Home About us Contact
|
Home About us Contact | ||
|
|
||
Action Potential Duration (action + potential_duration)
Selected AbstractsEffect of Action Potential Duration and Conduction Velocity Restitution and Their Spatial Dispersion on Alternans and the Stability of ArrhythmiasJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 11 2002ISABELLE BANVILLE Ph.D. Restitution and Spatial Heterogeneities vs Arrhythmias.Introduction: The slope of the action potential duration (APD) restitution curve has been used to explain wavebreaks during arrhythmia initiation and maintenance. This hypothesis remains incomplete to fully describe the experimental data. Other factors contributing to wavebreaks must be studied to further understand arrhythmia dynamics. Methods and Results: Control APDs were measured from isolated rabbit hearts using a monophasic action potential probe. APD and conduction velocity (CV) restitution were quantified over the heart surface for two drugs, diacetyl monoxime (DAM) and cytochalasin D (CytoD), using a dual camera video imaging system. For all pacing intervals: (1) control APDs were shorter than for CytoD but longer than for DAM; and (2) CV was greater for CytoD compared with DAM. APD dispersion increased as pacing interval decreased for both drugs. For DAM, increased dispersion was due to a difference in APD restitution between the right and left ventricle. For CytoD, increased dispersion was due to discordant alternans, with no significant spatial variation in restitution. Fibrillation was sustained only in the control hearts; with DAM, stable reentry was sustained with shorter APD and cycle length compared with CytoD for which only nonsustained unstable reentry occurred. Conclusion: Alternans and arrhythmia dynamics are affected by the spatial dispersion of APD restitution as well as CV restitution, not simply the slope of APD restitution. Therefore, a direct link of the APD restitution slope to alternans and arrhythmia dynamics in rabbit heart does not exist. Designing antiarrhythmic drugs to alter only the restitution slope may not be appropriate. [source] Prolonged Atrial Action Potential Durations and Polymorphic Atrial Tachyarrhythmias in Patients with Long QT SyndromeJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 10 2003PAULUS KIRCHHOF M.D. Introduction: Prolongation of the QT interval and torsades de pointes tachycardias due to altered expression or function of repolarizing ion channels are the hallmark of congenital long QT syndrome (LQTS). The same ion channels also contribute to atrial repolarization, and familial atrial fibrillation may be associated with a mutated KVLQT1 gene. We therefore assessed atrial action potential characteristics and atrial arrhythmias in LQTS patients. Methods and Results: Monophasic action potentials (MAPs) were simultaneously recorded from the right atrial appendage and the inferolateral right atrium in 10 patients with LQTS (8 with identifiable genotype) and compared to 7 control patients. Atrial arrhythmias also were compared to MAPs recorded in patients with persistent (n = 10) and induced (n = 4) atrial fibrillation. Atrial action potential durations (APD) and effective refractory periods (ERP) were prolonged in LQTS patients at cycle lengths of 300 to 500 msec (APD prolongation 30,41 msec; ERP prolongation 26,52 msec; all P < 0.05). Short episodes of polymorphic atrial tachyarrhythmias (polyAT, duration 4,175 sec) occurred spontaneously or during pauses after pacing in 5 of 10 LQTS patients, but not in controls (P < 0.05). P waves showed undulating axis during polyAT. Cycle lengths of polyAT were longer than during persistent and induced atrial fibrillation. Afterdepolarizations preceded polyAT in 2 patients. The electrical restitution curve was shifted to longer APD in LQTS patients and to even longer APD in LQTS patients with polyAT. Conclusion: This group of LQTS patients has altered atrial electrophysiology: action potentials are prolonged, and polyAT occurs. PolyAT appears to be a specific arrhythmia of LQTS reminiscent of an atrial form of "torsades de pointes."(J Cardiovasc Electrophysiol, Vol. 14, pp ***-***, October 2003) [source] Lack of Effect of Conduction Direction on Action Potential Durations in Anisotropic Ventricular Strips of Pig HeartJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 4 2002GUILLERMO BERTRAN B.Sc. Anisotropy and Repolarization.Introduction: The influence of activation sequence on the rate of rise of the depolarization phase of action potentials in atrial or ventricular muscles has been well established. However, whether myocardial fiber orientation is important in modulating the repolarization process is unclear. Methods and Results: We examined the influence of activation sequence on the repolarization phase of action potentials in epicardial tissues from the right and left ventricles of domestic pigs. Whereas cells from the right ventricle exhibited direction-dependent differences in action potential duration at 30%, 50%, and 90% of full repolarization (190.6 ± 31.1 msec vs 181.8 ± 32.8 msec, 240.3 ± 23.5 msec vs 236.7 ± 25.4 msec, and 291.3 ± 23.7 msec vs 287.4 ± 25.1 msec for longitudinal and transverse propagation, respectively; P < 0.001), a similar duration of repolarization during both directions of propagation was observed in cells from the left ventricle at 50% and 90% of full repolarization (241.4 ± 39.4 msec and 285.5 ± 39.5 msec vs 240.4 ± 38.9 msec and 284.9 ± 39.6 msec for longitudinal and transverse propagation respectively; P = NS). A slight but significant difference was found at 30% of full repolarization in cells from the left ventricle (190.4 ± 39.0 msec vs 187.0 ± 38.0 msec for longitudinal and transverse propagation, respectively; P < 0.05). In the left ventricle, the duration of repolarization did not change as the distance between the recording site and stimulation site increased. Conclusion: The direction of wavefront propagation with respect to fiber orientation may not play an important role in modulating the duration of repolarization in epicardial cells from the left ventricle. [source] Altered T Wave Dynamics in a Contracting Cardiac ModelJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 2003NICOLAS P. SMITH Ph.D. Introduction: The implications of mechanical deformation on calculated body surface potentials are investigated using a coupled biophysically based model. Methods and Results: A cellular model of cardiac excitation-contraction is embedded in an anatomically accurate two-dimensional transverse cross-section of the cardiac ventricles and human torso. Waves of activation and contraction are induced by the application of physiologically realistic boundary conditions and solving the bidomain and finite deformation equations. Body surface potentials are calculated from these activation profiles by solving Laplace's equation in the passive surrounding tissues. The effect of cardiac deformation on electrical activity, induced by contraction, is demonstrated in both single-cell and tissue models. Action potential duration is reduced by 7 msec when the single cell model is subjected to a 10% contraction ramp applied over 400 msec. In the coupled electromechanical tissue model, the T wave of the ECG is shown to occur 18 msec earlier compared to an uncoupled excitation model. To assess the relative effects of myocardial deformation on the ECG, the activation sequence and tissue deformation are separated. The coupled and uncoupled activation sequences are mapped onto the undeforming and deforming meshes, respectively. ECGs are calculated for both mappings. Conclusion: Adding mechanical contraction to a mathematical model of the heart has been shown to shift the T wave on the ECG to the left. Although deformation of the myocardium resulting from contraction reduces the T wave amplitude, cell stretch producing altered cell membrane kinetics is the major component of this temporal shift. (J Cardiovasc Electrophysiol, Vol. 14, pp. S203-S209, October 2003, Suppl.) [source] Changes in extracellular K+ concentration modulate contractility of rat and rabbit cardiac myocytes via the inward rectifier K+ current IK1THE JOURNAL OF PHYSIOLOGY, Issue 3 2004Ron Bouchard The mechanisms underlying the inotropic effect of reductions in [K+]o were studied using recordings of membrane potential, membrane current, cell shortening and [Ca2+]i in single, isolated cardiac myocytes. Three types of mammalian myocytes were chosen, based on differences in the current density and intrinsic voltage dependence of the inwardly rectifying background K+ current IK1 in each cell type. Rabbit ventricular myocytes had a relatively large IK1 with a prominent negative slope conductance whereas rabbit atrial cells expressed much smaller IK1, with little or no negative slope conductance. IK1 in rat ventricle was intermediate in both current density and slope conductance. Action potential duration is relatively short in both rabbit atrial and rat ventricular myocytes, and consequently both cell types spend much of the duty cycle at or near the resting membrane potential. Rapid increases or decreases of [K+]o elicited significantly different inotropic effects in rat and rabbit atrial and ventricular myocytes. Voltage-clamp and current-clamp experiments showed that the effects on cell shortening and [Ca2+]i following changes in [K+]o were primarily the result of the effects of alterations in IK1, which changed resting membrane potential and action potential waveform. This in turn differentially altered the balance of Ca2+ efflux via the sarcolemmal Na+,Ca2+ exchanger, Ca2+ influx via voltage-dependant Ca2+ channels and sarcoplasmic reticulum (SR) Ca2+ release in each cell type. These results support the hypothesis that the inotropic effect of alterations of [K+]o in the heart is due to significant non-linear changes in the current,voltage relation for IK1 and the resulting modulation of the resting membrane potential and action potential waveform. [source] Thyroid hormone receptor , can control action potential duration in mouse ventricular myocytes through the KCNE1 ion channel subunitACTA PHYSIOLOGICA, Issue 2 2010A. Mansén Abstract Aims:, The reduced heart rate and prolonged QTend duration in mice deficient in thyroid hormone receptor (TR) ,1 may involve aberrant expression of the K+ channel ,-subunit KCNQ1 and its regulatory ,-subunit KCNE1. Here we focus on KCNE1 and study whether increased KCNE1 expression can explain changes in cardiac function observed in TR,1-deficient mice. Methods:, TR-deficient, KCNE1-overexpressing and their respective wildtype (wt) mice were used. mRNA and protein expression were assessed with Northern and Western blot respectively. Telemetry was used to record electrocardiogram and temperature in freely moving mice. Patch-clamp was used to measure action potentials (APs) in isolated cardiomyocytes and ion currents in Chinese hamster ovary (CHO) cells. Results:, KCNE1 was four to 10-fold overexpressed in mice deficient in TR,1. Overexpression of KCNE1 with a heart-specific promoter in transgenic mice resulted in a cardiac phenotype similar to that in TR,1-deficient mice, including a lower heart rate and prolonged QTend time. Cardiomyocytes from KCNE1-overexpressing mice displayed increased AP duration. CHO cells transfected with expression plasmids for KCNQ1 and KCNE1 showed an outward rectifying current that was maximal at equimolar plasmids for KCNQ1-KCNE1 and decreased at higher KCNE1 levels. Conclusion:, The bradycardia and prolonged QTend time in hypothyroid states can be explained by altered K+ channel function due to decreased TR,1-dependent repression of KCNE1 expression. [source] Adenosine induces prolonged anti-,-adrenergic effects in guinea-pig papillary muscleACTA PHYSIOLOGICA, Issue 1 2002L. ARVOLA ABSTRACT A sustained anti- , -adrenergic effect of adenosine has been reported. This study was initiated to investigate this topic and especially elucidate the role of protein kinase C (PKC). Contractile force amplitude and action potential duration at 90% repolarization (APD90) were measured in guinea-pig papillary muscles before and after 5 min challenge with 5 nm isoproterenol. Protocols contained 30 min exposure to the test agents adenosine 33 ,m (ado), adenosine + PKC-inhibitor bisindolylmaleimide 20 nM (ado + BIM), PKC-activator 1,2-dioctanoyl-sn-glycerol 10 ,m (DOG) and , -agonist phenylephrine 5 ,m (phe). Isoproterenol was given at the end of test exposure and after 15 min washout. Results are mean ± SEM of percentage-change, P , 0.05 considered significant and labelled *. The first isoproterenol challenge significantly increased contractile force (27 ± 7%*) in the control group. Responses in the test groups were 2 ± 4 (ado), 1 ± 5 (ado + BIM), 14 ± 4* (DOG), 0 ± 2% (phe). After washout of adenosine, DOG and phenylephrine, isoproterenol induced 3 ± 8 (ado), 23 ± 5* (ado + BIM), 13 ± 5* (DOG), 15 ± 7% (phe) increase in test groups compared with 22 ± 5%* increase in contractile force in the control group. After 45 min washout of adenosine the inotropic response was still significantly reduced compared with control (29 ± 4 vs. 79 ± 8%*). Isoproterenol stimulation shortened APD90 in controls at both time points (5 ± 1%* and 4 ± 1%*), with no significant shortening in test groups. Adenosine induces sustained anti- , -adrenergic effects on contractile force as well as APD90. A role for PKC in signal transduction is supported with respect to contractile force. [source] Cardiac L-type calcium current is increased in a model of hyperaldosteronism in the ratEXPERIMENTAL PHYSIOLOGY, Issue 6 2009Beatriz Martin-Fernandez Accumulating evidence supports the importance of aldosterone as an independent risk factor in the pathophysiology of cardiovascular disease. It has been postulated that aldosterone could contribute to ventricular arrhythmogeneity by modulation of cardiac ionic channels. The aim of this study was to analyse ex vivo the electrophysiological characteristics of the L-type cardiac calcium current (ICaL) in a model of hyperaldosteronism in the rat. Aldosterone was administered for 3 weeks, and cardiac collagen deposition and haemodynamic parameters were analysed. In addition, RT-PCR and patch-clamp techniques were applied to study cardiac L-type Ca2+ channels in isolated cardiomyocytes. Administration of aldosterone induced maladaptive cardiac remodelling that was related to increased collagen deposition, diastolic dysfunction and cardiac hypertrophy. In addition, ventricular myocytes isolated from the aldosterone-treated group showed increased ICaL density and conductance and prolongation of the action potential duration. No changes in kinetics or in voltage dependence of activation and inactivation of ICaL were observed, but relative expression of CaV1.2 mRNA levels was higher in cardiomyocytes isolated from the aldosterone-treated group. The present study demonstrates that aldosterone treatment induces myocardial fibrosis, cardiac hypertrophy, increase of ICaL density, upregulation of L-type Ca2+ channels and prolongation of action potential duration. It could be proposed that aldosterone, through these mechanisms, might exert pro-arrhythmic effects in the pathological heart. [source] Chamber-specific effects of hypokalaemia on ventricular arrhythmogenicity in isolated, perfused guinea-pig heartEXPERIMENTAL PHYSIOLOGY, Issue 4 2009Oleg E. Osadchii Diuretic-induced hypokalaemia has been shown to promote cardiac arrhythmias in hypertensive patients. The present study was designed to determine whether hypokalaemia increases arrhythmic susceptibility of the left ventricle (LV) or the right ventricle (RV), or both. Proarrhythmic effects of hypokalaemic perfusion (2.5 mm K+ for 30 min) were assessed in isolated guinea-pig heart preparations using simultaneous recordings of volume-conducted electrocardiogram and monophasic action potentials from six ventricular epicardial sites. Effective refractory periods, ventricular fibrillation thresholds and inducibility of tachyarrhythmias by programmed electrical stimulation and tachypacing were determined at the LV and the RV epicardial stimulation sites. Hypokalaemia promoted spontaneous ventricular ectopic activity, an effect attributed to non-uniform prolongation of ventricular repolarization resulting in increased RV-to-LV transepicardial dispersion of refractoriness and action potential duration. Furthermore, hypokalaemic perfusion was associated with reduced ventricular fibrillation threshold and increased inducibility of tachyarrhythmias by programmed electrical stimulation and tachypacing as determined at the LV stimulation site. In contrast, the RV stimulation revealed no change in arrhythmic susceptibility of the RV chamber. Consistently, hypokalaemia reduced the LV effective refractory period but had no effect on the RV refractoriness. This change enabled generation of premature propagating responses by extrastimulus application at earlier time points during LV repolarization. Increased prematurity of extrastimulus-evoked propagating responses was associated with exaggerated local inhomogeneities in intraventricular conduction and action potential duration in hypokalaemic LV, thus creating a favourable stage for re-entrant tachyarrhythmias. Taken together, these findings suggest that proarrhythmic effects of hypokalaemia are mostly attributed to increased LV arrhythmogenicity in the guinea-pig heart. [source] Comparison of effects of acetylcholine on electromechanical characteristics in guinea-pig atrium and ventricleEXPERIMENTAL PHYSIOLOGY, Issue 1 2005W. J. Zang The direct negative effects of acetylcholine (ACh) on guinea-pig atria and ventricles were investigated using standard microelectrodes, a force transducer and a video edge-detection system. It was found that: (1) ACh (at 0.001,100 ,m) decreased the force of contraction and shortened the action potential duration (APD) in both atria and ventricles in a concentration-dependent manner, and that the atria were more sensitive to ACh than the ventricles; and (2) the direct negative inotropic effect of ACh (1 ,m) on an isolated cardiac cell was similar to that on the isolated myocardium. But this effect was not present in all isolated ventricular cells, while all the atrial cells responded to ACh. In conclusion, ACh had direct inhibitory effects on both atrial and ventricular tissue and myocytes, although the effects were greater in atria than in ventricles; and the negative inotropic effect of ACh was closely related to the shortening of the APD. [source] Phenotype and Function of Somatic Primary Afferent Nociceptive Neurones with C-, A,- or A,/,-FibresEXPERIMENTAL PHYSIOLOGY, Issue 2 2002S. N. Lawson Nociceptive dorsal root ganglion (DRG) neurones have fibres that conduct in the C, A, and A,/, conduction velocity range. The properties of nociceptive compared with non-nociceptive somatic afferent dorsal root ganglion neurones appear to fall into two patterns, A and B. Pattern A properties of nociceptive neurones, the more common type, include longer action potential duration and slower maximum rate of fibre firing, as well as a greater expression of substance P and calcitonin gene-related peptide immunoreactivity. The values of pattern A properties appear to be graded according to the conduction velocity group (C, A, or A,/,) of the fibres. The most pronounced forms of A-type properties are expressed by nociceptive neurones with C-fibres, and these become less pronounced in nociceptive neurones with A,-fibres and least pronounced in those with A,/, fibres (C > A, > A,/,). Some of these properties are also expressed in a less extreme but similarly graded manner through C, A, and A,/, groups of non-nociceptive low threshold mechanoreceptive (LTM) neurone. The less common pattern B properties of nociceptive neurones have similar values in C-, A,- and A,/,-fibre nociceptive neurones but these clearly differ from LTM units with C-, A,- and A,/,-fibre conduction velocities. These features of nociceptive neurones include consistently larger action potential overshoots and longer after-hyperpolarisation durations in nociceptive than in LTM neurones. [source] Role of Ca2+ -Activated Cl, Current in Ventricular Action Potentials of Sheep During Adrenoceptor StimulationEXPERIMENTAL PHYSIOLOGY, Issue 2 2001Arie O. Verkerk Adrenoceptor stimulation enhances repolarising and depolarising membrane currents to different extents in cardiac myocytes. We investigated the opposing effects of the repolarising Ca2+ -activated Cl, current (ICl(Ca)) and depolarising L-type Ca2+ current (ICa,L) on the action potential configuration of sheep ventricular myocytes stimulated with noradrenaline. Whole-cell current-clamp recordings revealed that noradrenaline accelerated and prolonged phase-1 repolarisation. We define the minimal potential at the end of phase-1 repolarisation as ,notch level'. Noradrenaline (1 ,M) caused the notch level to fall from 14 ± 2.6 to 7.8 ± 2.8 mV (n= 24), but left action potential duration, resting membrane potential or action potential amplitude unaffected. Whole-cell voltage-clamp recordings showed that 1 ,M noradrenaline increased both ICa,L and ICl(Ca), but it had no significant effect on the principal K+ currents. Blockage of ICl(Ca) by 0.5 mM 4,4,-diisothiocyanatostilbene-2,2,-disulphonic acid (DIDS) in both the absence and the presence of noradrenaline abolished phase-1 repolarisation. In the presence of noradrenaline, DIDS caused elevation of the plateau phase amplitude and an increase in the action potential duration. In conclusion, elevation of the plateau phase amplitude and action potential prolongation associated with an increased ICa,L upon adrenoceptor stimulation is prevented by an increased ICl(Ca) in sheep ventricular myocytes. [source] Evidences of the gender-related differences in cardiac repolarization and the underlying mechanisms in different animal species and humanFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2006Jianhua Cheng Abstract Clinical and experimental studies have shown that gender differences exist in cardiac repolarization in various animal species and human, as is evidenced by significantly longer QT, JT intervals and action potential duration in females than in males due to a reduced repolarization reserve in females. The latter is shown by the relatively greater increase in ventricular repolarization and higher incidence of torsades de pointes (TdP) in preparations from females by drugs blocking repolarizing K+ currents. These results can be modulated by gonadectomy, suggesting that gonadal steroids are important determinants of gender difference in repolarization. In human subjects, QT and JT intervals are longer in women, whereas QT dispersion and Tp-e interval (the interval from the peak to the end of T wave) are longer in men. At slow heart rates greater prolongation in QT and increase in transmural repolarization heterogeneity (i.e. increase in Tp-e) may predispose to TdP tachycardias in women. In healthy postmenopausal women, hormone replacement therapy with estrogen alone usually produced a prolongation of QT interval, while estrogen plus progesterone had no significant effects on QT interval but reduced QT dispersion. Along with these, there are still conflicting data reported. Further work is needed before the elucidation of the basis of gender differences in ventricular repolarization. [source] Molecular cloning, genomic organization and functional characterization of a new short-chain potassium channel toxin-like peptide BmTxKS4 from Buthus martensii Karsch(BmK)JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 4 2004Sheng Jiqun Abstract Scorpion venom contains many small polypeptide toxins, which can modulate Na+, K+, Cl,, and Ca2+ ion,channel conductance in the cell membrane. A full-length cDNA sequence encoding a novel type of K+ -channel toxin (named BmTxKS4) was first isolated and identified from a venom gland cDNA library of Buthus martensii Karsch (BmK). The encoded precursor contains 78 amino acid residues including a putative signal peptide of 21 residues, propeptide of 11 residues, and a mature peptide of 43 residues with three disulfide bridges. BmTxKS4 shares the identical organization of disulfide bridges with all the other short-chain K+ -channel scorpion toxins. By PCR amplification of the genomic region encoding BmTxKS4, it was shown that BmTxKS4 composed of two exons is disrupted by an intron of 87 bp inserted between the first and the second codes of Phe (F) in the encoding signal peptide region, which is completely identical with that of the characterized scorpion K+ -channel ligands in the size, position, consensus junctions, putative branch point, and A+T content. The GST-BmTxKS4 fusion protein was successfully expressed in BL21 (DE3) and purified with affinity chromatography. About 2.5 mg purified recombinant BmTxKS4 (rBmTxKS4) protein was obtained by treating GST-BmTxKS4 with enterokinase and sephadex chromatography from 1 L bacterial culture. The electrophysiological activity of 1.0,M rBmTxKS4 was measured and compared by whole cell patch-clamp technique. The results indicated that rBmTxKS4 reversibly inhibited the transient outward K+ current (Ito), delayed inward rectifier K+ current (Ik1), and prolonged the action potential duration of ventricular myocyte, but it has no effect on the action potential amplitude. Taken together, BmTxKS4 is a novel subfamily member of short-strain K+ -channel scorpion toxin. © 2004 Wiley Periodicals, Inc. J Biochem Mol Toxicol 18:187,195, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20026 [source] Potent Antiarrhythmic Effects of Chronic Amiodarone in Canine Pulmonary Vein Sleeve PreparationsJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 7 2009SERGE SICOURI M.D. Objectives: To examine the effects of chronic amiodarone on the electrophysiology of canine pulmonary vein (PV) sleeve preparations and left ventricular wedge preparation. Background: Amiodarone is commonly used for the treatment of ventricular and supraventricular arrhythmias. Ectopic activity arising from the PV plays a prominent role in the development of atrial fibrillation (AF). Methods: Standard microelectrode techniques were used to evaluate the electrophysiological characteristics of superfused PV sleeve (left superior or inferior) and arterially perfused left ventricular (LV) wedge preparations isolated from untreated and chronic amiodarone-treated dogs (amiodarone, 40 mg/kg daily for 6 weeks). Results: In PV sleeves, chronic amiodarone (n = 6) induced a significant increase in action potential duration at 90% repolarization (APD90) and a significant use-dependent reduction in Vmax leading to 1:1 activation failure at long cycle lengths (basic cycle length of 124 ± 15 ms in control vs 420 ± 320 ms after chronic amiodarone [P < 0.01]). Diastolic threshold of excitation increased from 0.3 ± 0.2 to 1.8 ± 0.7 mA (P < 0.01). Delayed and late phase 3 early afterdepolarizations and triggered activity could be induced in PV sleeve preparations using acetylcholine (ACh, 1 ,M), high calcium ([Ca2+]o= 5.4 mM), isoproterenol (Iso, 1 ,M), or their combination in 6 of 6 untreated PV sleeves, but in only 1 of 5 chronic amiodarone-treated PV sleeve preparations. Vmax, conduction velocity, and 1:1 activation failure were much more affected in PV sleeves versus LV wedge preparations isolated from amiodarone-treated animals. Conclusions: The results point to potent effects of chronic amiodarone to preferentially suppress arrhythmogenic substrates and triggers arising from the PV sleeves of the dog. [source] Effects of Wall Stress on the Dynamics of Ventricular Fibrillation: A Simulation Study Using a Dynamic Mechanoelectric Model of Ventricular TissueJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 7 2008SATOKO HIRABAYASHI master of environment Introduction: To investigate the mechanisms underlying the increased prevalence of ventricular fibrillation (VF) in the mechanically compromised heart, we developed a fully coupled electromechanical model of the human ventricular myocardium. Methods and Results: The model formulated the biophysics of specific ionic currents, excitation,contraction coupling, anisotropic nonlinear deformation of the myocardium, and mechanoelectric feedback (MEF) through stretch-activated channels. Our model suggests that sustained stretches shorten the action potential duration (APD) and flatten the electrical restitution curve, whereas stretches applied at the wavefront prolong the APD. Using this model, we examined the effects of mechanical stresses on the dynamics of spiral reentry. The strain distribution during spiral reentry was complex, and a high strain-gradient region was located in the core of the spiral wave. The wavefront around the core was highly stretched, even at lower pressures, resulting in prolongation of the APD and extension of the refractory area in the wavetail. As the left ventricular pressure increased, the stretched area became wider and the refractory area was further extended. The extended refractory area in the wavetail facilitated the wave breakup and meandering of tips through interactions between the wavefront and wavetail. Conclusions: This simulation study indicates that mechanical loading promotes meandering and wave breaks of spiral reentry through MEF. Mechanical loading under pathological conditions may contribute to the maintenance of VF through these mechanisms. [source] The Role of Cardiac Tissue Alignment in Modulating Electrical FunctionJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 12 2007CHIUNG-YIN CHUNG M.S. Introduction:,Most cardiac arrhythmias are associated with pathology-triggered ion channel remodeling. However, multicellular effects, for example, exaggerated anisotropy and altered cell-to-cell coupling, can also indirectly affect action potential morphology and electrical stability via changed electrotonus. These changes are particularly relevant in structural heart disease, including hypertrophy and infarction. Recent computational studies showed that electrotonus factors into stability by altering dynamic properties (restitution). We experimentally address the question of how cell alignment and connectivity alter tissue function and whether these effects depend on the direction of wave propagation. Methods and Results:,We show that cardiac cell arrangement can alter electrical stability in an in vitro cardiac tissue model by mechanisms both dependent and independent of the direction of wave propagation, and local structural remodeling can be felt beyond a space constant. Notably, restitution of action potential duration (APD) and conduction velocity was significantly steepened in the direction of cell alignment. Furthermore, prolongation of APD and calcium transient duration was found in highly anisotropic cell networks, both for longitudinal and transverse propagation. This is in contrast to expected correlation between wave propagation direction and APD based on electrotonic effects only, but is consistent with our findings of increased cell size and secretion of atrial natriuretic factor, a hypertrophy marker, in the aligned structures. Conclusion:,Our results show that anisotropic structure is a potent modulator of electrical stability via electrotonus and molecular signaling. Tissue alignment must be taken into account in experimental and computational models of arrhythmia generation and in designing effective treatment therapies. [source] Heterogeneity of Ventricular Fibrillation Dominant Frequency During Global Ischemia in Isolated Rabbit HeartsJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 8 2007Ch.B. , JANE CALDWELL M.B. Introduction: Ventricular fibrillation (VF) studies show that ECG-dominant frequency (DF) decreases as ischemia develops. This study investigates the contribution of the principle ischemic metabolic components to this decline. Methods and Results: Rabbit hearts were Langendorff-perfused at 40 mL/min with Tyrode's solution and loaded with RH237. Epicardial optical action potentials were recorded with a photodiode array (256 sites, 15 × 15 mm). After 60 seconds of VF (induced by burst pacing), global ischemia was produced by low flow (6 mL/min), or the solution changed to impose hypoxia (95% N2/5% CO2), low pHo (6.7, 80% O2/20% CO2), or raised [K+]o (8 mM). DF of the optical signals was determined at each site. Conduction velocity (CV), action potential duration (APD90), effective refractory period (ERP), activation threshold, dV/dtmax, and membrane potential were measured in separate experiments during ventricular pacing. During VF, ischemia decreased DF in the left ventricle (LV) (to [58 ± 6]%, P < 0.001), but not the right (RV) ([93 ± 5]%). Raised [K+]o reproduced this DF pattern (LV: [67 ± 12]%, P < 0.001; RV: [95 ± 9]%). LV DF remained elevated in hypoxia or low pHo. During ventricular pacing, ischemia decreased CV in LV but not RV. Raised [K+]o did not change CV in either ventricle. Ischemia and raised [K+]o shortened APD90 without altering ERP. LV activation threshold increased in both ischemia and raised [K+]o and was associated with diastolic depolarization and decreased dV/dtmax. Conclusions: These results suggest that during VF, decreased ECG DF in global ischemia is largely due to elevated [K+]o affecting the activation thresholds in the LV rather than RV. [source] Proarrhythmia as a Class Effect of Quinolones: Increased Dispersion of Repolarization and Triangulation of Action Potential Predict Torsades de PointesJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 6 2007PETER MILBERG M.D. Background: Numerous noncardiovascular drugs prolong repolarization and thereby increase the risk for patients to develop life-threatening tachyarrhythmias of the torsade de pointes (TdP) type. The development of TdP is an individual, patient-specific response to a repolarization-prolonging drug, depending on the repolarization reserve. The aim of the present study was to analyze the underlying mechanisms that discriminate hearts that will develop TdP from hearts that will not develop TdP. We therefore investigated the group of quinolone antibiotics that reduce repolarization reserve via IKr blockade in an intact heart model of proarrhythmia. Methods and Results: In 47 Langendorff-perfused, AV-blocked rabbit hearts, ciprofloxacin (n = 10), ofloxacin (n = 14), levofloxacin (n = 10), and moxifloxacin (n = 13) in concentrations from 100 ,M to 1,000 ,M were infused. Eight monophasic action potentials (MAPs) and an ECG were recorded simultaneously. After incremental pacing at cycle lengths from 900 ms to 300 ms to compare the action potential duration, potassium concentration was lowered to provoke TdP. All antibiotics led to a significant increase in QT interval and MAP duration, and exhibited reverse-use dependence. Eight simultaneously recorded MAPs demonstrated an increase in dispersion of repolarization in the presence of all antibiotics. MAP triangulation (ratio: MAP90/50) and fluctuation of consecutive action potentials were increased for all tested drugs at high concentrations. In the presence of low potassium concentration, all quinolones led to TdP: ciprofloxacin, 4 out of 10 (40%); ofloxacin, 3 out of 14 (21%); moxifloxacin, 9 out of 13 (69%); and levofloxacin, 2 out of 10 (20%). Hearts that developed TdP demonstrated a significant greater influence on dispersion of repolarization and on triangulation as compared with hearts without TdP. Conclusion: Quinolone antibiotics may be proarrhythmic due to a significant effect on myocardial repolarization. The individual response of a heart to develop TdP in this experimental model is characterized by a greater effect on dispersion of repolarization and on triangulation of action potential as compared with hearts that do not develop TdP. [source] Comparative Pharmacology of Guinea Pig Cardiac Myocyte and Cloned hERG (IKr) ChannelJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 11 2004CHRISTINA DAVIE Ph.D. Introduction: This study used whole-cell, patch clamp techniques on isolated guinea pig ventricular myocytes and HEK293 cells expressing cloned human ether-a-go-go-related gene (hERG) to examine the action of drugs causing QT interval prolongation and torsades de pointes (TdP) in man. Similarities and important differences in drug actions on cardiac myocytes and cloned hERG IKr channels were established. Qualitative actions of the drugs on cardiac myocytes corresponded with results obtained from Purkinje fibers and measurement of QT interval prolongation in animal and human telemetry studies. Methods and Results: Adult guinea pig ventricular myocytes were isolated by enzymatic digestion. Cells were continuously perfused with Tyrode's solution at 33,35°C. Recordings were made using the whole-cell, patch clamp technique. Action potentials (APs) were elicited under current clamp. Voltage clamp was used to study the effect of drugs on IKr (rapidly activating delayed rectifier potassium current), INa (sodium current), and ICa (L-type calcium current). Dofetilide increased the myocyte action potential duration (APD) in a concentration-dependent manner, with a pIC50 of 7.3. Dofetilide 1 ,M elicited early afterdepolarizations (EADs) but had little affect on ICa or INa. E-4031 increased APD in a concentration-dependent manner, with a pIC50 of 7.2. In contrast, 10 ,M loratadine, desloratadine, and cetirizine had little effect on APD or IKr. Interestingly, cisapride displayed a biphasic effect on myocyte APD and inhibited ICa at 1 ,M. Even at this high concentration, cisapride did not elicit EADs. A number of AstraZeneca compounds were tested on cardiac myocytes, revealing a mixture of drug actions that were not observed in hERG currents in HEK293 cells. One compound, particularly AR-C0X, was a potent blocker of myocyte AP (pIC50 of 8.4). AR-C0X also elicited EADs in cardiac myocytes. The potencies of the same set of drugs on the cloned hERG channel also were assessed. The pIC50 values for dofetilide, E-4031, terfenadine, loratadine, desloratadine, and cetirizine were 6.8, 7.1, 7.3, 5.1, 5.2, and <4, respectively. Elevation of temperature from 22 to 35°C significantly enhanced the current kinetics and amplitudes of hERG currents and resulted in approximately fivefold increase in E-4031 potency. Conclusion: Our study demonstrates the advantages of cardiac myocytes over heterologously expressed hERG channels in predicting QT interval prolongation and TdP in man. The potencies of some drugs in cardiac myocytes were similar to hERG, but only myocytes were able to detect important changes in APD characteristics and display EADs predictive of arrhythmia development. We observed similar qualitative drug profiles in cardiac myocytes, dog Purkinje fibers, and animal and human telemetry studies. Therefore, isolated native cardiac myocytes are a better predictor of drug-induced QT prolongation and TdP than heterologously expressed hERG channels. Isolated cardiac myocytes, when used with high-throughput patch clamp instruments, may have an important role in screening potential cardiotoxic compounds in the early phase of drug discovery. This would significantly reduce the attrition rate of drugs entering preclinical and/or clinical development. The current kinetics and amplitudes of the cloned hERG channel were profoundly affected by temperature, significantly altering the potency of one drug (E-4031). This finding cautions against routine drug testing at room temperature compared to physiologic temperature when using the cloned hERG channel. [source] Effect of Action Potential Duration and Conduction Velocity Restitution and Their Spatial Dispersion on Alternans and the Stability of ArrhythmiasJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 11 2002ISABELLE BANVILLE Ph.D. Restitution and Spatial Heterogeneities vs Arrhythmias.Introduction: The slope of the action potential duration (APD) restitution curve has been used to explain wavebreaks during arrhythmia initiation and maintenance. This hypothesis remains incomplete to fully describe the experimental data. Other factors contributing to wavebreaks must be studied to further understand arrhythmia dynamics. Methods and Results: Control APDs were measured from isolated rabbit hearts using a monophasic action potential probe. APD and conduction velocity (CV) restitution were quantified over the heart surface for two drugs, diacetyl monoxime (DAM) and cytochalasin D (CytoD), using a dual camera video imaging system. For all pacing intervals: (1) control APDs were shorter than for CytoD but longer than for DAM; and (2) CV was greater for CytoD compared with DAM. APD dispersion increased as pacing interval decreased for both drugs. For DAM, increased dispersion was due to a difference in APD restitution between the right and left ventricle. For CytoD, increased dispersion was due to discordant alternans, with no significant spatial variation in restitution. Fibrillation was sustained only in the control hearts; with DAM, stable reentry was sustained with shorter APD and cycle length compared with CytoD for which only nonsustained unstable reentry occurred. Conclusion: Alternans and arrhythmia dynamics are affected by the spatial dispersion of APD restitution as well as CV restitution, not simply the slope of APD restitution. Therefore, a direct link of the APD restitution slope to alternans and arrhythmia dynamics in rabbit heart does not exist. Designing antiarrhythmic drugs to alter only the restitution slope may not be appropriate. [source] Cellular Mechanisms of Vagally Mediated Atrial Tachyarrhythmia in Isolated Arterially Perfused Canine Right AtriaJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 9 2002MASAMICHI HIROSE M.D. Mechanism of Vagally Mediated AT.Introduction: Increased vagal tone significantly enhances susceptibility to atrial fibrillation (AF); however, the cellular mechanisms responsible for vagally mediated AF are not completely understood. Methods and Results: In 12 isolated arterially perfused canine right atria, high-resolution optical mapping techniques were used to measure action potentials during control conditions, during intracardiac parasympathetic nerve stimulation (IPS; 30 to 50 Hz) as a surrogate for vagal stimulation, and during acetylcholine (ACh) infusion (10 to 30 ,M). During steady-state pacing, action potential duration was shorter during ACh infusion (43 ± 9 msec) than during IPS (78 ± 7 msec, P < 0.001) or control (129 ± 5 msec, P < 0.001). In contrast, repolarization gradients were larger during IPS (13 ± 3 msec/mm) than during ACh infusion (3 ± 1 msec/mm, P < 0.01) or control (5 ± 1 msec/mm, P < 0.01). Transmural repolarization gradients were relatively small for each intervention tested. During ACh infusion, atrial tachyarrhythmia (AT) was easily initiated with a single premature stimulus and was associated with a focal pattern of activation (84%). AT also was easily initiated by a single premature stimulus during IPS; however, when repolarization gradients were large, patterns of conduction block and incomplete macroreentry were often observed (64%). Importantly, AT initiation during IPS was associated with focal activity (36%) when repolarization gradients were small. Conclusion: In contrast to ACh infusion, IPS generally increased dispersion of repolarization and was often associated with patterns of conduction block and incomplete macroreentry, similar to that associated with in vivo cervical vagal stimulation. However, IPS also was associated with a focal pattern of initiation that was independent of local repolarization gradients. These results suggest that during vagal stimulation, AT initiation does not always depend on repolarization gradients. [source] Adrenergic-Cholinergic Interaction that Modulates Repolarization in the Atrium is Altered with AgingJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 4 2002EUGENE A. SOSUNOV Ph.D. Autonomic Modulation of Atrial Repolarization.Introduction: Aging is associated with involution of both limbs of the autonomic nervous system, and the prejunctional and postjunctional effects of adrenergic and cholinergic stimulation are altered with senescence. Hence, postjunctional age-related changes in adrenergic-cholinergic interaction are a likely occurrence and may contribute to an altered substrate for arrhythmias. Methods and Results: Microelectrode techniques were used to record action potentials from epicardial slices of Bachmann's bundles of dogs aged 3 to 5 years (adult) and 8 to 12 years (old) in the absence or presence of acetylcholine and isoproterenol (separately and in combination). In control, action potential duration to 90% repolarization (APD) was longer in old atria. Acetylcholine (10,8 to 10,5 mol/L) in a concentration-dependent manner hyperpolarized and shortened APD in both tissues, with more prominent effects in the old. The effects of isoproterenol (10,9 to 10,6 mol/L) to elevate the plateau and shorten APD were about the same in both adult and old tissues. In adults, low concentrations of isoproterenol (10,9 and 10,8 mol/L) significantly prolonged APD, which had been first shortened by acetylcholine. This effect of isoproterenol was decreased in old atrial tissue, resulting in shorter APD in old than adult atria in the combined presence of beta-adrenergic and muscarinic agonists. Conclusion: In adult Bachmann's bundle, beta-adrenergic stimulation effectively operates as a "brake" to decrease the extent of cholinergic-induced APD shortening. The action of beta-adrenergic stimulation to antagonize acetylcholine-induced acceleration of repolarization declines with age, which may contribute to an altered arrhythmogenic substrate. [source] Lack of Effect of Conduction Direction on Action Potential Durations in Anisotropic Ventricular Strips of Pig HeartJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 4 2002GUILLERMO BERTRAN B.Sc. Anisotropy and Repolarization.Introduction: The influence of activation sequence on the rate of rise of the depolarization phase of action potentials in atrial or ventricular muscles has been well established. However, whether myocardial fiber orientation is important in modulating the repolarization process is unclear. Methods and Results: We examined the influence of activation sequence on the repolarization phase of action potentials in epicardial tissues from the right and left ventricles of domestic pigs. Whereas cells from the right ventricle exhibited direction-dependent differences in action potential duration at 30%, 50%, and 90% of full repolarization (190.6 ± 31.1 msec vs 181.8 ± 32.8 msec, 240.3 ± 23.5 msec vs 236.7 ± 25.4 msec, and 291.3 ± 23.7 msec vs 287.4 ± 25.1 msec for longitudinal and transverse propagation, respectively; P < 0.001), a similar duration of repolarization during both directions of propagation was observed in cells from the left ventricle at 50% and 90% of full repolarization (241.4 ± 39.4 msec and 285.5 ± 39.5 msec vs 240.4 ± 38.9 msec and 284.9 ± 39.6 msec for longitudinal and transverse propagation respectively; P = NS). A slight but significant difference was found at 30% of full repolarization in cells from the left ventricle (190.4 ± 39.0 msec vs 187.0 ± 38.0 msec for longitudinal and transverse propagation, respectively; P < 0.05). In the left ventricle, the duration of repolarization did not change as the distance between the recording site and stimulation site increased. Conclusion: The direction of wavefront propagation with respect to fiber orientation may not play an important role in modulating the duration of repolarization in epicardial cells from the left ventricle. [source] Entrainment by an Extracellular AC Stimulus in a Computational Model of Cardiac TissueJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 10 2001JASON M. MEUNIER B.S. Sinusoidal Stimulation of Cardiac Sheet.Introduction: Cardiac tissue can be entrained when subjected to sinusoidal stimuli, often responding with action potentials sustained for the duration of the stimulus. To investigate mechanisms responsible for both entrainment and extended action potential duration, computer simulations of a two-dimensional grid of cardiac cells subjected to sinusoidal extracellular stimulation were performed. Methods and Results: The tissue is represented as a bidomain with unequal anisotropy ratios. Cardiac membrane dynamics are governed by a modified Beeler-Reuter model. The stimulus, delivered by a bipolar electrode, has a duration of 750 to 1,000 msec, an amplitude range of 800 to 3,200 ,A/cm, and a frequency range of 10 to 60 Hz. The applied stimuli create virtual electrode polarization (VEP) throughout the sheet. The simulations demonstrate that periodic extracellular stimulation results in entrainment of the tissue. This phase-locking of the membrane potential to the stimulus is dependent on the location in the sheet and the magnitude of the stimulus. Near the electrodes, the oscillations are 1:1 or 1:2 phase-locked; at the middle of the sheet, the oscillations are 1:2 or 1:4 phase-locked and occur on the extended plateau of an action potential. The 1:2 behavior near the electrodes is due to periodic change in the voltage gradient between VEP of opposite polarity; at the middle of the sheet, it is due to spread of electrotonic current following the collision of a propagating wave with refractory tissue. Conclusion: The simulations suggest that formation of VEP in cardiac tissue subjected to periodic extracellular stimulation is of paramount importance to tissue entrainment and formation of an extended oscillatory action potential plateau. [source] Prolongation of Activation-Recovery Interval over a Preexcited Region before and after Catheter Ablation in Patients with Wolff-Parkinson-White SyndromeJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 8 2001YASUYA INDEN M.D. Activation-Recovery Interval in WPW Syndrome. Introduction: Preexisting changes in repolarization properties play an important role in T wave abnormalities (cardiac memory) after ablation in patients with Wolff-Parkinson-White (WPW) syndrome. However, no report has provided direct evidence for prolongation of action potential duration (APD) over a preexcited region before and after ablation. Methods and Results: We studied 10 patients with ventricular preexcitation due to a left-sided accessory pathway (AP) (group M) and 12 patients with concealed left-sided AP (group C) to clarify prolongation of APD using activation-recovery intervals (ARIs) from epicardial and endocardial unipolar electrograms in patients with WPW syndrome. ARI was calculated from unipolar electrograms at the His bundle and the coronary sinus adjacent to the AP during atrial pacing (100 beats/min) before and 30 minutes after ablation. Before ablation, ARIs at the AP site were significantly longer in group M than in group C (255 ± 21 msec vs 211 ± 24 msec; P < 0.01), whereas ARIs at the His bundle did not differ between the two groups (255 ± 20 msec vs 245 ± 27 msec; P = NS). After ablation, group M showed no significant changes in ARIs at the AP and His bundle (256 ± 19 msec and 253 ± 15 msec) compared with before ablation. Conclusion: We found by direct analysis of ARIs from the epicardium that APD prolongation over the preexcited region was present before catheter ablation and persisted after catheter ablation. The gradual changes in repolarization properties, including APD prolongation after discontinuation of AP, may be one mechanism of cardiac memory after catheter ablation in patients with WPW syndrome. [source] Chromanol 293B Inhibits Slowly Activating Delayed Rectifier and Transient Outward Currents in Canine Left Ventricular MyocytesJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 4 2001Ph.D., ZHUO-QIAN SUN M.D. Chromanol 293B on Ionic Currents.Introduction: Drugs that selectively inhibit the slowly activating component of the delayed rectifier potassium current (IKs) are being considered as possible antiarrhythmic agents, because they produce more prolongation of action potential duration at fast rates with less transmural dispersion of repolarization compared with blockers of the rapidly activating component (IKr). Although the chromanol derivative chromanol 293B has been shown to be relatively selective in blocking IKs in some species, its selectivity is far from established. Methods and Results: The present study uses whole-cell, patch-clamp technique to examine the selectivity of this compound for inhibition of IKs in comparison with other repolarizing ionic currents, such as IKr, inward rectifier potassium current (IK1), transient outward current (Ito), and L-type calcium current (ICa-L) in canine left ventricular mid-myocardial and endocardial cells. Chromanol 293B blocked IKs with an IC50 of 1.8 ,M and Ito with an IC50 of 38 ,M. Concentrations as high as 30 ,M did not affect IK1, IKr, or ICa-L. Higher concentrations of chromanol 293B (100 ,M) caused a slight, but statistically insignificant, inhibition of IKr. Conclusion: Our results indicate that chromanol 293B is a relatively selective blocker of IKs in canine left ventricular myocytes. [source] Changes in Left Ventricular Repolarization and Ion Channel Currents Following a Transient Rate Increase Superimposed on Bradycardia in Anesthetized DogsJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 6 2000MICHAEL RUBART M.D. Electrical Remodeling of the Heart due to Rate. Introduction: We previously demonstrated in dogs that a transient rate increase superimposed on bradycardia causes prolongation of ventricular refractoriness that persists for hours after resumption of bradycardia. In this study, we examined changes in membrane currents that are associated with this phenomenon. Methods and Results: The whole cell, patch clamp technique was used to record transmembrane voltages and currents, respectively, in single mid-myocardial left ventricular myocytes from dogs with 1 week of complete AV block; dogs either underwent 1 hour of left ventricular pacing at 120 beats/min or did not undergo pacing. Pacing significantly heightened mean phase 1 and peak plateau amplitudes by ,6 and ,3 mV, respectively (P < 0.02). and prolonged action potential duration at 90% repolarization from 235 ± 8 msec to 278 ± 8 msec (1 Hz; P = 0.02). Rapid pacing-induced changes in transmembrane ionic currents included (1) a more pronounced cumulative inactivation of the 4-aminopyridine-sensitive transient outward K+ current, I to over the range of physiologic frequencies, resulting from a ,30% decrease in the population of quickly reactivating channels; (2) increases in peak density of L-type Ca2+ currents, Ica.I.' by 15% to 35% between +10 and +60 mV; and (3) increases in peak density of the Ca2+ -activated chloride current, ICl.Ca' by 30% to 120% between +30 and +50 mV. Conclusion: Frequency-dependent reduction in Ito combined with enhanced ICa.I. causes an increase in net inward current that may he responsible for the observed changes in ventricular repolarization. This augmentation of net cation influx is partially antagonized by an increase in outward ICa.Cl. [source] Simultaneous Optical Mapping of Transmembrane Potential and Intracellular Calcium in Myocyte CulturesJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 5 2000VLADIMIR G. FAST Ph.D. Simultaneous Mapping of Vm and Cai2+. Introduction: Fast spatially resolved measurements of transmembrane potential (Vm) and intracellular calcium (Cai2+) are important for studying mechanisms of arrhythmias and defibrillation. The goals of this work were (1) to develop an optical technique for simultaneous multisite optical recordings of Vm and Cai2+, and (2) to determine the relationship between Vm and Cai2+ during normal impulse propagation in myocyte cultures. Methods and Results: Monolayers of neonatal rat myocytes were stained with fluorescent dye RH-237 (Vm) and Fluo-3AM (Cai2+). Both dyes were excited at the same wavelength range. The emitted fluorescent was optically separated into components corresponding to changes in Vm, and Cai2+ and measured using two 16 × 16 photodiode arrays at a spatial resolution of up to 27.5 ,m per diode and sampling rate of 2.5 kHz. The optical setup was adjusted so that there was no optical cross-talk between the two types of measurements, which was validated in experiments involving staining with either RH-237 or Fluo-3. The amplitude of Fluo-3 signals rapidly decreased during experiments due to dye leakage. Dye leakage was substantially reduced by application of 1 mM probenecid, a blocker of organic anion transport, which had no effect on action potential duration and only minor effect on conduction velocity. In double-stained preparations, during regular pacing Cai2+ transients had a rise time of 14.2 ± 2 msec, and they followed Vm upstrokes with a delay of 5.3 ± 1 msec (n = 9). Durations of Vm, and Cai2+ transients determined at 50% level of signal recovery were 54.6 ± 10 msec and 136 ± 8 msec, respectively. Application of 2 ,M nifedipine reduced the amplitude and duration of Cai2+ transients without significantly affecting conduction velocity. Conclusion: The results demonstrate feasibility of simultaneous optical recordings of Vm and Cai2+ transients with high spatial and temporal resolution. [source] Block of IKs Does Not Induce Early Afterdepolarization Activity but Promotes ,-Adrenergic Agonist-Induced Delayed Afterdepolarization ActivityJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 4 2000ALEXANDER BURASHNTKOV Ph.D. Block of IK Does Not Induce EADs.Introduction: An early afterdepolarization (EAD)-induced triggered heat is thought to precipitate torsade de pointes (TdP) in the long QT syndrome (LQTS). Previous studies demonstrated the development of EAD activity and dispersion of repolarization under LQT2 (reduced IKr) and LQT3 (augmented late INa). but not LQTl (reduced IKs), conditions. The present study examines these electrophysiologic characteristics during IKs block. Methods and Results: Canine epicardial (Epi), M, and endocardial (Endo) tissues and Purkinje fibers isolated from the canine left ventricle were studied using standard microelectrode recording techniques. The IKs blocker chromanol 293B (293B, 30 ,M), produced a homogeneous rate-independent prolongation of action potential duration (APD) in Epi, M, and Endo, but little to no APD prolongation in Purkinje. Chromanol 293B I to 30 ,M failed to induce EADs or delayed afterdepolarizations (DADs) in any of the four tissue types. Isoproterenol (ISO, 0.1 to 1.0 ,M) in the presence of 293B 30 ,M significantly prolonged the APD of the M cell (basic cycle length , sec), abbreviated that of Purkinje, and caused little change in that of Epi and Endo. The combination of 293B 30 ,M and ISO 0.2 ,M did not induce EADs in any of the four tissue types, but produced DAD activity in 4 of 8 Epi, 7 of 10 M cells, and 3 of 8 Endo. Conclusion: Our results indicate that IKs block alone or in combination with ,-adrenergic stimulation does not induce EADs in any of the four canine ventricular tissue types, but that the combination of the two induces DADs as well as accentuated dispersion of repolarization. [source] | ||||||||||||||||||||||||||||