Philippe Comtois
University of Montreal, BIOMEDICAL ENGINEERING, Faculty Member
- Our laboratory is interested in combining mathematical modeling and bio-instrumentation to study cardiac dynamics and electrophysiology.edit
<p>(<b>a</b>-<b>d</b>) For each group, and for [n>0], focal position of the last activation is plotted. Central foci are inside the red square, whose side is 50% of the monolayer side. The border foci in... more
<p>(<b>a</b>-<b>d</b>) For each group, and for [n>0], focal position of the last activation is plotted. Central foci are inside the red square, whose side is 50% of the monolayer side. The border foci in the longitudinal x-direction are the foci located outside the red box, exclusively to the left and to the right. The border foci in the transverse y-direction are exclusively at the top and the bottom. Non-exclusive border foci at the corners, i.e. foci that are common to longitudinal and transverse direction are in the blue areas and are not considered in the calculation of border foci anisotropy ratio (r) in Eq (<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005978#pcbi.1005978.e026" target="_blank">12</a>). (<b>e</b>,<b>f</b>) Proportions of central focals for [n = 8] and [0</p
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The endothelial dysfunction associated with arterial hypertension is characterized by a Ca2+ dyshomeostasis resulting in an alteration of the delicate balance between reactive oxygen species (ROS) and nitric oxide (NO). However, the... more
The endothelial dysfunction associated with arterial hypertension is characterized by a Ca2+ dyshomeostasis resulting in an alteration of the delicate balance between reactive oxygen species (ROS) and nitric oxide (NO). However, the underlying mechanisms remain controversial. It has been recently suggested that CaMKII, a Ca2+-calmodulin dependent kinase plays an important role in cardiovascular diseases such as diabetes-associated hypertension. Paradoxically, CaMKII also modulates eNOS expression and activity, and is thereby involved in the regulation of endothelial function. Indeed, acting as a Ca2+ sensor, CaMKII has the unique ability to integrate oscillatory Ca2+ signals into specific outcomes. We recently provided the first evidence that endothelial CaMKII is activated by a local Ca2+ signal, the Ca2+ pulsars, localized within myoendothelial projections (MEP), and results in an increased NO production. The characterization of this novel endothelial CaMKII signalling pathway in ...
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Background: Previous studies suggested that T-type Ca2+ -current (ICaT) blockers suppress disease-related cardiac remodeling, but all available ICaT-blockers have non-specific actions on other curr...
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Cell culture of cardiac tissue analog is becoming increasingly interesting for regenerative medicine (cell therapy and tissue engineering) and is widely used for high throughput cardiotoxicity. As a cost-effective approach to rapidly... more
Cell culture of cardiac tissue analog is becoming increasingly interesting for regenerative medicine (cell therapy and tissue engineering) and is widely used for high throughput cardiotoxicity. As a cost-effective approach to rapidly discard new compounds with high toxicity risks, cardiotoxicity evaluation is firstly done in vitro requiring cells/tissue with physiological/pathological characteristics (close to in vivo properties). Studying multicellular electrophysiological and contractile properties is needed to assess drug effects. Techniques favoring process automation which could help in simplifying screening drug candidates are thus of central importance. A lot of effort has been made to ameliorate in vitro models including several in vitro platforms for engineering neonatal rat cardiac tissues. However, most of the initial evaluation is done by studying the rate of activity. In this study, we present new approaches that use the videomicroscopy video of monolayer activity to st...
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Purkinje fibers (PFs) play a key role in cardiac conduction and arrhythmogenesis. Heart failure (HF) causes extensive electrical remodeling. HF-induced changes in atrial and ventricular ion channel subunit expression have been well... more
Purkinje fibers (PFs) play a key role in cardiac conduction and arrhythmogenesis. Heart failure (HF) causes extensive electrical remodeling. HF-induced changes in atrial and ventricular ion channel subunit expression have been well characterized, but little is known about HF-induced ion channel subunit remodeling and functional consequences in PFs. This study assessed ion channel subunit expression, action potential (AP) properties and conduction in cardiac PF false tendons from control and HF dogs. HF was induced by 2 wk ventricular tachypacing (240 bpm). Control and HF PFs were fast-frozen for ion channel subunit mRNA (RT-qPCR) and protein (Western Blot, immunohistochemistry) assessment. APs were studied with standard micro-electrodes. HF significantly downregulated mRNA expression of subunits involved in AP propagation (Nav1.5, by 56%**, **P<0.01; Cx40, by 66%**, Cx43, by 56%**), automaticity (HCN2, by 75%**; HCN4, by 78%**) and repolarization (Kv4.3, by 43%*, *P<0.05; minK...
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ABSTRACT
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Reentrant excitation, in which a wave of excitation reenters the territory it has previously excited, is an important mechanism of cardiac arrhy thmias. The focus of the present thesis is two-fold: 1to study the stability and diversit y... more
Reentrant excitation, in which a wave of excitation reenters the territory it has previously excited, is an important mechanism of cardiac arrhy thmias. The focus of the present thesis is two-fold: 1to study the stability and diversit y of anatomical reentry, from the 1-D loop model to the 2-D annulus model; and 2the clinic al necessity to terminate tue anatomical reentry that warrants an analysis of an annihilatio n protocol consisting of two electrical stimuli. The bifurcation analysis of a revised version of the integral-delay model representing the reentry in a l-D loop, including a spatial coupl ing in the calculation of the action potential duration (APD), is first presented. This couplin g is meant to reproduce the modulation of repolarisation by the diffusive current. Here the co upling is shown to modify the criterion for the stability of the period-1 solution, which is no longer uniquely related to the APD restitution curve, but depends also on the degree of c oupling betw...
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Fluctuations of the cardiac pacemaker cell membrane voltage can affect the regularity of the heartbeat. Understanding the effects of stochastic membrane variations on the period of spontaneous activity would help determine the stability... more
Fluctuations of the cardiac pacemaker cell membrane voltage can affect the regularity of the heartbeat. Understanding the effects of stochastic membrane variations on the period of spontaneous activity would help determine the stability and robustness of pacemaker cells. The specific dependency of these effects and the rate of spontaneous activity in presence of a bias parameter were studied in the Luo-Rudy model and a Fitzhugh-Nagumo type model. Important differences between models are found with interesting acceleration or deceleration effects and pauses of activity. These results highlight the need for further evaluation of more realistic ionic model.
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Autoantibodies directed against various cardiac receptors have been implicated in cardiomyopathy and heart rhythm disturbances. In a previous study among patients with dilated cardiomyopathy, autoantibodies targeting the cardiac... more
Autoantibodies directed against various cardiac receptors have been implicated in cardiomyopathy and heart rhythm disturbances. In a previous study among patients with dilated cardiomyopathy, autoantibodies targeting the cardiac voltage-gated KCNQ1 K(+) channel were associated with shortened corrected QT intervals (QTc). However, the electrophysiologic actions of KCNQ1 autoimmunity have not been assessed experimentally in a direct fashion. The purpose of this study was to investigate the cardiac electrophysiologic effects of KCNQ1 autoantibody production induced by vaccination in a rabbit model. Rabbits were immunized with KCNQ1 channel peptide. ECG recordings were obtained during a 1-month follow-up period. Rabbits then underwent in vivo electrophysiologic study, after which cardiomyocytes were isolated for analysis of slow delayed rectifier current (IKs) and action potential properties via patch-clamp. KCNQ1-immunized rabbits exhibited shortening of QTc compared to sham-immunized ...
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Research Interests: Cardiology, Nonparametric Statistics, MicroRNA, Medicine, Linear models, and 15 moreWestern blotting, Heart Failure, Internal Medicine, Animals, Male, Atrial Fibrillation, Fibrosis, microRNAs, Rats, Myocardial Infarction, Wistar Rats, Ventricular Remodeling, Random Allocation, real time polymerase chain reaction, and Collagen type I
Research Interests: Chemistry, Cardiovascular, Medicine, Electrocardiography, Internal Medicine, and 14 moreHemodynamics, Mice, Animals, Male, Heart rate, Myocardial Infarction, Myocardium, Time Factors, Ventricular Remodeling, Ejection Fraction, real time polymerase chain reaction, reverse transcriptase polymerase chain reaction, Ligation, and Cardiovascular medicine and haematology
ABSTRACT
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Research Interests: Endocrinology, Cardiology, Electrophysiology, Cardiovascular, Medicine, and 13 moreInternal Medicine, Mice, Animals, Male, Long QT syndrome, Cardiac Arrhythmias, Voltage-Gated Sodium Channels, Action Potentials, Patch Clamp, sodium channels, Ranolazine, Cardiovascular medicine and haematology, and Heart atria
24 times a year (twice monthly) by the American Physiological Society, 9650 Rockville Pike, Bethesda MD systems with techniques linking genes and pathways to physiology, from prokaryotes to eukaryotes. It is published publishes results of... more
24 times a year (twice monthly) by the American Physiological Society, 9650 Rockville Pike, Bethesda MD systems with techniques linking genes and pathways to physiology, from prokaryotes to eukaryotes. It is published publishes results of a wide variety of studies from human and from informative model Physiological Genomics
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Self-organization of spontaneous activity of a network of active elements is important to the general theory of reaction-diffusion systems as well as for pacemaking activity to initiate beating of the heart. Monolayer cultures of neonatal... more
Self-organization of spontaneous activity of a network of active elements is important to the general theory of reaction-diffusion systems as well as for pacemaking activity to initiate beating of the heart. Monolayer cultures of neonatal rat ventricular myocytes, consisting of resting and pacemaker cells, exhibit spontaneous activation of their electrical activity. Similarly, one proposed approach to the development of biopacemakers as an alternative to electronic pacemakers for cardiac therapy is based on heterogeneous cardiac cells with resting and spontaneously beating phenotypes. However, the combined effect of pacemaker characteristics, density, and spatial distribution of the pacemaker cells on spontaneous activity is unknown. Using a simple stochastic pattern formation algorithm, we previously showed a clear nonlinear dependency of spontaneous activity (occurrence and amplitude of spontaneous period) on the spatial patterns of pacemaker cells. In this study, we show that this behavior is dependent on the pacemaker cell characteristics, with weaker pacemaker cells requiring higher density and larger clusters to sustain multicellular activity. These multicellular structures also demonstrated an increased sensitivity to voltage noise that favored spontaneous activity at lower density while increasing temporal variation in the period of activity. This information will help researchers overcome the current limitations of biopacemakers.
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The atrial-specific ultrarapid delayed rectifier K(+) current (IKur) inactivates slowly but completely at depolarized voltages. The consequences for IKur rate-dependence have not been analyzed in detail and currently available... more
The atrial-specific ultrarapid delayed rectifier K(+) current (IKur) inactivates slowly but completely at depolarized voltages. The consequences for IKur rate-dependence have not been analyzed in detail and currently available mathematical action-potential (AP) models do not take into account experimentally observed IKur inactivation dynamics. Here, we developed an updated formulation of IKur inactivation that accurately reproduces time-, voltage-, and frequency-dependent inactivation. We then modified the human atrial cardiomyocyte Courtemanche AP model to incorporate realistic IKur inactivation properties. Despite markedly different inactivation dynamics, there was no difference in AP parameters across a wide range of stimulation frequencies between the original and updated models. Using the updated model, we showed that, under physiological stimulation conditions, IKur does not inactivate significantly even at high atrial rates because the transmembrane potential spends little ti...
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Angiotensin II-induced arterial hypertension (AngII-AH) is associated with an endothelial dysfunction characterized by a Ca2+ dyshomeostasis. Alteration of the delicate balance between reactive oxy...
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Résumé/Abstract L'électrocardiogramme (ECG) résulte de la propagation dans le torse des courants électriques générés par le tissu cardiaque. Le potentiel d'action produit par les cardiomyocytes, qui prélude à leur contraction,... more
Résumé/Abstract L'électrocardiogramme (ECG) résulte de la propagation dans le torse des courants électriques générés par le tissu cardiaque. Le potentiel d'action produit par les cardiomyocytes, qui prélude à leur contraction, est la source première de ces courants. L' ...
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Research Interests: Medicine and Circulation
Background: Vagal (VG) and atrial tachycardia remodeled (ATR) AF substrates share many features: reduced effective refractory period (ERP), increased ERP heterogeneity and some common molecular mechanisms (I KACh enhancement by... more
Background: Vagal (VG) and atrial tachycardia remodeled (ATR) AF substrates share many features: reduced effective refractory period (ERP), increased ERP heterogeneity and some common molecular mechanisms (I KACh enhancement by acetylcholine release in VG, constitutive I KACh enhancement in ATR). This study compared VG and ATR substrates at comparable ERP abbreviation. Methods: In each of 5 VG dogs, bilateral cervical VG stimulation parameters were adjusted (mean±SD: 3.6±1.7 V and 12.2±1.5 Hz; 0.2 ms) to produce the same mean ERP (at 4 RA and 4 LA sites) as a sex and weight matched ATR dog (RA paced 400 bpm × 7 days). Mean duration of burst pacing induced AF (DAF) and local dominant frequencies (DFs, analyzed by FFT at 240 bipolar electrodes, Fig A ) were determined. Results: Mean ERP was 79±13 ms in VG and 78±13 ms in ATR dogs. DAF was greater in VG than ATR dogs (1056±323 vs 289±510 s *P&lt;0.01; both significantly &gt; control, 43±61 s). Despite matched ERPs, there were significant differences in DF distribution (Fig B ): DF was faster (mean DF: 11.8±1.1 Hz VG vs 9.7±1.3 Hz ATR*) and DF variability greater (indicated by SD: 1.8±0.6 Hz VG vs 0.8±0.5 Hz ATR*) in VG dogs. AF drivers reflected by maximum DF zones were adjacent to autonomic ganglia (over RA in 4/5) for VG dogs; in ATR dogs driver zones were less clear and showed variable location. Conclusions: For a comparable atrial ERP, VG AF is faster and more persistent than AF with an ATR substrate. These results are consist with modeling work suggesting that VG-induced hyperpolarization is an important contributor to AF-maintaining rotor stabilization and acceleration, and indicate important differences between these superficially similar AF substrates.
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Background: Connexin alterations occur in various atrial fibrillation (AF) paradigms, but their functional significance remains unclear. No data are available regarding the effects of CHF on atrial connexin expression and phosphorylation.... more
Background: Connexin alterations occur in various atrial fibrillation (AF) paradigms, but their functional significance remains unclear. No data are available regarding the effects of CHF on atrial connexin expression and phosphorylation. We therefore analyzed connexin changes and their contribution to the AF substrate during the development and reversal ofCHF. Methods and Results: Dogs were allocated to three groups: CHF induced by 2-week ventricular tachypacing (CHF, n=15); CHF dogs allowed to recover for 4 weeks after 2-week tachypacing (REC, n=15) and non-paced shams (CTL, n=11). Left ventricular end-diastolic pressure increased with CHF (14.5±1.0*** vs.3.7±0.7, ***P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001 vs. CTL) and normalized upon CHF recovery (5.1±1.0^†††, ^††† P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001 vs. CHF). Real-time PCR and Western-blot analyses revealed connexin43 (Cx43) and connexin40 (Cx40) mRNA and protein expression to be unchanged by CHF and REC. However, CHF caused Cx43 dephosphorylation(by ~73%***) and increased Cx40/Cx43 protein ratio (by ~35%***), with both alterations completely reversing in REC. Immunofluorescent confocal microscopy confirmed connexin protein trends, with a reduction in phosphorylated Cx43 (by ~68%*** in CHF) that returned to control in REC. CHF caused conduction abnormalities (phasedelay-range and heterogeneity index, both P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01) and burst pacing-induced AF prolongation (CTL 22±7s, CHF 1100±171s***, REC 884±220s***) which persisted in the recovery period, along with residual fibrosis (CTL 3.6±0.7%, CHF 14.7±1.5%***, REC13.3±2.3%***). Fibrosis physically interrupted muscle bundle continuity and anionically-based action potential model of canine atrium showed that fibrosiswas able to account for the observed conduction abnormalities. Conclusions: CHF causes connexin-dephosphorylation and Cx40/Cx43ratio increases. With CHF reversal, atrial connexin alterations recover completely, but tissue fibrosis, conduction abnormalities and a substrate forAF remain with fibrosis accounting for conduction abnormalities. Thus, althougha trial connexin changes occur with CHF, they are not essential for conduction disturbances and AF promotion, which appear rather to be related primarily tofibrotic interruption of muscle-bundle continuity.
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Research Interests: Medicine and Circulation
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The biological pacemaker approach is an alternative to cardiac electronic pacemakers. Its main objective is to create pacemaking activity from added or modified distribution of spontaneous cells in the myocardium. This paper aims to... more
The biological pacemaker approach is an alternative to cardiac electronic pacemakers. Its main objective is to create pacemaking activity from added or modified distribution of spontaneous cells in the myocardium. This paper aims to assess how automaticity strength of pacemaker cells (i.e. their ability to maintain robust spontaneous activity with fast rate and to drive neighboring quiescent cells) and structural linear anisotropy, combined with density and spatial distribution of pacemaker cells, may affect the macroscopic behavior of the biological pacemaker. A stochastic algorithm was used to randomly distribute pacemaker cells, with various densities and spatial distributions, in a semi-continuous mathematical model. Simulations of the model showed that stronger automaticity allows onset of spontaneous activity for lower densities and more homogeneous spatial distributions, displayed more central foci, less variability in cycle lengths and synchronization of electrical activatio...
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Optical mapping technology is an important tool to study cardiac electrophysiology. Transmembrane fluorescence signals from voltage-dependent dyes need to be preprocessed before analysis to improve the signal-to-noise ratio. Fourier... more
Optical mapping technology is an important tool to study cardiac electrophysiology. Transmembrane fluorescence signals from voltage-dependent dyes need to be preprocessed before analysis to improve the signal-to-noise ratio. Fourier analysis, based on spectral properties of stationary signals, cannot directly provide information on the spectrum changes with respect to time. Fourier filtering has the disadvantage of causing degradation of abrupt waveform changes such as those in action potential signals. Wavelet analysis has the ability to offer simultaneous localization in time and frequency domains, suitable for the analysis and reconstruction of irregular, non-stationary signals like the fast action-potential upstroke, and better than conventional filters for denoising. We applied discrete wavelet transformation for temporal processing of optical mapping signals and wavelet packet analysis approaches to process activation maps from simulated and experimental optical mapping data f...
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In native conditions, cardiac cells must continuously comply with diverse stimuli necessitating a perpetual adaptation. Polydimethylsiloxane (PDMS) is commonly used in cell culture to study cellular response to changes in the mechanical... more
In native conditions, cardiac cells must continuously comply with diverse stimuli necessitating a perpetual adaptation. Polydimethylsiloxane (PDMS) is commonly used in cell culture to study cellular response to changes in the mechanical environment. The aim of this study was to evaluate the impact of using PDMS substrates on the properties of spontaneous activity of cardiomyocyte monolayer cultures. We compared PDMS to the gold standard normally used in culture: a glass substrate. Although mean frequency of spontaneous activity remained unaltered, incidence of reentrant activity was significantly higher in samples cultured on glass compared to PDMS substrates. Higher spatial and temporal instability of the spontaneous rate activation was found when cardiomyocytes were cultured on PDMS, and correlated with decreased connexin-43 and increased CaV3.1 and HCN2 mRNA levels. Compared to cultures on glass, cultures on PDMS were associated with the strongest response to isoproterenol and acetylcholine. These results reveal the importance of carefully selecting the culture substrate for studies involving mechanical stimulation, especially for tissue engineering or pharmacological high-throughput screening of cardiac tissue analog.
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Cardiac fibrosis is an important form of pathological tissue remodeling. Fibrosis can electrically-uncouple neighboring excitable cardiomyocytes thus acting as an obstacle to electrical propagation. In this study, we investigated the... more
Cardiac fibrosis is an important form of pathological tissue remodeling. Fibrosis can electrically-uncouple neighboring excitable cardiomyocytes thus acting as an obstacle to electrical propagation. In this study, we investigated the effects of fibrosis spatial pattern on electrical propagation in control, decreased maximum sodium conductance, and increased intracellular resistivity conditions. Simulations were performed with a monodomain approach and a realistic canine ionic model. We found that the propagation failure is highly dependent on the spatial pattern of fibrosis for all conditions studied with maximum sensitivity for patterns with combination of small and large clusters. However, the effect is particularly sensitive to reduced sodium current condition where conduction block occurred at lower fibrosis density.
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Obstructive sleep apnea (OSA) importantly contributes to the occurrence of atrial fibrillation (AF) in humans, but the mechanisms are poorly understood. Experimental research has provided insights into AF promotion by acute OSA episodes.... more
Obstructive sleep apnea (OSA) importantly contributes to the occurrence of atrial fibrillation (AF) in humans, but the mechanisms are poorly understood. Experimental research has provided insights into AF promotion by acute OSA episodes. However, patients with OSA usually have frequent nocturnal episodes for some time before manifesting AF. The goal of this study was to test the hypothesis that repetitive OSA causes cardiac remodeling that predisposes to AF. We mimicked OSA by using a mechanical ventilator and closing the airway at end-expiration with a 3-way stopcock (OSA rats). Matched control groups included rats with the ventilator stopped but airway left open (open airway rats) and continuously ventilated rats (sham rats). OSA rats were exposed to 20 consecutive 2-min cycles of 40 s of apnea/80 s of ventilation per day, 5 days per week for 4 weeks. OSA significantly increased the duration of AF from (median [interquartile range]) 2.6 s [1.9 s to 8.9 s] (shams) and 16 s [1.8 s t...
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The species-specific determinants of repolarization are poorly understood. This study compared the contribution of various currents to cardiac repolarization in canine and human ventricle. Conventional microelectrode, whole-cell... more
The species-specific determinants of repolarization are poorly understood. This study compared the contribution of various currents to cardiac repolarization in canine and human ventricle. Conventional microelectrode, whole-cell patch-clamp, molecular biological and mathematical modelling techniques were used. Selective IKr block (50-100 nmol l(-1) dofetilide) lengthened AP duration at 90% of repolarization (APD90) &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;3-fold more in human than dog, suggesting smaller repolarization reserve in humans. Selective IK1 block (10 μmol l(-1) BaCl2) and IKs block (1 μmol l(-1) HMR-1556) increased APD90 more in canine than human right ventricular papillary muscle. Ion current measurements in isolated cardiomyocytes showed that IK1 and IKs densities were 3- and 4.5-fold larger in dogs than humans, respectively. IKr density and kinetics were similar in human versus dog. ICa and Ito were respectively ~30% larger and ~29% smaller in human, and Na(+)-Ca(2+) exchange current was comparable. Cardiac mRNA levels for the main IK1 ion channel subunit Kir2.1 and the IKs accessory subunit minK were significantly lower, but mRNA expression of ERG and KvLQT1 (IKr and IKs α-subunits) were not significantly different, in human versus dog. Immunostaining suggested lower Kir2.1 and minK, and higher KvLQT1 protein expression in human versus canine cardiomyocytes. IK1 and IKs inhibition increased the APD-prolonging effect of IKr block more in dog (by 56% and 49%, respectively) than human (34 and 16%), indicating that both currents contribute to increased repolarization reserve in the dog. A mathematical model incorporating observed human-canine ion current differences confirmed the role of IK1 and IKs in repolarization reserve differences. Thus, humans show greater repolarization-delaying effects of IKr block than dogs, because of lower repolarization reserve contributions from IK1 and IKs, emphasizing species-specific determinants of repolarization and the limitations of animal models for human disease.