Vagal activity modulates spontaneous augmentation of J-wave elevation in patients with idiopathic ventricular fibrillation.

BACKGROUND: Although J-wave elevation in the inferolateral leads could be related to idiopathic ventricular fibrillation (IVF), little is known about the pathophysiologic characteristics of J-wave elevation in patients with IVF. OBJECTIVE: This study aimed to determine the relationship between augmentation of J-wave elevation and changes in RR interval or autonomic nervous activities in patients with IVF. METHODS: Eight patients with IVF and 22 controls with J-wave elevation (≥0.1 mV) in lead V5 were studied. The J-wave amplitude was automatically measured in lead CM5 of a digital Holter electrocardiogram, and the J-RR relationship was determined. Based on the analysis of heart rate variability, the relationship between the J-wave amplitude and the natural logarithm of high-frequency (HF) components (J-ln HF relationship) or the ratio of low frequency (LF) components to HF components (J-LF/HF relationship) was also determined. RESULTS: The J-RR slope (mm/s) was greater in patients with IVF than in controls (3.5 ± 0.7 vs 2.4 ± 0.8; P <.01), as was J-wave amplitude (mm) at an RR interval of 1.2 seconds (2.8 ± 0.9 vs 2.0 ± 0.6; P <.05). The J-wave amplitude was correlated positively with ln HF and negatively with LF/HF, and the slopes of both J-ln HF and J-LF/HF regression lines were greater in patients with IVF than in controls. During an entire 24-hour period, there was no difference between the 2 groups in either HF or LF/HF. Nine of the total 11 episodes (82%) of spontaneous ventricular fibrillation occurred between 18:00 and 6:00. CONCLUSIONS: In patients with IVF as compared with control subjects, J-wave elevation was more strongly augmented during bradycardia and was associated with an increase in vagal activity. This could be related to the occurrence of ventricular fibrillation predominantly at night in patients with IVF.

Angiotensin II type 1 receptor blocker attenuates diabetes-induced atrial structural remodeling.

BACKGROUND: Diabetes mellitus promotes atrial structural remodeling, thereby producing atrial arrhythmogenicity, where advanced glycation endproducts (AGEs) and their receptor (RAGE) are implicated to play a role in the pathogenesis. PURPOSE: We investigated the effects of candesartan, an angiotensin type II receptor blocker, on the diabetes-induced atrial structural change. METHODS AND RESULTS: Diabetes was induced in 8-week-old female Sprague-Dawley rats by intraperitoneal injection of streptozotocin at 70 mg/kg. Osmotic pumps were simultaneously set to infuse candesartan at a subdepressor dose of 0.05 mg/kg/day. Twelve weeks after the induction of diabetes, the blood glucose and glycated hemoglobin A1c were significantly higher in streptozotocin-injected rats than those in control rats, and were not affected by candesartan treatment. The atria of diabetic rats showed remarkable diffuse interstitial fibrosis with more enhanced protein expressions of RAGE and connective tissue growth factor (CTGF) compared with control ones. The treatment with candesartan significantly reduced CTGF expression and effectively suppressed the development of fibrotic deposition in diabetic animals. CONCLUSIONS: Candesartan reduced CTGF expression and attenuated the fibrosis in diabetic rat atria. These results implied the protective effects of candesartan on diabetes-related atrial arrhythmias.

Early repolarization in Wolff-Parkinson-White syndrome: prevalence and clinical significance.

AIMS: Idiopathic ventricular fibrillation (IVF) with early repolarization (ER) has recently been reported; however, ER is a common finding in healthy subjects and is also found sporadically in patients with Wolff-Parkinson-White (WPW) syndrome. The present study was designed to evaluate the prevalence and clinical significance of ER in patients with WPW syndrome. METHODS AND RESULTS: One hundred and eleven patients with WPW syndrome were studied retrospectively. Early repolarization was defined as QRS slurring or notching with J-point elevation ≥ 1 mm. The prevalence of ER was determined before and after successful catheter ablation. Before ablation, ER was found in 35 of 75 patients with a left free wall, 6 of 23 with a right free wall, and 7 of 13 with a septal accessory pathway (48 of 111, 43% as a whole). Early repolarization was always observed in leads with positive deflection of the initial part of the delta wave. After successful ablation of accessory pathways, ER was preserved in 28 (25%), disappeared in 20 (18%), and newly developed in 8 (7%) patients. In the remaining 55 (50%) patients, ER was not observed either before or after ablation. In patients with persistent ER, the amplitude and width of ER were significantly decreased 3-7 days after the ablation (1.7 ± 0.7 vs. 1.4 ± 0.6 mm, P < 0.005 and 42 ± 11 vs. 34 ± 9 ms, P < 0.001, respectively). CONCLUSION: In patients with WPW syndrome, ER could be partly related to early depolarization through the accessory pathway. However, persistent ER and new ER appearing after the ablation were frequently found. Therefore, in these patients, mechanisms other than early depolarization may be involved in the genesis of ER.

Deficiency of testosterone associates with the substrate of atrial fibrillation in the rat model.

BACKGROUND: Since the prevalence of atrial fibrillation (AF) increases progressively with aging, especially in men, we hypothesized that testosterone might affect the occurrence of AF. METHODS AND RESULTS: We examined the electrophysiological properties of the atria in isolated-perfused hearts of sham-operated male (SM), female (SF), orchiectomized male with and without administration of testosterone (ORCH-T and ORCH), and ovariectomized female (OVX) Sprague-Dawley rats. An electrophysiological study revealed that repetitive atrial responses induced by electrical stimuli significantly increased in ORCH rats without changes in other electrophysiological properties and were abolished by administration of testosterone. To investigate the underlying mechanisms, we evaluated the expression level of calcium-handling proteins. In ORCH rats, the immunoreactive protein level of ryanodine receptor type 2 (RyR2) and sodium-calcium exchanger significantly increased as compared with SM and ORCH-T rats without alterations in the level of FK506-binding protein (FKBP12.6), sarcoendoplasmic reticulum Ca-ATPase, and phospholamban. Immunoprecipitation analysis demonstrated decreased binding of FKBP12.6 to RyR2 in ORCH rats, which was prevented by testosterone. In contrast, the expression levels of these proteins showed no significant differences between SF and OVX rats. CONCLUSION: Deficiency of testosterone was arrhythmogenic in rat atria possibly through less binding of FKBP12.6 to RyR2, which could induce feasible calcium leakage from the sarcoendoplasmic reticulum. These results would explain, at least in part, the increase in the prevalence of AF in accordance with the decline of testosterone particularly in elderly men.

Junctional rhythm associated with ventriculoatrial block during slow pathway ablation in atypical atrioventricular nodal re-entrant tachycardia.

AIMS: We assessed responses to slow pathway ablation with respect to the appearance of ventriculoatrial (VA) block during junctional rhythm in both typical and atypical types of atrioventricular nodal re-entrant tachycardia (AVNRT). METHODS AND RESULTS: The 31 subjects included 16 patients with slow-fast type of typical AVNRT and 15 patients with atypical AVNRT (9 patients with fast-slow type and 6 patients with slow-slow type). During atypical AVNRT, the HA interval was prolonged (>70 ms) and the earliest atrial activation was located around the coronary sinus (CS) ostium. The difference in atrial activation times at the CS ostium and His-bundle area [A(CS-His)] during AVNRT was measured. Slow pathway ablation was performed using a classical electro-anatomical approach. In typical AVNRT, A(CS-His) was -21.3 +/- 3.4 ms, and the HA interval was 34 +/- 14 ms. During slow pathway ablation, all patients with typical AVNRT had junctional rhythm with retrograde atrial conduction. In contrast, in patients with atypical AVNRT, A(CS-His) was 12 +/- 19.3 ms and the HA interval was 189 +/- 77 ms. In 13 of the 15 patients with atypical AVNRT, slow pathway ablation induced junctional rhythm, which was not associated with retrograde atrial conduction. After ablation, AVNRT became non-inducible and antegrade atrioventricular (AV) conduction was preserved in all patients. CONCLUSION: In patients with atypical AVNRT, junctional rhythm with VA block during slow pathway ablation is commonly observed and indicates the success of the ablation of retrograde slow pathway conduction, but has no relation to the risk of subsequent AV block. During junctional rhythm, occasional appearance of the sinus beats with intact antegrade AV conduction is essential for safety of ablation.

AGEs-RAGE system mediates atrial structural remodeling in the diabetic rat.

BACKGROUND: Diabetes mellitus (DM) is one of the independent risk factors for atrial fibrillation (AF). Our previous study has indicated that DM causes atrial structural remodeling with intraatrial conduction disturbances. We tested the hypothesis that the advanced glycation end products (AGEs) and the receptor for AGE (RAGE), which have been implicated in diabetic complications, are responsible for the atrial structural remodeling. METHODS AND RESULTS: Diabetes was induced by streptozotocin (65 mg/kg i.p.) in 8-week-old female Sprague-Dawley rats. When 24 weeks old, their atria were subjected to histology, Western blotting, and immunohistochemistry. The HbA(1c) value of induced-DM rats was significantly higher than that of control rats. Histological and immunohistochemical examinations revealed that the atria of diabetic rats showed remarkable structural changes characterized by diffuse interstitial fibrosis with abundant expressions of RAGE and connective tissue growth factor (CTGF), which findings were also confirmed by Western blotting analysis. This diabetes-induced atrial fibrosis was remarkably prevented by administration of an inhibitor of AGEs formation, OPB-9195, along with reduction of CTGF expression. CONCLUSIONS: DM promoted atrial structural remodeling via the activation of the AGEs-RAGE system with upregulating CTGF. The inhibition of AGEs formation could be a novel upstream therapeutic approach for diabetes-related atrial fibrosis.

Angiotensin type 1 receptor blockade prevents endocardial dysfunction of rapidly paced atria in rats.

INTRODUCTION: Atrial fibrillation (AF) per se causes atrial endocardial dysfunction leading to local coagulation imbalance on the internal surface of the atrium, which contributes to thrombus formation in the fibrillating left atrium. MATERIALS AND METHODS: To test a hypothesis that blockade of angiotensin II type 1 receptor (AT1-receptor) prevents the endocardial dysfunction by AF, we examined the effects of olmesartan on the expression of tissue factor pathway inhibitor (TFPI), thrombomodulin (TM), endothelial nitric oxide synthase (eNOS) and plasminogen activator inhibitor-1 (PAI-1) in the endocardium of the rapidly paced rat atria. RESULTS: Rapid pacing induced a significant decrease in TFPI, TM and eNOS and an increase in PAI-1 protein in the left atrium. Pre-administration of low-dose olmesartan significantly prevented the down-regulation of TFPI, TM and eNOS and also attenuated the up-regulation of PAI-1. Immunohistochemistry identified these changes predominantly in the atrial endocardium. While the drug was without any effect on mRNA levels of TFPI, TM and eNOS, there was a significant decrease in its PAI-1 mRNA expression. CONCLUSIONS: AT1-receptor blocker could partially prevent the atrial endocardial dysfunction by rapid atrial pacing, which would provide one theoretical basis for beneficial effects for stroke prevention in AF.

Postprandial augmentation of bradycardia-dependent ST elevation in patients with Brugada syndrome.

INTRODUCTION: In patients with Brugada syndrome, the circadian variation of ST elevation could be modulated by the autonomic nervous activity and RR interval. Recently, glucose-induced insulin secretion was also reported to contribute to fluctuation of ST elevation. Therefore, we assessed the effects of taking meals on the ST-RR relationship in the daily life of patients with Brugada syndrome. METHODS AND RESULTS: Twenty-eight patients with Brugada syndrome, who had the type I ST elevation, were categorized into 12 symptomatic and 16 asymptomatic patients. Unipolar lead (V2) Holter ECG was recorded and ST-RR relationships for a 2-hour period were compared before and after each meal. From ST-RR linear regression lines, ST-RR slope (mm/sec) and ST(mm) at RR intervals of both 0.6 seconds and 1.2 seconds (ST(0.6) and ST(1.2)) were determined. The ST-RR slope increased significantly after lunch (2.6 +/- 0.4 vs 4.4 +/- 1.2, P < 0.05) and dinner (2.1 +/- 1.0 vs 5.2 +/- 1.9, P < 0.01) in symptomatic patients, but not in asymptomatic patients. In both groups, ST(0.6) was not different before or after each meal. However, ST(1.2) increased after each meal in symptomatic patients. After dinner, ST(1.2) was significantly higher in symptomatic patients than in asymptomatic patients (5.0 +/- 2.7 vs 3.6 +/- 0.8, P < 0.05). Postprandial increase in both ST-RR slope and ST(1.2) was greatest at dinner in symptomatic patients; however, this tendency was not seen in asymptomatic patients. CONCLUSIONS: In symptomatic patients with Brugada syndrome, bradycardia-dependent augmentation of ST elevation was enhanced for the postprandial period, especially after dinner. This could be related to occurrence of ventricular fibrillation in the late evening.

Rate control and quality of life in patients with permanent atrial fibrillation: the Quality of Life and Atrial Fibrillation (QOLAF) Study.

BACKGROUND: The present study aimed to determine whether quality of life (QOL) in permanent atrial fibrillation (AF) patients would be improved by monotherapy with beta-blocker (BB) or calcium antagonist (CAA) as compared with digitalis. METHODS AND RESULTS: Twenty-nine patients with permanent AF under digitalis were randomized into BB (bisoprolol, atenolol or metoprolol) or CAA (verapamil) monotherapy treatment group. Twenty-five were men and the mean age was 67+/-8 years. After the assigned monotherapy, 12 patients received the other monotherapy in a cross-over fashion. Under each treatment, efficacy of rate control was determined by Holter electrocardiogram (ECG), treadmill testing and QOL questionnaire (Short Form-36 (SF-36) and Quality of Life of Atrial Fibrillation (AFQLQ)), and compared with the baseline digitalis treatment. CAA significantly increased mean and minimum heart rate (HR) in Holter ECG as compared with digitalis, whereas BB increased only minimum HR. Exercise duration in treadmill testing was significantly prolonged by CAA treatment, although it only tended to be prolonged by BB treatment. CAA but not BB improved role function-physical score of SF-36, and frequency and severity of symptoms of AFQLQ. CONCLUSION: These results indicate that CAA is preferable to digitalis when monotherapy is selected for short-term improvement of QOL and exercise tolerance in patients with permanent AF.

Bradycardia-dependent ECG changes in Brugada syndrome.

BACKGROUND: In patients with Brugada syndrome (BS), ventricular fibrillation (VF) occurs mainly during sleep; therefore, not only vagal activity but also bradycardia dependent changes in ECG may relate to the nighttime occurrence of VF. The present study aimed to examine the difference in bradycardia-dependent changes in the ECG of symptomatic and asymptomatic BS patients. METHODS AND RESULTS: Twenty-one patients with BS were categorized into symptomatic (n = 9) and asymptomatic (n = 12) groups. During the electrophysiologic study, the ECG changes were evaluated at RR intervals of 400, 600, 750, 1,000 and 1,100 ms during extrastimulation from the right atrium. The ST levels in V2, and the QT interval in both V2 and V5 were measured. Along with an increase in the RR interval from 400 to 1,100 ms, the ST levels in V2 increased in both groups; the increase did not differ between the 2 groups. In both leads V2 and V5, the prolongation of the QT interval along with an increase in the RR interval from 400 to 1,100 ms was significantly smaller and the QT intervals at an RR interval of 1,100 ms were significantly shorter in the symptomatic than in the asymptomatic group. CONCLUSIONS: In patients with BS, the ST elevation was augmented during bradycardia to a similar extent in both symptomatic and asymptomatic patients. However, a inhibited prolongation of the QT interval during bradycardia was characteristic of symptomatic patients. These unique repolarization dynamics could relate to the nighttime occurrence of VF during bradycardia in patients with BS.

Enalapril preserves sinus node function in a canine atrial fibrillation model induced by rapid atrial pacing.

METHODS AND RESULTS: Seventeen beagles were pretreated with either placebo (group I, n = 9) or enalapril 1 mg/kg/day (group II, n = 8) and paced at 500/min from the right atrial appendage for 4 weeks. Every week, corrected sinus node recovery time (CSNRT) and sinus cycle length (SCL) were measured. Quantitative analysis of interstitial fibrosis (IF) and adipose tissue (AT) in the SN was performed with Masson's trichrome stain, and apoptosis of the sinus nodal cells were detected with terminal deoxynucleotidyl transferase nick end-labeling. In group I, rapid atrial pacing prolonged both CSNRT and SCL. After 4 weeks of pacing, CSNRT and SCL were significantly shorter in group II (CSNRT, 410 +/- 37 msec; SCL, 426 +/- 34 msec) than in group I (CSNRT, 717 +/- 52 msec, P < 0.005; SCL, 568 +/- 73 msec, P < 0.05). Both IF and AT of the SN were greater in group I (IF, 9.7 +/- 1.9%; AT, 32.6 +/- 5.9%) than in seven sham dogs (IF, 2.4 +/- 0.9%, P < 0.05; AT, 4.0 +/- 1.7%, P < 0.05) and in group II dogs (IF, 4.0 +/- 2.0%, P < 0.05; AT, 4.0 +/- 1.7%, P < 0.05). End-labeling assay was positive in three of nine dogs in group I, but negative in group II and sham dogs. CONCLUSIONS: Rapid atrial pacing impaired SN function through IF and AT of the SN. Enalapril prevented these pacing-induced degenerative changes and improved SN function.

Repolarization dynamics in patients with idiopathic ventricular fibrillation: pharmacological therapy with bepridil and disopyramide.

The electrocardiographic parameters relating occurrence of ventricular fibrillation (VF) episodes in patients with idiopathic VF (IVF) are still unknown. The aim of this study was to clarify efficacy of pharmacological therapy in patients with IVF with respect to repolarization dynamics. The study group consisted of 8 men (age 43.6 +/- 9.1 years) with IVF (Brugada type 5 patients, prominent J wave in the inferior leads 3 patients) who had documented spontaneous episodes of VF, 7 of whom had implantable cardioverter defibrillators. The relation between QT and RR interval was analyzed from 24-hour Holter ECG using an automatic analyzing system before and after pharmacological therapy (bepridil 5 and disopyramide 3). From QT-RR linear regression lines, QT intervals were determined at RR intervals of 0.6 second [QT(0.6)], 1.0 second [QT(1.0)], and 1.2 seconds [QT(1.2)]. Pharmacological therapy increased the slope of QT-RR regression line from 0.105 +/- 0.020 to 0.144 +/- 0.037 (P < 0.05). Accordingly, QT(1.0) and QT(1.2) became longer after drug therapy [QT(1.0), 0.382 +/- 0.016 seconds vs 0.414 +/- 0.016 seconds (P < 0.01); QT(1.2), 0.403 +/- 0.017 seconds vs 0.442 +/- 0.021 seconds (P < 0.01)]. However, QT(0.6) did not change after drug administration. Before drug therapy the average episodes of VF were 5.5 +/- 5.8 (range 1 to 17) during the observation period of 19.3 +/- 17.6 months (range 6 to 60 months). After drug therapy, 6 patients had no episode of VF for 24 to 120 months (66.0 +/- 38.5 months). Two patients had a single episode of VF for 12- and 96-month follow-ups. Pharmacological therapy decreased the frequency of VF episodes in association with prolongation of QT intervals at slower heart rates. Not only J wave and ST elevation but also shorter QT intervals at slower heart rates may represent an electrophysiological substrate for development of VF episodes in these specific IVF patients.

Dynamic changes in the QT-R-R relationship during head-up tilt test in patients with vasovagal syncope.

BACKGROUND: QT interval is influenced by preceding R-R intervals and autonomic nervous tone. Changes in QT intervals during vasovagal reflex might reflect autonomic modulation of ventricular repolarization; however, this issue has not been fully elucidated. This study aimed to evaluate dynamic response of QT interval to transient changes in R-R interval during vasovagal syncope (VVS) induced by head-up tilt test. METHODS: Eighteen patients with VVS and 18 age-and sex-matched controls were studied. All patients with VVS had a positive mixed-type response to head-up tilt and all controls had a negative response. CM5-lead digital electrocardiogram (ECG) was recorded and QT intervals were analyzed using Holter ECG analyzer. Using scatter plots of consecutive QT and the preceding R-R intervals, QT-R-R relations during tilt-up and tilt-back or during vasovagal reflex were independently fitted to an exponential curve: QT (second) = A + B x exp[k x R-R (second)]. RESULTS: During the tilt-up, A, B, and k did not differ between patients with VVS and controls. During the tilt back, k showed equivalent positive value compared to the tilt-up (4.1 +/- 1.3 vs -4.6 +/- 0.9) in controls. However, k remained negative (-1.3 +/- 1.5) during vasovagal reflex in patients with VVS. In six patients, in whom metoprolol was effective in eliminating VVS, QT-R-R relationship during the tilt-back became similar to that in controls. CONCLUSIONS: In patients with VVS, hysteresis of the QT-R-R relation is similarly shown during tilt-up as in controls, whereas this hysteresis is no longer evident and failure of QT prolongation is observed during VVS.

Drug-induced changes in fibrillation cycle length and organization index can predict chemical cardioversion of long-lasting atrial fibrillation with bepridil alone or in combination with aprindine.

BACKGROUND: The aim of this study was to investigate whether drug-induced changes in fibrillation wave characteristics can predict pharmacological conversion of long lasting persistent atrial fibrillation (AF). METHODS AND RESULTS: The study group comprised 23 consecutive patients with AF lasting > or =1 month. Patients first received bepridil (200 mg/day) for 2-4 weeks. When sinus rhythm was not restored with bepridil, oral aprindine (40 or 60 mg/day) was added to bepridil. Fast Fourier transform analysis of fibrillation waves using lead V1 was performed to calculate the fibrillation cycle length (FCL). The spectral areas were measured and the maximum area divided by the total area was termed the fibrillation organization index (FOI). Sinus rhythm was restored in 16 of 23 patients (70%); 8 of these 16 patients received only bepridil (Group I) and the other 8 responders received bepridil and aprindine (Group II). In Group I bepridil increased both FCL (p<0.001) and FOI (p<0.01) and terminated AF after 20+/-12 days. In Group II bepridil increased FCL (p<0.001), but did not change FOI. The addition of aprindine terminated AF in association with an increase in both FCL (p<0.005) and FOI (p<0.005) within 19+/-8 days. In the remaining 7 patients who did not have restoration of sinus rhythm, bepridil increased both FCL and FOI significantly, but less than in Group I, and the addition of aprindine did not further increase either of them. Chemical cardioversion of AF occurred in all patients with FCL > or =190 ms and FOI > or =45% after drug administration. CONCLUSION: Bepridil alone or in combination with aprindine converted long lasting persistent AF in association with an increase in both FCL and FOI. The combination of FCL and FOI after drug administration is helpful in predicting chemical cardioversion of persistent AF.

Maintenance of sinus rhythm and recovery of atrial mechanical function after cardioversion with bepridil or in combination with aprindine in long-lasting persistent atrial fibrillation.

BACKGROUND: The aim of this study was to evaluate pharmacological cardioversion of long-lasting persistent atrial fibrillation (AF) using bepridil in terms of recovery of atrial mechanical function and maintenance of sinus rhythm. Bepridil alone or in combination with aprindine is effective for termination of persistent AF. METHODS AND RESULTS: The study group comprised 38 consecutive patients (24 men, 58.8+/-9.3 years) with successful conversion of persistent AF lasting >1 month either pharmacologically (Group I) or electrically (Group II). Fast Fourier transform analysis of fibrillation waves was performed and fibrillation cycle length (FCL) was calculated from the peak frequency. In Group I, sinus rhythm was pharmacologically restored in 22 patients after an average 30 days (7-49 days) of bepridil administration, either alone (11) or in combination with oral aprindine (11); they were followed up while using the same drugs. In Group II, electrical conversion restored sinus rhythm in 16 patients, and they were followed up with conventional antiarrhythmic drugs other than bepridil and aprindine. After bepridil treatment FCL increased and became significantly longer in Group I than in Group II (190+/-39 vs 150+/-29 ms, p<0.001). Atrial peak velocity in transmitral flow within the first week after cardioversion was greater in Group I than in Group II (68+/-35 vs 32+/-20 cm/s, p<0.05). By Kaplan-Meier analysis, 83% of Group I patients were free of AF recurrence at the 12-month follow-up, compared with 36% in Group II (p<0.005). CONCLUSIONS: In patients with long-lasting AF, pharmacological conversion with bepridil alone or in combination with aprindine recovered atrial mechanical function better and maintained sinus rhythm longer than electrical conversion.

Canine model of Brugada syndrome using regional epicardial cooling of the right ventricular outflow tract.

INTRODUCTION: Myocardial cooling can induce J point elevation (Osborn wave) as seen on ECG of the Brugada syndrome by activating transient outward current (Ito) and causing a spike-and-dome configuration of the monophasic action potential (MAP) in the ventricular epicardium in isolated canine ventricular wedge preparations. We determined the effect of regional epicardial cooling of the right ventricular outflow tract (RVOT) on surface ECG and ventricular vulnerability in the dog. METHODS AND RESULTS: In 12 dogs, a cooling device (20-mm diameter) was attached to the RVOT epicardium, and surface ECG, epicardial MAP, and endocardial MAP were recorded. Regional cooling (29.7 degrees C +/- 2.2 degrees C) elevated the J point from 0.05 +/- 0.06 mV to 0.12 +/- 0.11 mV and induced T wave inversion (from 0.02 +/- 0.12 mV to -0.27 +/- 0.20 mV) in lead V1 in association with "spike-and-dome" configuration of the epicardial MAP. Cooling prolonged MAP duration in the RVOT epicardium from 172 +/- 27 ms to 213 +/- 30 ms (P < 0.01) but not in the RV endocardium and increased transmural dispersion of MAP duration from 9 +/- 8 ms to 44 +/- 21 ms (P < 0.01). Cooling also prolonged the QT interval in lead V1 from 191 +/- 19 ms to 212 +/- 23 ms (P < 0.05), but not in lead V5, and increased spatial dispersion of QT interval from 7 +/- 5 ms to 20 +/- 10 ms (P < 0.01). QT interval in lead V1 correlated positively with MAP duration in the RVOT epicardium (r = 0.75). T wave amplitude in lead V1 correlated inversely with transmural dispersion of MAP duration in the RVOT (r =-0.74). Vagal nerve stimulation accentuated the cooling-induced changes. During cooling, ventricular fibrillation was induced by a single extrastimulus in 2 of 4 dogs, and additional vagal nerve stimulation during isoproterenol administration induced spontaneous ventricular fibrillation in one dog. CONCLUSION: Localized epicardial cooling of the RVOT could be an in vivo experimental model of Brugada syndrome.

Vagal activity modulates spontaneous augmentation of ST elevation in the daily life of patients with Brugada syndrome.

INTRODUCTION: In Brugada syndrome, ventricular fibrillation (VF) occurs mainly during sleep, and Brugada ECG signs are intensified by parasympathomimetic drugs; therefore, vagal activity could be a precipitating factor of VF. The aim of the present study was to elucidate the relation between spontaneous augmentation of ST elevation and changes in autonomic nervous activities in the daily life of patients with Brugada syndrome. METHODS AND RESULTS: Twenty-three consecutive patients with Brugada syndrome were studied. Group VF(+) consisted of 7 symptomatic patients and 3 asymptomatic patients with inducible VF; group VF(-) consisted of 13 asymptomatic patients without documented or inducible VF. Two-channel unipolar lead (V(1) and V(2)) Holter ECG was recorded. Heart rate variability was analyzed by the maximum entropy method. Spontaneous augmentation of ST elevation (>/=1.5 mm/20 min) occurred more frequently during 24 hours in group VF(+) than in group VF(-) (5.7 +/- 2.5 times vs 2.3 +/- 2.4 times, P < 0.01). ST elevation was significantly greater in group VF(+) than in group VF(-) (2.1 +/- 0.2 mm vs 1.8 +/- 0.2 mm, P < 0.05). Power of the high-frequency component (HF: 0.15-0.4 Hz) and RR interval increased progressively, and the ratio of low-frequency component (LF; 0.04- 0.15 Hz) to high-frequency component (LF/HF) gradually decreased toward the time of maximum ST elevation. During an entire day, daytime (0-5 P.M.), and nighttime (0-5 A.M.), both HF and LF/HF were not different between groups VF(+) and VF(-). CONCLUSION: In Brugada syndrome, spontaneous augmentation of ST elevation in daily life occurred along with an increase in vagal activity. ST elevation was augmented more in patients with VF than in those without VF under similar vagal tone.

Entrainment mapping of dual-loop macroreentry in common atrial flutter: new insights into the atrial flutter circuit.

INTRODUCTION: The aim of this study was to determine using entrainment mapping whether the reentrant circuit of common type atrial flutter (AFL) is single loop or dual loop. METHODS AND RESULTS: In 12 consecutive patients with counterclockwise (CCW) AFL, entrainment mapping was performed with evaluation of atrial electrograms from the tricuspid annulus (TA) and the posterior right atrial (RA) area. We hypothesized that a dual-loop reentry could be surmised from "paradoxical delayed capture" of the proximal part of the circuit having a longer interval from the stimulus to the captured beat compared with the distal part of the circuit. In 6 of 12 patients with CCW AFL, during entrainment from the septal side of the posterior blocking line, the interval from the stimulus to the last captured beat was longer at the RA free wall than at the isthmus position. In these six patients with paradoxical delayed capture, flutter cycle length (FCL) was 227 +/- 12 ms and postpacing interval minus FCL was significantly shorter at the posterior blocking line than at the RA free wall (20 +/- 11 ms vs 48 +/- 33 ms, P < 0.05). In two of these patients, early breakthrough occurred at the lateral TA. A posterior block line was confirmed in all six patients in the sinus venosa area by intracardiac echocardiography. CONCLUSION: Half of the patients with common type AFL had a dual-loop macroreentrant circuit consisting of an anterior loop (circuit around the TA) and a posterior loop (circuit around the inferior vena cava and the posterior blocking line).

Enalapril prevents perpetuation of atrial fibrillation by suppressing atrial fibrosis and over-expression of connexin43 in a canine model of atrial pacing-induced left ventricular dysfunction.

UNLABELLED: Effects of enalapril on a canine model of atrial pacing-induced atrial fibrillation (AF) with rapid ventricular responses were determined. METHODS: Four weeks of atrial rapid pacing was performed on twenty-four beagles pretreated with placebo (Group I, n = 14) or enalapril 1 mg/kg (Group II, n = 10). Atrial effective refractory period (ERP), P-wave width, duration of AF, and left ventricular ejection fraction (LVEF) were evaluated every week. AF cycle length was determined by spectral analyses of fibrillation waves. Quantitative analysis of histology was added. RESULTS: After 4 weeks of pacing, P-wave width was longer in Group I than in Group II, and the duration of induced AF was significantly longer in Group I (59.6 +/- 66.3 seconds) than in Group II (3.6 +/- 3.4 seconds, P < 0.05). AF cycle length was longer in Group I than in Group II despite similar shortening of atrial ERP. Mean ventricular rate during rapid atrial pacing was not different between the two groups. LVEF similarly decreased in both groups. Interstitial fibrosis and expression of connexin43 was greater in Group I than in Group II (interstitial fibrosis, 9.2 +/- 8.4 versus 1.9 +/- 2.1%, P < 0.05; connexin43, 5.3 +/- 2.2 versus 1.1 +/- 1.1%, P < 0.05). CONCLUSIONS: Enalapril suppressed atrial pacing-induced AF with tachycardia-mediated cardiomyopathy by suppressing interstitial fibrosis, connexin43 over-expression and conduction delay.