家兔离体心脏组织的不应期及房室结的滤波特性

一般认为房室结具有滤波特性,即它能阻止过快或过于提前的心房冲动传到心室。本实验旨在研究家兔离体心脏组织的不应期及房室结的滤波牧场生（ｎ＝１８）。实验中发现：（１）在短基础周期（２００－３００ｍｓ）房室结的相对不应期最长,而在长基础周期（６００,７００ｍｓ）希浦系（ＨｉｓＰｕｒｋｉｎｊｅ ｓｙｔｅｍ）的相对不应期最长;（２）在多种基础周期下,大多数心脏（１６／１８）房室结有效不应期小于心房功能不应期     

On the possible role of focal cooling of the heart in the mechanism of repetitive ventricular extra beats

The role of myocardial foci in the mechanism of ventricular arrhythmias was studied by local cooling of the intact dog heart. At normal heart rate conduction delay in the focus is not sufficient to account for re-entry of impulses. However, a premature stimulus applied near the refractory period caused sudden prolongation of conduction giving rise to nonstimulated extra beats, arising probably as a result of re-entry. The phenomenon is presumably due to the fact that at this time a large portion of the fibres has not yet recovered excitability. With increasing size of the focus, there is increased asynchrony of recovery of excitability and premature stimuli falling later in the cycle are able to produce reentry. A negative correlation exists between cycle length and conduction delay and a positive correlation between cycle length and the coupling interval, i.e. the time interval between a premature stimulus and the first nonstimulated extra beat.     

Functional origin of rate-induced changes in atrioventricular nodal conduction time of premature beats in the rabbit

The characteristics and origin of the rate-induced changes in atrioventricular nodal conduction time of premature beats (A2H2 intervals) were studied in isolated rabbit heart preparations. Increasing the basic driving rate during a periodic premature stimulation prolonged (a net inhibitory effect) and shortened (a net facilitatory effect) significantly (p less than 0.01, n = 17) the A2H2 intervals associated with long and short recovery times (H1A2 intervals), respectively. The origin of these responses was sought for by analyzing interactions between facilitation and fatigue. When the fatigue developed at a fast basic rate was estimated from changes in conduction time of basic beats and subtracted from the corresponding A2H2 intervals, the calculated A2H2 intervals showed enhanced facilitation but no fatigue. When independently obtained fatigue and facilitation effects were added to the control A2H2 intervals for corresponding H1A2 intervals, resulting A2H2 intervals correlated strongly with the ones observed at the equivalent fast basic rate (r = 0.99, p less than 0.001). Moreover, changes in the A2H2 intervals of premature beats tested with constant coupling intervals during 5-min fast rates were biphasic, confirming the overlapping and competition between facilitation and fatigue effects. Hence, rate-induced deviations of premature nodal conduction time from that predicted by changes in recovery time are consistent and result from the interaction between the overlapping effects produced by two independent, antagonist, and dynamically distinct nodal properties (facilitation and fatigue).     

Vulnerability in simulated ischemic ventricular transmural tissues

Vulnerability is an effective index to evaluate increased risk for unidirectional conduction block and reentry in hearts. Recent reports in animal experiments have indicated an opposite characteristics of the vulnerability in normal and ischemic transmural tissues. In order to clarify the differences and to investigate the mechanisms, a computer simulation method was used in this study to investigate the vulnerability relative to the premature pacing sites in normal and ischemic transmural tissues. Endo-, mid- and epi-cardial myocytes incorporating different severities of ischemia were developed across a tissue strand. The sodium channel inactivation gating variable h was calculated to provide the degree of sodium current recovery preceding the premature pacing. In the normal tissue, the measured vulnerable window was demonstrated to be wider by delivering an endocardial premature beat than that by applying an epicardial premature pacing. On the contrary, during ischemia the epicardium showed a wider vulnerable window than the endocardium. The results illustrated that during ischemia h decreased with accumulation of [K?]o, and action potential duration dispersion was obviously altered due to anoxia. In contrast, the elevated [K?]o was suggested to play an important role in the difference of the location-dependent vulnerability in normal and ischemic tissues.     

Electrophysiological basis for antiarrhythmic drug action

Arrhythmias result from abnormalities of impulse initiation or impulse conduction or a combination of both. Abnormal impulse initiation results from either automaticity or triggered activity. Automaticity can further be subdivided into (1) automaticity caused by the normal automatic mechanism (a normal property of cardiac cells in the sinus node, in some parts of the atria, in the atrioventricular junctional region, and in the His-Purkinje system) and (2) automaticity caused by an abnormal mechanism (resulting from a decrease in membrane potential of cardiac fibers, which normally have a high level of membrane potential). Triggered activity is caused by afterdepolarizations, which are second depolarizations that occur either during repolarization (referred to as early afterdepolarizations) or after repolarization is complete or nearly complete (referred to as delayed afterdepolarizations). Abnormal impulse conduction results in reentrant excitation. Usually a combination of slowed conduction and unidirectional conduction block provides the conditions necessary for reentry to occur.     

On the mechanisms of coupling in adrenaline-induced bigeminy in sensitized hearts.

The mechanism of coupling in adrenaline-induced ventricular bigeminy in sensitized hearts has been investigated in intact animals, isolated preparations, and single cardiac fibers. The electrophysiological and cardiovascular dynamic changes during the development of fixed interval coupling strongly indicate that the coupled beats result from stretch of subsidiary pacemaker fibers in the specialized ventricular conduction system, induced by the mechanical response to the normally conducted sinus impulse. The resulting intraventricular pressure elicits an extrasystole when a certain critical end systolic pressure for a particular animal is reached. The interval between the normal and premature ventricular beat decreases progressively as the intraventricular pressure rises, as a result of the combined action of adrenaline and postextrasystolic potentiation. The onset of ventricular bigeminy is preceded by a shift in the pacemaker site to the A-V junctional area, due to a differential effect of the anesthetic-adrenaline combination on fibers of the S-A node and those in the junctional area. The degree of prematurity of the coupled beat shows an inverse linear relationship to the intraventricular pressure of the initiating beat at the end of systole. The premature QRS complex occurs after a period of mechano-electrical latency, the duration of which is directly related to this pressure.     

Simulation analysis of excitation conduction in the heart: Propagation of excitation in different tissues

The normal excitation and conduction in the heart are maintained by the coordination between the dynamics of ionic conductance of each cell and the electrical coupling between cells. To examine functional roles of these two factors, we proposed a spatially-discrete model of conduction of excitation in which the individual cells were assumed isopotential. This approximation was reasoned by comparing the apparent space constant with the measured junctional resistance between myocardial cells. We used the four reconstruction models previously reported for five kinds of myocardial cells. Coupling coefficients between adjacent cells were determined quantitatively from the apparent space constants. We first investigated to what extent the pacemaker activity of the sinoatrial node depends on the number and the coupling coefficient of its cells, by using a one-dimensional model system composed of the sinoatrial node cells and the atrial cells. Extensive computer simulation revealed the following two conditions for the pacemaker activity of the sinoatrial node. The number of the sinoatrial node cells and their coupling coefficients must be large enough to provide the atrium with the sufficient electric current flow. The number of the sinoatrial node cells must be large so that the period of the compound system is close to the intrinsic period of the sinoatrial node cell. In this simulation the same sinoatrial node cells produced action potentials of different shapes depending on where they were located in the sinoatrial node. Therefore it seems premature to classify the myocardial cells only from their waveforms obtained by electrical recordings in the compound tissue. Second, we investigated the very slow conduction in the atrioventricular node compared to, for example, the ventricle. This was assumed to be due to the inherent property of the membrane dynamics of the atrioventricular node cell, or to the small value of the coupling coefficient (weak intercellular coupling), or to the electrical load imposed on the atrioventricular node by the Purkinje fibers, because the relatively small atrioventricular node must provide the Purkinje fibers with sufficient electric current flow. Relative contributions of these three factors to the slow conduction were evaluated using the model system composed of only the atrioventricular cells or that composed of the atrioventricular and Purkinje cells. We found that the weak coupling has the strongest effect. In the model system composed of the atrioventricular cells, the propagation failure was not observed even for very small values of the coupling coefficient.(ABSTRACT TRUNCATED AT 400 WORDS)     

Visualization and functional characterization of the developing murine cardiac conduction system

The cardiac conduction system is a complex network of cells that together orchestrate the rhythmic and coordinated depolarization of the heart. The molecular mechanisms regulating the specification and patterning of cells that form this conductive network are largely unknown. Studies in avian models have suggested that components of the cardiac conduction system arise from progressive recruitment of cardiomyogenic progenitors, potentially influenced by inductive effects from the neighboring coronary vasculature. However, relatively little is known about the process of conduction system development in mammalian species, especially in the mouse, where even the histological identification of the conductive network remains problematic. We have identified a line of transgenic mice where lacZ reporter gene expression delineates the developing and mature murine cardiac conduction system, extending proximally from the sinoatrial node to the distal Purkinje fibers. Optical mapping of cardiac electrical activity using a voltage-sensitive dye confirms that cells identified by the lacZ reporter gene are indeed components of the specialized conduction system. Analysis of lacZ expression during sequential stages of cardiogenesis provides a detailed view of the maturation of the conductive network and demonstrates that patterning occurs surprisingly early in embryogenesis. Moreover, optical mapping studies of embryonic hearts demonstrate that a murine His-Purkinje system is functioning well before septation has completed. Thus, these studies describe a novel marker of the murine cardiac conduction system that identifies this specialized network of cells throughout cardiac development. Analysis of lacZ expression and optical mapping data highlight important differences between murine and avian conduction system development. Finally, this line of transgenic mice provides a novel tool for exploring the molecular circuitry controlling mammalian conduction system development and should be invaluable in studies of developmental mutants with potential structural or functional conduction system defects.     

Epicardial and intramural excitation during ventricular pacing: effect of myocardial structure

Published studies show that ventricular pacing in canine hearts produces three distinct patterns of epicardial excitation: elliptical isochrones near an epicardial pacing site, with asymmetric bulges; areas with high propagation velocity, up to 2 or 3 m/s and numerous breakthrough sites; and lower velocity areas (<1 m/s), where excitation moves across the epicardial projection of the septum. With increasing pacing depth, the magnitude of epicardial potential maxima becomes asymmetric. The electrophysiological mechanisms that generate the distinct patterns have not been fully elucidated. In this study, we investigated those mechanisms experimentally. Under pentobarbital anesthesia, epicardial and intramural excitation isochrone and potential maps have been recorded from 22 exposed or isolated dog hearts, by means of epicardial electrode arrays and transmural plunge electrodes. In five experiments, a ventricular cavity was perfused with diluted Lugol solution. The epicardial bulges result from electrotonic attraction from the helically shaped subepicardial portions of the wave front. The high-velocity patterns and the associated multiple breakthroughs are due to involvement of the Purkinje network. The low velocity at the septum crossing is due to the missing Purkinje involvement in that area. The asymmetric magnitude of the epicardial potential maxima and the shift of the breakthrough sites provoked by deep stimulation are a consequence of the epi-endocardial obliqueness of the intramural fibers. These results improve our understanding of intramural and epicardial propagation during premature ventricular contractions and paced beats. This can be useful for interpreting epicardial maps recorded at surgery or inversely computed from body surface ECGs.     

Echo-driven V-V optimization determines clinical improvement in non responders to cardiac resynchronization treatment

Echocardiography plays an integral role in the detection of mechanical dyssynchrony in patients with congestive heart failure and in predicting beneficial response to cardiac resynchronization treatment. In patients who derive sup-optimal benefit from biventricular pacing, optimization of atrioventricular delay post cardiac resynchronization treatment has been shown to improve cardiac output. Some recent reports suggest that sequential ventricular pacing may further improve cardiac output. The mechanism whereby sequential ventricular pacing improves cardiac output is likely improved inter and possibly intraventricular synchrony, however these speculations have not been confirmed. In this report we describe the beneficial effect of sequential V-V pacing on inter and intraventricular synchrony, cardiac output and mitral regurgitation severity as the mechanisms whereby sequential biventricular pacing improves cardiac output and functional class in 8 patients who had derived no benefit or had deteriorated after CRT. Online tissue Doppler imaging including tissue velocity imaging, tissue synchronization imaging and strain and strain rate imaging were used in addition to conventional pulsed wave and color Doppler during sequential biventricular pacemaker programming.     

Comparison of contractile function of diaphragm and cardiac muscle in response to paired electrical stimulation

Paired pacing has been shown to potentiate contractile function of cardiac muscle, and it has been suggested that this may enhance contractile function of diaphragmatic muscle. The primary goal of this study was to study the effect of paired pacing on potentiation of contractile function of diaphragmatic muscle compared to atrial and ventricular myocardium. Diaphragmatic muscle was isolated from mouse and rat, and atrial and ventricular myocardium from dogs. Potentiation was induced by isolated extrastimuli (equal in duration and intensity to the pacing stimulus) and by repetitive extrastimuli (i.e. paired pacing) at a paced rate of 12, 30 and 60 beats/min. Baseline studies were performed while preparations were isometrically contracting at L(max) in oxygenated Krebs-Henseleit solution at 28 degrees C. Maximal force generation in response to a premature stimulus was determined at each rate by scanning the coupling interval between paced beats. Under baseline conditions, diaphragmatic muscle contracted faster than atrial and ventricular muscle. In all tissues, maximum potentiation (increase in force above baseline) was approximately 100% of baseline force, and peak potentiation occurred at shorter coupling intervals with increasing rates of stimulation. Single and paired pacing of diaphragm potentiated the contraction during which the extrastimuli were introduced, while in cardiac muscle, extrastimuli potentiated the contraction following the extrastimulus. The maximum potentiated response occurred when the extrastimulus was introduced prior to the development of peak force in diaphragmatic muscle. In contrast, in atrial and ventricular muscle, a single or paired premature stimulus potentiated the subsequent beat when delivered late during relaxation. In cardiac muscle, maximal potentiation gradually occurred following several repetitive stimuli. Following cessation of single and paired pacing, the beat following the potentiated response immediately returned to baseline in diaphragmatic muscle, while a gradual decline was evident over several subsequent beats in cardiac muscle. Increasing the bath temperature from 28 to 37 degrees C resulted in a leftward shift in the peak potentiated force vs. coupling interval curve without a decline in the magnitude of potentiated force in diaphragmatic muscle. In diaphragm muscle, exposure to ryanodine markedly decreased baseline force and maximal potentiation. We conclude that closely timed extrastimuli applied to diaphragmatic muscle can potentiate developed force in a given contraction, while in cardiac tissue a delayed stimulus potentiates the subsequent beat. These differences in contractile responsiveness are not due to differences in loading conditions, but appear to reflect intrinsic differences in calcium handling.     

Vulnerable window for conduction block in a one-dimensional cable of cardiac cells, 1: single extrasystoles

Spatial dispersion of refractoriness, which is amplified by genetic diseases, drugs, and electrical and structural remodeling during heart disease, is recognized as a major factor increasing the risk of lethal arrhythmias and sudden cardiac death. Dispersion forms the substrate for unidirectional conduction block, which is required for the initiation of reentry by extrasystoles or rapid pacing. In this study, we examine theoretically and numerically how preexisting gradients in refractoriness control the vulnerable window for unidirectional conduction block by a single premature extrasystole. Using a kinematic model to represent wavefront-waveback interactions, we first analytically derived the relationship (under simplified conditions) between the vulnerable window and various electrophysiological parameters such as action potential duration gradients, refractoriness barriers, conduction velocity restitution, etc. We then compared these findings to numerical simulations using the kinematic model or the Luo-Rudy action potential model in a one-dimensional cable of cardiac cells. The results from all three methods agreed well. We show that a critical gradient in action potential duration for conduction block can be analytically derived, and once this critical gradient is exceeded, the vulnerable window increases proportionately with the refractory barrier and is modulated by conduction velocity restitution and gap junctional conductance. Moreover, the critical gradient for conduction block is higher for an extrasystole traveling in the opposite direction from the sinus beat than for one traveling in the same direction (e.g., an epicardial extrasystole versus an endocardial extrasystole).     

Multiple firing of single muscle vasoconstrictor neurons during cardiac dysrhythmias in human heart failure.

Single vasoconstrictor nerve fibers in humans normally fire only once but have the capacity to fire as many as eight times, per cardiac interval. Our laboratory recently demonstrated that the mean firing frequency of individual vasoconstrictor fibers is more than doubled in the sympathoexcitation associated with congestive heart failure (Macefield VG, Rundqvist B, Sverrisdottir YB, Wallin BG, and Elam M. Circulation 100: 1708--1713, 1999). However, the propensity to fire only once per cardiac interval was retained. In the present retrospective study, we tested the hypothesis that vasoconstrictor fibers fire more than once per cardiac interval in response to transient sympathoexcitatory stimuli, providing one mechanism for further increase of an already augmented sympathetic discharge. Six patients with congestive heart failure (New York Heart Association functional class II--IV; left ventricular ejection range 13--37%, average 22%) were studied at rest and during premature ectopic heartbeats. Analyzed for a total of 60 premature beats, the average firing probability of 10 vasoconstrictor fibers increased from 61 to 80% in the prolonged cardiac interval (i.e., reduced diastolic pressure) after premature beats. The incidence of multiple within-burst firing increased markedly, with two spikes being more common than one. Our results illustrate two different mechanisms (increases in firing probability and multiple within-burst firing), and indirectly indicate a third mechanism (recruitment of previously silent fibers), for acute sympathoexcitatory responses.     

Usefulness Of Ivabradine To Treat "unexpected" Heart Failure Caused By "acute" Right Ventricular Pacing

We present the case of a patient with a heart failure episode induced by acute right ventricular pacing. After reversal of beta-blockers because of chronic obstructive pulmonary disease (COPD) exacerbation, the following sinus tachycardia caused a 2:1 atrioventricular block and consequent continuous right ventricular pacing. He was treated with the selective I(f) inhibitor ivabradine, that reduced both ventricular pacing percentage and heart rate without affecting atrioventricular conduction. Ivabradine may be a valuable option in treatment of patients with atrioventricular conduction disturbances.     

Electrophysiological effects of ethmozine in perfused rabbit hearts

His-bundle electrocardiography was used to evaluate the effects of ethmozine on cardiac conduction in isolated perfused rabbit hearts electrically driven at cycle lengths of 320 and 250 ms. There was no significant change in conduction until high concentrations of ethmozine were reached. His-Purkinje and atrioventricular (AV) nodal conduction were slowed significantly at 0.1 microgram/mL and atrial conduction at 1.0 microgram/mL. Conduction block occurred at 10.0 micrograms/mL in all the hearts treated. Effects of the drug (0.1 and 0.01 microgram/mL) on conduction of extrasystoles were also studied in hearts driven at a basic cycle length of 270 ms. No significant change was observed in atrial conduction of extrasystoles throughout the coupling intervals tested at both concentrations. Ethmozine (0.01 and 0.1 microgram/mL) caused slowing of His-Purkinje conduction of extrasystoles but the effect of the drug did not change as a function of the coupling interval. An interval-dependent increase in AV-nodal conduction time was observed, with the maximum slowing of conduction occurring at coupling intervals close to the effective refractory period of the AV node. AV-nodal functional refractory period was increased significantly by ethmozine (0.01 and 0.1 microgram/mL). The effective refractory period was significantly increased only at the higher concentration.     

New concepts in pacemaker syndrome

After implantation of a permanent pacemaker, patients may experience severe symptoms of dyspnea, palpitations, malaise, and syncope resulting from pacemaker syndrome. Although pacemaker syndrome is most often ascribed to the loss of atrioventricular (A-V) synchrony, more recent data may also implicate left ventricular dysynchrony caused by right ventricular pacing. Previous studies have not shown reductions in mortality or stroke with rate-modulated dual-chamber (DDDR) pacing as compared to ventricular-based (VVI) pacing. The benefits in A-V sequential pacing with the DDDR mode are likely mitigated by the interventricular (V-V) dysynchrony imposed by the high percentage of ventricular pacing commonly seen in the DDDR mode. Programming DDDR pacemakers to encourage intrinsic A-V conduction and reduce right ventricular pacing will likely decrease heart failure and pacemaker syndrome. Studies are currently ongoing to address these questions.     

Physiological properties of afferents and synaptic reorganization in the rat cerebellum degranulated by postnatal x-irradiation

Elimination of most granule, basket, and stellate interneurons in the rat cerebellum was achieved by repeated doses of low level x-irradiation applied during the first two weeks of postnatal life. Electrical stimulation of the brain stem and peripheral limbs was employed to investigate the properties of afferent cerebellar pathways and the nature of the reorganized neuronal synaptic circuitry in the degranulated cerebellum of the adult. Direct contacts of mossy fibers on Purkinje cells were indicated by short latency, single spike responses: 1.9 msec from the lateral reticular nucleus of brain stem and 5.4 msec from ipsilateral forlimb. These were shorter than in normal rats by 0.9 and 2.1 msec, respectively. The topography of projections from peripheral stimulation was approximately normal. Mossy fiber responses followed stimulation at up to 20/sec, whereas climbing fiber pathways fatigued at 10/sec. The latency of climbing fiber input to peripheral limb stimulation in x-irradiated cerebellum was 23 ± 8 (SD) msec. In x-irradiated rats, the climbing fiber pathways evoked highly variable extracellular burst responses and intracellular EPSPs of different, discrete sizes. These variable responses suggest that multiple climbing fibers contact single Purkinje cells. We conclude that each type of afferent retains identifying characteristics of transmission. However, rules for synaptic specification appear to break down so that: (1) abnormal classes of neurons develop synaptic connections, i.e., mossy fibers to Purkinje cells; (2) incorrect numbers of neurons share postsynaptic targets, i.e., more than one climbing fiber to a Purkinje cell; and (3) inhibitory synaptic actions may be carried out in the absence of the major inhibitory interneurons, i.e., Purkinje cell collaterals may be effective in lieu of basket and stellate cells.