Mean Effective Refractory Period Research Articles

Location and coupling interval of an ectopic excitation determine the initiation of atrial fibrillation from the pulmonary veins.

IntroductionEctopic beats originating from the pulmonary vein (PV) trigger atrial fibrillation (AF). The purpose of this study was to clarify the electrophysiological determinant of AF initiation from the PVs.MethodsPacing studies were performed with a single extra stimulus mimicking an ectopic beat in the left superior PVs (LSPVs) in 62 patients undergoing AF ablation. Inducibility of AF, effective refractory period (ERP), and conduction properties within the PVs were analyzed.ResultsA single extra stimulus in LSPV induced AF in 20 patients (32% of all patients) at the mean coupling interval (CI) of 172 ms. A CI‐dependent anisotropic conduction at the AF onset was visualized in a three‐dimensional mapping. Onset of AF was site‐specific with reproducibility in each individual. Mean ERP in LSPV in the AF‐inducible group was shorter than that in the AF‐noninducible group (182 ± 55 vs. 254 ± 51 ms, p < .0001). LSPV ERP dispersion was greater in the AF‐inducible group than in the AF‐noninducible group (45 ± 28 vs. 27 ± 19 ms, p < .01). Circumferential intra‐PV conduction time (IPVCT) exhibited decremental properties in response to shortening of CI and the prolongation of IPVCT in the AF‐inducible site was greater than that in the AF‐noninducible site (p < .05) in each individual.ConclusionsLocation and CI of an ectopic excitation ultimately determine the initiation of AF from the PVs. ERP dispersion and circumferential conduction delay may lead to anisotropic conduction and reentry within the PVs that initiate AF.

Effects of post-treatment electroacupuncture on ventricular monophasic action potential and cardiac function in a rat model of ischemia/reperfusion injury.

To determine the effects of post-treatment electroacupuncture (EA) on the electrophysiological properties of ventricular muscle in rats with ischemia/reperfusion (IR) injury. Male Sprague-Dawley (SD) rats were randomly assigned into sham-operated (SH), IR and IR + EA groups (n = 8 each). The IR model was generated by ligation of the left anterior descending (LAD) coronary artery for 30 min. After establishing the IR model, EA was administered at PC6 for 30 min while opening the coronary artery and allowing reperfusion for 30 min. Heart rate (HR), mean arterial pressure and monophasic action potential (MAP) of cardiac muscle in the outer membrane of the antetheca of the left ventricle before coronary artery ligation (T0), after coronary artery ligation for 30 min (T1) and after reperfusion for 30 min (T2) were recorded. At the same time, ventricular electrophysiological parameters including ventricular effective refractory period (ERP), conduction velocity (CV) and ventricular fibrillation threshold (VFT) were measured. Then, the cardiac function and the levels of creatine kinase-muscle/brain (CK-MB) and cardiac troponin I (cTnI) were monitored. Based on these data, monophasic action potential amplitude (MAPA), the maximum depolarization velocity (Vmax) and the MAP durations at 50% and 90% repolarization (MAPD50 and MAPD90) were calculated to determine the incidence of arrhythmia during reperfusion. Compared with the SH group, the IR group showed an obviously decreased HR as well as reduced mean arterial pressure, Vmax, CV, ERP and MAPA. All indices of cardiac function except left ventricular end-diastolic pressure (LVEDP) decreased (i.e. ventricular systolic pressure (LVSP), left ventricular ejection fraction (LVEF), fractional shortening (FS) and rate of the ventricular pressure rise/drop (±dp/dt)). Furthermore, the MAPD50 and MAPD90 were prolonged, and the levels of CK-MB and cTnI increased (p < 0.05). In comparison to the IR group, HR and the mean arterial pressure were increased. All indices of cardiac function except LVEDP increased (LVSP, LVEF, FS and ±dp/dt). Vmax, CV, ERP and MAPA were also increased in the IR + EA group. However, MAPD50 and MAPD90 were distinctly shortened, and the levels of CK-MB and cTnI decreased (p < 0.05). There were no statistically significant differences in VFT between the three groups (p > 0.05). EA post-treatment can relieve prolongation of repolarization and slowed depolarization of ventricular muscle during IR, thus decreasing the rate of incidence of reperfusion arrhythmia.

Effect of Low-level Vagus Nerve Stimulation on Cardiac Remodeling in a Rapid Atrial Pacing-induced Canine Model of Atrial Fibrillation.

The aim of this study was to establish a rapid atrial pacing-induced canine model of atrial fibrillation in studying the effects of low-level vagus nerve stimulation (LLVNS) on atrial fibrillation and the underlying mechanisms for those effects. Adult beagle dogs were randomly assigned to 3 groups: a sham operation group (sham group), a fast left atrial appendage 12-hour pacing group (pacing group), and a 12-hour pacing + LLVNS group (LLVNS group). All dogs underwent tests for their left and right atrial effective refractory period at various time points, after which they were killed, and samples of atrial and anterior right ganglionated plexi tissue were removed and microscopically examined. As pacing times increased, the mean effective refractory period in the pacing group became significantly shortened. The pacing group and the LLVNS group did show significant differences (P < 0.001). Three groups showed significant differences in their atrial myocardial periodic acid-Schiff-positive area staining densities. Anterior right ganglionated plexi expressions of nerve growth factor and neurturin (NRTN) in the sham group and the LLVNS group were lower than those in the pacing group (nerve growth factor in 3 groups were (36.35 ± 6.18) × 1000, (86.35 ± 5.63) × 1000, and (40.50 ± 7.24) × 1000 μm²/mm², P < 0.001; NRTN in 3 groups were (39.28 ± 7.80) × 1000, (80.24 ± 6.56) × 1000, (40.45 ± 6.97) × 1000 μm²/mm², P < 0.001). Therefore, LLVNS not only reverses the effect of fast pacing-induced atrial electrical remodeling in dogs but also exerts structural effects and stimulates remodeling of autonomic nerves.

Prolonged Atrial Effective Refractory Periods in Atrial Fibrillation Patients Associated with Structural Heart Disease or Sinus Node Dysfunction Compared with Lone Atrial Fibrillation

Atrial fibrillation (AF) is commonly associated with structural heart disease (SHD) or sinus node dysfunction (SND). We hypothesized that regional atrial effective refractory period (ERP) is different in patients with SHD/SND from lone AF. We included 648 patients with AF (age, 56.0 ± 11.0 years; male, 77.3%; paroxysmal AF [PAF], 67.9%; persistent AF [PeAF], 32.1%) who underwent radiofrequency catheter ablation (RFCA), and compared the clinical characteristics in patients with SHD (n = 132) versus without SHD (n = 516) and those with SND (n = 74) versus without SND (n = 574). ERPs were measured at the high and low right atrium, proximal, and distal coronary sinus. (1) Patients with SHD had older age (P < 0.001), greater left atrial (LA) volume (P < 0.001), LA pressure (P = 0.002), and plasma proatrial natriuretic peptide (P = 0.005) than patients without SHD. (2) Patients with SND were older (P = 0.004), more likely female (P = 0.004), and had lower body weight (P < 0.001) and higher E/E' (P < 0.001) than those without SND. (3) The mean atrial ERP was significantly shorter in patients with PeAF than those with PAF (P < 0.001). The mean ERP was significantly longer in patients with AF with SHD/SND than those with lone AF (P = 0.006). (4) The clinical outcomes of RFCA were not significantly different between SHD/SND and lone AF for 14.8 ± 8.5 months of follow-up period. The mean atrial ERP was shorter in patients with PeAF than those with PAF due to electrical remodeling. In contrast, AF patients with SHD/SND showed a more prolonged mean atrial ERP than those with lone AF, associated with LA enlargement or left ventricular diastolic dysfunction.

259 Glibenclamide attenuates post-repolarization refractoriness in engineered heart tissue model

259 Glibenclamide attenuates post-repolarization refractoriness in engineered heart tissue model

Hypertension and atrial fibrillation: Evidence of progressive atrial remodeling with electrostructural correlate in a conscious chronically instrumented ovine model

Hypertension accounts for more atrial fibrillation (AF) than any other predisposing factor. The purpose of this study was to characterize the time course, extent, and electrostructural correlation of atrial remodeling in chronic hypertension. Thirty-two sheep were studied: 21 with induced "one-kidney, one-clip" hypertension and 11 controls. Sequential closed-chest electrophysiologic studies were performed in 12 conscious animals (6 hypertensive, 6 controls) to evaluate progressive remodeling over 15 weeks. Additional atrial structural/functional analyses were performed in 5 controls and at 5, 10, and 15 weeks of hypertension (five per time point) via histology/cardiac magnetic resonance imaging to correlate with open-chest electrophysiologic parameters. The hypertensive group developed a progressive increase in mean arterial pressure (P <.001). Mean effective refractory periods were uniformly higher at all time points (P <.001). Progressive biatrial hypertrophy (P = .003), left atrial dysfunction (P <.05) and greater AF inducibility were seen early with increased inflammation from 5 weeks of hypertension. In contrast, significant conduction slowing (P <.001) with increased heterogeneity (P <.001) along with increased interstitial fibrosis resulted in longer and more fractionated AF episodes only from 10 weeks of hypertension. Significant electrostructural correlation was seen in conduction abnormalities and AF inducibility with both atrial inflammation and fibrosis. Hypertension is associated with early and progressive changes in atrial remodeling. Atrial remodeling occurs at different time domains in chronic hypertension with significant electrostructural correlation of the remodeling cascade. Early institution of antihypertensive treatment may prevent formation of substrate capable of maintaining AF.

Short-term hypertension is associated with the development of atrial fibrillation substrate: A study in an ovine hypertensive model

Hypertension is frequently complicated by the development of atrial fibrillation (AF). However, the mechanisms of this link remain poorly understood. In addition, whether short-term hypertension can result in a substrate for AF is not known. The purpose of this study was to characterize the atrial substrate predisposing to AF due to short-duration hypertension. Sixteen sheep were studied: 10 had induced hypertension for 7 +/- 4 weeks via the "one-kidney, one-clip" model, and six were controls. Cardiac magnetic resonance imaging was used to assess functional changes. Open-chest electrophysiological study was performed using a custom-made 128-electrode epicardial plaque applied to both right (RA) and left atria (LA), including the Bachmann's bundle, to determine effective refractory periods (ERPs) and conduction velocity at four pacing cycle lengths from six sites. Tissue specimens were harvested for structural analysis. The hypertensive group demonstrated the following compared with controls: higher blood pressure (P <.0001), enlarged LA (P <.05), reduced LA ejection fraction (P <.05), uniformly higher mean ERP (P <.001), slower mean conduction velocity (P <.001), higher conduction heterogeneity index (P <.0001), greater AF inducibility (P = .03), and increased AF durations (P = .04). Picrosirius red staining of atrial tissues revealed increased interstitial fibrosis (P <.0001). There was also evidence of increased inflammatory cell infiltrates (P <.0001). Short-duration hypertension is associated with significant atrial remodeling characterized by atrial enlargement/dysfunction, interstitial fibrosis, inflammation, slowed/heterogeneous conduction, increased ERP, and greater propensity for AF.

There is no transmural heterogeneity in an index of action potential duration in the canine left ventricle

Transmural heterogeneity in ventricular repolarization demonstrated in vitro has been difficult to confirm in vivo. Whether this discrepancy reflects a physiological phenomenon or a methodological problem remains a vivid matter of debate despite a plethora of experimental work. Therefore, we have measured the relevant electrophysiological parameters first in vivo and repeated these in the same heart and at identical sites in vitro. Methodological issues were tackled by using both unipolar and bipolar recordings. Physiological issues were explored by measuring both local and functional electrophysiological parameters. In 10 healthy dogs, 2 high-resolution needle electrodes were inserted into the left ventricle. Effective refractory periods (ERP) as well as activation recovery intervals (ARI) were determined at each electrode along both needles at basic cycle lengths (BCL) of 850 and 300 ms, respectively. After excision of the heart, ERP and ARI measurements were repeated in the arterially perfused wedge preparations. First, we observed that ERPs and ARIs were significantly shorter in vivo than in vitro. Mean ERPs and ARIs of all muscle layers were relatively uniform throughout the ventricular wall in vivo. The transition from the in vivo to the in vitro preparation was associated with a significant albeit small increase of mean ARIs in the subendocardium, whereas interlayer differences in mean ERPs did not reach statistical significance as in vivo. In the intact canine left ventricular wall, a more or less homogeneous distribution in transmural ERP and ARI is present.

Effects of Verapamil and Procainamide on Acute Atrial Electrical Remodeling Induced by Short-term Rapid Atrial Pacing in Humans

Atrial electrical remodeling (ER) after spontaneous or pacing-induced atrial fibrillation has been previously described in humans. We investigated atrial ER induced by a 5-minute period of rapid atrial pacing and the pharmacologic effects of verapamil and procainamide on this atrial ER phenomenon. The atrial effective refractory periods (ERPs) at drive cycle lengths of 400 (ERP 400 ) and 600 (ERP 600 ) ms, at five representative atrial sites (high right atrium [HRA]; proximal, middle and distal coronary sinus; interatrial septum), were determined in 20 patients at baseline and immediately after cessation of a 5-minute period of rapid pacing from the HRA at a rate of 150 bpm. The degrees of atrial ERP 400 and ERP 600 shortening after pacing were calculated as acute atrial ER. The same protocol was repeated in another 15 patients after intravenous administration of verapamil (0.15 mg/kg) and in another 15 patients after intravenous administration of procainamide (15 mg/kg). The results demonstrated that, in the control state acute atrial ER can be significantly demonstrated at each atrial representative site ( p < 0.001). The mean ERP 400 and ERP 600 shortenings were 9 +/- 4% and 8 +/- 4%, respectively. After procainamide infusion, but not after verapamil, baseline ERP 400 and ERP 600 values were significantly prolonged at the five representative atrial sites ( p < 0.01). Acute atrial ER could still be demonstrated at each atrial site after procainamide or verapamil infusion ( p < 0.001). In conclusion, acute atrial ER can be demonstrated after only a 5-minute period of rapid atrial pacing in humans. Intravenous verapamil or procainamide does not abolish this ER process.

Abstract 1364: Not All Refractory Period Abbreviation Promotes Atrial Fibrillation Equally: A Comparison Between Vagal and Atrial Tachycardia Remodeled Substrates

Background: Vagal (VG) and atrial tachycardia remodeled (ATR) AF substrates share many features: reduced effective refractory period (ERP), increased ERP heterogeneity and some common molecular mechanisms (I KACh enhancement by acetylcholine release in VG, constitutive I KACh enhancement in ATR). This study compared VG and ATR substrates at comparable ERP abbreviation. Methods: In each of 5 VG dogs, bilateral cervical VG stimulation parameters were adjusted (mean±SD: 3.6±1.7 V and 12.2±1.5 Hz; 0.2 ms) to produce the same mean ERP (at 4 RA and 4 LA sites) as a sex and weight matched ATR dog (RA paced 400 bpm × 7 days). Mean duration of burst pacing induced AF (DAF) and local dominant frequencies (DFs, analyzed by FFT at 240 bipolar electrodes, Fig A ) were determined. Results: Mean ERP was 79±13 ms in VG and 78±13 ms in ATR dogs. DAF was greater in VG than ATR dogs (1056±323 vs 289±510 s *P&lt;0.01; both significantly &gt; control, 43±61 s). Despite matched ERPs, there were significant differences in DF distribution (Fig B ): DF was faster (mean DF: 11.8±1.1 Hz VG vs 9.7±1.3 Hz ATR*) and DF variability greater (indicated by SD: 1.8±0.6 Hz VG vs 0.8±0.5 Hz ATR*) in VG dogs. AF drivers reflected by maximum DF zones were adjacent to autonomic ganglia (over RA in 4/5) for VG dogs; in ATR dogs driver zones were less clear and showed variable location. Conclusions: For a comparable atrial ERP, VG AF is faster and more persistent than AF with an ATR substrate. These results are consist with modeling work suggesting that VG-induced hyperpolarization is an important contributor to AF-maintaining rotor stabilization and acceleration, and indicate important differences between these superficially similar AF substrates.

Pulmonary vein encircling ablation alters the atrial electrophysiologic response to autonomic stimulation

Pulmonary vein encircling ablation is often effective in the treatment of atrial fibrillation (AF). The success of the procedure does not depend upon creation of continuous lines of block. Thus mechanisms by which pulmonary vein encircling can cure AF remain unclear. Stimulation of cardiac autonomic ganglia alters atrial refractoriness and potentiates AF. We hypothesized that pulmonary vein encircling alters atrial autonomic function and that these alterations account in part for prevention of AF recurrences following ablation. Atrial effective refractory periods (ERP) and AF inducibility were quantified in ten dogs before and during central autonomic nerve stimulation. Pulmonary vein encircling ablation was then performed and electrophysiologic testing repeated. In two dogs subjected to sham procedures measurements were repeated without performance of ablation. Hearts were examined histologically. Autonomic nerve stimulation led to decreased atrial refractoriness and increased AF inducibility and duration. Each of these effects were attenuated following pulmonary vein encircling (e.g., mean ERP decreased before (-23.7 +/- 1.8, p < 0.001) but not after ablation (-2.3 +/- 1.9, p = 0.25); AF inducibility increased by 26% before vs. 5% after ablation). No attenuation was seen in the sham operated animals. Histologic analysis following pulmonary vein encircling demonstrated destruction of some but not all autonomic ganglia. Autonomic stimulation shortens atrial refractory periods and potentiates AF. Pulmonary vein encircling ablation partially destroys atrial autonomic inputs, attenuates the refractory period shortening effect of autonomic stimulation and decreases AF inducibility. Destruction of autonomic ganglia may contribute to the anti-fibrillatory effects of pulmonary vein encircling and warrants further investigation.

Unsuccessful Internal Defibrillation in Brugada Syndrome: Focus on Refractoriness and Ventricular Fibrillation Cycle Length

In patients with Brugada syndrome, implantable cardioverter defibrillator (ICD) is the only reliable treatment to prevent sudden death though, in some cases, internal defibrillation may be unsuccessful. The aim of this study was to examine the determinants of defibrillation failure, with a focus on electrophysiologic characteristics. The study included 51 patients treated with ICD: 22 with Brugada syndrome and 29 with structural heart disease (SHD). The prevalence of defibrillation energy requirement precluding the programming of a 10-J safety margin, the mean right ventricular effective refractory period (ERP), and mean induced ventricular fibrillation cycle length (VFCL) from the stored ICD electrograms, were compared between the two patient groups. High defibrillation requirements were observed in 18% of patients with Brugada syndrome versus 0% of patients with SHD. However, the patients with SHD had larger heart size than those with Brugada syndrome. Mean VFCL and mean ERP were both significantly shorter in patients with Brugada syndrome than in patients with SHD, and ERP and VFCL were significantly correlated. Patients with Brugada syndrome have a high prevalence of high defibrillation energy requirement, and short ventricular ERP and VFCL.

Effects of verapamil on atrial fibrillation and its electrophysiological determinants in dogs.

Atrial tachycardia-induced remodeling promotes the occurrence and maintenance of atrial fibrillation (AF) and decreases L-type Ca(2+) current. There is also a clinical suggestion that acute L-type Ca(2) channel blockade can promote AF, consistent with an AF promoting effect of Ca(2+) channel inhibition. To evaluate the potential mechanisms of AF promotion by Ca(2+) channel blockers, we administered verapamil to morphine-chloralose anesthetized dogs. Diltiazem was used as a comparison drug and autonomic blockade with atropine and nadolol was applied in some experiments. Epicardial mapping with 240 epicardial electrodes was used to evaluate activation during AF. Verapamil caused AF promotion in six dogs, increasing mean duration of AF induced by burst pacing, from 8+/-4 s (mean+/-S.E.) to 95+/-39 s (P<0.01 vs. control) at a loading dose of 0.1 mg/kg and 228+/-101 s (P<0.0005 vs. control) at a dose of 0.2 mg/kg. Underlying electrophysiological mechanisms were studied in detail in five additional dogs under control conditions and in the presence of the higher dose of verapamil. In these experiments, verapamil shortened mean effective refractory period (ERP) from 122+/-5 to 114+/-4 ms (P<0.02) at a cycle length of 300 ms, decreased ERP heterogeneity (from 15+/-1 to 10+/-1%, P<0.05), heterogeneously accelerated atrial conduction and decreased the cycle length of AF (94+/-4 to 84+/-3 ms, P<0.005). Diltiazem did not affect ERP, AF cycle length or AF duration, but produced conduction acceleration similar to that caused by verapamil (n=5). In the presence of autonomic blockade, verapamil failed to promote AF and increased, rather than decreasing, refractoriness. Neither verapamil nor diltiazem affected atrial conduction in the presence of autonomic blockade. Epicardial mapping suggested that verapamil promoted AF by increasing the number of simultaneous wavefronts reflected by separate zones of reactivation in each cycle. Verapamil promotes AF in normal dogs by promoting multiple circuit reentry, an effect dependent on intact autonomic tone and not shared by diltiazem.

Different patterns of atrial activation in idiopathic atrial fibrillation: simultaneous multisite atrial mapping in patients with paroxysmal and chronic atrial fibrillation

OBJECTIVESWe aimed to evaluate: 1) the behavior of electrical activity simultaneously in different atrial regions during atrial fibrillation (AF); 2) the difference of atrial activation between paroxysmal and chronic AF; 3) the atrial refractoriness dispersion; and 4) the correlation between the effective refractory periods (ERPs) and the FF intervals.BACKGROUNDLittle data exist on the electrophysiologic characteristics of the different atrial regions in patients with AF. A more detailed knowledge of the electrical activity during AF may provide further insights to improve treatment of AF.METHODSRight and left atria were extensively mapped in 30 patients with idiopathic AF (18 paroxysmal and 12 chronic). In different atrial locations, we analyzed 1) the FF interval duration; and 2) the grade of organization and, in case of organized electrical activity, the direction of atrial activation. Furthermore, in patients with paroxysmal AF, we determined the atrial ERP, evaluated the ERP dispersion and assessed the presence of a correlation between the ERPs and the FF intervals.RESULTSIn patients with chronic AF, we observed a shortening of the FF intervals and a greater prevalence of disorganized activity in all the atrial sites examined. In patients with paroxysmal AF, a significant dispersion of refractoriness was observed. The right lateral wall showed longer FF intervals and more organized atrial activity and, unexpectedly, the shortest mean ERPs. In contrast, the septal area showed shorter FF intervals, greater disorganization and the longest mean ERPs.CONCLUSIONSElectrical activity during AF showed a significant spatial inhomogeneity, which was more evident in patients with paroxysmal AF. The mean FF intervals did not correlate with the mean ERPs.

Modification of stretch-induced shortening of repolarization by streptomycin in the isolated rabbit heart.

The exact mechanism of mechano-electrical feedback and stretch-induced arrhythmias is unknown, but the role of stretch-activated ion channels and specific calcium channels has been proposed. The aim of the present study was to test the hypothesis that stretch-activated ion channels and not calcium channels contribute to stretch-related alterations of repolarization and that these effects can be neutralized by stretch-activated channel block. We studied the interaction of acute ventricular dilatation and the stretch-activated channel blocker streptomycin and the specific calcium channel blocker verapamil in an isolated retrogradely perfused rabbit heart model in which the left ventricular size is modified by abruptly changing the volume of a fluid-filled balloon placed in the left ventricle. Acute ventricular dilatation led to a rate-dependent decrease in repolarization. The mean effective refractory period (ERP) and monophasic action potential duration (MAP90) for cycle lengths between 300 and 1,000 ms decreased from 174.2+/-9 ms and 178.9+/-7 ms to 161.6+/-11 ms and 169.7+/-5 ms, respectively. Streptomycin (80 microM) inhibited this stretch-related shortening of repolarization (ERP: 175.4+/-8 ms; MAP90: 179.7+/-8 ms, p < 0.05) but had almost no effect on already dilated ventricles. Counteraction of the observed electrophysiologic changes could only be achieved by increasing the streptomycin concentration to 200 microM. Streptomycin nearly completely suppressed stretch-related ectopic ventricular complexes. In contrast, verapamil (1 microM) had no effect on stretch-related changes in repolarization and stretch-induced arrhythmias. The present study indirectly implicates stretch-activated ion channels in the genesis of stretch-related changes in repolarization and arrhythmias. The electrophysiologic changes after ventricular dilatation to a degree that increases left ventricular pressure in a clinically relevant range can be influenced by the stretch-activated channel blocker streptomycin but not by specific calcium channel block. This may have clinically important implications for the development of new antiarrhythmic drugs.

Postcardioversion atrial electrophysiologic changes induced by oral verapamil in patients with persistent atrial fibrillation

OBJECTIVESThe aim of our study was to verify the effect of oral administration of verapamil on atrial electrophysiologic characteristics after cardioversion of persistent atrial fibrillation (AF) in humans.BACKGROUNDDiscordant findings have been reported regarding the efficacy of verapamil in preventing the electrical remodeling induced by AF.METHODSWe determined the effective refractory periods (ERPs) at five pacing cycle lengths (300 to 700 ms) and in five right atrial sites after internal cardioversion of persistent AF (mean duration 238.1 ± 305.9 days) in 19 patients. Nine patients received oral verapamil (240 mg/day) starting four weeks before the electrophysiologic study, whereas the other 10 patients were in pharmacologic washout.RESULTSThe mean ERPs were 202.0 ± 22.7 ms in the washout group and 189.3 ± 18.5 ms in the verapamil group (p < 0.0001). The degree of adaptation of refractoriness to rate was similar in the two groups (mean slope value in the washout group and verapamil group: 0.07 ± 0.03 and 0.08 ± 0.05, respectively), showing a normal or nearly normal adaptation to rate in the majority of the paced sites in both groups. The mean ERP was slightly longer in the septum than in the lateral wall and in the roof, both in the washout and verapamil groups.CONCLUSIONSIn patients with persistent AF, long-term administration of verapamil before internal cardioversion resulted in 1) shortening of atrial ERPs; 2) no change in refractoriness dispersion within the right atrium; and 3) no change in atrial ERP adaptation to rate.

Electrophysiological and antiarrhythmic effects of the atrial selective 5-HT(4) receptor antagonist RS-100302 in experimental atrial flutter and fibrillation.

Stimulation of 5-HT(4) receptors increases atrial chronotropic and inotropic responses. Whether other electrophysiological effects are produced is unknown. In humans and swine, 5-HT(4) receptors are present only in atrium. Therefore, the effects of a novel 5-HT(4) receptor antagonist, RS-100302, and the partial agonist cisapride on atrial flutter and fibrillation induced in swine were studied to delineate the role of the 5-HT(4) receptor in modulating atrial electrophysiological properties and the antiarrhythmic potential of RS-100302. In 17 anesthetized, open-chest, juvenile pigs, atrial flutter or fibrillation was induced by rapid right atrial pacing with or without a right atrial free wall crush injury, respectively. Atrial effective refractory period (ERP), conduction velocity, wavelength, and dispersion of refractoriness were determined during programmed stimulation via a 56-electrode mapping plaque sutured to the right atrial free wall. Ventricular electrophysiological parameters were also measured. All electrophysiological parameters were measured at baseline and after infusion of RS-100302 and cisapride. In the atrium, RS-100302 prolonged mean ERP (115+/-8 versus 146+/-7 ms, P<0.01) and wavelength (8.3+/-0.9 versus 9.9+/-0.8 cm, P<0.01), reduced dispersion of ERP (15+/-5 versus 8+/-1 ms, P<0.01), and minimally slowed conduction velocity (72+/-4 versus 67+/-5 cm/s, P<0.01). These effects were all partially reversed by cisapride. RS-100302 produced no ventricular electrophysiological effects. RS-100302 terminated atrial flutter in 6 of 8 animals and atrial fibrillation in 8 of 9 animals and prevented reinduction of sustained tachycardia in all animals. The electrophysiological profile of RS-100302 suggests that it may have atrial antiarrhythmic potential without producing ventricular proarrhythmic effects.

Electrophysiological characteristics of the human atria after cardioversion of persistent atrial fibrillation.

In animal models, induced atrial fibrillation shortens the atrial effective refractory period (ERP) and reverses its physiological adaptation to rate. It is not clear whether this process, known as "electrical remodeling," occurs in humans. We determined the ERPs, at 5 pacing cycle lengths (300 to 700 ms) and in 5 right atrial sites, after internal cardioversion of chronic atrial fibrillation in 25 patients (14 in pharmacological washout and 11 on amiodarone). The ERPs were 195.5+/-18.8 ms in the washout and 206.3+/-17.9 ms in the amiodarone patients (P<0.0001). ERPs were closely correlated with the stimulation rates (r=0.95 in the washout and r=0.94 in the amiodarone group), and slope values indicating a normal (>/=0.07) or nearly normal (0.05 to 0.06) adaptation of ERP to rate were found in 77% of the 84 paced sites. The mean ERP was shorter in the lateral wall (198.1+/-17.9 ms) than in the atrial roof (203.3+/-21.5 ms) and in the septum (210.5+/-20.0 ms) (P<0.03). After 4 weeks of sinus rhythm, the mean ERP, determined again in 8 patients (4 in wash-out and 4 on amiodarone), was significantly increased compared with the basal study (221. 4+/-21.4 versus 197.8+/-18.3 ms, P<0.0001). After cardioversion of chronic atrial fibrillation, (1) atrial ERP adaptation to rate was normal or nearly normal in the majority of the cases, (2) a significant dispersion of refractoriness between different right atrial sites was present, and (3) ERPs were significantly increased after 4 weeks of sinus rhythm in both washout and amiodarone patients.

Effect of E-4031, a new class III antiarrhythmic drug, on reentrant ventricular arrhythmias: Comparison with conventional class I drugs

We evaluated the antiarrhythmic efficacy of E-4031, a new class III drug, and compared it with that of conventional class I and II antiarrhythmic agents in terms of electrophysiological actions on refractoriness and conduction in a 7-day-old canine model of myocardial infarction. Sustained monomorphic VT was reproducibly induced in 26 dogs by a premature stimulation method from the right ventricle. Class I drugs (disopyramide, aprindine, flecainide) prevented VT induction in 5 of 13 dogs, and propranolol and E-4031 prevented it in 6 of 6 and 6 of 7 dogs, respectively. The effective refractory period (ERP) was determined at 47 epicardial sites overlying the infarct in each experiment by a S1S2 method. The standard deviation (SD) of the mean ERP of these sites was used as an index of ERP dispersion. The extent of ERP prolongation produced by class I drugs and E-4031 was significantly more marked than that produced by propranolol. However, the SD was increased by class I drugs and E-4031, but not by propranolol. Class I drugs increased the ERP dispersion mainly by an effect on the transmural infarct zone in which the control ERP was more prolonged than in the normal zone. E-4031 tended to prolong the ERP in both the normal and infarct zones, and had a minimal tendency to increase ERP dispersion. In contrast, propranolol decreased the ERP dispersion between zones. Conduction velocity calculated by epicardial mapping was significantly decreased by flecainide, but not by E-4031. We conclude that the antiarrhythmic effect of E-4031 depends largely on its ability to prolong refractoriness without suppressing conduction.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiologic recovery in postischemic, stunned myocardium despite persistent systolic dysfunction

Previous investigators have hypothesized that myocardial “stunning” may result either from a primary impairment in excitation or from electromechanical dissociation. Thrombolytic therapy and angioplasty have increased the importance of understanding the electrophysiologic effects of brief ischemia followed by reperfusion. We investigated the electrophysiologic properties of mechanically dysfunctional stunned myocardium in 18 dogs anesthetized with pentobarbital (30 mg/kg, intravenously administered). After thoracotomy, the proximal anterior descending coronary artery was occluded for 15 minutes, which was followed by 20 minutes of reperfusion. At baseline, peak ischemia, and 20 minutes of reperfusion, local electrogram durations, activation times, and refractory periods were measured from 12 standardized sites within the ischemic and border zones. Echocardiographic percentage of systolic wall thickening confirmed normal preischemic and markedly reduced postischemic function in the investigated region. Depspite the marked electrophysiologic abnormalities observed in the ischemic zone during ischemia, mean electrogram duration, calculated conduction velocity, and mean effective refractory period after 20 minutes of reperfusion had returned almost to baseline values 39.2 ± 11.5 msec versus 37.2 ± 12.1 msec, 0.65 ± 0.15 m/sec versus 0.68 ± 0.15 m/sec, and 134 ± 14 msec versus 131 ± 8 msec, respectively. Corresponding mean values within the ischemic border zone were similarly close to baseline values after reperfusion. There was no significant difference in local heterogeneity (coefficient of variation) within the ischemic or border zone after reperfusion versus baseline values. Although the postischemic electrophysiologic status returned to normal, systolic thinning and dyskinesis persisted in the region of measurement. The contractile dysfunction that results from reperfusion-induced injury can thus occur in the setting of apparent excitation-contraction uncoupling.