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.

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.

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.

Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical model.

UNLABELLED: Recent advances in molecular electrophysiology have made possible the development of more selective ion channel blockers for therapeutic use. However, more information is needed about the effects of blocking specific channels on repolarization in normal human atrium and in atrial cells of patients with atrial fibrillation (AF). AF-induced electrical remodeling is associated with reductions in transient outward current (Ito), ultrarapid delayed rectifier current (IKur), and L-type calcium current (ICa,L). Direct evaluation of the results of ion channel depression is limited by the nonspecificity of the available pharmacological probes. OBJECTIVES: Using a mathematical model of the human atrial action potential (AP), we aimed to: (1) evaluate the role of ionic abnormalities in producing AP changes characteristic of AF in humans and (2) explore the effects of specific channel blockade on the normal and AF-modified AP (AFAP). METHODS: We used our previously developed mathematical model of the normal human atrial AP (NAP) based on directly measured currents. We constructed a model of the AFAP by incorporating experimentally-measured reductions in Ito (50%), IKur (50%), and ICa,L (70%) current densities observed in AF. RESULTS: The AFAP exhibits the reductions in AP duration (APD) and rate-adaption typical of AF. The reduction in ICa,L alone can account for most of the morphological features of the AFAP. Inhibition of Ito by 90% leads to a reduction in APD measured at -60 mV in both the NAP and AFAP. Inhibition of the rapid component of the delayed rectifier (IKr) by 90% slows terminal repolarization of the NAP and AFAP and increases APD by 38% and 34%, respectively. Inhibition of IKur by 90% slows early repolarization and increases plateau height, activating additional IK and causing no net change in APD at 1 Hz in the NAP. In the presence of AF-induced ionic modifications, IKur inhibition increases APD by 12%. Combining IKur and IKr inhibition under both normal and AF conditions synergistically increases APD. In the NAP, altering the model parameters to reproduce other typical measured AP morphologies can significantly alter the response to K(+)-channel inhibition. CONCLUSIONS: (1) The described abnormalities in Ito, IKur and ICa,L in AF patients can account for the effects of AF on human AP properties; (2) AP prolongation by IKur block is limited by increases in plateau height that activate more IK; (3) Blockers of IKur may be more effective in prolonging APD in patients with AF; 4) Inhibition of both IKur and IKr produces supra-additive effects on APD. These observations illustrate the importance of secondary current alterations in the response of the AP to single channel blockade, and have potentially important implications for the development of improved antiarrhythmic drug therapy for AF.

Local Ca2+ entry through L-type Ca2+ channels activates Ca2+-dependent K+ channels in rabbit coronary myocytes.

Large-conductance Ca2+-dependent K+ channels (KCa), which are abundant on the sarcolemma of vascular myocytes, provide negative feedback via membrane hyperpolarization that limits Ca2+ entry through L-type Ca2+ channels (ICaL). We hypothesize that local accumulation of subsarcolemmal Ca2+ during ICaL openings amplifies this feedback. Our goal was to demonstrate that Ca2+ entry through voltage-gated ICaL channels can stimulate adjacent KCa channels by a localized interaction in enzymatically isolated rabbit coronary arterial myocytes voltage clamped in whole-cell or in cell-attached patch clamp mode. During slow-voltage-ramp protocols, we identified an outward KCa current that is activated by a subsarcolemmal Ca2+ pool dissociated from bulk cytosolic Ca2+ pool (measured with indo 1) and is dependent on L-type Ca2+ channel activity. Transient activation of unitary KCa channels in cell-attached patches could be detected during long step depolarizations to +40 mV (holding potential, -40 mV; 219 pS in near-symmetrical K+). This local interaction between the channels required the presence of Ca2+ in the pipette solution, was enhanced by the ICaL agonist Bay K 8644, and persisted after impairment of the sarcoplasmic reticulum by incubation with 10 micromol/L ryanodine and 30 micromol/L cyclopiazonic acid for at least 60 minutes. Furthermore, we provide the first direct evidence of simultaneous openings of single KCa (67 pS) and ICaL (3.9 pS) channels in near-physiological conditions, near resting membrane potential. Our data imply a novel sensitive mechanism for regulating resting membrane potential and tone in vascular smooth muscle.

Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model.

The mechanisms underlying many important properties of the human atrial action potential (AP) are poorly understood. Using specific formulations of the K+, Na+, and Ca2+ currents based on data recorded from human atrial myocytes, along with representations of pump, exchange, and background currents, we developed a mathematical model of the AP. The model AP resembles APs recorded from human atrial samples and responds to rate changes, L-type Ca2+ current blockade, Na+/Ca2+ exchanger inhibition, and variations in transient outward current amplitude in a fashion similar to experimental recordings. Rate-dependent adaptation of AP duration, an important determinant of susceptibility to atrial fibrillation, was attributable to incomplete L-type Ca2+ current recovery from inactivation and incomplete delayed rectifier current deactivation at rapid rates. Experimental observations of variable AP morphology could be accounted for by changes in transient outward current density, as suggested experimentally. We conclude that this mathematical model of the human atrial AP reproduces a variety of observed AP behaviors and provides insights into the mechanisms of clinically important AP properties.

Impaired endothelin-1 release in tilt-induced syncope.

The neurohumoral events associated with neurocardiogenic syncope remain unclear. The simultaneous assessment of changes in endothelium-dependent and independent hormones and in autonomic balance in patients with tilt-induced syncope has been incompletely studied. Forty-six healthy subjects aged between 21 and 83 years (mean +/- SEM 47 +/- 3) underwent a 30-minute head-up tilt test at 60 degrees. Fourteen subjects (10 females and 4 male subjects) exhibited syncope at 16 +/- 2 minutes into the tilt. Hemodynamics were recorded every 5 minutes and blood samples for the measure of catecholamines, endothelin-1 (ET-1), and angiotensin-II (AT-II), were drawn at baseline, and 5, 10, 15, and 30 minutes into the tilt and immediately before syncope. Heart rate variability was analyzed by 5-minute segments during the test. Both catecholamines and ET-1 levels increased consistently in response to head-up tilt in subjects able to tolerate the test. Epinephrine increased to a greater extent before syncope. In contrast, ET-1 failed to increase at any time during the tilt and just before syncope. AT-II increased at 30 minutes into the tilt only in the control group. Finally, power in high-frequency bands decreased less in the group with syncope. Thus, compared with subjects able to tolerate a head-up tilt test, patients with syncope exhibit a greater increase in adrenomedullary activation, no significant increase in ET-1 levels, and a blunting in the decrease of vagal tone before syncope. The lack of increase in ET-1 during tilt may play a role in the inability to support orthostatic stress.

Age- and gender-related changes in endothelin and catecholamine release, and in autonomic balance in response to head-up tilt.

1. There is an increase in circulating levels of vasoconstrictive hormones and an alteration in baroreceptor responsiveness with aging. The role of changes in endothelium-dependent and -independent vasoconstrictive hormones in relation to age and gender, with simultaneous assessment of autonomic balance in response to head-up tilt, has been incompletely studied. 2. Sixteen young [25 +/- 3 years (mean +/- SEM)] and 16 older normal volunteers (68 +/- 7 years) underwent a 30 min head-up tilt test at 60 degrees. Haemodynamics were measured every 5 min and blood samples for neurohormone measurement were drawn at baseline, 5, 10, 15 and 30 min into the test. Heart rate variability was analysed in 5 min segments at the baseline, and during the test. The younger subjects exhibited a greater increase in heart rate and diastolic blood pressure, despite lower absolute levels of noradrenaline (norepinephrine) and endothelin-1. Analysis of heart rate variability yielded a decrease in both high- and low-frequency bands in the aged; power at low-frequency decreased only in the young subjects. The age-related differences in blood pressure and noradrenaline levels were markedly attenuated in the female subjects. In addition, endothelin-1 levels and power spectral measurements at low frequency were the lowest in younger females throughout the tilt. 3. Despite attenuated cardiovascular response to tilt, both systemic adrenergic 'drive' and endothelin-1 levels increase in parallel with aging. Thus, endothelium-dependent and -independent vasoconstrictive hormone levels increase with age in the resting state and in response to neurohumoral stimulation in humans.

Hydromorphone patient-controlled analgesia (PCA) after coronary artery bypass surgery.

We conducted a study to compare the effectiveness of patient-controlled analgesia (PCA) technique to conventional analgesic therapy (CAT) after coronary artery bypass graft (CABG). The PCA group received hydromorphone 0.1 mg.hr-1 basal infusion and bolus doses of 0.2 mg Q 5 min (maximum 1.2 mg.hr-1) while the CAT group received morphine 2.5 mg iv Q 30 min prn until extubation followed by prn meperidine 1 mg.kg-1 im Q 4 hr or acetaminophen 325 mg with codeine 30 mg po (1 or 2 tablets) when oral intake was possible. The degree of pain was assessed using a Visual Analogue Scale (VAS) starting after extubation and every 6-8 hr for the next 60 hr. Holter monitoring was initiated one hour after patient arrival in the Intensive Care Unit (ICU) and continued for 72 hr. Other measured variables were pulmonary function, sedation, side effects and total opioid requirements. Results show that the day-to-day VAS pain score decreased in the PCA group (P < 0.001) while it remained unchanged in CAT patients. The PCA patients had lower VAS pain scores at extubation (P < 0.05). During the third postoperative day, the PCA group had a lower VAS pain score, a lower incidence of severe pain defined as a score > 5 on the VAS scale, and a reduced incidence of myocardial ischaemia (P < 0.01). However, there was no difference in the duration, severity, area under the curve (AUC), or heart rate during ischaemic events. Postoperative pulmonary function was abnormal in both groups (NS) with minimal recovery by the fourth day.(ABSTRACT TRUNCATED AT 250 WORDS)

Theoretical computation of phase locking in embryonic atrial heart cell aggregates.

The effects of periodic stimulation of spontaneously beating aggregates of chick atrial heart cells are considered. Provided the effects of a single stimulus do not change the properties of the oscillation, and that the oscillation is re-established rapidly following a stimulus, this system can be modeled by one-dimensional finite difference equations. These equations employ experimentally generated phase resetting data that describe the effects of a single isolated stimulus at different phases of the oscillation. A complete analysis of the predicted dynamics is given over a broad range of stimulation frequencies and amplitudes. Prominent features of the dynamics include phase locking, bistability, chaos, and disappearance of Arnold tongues at large stimulation amplitudes. The fine details of the bifurcations are sensitive to properties of the phase resetting curves, and consequently, the observed bifurcations are not expected to be "universal" for larger stimulation amplitudes. Experimental traces show many correspondences with theoretical computations.

A clinical study of the dynamics of parasystole.

A mathematical model for pure parasystole and modulated parasystole leads to a number of quantitative predictions. The predictive power of the model is examined by confronting it with data obtained from a 16-year-old symptomatic male born with a ventricular septal defect that was surgically closed at 5 years of age. A diagnosis of ventricular parasystole and inducible ventricular tachycardia was made following a syncopal episode. The physiological variables required by the model to make specific predictions are the sinus and ectopic cycle lengths and the ventricular refractory period. From these three variables, a two-dimensional parameter space is constructed consisting of the ratio of the refractory period to the sinus cycle length and the ratio of the ectopic to sinus cycle length. For any set of parameters, predictions are made concerning the number of sinus beats between ectopic beats. The different behaviors exhibited in the electrocardiographic (ECG) data agree with theoretical predictions.

Beyond pure parasystole: promises and problems in modeling complex arrhythmias.

The dynamics of pure parasystole, a cardiac arrhythmia in which two competing pacemakers fire independently, have recently been fully characterized. This model is now extended in an attempt to account for the more complex dynamics occurring with modulated parasystole, in which there exists nonlinear interaction between the sinus node and the ectopic ventricular focus. Theoretical analysis of modulated parasystole reveals three types of dynamics: entrainment, quasiperiodicity, and chaos. Rhythms associated with quasiperiodicity obey a set of rules derived from pure parasystole. This model is applied to the interpretation of continuous electrocardiographic data sets from three patients with complicated patterns of ventricular ectopic activity. We describe several new statistical properties of these records, related to the number of intervening sinus beats between ectopic events, that are essential in characterizing the dynamics and testing mathematical models. Detailed comparison between data and theory in these cases show substantial areas of agreement as well as potentially important discrepancies. These findings have implications for understanding the dynamics of the heartbeat in normal and pathological conditions.