Long-term spinal cord stimulation modifies canine intrinsic cardiac neuronal properties and ganglionic transmission during high-frequency repetitive activation.

Long-term spinal cord stimulation (SCS) applied to cranial thoracic SC segments exerts antiarrhythmic and cardioprotective actions in the canine heart in situ. We hypothesized that remodeling of intrinsic cardiac neuronal and synaptic properties occur in canines subjected to long-term SCS, specifically that synaptic efficacy may be preferentially facilitated at high presynaptic nerve stimulation frequencies. Animals subjected to continuous SCS for 5-8 weeks (long-term SCS: n = 17) or for 1 h (acute SCS: n = 4) were compared with corresponding control animals (long-term: n = 15, acute: n = 4). At termination, animals were anesthetized, the heart was excised and neurones from the right atrial ganglionated plexus were identified and studied in vitro using standard intracellular microelectrode technique. Main findings were as follows: (1) a significant reduction in whole cell membrane input resistance and acceleration of the course of AHP decay identified among phasic neurones from long-term SCS compared with controls, (2) significantly more robust synaptic transmission to rundown in long-term SCS during high-frequency (10-40 Hz) presynaptic nerve stimulation while recording from either phasic or accommodating postsynaptic neurones; this was associated with significantly greater posttrain excitatory postsynaptic potential (EPSP) numbers in long-term SCS than control, and (3) synaptic efficacy was significantly decreased by atropine in both groups. Such changes did not occur in acute SCS In conclusion, modification of intrinsic cardiac neuronal properties and facilitation of synaptic transmission at high stimulation frequency in long-term SCS could improve physiologically modulated vagal inputs to the heart.

Biatrial neuroablation attenuates atrial remodeling and vulnerability to atrial fibrillation in canine chronic rapid atrial pacing.

AIMS: We investigated the proposition that an intact cardiac nervous system may contribute to electrophysiological remodeling and increased vulnerability to atrial fibrillation (AF) following chronic rapid atrial pacing (RAP). METHODS AND RESULTS: Baseline study was conducted prior to ablating right and left ganglionated plexuses (RAGP, LAGP) in 11 anesthetized canines (Neuroablation group) and in 11 canines without neuroablation (Intact GP). After being subjected to RAP (400 beats/min) for 6 weeks, animals were reanesthetized for terminal study. The ERP shortening typical of chronic RAP was significantly more pronounced in the Intact GP (baseline: 112 ± 12 to terminal: 80 ± 11 ms) than in the Neuroablation group (113 ± 18 to 102 ± 21 ms, p < .001), and AF inducibility (extrastimulus protocol) showed significantly greater increment in the Intact GP (baseline: 23 ± 19% to terminal: 60 ± 17% of trials) than in the Neuroablation group (18 ± 15% to 27 ± 17%, p = 0.029). Negative chronotropic responses to right vagus nerve stimulation were markedly reduced immediately after the neuroablation procedure but had recovered at terminal study. Vagally-evoked repolarization changes (from 191 unipolar electrograms) occurred in a majority of Intact GP animals in the superior, middle and inferior RA free wall, and in the LA appendage. In the Neuroablation group, repolarization changes were restricted to the superior RA free wall but none occurred in the inferior RA and only infrequently in the LA appendage, yielding significantly smaller affected areas in Neuroablation than in Intact GP animals. CONCLUSION: Persistent functional denervation in LA and RA regions other than RA pacemaker areas may contribute to prevent the development of a tachycardia-dependent AF substrate.

Chronic spinal cord stimulation modifies intrinsic cardiac synaptic efficacy in the suppression of atrial fibrillation.

We sought to determine whether spinal cord stimulation (SCS) therapy, when applied chronically to canines, imparts long-lasting cardio-protective effects on neurogenic atrial tachyarrhythmia induction and, if so, whether its effects can be attributable to i) changes in intrinsic cardiac (IC) neuronal transmembrane properties vs ii) modification of their interneuronal stochastic interactivity that initiates such pathology. Data derived from canines subjected to long-term SCS [(group 1: studied after 3-4 weeks SCS; n = 5) (group 2: studied after 5 weeks SCS; n = 11)] were compared to data derived from 10 control animals (including 4 sham SCS electrode implantations). During terminal studies conducted under anesthesia, chronotropic and inotropic responses to vagal nerve or stellate ganglion stimulation were similar in all 3 groups. Chronic SCS suppressed atrial tachyarrhythmia induction evoked by mediastinal nerve stimulation. When induced, arrhythmia durations were shortened (controls: median of 27 s; SCS 3-4 weeks: median of 16s; SCS 5 weeks: median of 7s). Phasic and accommodating right atrial neuronal somata displayed similar passive and active membrane properties in vitro, whether derived from sham or either chronic SCS group. Synaptic efficacy was differentially enhanced in accommodating (not phasic) IC neurons by chronic SCS. Taken together these data indicate that chronic SCS therapy modifies IC neuronal stochastic inter-connectivity in atrial fibrillation suppression by altering synaptic function without directly targeting the transmembrane properties of individual IC neuronal somata.

Simultaneous epicardial and noncontact endocardial mapping of the canine right atrium: simulation and experiment.

Epicardial high-density electrical mapping is a well-established experimental instrument to monitor in vivo the activity of the atria in response to modulations of the autonomic nervous system in sinus rhythm. In regions that are not accessible by epicardial mapping, noncontact endocardial mapping performed through a balloon catheter may provide a more comprehensive description of atrial activity. We developed a computer model of the canine right atrium to compare epicardial and noncontact endocardial mapping. The model was derived from an experiment in which electroanatomical reconstruction, epicardial mapping (103 electrodes), noncontact endocardial mapping (2048 virtual electrodes computed from a 64-channel balloon catheter), and direct-contact endocardial catheter recordings were simultaneously performed in a dog. The recording system was simulated in the computer model. For simulations and experiments (after atrio-ventricular node suppression), activation maps were computed during sinus rhythm. Repolarization was assessed by measuring the area under the atrial T wave (ATa), a marker of repolarization gradients. Results showed an epicardial-endocardial correlation coefficients of 0.80 and 0.63 (two dog experiments) and 0.96 (simulation) between activation times, and a correlation coefficients of 0.57 and 0.46 (two dog experiments) and 0.92 (simulation) between ATa values. Despite distance (balloon-atrial wall) and dimension reduction (64 electrodes), some information about atrial repolarization remained present in noncontact signals.

Bilateral atrial ganglionated plexus involvement in atrial responses to left-sided plexus stimulation in canines.

AIMS: Given the clinical interest concerning 'reflex vagal' responses to identify left atrial (LA) targets for ablative therapy of atrial fibrillation, we investigated whether vagal and bilateral atrial neural pathways may be involved in chronotropic and atrial repolarization responses to LA ganglionated plexus (GP) stimulation. METHODS AND RESULTS: Unipolar electrograms were recorded from 191 right atrial (RA) and LA sites in anaesthetized canines prior to and during electrical stimulation of the right vagus nerve (VgN), left VgN, or LAGP at baseline and following (i) bilateral VgN decentralization, and radiofrequency ablation of (ii) periaortic/superior vena cava (Ao/SVC) and (iii) RAGP in 14 animals (anterograde group), and in the reverse order in 7 (retrograde). Repolarization changes were also measured in similar preparations during Ao/SVC (n = 8) and RAGP stimulation (n = 23). Sinus cycle length (SCL) prolongation, and RA and LA repolarization changes (affected atrial surface area) were induced during LAGP stimulation. SCL prolongation and RA repolarization changes were unaffected by VgN decentralization but reduced following Ao/SVC and RAGP ablation in the anterograde group. In the retrograde group, chronotropic and RA repolarization changes were reduced following RAGP and abolished following Ao/SVC ablation. In contrast, LA repolarization responses to LAGP stimulation were reduced following VgN decentralization and each subsequent ablation step, with small residual responses after completing the anterograde protocol. Ao/SVC and RAGP stimulation exerted predominant influences in adjacent regions as well as demonstrating LA extensions. CONCLUSION: Vagal as well as bilateral atrial neural pathways are involved in mediating chronotropic and LA repolarization responses to LAGP stimulation.

Longterm effects of cardiac mediastinal nerve cryoablation on neural inducibility of atrial fibrillation in canines.

In canines, excessive activation of select mediastinal nerve inputs to the intrinsic cardiac nervous system induces atrial fibrillation (AF). Since ablation of neural elements is proposed as an adjunct to circumferential pulmonary vein ablation for AF, we investigated the short and long-term effects of mediastinal nerve ablation on AF inducibility. Under general anesthesia, in 11 dogs several mediastinal nerve sites were identified on the superior vena cava that, when stimulated electrically during the atrial refractory period, reproducibly initiated AF. Cryoablation of one nerve site was then performed and inducibility retested early (1-2 months post Cryo; n=7) or late (4 months post Cryo; n=4). Four additional dogs that underwent a sham procedure were retested 1 to 2 months post-surgery. Stimulation induced AF at 91% of nerve sites tested in control versus 21% nerve sites early and 54% late post-ablation (both P<0.05). Fewer stimuli were required to induce AF in controls versus the Early Cryo group; this capacity returned to normal values in the Late Cryo group. AF episodes were longer in control versus the Early or Late Cryo groups. Heart rate responses to vagal or stellate ganglion stimulation, as well as to local nicotine infusion into the right coronary artery, were similar in all groups. In conclusion, focal damage to intrinsic cardiac neuronal inputs causes short-term stunning of neuronal inducibility of AF without major loss of overall adrenergic or cholinergic efferent neuronal control. That recovery of AF inducibility occurs rapidly post-surgery indicates the plasticity of intrathoracic neuronal elements to focal injury.

Spinal cord stimulation causes potentiation of right vagus nerve effects on atrial chronotropic function and repolarization in canines.

INTRODUCTION: Experimental evidence suggests that spinal cord stimulation (SCS) can cause augmentation of parasympathetic influences on the heart via enhanced vagus nerve (VgN) activity. Herein, we investigated whether this might lead to enhanced inducibility of vagally mediated atrial tachyarrhythmias (AT) and whether such actions depend on intact autonomic neural connections with central neurons. METHOD AND RESULTS: Epidural SCS electrodes were implanted at T1-T4 in anesthetized canines. Sinus cycle length prolongation, atrial repolarization changes (191 epicardial electrode sites), and AT inducibility in response to right VgN stimuli applied at the cervical level were determined before and during SCS. VgN-induced sinus cycle length prolongation was potentiated during SCS among the animals with intact neural connections or bilateral vagotomy proximal to the stimulation site, whereas such prolongation was unaffected by SCS among animals with bilateral decentralization of stellate ganglia. Likewise, the atrial surface area in which VgN-induced repolarization wave form changes were identified was significantly augmented during SCS among the former but not among the latter. AT facilitation occurred during SCS in the majority of animals with intact neural connections, particularly among those displaying relatively greater potentiation of vagally mediated sinus cycle length prolongation. CONCLUSION: The data indicate that SCS may cause potentiation of parasympathetic influences on the atria in response to cervical VgN stimulation. Such SCS effects appear to be mediated via decreased tonic inhibitory sympathetic influences in the presence of intact stellate ganglion connections to central neurons.

Atrial tachyarrhythmias and repolarization changes induced by discrete activation of dorsal mediastinal cardiac nerves in canines.

BACKGROUND: Chronotropic "vagal responses" elicited by high-frequency stimulation have been used to identify atrial targets for ablative treatment of atrial tachyarrhythmias (AT), whereas an anatomic approach consisting of extensive ablation of the ganglionated plexus areas has been proposed as an alternative. Therefore, there is a need for precise delineation of juxtacardiac nerves involved in AT initiation and clarification of their regional influences throughout the atria in relation to AT sites of origin, beyond chronotropic effects related to sinus node modulation. METHODS AND RESULTS: Unipolar electrograms were recorded from 191 biatrial epicardial sites in 13 anesthetized canines, with concomitant left atrial endocardial recording from 63 sites in 5 of 13 animals. When electric stimuli were delivered to dorsal mediastinal nerves during the atrial refractory period, atrial premature depolarizations initiating AT were elicited in all animals, most frequently without prior sinus cycle length modification. Among 63 episodes, the sites of origin of early AT beats were localized to (1) the posterolateral left atrial wall in the pulmonary vein region (33%), (2) superior left atrial loci along the Bachmann bundle (55%), and (3) the region of Bachmann bundle insertion into the superior right atrial wall (11%). Moreover, the AT sites of origin were spatially concordant with regional waveform changes during the repolarization phase of unipolar recordings. AT induction and repolarization changes were abolished after atropine administration. CONCLUSIONS: Activation of individual dorsal mediastinal nerves induces AT arising from distinct sites of origin which are spatially concordant with regional atrial repolarization changes.

Dorsal spinal cord stimulation obtunds the capacity of intrathoracic extracardiac neurons to transduce myocardial ischemia.

Populations of intrathoracic extracardiac neurons transduce myocardial ischemia, thereby contributing to sympathetic control of regional cardiac indices during such pathology. Our objective was to determine whether electrical neuromodulation using spinal cord stimulation (SCS) modulates such local reflex control. In 10 anesthetized canines, middle cervical ganglion neurons were identified that transduce the ventricular milieu. Their capacity to transduce a global (rapid ventricular pacing) vs. regional (transient regional ischemia) ventricular stress was tested before and during SCS (50 Hz, 0.2 ms duration at 90% MT) applied to the dorsal aspect of the T1 to T4 spinal cord. Rapid ventricular pacing and transient myocardial ischemia both activated cardiac-related middle cervical ganglion neurons. SCS obtunded their capacity to reflexly respond to the regional ventricular ischemia, but not rapid ventricular pacing. In conclusion, spinal cord inputs to the intrathoracic extracardiac nervous system obtund the latter's capacity to transduce regional ventricular ischemia, but not global cardiac stress. Given the substantial body of literature indicating the adverse consequences of excessive adrenergic neuronal excitation on cardiac function, these data delineate the intrathoracic extracardiac nervous system as a potential target for neuromodulation therapy in minimizing such effects.

Spatially divergent cardiac responses to nicotinic stimulation of ganglionated plexus neurons in the canine heart.

Ganglionated plexuses (GPs) are major constituents of the intrinsic cardiac nervous system, the final common integrator of regional cardiac control. We hypothesized that nicotinic stimulation of individual GPs exerts divergent regional influences, affecting atrial as well as ventricular functions. In 22 anesthetized canines, unipolar electrograms were recorded from 127 atrial and 127 ventricular epicardial loci during nicotine injection (100 mcg in 0.1 ml) into either the 1) right atrial (RA), 2) dorsal atrial, 3) left atrial, 4) inferior vena cava-inferior left atrial, 5) right ventricular, 6) ventral septal ventricular or 7) cranial medial ventricular (CMV) GP. In addition to sinus and AV nodal function, neural effects on atrial and ventricular repolarization were identified as changes in the area subtended by unipolar recordings under basal conditions and at maximum neurally-induced effects. Animals were studied with intact AV node or following ablation to achieve ventricular rate control. Atrial rate was affected in response to stimulation of all 7 GPs with an incidence of 50-95% of the animals among the different GPs. AV conduction was affected following stimulation of 6/7 GP with an incidence of 22-75% among GPs. Atrial and ventricular repolarization properties were affected by atrial as well as ventricular GP stimulation. Distinct regional patterns of repolarization changes were identified in response to stimulation of individual GPs. RAGP predominantly affected the RA and posterior right ventricular walls whereas CMVGP elicited biatrial and biventricular repolarization changes. Spatially divergent and overlapping cardiac regions are affected in response to nicotinic stimulation of neurons in individual GPs.

Alpha-adrenoceptor blockade modifies neurally induced atrial arrhythmias.

Our objective was to determine whether neuronally induced atrial arrhythmias can be modified by alpha-adrenergic receptor blockade. In 30 anesthetized dogs, trains of five electrical stimuli (1 mA; 1 ms) were delivered immediately after the P wave of the ECG to mediastinal nerves associated with the superior vena cava. Regional atrial electrical events were monitored with 191 atrial unipolar electrodes. Mediastinal nerve sites were identified that reproducibly initiated atrial arrhythmias. These sites were then restimulated following 1 h (time control, n = 6), or the intravenous administration of naftopidil (alpha(1)-adrenergic blocker: 0.2 mg/kg, n = 6), yohimbine (alpha(2)-adrenergic blocker: 1 mg/kg, n = 6) or both (n = 8). A ganglionic blocker (hexamethonium: 1 mg/kg) was tested in four dogs. Stimulation of mediastinal nerves sites consistently elicited atrial tachyarrhythmias. Repeat stimulation after 1 h in the time-control group exerted a 19% decrease of the sites still able to induce atrial tachyarrhythmias. Hexamethonium inactivated 78% of the previously active sites. Combined alpha-adrenoceptor blockade inactivated 72% of the previously active sites. Bradycardia responses induced by mediastinal nerve stimulation were blunted by hexamethonium, but not by alpha(1,2)-adrenergic blockade. Naftopidil or yohimbine alone eliminated atrial arrhythmia induction from 31% and 34% of the sites (similar to time control). We conclude that heterogeneous activation of the intrinsic cardiac nervous system results in atrial arrhythmias that involve intrinsic cardiac neuronal alpha-adrenoceptors. In contrast to the global suppression exerted by hexamethonium, we conclude that alpha-adrenoceptor blockade targets intrinsic cardiac local circuit neurons involved in arrhythmia formation and not the flow-through efferent projections of the cardiac nervous system.

Cervical vagosympathetic and mediastinal nerves activation effects on atrial arrhythmia formation.

In anesthetized dogs both epi-and endocardial atrial activation maps and corresponding isointegral repolarization maps were created before and during right or left mediastinal nerve (RMN and LMN) and cervical vagus nerve (CVN) stimulation. Right mediastinal nerve stimulation typically caused sinus slowing, atrial tachycardia (AT), followed by atrial fibrillation (AF). Activation maps during AT showed epicardial breakthroughs from the right atrial free wall or Bachmann's bundle. Left mediastinal nerve stimulation (LMN) rarely caused sinus slowing and ATs originated mostly from Bachmann's bundle or from the pulmonary vein ostial region. Atrial repolarization changes induced by neural stimulation were measured by integrating the area subtended by 161 epicardial unipolar electrograms. Atrial tachycardia epicardial breakthrough sites were closely associated with the border zone where repolarization changes occurred. Both AT and AF were abolished by I.V. atropine, as were sinus bradycardia and atrial repolarization effects of nerve stimulation. Shortening of latency of onset and duration of AT by I.V. timolol suggest concurrent activation of adrenergic efferent neurons. In conclusion, juxta-cardiac mediastinal nerve stimulation can induce atrial fibrillation from multiple, discrete right and left atrial sites, which correspond to localized repolarization changes. Secondly, sinus bradycardia is not a necessary index of parasympathetic neurally induced atrial fibrillation.

Combined effects of reduced connexin 43, depressed active generator properties and energetic stress on conduction disturbances in canine failing myocardium.

To show that reductions in connexin43 (Cx43) can contribute, in association with electrophysiological alterations identified from unipolar recordings, to conduction disturbances in a realistic model of heart failure, canines were subjected to chronic rapid pacing (240/min for 4 weeks) and progressive occlusion of the left coronary circumflex artery (LCx) by an ameroid constrictor. Alterations identified from 191 epicardial recordings included abrupt activation delay, functional block, ST segment potential elevation, and reduced maximum negative slope (-dV/dt (max)). The LCx territory was divided into apical areas with depressed conduction velocity (LCx1: 0.06 +/- 0.04 m/s, mean +/- SD) and basal areas with relatively preserved conduction (LCx2: 0.28 +/- 0.01 m/s). Subepicardial Cx43 immunoblot measurements (percent of corresponding healthy heart measurements) were reduced in LCx1 ( approximately 40%) and LCx2 ( approximately 60%). In addition, -dV/dt (max) was significantly depressed (-3.8 +/- 3.3 mV/ms) and ST segment potential elevated (23.3 +/- 14.6 mV) in LCx1 compared to LCx2 (-9.5 +/- 3.4 mV/ms and 0.3 +/- 1.4 mV). Anisotropic conduction, Cx43 and ST segment potential measurements from the left anterior descending coronary artery territory, and interstitial collagen from all regions were similar to the healthy. Thus, moderate Cx43 reduction to "clinically relevant" levels can, in conjunction with regional energetic stress and depression of sarcolemmal active generator properties, provide a substrate for conduction disturbances.

Spinal cord stimulation suppresses bradycardias and atrial tachyarrhythmias induced by mediastinal nerve stimulation in dogs.

Spinal cord stimulation (SCS) applied to the dorsal aspect of the cranial thoracic cord imparts cardioprotection under conditions of neuronally dependent cardiac stress. This study investigated whether neuronally induced atrial arrhythmias can be modulated by SCS. In 16 anesthetized dogs with intact stellate ganglia and in five with bilateral stellectomy, trains of five electrical stimuli were delivered during the atrial refractory period to right- or left-sided mediastinal nerves for up to 20 s before and after SCS (20 min). Recordings were obtained from 191 biatrial epicardial sites. Before SCS (11 animals), mediastinal nerve stimulation initiated bradycardia alone (12 nerve sites), bradycardia followed by tachyarrhythmia/fibrillation (50 sites), as well as tachyarrhythmia/fibrillation without a preceding bradycardia (21 sites). After SCS, the number of responsive sites inducing bradycardia was reduced by 25% (62 to 47 sites), and the cycle length prolongation in residual bradycardias was reduced. The number of responsive sites inducing tachyarrhythmia was reduced by 60% (71 to 29 sites). Once elicited, residual tachyarrhythmias arose from similar epicardial foci, displaying similar dynamics (cycle length) as in control states. In the absence of SCS, bradycardias and tachyarrhythmias induced by repeat nerve stimulation were reproducible (five additional animals). After bilateral stellectomy, SCS no longer influenced neuronal induction of bradycardia and atrial tachyarrhythmias. These data indicate that SCS obtunds the induction of atrial arrhythmias resulting from excessive activation of intrinsic cardiac neurons and that such protective effects depend on the integrity of nerves coursing via the subclavian ansae and stellate ganglia.

Beta1-adrenoceptor blockade mitigates excessive norepinephrine release into cardiac interstitium in mitral regurgitation in dog.

Mitral regurgitation (MR) is associated with increased neuronal release of norepinephrine (NE) and epinephrine (EP) into myocardial interstitial fluid (ISF) that may be necessary in sustaining left ventricular (LV) function via activation of cardiomyocyte beta-adrenergic receptors (ARs). However, activation of neuronal beta-ARs on cardiac neurons may lead to further catecholamine release, with an attendant risk of functional deterioration. We hypothesize that a beneficial effect of beta-AR blockade may therefore mitigate excessive catecholamine release from cardiac adrenergic neurons in dogs with MR. We measured the effects of chronic beta-receptor blockade (beta-RB) on ISF NE and EP release using in vivo microdialysis in open-chest anesthetized dogs after 4 wk of MR with or without extended release of metoprolol succinate (100 mg/day) as well as in control dogs. Fractional shortening increased by 30% in both MR and MR + beta-RB dogs after 4 wk of MR. In MR + beta-RB dogs, stellate-stimulated heart rate change was attenuated compared with control and MR dogs, whereas peak change of LV pressure over time (+dP/dt) increased equally in all groups. Stellate-stimulated ISF NE increased fivefold over baseline in MR versus twofold in control dogs (< 0.05), but the NE release was significantly attenuated in MR + beta-RB dogs. In contrast, stellate-stimulated increases in ISF EP did not differ in control, MR, and MR + beta-RB dogs. This study demonstrates that beta-RB attenuates ISF NE release from cardiac neurons and that the LV functional response to MR is not dependent on an excess increase in ISF NE. Thus beta1-RB may exert a beneficial effect by attenuating untoward effects of excessive sympathetic efferent neural NE release while sustaining early LV functional adaptation to MR.

Differential effects of cervical vagosympathetic and mediastinal nerve activation on atrial arrhythmia formation in dogs.

To investigate the influence of the thoracic autonomic neuronal hierarchy on atrial arrhythmia formation, we compared the characteristics of atrial tachyarrhythmias induced by electrical stimulation of 1) the right vagosympathetic nerve complex at the cervical level and 2) the more caudal juxta-cardiac mediastinal nerves located on the anterior surface of the superior vena cava. Unipolar electrograms were recorded from 191 sites on the entire epicardial atrial surface and, in some experiments, from 63 right atrial endocardial sites. The sites of origin of initial beats at the onset of atrial tachyarrhythmias so induced were investigated analysing atrial activation maps. Neural effects on repolarization were determined by computing the integral surface subtended by unipolar recordings under basal conditions and at maximum neurally induced bradycardia, and calculating differences at each recording site. The mean area affected by nerve stimulation in all animals was significantly greater in response to vagosympathetic than mediastinal nerve stimulation. Atrial cycle length prolongation prior to tachyarrhythmia onset was more pronounced in response to vagosympathetic than mediastinal nerve stimulation. The earliest epicardial activations in early tachyarrhythmia beats were localized in the right atrial free wall and Bachmann bundle region in both cases, but with a higher incidence of double breakthroughs from septal sites of origin in response to vagosympathetic versus mediastinal nerve stimulation. Sites of early activation were associated with the areas of neurally induced repolarization changes. Thus, differential contributions are made to the electrophysiologic substrate of neurally induced atrial tachyarrhythmias depending on the pattern of engagement of neural elements within the autonomic neuronal hierarchy.

A comparison of monodomain and bidomain propagation models for the human heart.

A bidomain reaction-diffusion model of the human heart was developed and potentials resulting from normal depolarization and repolarization were compared with results from a compatible monodomain model. Comparisons were made for an empty isolated heart and for a heart with fluid-filled ventricles. Both sinus rhythm and ectopic activation were simulated. The model took 2 days on 32 processors to simulate a complete cardiac cycle. Differences between monodomain and bidomain results were very small, even for the extracellular potentials which, for the monodomain model, were computed with a high-resolution forward model. Electrograms computed with monodomain and bidomain models were visually indistinguishable. We conclude that, in the absence of applied currents, propagating action potentials on the scale of a human heart can be studied with a monodomain model.

ST elevation or depression in subendocardial ischemia?

ST-segment depression in epicardial electrograms can be a "reciprocal" effect of remote myocardial ischemia (MI), and can also be due to local partial-thickness or "subendocardial" MI. Experimental studies have shown either ST elevation or depression in leads overlying a subendocardial ischemic region. Those reporting elevation have shown depression over the lateral borders of the ischemia. Simulation studies with anisotropic models have explained the ST-elevation results. Presently, while experimentalists may have difficulty understanding the ST elevation, most model studies fail to explain ST depression in overlying leads during partial-thickness ischemia. We have simulated partial-thickness ischemia in a 3-dimensional model of the human heart. Our results show that the conductivity of the intracavitary blood, geometry of the ischemic region, and bidomain anisotropy ratios can all have a decisive influence on the sign of the ST deviation. We hypothesize that ST depression in leads overlying an ischemic zone is due to subendocardial ischemia in tissue where a redistribution of gap junctions has taken place.

Sustained cardioprotection afforded by A2A adenosine receptor stimulation after 72 hours of myocardial reperfusion.

This study was designed to determine whether cardioprotection afforded by A2A adenosine receptor stimulation can be sustained and to determine the effect of an A2A adenosine receptor agonist on Akt and cAMP response element binding protein (CREB) activation, as well as Hsp27 and Hsp70 protein expression in such events. The left anterior descending coronary artery was occluded for 40 minutes in anesthetized rats followed by 72 hours of reperfusion. A2A agonist (CGS21680 at 0.2 microg/kg/min) was administered for 120 minutes, starting either 5 minutes before (early) or after (late) the beginning of reperfusion. Infarct size was reduced significantly in the early compared with the control group (35.2 +/- 1.9% and 52.5 +/- 3.4%, respectively; P < 0.05), whereas no difference was observed with the late group (44.5 +/- 7.1%). After 72 hours of reperfusion, drug administration was accompanied by Akt activation (early, 121.8 +/- 17.6%; late, 118.1 +/- 16.4%; P < 0.05), as well as elevated Hsp27 expression (early, 197.2 +/- 27.7%; late, 203.8 +/- 36.8%; P < 0.05); CREB activation and Hsp70 expression were not altered. In another set of experiments in which reperfusion was limited to 15 minutes, Akt was activated only in the early group (121.8 +/- 17.6%; P < 0.05). Moreover, CREB was activated in both the early and late groups (98.4 +/- 8.3% and 107.0 +/- 6.5%, respectively; P < 0.05), whereas Hsp27 and Hsp70 expression were not altered. These results demonstrate that A2A adenosine receptor activation induces a sustained cardioprotection only if the therapy is instituted before reperfusion. This myocardial protection is associated by an early prosurvival Akt activation. CREB activation and Hsp27 content do not seem to be associated with cardioprotection because they are enhanced in both treated groups, suggesting indirect A2A agonist and pathology-related effects.

Origin and pharmacological response of atrial tachyarrhythmias induced by activation of mediastinal nerves in canines.

We sought to determine the sites of origin of atrial tachyarrhythmias induced by activating mediastinal nerves, as well as the response of such arrhythmias to autonomic modulation. Under general anaesthesia, atrioventricular block was induced after thoracotomy in 19 canines. Brief trains of 5 electrical stimuli were delivered to right-sided mediastinal nerves during the atrial refractory period. Unipolar electrograms were recorded from 191 right and left atrial epicardial sites under several conditions, i.e. (i) with intact nervous systems and following (ii) acute decentralization of the intrathoracic nervous system or administration of (iii) atropine, (iv) timolol, (v) hexamethonium. Concomitant right atrial endocardial mapping was performed in 7 of these dogs. Mediastinal nerve stimulation consistently initiated bradycardia followed by atrial tachyarrhythmias. In the initial tachyarrhythmia beats, early epicardial breakthroughs were identified in the right atrial free wall (28/50 episodes) or Bachmann bundle region (22/50), which corresponded to endocardial sites of origin associated with the right atrial subsidiary pacemaker complex, i.e. the crista terminalis and dorsal locations including the right atrial aspect of the interatrial septum. Neuronally induced responses were eliminated by atropine, modified by timolol and unaffected by acute neuronal decentralization. After hexamethonium, responses to extra-pericardial but not intra-pericardial nerve stimulation were eliminated. It is concluded that concomitant activation of cholinergic and adrenergic efferent intrinsic cardiac neurons induced by right-sided efferent neuronal stimulation initiates atrial tachyarrhythmias that originate from foci anatomically related to the right atrial pacemaker complex and tissues underlying major atrial ganglionated plexuses.