Physiological simulation of atrial-ventricular mechanical interaction in male rats during the cardiac cycle

doi:10.21203/rs.3.rs-4016166/v1

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Physiological simulation of atrial-ventricular mechanical interaction in male rats during the cardiac cycle

https://doi.org/10.21203/rs.3.rs-4016166/v1

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published 03 Sep, 2024

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Adequate assessment of the contribution of the different phases of atrial mechanical activity to the value of ejection volume and pressure developed by the ventricle is a complex and important experimental and clinical problem. A new method and an effective algorithm for controlling the interaction of isolated rat right atrial and right ventricular strips during the cardiac cycle were developed and tested in a physiological experiment. The presented functional model is flexible and has the ability to change many parameters (temperature, pacing rate, excitation delay, pre- and afterload levels, transfer length and force scaling coefficients) to simulate different types of cardiac pathologies. For the first time, the contribution of the duration of the excitation delay of the right ventricular strips to the amount of work performed by the muscles during the cardiac cycle was evaluated. Changes in the onset of atrial systole and the delay in activation of ventricular contraction may lead to a reduction in cardiac stroke volume, which should be considered in the diagnosis and treatment of cardiovascular disease and in resynchronization therapy.

ventricle

atrium

interaction

physiological mode of contraction

control algorithm

The assessment of the contractility of the heart is mainly concerned with the state of systolic and diastolic function of the ventricles. However, the complex nature of the mechanical interaction of the ventricles with the atria during the cardiac cycle is not considered [19, 20]. C.J. Wiggers and L.N. Katz estimated that the contribution of the atria to left ventricular filling averages about 35% [42]. Their conclusion that atrial systole significantly increases left ventricular filling and improves its work was subsequently confirmed by a number of authors in various animals [7, 25, 26, 28, 37] and humans [4, 6, 14]. The efficiency of ventricular ejection is due to the fact that at the end of the ventricular filling phase, at a strictly defined time after the reservoir and conduit phases of the atrium, there is an additional injection of blood from the atrium into the ventricular cavity. The walls of the ventricle are stretched and prepared for the next contraction. For a relatively short time, it has become possible to assess the contribution of the atria using ultrasound data in Doppler mode [27, 32, 40].

The subtle mechanisms of myocardial remodeling of the chambers of a healthy and, in particular, a pathologically altered heart during interaction in the atrioventricular system in the reservoir phase, conduit phase, and booster phase are still poorly understood [8, 13, 38]. The current view is that atrial and ventricular myocardial failure develop simultaneously [5]. Adequate evaluation of the contribution of the different phases of mechanical atrial activity to the value of stroke volume and pressure developed by the ventricle is a complex and at the same time important experimental and clinical problem [2, 41].

It is quite difficult to study in detail the contribution of each of the three phases of the atrial cycle to ventricular systole under whole-heart conditions at various loads, heart rates, etc. This paradigm prompted the development of a new experimental model to study the different phases of the mutual influence of atrial and ventricular contractile activity in real time on isolated samples of rat atrial and ventricular myocardium. This approach is distinguished by a number of features. First, there is no influence of neuro-humoral regulation. Second, it is possible to take into account the contribution of the connective tissue scaffold and neighboring cells to the mechanical response. Third, it allows a more accurate assessment of myocardial contractility due to the simpler sample geometry. In addition, physiological experiments with isolated myocardial strips allow the study of the selective effect of a variety of factors on cardiac function over a wide range. Isolated myocardial strips preserve the native tissue (structure) of the myocardium because they have connective tissue, fibroblasts and other cells, interactions between adjacent myocytes. In contrast to whole heart studies, isolated myocardial strips are more suitable for simultaneous acquisition of data such as force and calcium transients and work loops consisting of stress and strain [31].

The aims are to develop a method for implementing an experimental model that simulates the interaction of the atrium and ventricle during the cardiac cycle and an algorithm for step-by-step computer control in real time of the duration of the interaction cycle and the amplitude of the mutually transmitted deformations of isolated atrial and ventricular strips of a rat during the cardiac cycle. The objective is to perform preliminary experiments on the influence of the time delay in the onset of ventricular contraction on the amount of work performed by the atrial and ventricular strips during the cardiac cycle.

Experimental two-channel setup

A two-channel experimental setup is required to implement the experimental model that simulates the interaction between the atrium and the ventricle (Fig. 1).

Photograph of a two-channel experimental setup consisting of: linear servomotors a and b; temperature-controlled baths c and d; force transducers e and f

A strip of the atrium is placed in one bath, a strip of the ventricle is placed in another bath. The experimental setup contains a separate life support system for each myocardial strip. It is possible to study each myocardial strip in isolation to obtain individual contractility characteristics and perform various tests. To implement real-time interaction, myocardial strips are virtually connected to each other via the ADC/DAC of the computer using a special control program algorithm. Signal acquisition and control of linear servomotors is performed with a time sampling of 100 µs. These conditions make it possible to evaluate the state of each myocardial strip and realize their mutual influence on each other almost in an analogue mode. The two-channel stimulator provides excitation delays with different durations.

Functional model simulating the interaction of the atrium and ventricle

The control algorithm that simulates the interaction between the atrium and ventricle in real time and provides a P-V diagram in the cavity of both chambers, considers the following conditions:

1) the molecular mechanisms of force generation and shortening amplitude are concentrated at the level of sarcomeres in cardiomyocytes (native multicellular strips of heart chambers are used);

2) the nature of the behavior and mechanisms of regulation of the contractility of the segment of the wall of the heart chamber are well reproduced in isolated multicellular strips of the myocardium of the corresponding chamber of the heart [1, 26];

3) the change in pressure (P) and volume (V) of the atrium and the ventricle during the cardiac cycle (P-V diagram) can be reproduced by assuming that P(t) ≈ α*F(t) and V ≈ β*L(t), where F is the value of the force generated by all cardiomyocytes on the cross-section of the myocardial strip, L is the myocardial strip length, α and β are scale factors corresponding to the dimension;

4) the atrial and ventricular strips, which simulate the corresponding chambers, are connected according to the scheme of preload and afterload in the blood flow;

5) the data obtained by the echocardiographic method served as an example for the development of an algorithm to control the contraction modes of muscle samples [33].

The functional model is capable of introducing different excitation delays between the muscle strips, simulating the atrioventricular delay between the atrial and ventricular chambers. It is possible to study the effects of experimental atrial fibrillation or the effects of different physiologically active substances on samples of atrial or ventricular muscles in isolation and in the interaction of these muscles in a functional model. It is important to note that it is possible to simulate the interaction of muscle strips from both the right and left heart.

Block diagram of the algorithm for controlling the mutual length deformations of isolated atrial and ventricular strips. The main nodes of the algorithm are: a0 - comparison of values of total forces (active + passive) of atrial and ventricular strips; b1 and b2 - implementation of physiological contraction mode at a given afterload for atrial and ventricular strips, respectively; c1 and c2 - calculation and transmission of values of relative deformations of ventricular and atrial strips, respectively, at each control step (10 kHz). Abbreviations: Atr – atrial strip; Ventr – ventricular strip; F_Atr and F_Ventr – full forces (passive component + active component) of atrial and ventricular strips; L_Atr and L_Ventr – lengths of atrial and ventricular strips; dL_Atr and dL_Ventr – calculated length changes of atrial and ventricular strips; Afterload_Atr and Afterload_Ventr – afterload levels of atrial and ventricular strips; k_{dL_Atr} and k_{dL_Ventr} – the transfer length coefficients of atrial and ventricular strips; dL > 0 – means the muscle shortening; dL < 0 – means the muscle lengthening (stretching); dL = 0 – means the constant muscle length

A brief description of the operation of the algorithm for controlling the mutual deformations of the isolated atrial and ventricular strips follows. When the total force of the atrial strip exceeds the total force of the ventricular strip (Fig. 2, a0), the atrial strip shortens under its predetermined afterload (Fig. 2, b1) and stretches the ventricular strip (Fig. 2, c1). Conversely, when the total force of the ventricular strip exceeds the total force of the atrial strip (Fig. 2, a0), the ventricular strip shortens under its afterload (Fig. 2, b2) and stretches the atrial strip (Fig. 2, c2).

Registration of mechanical activity of muscle strips

Animal care and experiments were performed in accordance with the European Parliament Directive 2010/63/EU and the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85 − 23, revised 1985) and approved by the Institute of Immunology and Physiology Ethics Committee (Protocol No. 14/20, December 8, 2020). Male Wistar rats (n = 5) were kept in the Institute's vivarium under standard conditions (12-hour light-dark cycle, water and food ad libitum).

Rats were injected intramuscularly with sodium heparin (5000 IU/kg) to prevent blood clotting in the coronary vessels. After 30 minutes, the rats were anesthetized with Zoletil-100 (0.3 ml/kg body weight) and 2% Xylazine (1 ml/kg body weight). After 15–20 min, the rats were rapidly euthanized by cervical dislocation immediately before tissue sampling. After euthanasia, the chest cavity was opened, and the lung vessels were cut to ensure the outflow of blood. Approximately 40 mL of a modified hypocalcemic Krebs-Henseleit solution (CaCl₂ 0.2 mM/L, temperature 12–15°C) containing 30 mM 2,3-butanedione monoxime (BDM) was injected into the left ventricular cavity and through the inferior vena cava into the right atrium and the ventricle to remove blood from the circulatory system. BDM is necessary to prevent mechanical damage during dissection of myocardial preparations [24]. After blood washout, the heart was removed and placed in a Petri dish containing a modified hypocalcemic Krebs-Henseleit solution.

Strips from the right atrium and the right ventricle were used in the experiment. Typically, the muscle samples from the right heart are thinner than those from the left heart. The small transverse dimensions of the cardiac muscle samples contribute to better oxygen penetration and maintenance of contractility. Samples of the right atrium (n = 5) and the right ventricle (n = 5) were taken from the same heart. Isolated right atrial muscle strips (wall segments) and thin parietal right ventricular trabeculae were attached to the rods of the force transducer and length servomotor in the experimental chamber under continuous perfusion with a modified BDM-free Krebs-Henseleit solution. The composition of the modified Krebs-Henseleit solution in mM/L: NaCl 118.5; NaHCO₃ 14.5; KCl 4.2; KH₂PO₄ 1.2; MgSO₄ 1.2; glucose 11.1; CaCl₂ 1.9; insulin 5 units/L; pH adjusted to 7.35 at 25°C and bubbling with a gas mixture of 95% O₂ and 5% CO₂.

Mechanical activity of isolated right atrial and right ventricular strips was registered in isometric and physiological contraction mode in a two-channel setup using the developed hardware complex based on ADC/DAC (L-502, L-cards, Russian Federation) connected to a personal computer and allowing recording of signals with a time sampling of 100 µs. The micromechanographic equipment made it possible to register and control the contraction force and length of the muscles with an accuracy of ± 0.02 mN and ± 1 µm, respectively, and to set different values for preload and afterload at any time point and for any duration. The cardiac muscles were excited with electrical pulses (approximately 1.5 of the excitation threshold) at a frequency of 2 Hz. The temperature of both muscle baths was maintained at 35 ± 0,1°C. The dual-channel stimulator allowed the setting of different excitation delays between the atrial and ventricular muscle samples.

Statistical data processing

Statistical data processing was not performed as the trial experiments were conducted.

The results of preliminary experiments demonstrating the capabilities of the experimental interaction model are presented. Muscle strips of the atrium and the ventricle can operate in isolation in a physiological contraction mode and can interact virtually according to the software algorithm we developed (Fig. 3). Phases of the physiological contraction mode: isometric - analogous to the development of isovolumic pressure in the whole heart; isotonic - analogous to systolic ejection; isometric relaxation - analogous to the beginning of diastole; stretching - analogous to diastolic filling.

Representative recording curves of the change in force of the rat right atrial a and ventricular b strips in isolation (black curves) and when modeling the interaction during the cardiac cycle with a delay of 20 ms in the contraction excitation of the ventricular strip (gray curves) and changes in their lengths c and d, respectively. Panel a shows the contraction phases of the atrial strip during interaction with the ventricular strip. Panel b shows the contraction phases of the ventricular strip during the interaction. The temperature of the solution is 35°C, the stimulation frequency is 2 Hz, the working length (L_w) is 95% of the maximal length (L_max) for both muscle strips

In isolation, both muscle samples contract in physiological loading mode. A relative afterload of 0.5 P/P₀ was chosen for the ventricular strips (because such a load is physiological for the ventricle) and 0.2 P/P₀ for the atrial strips (because the atrial load is less than the ventricular load). When simulating the interaction, the onset of contraction of the ventricular strips is delayed by 20 ms.

The control algorithm performs all phases of force and length value changes of the atrial and ventricular strips during their interaction in cardiac cycle. In the booster or active phase, the atrial strip shortens after reaching its afterload level (Fig. 3a and 3c, gray curves) and stretches the ventricular strip (Fig. 3d, gray curve). In the reservoir phase, the ventricular strip shortens as it reaches its afterload (Fig. 3b and 3d, gray curves) and stretches the atrial strip (Fig. 3c, gray curve). The conduit phase corresponds to the relaxation phase of the ventricular strip and the passive restitution of the atrial strip.

Representative superposition of length-force loops (a) of the rat right atrial strip registered in isolation (black lines) and in simulated interaction (gray lines) during the cardiac cycle at different values of the excitation delay duration of the ventricular strip. The duration of the excitation delay of the ventricular strip is given in the legend to the figure and near the corresponding length-force loop. For a more detailed understanding of the change in loop shape depending on the excitation delay, some loops are shown in separate panels (b, c, d, e, and f) of the figure. The arrows indicate the direction of loop development. Counterclockwise loop development means that the work performed by the heart muscle has a positive value (the muscle shortens under the influence of its own afterload). Clockwise loop development means that the work performed by the heart muscle has a negative value (the muscle is stretched under the influence of external forces)

Representative superposition of length-force loops (a) of the rat right ventricular strip registered in isolation (black lines) and in simulated interaction (gray lines) during the cardiac cycle at different values of the excitation delay duration of the ventricular strip. The duration of the excitation delay of the ventricular strip is given in the legend to the figure and near the corresponding length-force loop. For a more detailed understanding of the change in loop shape depending on the excitation delay, some loops are shown in separate panels (b, c, d, e, and f) of the figure. The arrows indicate the direction of loop development. Counterclockwise loop development means that the work performed by the heart muscle has a positive value (the muscle shortens under the influence of its own afterload)

In length-force coordinates, the loop for the atrial strip is represented as a figure of eight (Fig. 4a), similar to the pressure-volume loop for the whole atrium [30]. The force-length loop of the atrial strip at zero excitation delay is located predominantly to the right of the loop obtained in isolation and has a clockwise course (Fig. 4a and 4b). The amount of work of the atrial loop (corresponding to the area of this loop) at zero excitation delay is negative. With increasing duration of the excitation delay, the loops expand to the left and partially repeat the contour of the loop obtained in isolation (Fig. 4a, left part of the loop). The second part of the loop of the atrial strip, located on the right side in the same figure, expands to the right with increasing duration of the excitation delay (Fig. 4a, 4c-4f).

The force-length loops of the ventricular strip expand to the right with increasing excitation delay compared to the loop obtained in isolation (Fig. 5a, 5b-5f). The direction of loop development does not change with the duration of the excitation delay. The area of the length-force loop for the ventricular strip is always positive. During the interaction, the loop area of the ventricular strip is larger than the loop area obtained in isolation. This indicates an increase in the amount of work performed by the ventricle and an increase in its ejection efficiency.

Dependence of the amount of work performed by the rat right atrial (RA) and ventricular (RV) strips during modeling cardiac cycle interactions on the duration of the ventricular strip excitation delay. The amount of work is presented as a percentage of the amount of work performed by the heart muscle in isolation. Data are presented as mean ± SD

The work values of the atrial strips at zero excitation delay average about − 100% (Fig. 6, gray curve) as it is stretched by the ventricle. As the duration of the excitation delay increases, the work values also increase and reach a maximum value of 90% (at an excitation delay of 20 ms). After reaching the maximum, there is a slow decrease and stabilization of the work values at 45% after an excitation delay of 50 ms.

In the ventricular strips, the work values are above 100% for all positive excitation delays. At zero excitation delay (simultaneous excitation of both cardiac muscles), the work values are minimal and average 108%. As the duration of the excitation delay increases, the work values increase and reach a level of 125% (at an excitation delay of 35 ms) and stabilize approximately at this level.

The shortening amplitude of the right atrial strip increases with an increase in the duration of the excitation delay from 0 to 35 ms. This results in an increase in the level of pre-stretch of the right ventricular strip before contraction (Fig. 5). In the experimental interaction model, the length of the myocardial strip is an analog of the volume of the cardiac chamber, and the force developed is an analog of the pressure. According to the Frank-Starling law, an increase in volume increases the pressure developed by the ventricle. The level of preload at the right ventricular strip is constant, only the amplitude of shortening increases by the level of pre-stretch. At a delay of 35 ms, the level of right ventricular pre-stretch is maximal under these contraction conditions. In the same way, the area of the length-force loop of the right ventricular strip changes (Fig. 5), and therefore the work performed per cycle. For excitation delay durations greater than 35 ms, the right ventricular pre-stretch level remains at the maximal level. In this way, the atrium modulates the performance of the ventricle by pre-stretching.

Every model has its limitations. Our functional model, which simulates the interaction of the atrial and ventricular chambers, does not take into account the viscous and elastic properties of the vascular circulatory system. In studies of the contractility of two-dimensional myocardial specimens, the afterload is usually defined as a constant. Therefore, our functional model does not use the three-element Windkessel model, and the level of afterload is expressed as a percentage of the myocardial strip force amplitude. Further development of the functional model involves the inclusion of the viscous properties of the vascular circulatory system.

It has been experimentally shown that the basic mechanical and energetic properties of an isolated cardiac fiber and the fundamental characteristics of the whole heart are closely correlated, being determined by the properties of the cardiomyocytes. Organ geometry only modulates these properties [43]. Our experiment with a functional model has shown that the process of mechanical interaction between atrial and ventricular chambers in the cardiac cycle is well reproduced in isolated myocardial strips of these chambers.

One of the stages in the development of cardiac physiology is associated with the development and implementation of a method for setting the physiological sequence of changes in the magnitude of load on an isolated myocardial preparation or on cardiomyocytes that simulates the functioning of a segment of the ventricular wall of the heart [12, 17, 18, 22]. This mode provides a change in loads on an isolated myocardial strip during a single force-length cycle, similar to the pressure-volume loop [3, 12, 17, 29, 31]. Pressure-volume loops have a number of hemodynamic parameters that are difficult to measure by other means. These include changes in contractility, elastance, power, energetics, and efficiency by assessing both load-dependent and load-independent states of the myocardium. At the same time, it becomes possible to evaluate the influence of various factors, including the ventricular excitation delay, contractility parameters of the healthy and diseased myocardium, and the duration and sequence of the different phases of interaction of the heart chambers in which the atrial contribution to systolic ventricular ejection is optimal [21].

In our experiment, the increase in work performed by the rat right ventricular strip in a single cardiac cycle when ventricular excitation is delayed by 35 ms relative to the atrium during their interaction is 25% compared to its work in isolation (Fig. 5). This is in good agreement with the data of many authors who have shown that at the end of the ventricular filling phase, an additional portion of blood is injected from the atrium into the ventricular cavity (about 25% of the end-diastolic volume of the ventricle). This injection occurs at a strictly defined time which stretches the ventricle and prepares it for the subsequent contraction. This effect has been observed in animals [7, 11, 15, 26, 28, 39] and humans [4, 6, 10, 14, 16, 34–36]. This process is clearly visible on ultrasound images in Doppler mode, when a second peak of increased blood pressure appears in the ventricle against the background of the first peak [23, 32, 40]. At the same time, the amount of work performed by the atrium during this cycle is almost zero, as the atrium is stretched by the ventricle during this period (the reservoir and conduit contraction phases of the atrial cycle). Atrial systole (the booster phase) contributes to the storage of the kinetic energy of the blood shock wave in the elastic structures of the ventricle and increases the degree of actin-myosin overlap in the ventricular cardiomyocytes (Frank-Starling law). Changes in the onset of atrial systole and the delay in activation of ventricular contraction may lead to a reduction in cardiac stroke volume, which should be considered in the diagnosis and treatment of cardiovascular disease and in resynchronization therapy [9].

A new method and an effective algorithm for controlling the interaction of isolated rat right atrial and right ventricular strips during the cardiac cycle were developed and tested in a physiological experiment. The presented functional model is flexible and has the ability to change many parameters (temperature, pacing rate, excitation delay, pre- and afterload levels, transfer length and force scaling coefficients) to simulate different types of cardiac pathologies. The experiments performed confirm the correctness of the developed algorithm. This approach offers wide possibilities for studying individual phases of the atrioventricular interaction process. For the first time, the contribution of the duration of the excitation delay of the right ventricular strips to the amount of work performed by the muscles during the cardiac cycle was evaluated.

Data Availability

Data will be made available upon reasonable request.

CONFLICT OF INTEREST STATEMENT

No conflicts of interest, financial or otherwise, are declared by the authors.

ACKNOWLEDGEMENTS

The authors are grateful to Professor Paolo N Marino for his stimulating discussions and very appreciated comments.

FUNDING INFORMATION

This work was supported by IIF UrB RAS theme no. 122022200089-4. This work was performed using the equipment of the Shared Research Center of Scientific Equipment SRC IIP UrB RAS.

Data Availability

Data will be made available upon reasonable request.

Competing Interests

No conflicts of interest, financial or otherwise, are declared by the authors.

Author Contribution

A.B.: Conceptualization; Methodology;Investigation; Writing - Review/Editing; Visualization.

Yu.P.: Conceptualization; Methodology; Writing - Original Draft and Review/Editing; Supervision; Project Administration.

All authors revised the manuscript.

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No competing interests reported.

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published 03 Sep, 2024

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Editorial decision: Revision requested
27 Apr, 2024
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Reviewers agreed at journal
16 Apr, 2024
Reviewers invited by journal
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Physiological simulation of atrial-ventricular mechanical interaction in male rats during the cardiac cycle

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Methods

Experimental two-channel setup

Functional model simulating the interaction of the atrium and ventricle

Registration of mechanical activity of muscle strips

Statistical data processing

Results

Discussion

Data Availability

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1