Philippe Comtois

Ionic mechanisms limiting cardiac repolarization reserve in humans compared to dogs.

•u2002 Cardiac repolarization, through which heart‐cells return to their resting state after having fired, is a delicate process, susceptible to disruption by common drugs and clinical conditions. •u2002 Animal models, particularly the dog, are often used to study repolarization properties and responses to drugs, with the assumption that such findings are relevant to humans. However, little is known about the applicability of findings in animals to man. •u2002 Here, we studied the contribution of various ion‐currents to cardiac repolarization in canine and human ventricle. •u2002 Humans showed much greater repolarization‐impairing effects of drugs blocking the rapid delayed‐rectifier current IKr than dogs, because of lower repolarization‐reserve contributions from two other important repolarizing currents (the inward‐rectifier IK1 and slow delayed‐rectifier IKs). •u2002 Our findings clarify differences in cardiac repolarization‐processes among species, highlighting the importance of caution when extrapolating results from animal models to man.

Fibroblast electrical remodeling in heart failure and potential effects on atrial fibrillation.

Fibroblasts are activated in heart failure (HF) and produce fibrosis, which plays a role in maintaining atrial fibrillation (AF). The effect of HF on fibroblast ion currents and its potential role in AF are unknown. Here, we used a patch-clamp technique to investigate the effects of HF on atrial fibroblast ion currents, and mathematical computation to assess the potential impact of this remodeling on atrial electrophysiology and arrhythmogenesis. Atrial fibroblasts were isolated from control and tachypacing-induced HF dogs. Tetraethylammonium-sensitive voltage-gated fibroblast current (IKv,fb) was significantly downregulated (by ?44%), whereas the Ba(2+)-sensitive inward rectifier current (IKir,fb) was upregulated by 79%, in HF animals versus controls. The fibroblast resting membrane potential was hyperpolarized (?53 ± 2 mV vs. ?42 ± 2 mV in controls) and the capacitance was increased (29.7 ± 2.2 pF vs. 17.8 ± 1.4 pF in controls) in HF. These experimental findings were implemented in a mathematical model that included cardiomyocyte-fibroblast electrical coupling. IKir,fb upregulation had a profibrillatory effect through shortening of the action potential duration and hyperpolarization of the cardiomyocyte resting membrane potential. IKv,fb downregulation had the opposite electrophysiological effects and was antifibrillatory. Simulated pharmacological blockade of IKv,fb successfully terminated reentry under otherwise profibrillatory conditions. We conclude that HF induces fibroblast ion-current remodeling with IKv,fb downregulation and IKir,fb upregulation, and that, assuming cardiomyocyte-fibroblast electrical coupling, this remodeling has a potentially important effect on atrial electrophysiology and arrhythmogenesis, with the overall response depending on the balance of pro- and antifibrillatory contributions. These findings suggest that fibroblast K(+)-current remodeling is a novel component of AF-related remodeling that might contribute to arrhythmia dynamics.

In Silico Optimization of Atrial Fibrillation-Selective Sodium Channel Blocker Pharmacodynamics

Atrial fibrillation (AF) is the most common type of clinical arrhythmia. Currently available anti-AF drugs are limited by only moderate efficacy and an unfavorable safety profile. Thus, there is a recognized need for improved antiarrhythmic agents with actions that are selective for the fibrillating atrium. State-dependent Na(+)-channel blockade potentially allows for the development of drugs with maximal actions on fibrillating atrial tissue and minimal actions on ventricular tissue at resting heart rates. In this study, we applied a mathematical model of state-dependent Na(+)-channel blocking (class I antiarrhythmic drug) action, along with mathematical models of canine atrial and ventricular cardiomyocyte action potentials, AF, and ventricular proarrhythmia, to determine the relationship between their pharmacodynamic properties and atrial-selectivity, AF-selectivity (atrial Na(+)-channel block at AF rates versus ventricular block at resting rates), AF-termination effectiveness, and ventricular proarrhythmic properties. We found that drugs that target inactivated channels are AF-selective, whereas drugs that target activated channels are not. The most AF-selective drugs were associated with minimal ventricular proarrhythmic potential and terminated AF in 33% of simulations; slightly fewer AF-selective agents achieved termination rates of 100% with low ventricular proarrhythmic potential. Our results define properties associated with AF-selective actions of class-I antiarrhythmic drugs and support the idea that it may be possible to develop class I antiarrhythmic agents with optimized pharmacodynamic properties for AF treatment.

Atrial repolarization alternans as a path to atrial fibrillation.

Atrial fibrillation (AF) affects millions of people in the United States.1 Not only does AF have adverse effects on quality of life but it is also a major cause of stroke, a most serious complication.2 In addition, AF constitutes an important economic burden with the overall cost of recurrent AF estimated to be more than

Induced KCNQ1 autoimmunity accelerates cardiac repolarization in rabbits: Potential significance in arrhythmogenesis and antiarrhythmic therapy

6.5 billion per year.3 AF shows progressive evolution, starting with episodes terminating spontaneously, often then arriving more frequently with longer duration before becoming permanent in many patients. New episodes of AF require both a trigger that initiates the arrhythmia and a substrate that maintains it. The most common triggers of atrial fibrillation are ectopic atrial beats that arise from the pulmonary veins.4 Spatial heterogeneity of repolarization in conjunction with faster ectopic activity would favor conduction block,5 thereby increasing the vulnerability to reentry. Repolarization alternans is thought to play an important role in producing spatial heterogeneity of refractoriness and fibrillation in ventricles. A hundred years ago, Lewis proposed that alternans of the T-wave (TWA) in the ECG could be a precursor to ventricular arrhythmias.6 Studies showed high correlation between large amplitude TWA, ventricular fibrillation,7 and formation of discordant alternans.8 Recently, it has been proposed that repolarization alternans could also be important in AF initiation.

Spatiotemporal Stability of Neonatal Rat Cardiomyocyte Monolayers Spontaneous Activity Is Dependent on the Culture Substrate

BACKGROUNDnAutoantibodies 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.nnnOBJECTIVEnThe purpose of this study was to investigate the cardiac electrophysiologic effects of KCNQ1 autoantibody production induced by vaccination in a rabbit model.nnnMETHODSnRabbits 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.nnnRESULTSnKCNQ1-immunized rabbits exhibited shortening of QTc compared to sham-immunized controls. Reduced ventricular effective refractory periods and increased susceptibility to ventricular tachyarrhythmia induction were noted in KCNQ1-immunized rabbits upon programmed ventricular stimulation. Action potential durations were shortened in cardiomyocytes isolated from KCNQ1-immunized rabbits compared to the sham group. IKs step and tail current densities were enhanced after KCNQ1 immunization. Functional and structural changes of the heart were not observed. The potential therapeutic significance of KCNQ1 immunization was then explored in a dofetilide-induced long QT rabbit model. KCNQ1 immunization prevented dofetilide-induced QTc prolongation and attenuated long QT-related arrhythmias.nnnCONCLUSIONnInduction of KCNQ1 autoimmunity accelerates cardiac repolarization and increases susceptibility to ventricular tachyarrhythmia induction through IKs enhancement. On the other hand, vaccination against KCNQ1 ameliorates drug-induced QTc prolongation and might be useful therapeutically to enhance repolarization reserve in long QT syndrome.

Multicellular automaticity of cardiac cell monolayers: effects of density and spatial distribution of pacemaker cells

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.

Rate-Dependent Role of IKur in Human Atrial Repolarization and Atrial Fibrillation Maintenance

Self-organization of pacemaker (PM) activity of interconnected elements is important to the general theory of reaction–diffusion systems as well as for applications such as PM activity in cardiac tissue to initiate beating of the heart. Monolayer cultures of neonatal rat ventricular myocytes (NRVMs) are often used as experimental models in studies on cardiac electrophysiology. These monolayers exhibit automaticity (spontaneous activation) of their electrical activity. At low plated density, cells usually show a heterogeneous population consisting of PM and quiescent excitable cells (QECs). It is therefore highly probable that monolayers of NRVMs consist of a heterogeneous network of the two cell types. However, the effects of density and spatial distribution of the PM cells on spontaneous activity of monolayers remain unknown. Thus, a simple stochastic pattern formation algorithm was implemented to distribute PM and QECs in a binary-like 2D network. A FitzHugh–Nagumo excitable medium was used to simulate electrical spontaneous and propagating activity. Simulations showed a clear nonlinear dependency of spontaneous activity (occurrence and amplitude of spontaneous period) on the spatial patterns of PM cells. In most simulations, the first initiation

Wavelet analysis of cardiac optical mapping data

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 time at voltages associated with inactivation. Thus, channel dynamics are determined principally by activation kinetics. IKur magnitude decreases at higher rates because of AP changes that reduce IKur activation. Nevertheless, the relative contribution of IKur to AP repolarization increases at higher frequencies because of reduced activation of the rapid delayed-rectifier current IKr. Consequently, IKur block produces dose-dependent termination of simulated atrial fibrillation (AF) in the absence of AF-induced electrical remodeling. The inclusion of AF-related ionic remodeling stabilizes simulated AF and greatly reduces the predicted antiarrhythmic efficacy of IKur block. Our results explain a range of experimental observations, including recently reported positive rate-dependent IKur-blocking effects on human atrial APs, and provide insights relevant to the potential value of IKur as an antiarrhythmic target for the treatment of AF.

Multiscale modeling of cardiac electrical activity

BACKGROUNDnOptical 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.nnnMETHODSnWe 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 from canine right atrium. We compared the results obtained with the wavelet approach to a variety of other methods (Fast Fourier Transformation (FFT) with finite or infinite response filtering, and Gaussian filters).nnnRESULTSnTemporal wavelet analysis improved signal-to-noise ratio (SNR) better than FFT filtering for 5-10dB SNR, and caused less distortion of the action potential waveform over the full range of simulated noise (5-20dB). Spatial wavelet filtering produced more efficient denoising and/or more accurate conduction velocity estimates than Gaussian filtering. Propagation patterns were also best revealed by wavelet filtering.nnnCONCLUSIONSnWavelet analysis is a promising tool, facilitating accurate action potential characterization, activation map formation, and conduction velocity estimation.