The augmentation of circulatory blood flow required to support dynamic exercise is contingent upon parallel increases in myocardial contractility. In the absence of an appropriate inotropic response, maximal stroke volume is limited, and, by extension, the ability to generate cardiac output to enhance oxygen delivery to exercising muscle is compromised (48,57). The quality of the myocardial functional response to exercise is linked thus directly to both markers of aerobic fitness (i.e., maximal oxygen uptake) and performance in endurance events.
Recognizing the role of alterations in myocardial contractility during exercise can provide insights into the basic mechanisms surrounding the normal cardiac responses to physical work. Such information may be translated, as well, into practical outcomes. Considerable interest, for example, surrounds identifying the unique features of myocardial function in highly trained endurance athletes that might contribute to their high levels of aerobic fitness compared with nonathletes (12). Assessment of inotropic function during exercise might prove useful, too, in identifying athletes with unrecognized cardiac abnormalities who may be at risk from sports participation.
At the other end of the activity spectrum, assessment of the contractile health of the ventricular myocardium bears importance for health care providers in the clinical setting. Establishing prognosis and timing for surgical and medical interventions in patients with heart disease often hinges on information indicating the functional state of myocardium (38). Means of assessing myocardial contractile function also may be of utility in examining the efficacy of exercise rehabilitation programs.
The level of myocardial contractility traditionally has been estimated with subjects lying supine in the resting state. The relevance of such information obtained when the heart pump is “idling” to myocardial functional capacity, the heart’s ability to generate cardiac output, either in the sports arena or in daily living, is problematic. Instead, a more precise indicator of myocardial health should be expected when contractile function is challenged by increases demanded by the stress of exercise (38).
In the past, estimation of myocardial functional responses to exercise has been difficult, limited mainly to measurement of global ventricular performance by radionuclide angiography (16,19,23,32,35). These studies have indicated that a rise in ejection fraction (volume of blood expelled per beat expressed as a percentage of ventricular end-diastolic volume) in healthy young subjects can be expected from 60% to 70% at rest to 70% to 90% at maximal exercise. The typical increase in myocardial contractility during progressive exercise by this measure is approximately +15% (change expressed as percent of resting value).
The recent development of novel echocardiographic techniques has permitted noninvasive assessment of myocardial and blood flow velocities as indicators of properties of myocardial systolic function (9,40,59). The use of this methodology during exercise, once confined to the research laboratory, is being applied now to assessment of patients with heart disease (3,18,30). During exercise, such techniques are confronted with the challenges of heart movement, hyperpnea, and motion artifact. Nonetheless, a growing number of reports have indicated that such techniques are feasible during exercise and that accurate and reproducible measures of ventricular contractility can be attained effectively by experienced operators in the exercise testing setting. This methodology now offers promise of providing insights into the nature of myocardial contractile responses during an exercise challenge as well as serving as a useful aid in guiding patient management.
The interpretation of echocardiographic measures of ventricular function during exercise in cardiac patients requires knowledge of the qualitative and quantitative responses expected in normal healthy individuals. It is the purpose of this review to a) examine the current understanding of the nature of myocardial contractile responses to dynamic exercise and b) present a survey of the published data, which have accumulated regarding the changes in markers of systolic function in the context of a typical progressive exercise test in healthy subjects.
It must be recognized that the elements and mechanisms surrounding cardiovascular responses to exercise encompass a classic example of a complex dynamic system. As such, it is characterized presumably by multiple feedback loops, nonlinear relationships, hierarchical structure, and functional redundancy. A reductionist approach of attempting to isolate the role of one factor — in this case, myocardial contractility — in such a system involves a gross oversimplification of reality. Still, it is expected that measures of inotropic function should serve as useful indicators of the system’s health, therefore providing an effective clinical tool for evaluating patients with heart disease as well as an understanding of the myocardial functional contribution to aerobic fitness.
Definitions, Conditions, and Caveats
In this review, augmented “myocardial contractility” is defined in a general, empiric sense as the increases observed in velocity and force of heart muscle contraction in the course of a progressive exercise test. The reader should be alerted that this definition differs from the traditional physiologic expression of “contractility” or “intrinsic contractility” as the extent of myocardial contraction, which occurs when loading conditions (pre-load, after-load) are maintained constant (22).
An explanation for selecting the particular definition of contractility utilized in this review is in order. As will be reviewed in the succeeding part of this article, multiple influences affect the extent of heart muscle contraction during exercise in a manner sufficiently complex that it is impossible to define the individual contributions of each to overall ventricular inotropic responses. That is, as opposed to experiments in the laboratory setting, it is not possible to isolate the separate influences of loading conditions and alterations in inherent contractile properties of myocytes during exercise in the intact human.
As Katz (20) has pointed out, “Unfortunately, simple definitions fail because myocardial contractility is the aggregate of all the mechanisms of a muscle to do work. Thus, myocardial contractility includes the ability of the myocardium to develop tension and to shorten, which can vary independently of each other, as well as the rate of onset, duration, and rate of decay of the active state. These active state characteristics are not the only determinants of contractility in the intact heart; for example, ejection is influenced also by heterogeneities that result from asynchronous activation, the amount of connective tissue in the walls of the ventricle, and even the architecture of the heart.”
The definition of contractility in this study is a utilitarian one, since it is the combined effect of these various factors on myocardial contractility that is observed and measured using echocardiographic techniques. For simplicity, the terms “contractility,” “inotropic function,” and “systolic myocardial function” here are used synonymously.
In this review, no effort is made to translate global ventricular performance (such as ejection fraction) from either the properties of contractile reserve of specific regions of ventricular myocardium or the functional status of individual myocardial fibers. In the healthy myocardium, it is assumed that the expression of inotropic function of each reflects that of the others.
Due to space limitations, this review will necessarily be limited to the research literature assessing systolic responses to exercise. Moreover, information will be restricted to investigations of left ventricular contractile responses, as right ventricular dynamics, being more difficult to visualize echocardiographically, have received less research attention (12). Stroke volume responses to exercise can be considered equivalent between the ventricles, but determinants of contractile responses of the right ventricle may differ from the left.
It is important to recognize that this review examines studies during maximal or near-maximal, upright, or semiupright cycle exercise in normothermic ambient conditions by healthy individuals who are nonobese and not engaged in sports or programs of athletic training. The age range includes subjects from late childhood to the midadult years, a span in which the observed contractile responses appear to be consistent. Older subjects have not been included since cardiac dynamics may be altered due to the aging process and/or occult heart disease (33,37). Most studies have reported findings in male subjects, and little information is available in female subjects. However, limited data suggest that in young subjects, contractile responses to exercise are independent of sex (51).
Factors Influencing Contractile Response to Exercise
Studies in animals suggest that the normal healthy myocardium has the capacity to augment contractility at least twofold above baseline conditions (20). Unlike skeletal muscle, the myocardium cannot enhance such force and speed of contraction by progressive recruitment of individual motor-neuron units. The muscle of the heart is a functional syncytium, whereby a single electrical signal spreads to activate the entire myocardial mass. Augmentation of myocardial contractility is effected instead by the collective influence of several triggers, each which may stimulate increases in inotropic function by different physical and/or biochemical processes (4,20). It is important to recognize that these factors, outlined briefly in the succeeding part of this article, all contribute to the myocardial contractile response to progressive exercise.
Increasing precontraction fiber length
Stretch of myocardial fibers before the initiation of ventricular contraction increases force of contraction, probably by enhancing the triggering effect of intracellular calcium on fiber contractile proteins. The force of contraction is correlated directly with initial fiber length (the length-tension relationship) until a critical length is attained. Beyond this point, further increases in resting fiber length results in a fall-off of force production with contraction. This is the familiar Frank-Starling curve, named after the investigators who described it at the beginning of the 20th century (29). In the intact ventricle, this effect is manifest as the generation of increased ventricular systolic pressure as ventricular end-diastolic volume and filling pressure, or ventricular preload, is increased.
It should be noted that this augmentation of myocardial contractility with increased filling volume occurs only with acute change in ventricular end-diastolic size. No change in contractility is observed with chronic changes in filling volumes, such as observed from athletic training or during the normal growth of children, since ventricular remodeling with increases in heart muscle mass maintains a constant inotropic state. Thus, for example, healthy individuals who vary markedly in heart size should be expected to exhibit similar ventricular systolic function.
Rise in heart rate
An increase in firing rate of the sinus node per se augments myocardial contractile force (54). This inotropic effect of shortening contraction interval time, called the staircase, or treppe, phenomenon, is explained by its effect of increasing intracellular calcium influx, which increases the number of active actin-myosin cross-bridges. This phenomenon can be demonstrated by artificially pacing the heart, indicating that the resultant increase in force of myocardial contraction from a rise in heart rate is independent of alterations of sympathetic and parasympathetic nervous tone as well as the effects of circulating catecholamines (see the succeeding part of this article).
Reduction in afterload
Afterload is an expression of the force which opposes left ventricular ejection of blood from the ventricle. Its major determinant is conductance of blood flow in the peripheral arterioles, where resistance is regulated by alterations in smooth muscle tone within the vessel walls. The more precise physiological definition of afterload takes into account not only the resulting variability in systemic vascular resistance and blood pressure but also the heart size (12). According to the law of Laplace, at a given arteriolar resistance, a greater ventricular size results in higher wall stress, an index of ventricular afterload (10).
Afterload is correlated inversely with velocity of ventricular contraction (12). The lower the wall stress or systemic vascular resistance, the more rapid is systolic function. Myocardial force of contraction and its velocity are related inversely as well (20). Thus, a fall in peripheral vascular resistance (with stable ventricular size) will reduce afterload or the work required by the heart (i.e., myocardial V˙O2) to propel blood flow downstream. The release of this “brake” will increase myocardial contractile velocity (by speeding the rate of turnover of cross-bridges of the cell’s contractile proteins).
An increase in cardiac sympathetic activity causes release of norepinephrine at nerve ends, which binds to B1 receptors (56). These in turn stimulate the activity of cellular adenosine monophosphate (AMP), which effects augmented inotropic function via increased intracellular calcium availability. The result is augmentation of generated peak ventricular pressure as well as an increased velocity and acceleration of myocardial contractile response. As noted previously, this inotropic response to enhanced sympathetic stimulation often is referred to as “intrinsic contractility” of heart muscle.
Action of circulating catecholamines
Circulating catecholamines, principally epinephrine, which are produced by the adrenal medulla, have a similar effect of stimulating B1 receptors on the surface of cardiac myocytes, activating calcium channels on the cell membrane, and improving myocardial contractility.
Role of Contractile Triggers During Progressive Exercise
With the potential triggers of enhanced myocardial contractility identified previously, it is now possible to examine their respective roles in the cardiac dynamics accompanying progressive exercise (see Ref. (39) for review and references for the discussion that follows). It will be observed, as noted previously, that each one of these factors contributes to the increase in ventricular inotropy observed during such dynamic exercise. It will be obvious that attempting to identify the magnitude of effect and relative importance of each within this mélange of cardiac stimulation represents a difficult challenge (55,60).
A specific pattern of stroke volume response has been observed consistently when subjects perform a progressive exercise test in the sitting or upright position. In the early phase of exercise, stroke volume rises, usually by about 20%, then demonstrates little or no change from low-moderate intensity levels to the point of exhaustion (the so-called “stroke volume plateau”). Evidence indicates that this initial rise reflects increased ventricular filling from mobilization of blood, which was sequestered by gravity in the lower extremities when the subject assumed the upright position.
When an adult sits or stands, blood volume in the legs expands by 500 to 1,000 mL, diminishing central blood volume and depressing stroke volume and cardiac output by approximately 20% to 40%. With the onset of exercise, a combination of skeletal muscle arteriolar dilatation and muscle pumping action mobilize this dependent blood volume, and cardiac filling and stroke volume return to levels observed at rest in the supine position. Supporting this concept, a limited or absent initial rise in stroke volume is observed typically when exercise is performed in conditions that are independent of gravity, such as supine cycling, prone simulated swimming, exercise in weightlessness conditions by astronauts, and upright exercise while submerged in a pool.
The early rise of stroke volume during progressive exercise performed in the upright position can therefore be interpreted simply as a “refilling” phenomenon and not a component of the fundamental cardiac response to exercise. Moreover, it is evident that except in this isolated condition, stroke volume does not increase significantly with progressive exercise in healthy, untrained subjects.
During this initial phase of upright exercise, the increased stroke volume reflects augmented cardiac contractility from a classic Frank-Starling mechanism, as the increased venous return from the legs increases left ventricular end-diastolic volume (preload). As noted previously, following this first portion of upright progressive exercise, stroke volume remains essentially stable. As work intensity rises, left ventricular end-diastolic volume also changes little (or may gradually decline). These phenomena occur while systemic venous return to heart is augmented up to three to four times that at rest. The Frank-Starling mechanism is clearly no longer operant, since this dramatic increase in heart filling during exercise would be expected, by this process, to augment both ventricular end-diastolic volume and, via increased contractility, a progressive rise in stroke volume. These effects are prevented by a rise in heart rate, which closely matches the increasing systemic venous return to maintain a constant left ventricular filling volume (preload). That is, the tachycardia of exercise serves to “defend” left ventricular end-diastolic size, which prevents any increases in wall stress that would be dictated by the law of Laplace (11).
Arteriolar vasodilatation in contracting muscle during dynamic exercise is evident as a steady decline in peripheral vascular resistance as work intensity increases. The resulting rise in vascular conductance facilitates augmented circulatory flow during exercise, an expression of Poiseuille’s law, Q∼P / R, where circulatory flow rate (Q) is increased by the fall in peripheral resistance (R), while the role of the heart is to maintain a pressure head (P). The declining resistance serves to reduce afterload (while ventricular end-diastolic size is relatively constant), triggering increases in the velocity of heart muscle contraction.
A progressive rise of sympathetic stimulation of both sinus node and the ventricular myocardium during progressive exercise is evidenced by a) both chronotropic and inotropic effects and b) a steady rise in serum norepinephrine levels (spill-over from nerve terminal transmission). A similar inotropic effect occurs from a rise in blood epinephrine concentrations, reflecting increased secretion from the adrenal medulla, although this action of circulating catecholamines is delayed typically until later portions of exercise.
In summary, then, increases in myocardial contractility during a progressive exercise test are a manifestation of the combined effects of a reduction in afterload (from a decline in peripheral vascular resistance), the step effect of increased rates of sinus node discharge, and the biochemical influences of augmented sympathetic stimulation and rise in circulating catecholamines. The Frank-Starling mechanism for enhancing ventricular contractility is evident only in the initial ventricular refilling phase of upright exercise.
“Purpose” of Augmented Contractility With Dynamic Exercise
It has often been assumed, as is intuitively attractive, that the increasing myocardial contractility evident during a progressive exercise test serves to deliver a greater stroke volume. This concept is not, however, consistent with the empirically derived observations outlined previously, indicating that, beyond the early phase of upright exercise, stroke volume is rather stable while measures of ventricular contractility steadily rise. This apparent paradox is reconciled by the idea that the “purpose” of augmentation of myocardial contractility in this setting is not to increase but rather to sustain stroke volume as the systolic ejection time shortens.
In the course of a typical progressive exercise test in the upright position, systolic ejection time falls from approximately 0.250 s to 0.180 s as heart rate rises. This shortening of ejection period is an obligatory feature of the cardiac responses to dynamic exercise, since it permits adequate time in diastole for both ventricular filling and coronary circulatory flow. Concomitantly, measures of contractility rise progressively. In patients lacking normal myocardial contractile reserve, such as those with congestive heart failure, stroke volume cannot be maintained as exercise intensity rises and is observed instead to decline (48).
It is interesting to note that the same several factors that are responsible for increasing myocardial contractility with dynamic exercise are also those that shorten the ejection period. This combined inotropic effect thus permits a) adequate time for critical diastolic events, b) increased systolic pressure to maintain flow as peripheral resistance falls, and c) maintenance of stroke volume as ejection time shortens with rising work intensity.
Ultrasound Measurements of Myocardial Contractility
The heart is a hollow organ whose muscular wall is designed by its contractile function to raise intracavitary pressure and expel blood volume. In the left ventricle, the musculature is wrapped around the cavity in spiral layers. During ventricular systole, this helical architecture effects a “wringing out” action, with clockwise rotation of the base (as viewed from below) and counterclockwise rotation at the apex (26,61). The result is a foreshortening of the ventricular cavity in all planes (15). This contractile force can be examined by measures of a) global ventricular performance, b) velocity and extent of contraction in specific longitudinal and radial planes, and c) rate of circumferential twist. As techniques have developed to assess these separate aspects of inotropy, it was hoped to discover methods that would define “pure” myocardial functional capacity or “intrinsic” contractility independent of loading conditions. As yet, this hope has been unfulfilled, as echocardiographic markers of contractile function all appear to be influenced by some degree to preload and/or afterload.
A limited number of reliability studies have indicated a satisfactory degree of test-retest reproducibility of these techniques, even at maximal exercise. Lacking a gold standard, validity of each in measuring increases in myocardial contractility during exercise cannot be verified easily. However, the consistency of findings both within and between studies supports their accuracy.
Space constraints limit a full discussion of these techniques and their application during exercise testing. Each are outlined briefly in the succeeding part of this article, with references provided for those seeking more in-depth information.
Left ventricular shortening fraction
Shortening fraction is the one-dimensional analog of the ejection fraction, calculated as the difference between the left ventricular end-diastolic and systolic dimensions in the transverse plane and expressed as a percentage of the end-diastolic dimension. Such measurements are made normally in M-mode in the parasternal long axis view (i.e., the sagittal plane) or directly on two-dimensional images. As noted previously, changes in left ventricular shortening fraction with exercise reflect global ventricular systolic performance and are modified by alterations in loading conditions.
Seven studies with nine subject groups have described increases in shortening fraction during maximal exercise (Table 1). The average rise in these reports has been from 34% ± 6% preexercise to 46% ± 6% at peak exercise, a mean 32% increase over resting values. In all of these studies, the augmentation of shortening fraction with exercise has been an expression solely of progressive reduction in end-systole dimension.
Left ventricular systolic ejection rate
Stroke volume during exercise can be estimated noninvasively by integration of the Doppler measurement of aortic outflow velocity (either from the suprasternal notch or inferiorly from an apical five-chamber view) over time (the velocity-time integral (VTI)), multiplied by the cross-sectional area of the outflow tract (46). At the same time, the duration of systolic ejection is measured directly from the VTI curve. Expressing volume ejected over time (systolic ejection rate) then provides an indirect measure of rise in ventricular pressure and, by extension, myocardial contractile force and velocity (7). In making interindividual comparisons, this value needs to be adjusted for left ventricular mass.
During a progressive cycle test, the left ventricular ejection time typically decreases from approximately 0.25 to 0.18 s (28,42,44,45,47–50). Normal increases in systolic ejection rate have been described during a bout of upright maximal exercise in five studies, with an average rise of approximately 70% to 80% over resting values (Table 1).
Peak aortic velocity
The peak blood flow velocity as the blood is expelled from the heart in systole reflects ventricular pressure generation and overall force of myocardial contraction (25). This velocity is measured from the peak of the VTI curve and is recognized to increase as the heart responds to increased exercise workloads. In 9 published reports including 11 groups, the average rise was from 106 ± 20 at rest to 181 ± 28 cm·s−1 (+70%) (13,24,47,50,52,56).
Tissue Doppler imaging
During ventricular systole, the cardiac base moves inferiorly toward the relatively fixed apex. The longitudinal velocity of the myocardium during this contraction can be measured by the tissue Doppler imaging technique (TDI), which is capable of identifying high-amplitude-low-frequency ultrasound signals that differentiate myocardial motion from blood flow with high-temporal and spatial resolution (8,34). From an apical four-chamber view, a sample volume placed at the septal or lateral aspect of the mitral valve annulus records a positive velocity, or S wave, which reflects the integral of the longitudinal velocity during systole from base to apex.
Tissue Doppler imaging longitudinal systolic myocardial velocity (TDI-S), which correlates well with ventricular ejection fraction (36), can be obtained by color-coded or pulse-wave imaging. The former provides mean velocity, while the latter indicates peak velocity. While TDI-S provides information regarding ventricular contractile function, its accuracy is dependent on transducer beam angulation. TDI-S values are affected also by translational cardiac motion (movement of the entire heart) as well as tethering effects (in which motion of one segment may affect that of adjacent segments).
Tissue Doppler S has been recorded successfully during maximal exercise in several studies (Table 2). These investigations indicate that in healthy individuals, TDI-S is expected to approximately double during a progressive exercise test. Acceptable levels of reliability in such determinations have been described, with coefficients of variation on repeated tests of 5.1% (6) and 7.4% (53).
Strain and strain rate (myocardial deformation)
Myocardial “strain” is defined as the distance heart musculature in a given plane is displaced during its contraction, expressed as a percentage of its original length in end diastole, while “strain rate” is the rate of this deformation per unit time. These variables were first measured with tissue Doppler technology, which provided greater information regarding regional wall motion and avoided the potential tethering influences of traditional TDI-measured myocardial longitudinal velocities (1,62). Currently, TDI strain has been replaced largely by speckle tracking, which offers the further advantages of a) being independent of insonation angle and b) assessing strain in two dimensions (longitudinal and radial) (14,59). In this method, strain and strain rate are calculated by computer software from the tracking of speckles, created by ultrasound interference patterns in the myocardium, as they are displaced during myocardial deformation.
Strain and strain rate are markers of contractility, as validated against other indicators of ventricular inotropic function (2). With current technology, use of speckle tracking is limited to low-moderate exercise, since the optimal frame rate (50 to 70 s−1) for spatial resolution would result in undersampling with high heart rates. Studies have indicated significant increases (generally about 20%) in strain and/or strain rate by TDI (3,30) and speckle tracking (15,17) during semisupine exercise up to heart rates of 100 to 150 bpm.
The magnitude and velocity of the opposite rotations of the cardiac base (clockwise) and apex (counterclockwise) during ventricular systole can be measured by the same speckle tracking techniques (58). Calculating the difference between the two provides an estimate of ventricular twist or the “wringing out” effect of contraction of the ventricle’s helical muscular architecture. These measures have been found to correlate with other indicators of myocardial contractility, such as ejection fraction, TDI-S, and strain rate (9). Theoretically, these measures of rotation should be expected to provide the most realistic estimate of contractile function, since they evaluate those motions that are most similar to the actual orientation of myocardial contraction.
Recent studies have indicated, as expected, that exercise of limited intensity is accompanied by increased rates of rotational ventricular twist. Doucende et al. (15) performed speckle tracking echocardiography in 20 young men while cycling in the semisupine position to a work rate of 40% V˙O2max (heart rate, 121 ± 12 bpm). Peak basal rotational rate rose from −72° ± 16.5°·s−1 at rest to −117.7° ± 29.4°·s−1 with exercise, while apical rotational rate increased from 79.1° ± 16.8° to 133.1° ± 23.7°·s−1. Torsion (twist relative to ventricular length) increased from 68.3° ± 15.6° to 124.1° ± 35.3°·s−1. Similar findings have been described by others with supine exercise (9,26). In the study by Burns et al. (9), 19 of the 33 original subjects were excluded from the analysis “because of inadequate frame rate and qualities of stress imagery.”
The qualitative and quantitative measures of left ventricular contractility outlined in this review offer to provide insights into the normal contractile responses to exercise as well as clinical markers of myocardial dysfunction in patients with heart disease. Technical constraints currently relegate some of these methods to the research laboratory. Others, such as assessment of aortic velocity, ejection rate, and pattern of stroke volume response, are measures that are not difficult to obtain and that deserve to be explored as feasible, useful clinical markers of the state of myocardial health.
Assessing contractile responses of the heart during exercise provides a unique opportunity to examine myocardial functional health. The practical implications of new techniques in defining this response are just beginning to be explored. For sports practitioners, these echocardiographic tools may be critical in identifying athletes with occult myocardial disease (cardiomyopathies) who might be at risk for sports play or in recognizing influences such as heat and dehydration on cardiac function during athletic performance. For those caring for cardiac patients, echocardiographic assessment of myocardial contractile responses to exercise offers the possibility of improved means of risk stratification, establishing safety of prescribing physical activity, and defining outcomes of structured rehabilitation programs.
No funding was received for this work. There is no conflict of interest for either author (T. Rowland, V. Unnithan).
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