Michel Vermeulen

Hôpital du Sacré-Coeur de Montréal, Montréal, Quebec, Canada

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Publications (32)110.57 Total impact

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    ABSTRACT: 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 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 16 s; SCS 5 weeks: median of 7 s). Phasic and accommodating right atrial neuronal somata displayed similar passive and active membrane properties in vitro, whether derived from sham or either chronic SCS groups. 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.
    Autonomic Neuroscience 09/2014; 186. DOI:10.1016/j.autneu.2014.09.017 · 1.56 Impact Factor
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    ABSTRACT: 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. 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. Activation of individual dorsal mediastinal nerves induces AT arising from distinct sites of origin which are spatially concordant with regional atrial repolarization changes.
    Circulation Arrhythmia and Electrophysiology 10/2010; 3(5):511-20. DOI:10.1161/CIRCEP.110.938050 · 4.51 Impact Factor
  • Jeffrey L Ardell · René Cardinal · Michel Vermeulen · J Andrew Armour ·
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    ABSTRACT: 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.
    AJP Regulatory Integrative and Comparative Physiology 07/2009; 297(2):R470-7. DOI:10.1152/ajpregu.90821.2008 · 3.11 Impact Factor
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    ABSTRACT: 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.
    Autonomic neuroscience: basic & clinical 01/2009; 145(1-2):55-62. DOI:10.1016/j.autneu.2008.11.007 · 1.56 Impact Factor
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    ABSTRACT: 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.
    Pflügers Archiv - European Journal of Physiology 10/2007; 454(6):999-1009. DOI:10.1007/s00424-007-0266-7 · 4.10 Impact Factor
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    ABSTRACT: 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.
    Anadolu kardiyoloji dergisi: AKD = the Anatolian journal of cardiology 08/2007; 7 Suppl 1:34-6. · 0.93 Impact Factor
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    ABSTRACT: 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.
    AJP Regulatory Integrative and Comparative Physiology 12/2006; 291(5):R1369-75. DOI:10.1152/ajpregu.00056.2006 · 3.11 Impact Factor
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    ABSTRACT: 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.
    Autonomic Neuroscience 08/2006; 128(1-2):9-18. DOI:10.1016/j.autneu.2005.11.006 · 1.56 Impact Factor
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    ABSTRACT: 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.
    Autonomic Neuroscience 04/2005; 118(1-2):68-78. DOI:10.1016/j.autneu.2005.01.006 · 1.56 Impact Factor
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    ABSTRACT: 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. Unipolar electrograms were recorded from 191 sites in the LCx territory in open-chest, anesthetized animals during sinus rhythm and while pacing at 120-150 beats/min, with bouts of transient rapid pacing (TRP; 240/min). In CRP-AM and AM, ST segment elevation was identified at central sites and ST depression at peripheral sites, both increasing with TRP. In CRP-AM and CRP, the maximum negative slope of unipolar activation complexes was significantly depressed and activation-recovery intervals prolonged. Areas of inexcitability as well as irregular isocontour patterns displaying localized activation-recovery intervals shortening and gradients >20 ms between neighboring sites were identified in one-third of CRP-AM at slow rate, with increasing incidence and magnitude in response to TRP. In CRP-AM, programmed stimulation-induced marked conduction delay and block as well as polymorphic ventricular tachycardias, which stabilized into monomorphic tachycardias with the use of lidocaine or procainamide. Whole cell Na(+) current and channel protein expression were reduced in CRP-AM and CRP. Despite complete constrictor closure, small areas of necrosis were detected in a minority of CRP-AM. Long-term electrical alterations and their exacerbation by TRP contribute to arrhythmia formation in collateral-dependent myocardium subjected to chronic tachycardic stress.
    AJP Heart and Circulatory Physiology 05/2004; 286(4):H1496-506. DOI:10.1152/ajpheart.00679.2003 · 3.84 Impact Factor
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    ABSTRACT: 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. We investigated the effect of SCS on ST segment displacements induced in the collateral-dependent myocardium in response to two stressors: (i) transient bouts of rapid ventricular pacing (TRP: 240/min for 1 min) and (ii) angiotensin II administered to right atrial neurons via their coronary artery blood supply. ST segment responses to TRP consisted of ST segment elevation in central areas of the LCx territory and ST depression at more peripheral areas. Such responses were unchanged when TRP was applied under SCS. Shortening of repolarization intervals in the metabolically compromised myocardium in response to TRP was also unaffected by SCS. In contrast, ST segment responses to intracoronary angiotensin II, which consisted of increased ST elevation, were attenuated by SCS in 6/8 preparations. The modulator effects of SCS were greatest at sites at which the greatest responses to angiotensin II occurred in the absence of SCS. These data indicate that spinal cord stimulation may attenuate the deleterious effects that stressors exert on the myocardium with reduced coronary reserve, particularly stressors associated with chemical activation of the intrinsic cardiac nervous system.
    Autonomic Neuroscience 04/2004; 111(1):37-47. DOI:10.1016/j.autneu.2004.02.005 · 1.56 Impact Factor
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    ABSTRACT: To corroborate alterations in the functional responses to beta-adrenergic receptor (beta-AR) stimulation with changes in beta-AR signaling in failing cardiomyocytes, contractile and L-type Ca(2+) current responses to isoproterenol along with stimulated cAMP generation were compared among cardiomyocytes isolated from canines with tachycardia-induced heart failure or healthy hearts. The magnitude of shortening of failing cardiomyocytes was significantly depressed (by 22 +/- 4.4%) under basal conditions, and the maximal response to isoproterenol was significantly reduced (by 45 +/- 18%). Similar results were obtained when the responses in the rate of contraction and rate of relaxation to isoproterenol were considered. The L-type Ca(2+) current amplitude measured in failing cardiomyocytes under basal conditions was unchanged, but the responses to isoproterenol were significantly reduced compared with healthy cells. Isoproterenol-stimulated cAMP generation was similar in sarcolemmal membranes derived from the homogenates of failing (45 +/- 6.8) and healthy cardiomyocytes (52 +/- 8.5 pmol cAMP. mg protein(-1). min(-1)). However, stimulated cAMP generation was found to be significantly reduced when the membranes were derived from the homogenates of whole tissue (failing: 67 +/- 8.1 vs. healthy: 140 +/- 27.8 pmol cAMP. mg protein(-1). min(-1)). Total beta-AR density was not reduced in membranes derived from either whole tissue or isolated cardiomyocyte homogenates, but the beta(1)/beta(2) ratio was significantly reduced in the former (failing: 45/55 vs. healthy: 72/28) without being altered in the latter (failing: 72/28, healthy: 77/23). We thus conclude that, in tachycardia-induced heart failure, reduction in the functional responses of isolated cardiomyocytes to beta-AR stimulation may be attributed to alterations in the excitation-contraction machinery rather than to limitation of cAMP generation.
    AJP Regulatory Integrative and Comparative Physiology 03/2001; 280(2):R355-64. · 3.11 Impact Factor
  • François Lemarbre · Alain Vinet · Michel Vermeulen · René Cardinal ·
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    ABSTRACT: To show that cycle-length (CL) prolongation occurring at the onset of reentrant tachycardias may be associated with an increase in conduction time (CT), and to investigate the involvement of Na+ and Ca2+ channel activity, reentrant activity was induced by programmed stimulation in thin ventricular muscle slices with a central cryothermal lesion, as documented with 7 to 12 bipolar recordings. We studied the course of the CL measured in successive tachycardia beats, as well as the course of conduction times after abrupt transition from a pacing CL of 1,000 to 400 ms (pacing paradigm). The majority of the tachycardias displayed a dynamic behavior in which CL increased progressively, with an exponential rate constant of 37 +/- 35 beats (mean +/- SD), stabilizing at 325 +/- 67 ms after a total increase of 17 +/- 17 ms. In the pacing paradigm, CT was prolonged from 68 +/- 21 ms to 79 +/- 24 ms according to a biphasic course consisting of an abrupt increase in the first response to 400 ms, followed up by an exponential increase, stabilizing with a rate constant of 18 +/- 23 beats. Lidocaine 5 x 10(-5) mol/L induced an increase in steady-state CT, which was not further modified by adding verapamil 10(-5) mol/L. However, verapamil prolonged the rate constant of the exponential course by 60 +/- 40 beats. Thus, the onset dynamics of reentrant tachycardias share common features with the dynamic behavior of CT in the pacing paradigm, in which both Na+ channel activity and Ca2+-modulated cellular coupling appear to be involved.
    Journal of Electrocardiology 11/2000; 33(4):349-60. DOI:10.1054/jelc.2000.18107 · 1.36 Impact Factor
  • C.A. Nour · L.J. Leon · M. Vermeulen · R. Cardinal · F.A. Roberge ·
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    ABSTRACT: Sustained reentry was initiated in a thin sheet of normal canine myocardium (40×40×1 mm) using a cross-shock stimulation protocol. A line stimulus applied to one side of the preparation was followed, some 175 ms later, by a field stimulus in the orthogonal direction. Mapping was carried out using a 121-unipolar electrode array and the intrinsic deflection at each site was used to plot activation isochrones. A given cycle of reentry was illustrated as a set of curved isochrones circling around an area of quasi-silent myocardium characterized by very low potentials and the absence of clear intrinsic deflections. A similar behavior was observed in a model study based on a sheet of cardiac fibers. The model results suggest that reentry occurs around a zone of unidirectional conduction block which is circumscribed, at each turn, by the displacement of the tip (extremity) of the isochrones across the sheet surface
    Engineering in Medicine and Biology Society, 1995., IEEE 17th Annual Conference; 10/1995
  • F Hélie · J Cossette · M Vermeulen · R Cardinal ·
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    ABSTRACT: Anisotropic conduction characteristics, which may be expressed as the ratio of conduction velocities in the longitudinal (Vlong) and transverse (Vtrans) fibre directions, have been shown to stabilise reentry and favour the induction of sustained, uniform ventricular tachycardia. The aim of this study was to investigate whether interventions affecting either excitability (lignocaine) or both excitability and cell coupling (hypercalcaemia) might produce differential effects on the Vlong/Vtrans ratio, and whether an intervention reducing this ratio might prevent the induction of sustained reentrant ventricular tachycardia. The effects of hypercalcaemia [8.2(SD 3.8) mmol.litre-1] and lignocaine infusion [to 24.4(19) and 42.3(29) mumol.litre-1] on Vlong and Vtrans were determined from 127 electrograms recorded with a plaque electrode on the anterior left ventricular wall of healthy dogs or 3 d after occlusion of the left anterior descending coronary artery. Vlong and Vtrans were computed from isochronal maps displaying ellipsoid patterns with a long axis corresponding to longitudinal conduction and a short axis corresponding to transverse conduction, as determined during basic (S1) and premature (S2) stimulation from the centre of the plaque electrode. Infarcted heart preparations were subjected to programmed stimulation for induction of reentrant ventricular tachycardias. Hypercalcaemia reduced both Vlong and Vtrans (P < 0.05) but did not modify either the Vlong/Vtrans ratio or the induction and patterns of ventricular tachycardias. Lignocaine reduced Vlong and the Vlong/Vtrans ratio during premature stimulation (S2) of infarcted heart preparations (P < 0.05) and stabilised reentrant ventricular tachycardias in preparations in which only nonsustained, multiform ventricular tachycardias were induced under control conditions. Conduction velocities in the longitudinal and transverse directions can be differentially affected by selected pharmacological interventions, but the Vlong/Vtrans ratio is not a representative index of the facilitating influence of tissue anisotropy on reentry. Therefore, the role of anisotropy in this model of reentry is not confined to establishing disparity of a functional character between conduction velocities in the longitudinal and transverse directions.
    Cardiovascular Research 04/1995; 29(3):359-72. DOI:10.1016/S0008-6363(96)88593-2 · 5.94 Impact Factor
  • C Ribuot · R Cardinal · L Gouin · P Moreau · D Godin · M Vermeulen · J de Champlain · L Rochette · R Nadeau ·
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    ABSTRACT: The aims were: (1) to study the acute effects of captopril on the action potential characteristics of ventricular fibres from the normal rat, (2) to compare the effects of captopril with those of perindoprilat, a non-thiol angiotensin I converting enzyme (ACE) inhibitor, (3) to determine the electrophysiological properties of the peptide substrates of converting enzyme, bradykinin and angiotensin I, and (4) to investigate whether the effects of captopril occurring in the healthy heart also occur in two models of ventricular hypertrophy. Action potentials were recorded with the standard glass microelectrode technique in right ventricular preparations excised from rat hearts and superfused under baseline conditions and with drug containing or peptide containing Tyrode solution. Ventricular hypertrophy was induced in response to hypertension (unilaterally nephrectomised, DOCA-salt model) or 4 week old left ventricular infarction. In preparations from normal rat hearts, captopril increased action potential duration in a concentration dependent fashion [EC50 = 3.5 x 10(-8) M; maximum effect = 44(SEM 5.1)% prolongation at 10(-5) M for action potential duration at 90% repolarisation, APD90]. Perindoprilat similarly caused a dose dependent increase in action potential duration, but with 100 times greater potency [EC50 = 3.1 x 10(-10) M; maximum effect = 71(11)% prolongation at 10(-5) M for APD90]. SQ 14,534, a stereoisomer of captopril with one hundredth the ACE inhibitor potency, had no significant effect on action potential duration at 10(-5) M. Angiotensin I and bradykinin caused concentration dependent prolongation of action potential, but angiotensin II (10(-6) M) had no effect. Captopril (10(-5) M) had no significant effect in the hypertrophied right ventricle from DOCA-salt hypertensive rats, but significantly increased APD90 [39(4.9)%] in right ventricular preparations from rats with 4 week old anterior left ventricular infarction. In the rat, captopril prolongs action potential duration, an effect possibly due to local accumulation of bradykinin and angiotensin I.
    Cardiovascular Research 03/1994; 28(2):221-7. DOI:10.1093/cvr/28.2.221 · 5.94 Impact Factor
  • Rene Cardinal · Benjamin J. Scherlag · Michel Vermeulen · J. Andrew Armour ·
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    ABSTRACT: To investigate mechanisms of ventricular impulse formation in response to sympathetic stimulation in the healthy canine heart in situ, we compared the patterns of ventricular activation during the idioventricular rhythms arising after complete atrioventricular (AV) block and ventricular tachycardias induced by RSG or LSG stimulation. Isochronal maps were generated by computer from 116-127 unipolar electrograms recorded from the entire ventricular epicardium in 15 open chest, anesthetized dogs. In eight of these, bipolar electrograms were recorded with plunge electrodes from 11 selected endocardial sites located below epicardial breakthrough areas. Intracardiac recordings from the His-Purkinje system were made with electrode catheters. After electrograms were recorded during sinus rhythm, complete AV block was induced by injecting formaldehyde into the AV node and idioventricular rhythms occurred spontaneously at a rate of 37 +/- 12 beats/min (mean +/- SD, n = 25). During idioventricular rhythms, endocardial activation preceded the earliest epicardial breakthrough, which occurred in either the right anterior paraseptal region, antero-apical left ventricle, or postero-apical left ventricle. These sites were consistent with a focal origin in the subendocardial His-Purkinje system. Total epicardial activation times lasted for 47 +/- 13 msec (n = 40). Idioventricular rhythms were suppressed by overdrive pacing (intermittent trains of ten beats with decremental cycle length from 500 to 200 msec) or by intravenous calcium infusion (to plasma levels of 10.1-15.2 mM). Right or left stellate ganglion stimulation increased idioventricular rhythm rates (to 52 +/- 13 beats/min, n = 28) and also induced, in all preparations, ventricular tachycardias that had significantly faster rates (189 +/- 55 beats/min, n = 27, P less than 0.005). Ventricular fibrillation was induced after brief runs of ventricular tachycardia in five of the preparations. During ventricular tachycardias, epicardial activation occurred on the right ventricular outflow tract or the postero-lateral wall of the left ventricle, and preceded endocardial activation in 50% of cases. Total epicardial activation times (103 +/- 29 beats/min) were significantly longer than during idioventricular rhythms (P less than 0.005). Ventricular tachycardias displayed overdrive excitation at critical pacing cycle lengths (360-280 msec) and were not suppressed by calcium infusion. Thus, differential mechanisms of impulse formation with distinct localizations can be elicited from healthy ventricular myocardium.
    Pacing and Clinical Electrophysiology 10/1992; 15(9):1300-16. DOI:10.1111/j.1540-8159.1992.tb03141.x · 1.13 Impact Factor
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    ABSTRACT: Left ventricular endocardial reentry is the conventional concept underlying surgery for ventricular tachycardia (VT). We assessed the incidences of patterns showing complete reentry circuits at either the subendocardial or subepicardial level and of patterns in which left ventricular endocardial mapping could only in part account for a reentrant mechanism. We retrospectively analyzed epicardial and left ventricular endocardial isochronal maps of 47 VTs induced in 28 patients with chronic myocardial infarction (inferior, 14 patients; anteroseptal, 14 patients). Electrograms were recorded intraoperatively from 128 sites with epicardial sock and transatrial left ventricular endocardial balloon electrode arrays. Given the methodology used in this study, the mapping characteristics of the tachycardias suggested five types of activation patterns: 1) complete (90% or more of VT cycle length) subendocardial reentry circuits in seven VTs (15%) and seven patients (25%), 2) complete subepicardial reentry circuits in four VTs (9%) and four patients (14%), 3) incompletely mapped circuits with a left ventricular endocardial breakthrough preceding the epicardial breakthrough in 25 VTs (53%) and 21 patients (75%), 4) incompletely mapped circuits with a left ventricular epicardial breakthrough preceding the endocardial breakthrough in three VTs (6%) and three patients (11%), and 5) a right ventricular epicardial breakthrough preceding the left ventricular endocardial breakthrough in eight VTs (17%) and seven patients (25%). After surgery, one type 3 VT and three type 5 VTs were reinducible. Thus, left ventricular endocardial reentry substrates (types 1 and 3) accounted for 68% of VTs, but substrates involving subepicardial (types 2 and 4) and deep septal layers (type 5) accounted for 32% of VTs. In a substantial number of VTs, a substrate localization that is at variance with the conventional concept can be detected by simultaneous epicardial and endocardial mapping and may require modification of the surgical approach conventionally aimed at endocardial layers.
    Circulation 10/1991; 84(3):1058-71. DOI:10.1161/01.CIR.84.3.1058 · 14.43 Impact Factor
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    ABSTRACT: The aim was to assess myocardial, electrophysiological, and adrenergic changes caused by chronic administration of doxorubicin. Doxorubicin induced cardiotoxicity was produced in three groups of rabbits by injecting doxorubicin 0.75 mg.kg-1 three times a week for 7, 9 and 11 weeks. There were 36 controls. All studies were conducted within 16 to 36 h after the last injection. Histological, mechanical, and action potential changes produced by doxorubicin were examined in vitro. The effects of doxorubicin on beta adrenergic receptors and cyclic adenosine monophosphate (AMP) generation in myocardial membrane preparations were also evaluated. 145 New Zealand white rabbits, 2.4-2.7 kg, were used. After excision of the heart, a papillary muscle was used for mechanical studies, a portion of the septum for intracellular action potential studies, and the rest of the heart for histological or biochemical studies. Histological studies showed widespread myocardial damage that became more severe as the cumulative doses increased. Right ventricular papillary muscles of doxorubicin treated rabbits had lower total tension (1.5 v 3.3 g.mm-2 for controls, p less than 0.05) and dT/dt, shorter contraction duration, and lower velocity of shortening than the control muscles under all loading conditions. The changes progressed as the cumulative doxorubicin dose increased. Action potential duration was shorter in the doxorubicin treated groups (APD50 = 76 v 62 ms for controls, p less than 0.01), although resting action potential amplitude was normal. Tension-frequency response (6-36 stimuli.min-1) and response to increasing calcium concentrations (2.54-6.32 mM) were attenuated in the doxorubicin group. Percent change in tension and dT/dt in response to noradrenaline (50 microM), isoprenaline (20 microM), or dibutyryl cyclic AMP (40 mM), was increased in the doxorubicin group v controls (300-600% v 100-200% respectively), despite chronic increase in circulating catecholamines, depletion of myocardial catecholamines, and no change in beta adrenergic receptor number or affinity. The apparent increase in beta adrenergic responsiveness in the doxorubicin group may have been partly due to decreased basal cyclic AMP production (13 v 31 pMol.mg-1 protein.min-1, p less than 0.01), although maximum catecholamine stimulated cyclic AMP production was only mildly decreased (251 v 315 pMol.mg-1 protein.min-1, p less than 0.05). CONCLUSIONS - The subacute effects of chronic doxorubicin become progressively more marked as the cumulative dose increases, and there are significant differences in the myocardial characteristics between this chronic model and other models of heart failure. These differences may be related to the cytotoxic effects of doxorubicin on membranes and membrane bound enzymes.
    Cardiovascular Research 08/1990; 24(7):591-604. · 5.94 Impact Factor

  • Cardiovascular Research 07/1990; 24(7):591-604. DOI:10.1093/cvr/24.7.591 · 5.94 Impact Factor

Publication Stats

460 Citations
110.57 Total Impact Points


  • 1987-2014
    • Hôpital du Sacré-Coeur de Montréal
      Montréal, Quebec, Canada
  • 1988-2010
    • Université de Montréal
      • • Department of Pharmacology
      • • Institute of Biomedical Engineering
      Montréal, Quebec, Canada
  • 2000
    • Université du Québec à Montréal
      Montréal, Quebec, Canada