioning. Minimal microbubbling was observed without significant skeletal muscle twitching/activation (mean acceleration: 0.05 m/s2 ). There was a marked reduction in post-PFA versus pre-PFA atrial electrogram amplitude (0.17 ± 0.21 vs. 1.18 ± 1.08 mV; p < .0001). Lesion durability was demonstrated up to 3 months in all targeted tissues. Histologically, lesions were contiguous and transmural, except in the atrial appendage, and without any thermal effects. Magnetic resonance, gross, and histologic examinations of the brain, rete mirabile, and kidneys revealed no thromboembolism. No acute/long-term phrenic nerve dysfunction was encountered. Although within 2 h of ablation, histologic examinations of the esophagus revealed acute PFA-related changes in the muscular layer, these completely resolved by 21 ± 5 days. CONCLUSION: A novel, single-shot, spiral PFA system is capable of safely creating large, durable atrial lesions without significant adverse effects on the phrenic nerve or the esophagus.

Catheter-Based Radiofrequency Renal Denervation: Location Effects on Renal Norepinephrine.

BACKGROUND: Clinical studies indicate that blood pressure (BP)-lowering effects of radiofrequency (RF) renal denervation (RD) are sustained for up to 2 years, although a recent clinical trial failed to find a major effect compared to sham treatment. In most previous studies, the efficacy of RD has not been assessed. The current study determined whether RD in different regions of the renal artery causes different degrees of RD as assessed with renal norepinephrine (NE) levels. METHODS AND RESULTS: Unilateral RD was performed on 14 pigs divided into 3 groups: RD near the ostium, in the main renal artery near the bifurcation, and in extrarenal branches of the renal artery. After 2 weeks post-RD, the pigs were euthanized, renal cortex tissue was collected for NE measurement, and renal arteries were prepared for histological analysis. Renal NE decreased by 12% with RD at the ostium, 45% with RD near the bifurcation in the main renal artery, and 74% when RD was performed in extrarenal artery branches. The number of renal nerves was greatest in extrarenal branches and in the main artery compared to the ostium and the average distance from the lumen was greatest for nerves at the ostium and least at the branches. CONCLUSIONS: RF RD lowers renal NE more significantly when performed in branches of the renal artery closer to the kidney. Increased efficacy of RF RD in extrarenal arterial branches may be due to the greater number of nerves in close proximity to the artery lumen in the branches.

Catheter-based radiorefrequency renal denervation lowers blood pressure in obese hypertensive dogs.

BACKGROUND: Obesity-induced hypertension appears to be due, in part, to increased renal sympathetic activity. Catheter-based renal denervation (RD) has been reported to lower arterial blood pressure (BP) in humans with resistant hypertension, many of whom are obese. This study was performed to assess the impact of radiofrequency-induced RD on renal function, BP, renal norepinephrine (NE), and histology of nerves along the renal artery in obese, hypertensive dogs, an experimental model that closely mimics cardiorenal and metabolic changes in obese hypertensive humans. METHODS: After control measurements of cardiovascular and renal function were obtained in obese dogs fed a high-fat diet, bilateral RD was performed using the St. Jude Medical EnligHTN RD system. After RD, BP was measured continuously for 8 weeks, and glomerular filtration rate (GFR) was measured biweekly for 6 weeks. At the end of the study, renal arteries were collected for histological analysis, and kidneys were obtained for NE measurement. RESULTS: Eight weeks after RD, systolic BP fell from 157 ± 5 mm Hg pre-RD to 133 ± 3 mm Hg (P < 0.01), and mean arterial pressure decreased by 9 mm Hg compared with pre-RD (P < 0.01). There were no significant changes in GFR. Renal nerve injury was most prevalent 0.28-3.5mm from the renal artery lumen. RD caused injury in 46% of the renal nerves observed and reduced renal tissue NE by 42% (P < 0.01). CONCLUSIONS: Catheter-based RD with the St. Jude Medical EnligHTN system lowers BP in obese dogs without significantly compromising renal function.

Catheter-based renal sympathetic denervation exerts acute and chronic effects on renal hemodynamics in swine.

OBJECTIVES: We investigated the acute and chronic effects of catheter-based renal sympathetic denervation (RSD) on renal hemodynamics assessed by average peak velocity (APV), renal blood flow (RBF), renal flow reserve (RFR) and resistive index (RI). BACKGROUND: Sympathetic overdrive is accompanied by impaired RBF, whereas there is no data on the effects of transcatheter RSD on renal hemodynamic balance. METHODS: Before and post-RSD (acutely and after 1 month), in 9 farm swines we measured APV by a 0.014-inch Doppler flow wire placed in the stem of the renal artery under baseline and hyperemic conditions, induced by intrarenal dopamine (50 µg/kg). RFR was calculated as the ratio of hyperemic to basal peak velocity, and RI was estimated as (peak systolic velocity-end-diastolic velocity)/peak systolic velocity. RSD was achieved via the lumen of the main renal artery with a specifically designed catheter connected to a radiofrequency generator according to prespecified algorithm. RESULTS: APV and RBF increased acutely post ablation in all animals, compared to APV and RBF before ablation (61.44 ± 32.6 vs 20.44 ± 6.38 cm/s, p<0.001 and 407.4 ± 335.1 vs 161.1 ± 76.6 ml/min, p=0.003; respectively), whereas RFR and RI were reduced (1.51 ± 0.59 vs 2.85 ± 1.33, p<0.001 and 0.67 ± 0.07 vs 0.74 ± 0.07, p=0.005; respectively). One month post ablation APV and RBF compared to APV and RBF before ablation remained significantly higher whereas RFR and RI remained lower as compared to baseline. CONCLUSIONS: Catheter-based RSD exerts acute and chronic effects on renal hemodynamics in a large animal model. If confirmed in humans RBF parameters may be used as direct markers of successful RSD.

Thoracic spinal cord stimulation improves cardiac contractile function and myocardial oxygen consumption in a porcine model of ischemic heart failure.

BACKGROUND: Prior experimental studies show that thoracic spinal cord stimulation (SCS) improves left ventricular (LV) ejection fraction (LVEF). The mechanism of this improvement in the LV contractile function after SCS and its effects on the myocardial oxygen consumption remains unknown. METHODS AND RESULTS: We performed thoracic SCS (T1-T2 level) followed by 4 weeks of rapid ventricular pacing in 9 adult pigs with ischemic heart failure (HF) induced by myocardial infarction (MI). At 24 hours off-pacing, detailed echocardiogram and invasive hemodynamic assessment were performed to determine LV contractile function and myocardial oxygen consumption. Serum norepinephrine level was measured before and after SCS. SCS was performed on 2 occasions for 15 minutes, 30 minutes apart (recovery) with 50 Hz frequency (pulse width 0.2 millisecond, 90% of motor threshold at 2 Hz output). Echocardiogram revealed significant decrease in LVEF (33.8 ± 1.8% vs 66.5 ± 1.7%, P < 0.01) after induction of MI and HF. Compared with MI and HF, acute SCS significantly increased LVEF and +dP/dt (all P < 0.05). Withdrawal of SCS during recovery decreased +dP/dt, but not LVEF that increased again with repeated SCS. Myocardial oxygen consumption also significantly decreased during SCS compared with MI and HF (P = 0.006) without any change in serum norepinephrine level (P = 0.9). Speckle tracking imaging showed significant improvement in global and regional circumferential strains over the infarcted mid and apical regions, decreased in time to peak circumferential strain over the lateral and posterior wall after SCS, and the degree of intraventricular dyssynchrony during SCS compared with MI and HF (P < 0.05). CONCLUSIONS: In a porcine model of ischemic HF, acute SCS improved global and regional LV contractile function and intraventricular dyssynchrony, and decreased myocardial oxygen consumption without elevation of norepinephrine level.

Nerve sprouting induced by radiofrequency catheter ablation in dogs.

OBJECTIVES: The purpose of this study was to test the hypothesis that radiofrequency (RF) catheter ablation results in cardiac nerve sprouting. BACKGROUND: Nerve sprouting plays a role in cardiac arrhythmogenesis. Whether or not nerve sprouting occurs after RF catheter ablation is unclear. METHODS: We performed RF catheter ablation in the right atrium (RA) and right ventricle (RV) in 10 dogs, which then were sacrificed in 2 hours (acute group, n = 5) or 1 month (chronic group, n = 5). Seven normal dogs were used as control. Immunohistochemical staining for growth-associated protein 43 (GAP-43) was performed to measure growing (sprouting) nerves. RESULTS: A significant increase of GAP-43 immunoreactive nerve fiber density was observed at the RA ablation sites in 2 hours (4,410 +/- 1,379 microm(2)/mm(2)) and in 1 month (2,948 +/- 666 microm(2)/mm(2)) after ablation compared to controls (1,377 +/- 471 microm(2)/mm(2), P = .0001). At remote sites (>2 cm away from ablation sites) of RA, RF ablation also resulted in robust nerve sprouting in both the acute group (5,846 +/- 3241 microm(2)/mm(2)) and the chronic group (6,030 +/- 2226 microm(2)/mm(2)). RF ablation in the RV did not increase nerve density at the ablation sites, but nerve density was increased at remote sites in 2 hours (1,345 +/- 451 microm(2)/mm(2), P = .0136) that was reduced down to the normal control level (722 +/- 337 microm(2)/mm(2)) in 1 month. CONCLUSIONS: Nerve sprouting occurred within 2 hours after RF ablation in both the RA and RV and persisted for at least 1 month in the RA but not the RV. The increased GAP-43(+) nerve densities developed at both the ablation and the remote sites.