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S Nattel

Publications and source records attributed to S Nattel.

At least 91 records · Page 5Linked to original sources
PubMed1997

Probucol and multivitamins in the prevention of restenosis after coronary angioplasty. Multivitamins and Probucol Study Group.

BACKGROUND: Oxidizing metabolites generated at the site of coronary angioplasty can induce chain reactions that may lead to restenosis. Antioxidants may counter oxidative stress and modify neointimal formation and vascular remodeling. Experimental data and small clinical studies have suggested that antioxidants may prevent restenosis after angioplasty. In a double-blind, randomized trial, we studied whether drugs with antioxidant properties decrease the incidence and severity of restenosis after angioplasty. METHODS: One month before angioplasty, 317 patients were randomly assigned to receive one of four treatments: placebo, probucol (500 mg), multivitamins (30,000 IU of beta carotene, 500 mg of vitamin C, and 700 IU of vitamin E), or both probucol and multivitamins-all given twice daily. Patients were treated for four weeks before and six months after angioplasty. Patients received an extra 1000 mg of probucol, 2000 IU of vitamin E, both probucol and vitamin E, or placebo 12 hours before angioplasty, according to their treatment assignments. Base-line and follow-up angiograms were interpreted by blinded investigators using a quantitative approach. RESULTS: The mean (+/-SD) reduction in luminal diameter six months after angioplasty was 0.12 +/- 0.41 mm in the probucol group, 0.22 +/- 0.46 mm in the combined-treatment group, 0.33 +/- 0.51 in the multivitamin group, and 0.38 +/- 0.50 mm in the placebo group (P = 0.006 for those receiving vs. those not receiving probucol, and P = 0.70 for those receiving vs. those not receiving vitamins. Restenosis rates per segment were 20.7 percent in the probucol group, 28.9 percent in the combined-treatment group, 40.3 percent in the multivitamin group, and 38.9 percent in the placebo group (P = 0.003 for probucol vs. no probucol). The rates of repeat angioplasty were 11.2 percent. 16.2 percent, 24.4 percent, and 26.6 percent, respectively (P = 0.009 for probucol vs. no probucol). CONCLUSIONS: The antioxidant probucol is effective in reducing the rate of restenosis after balloon coronary angioplasty.

Angioplasty, Balloon, Coronary↗
PubMed1997

Insights into mechanisms of antiarrhythmic drug action from experimental models of atrial fibrillation.

Atrial fibrillation (AF) remains a challenge to medical therapy. Over the past several years, a variety of experimental models of AF have been developed. These have provided insights into mechanisms underlying AF and antiarrhythmic drug action against the arrhythmia. A variety of drugs effective against clinical AF, including flecainide, propafenone, procainamide, and sotalol, have been found to terminate experimental AF. All of these agents appear to act by prolonging the wavelength for atrial reentry at rapid rates, thereby increasing the size and decreasing the number of functional circuits maintaining the arrhythmia. While the ability to terminate AF is determined by refractoriness prolongation at rapid rates, refractoriness prolongation at slow rates (e.g., sinus rhythm) can prevent AF induction by premature beats. Thus, drugs with strong reverse use-dependence (like sotalol) may be much more effective in preventing than in terminating AF. Spacial heterogeneity in refractoriness is an important contributor to AF occurrence in some models, particularly vagal AF, and is reduced by some (but not all) drugs that terminate AF. New insights are being gained into mechanisms of electrical remodeling, which promotes AF maintenance when rapid atrial rates are maintained, such as during AF. This electrical remodeling may be an interesting novel target for therapy of AF. Insights into AF mechanisms obtained in experimental models of AF should help in the development of new and improved therapeutic approaches.

Animals↗
PubMed1997

Properties of human atrial ICa at physiological temperatures and relevance to action potential.

There are no published characterizations of Ca2+ current (ICa) at physiological temperatures in human atrium. Depolarization of human atrial myocytes at 36 degrees C elicited ICa that peaked at +10 mV, with a mean maximum current density of 10.8 +/- 1.1 pA/pF and no evidence for T-type current. Overlap between activation and inactivation curves and incomplete inactivation during pulses comparable to normal action potential duration (APD) were compatible with the observed role of ICa in maintaining the plateau. ICa was frequency dependent between 0.1 and 2 Hz and ICa blockade with 0.2 mM Cd2+ reduced rate-dependent changes in APD: under control, APD at 90% repolarization was 230 +/- 15 ms at 0.1 Hz and 178 +/- 14 ms at 2 Hz (decrease of 52 +/- 5 ms); with Cd2+, values were 121 +/- 7 ms at 0.1 H2 and 115 +/- 6 ms at 2 Hz (decrease of 6 +/- 3 ms, P < 0.01) Isoproterenol (1 microM) increased ICa and prolonged APD from 138 +/- 13 to 199 +/- 15 ms (P < 0.01). These results indicate that, in human atrial cells at 36 degrees C, the properties of L-type ICa contribute importantly to the rate-dependent and autonomic control of APD.

Action Potentials↗
PubMed1997

Mechanisms of inactivation of L-type calcium channels in human atrial myocytes.

We used whole cell patch-clamp and microfluorimetric (indo 1) techniques to measure Ca2+ current through L-type Ca2+ channels (I(Ca)) and Ca2+ transients in human atrial myocytes. During 1-s depolarizing pulses, I(Ca) inactivation was biexponential. The rate of rapid inactivation was slowed by ryanodine and was correlated with the rate of rise of cytoplasmic free Ca2+ concentration (r = 0.80, P < 0.01). Slower-phase I(Ca) inactivation was not affected by ryanodine but was accelerated by increasing the availability of Ca2+ to permeate the Ca2+ channel. Thus Ca2+ released from the sarcoplasmic reticulum (SR) was responsible for most I(Ca) inactivation during the first 50 ms of a depolarization to 0 mV, and thereafter inactivation by Ca2+ permeating the channel predominated. Pure voltage-dependent inactivation had a much slower time course of development (tau > 2 s) and played a smaller role than Ca2+-dependent mechanisms over a duration comparable to that of an action potential. We conclude that human atrial myocytes show both voltage- and Ca2+-dependent I(Ca) inactivation, that Ca2+-dependent mechanisms predominate over the time course of an action potential, and that although both Ca2+ released from the SR and Ca2+ permeating Ca2+ channels play a role, SR-released Ca2+ is particularly important in early, rapid I(Ca) inactivation, whereas Ca2+ permeating Ca2+ channels is more important in the slower phase of Ca2+-dependent inactivation.

Calcium↗
PubMed1997

Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity.

Although sympathetic activation is believed to promote atrial fibrillation (AF), the effects of sympathetic stimulation on AF have not been systematically studied. In seven morphine-chloralose-anesthetized dogs, autonomic decentralization increased atrial effective refractory period (ERP) and reentrant wavelength (WL) and decreased the duration of AF induced by burst atrial pacing. Graded bilateral stellate ansa stimulation decreased ERP and WL to values similar to those before decentralization but did not return AF duration to predecentralization values. Sympathetic and bilateral vagal stimulation were adjusted in six additional dogs to produce similar effects on ERP and WL. Despite comparable effects on mean WL, the duration of AF was increased by vagal stimulation from 14 +/- 5 (control) to 372 +/- 96 s (P < 0.001) but was not altered significantly (26 +/- 10 s) by sympathetic stimulation. Vagal stimulation increased the variability in atrial refractoriness, as indicated by the standard deviation of ERP at seven atrial sites and of activation frequency during AF at 112 recording sites, whereas sympathetic stimulation had no significant effect on these indexes of ERP heterogeneity. We conclude that sympathetic stimulation is much less effective than vagal stimulation in promoting AF and that heterogeneity in atrial ERP may be important in determining the ability to sustain AF.

Animals↗
PubMed1997

Evidence that outwardly rectifying Cl- channels underlie volume-regulated Cl- currents in heart.

Swelling-induced Cl- current (ICl.swell) is present in most cardiac tissues, but the unitary channel underlying ICls.well is unknown. We used the cell-attached patch-clamp technique to assess the properties of single channels underlying ICls.well and the basally active Cl- current (ICl.b) in rabbit atrial myocytes. Under isotonic conditions, single outwardly rectifying Cl- channels (ORCCs) with a slope conductance of 28 +/- 1 pS at the reversal potential were observed in 21 (5.7%) of 367 patches. Unconditional kinetic analysis revealed at least three open and four closed-channel states. Hypotonic superfusion-induced swelling resulted in the appearance of active channels in 41 (15.5%) of 265 patches without channel activity under isotonic conditions and caused a second active channel to appear in 3 of 14 patches showing a single channel under isotonic conditions. Overall, channels were seen in 54 of 336 patches under hypotonic conditions (16.1%, P < .001 versus isotonic conditions). The current-voltage relations, reversal potential-[Cl-]o relations, open probability, and kinetics of swelling-induced channels were indistinguishable from those of ORCCs under isotonic conditions. Unitary ORCCs, ICl.b, and ICl.swell were strongly and similarly inhibited by tamoxifen. Swelling-induced increases in macroscopic Cl- current were attributable to an increase in the number of active ORCCs with no significant effects on single-channel amplitude or open probability. Estimated macroscopic currents based on cell surface area, patch dimensions, single-channel ORCC current amplitude, open probability, and density were consistent with measured values of ICl.b and ICl.swell. We conclude that ORCCs underlie volume-regulated basal and swelling-induced Cl- currents in isolated rabbit atrial myocytes.

Animals↗
PubMed1997

Antisense oligodeoxynucleotides directed against Kv1.5 mRNA specifically inhibit ultrarapid delayed rectifier K+ current in cultured adult human atrial myocytes.

Several cloned K+ channel subunits are candidates to underlie macroscopic currents in the human heart, but direct evidence bearing on their role is lacking. The Kv1.5 K+ channel subunit has been suggested to play a potential role in human cardiac ultrarapid delayed rectifier (IKur) and transient outward (Ito) currents. To evaluate the role of proteins encoded by the Kv1.5 gene, we incubated cultured human atrial myocytes for 48 hours in medium containing antisense phosphorothioate oligodeoxynucleotides directed against octodecameric segments of the Kv1.5 mRNA coding sequence, the same concentration of homologous oligodeoxynucleotides with four mismatch mutations, or vehicle (control group). Cells exposed to antisense showed a highly significant (approximately 50%) reduction in IKur whether measured by step current at the end of a 400-millisecond depolarizing pulse, tail current at -20 mV, or current sensitive to a concentration of 4-aminopyridine (50 mumol/L) that is highly selective for IKur compared with control cells or cells exposed to mismatch oligodeoxynucleotides. In contrast, Ito was not different among the three experimental groups. When cultured human ventricular myocytes were exposed to Kv1.5 antisense oligodeoxynucleotides with the same controls, no changes occurred in either Ito or the sustained current at the end of a depolarizing pulse. We conclude that Kv1.5 channel subunits are essential to the expression of IKur and do not play a role in Ito in cultured human atrial myocytes. These studies provide the first direct evidence with an antisense approach for the equivalence between a macroscopic cardiac K+ current and a cloned K+ channel subunit and offer insights into the molecular electrophysiology of the human heart.

Adult↗
PubMed1997

Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation.

Rapid electrical activation, as occurs during atrial fibrillation (AF), is known to cause reductions in atrial refractoriness and in adaptation to heart rate of the atrial refractory period, which promote the maintenance of AF, but the underlying ionic mechanisms are unknown. In order to determine the cellular and ionic changes caused by chronic atrial tachycardia, we studied right atrial myocytes from dogs subjected to 1, 7, or 42 days of atrial pacing at 400/min and compared them with myocytes from sham-operated dogs (pacemaker inserted but not activated). Rapid pacing led to progressive increases in the duration of AF induced by bursts of 10-Hz stimuli (from 3 +/- 2 seconds in sham-operated dogs to 3060 +/- 707 seconds in dogs after 42 days of pacing, P < .001) and reduced atrial refractoriness and adaptation to rate of the atrial refractory period. Voltage-clamp studies showed that chronic rapid pacing did not alter inward rectifier K+ current, rapid or slow components of the delayed rectifier current, the ultrarapid delayed rectifier current, T-type Ca2+ current, or Ca(2+)-dependent Cl- current. In contrast, the densities of transient outward current (Ito) and L-type Ca2+ current (ICa) were progressively reduced as the duration of rapid pacing increased, without concomitant changes in kinetics or voltage dependence. In keeping with in vivo changes in refractoriness, action potential duration (APD) and APD adaptation to rate were decreased by rapid pacing. The response of the action potential and ionic currents flowing during the action potential (as exposed by action-potential voltage clamp) to nifedipine in normal canine cells and in cells from rapidly paced dogs suggested that the APD changes in paced dogs were largely due to reductions in ICa. We conclude that sustained atrial tachycardia reduces Ito and ICa, that the reduced ICa decreases APD and APD adaptation to rate, and that these cellular changes likely account for the alterations in atrial refractoriness associated with enhanced ability to maintain AF in the model.

Action Potentials↗
PubMed1997

Tachycardia-induced changes in Na+ current in a chronic dog model of atrial fibrillation.

We have previously shown that chronic rapid atrial activation (400 bpm) reduces atrial conduction velocity in dogs, contributing to the development of a substrate supporting sustained atrial fibrillation (AF). However, the cellular and ionic mechanisms underlying these functional changes have not been defined. We applied whole-cell patch-clamp techniques to atrial myocytes from dogs subjected to atrial pacing at 400 bpm for 7 days (P7, n = 6) and 42 days (P42, n = 5) and compared the results with those from sham-operated dogs similarly instrumented but without pacemaker activation (P0, n = 6). Rapid atrial pacing allowed for the induction of sustained AF in 67% and 100% of dogs paced for 7 and 42 days, respectively, and significantly decreased conduction velocity under P7 and P42 conditions. In dogs paced for 7 days, Na+ current (INa) density was reduced by 28% at -40 mV (P < .0001, n = 59 cells). INa changes were even more decreased under P42 conditions, by approximately 52% at -40 mV (P < .0001): from -78.7 +/- 4.6 pA/pF (P0, n = 28 cells) to -37.7 +/- 3.0 pA/pF (P42, n = 43 cells). INa was significantly reduced at all voltages ranging from -65 to -10 mV. Voltage-dependent activation and inactivation properties, activation kinetics, and recovery from inactivation were not altered by rapid atrial pacing; however, inactivation kinetics were slowed. AF duration was related to mean INa in each dog (r2 = .573, P < .001). We conclude that rapid atrial activation significantly reduces both conduction velocity and INa density. Since INa is a major determinant of conduction velocity, our data point to INa reduction as a potentially important mechanism contributing to the substrate for AF in this model.

Animals↗
PubMed1997

Effects of class III antiarrhythmic drugs on transient outward and ultra-rapid delayed rectifier currents in human atrial myocytes.

A variety of class III antiarrhythmic agents have been shown to block the delayed rectifier current, but their effects on other K+ currents, particularly in human tissues, are less clear. We studied the concentration-dependent actions of the class III compounds d-sotalol, E-4031 and ambasilide on the transient outward current (I(to)) and the ultra-rapid delayed rectifier current (I(Kur)) in human atrial myocytes. d-Sotalol and E-4031 failed to alter I(to) or I(Kur) at concentrations up to 500 and 50 microM, respectively. In contrast, ambasilide produced a concentration-dependent inhibition of I(to) and I(Kur), with statistically significant effects at 10 microM and maximum effects at 100 microM. The 50% inhibitory concentration of ambasilide averaged 23 +/- 2 microM and 34 +/- 3 microM for I(to) and I(Kur) respectively. Ambasilide did not alter the voltage-dependence of activation or inactivation of I(to), or the voltage-dependence of I(Kur), and it did not affect I(to) recovery from inactivation. On the other hand, ambasilide accelerated I(to) inactivation, by introducing a more rapid component that accelerated with increasing drug concentration. Furthermore, block of both I(to) and I(Kur) developed over time after the onset of depolarization, with time constants of 5.8 +/- 0.8 msec and 2.5 +/- 0.4 msec at concentrations of 10 and 50 microM for I(to) and 6.1 +/- 0.8 msec and 2.1 +/- 0.3 msec at 10 and 50 microM for I(Kur). We conclude that neither d-sotalol nor E-4031 affects I(to) or I(Kur), whereas ambasilide produces efficacious open-channel block of both currents, in human atrial myocytes.

Aminobenzoates↗
PubMed1996

Characterization of an ultrarapid delayed rectifier potassium channel involved in canine atrial repolarization.

1. Depolarizing pulses positive to 0 mV elicit a transient outward current (Ito) and a sustained 'pedestal' current in canine atrial myocytes. The pedestal current was highly sensitive to 4-aminopyridine (4-AP) and TEA, with 50% inhibitory concentrations (EC50) of 5.3 +/- 0.7 and 307 +/- 25 microM, respectively. When the pedestal current was separated from Ito with prepulses or by studying current sensitive to 10 mM TEA, it showed very rapid activation and deactivation. We therefore designated the current IKur,d, for 'ultrarapid delayed rectifier, dog'. IKur,d inactivation was bi-exponential, with mean time constants of 609 +/- 91 and 5563 +/- 676 ms during a 20 s pulse to +40 mV. 2. The reversal potential of IKur,d tail currents are dependent on extracellular potassium concentration ([K+]o; slope, 54.7 mV decade-1). The envelope of tails test was satisfied and the current inwardly rectified at > or = +40 mV. The current was insensitive to E-4031, dendrotoxin and chloride substitution, but was inhibited by barium, with an EC50 of 1.65 mM. Lanthanum ions caused a positive shift in voltage dependence without producing direct inhibition. 3. Single-channel activity was observed in cell-attached, inside-out and outside-out patches. Upon depolarization from -50 to +30 mV, single channels had similar time constants and [K+]o dependence to whole-cell current. Channel open probability (Po) increased with depolarization in a saturable fashion and the Po-voltage relation had a half-activation voltage and slope factor similar to whole-cell IKur,d. 4. Unitary channel current was linearly related to depolarization potential to +40 mV; at more positive potentials, inward rectification occurred. The unitary conductance was 20.3 and 35.5 pS for an [K+]o of 5.4 and 130 mM, respectively. Single-channel activity was strongly inhibited by 50 microM 4-AP or 10 mM TEA. Both 4-AP and TEA decreased open time, suggesting open-channel block. 5. Selective inhibition of IKur,d with 50 microM 4-AP or 0.3-5 mM TEA prolonged canine atrial action potentials, indicating that IKur,d contributes to canine atrial repolarization. The single-channel and macroscopic properties of IKur,d have many similarities to those of currents carried by Kv3.1 cloned channels and our findings thus suggest a possible role for Kv3.1 channels in cardiac repolarization.

4-Aminopyridine↗
PubMed1996

Relative role of alkalosis and sodium ions in reversal of class I antiarrhythmic drug-induced sodium channel blockade by sodium bicarbonate.

BACKGROUND: Hypertonic sodium salts are used to treat sodium channel-blocking drug cardiotoxicity. The relative roles of alkalinization and increased sodium concentration ([Na+]o) for various drugs are incompletely known. METHODS AND RESULTS: The effects of four class I drugs on action potential characteristics of canine Purkinje fibers at equieffective concentrations (disopyramide 30 mumol/L, mexiletine 80 mumol/L, flecainide 7 mumol/L, imipramine 5 mumol/L) were studied in the presence of normal Tyrode solution and one altered solution (increased [Na+]o, increased bicarbonate concentration, or both) in each experiment. Combined increases in sodium and bicarbonate concentration significantly reduced the depressant effects of flecainide, imipramine, and mexiletine on phase 0 upstroke (Vmax) but did not alter the effects of disopyramide. The effects of sodium bicarbonate were entirely due to alkalinization in the case of imipramine, but both alkalinization and increased [Na+]o contributed to the interaction with flecainide and mexiletine. The reversal of Vmax depression by increased [Na+]o and pH was due in part to hyperpolarization. In addition, alkalosis directly reversed the hyperpolarizing shift in Vmax inactivation caused by flecainide and imipramine without altering the shift caused by disopyramide and mexiletine. CONCLUSIONS: Increases in sodium bicarbonate concentration reverse the effects of class I antiarrhythmic drugs to a varying extent, with drug-specific contributions of the sodium and bicarbonate moiety. The molecular basis for this drug specificity remains to be elucidated, but it has important potential implications for the use of hypertonic sodium salts to treat cardiotoxicity caused by sodium channel-blocking drugs.

Alkalosis↗
PubMed1996

Transmembrane chloride currents in human atrial myocytes.

The present study was designed to evaluate the presence of basal, swelling-induced, and cAMP-dependent Cl- currents in human atrial myocytes studied with the whole cell patch-clamp technique. Under basal conditions, a small outwardly rectifying background conductance was noted that reversed close to 0 mV and was not altered by Cl- replacement. Isoproterenol (1 microM), forskolin (3 microM), and 8-bromoadenosine 3',5'-cyclic monophosphate (50 microM) did not increase membrane conductance, even when responsiveness to isoproterenol was confirmed by an increase in Ca2+ current and when perforated-patch techniques (nystatin) were used. Exposure to hyposmotic solutions increased cell volume and induced a whole cell conductance that showed outward rectification, was inhibited by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (100 microM), and responded to changes in Cl- gradient in a fashion consistent with a Cl(-)-selective conductance, with estimated relative permeabilities of 1, 0.25, and 0.07 for Cl-, methanesulfonate, and aspartate, respectively. The results suggest that human atrial cells lack basal and adenosine 3',5'-cyclic monophosphate-dependent Cl- current but manifest a substantial Cl- conductance in the presence of cell swelling.

Animals↗
PubMed1996

Properties of sodium and potassium currents of cultured adult human atrial myocytes.

Cultured cell systems are valuable for the study of regulation of phenotypic expression, but little is known about the electrophysiological properties of human cardiac tissues in culture. The present studies were designed to determine the feasibility of maintaining human atrial myocytes in primary culture and to assess changes in Na+ (INa) and K+ (Ito, transient outward, and Ikur, ultra-rapid delayed rectifier) currents. Within 24 h of culture, cells assumed an avoid shape, which they maintained for up to 7 days. The voltage dependence, kinetics, and density of INa were unchanged in culture. The activation properties of Ito (kinetics and voltage dependence) were not altered, but Ito density (current normalized to cell capacitance) was reduced and inactivation properties were altered (negative shift in voltage dependence and slowed kinetics) in cultured compared with fresh cells. The absolute current amplitude, kinetics, voltage dependence, and 4-aminopyridine sensitivity of IKur were unchanged, but current density was increased. All changes in ionic currents occurred within 24 h of culture and remained stable for the next 4 days. We conclude that human atrial myocytes can be maintained in primary culture, that the qualitative properties of INa, Ito, and IKur remain constant but that some quantitative changes occur, and that cultured human atrial myocytes may be valuable for studies of the molecular mechanisms and regulation of cardiac channel function in humans.

4-Aminopyridine↗
PubMed1996

Transient outward and delayed rectifier currents in canine atrium: properties and role of isolation methods.

Although the dog is the principal species used for in vivo studies of atrial arrhythmias, little is known about currents governing canine atrial repolarization. Cells were isolated from dog atria by exposure to collagenase of tissue in vitro ("chunk cells") and by arterial perfusion ("perfusion cells"). Whole cell voltage clamp revealed transient outward K+ current (Ito1), Ca(2+)-dependent Cl- current (Ito2), and delayed rectifier K+ current (IK). Ito1 recovered rapidly and showed little frequency dependence. Two components of IK were present as follows: a rapidly activating E-4031-sensitive current with marked inward recitification and a slower-activating E-4031-insensitive component. Ito1 and IK resembled corresponding currents previously described in human atrium. Transient outward currents were similar in chunk and perfusion cells, but IK was seen in 4% of chunk cells vs. 99% of perfusion cells (P < 0.001). Suppression of each identified current retarded canine action potential repolarization. We conclude that Ito1, Ito2, and both components of IK are present in dog atrium, IK is much more sensitive to the isolation method than Ito1 or Ito2, and the properties of two important repolarizing currents (Ito1 and IK) previously described in human atrium are similar to those in dog atrium.

Action Potentials↗
PubMed1996

Regional and functional factors determining induction and maintenance of atrial fibrillation in dogs.

The present study was designed to determine the factors governing the ability of premature beats at various atrial sites to initiate atrial fibrillation (AF) and the determinants of the duration of AF in dogs at 1-10 Hz. The site of atrial extrasystoles determined their ability to induce AF. Regional differences in AF inducibility were due to differences in local refractoriness. Premature beats initiated AF by blocking in regions of greater refractoriness, causing macroreentrant activation with subsequent disorganization producing fibrillation. The atrial refractory period and wavelength during rapid 1:1 atrial pacing were weak predictors of AF duration (r = 0.24 and 0.23, respectively), which depended strongly on variability in regional refractoriness measured by the standard deviation in local refractory periods (r = 0.80, P < 0.001) and on the heterogeneity of activation during AF (r = 0.74, P < 0.001). Thus, premature beats cause AF by initiating a single macroreentrant cycle that degenerates into multiple wavefronts, regional refractoriness is the primary determinant of AF induction by premature beats, and variability in refractoriness may be an important determinant of the ability of AF to sustain itself.

Animals↗