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).

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

Spinal cord activation differentially modulates ischaemic electrical responses to different stressors in canine ventricles.

Spinal cord stimulation (SCS) represents an acceptable treatment modality for patients with chronic angina pectoris refractory to standard therapy, but its mechanism of action remains unclear. To develop an experimental paradigm to study this issue, ameroid (AM) constrictors were implanted around the left circumflex coronary artery (LCx) in canines. Six weeks later, unipolar electrograms were recorded from 191 sites in the LCx territory in the open-chest, anesthetized state under basal pacing at 150 beats/min.

Post-ischemic cardioprotection by A2A adenosine receptors: dependent of phosphatidylinositol 3-kinase pathway.

Activation of myocardial A2A adenosine receptors during reperfusion has been shown to be cardioprotective. The intracellular mechanisms underlying this protection remain unknown. To understand the beneficial effects of activated A2A adenosine receptors in such a state, we investigated whether the enzymes phosphatidylinositol 3-kinase (PI3K) and caspase-3 can account for this post-ischemic cardioprotective effect in an anesthetized rabbit model of myocardial infarction (30 minutes ischemia; 5 hours reperfusion).

Myocardial electrical alteration in canine preparations with combined chronic rapid pacing and progressive coronary artery occlusion.

Our objective was to create an animal preparation displaying long-term electrical alterations after chronic regional energetic stress without myocardial scarring. An Ameroid (AM) constrictor was implanted around the left circumflex coronary artery (LCx) 2 wk before chronic rapid ventricular pacing (CRP) was initiated at 240 beats/min for 4 wk (CRP-AM). Comparisons were made with healthy canines and canines with either AM or CRP.

Intrinsic cardiac nervous system in tachycardia induced heart failure.

The purpose of this study was to test the hypothesis that early-stage heart failure differentially affects the intrinsic cardiac nervous system's capacity to regulate cardiac function. After 2 wk of rapid ventricular pacing in nine anesthetized canines, cardiac and right atrial neuronal function were evaluated in situ in response to enhanced cardiac sensory inputs, stimulation of extracardiac autonomic efferent neuronal inputs, and close coronary arterial administration of neurochemicals that included nicotine. Right atrial neuronal intracellular electrophysiological properties were then evaluated in vitro in response to synaptic activation and nicotine.

Spatiotemporal dynamics of reentrant ventricular tachycardias in canine myocardial infarction: pharmacological modulation.

During the transition from a slow to rapid depolarization rhythm, rate-dependent sodium channel blockade develops progressively and increases from beat to beat under procainamide but more abruptly under lidocaine. We investigated the consequences of such differences on the dynamic course and stability of reentrant tachycardias at their onset. Procainamide and lidocaine were infused to equipotent plasma concentrations in canines with three-day-old myocardial infarction.