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V S Markhasin

Publications and source records attributed to V S Markhasin.

At least 19 recordsLinked to original sources
PubMed2006

Activation sequence as a key factor in spatio-temporal optimization of myocardial function.

Using one-dimensional models of myocardial tissue, implemented as chains of virtual ventricular muscle segments that are kinematically connected in series, we studied the role of the excitation sequence in spatio-temporal organization of cardiac function. Each model element was represented by a well-verified mathematical model of cardiac electro-mechanical activity. We found that homogeneous chains, consisting of identical elements, respond to non-simultaneous stimulation by generation of complex spatio-temporal heterogeneities in element deformation. These are accompanied by the establishment of marked gradients in local electro-mechanical properties of the elements (heterogeneity in action potential duration, Ca2+ transient characteristics and sarcoplasmic reticulum Ca2+ loading). In heterogeneous chains, composed of elements simulating fast and slow contracting cardiomyocytes from different transmural layers, we found that only activation sequences where stimulation of the slower elements preceded that of faster ones gave rise to optimization of the system's electro-mechanical function, which was confirmed experimentally. Based on the results obtained, we hypothesize that the sequence of activation of cardiomyocytes in different ventricular layers is one of the key factors of spatio-temporal organization of myocardium. Moreover, activation sequence and regional differences in intrinsic electro-mechanical properties of cardiac muscle must be matched in order to optimize myocardial function.

Action Potentials↗
PubMed2005

Electron-conformational model of ryanodine receptor lattice dynamics.

We propose a simple, physically reasonable electron-conformational model for the ryanodine receptor (RyR) and, on that basis, present a theory to describe RyR lattice responses to L-type channel triggering as an induced non-equilibrium phase transition. Each RyR is modelled with a single open and a single closed (electronic) state only, described utilizing a s=12 pseudospin approach. In addition to the fast electronic degree of freedom, the RyR channel is characterized by a slow classical conformational coordinate, Q, which specifies the RyR channel calcium conductance and provides a multimodal continuum of possible RyR states. The cooperativity in the RyR lattice is assumed to be determined by inter-channel conformational coupling. Given a threshold sarcoplasmic reticulum (SR) calcium load, the RyR lattice fires due to a nucleation process with a step-by-step domino-like opening of a fraction of lattice channels, providing for a sufficient release to generate calcium sparks. The optimal mode of RyR lattice functioning during calcium-induced calcium release implies a fractional release with a robust termination due to a decrease in SR calcium load, accompanied by a respective change in effective conformational strain of the lattice. SR calcium overload is shown to result in excitation of RyR lattice auto-oscillations with spontaneous RyR channel opening and closure.

Animals↗
PubMed2004

[Electromechanical heterogeneity of the myocardium].

Herein we discuss modem data showing that ventricle's working myocardium is highly heterogeneous. Significant transmural differences in electrophysiological and biomechanical properties of cardiomyocytes are reviewed. The reviewed evidence of myocardial heterogeneity constitutes the basis for modem assessment of segmental kinetics of different regions in intact heart. We used muscle duplexes as condensed models of a heterogeneous myocardial system. Experimental data, presented here were obtained both in biological duplexes formed by isolated myocardial preparations and in mathematical models of muscle duplexes. We showed that specific functional heterogeneity of cardiomyocytes, related to their excitation sequence, allowed the myocardium to optimise its contractile function and smooth dispersion of repolarisation.

Animals↗
PubMed2002

Effects of mechanical interaction between two rabbit cardiac muscles connected in parallel.

The hypothesis that myocardium mechanical inhomogeneity produces a substantial effect on mechanical function was tested. Muscle inhomogeneity was studied in isolated papillary muscles or trabeculae excised from rabbit right ventricle and connected in a parallel duplex. Each muscle was placed in a separate perfusion bath. One end of each muscle was fastened to an individual force transducer and the other to the common lever of a servomotor. This arrangement allowed both muscles, being excited independently, to pull jointly a load applied to the lever. Separate electrodes for each perfusion bath allowed to stimulate muscles with a time delay. Tension developed in the individual muscles and their interaction were studied. Developed tension was critically dependent on the timing and sequence of excitation. Using mathematical modeling, patterns of tension distribution experimentally observed in parallel duplexes were simulated. These results suggest that changes both in Ca(2+) transients and in the time course of Ca(2+)-troponin complexion due to the duplexed muscles interaction offset the effect of mechanical inhomogeneity.

Animals↗
PubMed2001

[Contraction-relaxation dynamics and mechanical restitution in the developing myocardium of the chick embryo].

Parameters of the contraction-relaxation cycle and mechanical restitution (MR) were assessed in isolated ventricular preparations of 3- and 4-day chick embryos (EM) and posthatched (PH) chicks. Ryanodine reduced the relaxation rate in the EM but increased it in the PH chicks. It also suppressed a rest-induced potentiation and the MR in all the preparations. Low Na superfusion significantly suppressed the relaxation and decreased the rest potentiation in the myocardial preparations all ages. The findings substantiate existence of a sarcolemmal Ca pool which participates in regulation of twitch parameters and Ca outflux via the Na-Ca exchange.

Animals↗
PubMed2000

Mathematical modeling of the effect of the sarcoplasmic reticulum calcium pump function on load dependent myocardial relaxation.

Earlier, we developed a mathematical model of myocardial contraction-relaxation cycle regulation. A great number of mechanical experiments was simulated in the model, the phenomenon of load dependent relaxation (LDR) included. In the present work we used the same model to analyze experimental data revealing that high temperature leads to reduction of LDR. We simulated three main factors arising due to high temperature, which a priori may cause LDR reduction: increasing the cross-bridges cycling rate, decreasing the duration of the Ca transient ascending limb, and increasing Ca pumping rate. Indeed, these factors together result in LDR reduction; i.e., the model correctly simulates the effect of high temperature on LDR in general. At the same time, the sensitivity of LDR to the third factor is much higher than to the first and the second ones; i.e., increasing the rate of Ca pumping is sufficient to induce the observed effect in the framework of the model. This seems to contrast with the result of our previous study dealing with the simulation of LDR disappearance due to increasing Ca pumping rate as it happens during relatively severe cardiac hypertrophy. However, the model analysis shows that the specific mechanism underlying the change in Ca pumping rate in either case is extremely important for the effect on LDR. Particularly, the model predicts that LDR will reduce if this rate increases due to enhanced ATP hydrolysis rate by the Ca pump; and vice versa, if this rate increases due to decreasing retroinhibition of the pump ATPase, it may result in LDR increase. Probably, but the first mechanism is operational due to high temperature and makes LDR to reduce, whereas slowing down Ca pumping due to increasing retroinhibition results in LDR disappearance during severe cardiac hypertrophy.

Adenosine Triphosphate↗
PubMed1997

Mathematical modelling of the contribution of mechanical inhomogeneity in the myocardium to contractile function.

Earlier we developed a mathematical model of the cardiac muscle that allowed for inactivation through the effects of cooperativity of contractile proteins. In the present work we used the model to analyze the mechanical function of an inhomogeneous myocardium. To simulate the latter we chose, as the simplest sytstem, a duplex in which muscles with different mechanical properties were connected in series and in parallel. Numerical experiments showed that the basic effect due to the inhomogeneity consists in the non-additivity of the mechanical characteristics of the muscle, e.g., of the relationship between end-systolic length and end-systolic force (Les - Pes). As a rule, non-additivity consists in a negative inotropic effect. The analysis showed that the cause of non-additivity is redistribution of loads between muscles (in a parallel duplex), redistribution of lengths (in a serial duplex), changes in the rate of contraction of each muscle compared to contraction that when working separately, shifts in time to Les. Also, the model predicts that additional inactivation of contractile proteins in a muscle within a duplex against isolation is the substantial mechanism of enhanced non-additivity. Among the factors of inhomogeneity studied the basic determinants are difference in amplitudes between isometric tensions developed by each muscle in isolation and the asynchronism in the development of these tensions.

Biomechanical Phenomena↗
PubMed1996

Mathematical modeling of relations between the kinetics of free intracellular calcium and mechanical function of myocardium.

The paper describes a mathematical model of cardiac muscle contraction based on the assumption of two types of co-operativity which control the formation of calcium-troponin complexes and on a simplified scheme of free intracellular calcium kinetics. Calcium transients are shown to be different in isotonic and isometric conditions, being dependent on initial muscle length as well. Numerical experiments and analysis of the model suggest that calcium uptake by the sarcoplasmic reticulum slows down with an increase in the intracellular concentration of free calcium. This suggestion enables the model to explain the disappearance of load-dependent relaxation observed experimentally at cardiac hypertrophy.

Calcium↗
PubMed1996

Effect of cellular inhomogeneity on cardiac tissue mechanics based on intracellular control mechanisms.

Our earlier description of the intracellular control (IC) of contraction of a single cell, based on coupling calcium kinetics with cross-bridge cycling, is extended here to study the performance of a multicellular inhomogeneous tissue common in pathophysiological situations. Inhomogeneity in calcium affinity or in cross-bridge kinetics is first simulated by analyzing two fiber segments connected as parallel or serial duplexes. The calculated characteristics of the parallel duplex are tested against our experimental data with two parallel nonuniform rat papillary fibers. The predicted serial duplex behavior is compared with reported experimental data of the effects of segmental hypoxia along a papillary fiber. Fiber inhomogeneity leads to polyphasic contraction of the fiber segments, reduces muscle length shortening, and affects the control of relaxation. We next investigated the force generated by a nonuniform tissue containing small areas of necrosis, evident in subendocardial infarction. Theoretical analysis suggests that the IC mechanism decreases the extension of cell necrosis by lowering the energy consumption of the viable cells in the ischemic zone. The study emphasizes the importance of IC in determining the global and local function of the inhomogeneous myocardium.

Animals↗
PubMed1994

[The contribution of the myocardial segmental nonhomogeneity of the left ventricular walls to its contractile and pumping functions].

A normalised variation coefficient of the partial systolic fraction served as the measure of nonhomogeneity of the segmentary kinetics of the left ventricle's wall (parameter J). A significant correlation was found between the parameter J and the fraction of the ventricle output (the correlation being negative one) both in normal subjects and in patients with cardiac pathology. The parameter J was also found to be a sensitive index of the heart pumping and contractile functions. The local cardiotopodynamics as expressed via the segmentary nonhomogeneity seems to be able to contribute much into the regulation or modulation of the heart pumping function.

Adult↗
PubMed1992

[The characteristics of the effect of parathyroid hormone on the mechanical activity of the myocardium in rats with a deficiency of Ca and Mg in the drinking water].

Inotropic and lusitropic effects of the parathyroid hormone (PTH) upon the rat heart ventricle myocardium were studied in conditions of calcium and magnesium deficit in drinking water. The control rats revealed two phases of the hormone effect: the positive and negative ones, whereas the experimental rats only revealed the negative inotropic effect. Both the negative and positive inotropic effects were followed by an acceleration of the relaxation.

Animals↗
PubMed1991

Cooperative effects due to calcium binding by troponin and their consequences for contraction and relaxation of cardiac muscle under various conditions of mechanical loading.

A mathematical model for the regulation of mechanical activity in cardiac muscle has been developed based on a three-element rheological model of this muscle. The contractile element has been modeled taking into account the results of extensive mechanical tests that involved the recording of length-force and force-velocity relations and muscle responses to short-time deformations during various phases of the contraction-relaxation cycle. The best agreement between the experimental and the mathematical modeling results was obtained when a postulate stating two types of cooperativity to regulate the calcium binding by troponin was introduced into the model. Cooperativity of the first type is due to the dependence of the affinity of troponin C for Ca2+ on the concentration of myosin crossbridges in the vicinity of a given troponin C. Cooperativity of the second type assumes an increase in the affinity of a given troponin C for Ca2+ when the latter is bound by molecules neighboring troponin.

Animals↗
PubMed1990

[The activation and mechanical determinants of the rate of isometric relaxation of the heart muscle].

In experiments with sequential loads, the relative velocity of cardiac muscle relaxation was found to be affected by the calcium ions concentration, velocity of shortening and by the terminal systolic length. Mechano-chemical dissociation played a major role, too, in the relaxation determination. The shifts in mechanical relaxation seem to be based on the cooperation phenomena in the troponine regulation of contraction and relaxation.

Animals↗
PubMed1990

Heart muscle: mathematical modelling of the mechanical activity and modelling of mechanochemical uncoupling.

A mechanical model of heart muscle is proposed which includes rheological equations and equations for Ca-troponin interaction, for the dependences of the number of myosin cross-bridges on the length of sarcomere and on the speed of motion. The main assumption of the model is the dependence of the troponin affinity to calcium ions on the number of myosin cross-bridges attached. The model successfully imitates isometric and isotonic contractions, the "length-force" relationships, load-dependent relaxation, and the group of mechanical phenomena known as mechanochemical uncoupling.

Actins↗
PubMed1989

[The effect of stimulation frequency on the speed of isometric myocardial relaxation in mammals].

The relaxation of tension of the rabbit and rat heart right ventricle papillary muscles was estimated by the characteristic time t30. An increase in the stimulation rate as well as an increase in extracellular concentration of Ca ions decelerated the relaxation in the rabbit myocardium, whereas in the rat myocardium a shortening of interimpulse interval accelerated isometric relaxation. Constant administration of reserpine and beta-blocking agents did not alter the effects. The mechanism of the stimulation rate effect on the velocity of relaxation are discussed.

Adrenergic beta-Antagonists↗