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Stanley Nattel

Publications and source records attributed to Stanley Nattel.

At least 37 records · Page 2Linked to original sources
PubMed2006

Characterization of the in vivo and in vitro electrophysiological effects of the novel antiarrhythmic agent AZD7009 in atrial and ventricular tissue of the dog.

This study evaluated the effects of the novel antiarrhythmic agent AZD7009 on atrial and ventricular repolarization and on the Na+-current system, using Vmax as an index. Anesthetized dogs were infused with AZD7009 or azimilide to produce three pseudo steady-state plasma concentrations in vivo. Microelectrode techniques were used to record action potentials and effective refractory period (ERP) in vitro. Whereas AZD7009 concentration-dependently increased atrial ERP (AERP, by 48 +/- 7 milliseconds maximum, P < 0.001 versus vehicle), the increases in ventricular ERP (VERP, 8 +/- 4 milliseconds) and QT interval (2 +/- 5.5 milliseconds) were small and not concentration-dependent. For azimilide, the AERP increase was less, whereas VERP and QT increases were substantially larger than with AZD7009. In vitro, AZD7009 concentration-dependently reduced Vmax and increased action potential duration (APD). ERP was increased through APD lengthening and post-repolarization refractoriness. The suppression of Vmax, but not APD prolongation, showed frequency-dependence. APD and ERP increases were more pronounced in atrial than ventricular tissue: in atria, 2 microM AZD7009 increased APD90 and ERP from 224 +/- 7 to 318 +/- 7 milliseconds and 241 +/- 7 milliseconds to 378 +/- 17 milliseconds; versus 257 +/- 5 to 283 +/- 7 milliseconds and 253 +/- 12 to 300 +/- 11 milliseconds respectively in ventricles. Thus, AZD7009 potently and predominantly increases atrial refractoriness in the dog, with actions mediated by combined effects on repolarization and the Na+-current system.

Action Potentials↗
PubMed2005

Role of angiotensin system and effects of its inhibition in atrial fibrillation: clinical and experimental evidence.

Atrial fibrillation (AF) is a common arrhythmia that is difficult to treat. Anti-arrhythmic drug therapy, to maintain sinus-rhythm, is limited by inadequate efficacy and potentially serious adverse effects. There is increasing interest in novel therapeutic approaches that target AF-substrate development. Recent trials suggest that angiotensin converting-enzyme (ACE)-inhibitors and angiotensin-receptor blockers (ARBs) may be useful, particularly in patients with left ventricular hypertrophy or failure. The clinical potential and mechanisms of this approach are under active investigation. Angiotensin-II is involved in remodelling and may have direct electrophysiological actions. Experimental studies show protection from atrial structural and possibly electrical remodelling with ACE-inhibitors and ARBs, as well as potential effects on cardiac ion-channels. This article reviews information pertaining to the clinical use and mechanism of action of ACE-inhibitors and ARBs in AF. A lack of prospective randomized double-blind trials data limits their application in AF patients without another indication for their use, but studies under way may alter this in the near future. This exciting field of investigation may lead to significant improvements in therapeutic options for AF patients.

Angiotensin Receptor Antagonists↗
PubMed2005

Gene expression profile associated with chronic atrial fibrillation and underlying valvular heart disease in man.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans. The pathophysiology of AF involves electrical, structural and contractile remodeling, which is associated with changes in cardiac gene expression. Previous studies of gene-expression changes in clinical AF have mostly been limited to a small number of candidate genes and have not all been well controlled for underlying heart disease. The present study assessed AF-related gene-expression changes in valve-disease patients with microarrays representing the cardiac transcriptome. Right atrial appendages from 11 patients with chronic AF and underlying valvular heart disease (AF-VHD) and seven patients in sinus rhythm with VHD (SR-VHD) were individually compared to an age-matched sinus-rhythm control group (SR-CTRL, 11 patients) using cardiac-specific microarray analysis. One-class statistical analysis was used to identify genes differentially expressed between SR-VHD and SR-CTRL patients. Two-class statistical analysis was used to identify genes differentially expressed between AF-VHD and SR-VHD patients. Out of 3863 analyzed genes, 832 genes were differentially expressed between SR-VHD and SR-CTRL patients, and 169 genes were differentially expressed between AF-VHD and SR-VHD patients. Striking AF-related changes included altered expression of nine genes pointing towards the development of fibrosis (e.g. upregulation of transforming growth factor beta1), and changes in eight genes potentially related to an increased risk of thromboembolic events (e.g. upregulation of alpha2 macroglobulin). Microarray results were confirmed by quantitative PCR. Our results suggest that AF produces a characteristic profile of gene-expression changes that may be related to the pathophysiology of the arrhythmia.

Aged↗
PubMed2005

Wave block formation in homogeneous excitable media following premature excitations: dependence on restitution relations.

Spiral wave formation and disorganized activity in excitable media require the existence of broken waves and are related to partial wave block. The determinants of wave block in excitable systems are incompletely understood, especially for cardiac excitable tissue. Previous work in one-dimensional cardiac models has suggested that wave break of a premature excitation (PE) requires critical timing and that the conditions for broken waves are improbable. We analyzed the mechanism of unidirectional wave block that occurs when two consecutive PEs interact with a normal plane wave in a generic one-dimensional spatial excitable medium. A nondimensional coupled-map model built from mesoscopic characteristics of the substrate (the velocity and action potential duration restitution functions) shows that block can occur over a large interval of timing between the two PEs and leads to wave break in two-dimensional media. This mechanism may be an important determinant of spiral wave formation by the response to premature excitations.

Action Potentials↗
PubMed2005

Human atrial ion channel and transporter subunit gene-expression remodeling associated with valvular heart disease and atrial fibrillation.

BACKGROUND: Valvular heart disease (VHD), which often leads to atrial fibrillation (AF), and AF both cause ion-channel remodeling. We evaluated the ion-channel gene expression profile of VHD patients, in permanent AF (AF-VHD) or in sinus rhythm (SR-VHD), in comparison with patients without AF or VHD, respectively. METHODS AND RESULTS: We used microarrays containing probes for human ion-channel and Ca2+-regulator genes to quantify mRNA expression in atrial tissues from 7 SR-VHD patients and 11 AF-VHD patients relative to 11 control patients in SR without structural heart disease (SR-CAD). From the data set, we selected for detailed analysis 59 transcripts expressed in the human heart. SR-VHD patients differentially expressed 24/59 ion-channel and Ca2+-regulator transcripts. There was significant overlap between VHD groups, with 66% of genes altered in SR-VHD patients being similarly modified in AF-VHD. Statistical differences between the AF- and SR-VHD groups identified the specific molecular portrait of AF, which involved 12 genes that were further confirmed by real-time reverse transcription-polymerase chain reaction. For example, phospholamban, the beta-subunit MinK (KCNE1) and MIRP2 (KCNE3), and the 2-pore potassium channel TWIK-1 were upregulated in AF-VHD compared with SR-VHD, whereas the T-type calcium-channel Cav3.1 and the transient-outward potassium channel Kv4.3 were downregulated. Two-way hierarchical clustering separated SR-VHD from AF-VHD patients. AF-related changes in L-type Ca2+-current and inward-rectifier current were confirmed at protein and functional levels. Finally, for 13 selected genes, SR restoration reversed ion-channel remodeling. CONCLUSIONS: VHD extensively remodels cardiac ion-channel and transporter expression, and AF alters ion-channel expression in VHD patients.

Atrial Fibrillation↗
PubMed2005

Functional expression of Kir2.x in human aortic endothelial cells: the dominant role of Kir2.2.

Inward rectifier K(+) channels (Kir) are a significant determinant of endothelial cell (EC) membrane potential, which plays an important role in endothelium-dependent vasodilatation. In the present study, several complementary strategies were applied to determine the Kir2 subunit composition of human aortic endothelial cells (HAECs). Expression levels of Kir2.1, Kir2.2, and Kir2.4 mRNA were similar, whereas Kir2.3 mRNA expression was significantly weaker. Western blot analysis showed clear Kir2.1 and Kir2.2 protein expression, but Kir2.3 protein was undetectable. Functional analysis of endothelial inward rectifier K(+) current (I(K)) demonstrated that 1) I(K) current sensitivity to Ba(2+) and pH were consistent with currents determined using Kir2.1 and Kir2.2 but not Kir2.3 and Kir2.4, and 2) unitary conductance distributions showed two prominent peaks corresponding to known unitary conductances of Kir2.1 and Kir2.2 channels with a ratio of approximately 4:6. When HAECs were transfected with dominant-negative (dn)Kir2.x mutants, endogenous current was reduced approximately 50% by dnKir2.1 and approximately 85% by dnKir2.2, whereas no significant effect was observed with dnKir2.3 or dnKir2.4. These studies suggest that Kir2.2 and Kir2.1 are primary determinants of endogenous K(+) conductance in HAECs under resting conditions and that Kir2.2 provides the dominant conductance in these cells.

Aorta↗
PubMed2005

A single residue in the S6 transmembrane domain governs the differential flecainide sensitivity of voltage-gated potassium channels.

Flecainide has been used to differentiate Kv4.2-based transient-outward K(+)-currents (flecainide-sensitive) from Kv1.4-based (flecainide-insensitive). We found that flecainide also inhibits ultrarapid delayed rectifier (I(Kur)) currents in Xenopus laevis oocytes carried by Kv3.1 subunits (IC(50), 28.3 +/- 1.3 microM) more strongly than Kv1.5 currents corresponding to human I(Kur) (IC(50), 237.1 +/- 6.2 microM). The present study examined molecular motifs underlying differential flecainide sensitivity. An initial chimeric approach pointed to a role for S6 and/or carboxyl-terminal sites in Kv3.1/Kv1.5 sensitivity differences. We then looked for homologous amino acid residues of the two sensitive subunits (Kv4.2 and Kv3.1) different from homologous residues for insensitive subunits (Kv1.4 and Kv1.5). Three candidate sites were identified: two in the S5-S6 linker and one in the S6 segment. Mutation of the proximal S5-S6 linker site failed to alter flecainide sensitivity. Mutation at the more distal site in Kv1.5 (V481L) modestly increased sensitivity, but the reciprocal Kv3.1 mutation (L401V) had no effect. S6 mutants caused marked changes: flecainide sensitivity decreased approximately 8-fold for Kv3.1 L422I (IC(50), 213 +/- 9 microM) and increased approximately 7-fold for Kv1.5 I502L (IC(50), 35.6 +/- 1.9 microM). Corresponding mutations reversed flecainide sensitivity of Kv1.4 and Kv4.2; L392I decreased Kv4.2 sensitivity by approximately 17-fold (IC(50) of 37.4 +/- 6.9 to 628 +/- 36 microM); I547L increased Kv1.4 sensitivity by approximately 15-fold (IC(50) of 706 +/- 37 to 40.9 +/- 7.3 microM). Our observations indicate that the flecainide sensitivity differences among these four voltage-gated K(+)-channels are determined by whether an isoleucine or a leucine is present at a specific amino acid location.

Amino Acid Sequence↗
PubMed2005

Substrate size as a determinant of fibrillatory activity maintenance in a mathematical model of canine atrium.

Tissue size has been considered an important determinant of atrial fibrillation (AF), but recent work has questioned the critical size hypothesis. Here, we use a previously developed mathematical model of the two-dimensional canine atrium with realistic action potential, ionic, and conduction properties to address substrate size effects on the maintenance of fibrillatory activity. Cholinergic AF was simulated at different acetylcholine (ACh) concentrations ([ACh]) and distributions, with substrate area varied 11.1-fold. Automated phase singularity detection was used to facilitate the analysis of arrhythmic activity. The duration of activity induced by a single extrastimulus increased with increasing substrate dimensions. Two general mechanisms underlying activity were observed and were differentially affected by substrate size. For large mean [ACh], single primary rotors anchored in low-[ACh] zones maintained activity and substrate dimensions were not critical. At lower mean [ACh], extensive spiral wave meander prevented the emergence of single stable rotors. Prolonged activity was favored when substrate size permitted a sufficiently large number of simultaneous longer-lasting rotors that extinction of all was unlikely. Thus either single dominant rotor or multiple reentrant spiral generator mechanisms could maintain fibrillatory activity in this model and were differentially dependent on substrate size. These results speak to recent debates about the role in AF of single driver rotors versus multiple reentrant circuit mechanisms by suggesting that either may maintain fibrillatory atrial activity depending on atrial size and electrophysiological properties.

Action Potentials↗
PubMed2005

Atrial fibrillation-associated minK38G/S polymorphism modulates delayed rectifier current and membrane localization.

BACKGROUND: Atrial fibrillation (AF) is a common acquired arrhythmia with multi-factorial pathogenesis. Recently, a single nucleotide polymorphism (SNP, A/G) at position 112 in the KCNE1 gene, resulting in a glycine/serine amino acid substitution at position 38 of the minK peptide, was associated with AF occurrence (AF more frequent with minK38G); however, the functional effect of this SNP is unknown. METHODS AND RESULTS: We used patch clamp recording, confocal microscopy and protein biochemistry to study the effect of this SNP on delayed-rectifier current expression and mathematical simulation to identify potential functional consequences. The density of slow delayed rectifier current (I(Ks)) resulting from co-expression with KvLQT1 was smaller with minK38G (e.g. at +10 mV: 50+/-7 pA/pF in Chinese hamster ovary (CHO) cells, 45+/-14 pA/pF for COS-7 cells) compared to minK38S (93+/-17 pA/pF, 104+/-23 pA/pF, respectively, P<0.05 for each). I(Ks) kinetics and voltage-dependence were unaffected. Currents resulting from co-expression of human ether-a-go-go-related gene (HERG) were similar for minK38G and minK38S, e.g. upon repolarization from +10 to -50 mV: tail currents 23+/-4 pA/pF versus 22+/-5 pA/pF (P=ns). KvLQT1 membrane immunofluorescence was less in CHO cells co-expressing minK38G versus minK38S, and surface expression of KvLQT1, as determined by labelling with streptavidin/biotin, was increased with minK38S co-expression. Computer simulations with a human atrial action potential model predicted that the minK38G SNP would slightly prolong the atrial action potential and reduce the frequency for alternans behaviour. In the presence of reduced repolarization reserve, these effects were enhanced and under specific conditions early afterdepolarizations occurred. CONCLUSIONS: The minK38G isoform is associated with reduced I(Ks), likely due to decreased KvLQT1 membrane expression. This study reveals a novel amino acid determinant of the minK-KvLQT1 interaction, and if the role of minK38G in AF is confirmed, would suggest mechanistic heterogeneity in genetic determinants of AF.

Animals↗
PubMed2005

Ionic determinants of functional reentry in a 2-D model of human atrial cells during simulated chronic atrial fibrillation.

Recent studies suggest that atrial fibrillation (AF) is maintained by fibrillatory conduction emanating from a small number of high-frequency reentrant sources (rotors). Our goal was to study the ionic correlates of a rotor during simulated chronic AF conditions. We utilized a two-dimensional (2-D), homogeneous, isotropic sheet (5 x 5 cm(2)) of human atrial cells to create a chronic AF substrate, which was able to sustain a stable rotor (dominant frequency approximately 5.7 Hz, rosette-like tip meander approximately 2.6 cm). Doubling the magnitude of the inward rectifier K(+) current (I(K1)) increased rotor frequency ( approximately 8.4 Hz), and reduced tip meander (approximately 1.7 cm). This rotor stabilization was due to a shortening of the action potential duration and an enhanced cardiac excitability. The latter was caused by a hyperpolarization of the diastolic membrane potential, which increased the availability of the Na(+) current (I(Na)). The rotor was terminated by reducing the maximum conductance (by 90%) of the atrial-specific ultrarapid delayed rectifier K(+) current (I(Kur)), or the transient outward K(+) current (I(to)), but not the fast or slow delayed rectifier K(+) currents (I(Kr)/I(Ks)). Importantly, blockade of I(Kur)/I(to) prolonged the atrial action potential at the plateau, but not at the terminal phase of repolarization, which led to random tip meander and wavebreak, resulting in rotor termination. Altering the rectification profile of I(K1) also slowed down or abolished reentrant activity. In combination, these simulation results provide novel insights into the ionic bases of a sustained rotor in a 2-D chronic AF substrate.

Action Potentials↗
PubMed2005

Sinus node dysfunction and hyperpolarization-activated (HCN) channel subunit remodeling in a canine heart failure model.

BACKGROUND: The hyperpolarization-activated cation current I(f) contributes significantly to sinoatrial node pacemaker function and possibly to ectopic arrhythmogenesis. Little is known about the expression of corresponding hyperpolarization-activated cyclic nucleotide-gated (HCN) channel subunits in normal hearts and HCN remodeling by diseases, like congestive heart failure (CHF), associated with disturbances of cardiac rhythm. METHODS AND RESULTS: We assessed expression of HCN1, 2 and 4 in normal mongrel dogs and dogs subjected to 2-week ventricular tachypacing-induced CHF. Competitive RT-PCR, Western blot and immunohistochemistry were used to quantify HCN subunit mRNA and protein expression in the right atrium (RA) and sinoatrial node. CHF approximately doubled sinus node recovery time, indicating suppressed sinus node pacemaker function. HCN expression under control conditions was HCN4 > HCN2 >> HCN1. HCN2 and HCN4 expression was greater at both protein and mRNA levels in sinoatrial node than RA. CHF significantly decreased sinus node HCN expression at both mRNA and protein levels (HCN2 by 78% and 82%; HCN4 by 42% and 77%, respectively). RA HCN2 expression was unaltered by CHF, but HCN4 was significantly upregulated (by 209%). CONCLUSIONS: HCN4 is the dominant subunit in canine sinoatrial node and RA; strong sinus node HCN expression likely contributes to its pacemaker function; downregulation of HCN4 and HCN2 expression contribute to CHF-induced sinus node dysfunction; and upregulation of atrial HCN4 may help to promote atrial arrhythmia formation. These findings provide novel information about the molecular basis of normal and disease-related impairments of cardiac impulse formation.

Animals↗
PubMed2005

Mechanisms of atrial fibrillation termination by pure sodium channel blockade in an ionically-realistic mathematical model.

The mechanisms by which Na+-channel blocking antiarrhythmic drugs terminate atrial fibrillation (AF) remain unclear. Classical "leading-circle" theory suggests that Na+-channel blockade should, if anything, promote re-entry. We used an ionically-based mathematical model of vagotonic AF to evaluate the effects of applying pure Na+-current (I(Na)) inhibition during sustained arrhythmia. Under control conditions, AF was maintained by 1 or 2 dominant spiral waves, with fibrillatory propagation at critical levels of action potential duration (APD) dispersion. I(Na) inhibition terminated AF increasingly with increasing block, terminating all AF at 65% block. During 1:1 conduction, I(Na) inhibition reduced APD (by 13% at 4 Hz and 60% block), conduction velocity (by 37%), and re-entry wavelength (by 24%). During AF, I(Na) inhibition increased the size of primary rotors and reduced re-entry rate (eg, dominant frequency decreased by 33% at 60% I(Na) inhibition) while decreasing generation of secondary wavelets by wavebreak. Three mechanisms contributed to I(Na) block-induced AF termination in the model: (1) enlargement of the center of rotation beyond the capacity of the computational substrate; (2) decreased anchoring to functional obstacles, increasing meander and extinction at boundaries; and (3) reduction in the number of secondary wavelets that could provide new primary rotors. Optical mapping in isolated sheep hearts confirmed that tetrodotoxin dose-dependently terminates AF while producing effects qualitatively like those of I(Na) inhibition in the mathematical model. We conclude that pure INa inhibition terminates AF, producing activation changes consistent with previous clinical and experimental observations. These results provide insights into previously enigmatic mechanisms of class I antiarrhythmic drug-induced AF termination. The full text of this article is available online at http://circres.ahajournals.org

Algorithms↗
PubMed2005

Atrial tachycardia remodeling of pulmonary vein cardiomyocytes: comparison with left atrium and potential relation to arrhythmogenesis.

BACKGROUND: The pulmonary veins (PVs) are important in the pathophysiology of atrial fibrillation (AF), as is atrial tachycardia (AT) remodeling. The relative importance of AT remodeling in PVs versus other atrial sites is unknown. The present study assessed AT-induced cellular changes in PVs versus left atrium (LA) and their relationship to arrhythmogenesis. METHODS AND RESULTS: We studied ionic currents (single-cell patch clamp) and action potentials (APs; coronary-perfused multicellular preparations) in the PVs and LA free wall of dogs after 7-day AT pacing (400 bpm), as well as in nonpaced control dogs. In controls, rapid (I(Kr)) and slow (I(Ks)) delayed-rectifier currents were larger in PVs; transient-outward (I(to)), inward-rectifier (I(K1)), and L-type Ca2+ (I(Ca)) currents and AP duration were smaller. AT remodeling reduced I(Ca) and I(to), left I(Kr) and I(Ks) unchanged, and increased I(K1) in both LA and PV. AT reduced action potential duration in both LA and PV. LA-PV AP differences became smaller in AT than in control dogs. Premature extrastimuli induced atrial tachyarrhythmias at 4.5+/-2.8% (mean+/-SEM) sites in 6 control multicellular preparations compared with 64.2+/-7.3% sites in 9 AT-remodeled preparations (P<0.001). Resection of all PVs failed to alter atrial tachyarrhythmia inducibility in AT-remodeled preparations (67.5+/-13.1%). PV resection did not significantly change tachyarrhythmia duration (mean 3.9 seconds per heart, range 0.7 to 15.7 seconds before resection; mean 7.0 seconds per heart, range 0.9 to 36.0 seconds after resection) or cycle length (120+/-6 ms before resection, 115+/-8 ms after resection). CONCLUSIONS: AT produces qualitatively similar ionic remodeling in LA and PVs but reduces PV-LA AP differences. PVs are not essential for AT-induced atrial tachyarrhythmia promotion in this model, which may relate to the failure of PV isolation to prevent AF in some patient populations.

Action Potentials↗
PubMed2005

Comparison of ion channel distribution and expression in cardiomyocytes of canine pulmonary veins versus left atrium.

BACKGROUND: Cardiomyocytes in pulmonary vein (PV) sleeves are important in atrial fibrillation (AF), but underlying mechanisms are poorly understood. Pulmonary veins have different ionic current properties compared to left atrium, with pulmonary vein inward-rectifier currents being smaller and delayed-rectifier currents larger than in left atrium. METHODS: Expression and distribution of the inward-rectifier subunits Kir2.1 and Kir2.3, the rapid delayed-rectifier alpha-subunit ERG, the slow delayed-rectifier alpha-subunit KvLQT1, the beta-subunit minK, the L-type Ca(2+)-subunit Ca(v)1.2, and the Na(+),Ca(2+)-exchanger were quantified by Western blot on isolated cardiomyocytes and localized by immunohistochemistry in tissue sections obtained from canine hearts. RESULTS: Western blotting indicated significantly greater expression of ERG (by 28%, P<0.05) and KvLQT1 (by 34%, P<0.05) in pulmonary vein versus left atrial (LA) cardiomyocytes, but smaller Kir2.3 and similar Kir2.1, Ca(v)1.2 and Na(+),Ca(2+)-exchanger expression in PV. Kir2.1 exhibited weak transverse tubular distribution in both regions. Kir2.3 localized to intercalated disks in both regions, and to transverse tubules in left atrium but not pulmonary vein. ERG staining was more intense in pulmonary vein than left atrium, localizing to transverse tubules in both regions and intercalated disks in pulmonary veins. KvLQT1 was more intensely expressed in pulmonary veins, with a transverse tubular and intercalated disk localization, versus a more diffuse signal in left atrium. The Na(+),Ca(2+)-exchanger localized to transverse tubules, plasma membranes and intercalated disks with similar intensity in each region. CONCLUSIONS: Greater ERG and KvLQT1 abundance in pulmonary vein cardiomyocytes, lower abundance of Kir2.3 in pulmonary veins and differential pulmonary vein subcellular distribution of Kir2.3, ERG and KvLQT1 subunits may contribute to ionic current differences between pulmonary vein and left atrial cardiomyocytes.

Animals↗