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Myocardial fiber orientation influences the series of activation, repolarization, gradient filed distribution and the stimulation threshold during electrical induction of ventricular fibrillation (VF). Myocardial fiber orientation is essential for generation and maintenance of reentrant arrhythmia. Computerized mapping analysis of patterns of activation, as a result of application of stimulus, using 56 closely spaced epicardial bipolar electrodes, is carried out on six open-chest dogs. The results suggest the important contribution made by myocardial fiber orientation in determining the patterns of activation during the electrical induction of VF.

Open-chest dogs were examined to test the theory that ventricular fibrillation (VF) threshold testing is a probability activity, and the T wave was scanned with either the single premature stimulus method or with the train stimulus method for testing VF thresholds. VF threshold is a probability function, and is the perfect alternative to the dose response curve procedure to assess 50% probability of causing the triplicate VF threshold obtained by the up-down logarithm procedure.

Spiral wave reentry as a mechanism of lethal ventricular arrhythmias has been widely demonstrated in animal experiments and recordings from human hearts. It has been shown that in structurally normal hearts spiral waves are unstable, breaking up into multiple wavelets via dynamical instabilities. However, many of the second-generation action potential models give rise only to stable spiral waves, raising issues regarding the underlying mechanisms of spiral wave breakup. In this study, we carried out computer simulations of two-dimensional homogeneous tissues using five ventricular action potential models. We show that the transient outward potassium current (Ito), although it is not required, plays a key role in promoting spiral wave breakup in all five models. As the maximum conductance of Ito increases, it first promotes spiral wave breakup and then stabilizes the spiral waves. In the absence of Ito, speeding up the L-type calcium kinetics can prevent spiral wave breakup, however, with the same speedup kinetics, spiral wave breakup can be promoted by increasing Ito. Increasing Ito promotes single-cell dynamical instabilities, including action potential duration alternans and chaos, and increasing Ito further suppresses these action potential dynamics. These cellular properties agree with the observation that increasing Ito first promotes spiral wave breakup and then stabilizes spiral waves in tissue. Implications of our observations to spiral wave dynamics in the real hearts and action potential model improvements are discussed. [ABSTRACT FROM AUTHOR]

Cardiomyocyte-restricted overexpression of FK506-binding protein 12 transgenic (αMyHC-FKBP12) mice develop spontaneous atrial fibrillation (AF). The aim of the present study is to explore the mechanisms underlying the occurrence of AF in αMyHC-FKBP12 mice. Spontaneous AF was documented by telemetry in vivo and Langendorff-perfused hearts of αMyHC-FKBP12 and littermate control mice in vitro. Atrial conduction velocity was evaluated by optical mapping. The patch-clamp technique was applied to determine the potentially altered electrophysiology in atrial myocytes. Channel protein expression levels were evaluated by Western blot analyses. Spontaneous AF was recorded in four of seven αMyHC-FKBP12 mice but in none of eight nontransgenic (NTG) controls. Atrial conduction velocity was significantly reduced in αMyHC-FKBP12 hearts compared with NTG hearts. Interestingly, the mean action potential duration at 50% but not 90% was significantly prolonged in αMyHC-FKBP12 atrial myocytes compared with their NTG counterparts. Consistent with decreased conduction velocity, average peak Na+ current (INa) density was dramatically reduced and the INa inactivation curve was shifted by approximately +7 mV in αMyHC-FKBP12 atrial myocytes, whereas the activation and recovery curves were unaltered. The Nav1.5 expression level was significantly reduced in αMyHC-FKBP12 atria. Furthermore, we found increases in atrial Cav1.2 protein levels and peak L-type Ca2+ current density and increased levels of fibrosis in αMyHC-FKBP12 atria. In summary, cardiomyocyte-restricted overexpression of FKBP12 reduces the atrial Nav1.5 expression level and mean peak INa, which is associated with increased peak L-type Ca2+ current and interstitial fibrosis in atria. The combined electrophysiological and structural changes facilitated the development of local conduction block and altered action potential duration and spontaneous AF. NEW & NOTEWORTHY This study addresses a long-standing riddle regarding the role of FK506-binding protein 12 in cardiac physiology. The work provides further evidence that FK506-binding protein 12 is a critical component for regulating voltage-gated sodium current and in so doing has an important role in arrhythmogenic physiology, such as atrial fibrillation. [ABSTRACT FROM AUTHOR]

Apamin-sensitive small-conductance Ca2+-activated K+ (SK) current (IKAS) is encoded by Ca2+-activated K+ channel subfamily N (KCNN) genes. IKAS importantly contributes to cardiac repolarization in conditions associated with reduced repolarization reserve. To test the hypothesis that IKAS inhibition contributes to drug-induced long QT syndrome (diLQTS), we screened for KCNN variants among patients with diLQTS, determined the properties of heterologously expressed wild-type (WT) and variant KCNN channels, and determined if the 5-HT3 receptor antagonist ondansetron blocks IKAS. We searched 2,306,335 records in the Indiana Network for Patient Care and found 11 patients with diLQTS who had DNA available in the Indiana Biobank. DNA sequencing discovered a heterozygous KCNN2 variant (p.F503L) in a 52-yr-old woman presenting with corrected QT interval prolongation at baseline (473 ms) and further corrected QT interval lengthening (601 ms) after oral administration of ondansetron. That patient was also heterozygous for the p.S38G and p.P2835S variants of the QT-controlling genes KCNE1 and ankyrin 2, respectively. Patch-clamp experiments revealed that the p.F503L KCNN2 variant heterologously expressed in human embryonic kidney (HEK)-293 cells augmented Ca2+ sensitivity, increasing IKAS density. The fraction of total F503L-KCNN2 protein retained in the membrane was higher than that of WT KCNN2 protein. Ondansetron at nanomolar concentrations inhibited WT and p.F503L SK2 channels expressed in HEK-293 cells as well as native SK channels in ventricular cardiomyocytes. Ondansetron-induced IKAS inhibition was also demonstrated in Langendorff-perfused murine hearts. In conclusion, the heterozygous p.F503L KCNN2 variant increases Ca2+ sensitivity and IKAS density in transfected HEK-293 cells. Ondansetron at therapeutic (i.e., nanomolar) concentrations is a potent IKAS blocker. [ABSTRACT FROM AUTHOR]

Selective glycolytic inhibition (GI) promotes electromechanical alternans and triggered beats in isolated cardiac myocytes. We sought to determine whether GI promotes triggered activity by early afterdepolarization (EAD) or delayed afterdepolarizations in intact hearts isolated from adult and aged rats. Dual voltage and intracellular calcium ion (Cai2+) fluorescent optical maps and single cell glass microelectrode recordings were made from the left ventricular (LV) epicardium of isolated Langendorff-perfused adult (~4 mo) and aged (~24 mo) rat hearts. GI was induced by replacing glucose with 10 mM pyruvate in oxygenated Tyrode's. Within 20 min, GI slowed Cai2+ transient decline rate and shortened action potential duration in both groups. These changes were associated with ventricular fibrillation (VF) in the aged hearts (64 out of 66) but not in adult hearts (0 out of 18; P < 0.001). VF was preceded by a transient period of focal ventricular tachycardia caused by EAD-mediated triggered activity leading to VF within seconds. The VF was suppressed by the ATP-sensitive K (KATP) channel blocker glibenclamide (1 μM) but not (0 out of 7) by mitochondrial KATP block. The Ca-calmodulin-dependent protein kinase II (CaMKII) blocker KN-93 (1 μM) prevented GI-mediated VF (P < 0.05). Block of Na-Ca exchanger (NCX) by SEA0400 (2 μM) prevented GI-mediated VF (3 out of 6), provided significant bradycardia did not occur. Aged hearts had significantly greater LV fibrosis and reduced connexin 43 than adult hearts (P < 0.05). We conclude that in aged fibrotic unlike in adult rat hearts, GI promotes EADs, triggered activity, and VF by activation of KATP channels CaMKII and NCX. [ABSTRACT FROM AUTHOR]

The mechanisms of sinoatrial node (SAN) dysfunction in heart failure (HF) remain unclear. We hypothesized that impaired rhythmic spontaneous sarcoplasmic reticulum Ca2+ release (Ca2+ clock) plays an important role in SAN dysfunction in HF. HF was induced in canine hearts by rapid ventricular pacing. The location of pacemaking sites was determined in vivo using computerized electrical mapping in acute open-chest preparations (normal, n = 3; and HF, n = 4). Isoproterenol (Iso, 0.2 μg·kg-1·min-1) infusion increased heart rate and shifted the pacemaking site to the superior SAN in all normal hearts. However, in failing hearts, Iso did not induce superior shift of the pacemaking site despite heart rate acceleration. Simultaneous optical recording of intracellular Ca2+ and membrane potential was performed in Langendorff-perfused isolated right atrium (RA) preparations from normal (n = 7) and failing hearts (n = 6). Iso increased sinus rate, enhanced late diastolic Ca2+ elevation (LDCAE), and shifted the pacemaking sites to the superior SAN in all normal but in none of the HF RAs. Caffeine (2 ml, 20 mmol/l) caused LDCAE and increased heart rate in four normal RAs but in none of the three HF RAs. Iso induced ectopic beats from lower crista terminalis in five of six HF RAs. These ectopic beats were suppressed by ZD-7288, a specific pacemaker current (If) blocker. We conclude that HF results in the suppression of Ca2+ clock, resulting in the unresponsiveness of superior SAN to Iso and caffeine. HF also increases the ectopic pacemaking activity by activating the If at the latent pacemaking sites in lower crista terminalis. [ABSTRACT FROM AUTHOR]

The mechanisms of sinoatrial node (SAN) dysfunction in patients with chronically elevated sympathetic tone and reduced pacemaker current (Ii; such as heart failure) are poorly understood. We simultaneously mapped membrane potential and intracellular Ca2+ in the Langendorff-perfused canine right atrium (RA). Blockade of either h (ZD-7288) or sarcoplasmic reticulum Ca2+ release (ryanodine) alone decreased heart rate by 8% (n = 3) and 16% (n = 3), respectively. Combined treatment of ZD-7288 and ryanodine consistently resulted in prolonged (≥3 s) sinus pauses (PSPs) (n = 4). However, the middle SAN remained as the leading pacemaking site after these treatments. Prolonged exposure with isoproterenol (0.01 μmol/l) followed by ZD-7288 completely suppressed SAN but triggered recurrent ectopic atrial tachycardia. Cessation of tachycardia was followed by PSPs in five of eight RAs. Isoproterenol initially increased heart rate by 75% from baseline with late diastolic intracellular Ca2+ elevation (LDCAE) from the superior SAN. However, after a prolonged isoproterenol infusion, LDCAE disappeared in the superior SAN, the leading pacemaker shifted to the inferior SAN, and the rate reduced to 52% above baseline. Caffeine (2 ml, 20 mmolll) injection after a prolonged isoproterenol infusion produced LDCAE in the SAN and accelerated the SAN rate, ruling out sarcoplasmic reticulum Ca2+ depletion as a cause of Ca2+ clock malfunction. We conclude that in an isolated canine RA preparation, chronically elevated sympathetic tone results in abnormal pacemaking hierarchy in the RA, including suppression of the superior SAN and enhanced pacemaking from ectopic sites. Combined malfunction of both membrane and Ca2+ clocks underlies the mechanisms of PSPs. [ABSTRACT FROM AUTHOR]

Oxidative stress with hydrogen peroxide (H2O2) readily promotes early after depolanzations (EADs) and triggered activity (TA) in isolated rat and rabbit ventricular myocytes. Here we examined the effects of H2O2 on arrhythmias in intact Langendorif rat and rabbit hearts using dual-membrane voltage and intracellular calcium optical mapping and glass microelectrode recordings. Young adult rat (3-5 mo, N = 25) and rabbit (3-5 mo, N = 6) hearts exhibited no arrhythmias when perfused with H2O2 (0.1-2 mM) for up to 3 h. However, in 33 out of 35 (94%) aged (24-26 mo) rat hearts, 0.1 mM H2O2 caused EAD-mediated TA, leading to ventricular tachycardia (VT) and fibrillation (VF). Aged rabbits (lifespan, 8-12 yr) were not available, but 4 of 10 middle-aged rabbits (3-5 yr) developed EADs, TA, VT, and VF. These arrhythmias were suppressed by the reducing agent N-acetylcysteine (2 mM) and CaMKII inhibitor KN-93 (1 μM) but not by its inactive form (KN-92, 1 μM). There were no significant differences between action potential duration (APD) or APD restitution slope before or alter H2O2 in aged or young adult rat hearts. In histological sections, however, trichrome staining revealed that aged rat hearts exhibited extensive fibrosis, ranging from 10-90%; middle-aged rabbit hearts had less fibrosis (5-35%), whereas young adult rat and rabbit hearts had <4% fibrosis. In aged rat hearts, EADs and TA arose most frequently (70%) from the left ventricular base where fibrosis was intermediate (-30%). Computer simulations in two-dimensional tissue incorporating variable degrees of fibrosis showed that intermediate (but not mild or severe) fibrosis promoted EADs and TA. We conclude that in aged ventricles exposed to oxidative stress, fibrosis facilitates the ability of cellular EADs to emerge and generate TA, VT, and VF at the tissue level. [ABSTRACT FROM AUTHOR]

A strong premature electrical stimulus (S2) induces both virtual anodes and virtual cathodes. The effects of virtual electrodes on intracellular Ca2+ concentration ([Ca2+]i) transients and ventricular fibrillation thresholds (VETs) are unclear. We studied 16 isolated, Langendorff-perfused rabbit hearts with simultaneous voltage and [Ca2+]i optical mapping and for vulnerable window determination. After baseline pacing (S1), a monophasic (10 ms anodal or cathodal) or biphasic (5 ms-5 ms) S2 was applied to the left ventricular epicardium. Virtual electrode polarizations and [Ca2+]i varied depending on the S2 polarity. Relative to the level of [Ca2+]i during the S1 beat, the [Ca2+]i level 40 ms after the onset of monophasic S2 increased by 36 ± 8% at virtual anodes and 20 ± 5% at virtual cathodes (P < 0.01), compared with 25 ± 5% at both virtual cathode-anode and anode-cathode sites for biphasic S2. The VET was significantly higher and the vulnerable window significantly narrower for biphasic S2 than for either anodal or cathodal S2 (n = 7, P < 0.01). Treatment with thapsigargin and ryanodine (n = 6) significantly prolonged the action potential duration compared with control (255 ± 22 vs. 189 ± 6 ms, P < 0.05) and eliminated the difference in VET between monophasic and biphasic S2, although VET was lower for both cases. We conclude that virtual anodes caused a greater increase in [Ca2+]i than virtual cathodes. Monophasic S2 is associated with lower VET than biphasic S2, but this difference was eliminated by the inhibition of the sarcoplasmic reticulum function and the prolongation of the action potential duration. However, the inhibition of the sarcoplasmic reticulum function also reduced VET, indicating that the [Ca2+]i dynamics modulate, but are not essential, to ventricular vulnerability. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to determine whether thoracic veins may act as ectopic pacemakers and whether nodelike cells and rich sympathetic innervation are present at the ectopic sites. We used a 1,792-electrode mapping system with 1-mm resolution to map ectopic atrial arrhythmias in eight nonnal dogs during in vivo right and left stellate ganglia (SG) stimulation before and after sinus node crushing. SG stimulation triggered significant elevations of transcardiac norepinephrine levels, sinus tachycardia in all dogs, and atrial tachycardia in two of eight dogs. Sinus node crushing resulted in a slow junctional rhythm (51 ± 6 beats/mm). Subsequent SG stimulation induced 20 episodes of ectopic beats in seven dogs and seven episodes of pulmonary vein tachycardia in three dogs (cycle length 273 ± 35 ms, duration 16 ± 4 s). The ectopic beats arose from the pulmonary vein (n = 11), right atrium (n = 5), left atrium (n 2), and the vein of Marshall (n 2). There was no difference in arrhythmogenic effects of left vs. right SG stimulation (13/29 vs. 16/29 episodes, P = nonsignificant). There was a greater density of periodic acid Schiff-positive cells (P < 0.05) and sympathetic nerves (P < 0.05) at the ectopic sites compared with other nonectopic atrial sites. We conclude that, in the absence of a sinus node, thoracic veins may function as subsidiary pacemakers under heightened sympathetic tone, becoming the dominant sites of initiation of focal atrial arrhythmias that arise from sites with abundant sympathetic nerves and periodic acid Schiff-positive cells. [ABSTRACT FROM AUTHOR]

In vitro models of sustained monomorphic ventricular tachycardia (MVT) are rare and do not usually show spiral reentry on the epicardium. We hypothesized that MVT is associated with the spiral wave in the endocardium and that this stable reentrant propagation is supported by a persistently elevated intracellular calcium (Cai) transient at the core of the spiral wave. We performed dual optical mapping of transmembrane potential (Vm) and Cai dynamics of the right ventricular (RV) endocardium in Langendorff-perfused rabbit hearts (n = 12). Among 64 induced arrhythmias, 55% were sustained MVT (>10 min). Eighty percent of MVT showed stationary spiral waves (>10 cycles, cycle length: 128 ± 14.6 ms) in the endocardial mapped region, anchoring to the anatomic discontinuities. No reentry activity was observed in the epicardium. During reentry, the amplitudes of Vm and Cai signals were higher in the periphery and gradually decreased toward the core. At the core, maximal Vm and Cai amplitudes were 42.95 ± 5.89% and 43.95 ± 9.46%, respectively, of the control (P < 0.001). However, the trough of the Vm and Cai signals at the core were higher than those in the periphery, indicating persistent Vm and Cai elevations during reentry. BAPTA-AM, a calcium chelator, significantly reduced the maximal Cai transient amplitude and prevented sustained MVT and spiral wave formation in the mapped region. These findings indicate that endocardial spiral waves often anchor to anatomic discontinuities causing stable MVT in normal rabbit ventricles. The spiral core is characterized by diminished Vm and Cai amplitudes and persistent Vm and Cai elevations during reentry. [ABSTRACT FROM AUTHOR]

Aging and glycolytic inhibition (GI) are known to alter intracellular calcium ion (Cai2+) handling in cardiac myocytes, causing early afterpotentials (EADs) and delayed afterpotentials. We hypothesized that aging and GI interact synergistically in intact hearts to generate EADs and triggered activity leading to atrial fibrillation (AF). We studied isolated and Langendorff-perfused hearts of young (age 3-5 mo, N = 8) and old (age 27-29 mo, N = 14) rats subjected to GI (0 glucose + 10 mmol/l pyruvate). Epicardial atrial activation maps were constructed using optical action potentials, while simultaneously monitoring Cai2+ by means of dual-voltage and calcium-sensitive fluorescent dyes. During GI, spontaneous AF occurred in 13 of 14 old but in no young rats. AF was initiated by EAD-induced triggered activity at the left atrial pulmonary vein junction (LA-PVJ). The triggered activity initially propagated as single wave front, but within 1 s degenerated into multiple wavelets. The EADs and triggered activity in the old atria were associated with significantly elevated diastolic Cai2+ levels at the LA-PVJ, where the time constant τ of the Cai2+ transient decline and action potential duration were significantly (P < 0.01) prolonged compared with atrial sites 5 mm away from LA-PVJ. During GI and rapid atrial pacing, spatially discordant APD and Cai2+ transient alternans developed in the old but not young atria, leading to AF. Atria in old rats had significantly more fibrotic tissue than atria in young rats. We conclude that GI interacts with the aged and fibrotic atria to amplify Cai2+ handling abnormalities that facilitate EAD-mediated triggered activity and AF. [ABSTRACT FROM AUTHOR]

The importance of the ligament of Marshall (LOM) to rapid activations within the left superior pulmonary vein (LSPV) during atrial fibrillation (AF) remains poorly understood. We aimed to characterize the importance of electrical coupling between the LSPV with the left atrium (LA) and the LOM in the generation of high-frequency activations within this PV. We performed high-density mapping of the LSPV-LA-LOM junction in eight dogs, using 1,344 electrodes with a 1-mm resolution before and after posterior ostial ablation to diminish PV-LA electrical connections. A LOM potential was recordable up to 6.5 mm (SD 2.2) into the LSPV in all dogs during sinus rhythm (SR) and LA pacing. Functional LOM-LSPV electrical connections bypassing the PV-LA junction were present in five of eight dogs. Direct LOM-LSPV connections contributed to 46.5% (SD 16.0) of LSPV activations during AF, resulting in a greater propensity to develop focal activations (P < 0.05) and a higher activation rate during AF of LSPVs with direct LOM connections compared with those without (P < 0.03). Posterior LSPV ostial ablation without damaging the anterior wall or LOM slowed residual LA-PY conduction (P < 0.001). This diminished PV-LA coupling prevented the reinduction of LSPV focal activations in all dogs. However, persistent LOM focal activations in two dogs continued to activate the LSPV rapidly [cycle length 151.8 ms (SD 4.8)] via direct LOM-LSPV connections. LOM-LSPV connection forms an accessory pathway that contributes to the electrical coupling between LSPV and LA during SR and AF. This pathway may contribute to rapid activations within the LSPV during AF. [ABSTRACT FROM AUTHOR]

Ibutilide can prolong refractory period and terminate reentry. Whether ibutilide has the same effects on pulmonary vein (PV) focal discharge (FD) is unclear. We induced sustained atrial fibrillation (AF) in seven dogs by rapid left atrial (LA) pacing for 74 ± 46 days. Ibutilide was repeatedly infused until it terminated AF (0.02 ± 0.01 mg/kg) or when a cumulative dose was reached (0.04 mg/kg). High-resolution computerized epicardial mapping was performed. We found intermittent PD at the PVs and reentry at the PV-LA junction during AF. Ibutilide increased the cycle length of consecutive reentry from 97 ± 13 to 112 ± 18 ms and increased FD from 96 ± 7 to 113 ± 9 ms. In four dogs with both FD and reentry at the PVs, the incidence of reentry decreased from 3.5 ± 1.9/s at baseline .to 2.2 ± 1.8/s after ibutilide administration. However, the incidence of FD remained unchanged. The conducted wave fronts between PV and LA were significantly reduced by ibutilide (10.4 ± 2.0/s vs. 8.0 ± 1.6/s). The ibutilide dose needed to terminate AF correlated negatively with the baseline effective refractory period of PV and LA. We conclude that ibutilide reduces reentrant wave fronts but not PV FD in a canine model of pacing-induced sustained AF. These findings suggest that the PV FD during AF is due to nonreentrant mechanisms. High doses of ibutilide may completely terminate all reentrant activity, converting AF to PV tachycardia before the resumption of sinus rhythm. [ABSTRACT FROM AUTHOR]

Both autonomic nerve activity and electrical remodeling are important in atrial arrhythmogenesis. Therefore, dogs with sympathetic hyperinnervation, myocardial infarction (MI), and complete atrioventricular block (CAVB) may have a high incidence of atrial arrhythmias. We studied eight dogs (experimental group) with MI, CAVB, and sympathetic hyperinnervation induced either by nerve growth factor infusion (n = 4 dogs) or subthreshold electrical stimulation (n = 4 dogs) of the left stellate ganglion. Cardiac rhythm was continuously monitored by a Data Sciences International transmitter for 48 (SD 27) days. Three normal control dogs were also monitored. Six additional normal dogs were used for histology control. Paroxysmal atrial fibrillation (PAF) and paroxysmal atrial tachycardia (PAT) were documented in all dogs in the experimental group, with an average of 3.8 (SD 3) episodes/day, including 1.3 (SD 1.6) episodes of PAF and 2.5 (SD 2.2) episodes of PAT. The duration averaged 298 (SD 745) s (range, 7-4,000 s). There was a circadian pattern of arrhythmia onset (P < 0.01). Of 576 episodes of PAF and PAT, 236 (41%) episodes occurred during either sustained or nonsustained ventricular tachycardia (VT). Among these 236 episodes, 53% started before VT, whereas 47% started after the onset of VT. Normal dogs did not have either PAF or PAT. The hearts from the experimental group had a higher density of nerve structures immunopositive (P < 0.01) for three different nerve specific markers in both right and left atria than those of the control dogs. We conclude that the induction of nerve sprouting and sympathetic hyperinnervation in dogs with CAVB and MI creates a high yield model of PAF and PAT. [ABSTRACT FROM AUTHOR]

The potential of chronic nicotine exposure for atrial fibrillation (AF) and atrial flutter (AFL) in hearts with and without chronic myocardial infarction (MI) remains poorly explored. MI was created in dogs by permanent occlusion of the left anterior descending coronary artery, and dogs were administered nicotine (5 mg kg-1 day-1 sc) for 1 mo using osmotic minipumps. High-resolution epicardial (1,792 bipolar electrodes) and endocardial Halo catheters were used to map activation during induced atrial rhythms. Nicotine promoted inducible sustained AFL at a mean cycle length of 134 ± 10 ms in all MI dogs (n = 6) requiring pacing and electrical shocks for termination. No AFL could be induced in MI dogs (n = 6), control (non-MI) dogs (n = 3) not exposed to nicotine, and dogs with no MI and exposed to nicotine (n = 3). Activation maps during AFL showed a single reentrant wavefront in the right atrium that rotated either clockwise (60%) or counterclockwise (40%) around the crista terminalis and through the isthmus. Ablation of the isthmus prevented the induction of AFL. Nicotine caused a significant (P < 0.01) but highly heterogeneous increase in atrial interstitial fibrosis (2- to 10-fold increase in left and right atria, respectively) in the MI group but only a 2-fold increase in the right atrium in the non-MI group. Nicotine also flattened (P < 0.05) the slope of the epicardial monophasic action potential duration (electrical restitution) curve of both atria in the MI but not in non-MI dogs. Two-dimensional simulation in an excitable matrix containing an isthmus and nicotine's restitutional and reduced gap junctional coupling (fibrosis) parameters replicated the experiments. Chronic nicotine in hearts with MI promotes AFL that closely resembles typical human AFL. Increased atrial interstitial fibrosis and flattened electrical restitution are important substrates for the AFL. [ABSTRACT FROM AUTHOR]

Focal discharges (FDs) are present in thoracic veins during atrial fibrillation (AF). We hypothesize that procainamide exerts its anti-AF action by suppressing FDs in the thoracic veins. We studied six mongrel dogs (22–27 kg) with sustained (>6 h) AF induced by 47 ± 20 days of chronic rapid LA appendage (LAA) or pulmonary vein (PV) pacing. Procainamide was infused intravenously until AF was terminated or a cumulative dose of 20 mg/kg was reached. High-resolution mapping during AF showed FDs in the vein of Marshall. PVs. and the LAA. Procainamide significantly (P < 0.05) reduced the frequency of these FDs and suppressed the interactions of wave fronts between PVs and LA. The cumulative dose of PA needed to terminate AF correlated negatively (r = −0.9, P < 0.05) with the baseline effective refractory period (ERP) of PV and positively (r = 0.8. P < 0.05) with the baseline maximum dominant frequency (DF) of AF. In four of five dogs, AF converted to atrial tachycardia originating from the PVs before termination. Attempts to reinduce sustained AF were unsuccessful in these five dogs. AF was resistant to procainamide in the sixth dog. In conclusion, procainamide reduced the rate of FDs in the thoracic veins and the LA and suppressed the interaction between PVs and LA. Second, FDs in the PV are more resistant to procainamide's action than FDs in the atria. Third, inherent PV ERP is important in determining the antifibrillatory efficacy of procainamide. [ABSTRACT FROM AUTHOR]

In the heart, membrane voltage (Vm) and intracellular Ca (Cai) are bidirectionally coupled, so that ionic membrane currents regulate Cai cycling and Cai affects ionic currents regulating action potential duration (APD). Although Ca~ reliably and consistently tracks Vm at normal heart rates, it is possible that at very rapid rates, sarcoplasmic reticulum Cai cycling may exhibit intrinsic dynamics. Non-voltage-gated Cai release might cause local alternations in APD and refractoriness that influence wavebreak during ventricular fibrillation (VF). In this study, we tested this hypothesis by examining the extent to which Cal is associated with Vm during VF. Cai transients were mapped optically in isolated arterially perfused swine right ventricles using the fluorescent dye rhod 2 AM while intracellular membrane potential was simultaneously recorded either locally with a microelectrode (5 preparations) or globally with the voltage-sensitive dye RH-237 (5 preparations). Mutual information (MI) is a quantitative statistical measure of the extent to which knowledge of one variable (Vm) predicts the value of a second variable (Cai). MI was high during pacing and ventricular tachycardia (VT; 1.13 ± 0.21 and 1.69 ± 0.18, respectively) but fell dramatically during VF (0.28 ± 0.06. P < 0.001 ). Cai at sites 4–6 mm apart also showed decreased MI during VF (0.63 ± 0.13) compared with pacing (1.59 ± 0.34, P < 0.001) or VT (2.05 ± 0.67. P < 0.001). Spatially, Cai waves usually bore no relationship to membrane depolarization waves during nonreentrant fractionated waves typical of VF, whereas they tracked each other closely during pacing and VT. The dominant frequencies of Vm and Cai signals analyzed by fast Fourier transform were similar during VT but differed significantly during VF. Cai is closely associated with Vm closely during pacing and VT but not doting VF These findings suggest that during VF, non-voltage-gated Cai release events occur and may influence wavebreak by altering Vm and APD locally. [ABSTRACT FROM AUTHOR]

Although the enteric reflex pathway triggered by volume distension is known to depend on an adrenergic nerve, it is not known whether the slowing of intestinal transit by fat or peptide YY (PYY) also depends on an adrenergic pathway. The aim of this study was to test the hypotheses that the slowing of transit by fat or PYY may depend on a β-adrenergic pathway, and this adrenergic pathway may act via the serotonergic and opioid pathways previously observed for the slowing of transit by fat. Eighteen dogs were equipped with duodenal and midgut fistulas. The small intestine was compartmentalized into the proximal and distal half of gut. The role of adrenergic, serotonergic, and opioid pathways was then tested in the slowing of intestinal transit by fat, PYY, and norepinephrine. Intestinal transit results were compared as the cumulative percent marker of recovery over 30 min. We found that the slowing of transit by fat, PYY, or norepinephrine was reversed by propranolol. In addition, the slowing effect of fat was reversed by metoprolol (β[sub 1]-adrenoreceptor antagonist) but not phentolamine (α-adrenoreceptor antagonist). Furthermore, norepinephrine-induced slowing of transit was reversed by ondansetron (5-HT[sub 3] receptor antagonist) or naloxone (opioid receptor antagonist). Extending these physiological results, we also found by immunohistochemistry that β[sub 1]-adrenoreceptors are expressed by neurons of the intrinsic plexuses of the small intestine. We conclude that the slowing of intestinal transit by fat or PYY depends on a β-adrenergic pathway and that this adrenergic pathway acts on serotonergic and opioid pathways. [ABSTRACT FROM AUTHOR]

The probabilistic nature of the ventricular defibrillation threshold (DFT) remains poorly understood. We hypothesized that shock outcome is a function of the amount of myocardium in its vulnerable period (VP). The endocardial surface of five isolated, perfused swine right ventricles was mapped with 477 bipolar electrodes during ventricular fibrillation (VF). Shock parameters and VF cycle length were not significantly different in the successful (S; n = 26) and failed (F; n = 26) trials. At the instant of the shock, the number of sites with 45- to 55-ms recovery was significantly smaller in the S trials than the F trials (P < 0.04). No significant difference in the number of sites with recovery intervals outside the 45- to 55-ms range was seen in S and F shocks. Endocardial action potential showed that a recovery time of 45-55 ms corresponded to the VP spanning -15 to -60 mV in 92% of the regenerative action potentials. We conclude that the probabilistic nature of the DFT is related to the amount of myocardium in its VP. [ABSTRACT FROM AUTHOR]

Reports on the nonreentrant focal activations in pulmonary veins in canine model of sustained atrial fibrilation (AF). Induction of sustained AF; Sustained AF induced by left atrium pacing; Activation patterns of AF in normal dogs.

Focuses on a study which investigated action potential duration restitution and ventricular fibrillation. Mechanism of ventricular fibrillation; Induction of ventricular tachycardia and ventricular fibrillation by aconitine.

Deals with a study which examined the effects of sildenafil combined with nitric oxide donor on ventricular tachyarrhythmias. Incidence of adverse effects associated with sildenafil use; Vulnerability to ventricular fibrillation; Implications of the study results for clinical practice.

Discusses a study that investigated the mechanisms underlying antifibrillatory effects of amiodarone. Effects of amiodarone infusion on ventricular fibrillation; Effects of amiodarone on action potential duration restitution; Comparison of amiodarone with bretylium and verapamil.

Investigates the mechanism of wave break generation during ventricular fibrillation. Production of wave through head-tail interaction between waves and filament break.