Instantaneous alteration of the dog heart contractility under instantaneous change in the stimulation rhythm

Isolated canine heart has an expressed ability for an instantaneous alteration in the sense of re-tuning, of contractility (of the speed of mechanical restitution in diastolic period) under instantaneous change of stimulation rhythm. Postextrasystolic potentiation reflects instantaneous rising of the speed of mechanical restitution under the influence of extrasystole in the condition of instantaneous transition to a higher rhythm. Depression of contractility reflects instantaneous decreasing of the speed of mechanical restitution under the influence of delayed stimulus in the condition of instantaneous transition to a slower rhythm. Alteration (re-tuning) of heart contractility occurred irrespective of the influence of neurohumoral factor and Frank-Starling law on the work of the heart. Alteration (re-tuning) of contractility occurs at an organ (cell) level.     

Rhythm assimilation in the isolated canine heart under isovolumic conditions

Isolated canine heart has an expressed ability for autoregulation of bioelectrical and contractile functions irrespective of the neurohumoral factors influence on the work of the heart, and Frank-Starling law. Under the change of stimulation frequency, the autoregulation of heart functions is carried out as rhythm assimilation at organ (cell) level. The heart has a higher ability to bioelectrical rhythm assimilation rather than the mechanical rhythm assimilation. Incomplete rhythm assimilation is characterised by the alternation of contractions. The "Everything or nothing" law has no applicability to the work of the heart.     

Chronotropic and inotropic dependence of the myocardium in patients with rheumatic heart disease before and after amiodarone treatment

Characteristic features of the electromechanical coupling of the myocardium were studied in patients with heart failure caused by rheumatic heart disease. Experiments were performed on muscle trabeculae isolated from the right atrial auricle in the course of surgical correction of a valve defect. The trabeculae displayed two types of mechanical responses, recorded in the isometric mode, to the postrest test. In the type I response, the mechanical restitution had an ascending pattern, the interval between electrical stimuli increasing. In type II, the mechanical restitution pattern was descending. Amiodarone (1 μM) treatment of the myocardium with the type I response enhanced the postrest potentiation of the mechanical response of trabeculae by more than 30%, but it had no effect on the muscles with the type II response. All patients whose biopsy material displayed the type II response had long episodes of atrial fibrillation. It is conceivable that the observed differences in the rhythm inotropic dependence of the human myocardium in rheumatic heart disease reflect different degrees of cardiomyocyte remodeling. The direction of this process is determined by the range of adaptive changes in intracellular structures, primarily, the sarcoplasmic reticulum.     

Mechanical signal influence on mesenchymal stem cell fate is enhanced by incorporation of refractory periods into the loading regimen

Mechanical signals of both low and high intensity are inhibitory to fat and anabolic to bone in vivo, and have been shown to directly affect mesenchymal stem cell pools from which fat and bone precursors emerge. To identify an idealized mechanical regimen which can regulate MSC fate, low intensity vibration (LIV; <10 microstrain, 90 Hz) and high magnitude strain (HMS; 20,000 microstrain, 0.17 Hz) were examined in MSC undergoing adipogenesis. Two x twenty minute bouts of either LIV or HMS suppressed adipogenesis when there was at least a 1h refractory period between bouts; this effect was enhanced when the rest period was extended to 3h. Mechanical efficacy to inhibit adipogenesis increased with additional loading bouts if a refractory period was incorporated. Mechanical suppression of adipogenesis with LIV involved inhibition of GSK3β with subsequent activation of β-catenin as has been shown for HMS. These data indicate that mechanical biasing of MSC lineage selection is more dependent on event scheduling than on load magnitude or duration. As such, a full day of rest should not be required to "reset" the mechanical responsiveness of MSCs, and suggests that incorporating several brief mechanical challenges within a 24h period may improve salutary endpoints in vivo. That two diverse mechanical inputs are enhanced by repetition after a refractory period suggests that rapid cellular adaptation can be targeted.     

Cardiac mechano-electric feedback and electrical restitution in humans

Electrical restitution in the heart is the property whereby the action potential duration and conduction velocity of a beat of altered cycle length vary according to its immediacy to the preceding basic beat--the coupling interval, usually the diastolic interval. In general, action potential duration (APD) increases with increasing coupling interval, and the relation between action potential duration and the preceding diastolic interval describes the APD restitution curve. The latter has recently been the focus of considerable interest since the steepness of the initial part of the restitution curve plays an important role in electrical stability and arrhythmogenesis. Mechanical stretch has been shown to alter APD and hence refractoriness either through stretch activated channels or by influencing calcium cycling. Such an effect on refractoriness has been proposed as a mechanism of arrhythmogenesis particularly if spatially inhomogeneities manifest within the heart. Here, we review (1) the spatial and temporal characteristics of APD restitution in humans; (2) previously reported work showing that mechanical loading differentially effects APD of interpolated beats of altered cycle length, and hence alters the slope of the APD restitution curve; and (3) evidence that inhomogeneity of APD restitution slope may be an important factor in arrhythmogenesis.     

Na+ channel distribution and electrophysiological heterogeneities in guinea pig ventricular wall

We sought to explore the distribution pattern of Na(+) channels across ventricular wall, and to determine its functional correlates, in the guinea pig heart. Voltage-dependent Na(+) channel (Na(v)) protein expression levels were measured in transmural samples of ventricular tissue by Western blotting. Isolated, perfused heart preparations were used to record monophasic action potentials and volume-conducted ECG, and to measure effective refractory periods (ERPs) and pacing thresholds, in order to assess excitability, electrical restitution kinetics, and susceptibility to stimulation-evoked tachyarrhythmias at epicardial and endocardial stimulation sites. In both ventricular chambers, Na(v) protein expression was higher at endocardium than epicardium, with midmyocardial layers showing intermediate expression levels. Endocardial stimulation sites showed higher excitability, as evidenced by lower pacing thresholds during regular stimulation and downward displacement of the strength-interval curve reconstructed after extrasystolic stimulation compared with epicardium. ERP restitution assessed over a wide range of pacing rates showed greater maximal slope and faster kinetics at endocardial than epicardial stimulation sites. Flecainide, a Na(+) channel blocker, reduced the maximal ERP restitution slope, slowed restitution kinetics, and eliminated epicardial-to-endocardial difference in dynamics of electrical restitution. Greater excitability and steeper electrical restitution have been associated with greater arrhythmic susceptibility of endocardium than epicardium, as assessed by measuring ventricular fibrillation threshold, inducibility of tachyarrhythmias by rapid cardiac pacing, and the magnitude of stimulation-evoked repolarization alternans. In conclusion, higher Na(+) channel expression levels may contribute to greater excitability, steeper electrical restitution slopes and faster restitution kinetics, and greater susceptibility to stimulation-evoked tachyarrhythmias at endocardium than epicardium in the guinea pig heart.     

Mechanical restitution at different temperatures in papillary muscles from rabbit, rat, and hedgehog

Mechanical restitution curves, i.e., peak isometric force as a function of the duration of the preceding test interval, were investigated in papillary muscles from rabbit, rat, and hedgehog. Peak force of rabbit papillary muscle increased with prolongation of the test interval from about 0.3 s to about 1.0 s and for longer intervals peak force declined (called type I mechanical restitution). On the other hand, in rat and hedgehog, papillary muscles' force reached a maximum value at intervals of 30-120 s (called type II mechanical restitution). When temperature was decreased from 35 to 15 degrees C, maximum force of type I mechanical restitution shifted from 1.0 to 10 s, whereas maximum force of type II restitution did not change significantly. Type II mechanical restitution consisted of two different phases, designated phase A and phase B, respectively. As temperature was decreased from 35 to 0 degree C in the hedgehog preparation, the two phases became even more separated. At 35 degrees C, the rising part of mechanical restitution in the rabbit muscle could not be distinguished from phase A of the hedgehog preparation and was also very similar to phase A of the rat muscle. Phase A is thus present in both type I and type II mechanical restitution, but phase B is a special feature of type II mechanical restitution. Phase A and phase B might be a manifestation of activator calcium originating from two different sources, e.g., the sarcoplasmic reticulum and the sarcolemma.     

Qualitative modeling of mechanoelectrical feedback in a ventricular cell

Mechanical changes in the heart muscle can influence its electrical properties through a process called mechanoelectrical feedback (MEF). This feedback can operate via changes in calcium dynamics during the cross-bridge cycle or via mechanosensitive (stretch-activated) channels. We present a four-variable ordinary differential equation (ODE) system that caricatures the electrical and mechanical activity of a ventricular cell and their mutual interactions. A three-variable excitable system with restitution properties of the FitzHugh-Nagumo type is coupled to a fourth equation which describes changes in cell length during a lightly loaded contraction. The resulting four-variable system models MEF in a cell and can be incorporated into spatially distributed models for mechanoelectric behavior during wave propagation in the cardiac tissue.     

Multistability property in cardiac ionic models of mammalian and human ventricular cells

The underlying mechanisms of irregular cardiac rhythms are still poorly understood. Many experimental and modeling studies are aimed at identifying factors which cause cardiac arrhythmias. However, a lack of understanding of heart rhythm dynamical properties makes it difficult to uncover precise mechanisms of electrical instabilities, and hence to predict the onset of heart rhythm disorders. We review and compare the existing methods of studying cardiac dynamics, including restitution protocol (S1-S2), dynamic restitution protocol and multistability test protocol (S1-CI-S2). We focus on cardiac cell dynamics to elucidate regularities of heart rhythm. We demonstrate the advantages of our newly proposed systematic approach of analysis of cardiac cell dynamics using mammalian Luo Rudy 1991 and human ventricular Ten Tusscher 2006 single cell models under healthy and diseased conditions such as altered K⁺ or Ca²⁺ related currents. We investigate the role of ionic properties and the shape of an action potential on the nonlinear dynamics of electrical processes in periodically stimulated cardiac cells. We show the existence of multistability property for human ventricular cells. Moreover, the multistability is proposed to be an intrinsic property of cardiac cells, and is also suggested to be one of the mechanisms which could underlie the sudden triggering of life-threatening ventricular arrhythmias in the human heart.     

Influence of ryanodine on the mechanical restitution and on the post-extrasystolic potentiation of the guinea-pig ventricular myocardium

This paper records the results of an investigation into potentiation and staircase phenomena in rightventricular guinea-pig papillary muscles with particular reference to the sarcoplasmic Ca²⁺-channel. As a tool to isolate the second (late, 1tonic) component of isoproterenol-induced biphasic contractions ryanodine was used. On the evidence at present available the monophasic ryanodine-resistant component of the twitch represents that portion of the activator calcium which reaches the troponin C directly, that is, not taking the roundabout way through the intracellular storage structures. In order to avoid functional instabilities of the isolated muscle preparation a short-time double rest stimulation programme was used which combines a number of different tests and gives information on (1) the post-rest potentiation, (2) the post-extrasystolic potentiation, (3) the mechanical post-rest recovery, (4) the interval-strength relationship, and (5) the mechanical restitution. The results of the present work show that under the influence of ryanodine (1) the BOWDITCH staircase, a typical feature of normodynamic mammalian ventricular preparations as well as of hypodynamic frog heart preparations, does not exist, (2) the post-extrasystolic potentiation disappears, (3) the curve reflecting the mechanical restitution, under normal in vitro conditions a monotonically increasing function, becomes biphasic within the relative refractory period, (4) the conspicuous depression of the isometric post-rest contraction for long iasting pauses interrupting the regular pacing rhythm, a typical feature of isolated guinea-pig ventricular tissue, is clearly diminished, and (5) the characteristic curve, reflecting the potentiation of the post-extrasystolic post-rest contraction as a function of the delay time preceding the extrastimulus, becomes displaced to the premature interstimulus interval. The concept of an extended 2-calcium-store model is supported by this work.     

Assimilation of rhythm by the isolated dog heart during gradual raising of stimulation frequency

An ability for a forestalling regulation of contractility of the heart with calculation of the tendency of rhythm increasing was revealed under a gradual increasing of heart rhythm. A forestalling regulation of heart contractility occurs with rhythm assimilation at the cell level of the heart and irrespective of the influence of Frank-Starling law and neurohumoral factors on the work of the heart. A 5-10% increasing of heart rhythm is characterized by optimal rhythm assimilation. A 15-40% increasing of heart rhythm is not optimal and results in transformation of the rhythm. The following sequence of events take place in the process of transition from rhythm assimilation to rhythm transformation under a gradual increasing of heart rhythm: rhythm assimilation--rhythm by mechanical function--incomplete rhythm assimilation by electrical function-transformation of rhythm by electrical function.     

Models of cardiac electromechanics based on individual hearts imaging data Image-based electromechanical models of the heart

Current multi-scale computational models of ventricular electromechanics describe the full process of cardiac contraction on both the micro- and macro- scales including: the depolarization of cardiac cells, the release of calcium from intracellular stores, tension generation by cardiac myofilaments, and mechanical contraction of the whole heart. Such models are used to reveal basic mechanisms of cardiac contraction as well as the mechanisms of cardiac dysfunction in disease conditions. In this paper, we present a methodology to construct finite element electromechanical models of ventricular contraction with anatomically accurate ventricular geometry based on magnetic resonance and diffusion tensor magnetic resonance imaging of the heart. The electromechanical model couples detailed representations of the cardiac cell membrane, cardiac myofilament dynamics, electrical impulse propagation, ventricular contraction, and circulation to simulate the electrical and mechanical activity of the ventricles. The utility of the model is demonstrated in an example simulation of contraction during sinus rhythm using a model of the normal canine ventricles.     

Mechanisms of the acute ischemia-induced arrhythmogenesis--a simulation study

The underlying ionic mechanisms of ischemic-induced arrhythmia were studied by the computer simulation method. To approximate the real situation, ischemic cells were simulated by considering the three major component conditions of acute ischemia (elevated extracellular K(+) concentration, acidosis and anoxia) at the level of ionic currents and ionic concentrations, and a round ischemic zone was introduced into a homogeneous healthy sheet to avoid sharp angle of the ischemic tissue. The constructed models were solved using the operator splitting and adaptive time step methods, and the perturbation finite difference (PFD) scheme was first used to integrate the partial differential equations (PDEs) in the model. The numerical experiments showed that the action potential durations (APDs) of ischemic cells did not exhibited rate adaptation characteristic, resulting in flattening of the APD restitution curve. With reduction of sodium channel availability and long recovery of excitability, refractory period of the ischemic tissue was significantly prolonged, and could no longer be considered as same as APD. Slope of the conduction velocity (CV) restitution curve increased both in normal and ischemic region when pacing cycle length (PCL) was short, and refractory period dispersion increased with shortening of PCL as well. Therefore, dynamic changes of CV and dispersion of refractory period rather than APD were suggested to be the fundamental mechanisms of arrhythmia in regional ischemic myocardium.     

Model of mechanical alternans in the mammalian myocardium

A model is proposed to elucidate the cause and mechanism of mechanical alternans in cardiac muscle in terms of discrete calcium movements. Mechanical alternans, the cause of which lies within the borders of excitation-contraction-coupling (ECC), is analyzed. In this case, the "input" of the ECC system (the action potentials and intervals) is constant while the "output" (contractile force) oscillates between two constant values, indicating that the system has a "memory" with two "internal states". It is proposed that these two "states" are associated with a part of the sarcoplasmic reticulum ("releasable terminal") containing the readily releasable calcium. A mechanism of "calcium-concentration-dependent threshold" is suggested to govern the "release function", i.e. the release of calcium from the "releasable terminal" to the myofilaments. The "release function" is analyzed in both the linear and the non-linear cases and its implication on the initiation of sustained and transient mechanical alternans are described. The dependence of mechanical alternans on a disturbance is also explained. The model response resembles the experimental observations of mechanical alternans in mammalian myocardium in the following manners: abrupt transition from low to high heart rates, slow progressive acceleration of rate, variations in persistence at subthreshold rates, effect of premature and delayed beat following the small and large beats, restitution curves, and transient mechanical alternans initiated by a delayed beat.     

Effects of [K(+)](o) on electrical restitution and activation dynamics during ventricular fibrillation

To test whether hyperkalemia suppresses ventricular fibrillation (VF) by reducing the slope of the action potential duration (APD) restitution relation, we determined the effects of the extracellular K(+) concentration ([K(+)](o)) ([KCl] = 2.7-12 mM) on the restitution of APD and maximum upstroke velocity (V(max)) the magnitude of APD alternans and spatiotemporal organization during VF in isolated canine ventricle. As [KCl] was increased incrementally from 2.7 to 12 mM, V(max) was reduced progressively. Increasing [KCl] from 2.7 to 10 mM decreased the slope of the APD restitution relation at long, but not short, diastolic intervals (DI), decreased the range of DI over which the slope was >/=1, and reduced the maximum amplitude of APD alternans. At [KCl] = 12 mM, the range of DI over which the APD restitution slope was >/=1 increased, and the maximum amplitude of APD alternans increased. For [KCl] = 4-8 mM, the persistence of APD alternans at short DI was associated with maintenance of VF. For [KCl] = 10-12 mM, the spontaneous frequency during VF was reduced, and activation occurred predominantly at longer DI. The lack of APD alternans at longer DI was associated with conversion of VF to a periodic rhythm. These results provide additional evidence for the importance of APD restitution kinetics in the development of VF.     

Influence of sarcoplasmic reticulum calcium loading on mechanical and relaxation restitution

Mechanical and relaxation restitution represent the restoration of contractile force and relaxation, respectively, in premature beats having progressively longer extrasystolic intervals (ESI); these phenomena are related to intracellular activator Ca(2+) by poorly defined mechanisms. We tested the hypothesis that the level of phospholamban [which modulates the affinity of the sarcoplasmic reticulum (SR) Ca(2+)-ATPase for Ca(2+), and thus the SR Ca(2+) load] may be an important determinant of both mechanical and relaxation restitution. Five mice with ablation of the phospholamban (PLB) gene (PLBKO), eight isogenic wild-type controls (129SvJ), eleven mice with PLB overexpression (PLBOE), and nine isogenic wild-type (FVB/N) controls were anesthetized and instrumented with a 1.4-Fr Millar catheter in the left ventricle and a 1-Fr pacemaker in the right atrium. At a cycle length of 200 ms, extrastimuli with increasing ESI were introduced, and the peak rates of left ventricular isovolumic contraction (+/-dP/dt(max)) were normalized and fit to monoexponential equations. In a subset, the protocols were repeated after ryanodine (4 ng/g) was administered to deplete SR Ca(2+) stores. The time constant of mechanical restitution in PLBKO was significantly shorter [6.3 +/- 1.2 (SE) vs. 47.7 +/- 7.6 ms] and began earlier (50 +/- 10 vs. 70 +/- 19 ms) than in 129SvJ. In contrast, the time constant of mechnical restitution was significantly longer (80.3 +/- 7.6 vs. 54.1 +/- 9.2 ms) in PLBOE than in FVB/N. The time constant of relaxation restitution was less in PLBKO than in 129SvJ (26.2 +/- 9.9 vs. 44.6 +/- 3.3, P < 0.05) but was similar in PLBOE and FVB/N (21.1 +/- 6.3 vs. 20.5 +/- 5.7 ms). Intravenous ryanodine decreased significantly the time constants of mechanical restitution in PLBOE, 129SvJ, and FVB/N but was lethal in PLBKO. In contrast, ryanodine increased the time constant of relaxation restitution. Thus 1) the phospholamban level is a critical determinant of mechanical restitution and (to a lesser extent) relaxation restitution in these transgenic models, and 2) ryanodine differentially affects mechanical and relaxation restitution. Furthermore, our data suggest a dissociation of processes within the SR that govern contraction and relaxation.     

窦性节律下家兔心率与在位心室肌纤维有效不应期的关系

在自然呼吸和窦性节律下,用浮置式玻璃微电极引导在体单个左心室肌纤维动作电位,作为兴奋的指标,以其 0相触发产生期前的试验刺激,测定有效不应期(ERP)。38只家兔的测定结果表明,在R-R间期为205—330ms的范围内,随着心率加快(R-R间期缩短),ERP减小,而 ERP/RR 间期增大,说明 ERP 与心率直接有关。并且,在较快的心率时,ERP 相对延长。通过相关与回归分析,制出了能够删除心率影响的校正公式。静脉注射酒石酸锑钾(50mg/kg)发现,在窦性和起搏节律下,酒石酸锑钾均能轻度延长 ERP(P<0.001)。窦性节律下的校正后值与起搏节律的测定结果完全一致。证明校正后值能够用来比较处理前后不同心率条件下,各种药物、离子及其它因素对ERP 的影响。 本文的校正公式虽然只适用于同种动物和方法,但此校正公式的制作原理也可以广泛应用到其它多种动物。     

Electrical refractory period restitution and spiral wave reentry in simulated cardiac tissue

Theoretical and experimental studies have shown that restitution of the cardiac action potential (AP) duration (APD) plays a major role in predisposing ventricular tachycardia to degenerate to ventricular fibrillation, whereas its role in atrial fibrillation is unclear. We used the Courtemanche human atrial cell model and the Luo-Rudy guinea pig ventricular model to compare the roles of electrical restitution in destabilizing spiral wave reentry in simulated two-dimensional homogeneous atrial and ventricular tissue. Because atrial AP morphology is complex, we also validated the usefulness of effective refractory period (ERP) restitution. ERP restitution correlated best with APD restitution at transmembrane potentials greater than or equal to -62 mV, and its steepness was a reliable predictor of spiral wave phenotype (stable, meandering, hypermeandering, and breakup) in both atrial and ventricular tissue. Spiral breakup or single hypermeandering spirals occurred when the slope of ERP restitution exceeded 1 at short diastolic intervals. Thus ERP restitution, which is easier to measure clinically than APD restitution, is a reliable determinant of spiral wave stability in simulated atrial and ventricular tissue.     

Effects of Regulatory Peptides on Electrophysiological Properties of the Human Heart

During transesophageal electrical stimulation of the left atria in patients with heart diseases, an intravenous administration of Sandostatin prolonged the cardiac cycle and the effective refractory period of the atrioventricular junction, slowed down the sinoatrial conduction and the sinus node recovery time, and shifted the Wenckebach's point downwards. Neurotensin produced effects opposite to those of Sandostatin. During the Valsalva maneuver, Sandostatin strengthened bradycardia and broadened the range of heart rate changes associated with the vagal tone variations. The latter effect was also observed after the administration of neurotensin. Met-enkephalin and dalargin shortened the cardiac cycle, increased the corrected time of sinus node recovery time, but did not affect the cardiac rhythm dynamics during the Valsalva maneuver. These findings suggest that the regulatory peptides can be involved in control mechanisms determining the electrophysiological parameters of the human heart.