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Innovations and Ideas
1 Department of Medical Physiology, Texas A&M University System Health Science Center, College Station, Texas 77843
2 Department of Physiology, University of Arizona Health Science Center, Tucson, Arizona 85724
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Abstract |
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 TOP Abstract IntroductionMETHODSRESULTSDISCUSSIONAPPENDIXREFERENCES |
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Key words: pressure-volume plot; preload; afterload; contractility; heterometric regulation; homeometric regulation; Frank-Starling relationship; Starling’s law of the heart
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Introduction |
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TOPAbstractIntroductionMETHODSRESULTSDISCUSSIONAPPENDIXREFERENCES |
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In this article, we describe a computer model that simulates the cardiac cycle of a mammalian heart with accuracy appropriate for instruction of medical, graduate, and undergraduate students. Our goal in developing the model was to use the pressure-volume plot as a teaching tool, in conjunction with a system diagram, to explain the behavior of the heart as a pump. The model exhibits realistic responses to changes in preload, afterload, Cont, and HR while displaying time-dependent changes in pressure and volume in addition to a pressure-volume plot. It differs from previous models (1, 3, 5) by graphing these parameters on a beat-to-beat basis that is particularly useful when describing the dynamic adaptation of the pumping heart to various stimuli. The model emphasizes intrinsic regulation of myocardial function and therefore does not include specific simulated effects of peripheral baroreceptors, venoatrial receptors, and other extrinsic cardiovascular reflexes. However, the consequences of extrinsic reflex responses can be simulated by manually changing preload, total peripheral resistance (TPR; afterload), Cont, and HR.
The model is designed to operate in one of two different modes: the isolated heart mode and the intact heart mode. The isolated heart mode is used to isolate an individual variable, such as preload, to demonstrate the most basic effect of that variable without subsequent changes in other parameters. In this mode, secondary changes in mean arterial pressure do not "feed back" to subsequently alter function. In engineering terms, this is the "open-loop" mode. The intact heart mode is used to show how the pumping function of the heart will behave when one or more of the variables is changed and the system is allowed to come to a new equilibrium. In this mode, secondary changes in mean arterial pressure are allowed to feed back and subsequently alter function. In engineering terms, this is the "closed-loop" mode.
The model is written in the LabView programming language and compiled for stand-alone use on Macintosh Power-PC and Pentium-based microcomputers. It is appropriate as a classroom teaching tool or as a self-directed student laboratory. It can serve simply as a tool to explain the timing of pressure and volume traces using the Wigger’s diagram or to introduce students to the concept of the pressure-volume plot. However, the most useful feature of the model is the way shifts in the pressure-volume loop can be visualized in response to changes in preload, afterload, Cont, and HR. Compiled versions are available for free distribution over the internet to students and faculty along with a detailed worksheet that can be used for step-by-step classroom instruction or for self-directed laboratory exercises.
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METHODS |
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TOPAbstractIntroductionMETHODSRESULTSDISCUSSIONAPPENDIXREFERENCES |
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750 kb of disk space, whereas the compiled code with embedded libraries occupies 2.5 Mb of disk space and requires 6 Mb of system memory to execute. Macintosh and Windows versions, along with the worksheet found in the APPENDIX can be downloaded from the following internet address: (http//mphywww.tamu.edu/davis/models/pvmodel.html).
Timing.
The basic timing for the model is derived from a sine-wave generator, adapted from Kiel and Shepherd (3). Display speed is limited primarily by the number of points displayed per cardiac cycle, with a minimum of 50 points required for adequate resolution of a pressure-volume loop. The model generates 100 points per cycle at a HR of 60 beats/min. The number of points, and hence trace resolution, changes with HR.
Pressure and volume waveforms.
The systolic portion of the left ventricular pressure wave was simulated by clipping the sine wave (segment A in Fig. 1). This function was combined with a linearly increasing ramp (segment B in Fig. 1) to simulate the diastolic filling phase of the cardiac cycle. The aortic pressure wave (not shown) between the opening of the aortic valve and the closing of the aortic valve was made equal to the ventricular pressure wave. The aortic pressure wave in diastole was simulated using a linearly decreasing ramp function.
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Displays.
When the model is loaded, there are four general areas displayed on the screen (Fig. 2): a strip chart record, a graph of ventricular pressure versus ventricular volume, a system diagram, and a set of four sliders to manipulate the four determinants of cardiac function. For the sake of clarity or emphasis, each of the four areas can be turned off or on with buttons located at the bottom of the screen.
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The instantaneous values for left ventricular pressure are plotted as a function of the corresponding values for left ventricular volume, and the data are displayed in the top right quadrant of the computer screen. The plot is designed to retain the most recent pressure-volume loops, after which all traces are automatically cleared. The advantages of representing the data as pressure-volume loops are that 1) all four determinants of myocardial function can be represented or demonstrated on this graph; 2) other parameters important for understanding the pumping function of the heart, such as end-diastolic volume (EDV) and pressure (EDP), end-systolic volume (ESV) and pressure (ESP), and stroke volume (SV) are represented on the graph and can be observed directly as they change; and 3) all phases of the cardiac cycle are more easily viewed on a pressure-volume loop than on a chart record.
A system diagram showing the relationships among the different parameters that contribute to the pumping function of the heart is located in the bottom right quadrant of the computer screen. A continuous display of the numeric values is shown in a small window for each parameter. The parameters associated with the heart are shown in black letters and include 1) EDV and ESV of the ventricle; 2) SV, which is the difference between EDV and ESV; 3) cardiac output (CO), which is the product of HR and SV; and 4) Cont, which determines the rate and magnitude of force generated by the cardiac muscle and, therefore, the magnitude of ESV.
Parameters associated with the peripheral vasculature, external to the heart, are shown in red letters. They include TPR and mean arterial pressure (Pã). Pã is proportional to the product of TPR and CO. The digital displays are color coded so that dependent parameters have black backgrounds, independent (fixed) parameters have white backgrounds, and external parameters have pink backgrounds. These colors change appropriately as the model is switched between isolated- and intact-heart modes (see explanation below).
Three additional buttons labeled "pause," "act tension," and "clear graph" are also included in the lower right quadrant. They provide the following display enhancements: 1) the pause button causes the strip chart recorder to pause and inserts a new display with a sliding vertical line (blue line, Fig. 3) that can be used to identify the elements on the strip chart record (Wiggers’ Diagram) that correspond to those same elements in the pressure-volume loop. It is useful for locating the boundaries between the different phases of the cardiac cycle. Students find this especially helpful when trying to visualize the connection between the Wiggers’ Diagram and the "pressure-volume loop." 2) The act tension button will display a red line on the pressure-volume graph approximating the active tension curve for the myocardium. It defines the limit of isotonic shortening during the ejection phase and provides a visual demonstration of the effect of changes in Cont on ESV and, hence, on SV, CO, and Pã. 3) The clear graph button clears the pressure-volume graph when it becomes "cluttered" with accumulated tracings. Although the graph clears automatically every 15 cycles, this button can be used to clear it at any time.
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RESULTS |
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TOPAbstractIntroductionMETHODSRESULTSDISCUSSIONAPPENDIXREFERENCES |
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When the pause button is depressed, all action is frozen, a horizontal slider appears under the chart record, and cursors are displayed on both graphs (Fig. 3). This mode is designed to help students better visualize the relationship between the timing of the ventricular pressure and volume changes in the chart record and the timing of the different phases of the cardiac cycle on the corresponding pressure-volume plot. A slider control (note the "hand" symbol near bottom of Fig. 3) synchronizes the movement of a vertical time cursor on the pressure-versus-time and volume-versus-time plots, with the movement of a point cursor on the pressure-versus-volume plot. This allows each phase of the cardiac cycle to be examined sequentially.
Each cardiac cycle is associated with a single loop on the pressure-volume diagram and is plotted in a counterclockwise direction. In pause mode, this can be demonstrated by slowly moving the cursor slide control from left to right. Starting from the end of systole, ESV (point A on both graphs in Fig. 3), the ventricle fills to point B (EDV), along a passive pressure-volume curve that corresponds to the "passive" length-tension curve for ventricular muscle. When the ventricle is electrically excited, the heart enters the isovolumetric contraction phase, illustrated by the vertical line from B to C on the diagram. At point C, pressure in the ventricle exceeds the pressure in the aorta, the aortic valve opens, and the ejection phase begins (point C to D). At point D, ventricular contraction ceases and ventricular pressure falls below aortic pressure. At that time, the aortic valve closes, and the isovolumetric relaxation phase begins (point D to A). Ideally, the line from D to A should be perfectly vertical but is not because the clipped sine wave used in the model does not simulate perfectly the shape of the actual ventricular pressure waveform. For the pause mode to work properly, at least five cardiac cycles must be stored in the model’s internal buffer before depressing the pause button.
Changes in preload.
When the model is not paused, upward movement of the preload control slider initiates an increase in filling pressure (preload), which shifts EDV to a larger value. The model uses an integrator to gradually introduce the effects of preload (or other) variables into the waveform generator so that progressive shifts in the pressure-volume loop can be seen clearly and compared from cycle to cycle. The initial (control) loop and the next several loops generated after a 25% increase in preload are shown in Fig. 4.
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In the intact (closed loop) heart mode, important differences are introduced into the behavior of the system as preload is increased (Fig. 4B). In this mode, systemic arterial pressure is allowed to change. A new digital display showing diastolic pressure in the aorta (Pdia) and a red arrow pointing to the ESV display (now black) is introduced into the system diagram to indicate that aortic pressure feeds back to alter ESV. Pã is calculated from the simple product of TPR and CO, whereas Pdia is displayed as an estimate of the initial afterload seen by the heart (see Ref. 2, Fig. 15.8, p. 358). The immediate effect of an increase in preload is to shift EDV (point B) to the right (point B'), resulting in an increase in SV (because B'-A' > B-A). In this first cycle, the aortic valve opens at the same point (i.e., C' = C) and ejection finishes at about the same point (D 
D') as in the control loop. However, in subsequent loops, SV and CO increase as does Pã, so that the heart is now working against an elevated afterload. Ejection, therefore, begins at a higher diastolic pressure (C'') and ends at a new point (D''), resulting in a secondary increase in ESV and secondary drop in SV (because B'-A' > B''-A''). Nevertheless, SV is still higher than it was initially, thereby sustaining the increase in CO and Pã. Subsequent cycles show that the loop continues to shift upward and to the right in this manner until the increase in preload is complete.
If preload is lowered from its initial (control) value, the reverse behavior is seen. The resulting sequence of pressure-volume loops shifts instead down and to the left. These progressive changes with successive cardiac cycles can be illustrated effectively to students in the classroom, first by pausing the model a few cycles after the preload is changed and then by manipulating the cursor to incrementally step through the time sequence on the two displays.
An additional point to be made while illustrating the effects of changing preload is that shifts in the pressure-volume relationship are independent of any change in Cont under these conditions. This can be illustrated by clicking on the act tension control button, which displays a red line (shown in Fig. 4B) approximating the length versus active-tension relationship for cardiac muscle. When preload is changed, each of the successive pressure-volume loops intersects this line at points D, D', D'', and so forth.
Changes in afterload.
Changes in afterload are initiated by moving the TPR/afterload control slider. Physiologically, afterload is the instantaneous value of aortic pressure (force per unit area) that the heart "sees" throughout the ejection phase. It is determined primarily by the TPR into which the heart must eject the blood volume. The aortic compliance also is an important factor. However, to simplify the model, we have accepted Katz’s convention that Pdia is a good index of afterload (Ref. 2, Fig. 15.8, p. 358). Indeed, the afterload would be equal to diastolic pressure if the heart contracted in a purely isotonic manner from the moment the aortic value opened and continued to contract isotonically throughout the ejection phase.
The effects of increasing afterload are illustrated in Fig. 5. The afterload control is slightly different from the controls for preload and HR in that there are three, not two, possible conditions to consider. When the model is working in the isolated heart mode, an increase in TPR/afterload simply results in an increase in Pã, as evident on the digital Pã display. There is no change in the pressure-volume display in this state, and all of the traces are grayed out to indicate the only changes that occur are those external to the heart (traces not shown).
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In the case of an afterload change, the act tension button can again be switched on to illustrate that all of the pressure-volume loops intersect the same length versus active-tension line to demonstrate that no change in Cont occurs (Fig. 5B).
Changes in Cont.
An increase in Cont is simulated by moving the Cont slider upward, as illustrated in Fig. 6. In the isolated heart (open loop) mode, secondary changes in afterload are not allowed to occur. Hence, as Cont increases (from 1.0 to 1.3 in this example), the simulated heart contracts more forcefully and empties more completely. Thus there is a reduction in ESV (A to A') and subsequent enhancement in SV and CO (Fig. 6A). The pressure-volume loop shows a characteristic shift to the left. If the active tension line is displayed, each incremental increase in Cont is associated with a corresponding shift in the line to the left (as the slope increases). Thus an increase in Cont can serve to recapture or conserve heterometric reserve. Because changes in afterload are not allowed to occur in this mode, the aortic valve opens at the same point (C = C') as before and there is no change in peak systolic pressure.
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If the Cont control is put into auto preload on mode, by depressing the button below the "Cont" slider, the behavior of the model is slightly altered from that described above. The model now performs an automatic adjustment in EDV subsequent to a change in Cont. Manual changes in the preload slider are not required. This is useful for demonstrating to students in the classroom how an increase in Cont will cause the pressure-volume curve to "shift to the left" with subsequent restoration of the "heterometric reserve capacity."
Changes in HR.
An increase in HR is easily noted on the chart recorder display, but not on the pressure-volume graph. Because each pressure-volume loop corresponds to a single heart beat, individual loops are drawn faster at higher HRs yet all of the loops are superimposed (not shown).
In the intact heart mode, moderate increases in HR cause a decrease in diastolic filling time, resulting in a secondary rise in ESV and subsequent fall in SV (see Fig. 7A). The rise in ESV is apparent on the pressure-volume display as a progressive shift in point A to A'. The fall in SV is evident as a narrowing of the loop along the ventricular volume axis. Because CO is the product of HR and SV, it follows that CO and Pã rise as HR increases (in this model) up to 140 beats/min (point D'), reflecting the fact that the fall in SV is smaller than the corresponding increase in HR over the range 30–140 beats/min. However, as HR increases to 140 beats/min, it is balanced progressively more by the fall in SV so that CO and Pã tend to plateau.
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Changes in the various ventricular volumes as a function of HR recorded from the model (and as displayed in the systems diagram windows) are shown in Fig. 8A. The corresponding data for the relationship between CO and HR for the control state are shown in Fig. 8B. The point at which ventricular filling becomes the primary limiting factor is most evident in Fig. 8B. Although in trained athletes, CO continues to rise with HR until HR exceeds 180 beats/min, we decided this model would be most useful and relevant if it approximated the relationship between volume and HR for middle-aged men whose physical conditioning is comparable with the average physiology department head. Therefore, EDV is held constant at HRs from 30 to 140 beats/min, and ESV rises in a linear fashion. Consequently, SV falls linearly over this range. When HR exceeds 140 beats/min, diastolic filling is compromised so that EDV falls linearly. ESV remains fairly constant over the range 140–180 beats/min, so that SV falls even more dramatically as HR exceeds 140 beats/min. The overall impact on CO is shown in Fig. 8B.
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An increase in afterload in the intact heart mode shifts the pressure-volume loop to the right (Fig. 9A), as described previously. When Anrep compensation occurs, the heart intrinsically undergoes a slight compensatory increase in Cont and is thereby able to "recapture" or maintain its initial, heterometric reserve capacity. This effect can be demonstrated by comparing the effects of an afterload increase with or without a slight increase in Cont. It is apparent on the graph as a leftward shift in ESV from A' to A'' if Cont is increased secondary to an increase in afterload. A corresponding increase in peak systolic pressure occurs, evidence that the heart has recaptured some of its heterometric reserve.
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Interactions of multiple parameters.
Interactions between changes in preload, afterload, Cont, and HR can be further simulated with this model to illustrate more complex physiological reactions. For example, moderate activation of the sympathetic system would typically produce simultaneous increases in preload, Cont, and HR. If the slide controls for each of these parameters are moved slightly upward, the combined effects of all three mechanisms in concert or in temporal sequence can be simulated. Likewise, it is possible to illustrate how compensatory changes in one parameter can counteract alterations in another parameter. For example, the hemodynamic impact of a mild hemorrhage can be simulated by first decreasing preload and then increasing HR and Cont to simulate sympathetic compensation. A number of other scenarios could be devised by the motivated and imaginative student or instructor to illustrate the integrated behavior of the cardiovascular system. However, the model is a linear system designed to demonstrate the basic pumping functions of the heart, which are nonlinear by nature. The model therefore comes with the caveat that, like any simulation, it will crash if pushed beyond its design limits, and confusion rather than enlightenment will result.
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DISCUSSION |
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TOPAbstractIntroductionMETHODSRESULTSDISCUSSIONAPPENDIXREFERENCES |
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To facilitate the latter purpose, the model has been compiled for use with Macintosh or Windows operating systems and is available for free download by faculty and students at the following internet address: (http://mphywww.tamu.edu/davis/models/pvmodel.) html. A comprehensive worksheet is provided in the APPENDIX to this manuscript, and the worksheet is available for download as a Microsoft Word file at the same URL address. The worksheet may also be used by an instructor to lead students through a step-by-step discussion of cardiac function, or it can be assigned (in whole or in part) to students as a computer laboratory exercise.
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APPENDIX |
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TOPAbstractIntroductionMETHODSRESULTSDISCUSSIONAPPENDIXREFERENCES |
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II. STUDENT PREPARATION FOR THIS LABORATORY EXERCISE:
It is assumed that students have attended lectures on the appropriate subjects or done preliminary readings before doing this exercise. Students should at least know the definitions of the terms preload, afterload, contractility, and HR before doing the laboratory exercise. They should also have a basic understanding of the mechanisms of muscle contraction and force generation.
III. GENERAL INFORMATION:
The simulation program name is "pvmodel.rt" or "pvmodel.exe" and is located on both the PowerMac and Pentium-based computers in the College of Medicine, Learning Resource Center (LRC). The program may also be downloaded from the World Wide Web for use at home. Use of the model in the LRC or acquisition of the model from the course website requires a password. For best results, the program should be run on a computer with a processor speed of 300 MHz or greater.
IV. START/STOP/RESET DIRECTIONS:
Double-click on the program icon to load the program. Wait until the program is fully loaded before proceeding. Start the program by either clicking on the run button (
) in the upper left-hand corner of the program window or by selecting "Run" from the "Operate" menu at the top of the program page. The program can be stopped at any time by clicking on the stop button (stop-sign symbol) in the upper left-hand corner of the program window. If necessary, the model parameters can be reset to their initial conditions at any time by selecting "Reinitialize All to Default" from the "Operate" menu at the top of the program page.
V. ORIENTATION AND BRIEF DESCRIPTION OF THE MODEL (with "warm-up questions"):
Load and start the program as described above. While the program is running but before beginning the laboratory exercises, look at the computer screen and note that there are four general areas displayed on the screen that comprise the model. These four areas include: a strip chart record, a graph of ventricular volume versus ventricular pressure, a system diagram, and a set of four sliders to manipulate the four determinants of cardiac function. Each of the four areas can be turned off or on with the four buttons located at the bottom of the screen labeled "Chart On," "Pressure-Volume Loop On," "Diagram On," "Sliders On." Test these buttons to identify the four areas on the computer screen by pressing each button off and then on in turn. The functions of each of these four parts of the model are described next.
A. Strip Chart Record (top left quadrant in computer screen):
A simulated strip chart recorder is displayed in the top left quadrant of the computer screen and shows time-based records of three basic parameters of a Wiggers’ Diagram for the left ventricle. Looking from the top chart down, these include displays of aortic pressure (mmHg) in red, left ventricular pressure (mmHg) in black, and left ventricular volume (ml) in black.
Watch the strip chart and answer the following questions:
B. Pressure-Volume Graph (top right quadrant in computer screen):
The instantaneous values for left ventricular pressure are plotted as a function of the corresponding values for left ventricular volume, and the data are displayed in the top right quadrant of the computer screen. This graph is what physiologists and cardiologists call The Pressure-Volume Loop.
At the bottom right corner of the computer screen is a button labeled "Clear Graph." This button is used to clear the graph when it becomes "cluttered" with accumulated tracings. Its value will become more evident as the students proceed with the study exercises. Test its function by pressing and quickly releasing it.
Next, let the chart recorder run for awhile and press the button again, but this time hold it down for several cycles. Note that as the program runs for awhile, the speed of the chart recording and the cycle rate of the Pressure-Volume Loop both tend to slow down. This is because the model accumulates data for the graph in a buffer, which slows the computer down. By holding the button down, however, the buffer is cleared continuously so the computer will continue to run at full speed. Students who choose to do the exercise on a slower machine at home can use this function to run the model more efficiently.
The Pressure-Volume Loop is comparable to (but not the same as) the length-tension diagram for muscle and the Frank-Starling Curve for the heart. The advantages of representing the data from the strip chart records as Pressure-Volume Loops are that: 1) all four determinants of myocardial function can be represented or demonstrated on this graph. 2) Other parameters important for understanding the pumping function of the heart, such as End-Diastolic Volume (EDV) and Pressure (EDP), End-Systolic Volume (ESV) and Pressure (ESP), SV, and Stroke Work are represented on the graph and can be observed directly as they change. 3) All Phases of the Cardiac Cycle are more easily represented and viewed on a Pressure-Volume Loop then on a chart record.
Watch the Pressure-Volume Loop and answer the following questions:
C. System Diagram of Cardiac Function (bottom right quadrant of computer screen):
A system diagram that shows the relationships among the different parameters that contribute to the pumping function of the heart is located in the bottom right quadrant of the computer screen. A continuous display of the numeric values is shown in the small window for each parameter. The parameters associated with the heart are shown in black letters and include:
The parameters associated with the peripheral vasculature, external to the heart, are shown in red letters. They include Total Peripheral Resistance (TPR) and Pã. Recall that Pã is proportional to the product of TPR and CO.
Two additional buttons labeled "Act Tension" and "Pause" are also included in the lower right quadrant. They provide the following display enhancements:
To make this feature work properly, first, press the "Clear Graph" button to clear the graph and the internal buffer. Wait a minimum of five cycles while the internal buffer accumulates sufficient data. Next, press the "Pause" button. Finally, manipulate the blue line back and forth or click on the right and left arrowheads to see what happens. This tool is particularly useful for students who have trouble visualizing the relationship between left ventricular pressure and volume when displayed as a Wigger’s Diagram and as a Pressure-Volume Loop.
D. Controls for Manipulating the Determinants of Cardiac Function (bottom left quadrant of computer screen):
"Slider" controls for manipulating the four determinants of cardiac function are located in the bottom left quadrant of the computer screen. These are used to manipulate Preload; TPR, which affects changes in Afterload; Contractility, and HR. In the starting, initial condition, note that three of the variables are grayed out, and only the Preload Slider is operative. The reason for this will become obvious in a moment.
The model is designed to operate in one of two different modes: 1) The Isolated Heart (single variable active) mode and 2) The Intact Heart (all variables active) mode. The Isolated Heart mode is used to isolate an individual variable, such as Preload, to demonstrate the most basic effect of the variable without subsequent changes in other parameters. The Intact Heart mode is used to show how the pumping function of the heart will behave when one or more of the variables is changed and the other parameters in the system are allowed to come to a new equilibrium. Keep in mind that this model does NOT include simulated effects of baroreceptors and other extrinsic cardiovascular reflexes. Familiarize yourself with the two operating modes (Isolated Heart and Intact Heart) by performing the following procedures.
VI. LABORATORY EXERCISE:
Start the laboratory exercise by first reinitializing everything to the default condition. Press the "Act Tension" button so the active tension line (red line) is displayed on the Pressure-Volume Loop. Then, click the "Clear Graph" button.
A. Preload:
The purpose of this part of the exercise is to observe how changes in preload during the filling phase of the cardiac cycle influence the pumping function of the heart. While performing this part of the exercise, consider the following general questions:
What is the effect of an increase in preload on the pumping functions of the heart and the mean arterial pressure?
Define Starling’s Law of the Heart.
Define Heterometric Autoregulation of the Heart.
What is the physiological significance of Heterometric Autoregulation of the Heart?
What are the underlying molecular mechanisms that account for the length-tension relationship for cardiac muscle?
1. Isolated Heart Mode (no feedback):
With the Preload radio button pressed and set to the Isolated Heart mode and the Preload Slider in the initial control position (5.0 mmHg, red dot), watch the Pressure-Volume Loop for several cycles. Next, look at the system diagram and write down the Control Values for the different parameters in the Data Table 1A below. Next, quickly increase the preload to 7.0 mmHg so that the EDV increases to 134 ml. This can be done by either double-clicking on the "Up Arrow" above the slider or by simply clicking in the vertical slider scale (white column) in the 7.0 position. For best results, increase the preload at the very end of the filling phase just before the beginning of the isovolumetric contraction phase in the cardiac cycle.
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What parameters have changed and why?
What was the sequence of changes that occurred during the cardiac cycle after increasing the preload?
After studying the above data and thinking about the sequence of events during the cardiac cycle, it should become obvious that in the INTACT HEART, something else must change in both the strip chart record and on the Pressure-Volume Loop. What other changes would you anticipate? Why?
If you are stumped by these questions about the INTACT HEART, continue with the next part of the procedure and the answers should become self-evident.
2. Intact Heart Mode (feedback):
To see a visual representation of the answer to the above question, do the following. Leave the preload radio button depressed and in the Isolated Heart mode with the preload set at 7.0 so that EDV is at 134 ml. Clear the graph and let the Pressure-Volume Loop run for several cycles. When the cardiac cycle enters the filling phase, quickly press the radio button over the Preload Slider to switch the system to the Intact Heart mode. This procedure introduces the passive "feedback" effect of the systemic arterial pressure on the performance of the heart during the Ejection Phase of the Cardiac Cycle. Indeed, what is now introduced into the model is the effect of afterload on the final equilibrium condition.
To better understand the sequence of events associated with an increase in preload in the intact heart with "feedback" allowed to occur, perform the following procedures:
Adjust the Preload Slider back to the control condition (5.0 mmHg) so that the EDV returns to 120 ml. Make certain that the Preload radio button is set so the system is in the Intact Heart Mode. Clear the Pressure-Volume Loop graph.
Let the model run for several cycles, then look at the system diagram and write down the Control Values for the different parameters in Data Table 1B below. Next, quickly increase the preload to 7.0 mmHg so that the EDV increases to 134 ml. Remember that for best results, preload should be increased at the very end of the filling phase or at the beginning of the isovolumetric contraction phase in the cardiac cycle. Watch the changes develop in the Pressure-Volume Loop and also observe the changes in the system diagram. When a new equilibrium is achieved, record the new values for the different parameters in Data Table 1B below. If you have trouble seeing the changes or if you are confused, then simply clear the graph and repeat the procedures until you get a better picture of the sequence of events.
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What happened to the ESV? Why?
What did the introduction of "feedback" do to the equilibrium value for Pã? Why?
Use the data in Table 1B to calculate values for Systolic Pressure in the Aorta for the control case and following the increase in preload .
How does this change in Pã relate to Heterometric Autoregulation of the Heart?
Why is it important for normal function? What is its physiological significance?
3. Explore:
Before moving on to the next part of the exercise, try changing the preload up and down over a wider range to see what happens to the performance of the simulated heart. Try it in both the Isolated Heart and Intact Heart modes.
B. TPR (Afterload):
The purpose of this part of the exercise is to observe how changes in afterload affect the pumping function of the heart. The afterload is manipulated in the model by changing the TPR. While performing this part of the exercise, consider the following general questions:
Define the term afterload for the left ventricle.
Hypertension is a major cardiovascular health problem. How does hypertension, if not controlled, compromise the pumping ability of the heart?
Define Stroke Work. How would you calculate it?
Define Cardiac Efficiency. How would you measure it?
What other data, not included in this exercise, would you need to estimate Cardiac Efficiency?
1. Isolated Heart Mode (no feedback):
Return all the sliders to their initial conditions (red dots). Depress the "Act Tension" button so that the active tension line is visible on the Pressure-Volume Graph. Switch into the Isolated Heart Mode by clicking the radio button above the TPR Slider. Notice that all the chart functions are now "grayed out."
Recall that TPR is controlled primarily by neural and humoral stimuli "extrinsic" to the heart. Indeed, those parameters that influence the pumping function of the heart, but are in the peripheral vasculature or are part of extrinsic regulatory mechanisms, are represented in the system diagram in red.
The equations that relate flow (i.e., CO) and pressure (i.e., Pã) in the peripheral vasculature dictate that flow and pressure are directly proportional, and the proportionality constant is a measure of the resistance (i.e., TPR) to flow.
This relationship is demonstrated in its simplest form in this part of the exercise. Look at the system diagram while moving the TPR Slider up and down through a series of steps. Note that CO is held constant in this demonstration. It should be obvious that when TPR is changed during the filling phase of the cardiac cycle, the Pã will change in direct proportion following the ejection of fluid from the heart into the aorta in the face of the new resistance.
Move the TPR Slider up and down several times and watch to values for TPR and Pã change in the system diagram windows. Next, return the TPR Slider to the control position (red dot) and proceed with the next part of the exercise.
2. Intact Heart Mode (feedback):
Click on the radio button over the TPR Slider to set the system to the Intact Heart mode. Make certain that all the sliders are set to the control conditions (red dots). Watch the chart record and the Pressure-Volume Loop for several cycles and record the control data in the appropriate box in Data Table 2, below. Calculate the Ejection Fraction for the control condition.
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a) Increase TPR (Manual Preload On):
Make certain the "Act Tension" button is on. Press the "Clear Graph" button to clear the Pressure-Volume Loop and the internal buffer. Let the model cycle for two or three cycles, then suddenly increase TPR to 35 by clicking in the TPR Slider Scale (white column) at the 35 position. Watch what happens. For best results, increase TPR at the beginning of the filling phase in the cardiac cycle. Try this procedure several times, if you wish, to get a clear record. Record the new equilibrium data [TPR Increased to 35 (Manual Preload On)] in Data Table 2 and calculate the new value for the Ejection Fraction.
What changed? Why?
In the intact heart at equilibrium, Cardiac Output must always equal Venous Return; otherwise blood will accumulate in the lungs. Consequently, whenever CO changes, there will be a corresponding adjustment in Venous Return and hence the filling characteristics of the heart.
To simulate this effect and to complete the sequence of events resulting from an increase in afterload, do the following. Simply click on the large, rectangular button below the TPR radio button to switch from the fixed preload condition (Manual Preload On) to the automatic preload condition (Auto Preload On). Make this change during the filling phase of the cardiac cycle, then watch what happens. After four or five cycles, record the new equilibrium data [TPR Increased to 35 (Auto Preload ON)] in Data Table 2 and calculate the new value for the Ejection Fraction.
What changed? Why? How do the data compare with the case when the preload was held constant?
b) Increase TPR (Auto Preload On):
To see the full sequence of events in response to a change in TPR-afterload, repeat the procedure with the automatic preload condition set as follows. Return the TPR Slider to the control position (Red Dot). Press the "Clear Graph" button to clear the Pressure-Volume Loop. After two or three cycles, suddenly increase TPR to 35 by clicking the slider scale at the appropriate level during the filling phase in the cardiac cycle. Watch what happens as the cardiac cycle changes and shifts to the right on the passive, filling curve.
Knowing that CO must always be equal to venous return when the system is in steady state, what do you think is the most important function of Heterometric Autoregulation of the Heart?
3. Explore:
Before moving on to the next part of the exercise, try changing TPR (afterload) up and down over a wider range in the Intact Heart mode to see what happens to the performance of the simulated heart. Try it in the automatic preload mode (Auto Preload On) and also in the manual, or fixed, preload mode (Manual Preload On). Try changing TPR in the "Manual Preload ON" mode and then adjust the preload slider to see what happens.
C. Contractility:
The purpose of this part of the exercise is to observe how changes in contractility affect the pumping function of the heart. While performing this part of the exercise, consider the following general questions:
Define Homeometric Autoregulation of the Heart.
What is the physiological significance of Homeometric Autoregulation of the Heart?
What is the Bowditch Effect?
What is the Anrep Effect?
What is the Woodworth Effect?
What is the difference between "intrinsic regulation" and "extrinsic regulation" of myocardial contractility?
What are the basic molecular and cellular mechanisms that account for changes in myocardial contractility as a result of sympathetic stimulation of the heart? Are these mechanisms the same for the Bowditch Effect? Explain.
1. Isolated Heart Mode (no feedback):
Return all the sliders to their initial conditions (red dots). Return the system back to the (Manual Preload On) condition by clicking on the rectangular button below the TPR and Contractility Sliders. Now, press the radio button above the Contractility Slider to put the system into the Isolated Heart Mode. Notice that the arbitrary value (1.0) for contractility is displayed in the appropriate window in the system diagram. Make certain that the "Act Tension" button is depressed so that the active tension line is visible on the Pressure-Volume Graph.
Let the Pressure-Volume Loop run for several cycles, then look at the system diagram and write down the Control Values for the different parameters in Data Table 3A below.
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For best results, click the "Up Arrow" to increase the contractility just as the isovolumetric relaxation phase ends and the filling phase begins. This may take a little practice, so try it several times until you get a nice family of curves. Also, remember that you can use the "Clear Graph" button under the Pressure-Volume Loop to clear the computer screen if it gets too cluttered with multiple traces.
After you have accumulated a family of three or four curves and set the "Pause" button, look at the resulting Pressure-Volume Graph and see how the increases in contractility caused the ESV to change.
What happened to SV?
What happened to CO and Pã? Why?
After examining the results and thinking about the above questions, release the "Pause" button and let the system continue to cycle with the contractility set at 1.3.
Look at the system diagram and record in Data Table 3A the new values for the parameters with the contractility at 1.3. Compare the control data with the experimental data; note what parameters have changed and think again about your answers the above questions.
Finally, in preparation for the next part of the contractility demonstration, return the contractility back to the control level by clicking in the slider column (white column) next to the red dot. Watch what happens.
2. Intact Heart Mode (feedback):
Click on the radio button over the Contractility Slider to set the system in the Intact Heart mode. Make certain that all the sliders are set to the control conditions (red dots). Look at the system diagram and write down the Control Values for the different parameters in Data Table 3B below. They should be the same as the control values in Data Table 3A.
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Compare the results in the Intact Heart mode when contractility is 1.3 (Table 3B) with the comparable data in the Isolated Heart mode (Table 3A).
How have ESV, SV, CO, and Pã changed?
Why are they different?
What caused them to change?
Use the data in Table 3B and calculate the Ejection Fraction when Contractility was set at the control level and when it was elevated to 1.3 . Now, think again about the definition of Homeometric Autoregulation of the Heart and its physiological significance.
3. Explore:
Before moving on to the next part of the exercise, try changing the contractility up and down in the Intact Heart mode over a wider range to see what happens to the performance of the simulated heart. Also, watch the strip chart to see what happens. While doing this, you may wish to manipulate the preload up and down to simulate compensatory changes in venous return and the filling of the heart following changes in contractility. Finally, to better simulate what you have just done, leave the system in the Intact Heart mode. Then, return the Preload to the original setting (red dot). Next, click the rectangular button above the TPR and Contractility Slides to set the system so that preload will adjust automatically (Auto Preload ON) when contractility is changed. Now, manipulate the Contractility Slide and see what happens. The physiological significance of Homeometric Autoregulation of the Heart should be on your mind when you do this manipulation.
D. HR:
The purpose of this part of the exercise is to observe how changes in HR affect the pumping function of the heart. While performing this part of the exercise, consider the following general questions:
How does heart rate affect EDV and the filling of the heart?
How does heart rate affect ESV?
What is the Bowditch Effect? How does it affect the relationship between CO and HR?
1. Isolated Heart Mode (no feedback):
Return all the sliders to their initial conditions (red dots). Again, make certain the "Act Tension" button is depressed. Make certain that the rectangular button below the TPR and Contractility Sliders is returned to the (Manual Preload ON) position. Switch into the Isolated Heart Mode by clicking the radio button above the HR Slider. Notice that all the chart functions are now "grayed out."
The primary determinants of CO are HR and SV. Indeed, the product of HR and SV equals CO.
This relationship is demonstrated in its simplest form in this part of the exercise. Look at the system diagram while moving the HR Slider up and down through a series of steps and watch what happens. Note that SV is held constant in this demonstration. It should be obvious that when HR is increased at any time during the cardiac cycle, CO increases, and therefore Pã increases because the cycling rate of the heart increases. However, in the intact heart, it is clear that the relationship between CO and HR is not linear and increases in HR can severely limit the output of the heart at very high HRs (tachycardia).
To better understand the effect of HR on the pumping function of the heart, proceed with the next part of this exercise.
2. Intact Heart Mode (feedback):
Click on the radio button over the HR Slider to set the system to the closed loop mode. Make certain that ALL the sliders are set to the control conditions (red dots) and that the "Act Tension" button is pressed.
Slowly move the HR Slider up and down, watch the strip chart recording and the Pressure-Volume Loop, and see what happens. Depending upon the speed of your computer, you may find it necessary to periodically clear the Pressure-Volume Loop by briefly holding down the "Clear Graph" button to obtain a more realistic simulation at the higher HRs. When you have familiarized yourself with the manipulations, then continue with the next procedure to generate a more quantitative picture of the effect of HR on the pumping function of the heart.
Reduce the HR to 42 beats/min by pulling the HR Slider down to the appropriate level. You may find it easier to click on the "Down Arrow" at the bottom of the HR Slider. Wait until a steady state is achieved. Again, if the system seems to run too slowly, then briefly hold down the "Clear Graph" button. Now, record the values for EDV, ESV, and SV in the appropriate columns in Data Table 4A and record the value for CO in the appropriate column (control contractility level = 1.0) in Data Table 4B. Next, increase the HR in 6-beats/min steps by clicking once for each step on the "Up Arrow" above the HR Slider. Watch
