Recovery of the dog myocardial contractile function in the diastolic period

Isolated canine heart has an expressed ability for autoregulation of mechanical restitution irrespective of the influence of neurohumoral factors and Frank-Starling law on the work of the heart. Mechanical restitution of canine heart in diastolic period starts after the end of mechanical refractory period of the heart and develops exponentially. The higher the heart rhythm the faster the speed of mechanical restitution. The higher the heart rhythm the shorter the mechanical refractory period. Mechanical refractory period of the heart is longer than bioelectrical refractory period.     

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.     

The effect of chlorpromazine on the mechanogram, electrocardiogram and membranopotential of the frog heart]

The action of chloropromazine in concentrations between 10(-6) and 10(-3) M was studied with regard to its effect on contractility, ECG, and membrane potential of the isolated frog heart. In concentrations above 10(-6) a depressive influence on the amplitude of contraction was observed; the speed of contraction was reduced. The heart rate showed negatively chronotropic changes. In the ECG there was a striking expansion of the PQ interval. The membrane potential was reduced under the effect of chloropromazine depending on the concentration used. The negative influence on mechanical and bioelectrical parameters of the myocardium is interpreted to be due to membrane-related factors. A vagus-like effect is discussed, particular importance being attached to the mechanisms of the "slow-channel" system.     

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.     

Effect of ectopic excitation on the ventricular pump function in chicken

The pump function of the heart ventricles was studied in chest-open anaesthetized adult female chickens under sinus rhythm and ectopic excitation of different localization. The intraventricular pressure in the right and left heart ventricles was measured by insertion of catheters through the ventricular free walls. Maximum systolic pressure, end-diastolic pressure, contractility (dP/dtmax) and relaxation (dP/dtmin) of both heart ventricles, and duration of the asynchronous contraction time of the left ventricle were analyzed. It was revealed that reduction of the pump function of the left ventricle tends to be greater under right ventricular ectopic excitation compared with left ventricular one. In comparison with the sinus rhythm, the pump function of the right ventricle was preserved to a greater extent under stimulation of the left ventricular apex and was significantly impaired under right ventricular ectopic excitation. Relaxation of both heart ventricles was more susceptible to ventricular ectopic excitation than contractility, and was more vulnerable in the right ventricle than in the left one. The direction of changes of the pump function of the heart ventricles in chickens under ventricular ectopic excitation was similar to changes of the pump function of mammalian hearts.     

Minimal oxygen consumption and optimal contractility of the heart: Theoretical approach to principle of physiological control of contractility

Oxygen consumption of the left ventricle (MVO ₂) was evaluated theoretically under the condition that the ventricle pumps a constant stroke volume against a constant arterial pressure, hence producing a constant external mechanical stroke work, with a widely varied contractility.MVO ₂ was calculated by an empirical equation which had been inferred previously. Theoretical results indicated that the ventricle has a contractility at whichMVO ₂ is minimal in spite of constant external work and therefore the mechanical efficiency as a pump is maximal. Such a contractility can be considered to be optimal from a standpoint of metabolic economy. The optimal contractility fell within the physiological range of contractility which had been observed experimentally. The result suggests a possibility that the contractility of a normal heart might be physiologically adapted to such an optimal 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.     

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.     

Cardiac matrix: A clue for future therapy

Cardiac muscle is unique because it contracts ceaselessly throughout the life and is highly resistant to fatigue. The marvelous nature of the cardiac muscle is attributed to its matrix that maintains structural and functional integrity and provides ambient micro-environment required for mechanical, cellular and molecular activities in the heart. Cardiac matrix dictates the endothelium myocyte (EM) coupling and contractility of cardiomyocytes. The matrix metalloproteinases (MMPs) and their tissue inhibitor of metalloproteinases (TIMPs) regulate matrix degradation that determines cardiac fibrosis and myocardial performance. We have shown that MMP-9 regulates differential expression of micro RNAs (miRNAs), calcium cycling and contractility of cardiomyocytes. The differential expression of miRNAs is associated with angiogenesis, hypertrophy and fibrosis in the heart. MMP-9, which is involved in the degradation of cardiac matrix and induction of fibrosis, is also implicated in inhibition of survival and differentiation of cardiac stem cells (CSC). Cardiac matrix is distinct because it renders mechanical properties and provides a framework essential for differentiation of cardiac progenitor cells (CPC) into specific lineage. Cardiac matrix regulates myocyte contractility by EM coupling and calcium transients and also directs miRNAs required for precise regulation of continuous and synchronized beating of cardiomyocytes that is indispensible for survival. Alteration in the matrix homeostasis due to induction of MMPs, altered expression of specific miRNAs or impaired signaling for contractility of cardiomyocytes leads to catastrophic effects. This review describes the mechanisms by which cardiac matrix regulates myocardial performance and suggests future directions for the development of treatment strategies in cardiovascular diseases.     

Do studies of mechanical restitution tell us anything about the mechanism of Ca2+ release in myocardial cells?

We present information from the literature which is discordant with the idea that the trigger Ca2+ for Ca2(+)-induced Ca2+ release from the myocardial sarcoplasmic reticulum (SR) is carried by the inward current. In addition, evidence is emerging to show that recovery of contractility with increasing interval after an excitation-contraction-relaxation cycle (mechanical restitution) begins with repolarization of the sarcolemma, not mechanical relaxation (SR Ca2+ uptake). These two phenomena, if confirmed, would be compatible with a sarcolemmal source of trigger Ca2+.     

Relation between the electrical and mechanical activity of the stomach. In situ study of the anesthetized rat

The relations between the electrical and mechanical activity of the corpus and the antrum have been studied by means of several microelectrodes and enterographic transducer under binocular control (X 5) in anaesthetized rats (pentobarbital Na, 4 mg/kg). The recording period starts from 30 min after the onset of anaesthesia. This time corresponds to the release of the post operative inhibitions. Several rhythms of slow components have been in evidence thanks to a long time constant (5 sec): the dominant component with his frequency 4.04 +/- 1.06 c/min (n = 302 values). This frequency increases (5.11 +/- 1.3 c/min) during the antropyloric evacuation. Other rhythmic components of smaller amplitude (less than 200 microV) and frequency ranging between 7-16 c/min have been seen in quiescent conditions. In contractile state, the incidence of such rhythms decreases. The weakest manifestations of mechanical activity consist of small rhythmic variations of volume, the frequency corresponding to the main gastric rhythm of 4.5 c/min; however any spiking activity is observed. The second step of activity is the peristalsis (speed: 1 mm/sec), the circular contractility is accompanied by small spikes (less than 200 microV) in short salves. The third step is marked by the antral contraction with an important volume of variation, spike bursts of greater amplitude and biphasic slow wave are recorded. The antral activity is followed by a break of the main rhythm activity during 20 sec. These activities appear as a result from a structuration of local oscillators of relatively high frequency, in this species.     

Sympathetic mechanism of regulating heart function in acute transitory coronary insufficiency of different duration

Experiments on 102 outbred white male rats with experimental acute transitory coronary insufficiency (ATCI) were carried out to show a consistent phasic time course of the functioning of the sympathetic cardiac activity regulation mechanism. The sympathetic neuroeffector influence on the myocardium with ATCI depends to a large measure on the intensity of the neurotransmitter biosynthesis and function of cardiomyocyte adrenoreceptors. It is suggested that the time couse of heart contractility and rhythm under ATCI is related to changes in the pre- and post-synaptic component of the sympathetic regulation mechanism of cardiac function. It is also assumed that cardiomyocyte receptors might exert a substantial influence on the possibility and development of arrhythmias. The advantages of pharmacological correction (as compared with the blockade) of sympathetic neuroeffector influences on the myocardium under ATCI are emphasized.     

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.     

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.     

The investigation of the synchronization between rhythms in the human cardiovascular system from time series of R-R-intervals

We demonstrated that, from the sequence of R-R intervals, it is possible to calculate the instantaneous phases and instantaneous frequencies of the main rhythmic processes governing the cardiovascular dynamics in humans, namely, the main heart rhythm, respiration, and the process of slow regulation of blood pressure with basic frequency close to 0.1 Hz. For the cases of spontaneous respiration and paced respiration with a fixed frequency, the synchronization between the rhythms of the cardiovascular system was investigated based on the analysis of only the time series of R-R intervals. It is shown that the main heart rhythm and the rhythm of low-frequency regulation of blood pressure can be synchronized with respiration.     

Nonlinearity between action potential alternans and restitution, which both predict ventricular arrhythmic properties in Scn5a+/- and wild-type murine hearts

Electrocardiographic QT- and T-wave alternans, presaging ventricular arrhythmia, reflects compromised adaptation of action potential (AP) duration (APD) to altered heart rate, classically attributed to incomplete Na(v)1.5 channel recovery prior to subsequent stimulation. The restitution hypothesis suggests a function whose slope directly relates to APD alternans magnitude, predicting a critical instability condition, potentially generating arrhythmia. The present experiments directly test for such correlations among arrhythmia, APD alternans and restitution. Mice haploinsufficient in the Scn5a, cardiac Na(+) channel gene (Scn5a(+/-)), previously used to replicate Brugada syndrome, were used, owing to their established arrhythmic properties increased by flecainide and decreased by quinidine, particularly in right ventricular (RV) epicardium. Monophasic APs, obtained during pacing with progressively decrementing cycle lengths, were systematically compared at RV and left ventricular epicardial and endocardial recording sites in Langendorff-perfused Scn5a(+/-) and wild-type hearts before and following flecainide (10 μM) or quinidine (5 μM) application. The extent of alternans was assessed using a novel algorithm. Scn5a(+/-) hearts showed greater frequencies of arrhythmic endpoints with increased incidences of ventricular tachycardia, diminished by quinidine, and earlier onsets of ventricular fibrillation, particularly following flecainide challenge. These features correlated directly with increased refractory periods, specifically in the RV, and abnormal restitution and alternans properties in the RV epicardium. The latter variables were related by a unique, continuous higher-order function, rather than a linear relationship with an unstable threshold. These findings demonstrate a specific relationship between alternans and restitution, as well as confirming their capacity to predict arrhythmia, but implicate mechanisms additional to the voltage feedback suggested in the restitution hypothesis.     

Method for the immediate measurement of myocardial pressure velocity relationships in situ]

A method for instantaneous measurements and representations of myocardial pressure-velocity relations permitting the analysis of various contractility parameters is described. Basing on a modified two-element model of cardiac muscle the measurement of the relative shortening velocity vce = dp/dt(p) of the contractile elements is carried out by a special analog computer, which calculates the quotient (dp/dt) to the simultaneous left ventricular pressure p. Electronic differentiation of the logarithm of pressure-proportional input voltages is used. The p-v-diagram can be displayed on x-y-oscilloscopes. Over an input voltage range of 20 mV---20V the quotient can be measured within the range of 20 sec-1---250 sec-1. Output voltages can be calibrated automatically. Between (dp/dt)p-1 determined by conventional methods and the dlnp/dt calcuated electronically there exists a correlation gamma = 0.995. An additional electronic circuit which permits the determination of a contractility parameter indicates the point of (dp/dt)max on the p-v-relation display. The application of the method in experimental studies under inotropic changes in the rabbit heart in situ following beta-receptor blockade is demonstrated.     

Cardiorespiratory interactions during periodic breathing in awake chronic heart failure patients

We applied spectral techniques to the analysis of cardiorespiratory signals [instantaneous lung volume (ILV), instantaneous tidal volume (ITV), arterial O(2) saturation (Sa(O(2))) at the ear, heart rate (HR), systolic (SAP), and diastolic (DAP) arterial pressure] during nonapneic periodic breathing (PB) in 29 awake chronic heart failure (CHF) patients and estimated the timing relationships between respiratory and slow cardiovascular (<0.04 Hz) oscillations. Our aim was 1) to elucidate major mechanisms involved in cardiorespiratory interactions during PB and 2) to test the hypothesis of a central vasomotor origin of PB. All cardiovascular signals were characterized by a dominant (>/=84% of total power) oscillation at the frequency of PB (mean +/- SE: 0.022 +/- 0.0008 Hz), highly coherent (>/=0.89), and delayed with respect to ITV (ITV-HR, 2.4 +/- 0.72 s; ITV-SAP, 6.7 +/- 0.65 s; ITV-DAP, 3.2 +/- 0.61 s; P < 0.01). Sa(O(2)) was highly coherent with (coherence function = 0.96 +/- 0. 009) and almost opposite in phase to ITV. These findings demonstrate the existence of a generalized cardiorespiratory rhythm led by the ventilatory oscillation and suggest that 1) the cyclic increase in inspiratory drive and cardiopulmonary reflexes and 2) mechanical effects of PB-induced changes in intrathoracic pressure are the more likely sources of the HR and blood pressure oscillations, respectively. The timing relationship between ITV and blood pressure signals excludes the possibility that PB represents the effect of a central vasomotor rhythm.     

Acceleration generated by the myocardium as a criterion of its contractility

In experiments on cat heart-lung preparations cooled from 38 to 25 degrees C, acceleration of the heart muscle (in mm Hg . s-2) was the only criterion of myocardial contractility, which showed identical changes under an equivalent increase (1.5-fold) of heart load with volume or resistance. The latter indicates that acceleration of the myocardium is the most adequate criterion of myocardial contractility.     

Enhanced effect of daytime restricted feeding on the circadian rhythm of streptozotocin-induced type 2 diabetic rats

There is increasing awareness of the link between impaired circadian clocks and multiple metabolic diseases. However, the impairment of the circadian clock by type 2 diabetes has not been fully elucidated. To understand whether and how the function of circadian clock is impaired under the diabetic condition, we examined not only the expression of circadian genes in the heart and pineal gland but also the behavioral rhythm of type 2 diabetic and control rats in both the nighttime restricted feeding (NRF) and daytime restricted feeding (DRF) conditions. In the NRF condition, the circadian expression of clock genes in the heart and pineal gland was conserved in the diabetic rats, being similar to that in the control rats. DRF shifted the circadian phases of peripheral clock genes more efficiently in the diabetic rats than those in the control rats. Moreover, the activity rhythm of rats in the diabetic group was completely shifted from the dark phase to the light phase after 5 days of DRF treatment, whereas the activity rhythm of rats in the control group was still under the control of the suprachiasmatic nucleus (SCN) after the same DRF treatment. Furthermore, the serum glucose rhythm of type 2 diabetic rats was also shifted and controlled by the external feeding schedule, ignoring the SCN rhythm. Therefore, DRF shows stronger effect on the reentrainment of circadian rhythm in the type 2 diabetic rats, suggesting that the circadian system in diabetes is unstable and more easily shifted by feeding stimuli.