Hysteresis phenomena were demonstrated in the excitability of single, enzymatically dissociated guinea pig ventricular myocytes. Membrane potentials were recorded with patch pipettes in the whole-cell current-clamp configuration. Repetitive stimulation with depolarizing current pulses of constant cycle length and duration but varying strength led to predictable excitation (1:1) and nonexcitation (1: 0) patterns depending on current strength. However, transition between patterns depended on the direction of current strength change, and stable hysteresis loops were obtained in stimulus-response pattern versus current strength plots in 31 cells. Increase of pulse duration and decrease of stimulation rate contributed to a reduction in hysteresis loop areas. In addition, at the abrupt transitions from 1:0 to 1:1 patterns, a latency adaptation phenomenon was consistently observed. Bath application of tetrodotoxin (30 ,M) produced no change of hysteresis, whereas hysteresis was substantially decreased in cobalt (2 mM) superfusion experiments. Analysis of the changes in amplitude and shape of the subthreshold responses during the transitions from one stable pattern to the other suggested that activity led to an increase in membrane resistance, particularly in the voltage domain between resting and threshold potentials. We therefore modeled the dynamic behavior of the single cells, using an analytical solution aimed at calculating the recovery of activation latency as a function of diastolic membrane resistance. Numerical iteration of the analytical model equations closely reproduced the experimental hysteresis loops in both qualitative and quantitative ways. The effect of stimulation frequency on the model was similar to the experimental findings. The overall study suggests that the excitability pattern of guinea pig ventricular myocytes is responsible for hysteresis and bistabilities when current intensity is allowed to fluctuate around threshold levels. (Circulation Research 1991;69:1301-1315)

Subthreshold potentials are thought to be mediated by time-independent, "passive" background currents. In this study, we show that the background current-voltage (I-V) relation of guinea pig ventricular myocytes is changed significantly by repetitive stimulation, in such a way that cell excitability becomes enhanced. Myocytes were used for whole-cell voltage-clamp experiments. A voltage-clamp ramp (100 mV/sec) to -50 mV was applied from a holding potential of -100 mV. Subsequently, a train of square voltage-clamp pulses to + 10 mV (duration, 300 msec; interpulse interval, 300 msec) was delivered from a holding potential of -85 mV. A new ramp was applied again immediately after the train, and the resulting I-V curve

Left ventricular remodeling after myocardial infarction is accompanied by electrical abnormalities that might predispose to rhythm disturbances. To get insight into the ionic mechanisms involved, we studied myocytes isolated from four different regions of the rat ventricles, 4–6 months after ligation of the left coronary artery. Using the whole-cell patch-clamp technique, we never observed T-type Ca2+current in both diseased and control hearts. In contrast, in 41 out of 78 cells isolated from 16 post-myocardial infarcted rats, analysed in the presence of 30 m m Na+ions, we found a tetrodotoxin (TTX)-resistant Na+current with quite variable amplitude in every investigated region. Albeit being resistant to 100 μM TTX, this Na+-dependent current was highly sensitive to lidocaine since 3 μM lidocaine induced about 65% tonic block. It was also inhibited by 5 μM nifedipine and 2 m m Co2+, but was insensitive to 100 μM Ni2+. The TTX-resistant Na+channel availability was shifted rightward by 25–30 mV with respect to TTX-sensitive Na+current; therefore, a large “window current” might flow in the voltage range from −70 to −20 mV. In conclusion, in late post-myocardial infarction, a Na+current with specific kinetics and pharmacology may provide inward charges in a critical range of membrane voltages that are able to alter action potential time course and trigger ventricular arrhythmia. These apparent new characteristics of the Na+channel might result in part from environmental changes during heart remodeling.

1. This work determines the effects of quinidine, verapamil, nifedipine and ouabain on the hysteresis of the atrial effective refractory period (AERP) in the conscious dog. 2. AERP was always longer in the increasing phase than in the decreasing phase of the extrastimulus method, thus demonstrating the existence of AERP hysteresis. Calculated as the difference between the two values, hysteresis was between 8+/-0.8 and 11+/-1.0 msec. 3. Quinidine increased hysteresis from 9+/-0.7 to 13+/-0.7 msec, whereas verapamil decreased it from 10+/-0.9 to 5+/-0.5 msec and nifedipine did not affect it. Ouabain also lengthened hysteresis from 8+/-0.8 to 11+/-1.2 msec. 4. Thus, these results confirm the existence of a hysteresis phenomenon in the AERP in the conscious dog and are evidence that the fast sodium and slow calcium specific membrane currents participate in this phenomenon.

This work (a) provides evidence for hysteresis in the atrial effective refractory period (AERP) in the conscious dog; (b) studies the main stimulation parameters that may affect this phenomenon; and (c) evaluates the influence of the autonomic nervous system. AERP was measured by the extrastimulus method in the conscious dog with chronic atrioventricular block (n = 6) during the increasing and decreasing phases of an S1S2 fixed protocol. AERP was longer during the increasing phase than during the decreasing phase, thus demonstrating hysteresis, calculated as the difference between the two values. Hysteresis was greater with an S1S1 basic cycle length of 300 ms than with a basic cycle length of 400 ms, 9 +/- 0.9, and 7 +/- 0.9 ms, respectively. It was also greater with trains of six basic cycles before each extrastimulus S2 than with trains of 12 basic cycles, 9 +/- 0.9 and 7 +/- 1.0 ms, respectively. Suppression of vagal tone with atropine reduced hysteresis from 8 +/- 0.6 to 4 +/- 0.6 ms, whereas suppression of cardioaccelerator tone with propranolol increased it from 9 +/- 0.9 to 14 +/- 1.2 ms. These data were confirmed by the neostigmine-induced increase in hysteresis from 8 +/- 0.8 to 11 +/- 0.8 ms and the isoproterenol-induced decrease in hysteresis from 9 +/- 0.6 to 4 +/- 0.4 ms. Overall, these results provide evidence for a hysteresis effect in the AERP in the conscious dog that is stimulation frequency-dependent and modulated by the autonomic nervous system with permanent increase by vagal tone and decrease by cardioaccelerator tone.

We have investigated the oscillatory behaviour of a cardiac electrophysiological system model including coupled pacemaker and non-pacemaker cells. A previously reported version of the van Capelle and Dürrer model was used for both the pacemaker and the non-pacemaker cells, which were linked by an Ohmic coupling resistance (CR). In order to investigate the influence of respective cell sizes and electrotonic load, we examined the oscillatory behaviour of the system by using a pacemaker: non-pacemaker size ratio ranging from 0.1 to 0.5. Numerical simulations and continuation techniques disclosed three zones from low to high CR values: a zone of quiescence (0:0 pattern), a zone of effective entrainment (1:1 pattern), and a zone of total block (1:0) pattern. At the boundary between 1:1 and 1:0 patterns, for relatively CR values, period-doubling bifurcation points emerged as a cascade of nested bifurcations corresponding to discrete decreases of propagation patterns. The major issues were the finding of multistabilities between different patterns and above all the presence in the parameter space of irregular chaotic dynamics. This suggest that the interplay between loading and cellular coupling might be the underlying mechanism of the propagation patterns detected in the system under study.

The chronotropic cardiac effects of neuropeptide Y (NPY) were studied in the conscious dog with chronic atrioventricular block. NPY (0.2-5 micrograms/kg i.v.) produced no effect on atrial cycle length (ACL), and increased ventricular cycle length (VCL) and mean arterial blood pressure (MBP). After atropine, NPY produced no effect on ACL and increased MBP. At 0.2 microgram/kg, it shortened VCL, whereas at 1 and 5 micrograms/kg, it lengthened this parameter. After pindolol, NPY produced no effect on ACL, shortened VCL and increased MBP. These results indicate that in the conscious dog, NPY (0.2-5 microgram/kg i.v.) does not exert any chronotropic effect on the sinoatrial node, most likely because of competition between opposite chronotropic effects and/or absence of specific NPY receptors in the sinoatrial node. They also suggest that the ventricular bradycardic effects produced by NPY result mainly from a reflex withdrawal of beta-adrenergic tone and that its ventricular tachycardic effects result from a direct action of NPY on specific receptors located in the His bundle.

In the present study, we have demonstrated hysteresis phenomena in the excitability of single, enzymatically dissociated guinea pig ventricular myocytes. Membrane potentials were recorded with patch pipettes in the whole-cell current clamp configuration. Repetitive stimulation with depolarizing current pulses of constant cycle length and duration but varying strength led to predictable excitation (1:l) and non-excitation (1:0) patterns depending on current strength. In addition, transition between patterns depended on the direction of current intensity change and stable hysteresis loops were obtained in stimulus:response pattern vs. current intensity plots in 14 cells. Increase of pulse duration and decrease of stimulation rate contributed to a reduction in hysteresis loop areas. Changes in amplitude and shape of the subthreshold responses during the transitions from one stable pattern to the other, suggested that activity led to an increase in membrane resistance, particularly in the voltage domain between resting potential, and threshold. Therefore, we modelled the dynamic behaviour of the single cells as a function of diastolic membrane resistance, using previously published analytical solutions. Numerical iteration of the analytical model equations closely reproduced the experimental hysteresis loops in both qualitative and quantitative ways. In particular, the effect of stimulation frequency on the model was similar to the experimental findings. The overall study suggests that the excitability pattern of guinea pig ventricular myocytes accounts for hysteresis and bistabilities when current intensity is allowed to fluctuate around threshold levels.

Complex multidimensional interactions between spatial distributions of Intrinsic cellular electrical properties and intercellular coupling resistances underlie the activation patterns related to sinus node function. In the present study we have used a model of two coupled cardiac cells, a pacemaker and a non pacemaker cell, to investigate the dependence of successful conduction on three components of the system: (1) the intrinsic cellular properties, (2) the intercellular resistance, and (3) the pacemaker: non pacemaker size ratio between the two cells. The use of numerical simulations and continuation — bifurcation techniques demonstrated the presence of period doubling bifurcations and abrupt decreases of the activation ratio similar to sino-atrial exit blocks associated with bi- and even tristabilities. A stable entrainment was obtained with a size ratio as low as 0.1, but this geometrical configuration induced a large early repolarisation in the pacemaker cell during the conduction process due to the loading influence of the large non pacemaker cell.

Characteristics of the slow inward current (Isi) in human ventricular myocytes isolated from septal specimens obtained in patients undergoing corrective cardiac surgery were studied using the whole-cell clamp method. A first series of experiments was performed under normal standard superfusion. Clamping from −60 mV evoked an inward current with a threshold at about −35 mV, a maximum around +10 mV and an apparent reversal potential at about +55 mV. No overlapping transient or background outward currents were detected in the −60 to +30 mV potential range, but time-dependent and steady-state outward currents were elicited at potentials above +30 mV. An overlap of steady-state activation and inactivation curves was present between −30 and +10 mV and a slight relief from inactivation was observed for voltages positive to +10mV. The time course of inactivation consisted of fast and slow phases with time constants differing by a factor of eight. Slow time constants of inactivation were shorter at potentials that elicited larger Isi, and longer at potentials inducing smaller Isi. Recovery from inactivation evolved slowly with 100% reactivation occurring in about 4000 ms. Switching the holding potential from −60 to −40 mV led to a reversible decline of Isi without any change of the decay time constants. Isi was significantly increased by 0.1 μM isoproterenol. Total or partial inhibition by inorganic (2 mM Mn2+, 3 mM Co2+, 1 mM Cd2+) and organic (1 μM methoxyverapamil, 5 μM diltiazem) calcium antagonists did not unmask any transient outward current. However, a consistent increase of Isi was reversibly observed with 3 mM 4-aminopyridine while using standard solutions. A second series of experiments carried out with K+- and Na+-free solutions did not demonstrate any significant change from data observed with standard solutions except a reduction of outward currents at steps above +30 mV and alteration of inactivation kinetics. In this experimental setting, 4-aminopyridine also increased Isi but to a lesser degree. We conclude that Isi, as compared to the outward currents, is dominant in the diseased human ventricular cells we have studied.

The present study describes the resting potential behavior of a non pacemaker element derived from the van Capelle and Durrer model. By the use of continuation-bifurcation techniques, we could evidence a particular bifurcation structure comprising, in addition to two stable stationary states, a stable limit cycle, two unstable equilibrium points and one asymptotically stable equilibrium point.

The authors have used continuation-bifurcation techniques to explore phase transitions between automaticity and nonautomaticity in cardiac pacemaker cells. From the findings, they were able to describe the entire behavior of a single element and to define bistabilities and hysteresis patterns around two Hopf bifurcation points. Computation of attractor basins delineated the topological conditions allowing the cell to pass from one state to another as a result of brief perturbing impulses.<>

We assessed the effects of the iron chelator deferoxamine in 24 adult patients (12 controls, 12 treated) undergoing cardiopulmonary bypass for various cardiac operations. Deferoxamine was given both intravenously (30 mg/kg of body weight, starting 30 minutes before and ending 30 minutes after bypass) and as an additive to the cardioplegic solution (250 mg/L). Right atrial blood samples were taken before, during, and after bypass, and isolated polymorphonuclear neutrophils were evaluated for their capacity to generate superoxide radicals after stimulation with N-formyl-methionyl-leucyl-phenylalanine (FLMP, 10(-7) mol) and phorbol myristate acetate (100 ng/ml). At the same sampling times, measurement of the plasma levels of 6-keto-prostaglandin F1 alpha, the stable derivative of prostacyclin, was used as an index of membrane phospholipid breakdown. The two groups were not significantly different with regard to age, duration of bypass, and quantitative changes in polymorphonuclear neutrophil counts during the operation. Before bypass, the superoxide production of FMLP-stimulated polymorphonuclear neutrophils was comparable in the two groups. Conversely, after bypass, polymorphonuclear neutrophils harvested from deferoxamine-treated patients produced significantly fewer superoxide radicals than those of control patients (1.9 +/- 0.3 versus 3.7 +/- 0.2 nmol/10(6) polymorphonuclear neutrophils per minute, p less than 0.05). Stimulation of polymorphonuclear neutrophils by phorbol myristate acetate yielded similar changes, as the postbypass superoxide production was 12.6 +/- 2.5 nmol/10(6)/min in control patients and 7.1 +/- 0.9 nmol/10(6)/min in those receiving deferoxamine (p less than 0.05). In contrast, plasma levels of 6-keto-prostaglandin F1 alpha were not significantly different between the two groups. We conclude that deferoxamine-exposed polymorphonuclear neutrophils have a decreased oxidative responsiveness, compatible with the fact that they may have been less "primed" by secretagogues released during bypass, as compared with cells of untreated patients. Our results are consistent with the hypothesis that deferoxamine, by inhibiting iron-catalyzed free radical production, may limit the free radical-mediated amplification of the inflammatory response to bypass and as such could be effective in reducing the harmful effects of extracorporeal circulation.

The authors describe the behavior of a single cardiac element with respect to the possible transitions between automatic and steady stable states. Bifurcation techniques enabled them to classify behavior patterns in this cellular element by using the model of F.J.L. Van Capelle and D. Durrer (1980). Five behavioral pattern domains were delineated: (1) a nonautomatic zone with a single stationary stable state, (2) a zone where a steady-state solution and a pacemaker stable state coexist, (3) an automatic zone with a single oscillatory stable state, (4) an overlap between high- and low-amplitude oscillator states, and (5) a nonautomatic zone with a single steady state. In the transitional zones separatrices, represented by unstable orbits, provided a topological means of predicting the annihilation of rhythmic activity by either depolarizing or hyperpolarizing pulse of proper amplitude and proper phase. The coexistence of stable states near the two Hopf bifurcation points implies hysteresis phenomena. Consequently, small fluctuations of some parameter governing the cyclic regenerative process of transitional cells would be able to bring about burstlike intermittent activities

The authors test the hypothesis that hysteresis phenomena may exist in normally depolarized cardiac cells when an external stimulation parameter is allowed to changed. The underlying assumption is that cardiac cells may have intrinsic properties involving the memory of past events, independent of pacemaker and nonpacemaker interactions. This kind of behavior is found in 11 of 14 quiescent sheep Purkinje fibers which were rhythmically driven by depolarizing pulses, and in 13 of 14 isolated guinea-pig ventricular myocytes in which transmembrane potentials were recorded by the whole-cell current-clamp technique. Changes of pulse duration and temperature modulated the degree of hysteresis. The authors conclude that hysteresis may express some kind of memory in cardiac cells, probably enhancing stability against noise in the vicinity of threshold, while allowing cardiac cells to remain excitable at the lowest possible level of energy expenditure

The cardiac myosin phenotype, an important determinant of myocardial contractility, is modified by chronic increases in hemodynamic load. To quantify the proportion of atrial alpha-myosin heavy chain in various types of left atrial overload and to assess the possible relation between this proportion and atrial size, 34 patients were studied, 4 with Wolff-Parkinson-White syndrome, 29 with various types of mitral valve dysfunction and 1 with an atrial septal defect. Four normal autopsy hearts were also studied. The proportion of alpha-myosin heavy chain among total (alpha plus beta) myosin heavy chains was determined in each atrial sample, using an enzyme-linked immunosorbent assay. The size of the left atrium was assessed by one- and two-dimensional echocardiography. Alpha-myosin heavy chain was the main isoform present in the normal atria (85.5 +/- 9% of total myosin heavy chains). Patients with pure tight mitral stenosis (n = 9), mitral stenosis plus mild regurgitation (n = 8) and severe mitral regurgitation (n = 8), who had a higher indexed left atrial transverse diameter than those with Wolff-Parkinson-White syndrome (33 +/- 6, 39 +/- 10 and 46 +/- 5 versus 19.5 +/- 2 mm/m2, p less than 0.01, p less than 0.001 and p less than 0.001, respectively), also demonstrated a much smaller percent of alpha-myosin heavy chain content (28 +/- 20, 23.5 +/- 13 and 12 +/- 10 versus 58 +/- 18%, p less than 0.01, p less than 0.01 and p less than 0.001, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

We were interested in investigating the behaviour of a cardiac electrophysiological model including coupled pacemaker (PM) and nonpacemaker (NPM) cells. To this aim, a modified version of the model of Van Capelle and Durrer was used. First, few discrete values were assigned to coupling resistance (CR) and respective cell sizes and numerical simulations versus time showed three possible kinds of response pattern: sustained rhythmic activity, subthreshold oscillations, and complete inhibition. Then, after setting a fixed value to PM cell size, we undertake a thorough study of the system by using bifurcation-continuation techniques and CR was chosen as the continuation parameter. On the maximum action potential--CR plane representation, we could describe five behavioural zones: complete inhibition, coexistence of complete inhibition and NPM large oscillations, NPM large oscillations, coexistence of NPM large oscillations and subthreshold oscillations, subthreshold oscillations. Within the zones of qualitatively different coexisting solutions, a detailed exploration clearly demonstrated the presence of hysteresis cycles. Indeed, the status of the system depended on its immediate previous story within narrow ranges of CR values. Such a coexistence of stable solutions for identical values of CR may suggest an explanation of the intermittant activity elicited from abnormal ectopic foci observed in certain ventricular rhythm disturbances. In addition, a Hopf bifurcation point, from which emerged stationary and periodic solutions, was followed on the PM cell size--CR plane and from this representation we could deduce that the smaller the PM cell, the higher the CR must be for the PM cell to escape from the NPM cell inhibition.

Inadequate atrial hypothermia and subsequent ischemic injury have been recognized as the major causes of supraventricular arrhythmias (SVAs) and conduction defects following cold chemical cardioplegia. This study was designed to assess the effects of right atrial cooling (15 degrees-20 degrees C) during cardioplegic arrest upon the incidence of postoperative SVAs and conduction defects in 40 consecutive patients undergoing isolated aortic valve replacement. Atrial preservation was ensured by combining systemic (24 degrees C) and topical hypothermia with snared double caval cannulation during arrest. Myocardial temperatures in the right atrial septum and anterior wall of the right ventricle were recorded before and after each cardioplegic infusion and upon release of caval tapes. Postoperatively, the incidence of SVAs and conduction defects was assessed by continuous rhythm monitoring, bipolar atrial electrograms and, in ten patients, 24-h Holter recordings during the first postoperative day. With the venae cavae snared, temperatures in the right atrial septum were not significantly different from those measured simultaneously in the right ventricle. Release of caval tapes resulted in right atrial temperatures increasing to systemic temperature (from 17.1 +/- 2.9 degrees C to 25.9 +/- 5.6 degrees C [m +/- SD]; P less than 0.01). Atrial rewarming between cardioplegic infusions did not exceed 2.9 degrees +/- 3.2 degrees C. Postoperatively, four patients (10%) developed sustained atrial fibrillation. One additional patient had a single episode of paroxysmal atrial fibrillation and two patients experienced asymptomatic episodes of junctional rhythm.(ABSTRACT TRUNCATED AT 250 WORDS)