Prospective randomized comparison between upgraded '2C3L' vs. PVI approach for catheter ablation of persistent atrial fibrillation: PROMPT-AF trial design.

BACKGROUND: In randomized studies, the strategy of pulmonary vein antral isolation (PVI) plus linear ablation has failed to increase success rates for persistent atrial fibrillation (PeAF) ablation when compared with PVI alone. Peri-mitral reentry related atrial tachycardia due to incomplete linear block is an important cause of clinical failures of a first ablation procedure. Ethanol infusion (EI) into the vein of Marshall (EI-VOM) has been demonstrated to facilitate a durable mitral isthmus linear lesion. OBJECTIVE: This trial is designed to compare arrhythmia-free survival between PVI and an ablation strategy termed upgraded '2C3L' for the ablation of PeAF. STUDY DESIGN: The PROMPT-AF study (clinicaltrials.gov 04497376) is a prospective, multicenter, open-label, randomized trial using a 1:1 parallel-control approach. Patients (n = 498) undergoing their first catheter ablation of PeAF will be randomized to either the upgraded '2C3L' arm or PVI arm in a 1:1 fashion. The upgraded '2C3L' technique is a fixed ablation approach consisting of EI-VOM, bilateral circumferential PVI, and 3 linear ablation lesion sets across the mitral isthmus, left atrial roof, and cavotricuspid isthmus. The follow-up duration is 12 months. The primary end point is freedom from atrial arrhythmias of >30 seconds, without antiarrhythmic drugs, in 12 months after the index ablation procedure (excluding a blanking period of 3 months). CONCLUSIONS: The PROMPT-AF study will evaluate the efficacy of the fixed '2C3L' approach in conjunction with EI-VOM, compared with PVI alone, in patients with PeAF undergoing de novo ablation.

Exogenous nerve growth factor promotes the repair of cardiac sympathetic heterogeneity and electrophysiological instability in diabetic rats.

OBJECTIVES: Diabetic cardiac autonomic neuropathy can lead to an increased incidence of ventricular arrhythmias (VAs). However, few data are available regarding the pathogenesis and therapy of the VAs accompanying diabetic cardiac autonomic neuropathy. We aimed to explore whether or not exogenous nerve growth factor (NGF) can reduce the sympathetic heterogeneity and the incidence of VAs in diabetes mellitus (DM). METHODS: Male Wistar rats were randomly divided into 3 groups: controls, rats with DM with saline infused into the left stellate ganglion (LSG), i.e. the DS group and rats with DM with NGF infused into the LSG, i.e. the DN group. After 28 weeks, all rats were subjected to electrophysiological experiments. Sympathetic innervations and NGF were studied by immunostaining, RT-PCR or Western blot analysis. RESULTS: The incidence of inducible VAs was significantly higher in the DS group than in the control group, but was markedly decreased in the DN group. In the DS group, the tyrosine hydroxylase (TH) and NGF expression were significantly lower than in the other groups, and significant proximal-distal heterogeneities existed regarding the TH and NGF expression in the left ventricle, but were markedly repaired in the DN group. CONCLUSIONS: NGF intervention in the LSG can reduce the heterogeneity of cardiac sympathetic innervations and the incidence of VAs in diabetic rats.

Metoprolol-mediated amelioration of sympathetic nerve sprouting after myocardial infarction.

OBJECTIVES: Systemic or local inflammation causes cardiac nerve sprouting and consequent arrhythmia. Metoprolol can prevent sympathetic nerve remodeling after myocardial infarction (MI), but the underlying mechanism is unclear. In this study, we evaluated the role of metoprolol in ameliorating sympathetic sprouting. METHODS: Rabbits underwent ligation of the coronary artery for MI. MI rabbits received metoprolol or saline for 7 days. Immunohistochemistry was used to measure cardiac nerve sprouting and sympathetic innervations. Nuclear factor-κB (NF-κB) DNA binding activity was analyzed by electrophoretic mobility shift assay. The protein levels of NF-κB p65, inhibitor κBα (IκBα) and nerve growth factor (NGF) were detected by Western blot analysis. The mRNA levels of NGF, interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) were examined by quantitative real-time PCR. RESULTS: MI rabbits showed nerve sprouting and sympathetic hyperinnervation. In MI rabbits, as compared with saline treatment, metoprolol reduced NF-κB DNA binding activity and NF-κB p65 level, and increased IκBα level. Moreover, metoprolol downregulated IL-1ß, TNF-α and NGF levels, and reduced the density of sympathetic nerve fibers. CONCLUSIONS: Metoprolol ameliorates sympathetic nerve sprouting in rabbits after MI and is associated in part with inhibiting NF-κB activity.

Mesenchymal stem cell therapy improves diabetic cardiac autonomic neuropathy and decreases the inducibility of ventricular arrhythmias.

BACKGROUND: Diabetic cardiac autonomic neuropathy (DCAN) may cause fatal ventricular arrhythmias and increase mortality in diabetics. Mesenchymal stem cells (MSCs) can secrete various cytokines and growth factors exerting neurosupportive effects. In this study, we investigated the effect of MSC on DCAN in diabetic rats. METHODS: Forty rats were divided into normal control, diabetes mellitus (DM) control, MSC treatment (6 × 10(6) MSCs via direct myocardial injection) and MSC-conditioned medium group (100 µl via direct myocardial injection). Immunohistochemistry was used to measure choline acetyltransferase (ChAT, a marker for parasympathetic nerves) and tyrosine hydroxylase (TH, a marker for sympathetic nerves) positive nerve fibres in the ventricular myocardium. Heart rate variability and programmed electrical stimulation was used to assess the inducibility of ventricular arrhythmias in the animals. RESULTS: Two weeks after MSC treatment, the density of ChAT- and TH-positive nerve fibres in MSCs and MSC-conditioned medium group was higher than in DM control group (P < 0.05 or P < 0.01). The ChAT/TH ratio in MSC group was higher than in DM control group (0.37 ± 0.014 vs. 0.27 ± 0.020, P < 0.01). The standard deviation of normal-to-normal R-R intervals in MSCs (5.13 ± 0.69) and MSC-conditioned medium group (4.30 ± 0.56) was higher than in DM control group (3.45 ± 0.60, P < 0.05). The inducibility of VAs in the MSC group was lower than in the DM control group. CONCLUSIONS: MSC therapy may promote cardiac nerve sprouting and increase the ratio of parasympathetic to sympathetic nerve fibres. It may also suppress the inducibility of ventricular arrhythmias in the diabetic rats.

Risk of ventricular arrhythmias after myocardial infarction with diabetes associated with sympathetic neural remodeling in rabbits.

BACKGROUND: Abnormal sympathetic innervation underlies both long-term hyperglycemia and myocardial infarction (MI). The incidence of ventricular arrhythmias (VAs) after MI is higher in diabetic than in nondiabetic patients. However, the exact mechanism remains unclear. In this study, we aimed to explore sympathetic neural remodeling after MI in diabetic rabbits and its relationship with VAs. METHODS: Rabbits were randomly assigned to 4 groups: control, diabetes mellitus (DM), MI and diabetic myocardial infarction (DI). After electrophysiological experiments in vivo, immunohistochemistry and real-time RT-PCR were used to measure sympathetic innervations. To test the function of sympathetic nerve fibers, norepinephrine levels were measured by high-performance liquid chromatography. RESULTS: The corrected QT interval and QT dispersion were significantly more prolonged with DI than other conditions. The density of tyrosine hydroxylase-positive fibers and corresponding mRNA abundance was significantly higher with DI than with DM and under control conditions, but was lower than with the MI group. Moreover, the distribution and structure of regenerated nerve was heterogeneous in DI rabbits. Norepinephrine content was higher in the DI group, and accompanied by an increased quantity of tyrosine hydroxylase-positive fibers. CONCLUSION: MI results in sympathetic neural remodeling in diabetic rabbits, which may be responsible in part for the increased occurrence of VAs.

Mechanisms of atypical flutter wave morphology in patients with isthmus-dependent atrial flutter.

Sixty-three episodes of isthmus-dependent atrial flutter (AFL) in 55 patients were studied to characterize variations in flutter wave morphology and to investigate the mechanisms of the atypical flutter waves on surface ECG. The activation patterns of coronary sinus (CS) and their relationship with flutter wave morphology on the ECG were analyzed. In 46 episodes of counterclockwise AFL (CCW-AFL), there were four types of flutter waves on ECG. Typical and atypical flutter waves were found in 47.8% and 13.0% of the episodes, respectively. Atypical flutter waves had broad positive terminal portion or entirely positive wave in the inferior leads and in V(1), with a distal-to-proximal or fused activation pattern in the CS, and an average activation time of 21.3 +/- 11.4 ms. In 17 episodes of clockwise AFL (CW-AFL), typical and atypical flutter waves were identified in 41.2% and 41.2%, respectively. Atypical flutter waves had negative waves in the inferior ECG leads and in V1, a proximal-to-distal activation pattern in the CS, and an average activation time of 42.4 +/- 14.4 ms. We conclude that atypical flutter waves are common in the isthmus-dependent AFL. The clockwise or counterclockwise conduction in the right atrium, and the activation patterns or conduction sequences between the right and the left atrium, are associated with the variations in the flutter wave morphology on body surface ECG.

Effects of angiotensin converting enzyme inhibition on cardiac innervation and ventricular arrhythmias after myocardial infarction.

PURPOSE: To investigate the influence of angiotensin-converting enzyme inhibitor (ACEI) on cardiac innervation and inducible ventricular arrhythmias (VAs) in healed myocardial infarction (MI). METHODS: Left anterior descending coronary artery was ligated to induce MI in 30 rabbits. After oral captopril (10mg/kg/d) for 8 weeks, electrophysiological study was performed to evaluate the incidence of inducible VAs. RT-PCR and immunohistochemistry were used to measure the cardiac innervation. RESULTS: Eight weeks after the operation, the incidence of inducible VAs in the MI-placebo group was higher (58.3%, 7/12) than in the sham operation group (16.7%, 2/12, P < 0.05). However, the incidence of inducible VAs in the MI-captopril group was lower (27.2%, 3/11) than in the MI-placebo group (P < 0.05). Proliferation and growth of nerve fibres in the MI-placebo group were mainly distributed at the periphery of the infarcted and perivascular regions of the myocardium. The density of nerve fibres increased in the MI-placebo group (3889+/-521 microm2/mm2) compared with the sham group (1727+/-304 microm2/mm2, P < 0.01) at the infarct border. In the MI-captopril group, the density of nerve fibres (3507+/-433 microm2/mm2) at the infarct border did not differ from that in the MI-placebo group (P=0.07). MI-induced abnormal nerve fibre distribution was partly restored by captopril treatment. CONCLUSION: In this study, prolonged captopril treatment was effective in preventing VAs in healed MI, partly by attenuating the spatial heterogeneity of cardiac innervation.

In rats the duration of diabetes influences its impact on cardiac autonomic innervations and electrophysiology.

Diabetic cardiac autonomic neuropathy (DCAN) may cause fatal ventricular arrhythmias and increase mortality in diabetics. However, limited data are available with regard to the precise changes in cardiac autonomic denervation after diabetes onset. In this study, we dynamically observed the progression of DCAN and its relationship with the inducibility of ventricular arrhythmias in diabetic rats. Rats were randomly divided into normal control and diabetes mellitus (DM) groups. The rats were sacrificed at 3 or 6 months post-treatment. Heart rate variability and programmed electrical stimulation were used to assess the electrophysiological characteristics and the inducibility of ventricular arrhythmias in the animals. Immunohistochemistry and real-time RT-PCR were used to measure choline acetyltransferase and tyrosine hydroxylase-positive nerve fibers and the corresponding mRNA expression levels in the proximal and distal regions of the left ventricle. Short-term diabetes resulted in distal myocardial parasympathetic denervation with sparing of the proximal myocardium. By 6 months, both parasympathetic and sympathetic denervation were further aggravated. Moreover, electrophysiological experiments demonstrated a sympatho-parasympathetic imbalance and an increase in ventricular arrhythmia inducibility in the diabetic rats. These results suggest that DM causes cardiac nerve denervation, relative sympathetic hyperinnervation and inhomogeneous neural innervations, which may be associated with an increase in the induction of ventricular arrhythmia in diabetic rats.

Sudden asystole during radiofrequency ablation: a case report and literature review.

BACKGROUND: Radiofrequency (RF) ablation is a widely accepted and ideal therapeutic tool to cure some tachycardias. The occurrence of complications varies depending on the procedure being performed. Sudden unexpected prolonged asystole is rare for most ablation procedures and the underlying mechanisms remain unclear. CASE PRESENTATION: A case of sudden prolonged asystole induced by RF ablation of a concealed left free wall accessory in a 59-year-old woman with recurrent tachycardia. RF application provoked progressive slowing of the sinus rhythm and then a 13.2-second period of asystole ensued. Asystole was self-healing and no complications were seen in the following follow-up. CONCLUSIONS: RF ablation may develop prolonged asystole due to vagus response caused by stimulation of unmyelinated vagal C-fibers or ganglionated plexus (GP). Reflexible asystole is reproducible and resolves independently, without affecting the procedure of RF ablation.

Evaluation of the surface ECG in detecting isthmus conduction block after ablation of typical atrial flutter.

OBJECTIVES: To investigate the value of changes in P wave morphology and duration detected by surface electrocardiogram (ECG) during proximal coronary sinus (PCS) and low lateral right atrial (LLRA) stimulation as a marker for complete bidirectional isthmus conduction block in the procedure of typical atrial flutter ablation. METHODS: Morphology, duration, and ratio of a positive terminal P wave were estimated in 52 typical atrial flutter patients before and after radiofrequency catheter ablation (RFCA). RESULTS: Atrial flutter ablation resulted in a complete bidirectional isthmus block in all 52 patients. The terminal portion of the P wave towards a positive morphology was detected in 90.7% (47/52) patients both during PCS and LLRA stimulation. These changes were predominantly observed in the inferior leads. Positive morphological changes of the terminal P wave portion and the measured P wave ratio (40% +/- 12%) in the inferior leads indicating bidirectional isthmus conduction block with a sensitivity of 87.5% and a specificity of 91.7% were observed. An increment of 20 ms or more in P wave duration during the PCS stimulation and 10 ms or more during the LLRA stimulation indicating the conduction block with a sensitivity of 90% and a specificity of 100%. CONCLUSIONS: The variation of P wave morphology and duration in inferior leads of the surface ECG is a helpful technique to assess the complete bidirectional isthmus conduction block in the procedure of typical atrial flutter ablation.

Effects of prolonged metoprolol treatment on neural remodeling and inducible ventricular arrhythmias after myocardial infarction in rabbits.

BACKGROUND: Neural remodeling is part of the pathophysiology of ventricular arrhythmias after myocardial infarction (MI). In this study, we developed a rabbit model of MI to investigate the effect of the beta-blocker metoprolol on ventricular neural remodeling and susceptibility to ventricular arrhythmias. METHODS: MI was induced by ligation of the left anterior descending coronary artery in 30 rabbits, and sham operations were performed in 12 control animals. Metoprolol was then administered to 15 of the MI animals. After electrophysiological recordings, the expression of nerve markers was studied at the infarct border and the non-infarct left ventricle free wall (LVFW) by immunostaining or RT-PCR. RESULTS: Eight weeks after MI, the incidence of inducible ventricular arrhythmias was significantly (P<0.01) higher in the MI group than in the sham group. However, metoprolol treatment decreased incidence of post-MI ventricular arrhythmias (8.3%) compared to those without treatment (58.3%, P<0.001). The density of nerve fibers was increased in MI group (3889+/-521 microm(2)/mm(2)) compared to the sham group (1727+/-304 microm(2)/mm(2)). Treatment of MI rabbits with metoprolol resulted in a partial reduction (2725+/-283 microm(2)/mm(2)). However, the shape and imbalance of nerve fibers appeared to be normalized by the metoprolol treatment. The expression levels of TH mRNA were reduced (P<0.01) by metoprolol treatment. CONCLUSION: Metoprolol reduces post-MI ventricular arrhythmias, partly by altering the neural remodeling process.