Impact of transforming growth factor-beta1 on atrioventricular node conduction modification by injected autologous fibroblasts in the canine heart.

BACKGROUND: Atrioventricular (AV) nodal ablation for management of atrial fibrillation (AF) is irreversible and requires permanent pacemaker implantation. We hypothesized that as an alternative, implantation of autologous fibroblasts in the perinodal region would focally modify AV nodal conduction and that this modulation would be enhanced by pretreatment with transforming growth factor-beta1 (TGF-beta1), a stimulant of fibroblasts. METHODS AND RESULTS: Skin biopsies were taken from 12 mongrel dogs, and derived fibroblasts were dissociated and grown in culture for 2 weeks. Multiple injections (0.25 mL) were made through an 8F NOGA catheter along the fast/slow AV nodal pathways as guided by an electroanatomic mapping system. Seven dogs received fibroblasts alone (1x10(6) cells/mL), 7 dogs received TGF-beta1 (5 microg), 4 dogs received fibroblasts and TGF-beta1 (1x10(6) cells/mL+5 microg), and 4 dogs received saline only. AV node function was assessed at baseline and after 4 weeks. Saline (80 mL) with assigned therapy (0.25 mL per injection) was injected into the peri-AV nodal region in each dog. At baseline, the AH interval (66+/-3 ms) and the average RR interval (331+/-17 ms) in pacing-induced AF were similar in each cohort. The increase in AH interval in normal sinus rhythm was longer after fibroblast (23+/-4 versus 5+/-5 ms; P=0.05) and fibroblast plus TGF-beta1 (50+/-5 versus 5+/-5 ms; P<0.001) injections than with saline alone, with similar findings during high right atrium and distal coronary sinus pacing. The AH interval was not significantly increased after TGF-beta1 injections. The AH interval was significantly longer after fibroblast plus TGF-beta1 injections than with either therapy (TGF-beta1 or fibroblasts) alone. The RR interval during AF was increased in dogs that received fibroblasts alone (110+/-36 versus -41+/-34 ms) and to a greater extent with the addition of TGF-beta1 (294+/-108 versus -41+/-34 ms). No AV block was seen in any cohort at 4 weeks. Labeled fibroblasts that expressed vimentin were identified in all dogs that received cell injections at 4 weeks. CONCLUSIONS: AV nodal modification can be achieved with injected fibroblasts without the creation of AV block. The effect on AV node conduction is substantially enhanced by pretreatment of fibroblasts with TGF-beta1. These data have therapeutic potential for the management of rapid ventricular rate during AF without pacemaker implantation.

Efficacy and safety of circumferential pulmonary vein isolation using a novel cryothermal balloon ablation system.

OBJECTIVES: We sought to evaluate the efficacy and safety of a novel cryothermal balloon ablation system in creating pulmonary vein (PV) isolation. BACKGROUND: Pulmonary vein isolation using standard radiofrequency ablation techniques is limited by procedure-related complications, such as thrombus formation and PV stenosis. Cryothermal ablation may reduce the risk of such complications. METHODS: Eight dogs underwent circumferential ablation of both superior PVs for either 4 or 8 min using a cryothermal balloon catheter (CryoCath Technologies Inc., Kirkland, Canada). Both fluoroscopy and intracardiac ultrasound (ICE)-guided balloon and Lasso catheter positioning at the PV ostia assessed short-term PV integrity. In six additional dogs, long-term PV integrity was assessed by computed tomography at 16 weeks after ablation. RESULTS: Successful electrical isolation was achieved acutely in 14 of 16 (87.5%) PVs and was confirmed in one-week survival studies in 10 of 12 (83%) PVs. Successful isolation was higher in the absence of any peri-balloon flow leak as seen by ICE (p = 0.015), and with balloon temperatures < or =-80 degrees C (p = 0.015). Cryolesions were located at the veno-atrial junction and were homogeneous, with intact endothelium and free of thrombus formation. Although limited angiographic PV narrowing was noted in the early follow-up period, no significant PV narrowing was seen long-term. Right phrenic nerve injury was seen in 50% of the animals studied at one week. CONCLUSIONS: This novel cryothermal balloon ablation system is effective for isolating PVs, but injury to the right phrenic nerve was noted in this early experience. Further studies are needed to assess the long-term efficacy and safety of this technique.

Discrepancies between catheter tip and tissue temperature in cooled-tip ablation: relevance to guiding left atrial ablation.

BACKGROUND: It is not known whether catheter tip temperatures with a cooled-tip ablation can be reliably extrapolated to estimate actual tissue temperatures. The relationship between catheter tip temperatures, tissue temperatures, power, and microbubble formation is not known. METHODS AND RESULTS: Nine dogs underwent 111 radiofrequency energy deliveries at the pulmonary vein ostia with a cooled-tip catheter. Catheter tip and tissue temperatures were markedly discrepant. Catheter tip temperature plateaus at 36 degrees C to 39 degrees C with increasing power, whereas tissue temperature increases to a mean of 75+/-3 degrees C at 45 W (maximum temperature >100 degrees C). Seventy-two energy deliveries were performed, titrating power to microbubble formation guided by intracardiac echocardiography. Type I and II microbubble formation occurred in 45 (63%) and 19 (26%) ablations, respectively. Type I microbubble emergence occurred at lower powers (21+/-8 versus 26+/-4 W; P=0.05), catheter tip temperatures (38+/-5 degrees C versus 48+/-10 degrees C; P=0.02), and tissue temperatures (65+/-19 degrees C versus 81+/-9 degrees C; P<0.001) than type II microbubble formation. Maximum impedance decreases during ablation before microbubble formation were less with type I microbubble (20+/-9 versus 37+/-11 Omega; P<0.001) compared with type II microbubbles. One quarter of type I microbubbles abruptly transitioned to type II microbubbles with significant changes in power or catheter tip temperature. No microbubbles were seen in 19 ablations (26%) despite powers up to 26+/-9 W and tissue temperatures up to 81+/-17 degrees C. CONCLUSIONS: Catheter tip and tissue temperatures are markedly discrepant during cooled-tip ablation. Type I and II microbubble formation occurs at overlapping power and catheter tip and tissue temperature ranges. Neither the absence of microbubbles nor the presence of type I microbubble formation ensures against excessive tissue heating. The appearance of microbubbles may indicate possible tissue overheating and signal a need to decrease energy.

Mechanisms of phrenic nerve injury during radiofrequency ablation at the pulmonary vein orifice.

BACKGROUND: The phrenic nerve can be injured with radiofrequency energy delivery. Nevertheless, the mechanisms of injury are unknown. This study was undertaken to examine phrenic nerve tissue temperatures during ablation at the pulmonary vein (PV) orifice, assess the temperature dependence of injury, and to delineate the possible mechanisms of untoward nerve effects. METHODS: Ten dogs underwent ablation at the right superior PV (RSPV) orifice. Phrenic nerve temperatures were assessed with implanted thermocouples overlying the endocardial ablation site. Using an 8-mm ablation catheter tip, energy was titrated to 50 degrees C and incremented by 5 degrees C for 120 seconds. RESULTS: Phrenic nerve capture was achieved in nine (90%) dogs after thermocouple implantation. A RSPV orifice tissue temperature >60 degrees C occurred in 32 (84%) of energy deliveries with a power of 34 +/- 22 W. In three (33%) dogs, this resulted in nerve dysfunction (maximum nerve temperature: 41 degrees C, 41 degrees C, and 91 degrees C) with histology consistent with acute thermal injury. In four additional dogs, 17 energy deliveries were made directly to the phrenic nerve using a novel in situ model. In 5 (29%) energy deliveries, nerve function was impacted immediately by the generated current, with resolution simultaneous with discontinuing radiofrequency. Transient phrenic nerve injury occurred in all dogs at a temperature of 47 +/- 3 degrees C (range: 43-53 degrees C) after 38 +/- 32 seconds (range: 20-120 seconds). After termination of the energy delivery, nerve function returned in 15(88%) during 30 seconds of postablation pacing. In two (12%) ablation attempts, nerve recovery was delayed (>3 minutes). Permanent injury occurred in all dogs after 92 +/- 83 seconds (range: 20-280 seconds) of additional energy delivery at a temperature of 51 +/- 6 degrees C (range: 45-65 degrees C). CONCLUSION: Phrenic nerve injury can be more common than anticipated with RF ablation at the RSPV orifice. Relatively low tissue temperatures can injure the nerve. Immediate nerve effects suggest a second mechanism of nerve dysfunction related to electrical current. Transient nerve effects occur prior to permanent damage, providing an opportunity to discontinue energy delivery before permanent injury.

Prediction of short- and long-term outcomes by electrocardiography in survivors of out-of-hospital cardiac arrest.

BACKGROUND: Programs focusing on early defibrillation have improved both short- and long-term survival of patients with VF out-of-hospital cardiac arrest (OHCA). Subsequent long-term management of survivors would be facilitated by a straight-forward, non-invasive method of identifying those at highest risk for recurrence. Therefore, we assessed the predictive value of the standard ECG to determine both short- and long-term outcomes in survivors of VF OHCA to assist in risk stratification of those patients at highest risk of sudden death. METHODS: All patients with an OHCA between November 1990 and December 2000 who received early defibrillation for VF in Olmsted County Minnesota (MN) were included. Cox proportional hazards modeling was used to examine ECG variables and subsequent ICD deployment and death. RESULTS: Two hundred patients presented in VF OHCA; of these 138 (69%) survived to hospital admission (seven died in the emergency department prior to admission) and 79 (40%) were discharged. The QRS duration (141 +/- 41ms in nonsurvivors, 123 +/- 35 in survivors, P = 0.004) was predictive of short-term mortality in patients who did not survive to hospital discharge. The ventricular rate, PR interval, presence of right or left bundle branch block, QTc, ST elevation myocardial infarction, and atrial fibrillation/flutter were nonpredictive. The average length of follow up for hospital dismissal survivors was 4.8 +/- 3.0 years. In univariate analysis, each 30 ms interval increase in the QRS width and PR interval was associated with increased mortality and ICD deployment hazard ratio of 1.6 (CI 1.1-2.5, P = 0.02) and 1.12 (CI 1.0-1.2, P = 0.05), respectively. In multivariate analysis accounting for admission ejection fraction, a PR > 200 ms [HR 4.5 (CI 1.7-11.8, P = 0.022)], QRS width increase greater than 30 ms [HR 1.9 (CI 1.3-2.8, P < 0.001)], and a QRS > 120 ms [HR 2.4 (CI 1.1-5.4, P = 0.032)] were predictive of long-term mortality and ICD shocks. CONCLUSION: Careful evaluation of the admitting and discharge ECG provides prognostic information for in-hospital and long-term outcomes, respectively in this cohort of out-of-hospital cardiac arrest survivors. The QRS duration on the dismissal ECG following VF OHCA provides prognostic information which might be useful to identify those at highest risk long-term, and who would benefit from more aggressive antiarrhythmic therapy and cardiac stabilization.

Analysis of catheter-tip (8-mm) and actual tissue temperatures achieved during radiofrequency ablation at the orifice of the pulmonary vein.

BACKGROUND: Many ablative approaches in or near the orifice of the pulmonary vein (PV) have demonstrated success in eliminating atrial fibrillation. Despite current practice, there are no data regarding the in vivo efficacy and safety of an 8-mm catheter tip for ablation at the PV orifice. METHODS AND RESULTS: Ten mongrel dogs were studied. Thermocouples were implanted in the atrial muscle of the PV orifice. Intracardiac echocardiography monitored catheter position, tip/tissue orientation, and microbubble formation. Ninety-four ablations were performed for 120 seconds. A temperature discrepancy >10 degrees C between the catheter tip and tissue occurred during 47 (50%) of the ablations. Despite termination of energy delivery, the average tissue temperature remained within 1 degrees C of the achieved steady state for 9 seconds. A temperature discrepancy >10 degrees C was more common in the right superior PV, with oblique catheter positioning, when tissue temperatures were >60 degrees C or 80 degrees C, and with type 1 or type 2 microbubble formation. However, microbubbles were not present in 7 (13%, type 1) and 10 (40%, type 2) ablations with tissue temperatures >80 degrees C. The maximum tissue temperature achieved with non-full-thickness lesions was 47.3+/-7.4 degrees C vs 75.9+/-11.7 degrees C (P<0.0001) for full-thickness lesions. CONCLUSIONS: Marked discrepancies between catheter-tip and tissue temperatures occurred with higher temperatures, prolonged ablation times, and unfavorable catheter thermistor-tissue contact. Also, these data suggest a conservative approach to atrial ablation, because full-thickness lesions were obtained when tissue temperatures reached 50 degrees C to 60 degrees C and the tissue retained high heat levels despite termination of radiofrequency energy. Finally, microbubbles are inconsistent markers of tissue overheating.

Eosinophilic-lymphocytic myocarditis after smallpox vaccination.

Smallpox is an eradicated viral disease that has re-emerged as a potential bioterrorism threat. Smallpox vaccination was historically the most effective defence measure against wild smallpox virus. The risk of myopericarditis after vaccination might limit this option. We report a case of biopsy-proven eosinophilic-lymphocytic myocarditis diagnosed in vivo with histological evidence for eosinophil-mediated cardiac myocyte necrosis shortly after smallpox vaccination. Furthermore, we report a beneficial haemodynamic response to high-dose corticosteroids. A better understanding of the aberrant immune mechanism of myocyte injury after smallpox vaccination might improve the risk/benefit assessment for people considering smallpox vaccination and better smallpox vaccines in the future.