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S Nattel

Publications and source records attributed to S Nattel.

At least 37 records · Page 2Linked to original sources
PubMed2001

Method for simultaneous epicardial and endocardial mapping of in vivo canine heart: application to atrial conduction properties and arrhythmia mechanisms.

INTRODUCTION: It has been suggested that the three-dimensional structure of the atria may be crucial in arrhythmogenesis; however, previous in vivo atrial activation mapping studies have been limited to either endocardial or epicardial approaches. METHODS AND RESULTS: To investigate the role of endocardial and epicardial structures and their interaction in atrial conduction and arrhythmias, we used five epicardial plaques and two intra-atrial balloon arrays to record a total of 368 unipolar electrograms from the entire epicardial and endocardial surface of both atria. During regular 1:1 pacing from the right atrial appendage, right atrial endocardial activation spread considerably faster than epicardial (total activation time 45+/-12 msec vs 60+/-19 msec, respectively [mean +/- SD]; P < 0.05), pointing to preferential conduction over structures like the crista terminalis and pectinate muscles. No such differences were noted in the left atrium. Transseptal spread occurred via discrete anterior and posterior pathways, causing separate breakthroughs in anterior and posterior atrial regions, respectively. Dissociation between septal pathways played a role in reentry during vagal atrial fibrillation. In 2 of 4 dogs with atrial fibrillation associated with congestive heart failure, single macroreentrant circuits involving endocardial and epicardial components were revealed during the arrhythmia. CONCLUSION: We conclude that activation mapping using simultaneous recording from both epicardial and endocardial surfaces provides potentially important insights into the mechanisms of atrial conduction and arrhythmogenesis.

Activation Analysis↗
PubMed2001

Expression of multiple subtypes of muscarinic receptors and cellular distribution in the human heart.

Five isoforms of the muscarinic acetylcholine receptor (mAChR) have been identified by molecular cloning and designated m(1)-m(5), of which four correspond to the functional subtypes M(1), M(2), M(3), and M(4) in primary tissues. The presence of M(5) receptors in tissues remains uncertain. The present study was designed to explore the diversity and cellular distribution of various mAChR subtypes in human hearts. Competition binding of [N-methyl-(3)H]-scopolamine methyl chloride with various mAChR antagonists yielded data consistent with the presence of multiple subtypes (M(1)/M(2)/M(3)/M(5)) of mAChRs in both human atrial (HA) and ventricular (HV) tissues. Expression of mRNAs encoding all five subtypes was readily detected by reverse transcription-polymerase chain reaction in both HA and HV samples. Immunoblotting with subtype-specific antibodies confirmed the presence of M(1), M(2), M(3), and M(5), but not M(4), proteins in membrane preparations from both HA and HV. The protein levels of M(1) and M(2) were comparable between HA and HV. Although the density of M(3) appeared approximately 10-fold higher in HV than HA, that of M(5) was approximately 5 times lower in HV than in HA. Positive immunostaining of single ventricular myocytes by M(1), M(2), M(3), and M(5) antibodies, respectively, was consistently detected. Under confocal microscopy, M(5) showed characteristic localization to the intercalated discs, whereas other subtypes were more evenly distributed throughout the surface membrane. Our results provide the first molecular evidence for the presence of multiple subtypes of mAChR, including endogenous M(5) receptors, in human hearts and suggest that different subtypes have different tissue distributions and cellular localization.

Binding, Competitive↗
PubMed2001

Slow delayed rectifier current and repolarization in canine cardiac Purkinje cells.

Although cardiac Purkinje cells (PCs) are believed to be the source of early afterdepolarizations generating ventricular tachyarrhythmias in long Q-T syndromes (LQTS), the ionic determinants of PC repolarization are incompletely known. To evaluate the role of the slow delayed rectifier current (I(Ks)) in PC repolarization, we studied PCs from canine ventricular false tendons with whole cell patch clamp (37 degrees C). Typical I(Ks) voltage- and time-dependent properties were noted. Isoproterenol enhanced I(Ks) in a concentration-dependent fashion (EC(50) approximately 30 nM), negatively shifted I(Ks) activation voltage dependence, and accelerated I(Ks) activation. Block of I(Ks) with 293B did not alter PC action potential duration (APD) in the absence of isoproterenol; however, in the presence of isoproterenol, 293B significantly prolonged APD. We conclude that, without beta-adrenergic stimulation, I(Ks) contributes little to PC repolarization; however, beta-adrenergic stimulation increases the contribution of I(Ks) by increasing current amplitude, accelerating I(Ks) activation, and shifting activation voltage toward the PC plateau voltage range. I(Ks) may therefore provide an important "braking" function to limit PC APD prolongation in the presence of beta-adrenergic stimulation.

Acetamides↗
PubMed2000

Molecular evidence for a role of Shaw (Kv3) potassium channel subunits in potassium currents of dog atrium.

We previously described an ultrarapid delayed rectifier current in dog atrial myocytes (IKur,d) with properties resembling currents reported for Kv3.1 channels in neural tissue; however, there was no direct molecular evidence for Shaw subfamily (Kv3) subunit expression in the heart. To identify the molecular basis of IKur,d, we cloned a full-length cDNA (dKv3.1) from canine atrium with homology-based reverse transcription (RT)- polymerase chain reaction (PCR) cloning techniques. A 1755 bp full-length cDNA (dKv3.1) was obtained, with 94.2 % homology to rat brain Kv3.1 (rbKv3.1). The deduced amino acid sequence had 99.3 % homology with rbKv3.1. Heterologous expression of dKv3.1 in Xenopus oocytes produced currents with activation voltage dependence, rectification, and activation and deactivation kinetics that strongly resemble native IKur,d. Like IKur,d, dKv3.1 was found to be highly sensitive to extracellular 4-aminopyridine (4-AP) and tetraethylammonium (TEA). RNase protection assays, Western blots and immunohistochemical studies demonstrated the presence of dKv3.1 transcripts and proteins in dog atrial preparations and isolated canine atrial myocytes. Protein corresponding to the Kv1.5 subunit, which can also carry ultrarapid delayed rectifier current, was absent. Unlike neural tissues, which express two splice variants (Kv3.1a and Kv3.1b), canine atrium showed only Kv3.1b transcripts. Whole-cell patch-clamp studies showed that IKur,d is absent in canine ventricular myocytes, and immunohistochemical and Western blot analysis demonstrated the absence of dKv3.1 protein in canine ventricle. We conclude that the Shaw-type channel dKv3.1 is present in dog atrium, but not ventricle, and is the likely molecular basis of canine atrial IKur,d.

4-Aminopyridine↗
PubMed2000

Ionic remodeling in the heart: pathophysiological significance and new therapeutic opportunities for atrial fibrillation.

Heart disease has long been recognized to alter cardiac electrical function. Detailed studies of disease-induced remodeling of ionic transport processes that underlie ventricular electrophysiological alterations have been performed over the past 10 years, but our knowledge of atrial ionic remodeling is more limited and has emerged much more recently. The present review focuses on recent findings regarding ionic remodeling at the atrial level, particularly with respect to two conditions that promote atrial fibrillation (AF) in well-developed clinically relevant animal models: (1) sustained atrial tachycardia and (2) ventricular tachypacing-induced congestive heart failure. Complementary data from experimental models and from observations in atrial tissue samples from patients are examined critically and integrated. Consideration is also given to potential molecular mechanisms underlying remodeling, the relationship between atrial and ventricular ionic remodeling in response to similar stimuli, and the potential relevance of insights into ionic remodeling for understanding the pathophysiology of AF and developing improved therapeutic approaches.

Animals↗
PubMed2000

Nicotine is a potent blocker of the cardiac A-type K(+) channels. Effects on cloned Kv4.3 channels and native transient outward current.

BACKGROUND: Nicotine is a main constituent of cigarette smoke and smokeless tobacco, known to increase the risk of sudden cardiac death. This study aimed at establishing ionic mechanisms underlying potential electrophysiological effects of nicotine. METHODS AND RESULTS: Effects of nicotine on Kv4.3 and Kv4.2 channels expressed in Xenopus oocytes were studied at the whole-cell and single-channel levels. The effects of nicotine on the transient outward K(+) current (I:(to)) were studied by use of whole-cell patch-clamp techniques in canine ventricular myocytes. Nicotine potently inhibited Kv4 current. The concentration for half-maximal inhibition (IC(50)) was 40+/-4 nmol/L, and the current was abolished by 100 micromol/L nicotine. The IC(50) for block of native I:(to) was 270+/-43 nmol/L. The steady-state activation properties of Kv4.3 and I:(to) were unaltered by nicotine, whereas positive shifts of the inactivation curves were observed. Of the total inhibition of Kv4.3 and I:(to) by nicotine, 40% was due to tonic block and 60% was attributable to use-dependent block. Activation, inactivation, and reactivation kinetics were not significantly changed by nicotine. Nicotine reduced single-channel conductance, open probability, and open time but increased the closed time of Kv4.3. The effects of nicotine were not altered by antagonists to various neurotransmitter receptors, indicating direct effects on I:(to) channels. CONCLUSIONS: Nicotine is a potent inhibitor of cardiac A-type K(+) channels, with blockade probably due to block of closed and open channels. This action may contribute to the ability of nicotine to affect cardiac electrophysiology and induce arrhythmias.

Animals↗
PubMed2000

State-dependent barium block of wild-type and inactivation-deficient HERG channels in Xenopus oocytes.

The effects of Ba2+ on current resulting from the heterologous expression of the human ether-à-go-go related gene (HERG) (IHERG) was studied with two-electrode voltage clamp techniques in Xenopus oocytes. Ba2+ produced time- and voltage-dependent block of IHERG. Significant inhibition was seen at concentrations as low as 1 microM. Inhibition was greatest at step potentials between -40 and 0 mV; at more positive potentials, inhibition decreased in association with time-dependent unblocking of channels. An inactivation-attenuated mutant of HERG (S631A) was prepared and expressed in Xenopus oocytes. Ba2+ block of S631A differed from that of HERG in that extensive unblocking was no longer seen at positive potentials and the voltage dependence of step current block was greatly attenuated. A mathematical model was applied to analyse quantitatively the inhibitory effects of Ba2+ on IHERG. The model suggested similar voltage-dependent affinity of Ba2+ for the open and closed states, along with absence of binding to the inactivated state, and accounted well for Ba2+ effects on both wild-type and S631A channels. We conclude that Ba2+ potently inhibits IHERG in a characteristic state-dependent fashion, with strong unblocking at positive potentials related to the presence of an intact C-type inactivation mechanism.

Amino Acid Substitution↗
PubMed2000

Contrasting efficacy of dofetilide in differing experimental models of atrial fibrillation.

BACKGROUND: Rapid atrial pacing (RAP) and congestive heart failure (CHF) produce different experimental substrates for atrial fibrillation (AF). We tested the hypothesis that AF maintained by different substrates responds differently to antiarrhythmic-drug therapy. METHODS AND RESULTS: The class III antiarrhythmic agent dofetilide was given intravenously at doses of 10 (D10) and 80 (D80) microg/kg to dogs with AF induced either (1) after 7 days of RAP at 400 bpm or (2) in the presence of CHF induced by rapid ventricular pacing. Dofetilide terminated AF in all CHF dogs, but D10 failed to terminate AF in any RAP dog, and D80 terminated AF in only 1 of 5 RAP dogs (20%) (P<0.01 for efficacy in CHF versus RAP dogs). Dofetilide was highly effective in preventing AF induction by atrial burst pacing in dogs with CHF but was totally ineffective in dogs with RAP. Dofetilide increased atrial effective refractory period and AF cycle length to a greater extent in CHF dogs. Epicardial mapping with 248 bipolar electrodes showed that CHF-related AF was often due to macroreentry, with dofetilide terminating AF by causing block in reentry circuits. RAP-related AF was due to multiple-wave front reentry, with dofetilide slowing reentry and decreasing the number of simultaneous waves, but not sufficiently to stop AF. CONCLUSIONS: The mechanism underlying AF importantly influences dofetilide efficacy. The dependence of drug efficacy in AF on the underlying mechanism has potentially significant implications for antiarrhythmic drug use and development and may explain the well-known therapeutic resistance of longer-duration AF.

Animals↗
PubMed2000

Effects of experimental heart failure on atrial cellular and ionic electrophysiology.

BACKGROUND: Congestive heart failure (CHF) is frequently associated with atrial fibrillation (AF), but little is known about the effects of CHF on atrial cellular electrophysiology. METHODS AND RESULTS: We studied action potential (AP) properties and ionic currents in atrial myocytes from dogs with CHF induced by ventricular pacing at 220 to 240 bpm for 5 weeks. Atrial myocytes from CHF dogs were hypertrophied (mean+/-SEM capacitance, 89+/-2 pF versus 71+/-2 pF in control, n=160 cells per group, P<0.001). CHF significantly reduced the density of L-type Ca(2+) current (I(Ca)) by approximately 30%, of transient outward K(+) current (I(to)) by approximately 50%, and of slow delayed rectifier current (I(Ks)) by approximately 30% without altering their voltage dependencies or kinetics. The inward rectifier, ultrarapid and rapid delayed rectifier, and T-type Ca(2+) currents were not altered by CHF. CHF increased transient inward Na(+)/Ca(2+) exchanger (NCX) current by approximately 45%. The AP duration of atrial myocytes was not altered by CHF at slow rates but was increased at faster rates, paralleling in vivo refractory changes. CHF created a substrate for AF, prolonging mean AF duration from 8+/-4 to 535+/-82 seconds (P<0.01). CONCLUSIONS: Experimental CHF selectively decreases atrial I(to), I(Ca), and I(Ks), increases NCX current, and leaves other currents unchanged. The cellular electrophysiological remodeling caused by CHF is quite distinct from that caused by atrial tachycardia, highlighting important differences in the cellular milieu characterizing different clinically relevant AF substrates.

Action Potentials↗
PubMed2000

Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators.

BACKGROUND: The restoration and maintenance of sinus rhythm is a desirable goal in patients with atrial fibrillation, because the prevention of recurrences can improve cardiac function and relieve symptoms. Uncontrolled studies have suggested that amiodarone in low doses may be more effective and safer than other agents in preventing recurrence, but this agent has not been tested in a large, randomized trial. METHODS: We undertook a prospective, multicenter trial to test the hypothesis that low doses of amiodarone would be more efficacious in preventing recurrent atrial fibrillation than therapy with sotalol or propafenone. We randomly assigned patients who had had at least one episode of atrial fibrillation within the previous six months to amiodarone or to sotalol or propafenone, given in an open-label fashion. The patients in the group assigned to sotalol or propafenone underwent a second randomization to determine whether they would receive sotalol or propafenone first; if the first drug was unsuccessful the second agent was prescribed. Loading doses of the drugs were administered and electrical cardioversion was performed (if necessary) within 21 days after randomization for all patients in both groups. The follow-up period began 21 days after randomization. The primary end point was the length of time to a first recurrence of atrial fibrillation. RESULTS: Of the 403 patients in the study, 201 were assigned to amiodarone and 202 to either sotalol (101 patients) or propafenone (101 patients). After a mean of 16 months of follow-up, 71 of the patients who were assigned to amiodarone (35 percent) and 127 of those who were assigned to sotalol or propafenone (63 percent) had a recurrence of atrial fibrillation (P<0.001). Adverse events requiring the discontinuation of drug therapy occurred in 18 percent of the patients receiving amiodarone, as compared with 11 percent of those treated with sotalol or propafenone (P=0.06). CONCLUSIONS: Amiodarone is more effective than sotalol or propafenone for the prevention of recurrences of atrial fibrillation.

Aged↗
PubMed2000

Dose-dependence of 4-aminopyridine plasma concentrations and electrophysiological effects in dogs : potential relevance to ionic mechanisms in vivo.

BACKGROUND: Previous investigators have administered 4-aminopyridine (4AP) to dogs to evaluate the role of transient outward current (I(to)) in vivo; however, plasma concentrations of 4AP were not measured, and it is therefore uncertain which cardiac ion channels were blocked at the concentrations achieved. METHODS AND RESULTS: We applied high-performance liquid chromatography to measure 4AP concentrations produced by intravenous 4AP administration to dogs. A previously described dose regimen produced plasma concentrations that increased during the maintenance infusion but never exceeded 250 micromol/L and caused significant mortality. Whole-cell patch-clamp experiments on isolated canine myocytes showed that even the maximum 4AP concentrations achieved in vivo failed to alter ventricular I(to) and had very small effects on atrial I(to); however, concentrations achieved in vivo had a strong inhibitory effect on the dog ultrarapid delayed rectifier (I(Kur.d)), present only in atrial cells. We designed a loading and maintenance infusion regimen to produce stable 4AP plasma concentrations. At concentrations in the range of 25 and 50 micromol/L, 4AP had no effect on ventricular refractory period but increased atrial refractoriness significantly, consistent with the results of voltage clamp studies. CONCLUSIONS: The interpretation of previous studies using intravenous 4AP administration to inhibit I(to) in dogs in vivo needs to be reevaluated in light of the fact that the infusion regimens used produce plasma concentrations that are inadequate to affect ventricular I(to). Our findings also support the concept that selective inhibition of ultrarapid delayed rectifier current can prolong atrial refractory periods without affecting ventricular refractoriness.

4-Aminopyridine↗
PubMed2000

Randomized trial comparing intravenous nitroglycerin and heparin for treatment of unstable angina secondary to restenosis after coronary artery angioplasty.

BACKGROUND: The treatment of unstable angina targets the specific pathophysiological thrombotic process at the site of the active culprit lesion. In unstable angina due to a restenotic lesion, smooth muscle cell proliferation and increased vasoreactivity may play a more important role than thrombus formation. Therefore, the relative benefits of nitroglycerin and heparin might differ in unstable angina associated with restenosis compared with classic unstable angina. METHODS AND RESULTS: We randomized 200 patients hospitalized for unstable angina within 6 months after angioplasty (excluding those with intracoronary stents) to double-blind administration of intravenous nitroglycerin, heparin, their combination, or placebo for 63+/-30 hours. Recurrent angina occurred in 75% of patients in the placebo and heparin-alone groups, compared with 42.6% of patients in the nitroglycerin-alone group and 41.7% of patients in the nitroglycerin-plus-heparin group (P<0.003). Refractory angina requiring angiography occurred in 22.9%, 29.2%, 4. 3%, and 4.2% of patients, respectively (P<0.002). The odds ratios for being event free were 0.24 (95% CI, -0.13 to 0.45, P=0.0001) for nitroglycerin versus no nitroglycerin and 0.98 (95% CI, -0.55 to 1. 73, P=NS) for heparin versus no heparin. No patient died or suffered myocardial infarction. CONCLUSIONS: Intravenous nitroglycerin is highly effective in preventing adverse ischemic events (recurrent or refractory angina) in patients with unstable angina secondary to restenosis, whereas heparin has no effect.

Aged↗
PubMed2000

Effects of ambasilide, quinidine, flecainide and verapamil on ultra-rapid delayed rectifier potassium currents in canine atrial myocytes.

OBJECTIVE: A dog atrial ultra-rapid delayed rectifier current (I(Kur. d)) is involved in canine atrial repolarization and shares similarities with the human atrial ultra-rapid delayed rectifier (I(Kur)). Almost no information is available about the actions of antiarrhythmic drugs on I(Kur.d). This study evaluated effects of ambasilide, quinidine, flecainide and verapamil on I(Kur.d) in isolated canine atrial myocytes. METHODS: Standard whole-cell patch clamp techniques were used to study the effects of multiple concentrations of each drug. RESULTS: All drugs produced reversible concentration-, voltage- and time-dependent I(Kur.d) inhibition. Significant effects of quinidine, flecainide and ambasilide were noted at atrial-effective antiarrhythmic concentrations in the dog. Upon the onset of a depolarizing pulse, block developed exponentially in relation to time, with the blocking rate-constant increasing with drug concentration, consistent with open-channel blockade and permitting the calculation of forward and reverse rate-constants. For all drugs, the 50% blocking concentration (EC(50)) showed significant voltage-dependence, decreasing at more positive potentials. The magnitude of voltage-dependent block was directly related to the degree of drug-induced shift in the voltage dependence of activation (r=0.97), pointing to open-channel block as a mechanism for voltage-dependent action. An additional component of voltage-dependence suggested that blocking sites were subjected to 17-21% of the transmembrane voltage field. CONCLUSIONS: Ambasilide, quinidine, flecainide and verapamil inhibit I(Kur.d), with preferential action on the open state. I(Kur.d) inhibition may play a role in antiarrhythmic effects in canine atrial arrhythmia models. Comparisons between the effects of these drugs on I(Kur.d) and previously studied effects on I(Kur) suggest potential opportunities for investigating the molecular structural determinants of drug-blocking action on atrial-specific ultrarapid delayed rectifiers.

Aminobenzoates↗
PubMed2000

Basic mechanisms of atrial fibrillation--very new insights into very old ideas.

Atrial fibrillation (AF) was recognized and studied extensively in the early twentieth century, but many fundamental aspects of the arrhythmia were poorly understood until quite recently. It is now recognized that AF can be initiated by a variety of mechanisms that share the ability to cause extremely rapid, irregular atrial electrical activity. Once initiated, AF causes alterations in atrial electrical properties (electrical remodeling), including both rapid functional changes and slower alterations in ion channel gene expression, which promote the maintenance of AF and facilitate reinitiation of the arrhythmia should it terminate. Electrical remodeling decreases the atrial refractory period in a heterogeneous way, thus decreasing the size and stability of potential functional atrial reentry waves and promoting multiple-circuit reentry. Whatever the initial cause of AF, electrical remodeling is likely to be a final common pathway that ultimately supervenes. Recent advances in understanding ion channel function, regulation, and remodeling at the molecular level have allowed for a much more detailed appreciation of the basic determinants of AF. Improvements in the clinical management of AF will inevitably follow the recent advances in our understanding of its detailed pathophysiology.

Animals↗
PubMed2000

A comparison of transient outward currents in canine cardiac Purkinje cells and ventricular myocytes.

Although abnormalities in Purkinje cell (PC) repolarization are important causes of cardiac arrhythmias, the detailed properties of repolarizing currents in PCs are incompletely understood. We compared transient outward K(+) current (I(to)) in single PCs from canine false tendons with midmyocardial ventricular myocytes (VMs). I(to) reactivation was biexponential, with a similar rapid-phase time constant (30 +/- 5 and 35 +/- 4 ms for VM and PC, respectively) but a large, slow component in PCs with a much greater time constant than VM (1,427 +/- 70 vs. 181 +/- 24 ms, P < 0.001). Tetraethylammonium had no effect on VM I(to) but reversibly inhibited PC I(to) (IC(50) = 2.4 +/- 0.4 mM). PC I(to) was also more sensitive to 4-aminopyridine (IC(50) = 50 +/- 7 vs. 526 +/- 49 microM in VM, P < 0.0001). H(2)O(2) slowed I(to) inactivation in PCs but did not affect VM I(to). We conclude that PC I(to) shows significant differences from VM I(to), with some features, such as tetraethylammonium sensitivity, that have been reported in neither cardiac I(to) of atrial or ventricular myocytes nor cloned K(+) channel subunits (Kv1.4, Kv4.2, or Kv4.3) known to participate in cardiac I(to).

4-Aminopyridine↗
PubMed2000

Mathematical analysis of canine atrial action potentials: rate, regional factors, and electrical remodeling.

Dogs have been used extensively to study atrial arrhythmias, but there are no published mathematical models of the canine atrial action potential (AP). To obtain insights into the ionic mechanisms governing canine atrial AP properties, we incorporated formulations of K(+), Na(+), Ca(2+), and Cl(-) currents, based on measurements in canine atrial myocytes, into a mathematical model of the AP. The rate-dependent behavior of model APs corresponded to experimental measurements and pointed to a central role for L-type Ca(2+) current inactivation in rate adaptation. Incorporating previously described regional ionic current variations into the model largely reproduced AP forms characteristic of the corresponding right atrial regions (appendage, pectinate muscle, crista terminalis, and atrioventricular ring). When ionic alterations induced by tachycardia-dependent remodeling were incorporated, the model reproduced qualitatively the AP features constituting the cellular substrate for atrial fibrillation. We conclude that this ionic model of the canine atrial AP agrees well with experimental measurements and gives potential insights into mechanisms underlying functionally important electrophysiological phenomena in canine atrium.

Action Potentials↗