clinical utility of exercise, pacing, and pharmacologic stress testing for the noninvasive...

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Number 1, Pari 1 Cellular basis for inotropic changes

heart muscle at rest and during contraction measured with Ca*+-sensitive microelectrodes. Nature (Land) 1980;286:845- 50.

31. Fabiato A, Fabiato F. Effects of pH on the myofilaments and the sarcoplasmic reticulum of skinned cells from cardiac and skeletal muscle. J Physiol 1978,276:233-55.

32. Tobacman LS, Lee R. Isolation and functional comparison of bovine cardiac troponin T isoforms. J Biol Chem 1987; 262:4059-64.

33. Mahdavi V, Izumo S, Nadal-Ginard G. Developmental and

hormonal regulation of sarcomeric myosin heavy chain gene family. Circ Res 1987;60:804-14.

34. Allen DG, Morris PG, Orchard CH, Pirolo JS. A nuclear magnetic resonance study of metabolism in the ferret heart during hypoxia and inhibition of glycolysis. J Physiol 1985;361:185-204.

35. Nosek TM, Fender KY, Godt RE. It is diprotonated inorgan- ic phosphate that depresses force in skinned sleletal muscle fibers. Science 1987;236:191-3.

Clinical utility of exercise, pacing, and pharmacologic stress testing for the noninvasive determination of myocardial contractility and reserve

The ability of the left ventricle to modulate its performance is an important and integral component in the cardiovascular system’s adaptive response to increased workload. Abnormalities in ventricular contractility can blunt this response and thus slgniflcantly limit the patient’s functional capacity. The accurate determination and quantitatlon of cardiac contractility and reserve is a dlfficutt task in the symmetrically contracting ventricle and more so when regional contraction abnormalities are present. Moreover, derangements In other physiologic variables, such as ventricular loading conditions, heart rate, systemic vascular tone, cardiac autonomic function, and Pulmonary gas exchange, can diminish cardiopulmonary reserve. This report relates the determinants of myocardiai oxygen demand and efficiency to the currently available forms of exercise, Pacing, and pharmacologic stress testing. Within this framework, commonly used as well as newer approaches to the noninvasive assessment of stress-induced changee In left ventricular performance and contractility are addressed. In addition, several examples are presented in which noninvasive techniques for assessing intracardiac structures, pressures, and flows (es, echo/Doppler, radionuclide angiography, rapid acqulsitlon computed tomography, and magnetic resonance imaging) are combined with various cardiovascular stress tests to achieve more reliable measures of myocardial contractility and reserve. (AM HEART J 1988;116:235.)

Daniel David, MD, Roberto M. Lang, MD, and Kenneth M. Borow, MD. Chicago, IU.

Clinical evaluation of ventricular contractility has always been a major focus of investigation in the field of cardiovascular physiology. This long-standing interest is justified by three important facts.

From the Section of Cardiology, Department of Medicine, The University

of Chicago Medical Center.

Supported in part by National Institute of Health grant AA-006677, and by a grant-in-aid from the American Heart Association, Chicago Affiliate.

Reprint requests: Kenneth M. Borow, MD, Cardiac Noninvasive Physiolo- gy Lab, University of Chicago Medical Center, 5641 South Maryland Ave., Box 44, Chicago, IL 60637.

First, left ventricular (LV) contractile state reflects the calcium-dependent interaction between actin and myosin filaments. As such, it is a fundamental property of the myocardium. Second, contractility is a major determinant of overall LV performance, myocardial oxygen consumption, and long-term clinical prognosis. Finally, information about time- related changes in contractility and reserve is useful for assessing the efficacy of pharmacologic, surgical, and other therapeutic interventions in various disease states.

However, accurate quantitation of cardiac con-

235

236 Dauid, Lang, and Borow July 196E

American Heart Journal

CONTRACTILITY HEART WALL

RATE FORCES

MVO, CARDIAC WORK

1 EFFICIENCY 1

Fig. 1. A schematic depiction of the factors governing cardiac efficiency. Wall forces, which are the product of pressure, volume, and muscle mass, are major determinants of cardiac work and oxygen consumption. Heart rate and contractility are additional factors that determine cardiac work and myocardial oxygen demand and thus affect cardiac efficiency.

tractility in humans remains difficult. In recent years, sophisticated noninvasive methods of assessing the functional capacity of the cardiovascular system have been developed and applied to solving this problem. Most of these techniques have utilized a controlled challenge to test the competency of the system as a whole. Although useful in many ways, these approaches have had limited clinical utility as specific measures of LV contractility due to the complexity of the hemodynamic changes engen- dered by the stress test itself, as well as by the use of highly load-dependent indices of cardiac perfor- mane. The following report will develop the physiologic rationale for exercise, pacing, and pharmacologic challenges to the heart and will discuss the advantages zind limitations of currently available techniques. In addition, it will describe how the combination of stress testing and noninvasive cardiac imaging can be used to expand our current clinical capabilities and develop new load-independent indices of myocardial contractility and reserve.

HISTORICAL PERSPECTIVE

The modern era of cardiac stress testing dates hnplr tn Rn,.oGnlrl’n ,-I’ ~~___. __ IcpnT=ry in 1918l of ischemia- iv ..“IIIIU u UIUU” * u

induced ST-T changes on the electrocardiogram (ECG). This led to the description of exercise- induced ST-T changes by Feil and Siegel in 1928.’ In 1929, Master3 published his initial experience with

dynamic exercise testing. Despite the recognized limitations of his step test technique, it constituted the standard for stress testing until the late 1950s. In 1958, Bruce* used treadmill and bicycle ergometry to establish the basis for his widely used exercise protocol. Other investigators have subsequently devised a vairety of protocols for submaximal as well as maximal dynamic exercise testing. Additional forms of stressing the cardiovascular system have also been developed. These include isometric exercise, atrial pacing, biochemical and pharmacologic stimulation, and cardiopulmonary stress testing.

DETERMINANTS OF CARDIAC METABOLIC DEMAND AND EFFICIENCY

The use of stress testing to unmask LV contractile abnormalities is based upon the concept of myocardial metabolic supply and demand. The demand side of the equation is highly dependent upon many factors including LV pressure, volume, wall mass, heart rate, and contractility. All of these parameters relate to myocardial oxygen consumption (MVO,), mainly through their combined effect on LV wall forces. The interrelation between IWO, and the product of developed pressure and heart rate was demonstrated by Rohde in 1912.6 Evans and Matsu- oka in 19X8 established the dependence of MVO, on developed wall tension during the contractile process. The concept of “tension-time index” was intro- duced by Sarnoff et al.?-‘O and was further elucidated by others.“-l3 These studies demonstrated that an increase in preload combined with a decrease in afterload (the actual initial physiologic adaptation to exercise) is the most “cost effective” way to increase myocardial efficiency.

At the present time, it is thought that the major determinants of myocardial oxygen demand are (1) ventricular contractile state, (2) the integral of systolic force per unit time as measured by ventricular wall stress (i.e., product of intracavitary pressure and radius of curvature of the myocardial segment divided by wall thickness), and (3) heart rate.14-le Alterations in ventricular preload and afterload can have profound effects of MVO, through changes in wall stress, which are independent of changes in contractility or heart rate. Changes in myocardial oxygen extraction can also be important. In the resting state, myocardial oxygen extraction approximates 60%. However, it can be increased to 70% to 75% by a predominant increase in coronary blood flow. Once maximal coronary flow has been attained, the heart is capable of further increasing its oxygen (0,) extraction capabilities to approxi- mately 80%. At the point where the additional

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Number 1, Part 1 Noninvasive determination of myocardial contractility 237

increase in 0, extraction is not accompanied by a concomitant increase in coronary flow, the aerobic limit of the heart is reached. In this phase, anaero- biosis occurs, resulting in metabolic acidosis and lactate production, followed by a rapid reduction in cardiac efficiency. This “anaerobic threshold” is an important marker during the evolution of the exercise test, and seems to have important diagnostic and prognostic significance.

Myocardial MVO, is only one of the factors determining the efficiency of the heart. Myocardial efficiency or “cost effectiveness” is defined as the amount of useful work performed per energy equivalent utilized (i.e., unite of myocardial oxygen consumption multiplied by 20.3 J/ml of 0,). Changes in arterial load, end-diastolic volume, heart rate, and contractility will affect myocardial efficiency by their direct effect on MVO, as well as by their effect on myocardial work (Fig. 1). If one increases afterload to a degree that completely abolishes LV ejection (isovolumic contraction), the heart is ren- dered totally inefficient despite the continued, albe- it reduced, consumption of 0, by the ongoing contractile process. Under these conditions, changes in contractility, preload, or heart rate will alter myocardial MVO, without altering cardiac efficiency. Conversely, if contractile state, heart rate, and preload are maintained constant, a gradual reduction in afterload will result in a progressive increase in cardiac efficiency to some maximal value. A further decrease in afterload will have little or no effect on cardiac efficiency (Fig. 2). With this physiologic framework in mind, we shall explore the various options available to the clinician for myocardial stress testing.

TYPES OF MYOCARDIAL STRESS TESTING

The cardiovascular system can be stressed using either active (e.g., dynamic exercise) or passive (e.g., pacing, pharmacologic) techniques.

Active stress testing. Stressing the cardiovascular system through increased work of the skeletal muscles can be divided into isotonic and isometric exercise. These two forms of muscle activity differ in the load imparted on the exercising muscle and, more importantly, in the way they alter global cardiovascular physiology.

1. Isotonic exercise. Isotonic exercise, the most common type of exercise, involves the dynamic activation of skeletal muscles producing work mainly through muscle fiber shortening. This type of exercise is accompanied by a multitude of complex adaptive changes in the cardiovascular and respiratory systems (Fig. 3). These changes are necessary to

LV VOLUME

Fig. 2. Left ventricular pressure-volume loops represent- ing cardiac work (WI., shaded area under the curves) of three different afterload conditions (A&C). Note that preload is constant (i.e., departure from the same end- diastolic pressure-volume point D) as is contractility (i.e., linear end-systolic pressure-volume relationship). Exter- nal work W, is zero, since it represents an isometric contraction. Reducing afterload to points B or C allows for ejection of blood into the aorta. Since external work is now being performed (W,, W,), a value for cardiac efficiency can be calculated (see text for details).

adapt the organism to the increase in metabolic demands and are controlled by a combination of factors, including the peripheral and cardiac autonomic nervous system, horomoral activity, and local feedback mechanisms.

In normal subjects, one of the first changes that occur in response to isotonic exercise is augmented venous return to the heart, leading to increased ventricular preload. This is accomplished by an autonomically mediated increase in venous tone, accelerated pumping action of the exercising muscles, increased negative intrathoracic pressure pro- duced by deep inspiration, and preferential shunting of blood from the splanchnic and renal vascular beds into the systemic venous circulation.17 Arteriolar dilation, mainly in the skin and exercising muscles, results in a gradual lowering of the peripheral vascular resistance.18r lg The initial acceleration of heart rate is mediated primarily by inhibition of vagal tone, and is further maintained by an increase in sympathetic-induced beta-, adrenoceptor stimu-

238 David, Lang, and Borow

SYMPATHETIC TONE 4 CATECNOLAYINE 4

PARASVYPATNETIC TONE)

AQE

MVOSIN COMPOSITION

w,, v*, V,)

NEART RATE

CONTRACTILITV

YVOCARDIAL OXVQEN CONSUYPTION

Fig. 3. The adaptation of the cardiovascular system to isotonic exercise. Heart rate, contractility, and left ventricular systolic wall forces determine myocardial oxygen demand. The interplay between autonomic, humoral, and local factors controlling exercise-induced changes in preload, afterload, heart rats, and contractility are depicted (see text for details).

lation. Increases in circulating catecholamine levels are less important mediators of the initial tachycar- die response to exercise. In most cases, changes in LV loading conditions and heart rate are associated with an increase in overall LV fiber shortening. This results from the preload-dependent stretching of the myocardial fibers (Starling effect) as well as from augmented contractility due to catecholamine- induced acceleration of intracellular phosphoryla- tion and metabolism. Depending upon the changes that occur in LV pressure during ejection, ventricular afterload (i.e., wall stress) can decrease or remain unchanged. All of these simultaneously occurring hemodynamic alterations are interactive, with the end product determining myocardial efficiency.

Differences in cardiovascular physiology exist between dynamic exercise performed in the supine position and that performed in the upright position. Supine exercise involves a higher initial LV filling volume (due to facilitated venous return) than is absent when the subject is sitting or standing. This positional difference in filling volume is largely abolished in the later phases of exercise due to mnaimnl venrm~ return induced by venoconstriction and other adaptive mechanisms.

2. Isometric exercise. Many of our daily activities involve the use of isometric muscle work. Moreover, the combination of isotonic and isometric effort is

common. In contrast to the volume challenge elici- ted by isotonic exercise, isometric stress poses pre- dominantly a pressure load to the heart. This occurs in the absence of a reduction in peripheral vascular resistance. LV ejection fraction falls due to an increase in end-systolic volume and a decrease in end-diastolic volume.23-27 The rate of increase in blood pressure is dependent upon the mass of the isometrically contracting muscle groups as well as on the weight to be lifted. 1b28 This form of inefficient work can be maintained for only short periods of time due to the inability of the contracting muscles to appropriately increase their supply of OP In addition, there is the rapid development of anaerobic metabolism, which further limits duration of contraction. One of the possible problems in assessing the cardiovascular response to isometric stress testing is the inadvertent Valsalva maneuver that may be performed by the patient during the test. In order to unmask the true hemodynamic changes pertaining to the isometric stress itself, it is important to avoid the physiologic changes that accompa- ny the Valsalva maneuver.

Passive stress testing 1. Atria1 pacing. Atrial pacing is an easy and

convenient way of stressing the heart, especially in patients in whom dynamic exercise is not feasible.% However, it must be noted that the hemodynamic changes associted with atrial pacing are different

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NumBor 1, Part 1 Noninvasive determination of myocardial contractility 239

from those associated with isotonic or isometric exercise. The major difference emanates from the fact that during atrial pacing the heart is stressed without primary autonomic or humoral input. The main hemodynamic changes with atrial pacing are a decrease in LV stroke volume, due to a decrease in LV filling time that is not accompanied by an adequate compensatory increase in systemic venous return.s Recently, Txivoni et al.30*31 compared atria1 pacing to treadmii exercise testing and were able to achieve comparable levels of external cardiac work as expressed by the maximal heart rate-blood pressure product. Interestingly, these investigators found that most of the patients with coronary artery disease could be brought to their ischemia and pain threshold by atrial pacing.20,30,31 In recent years, the advent of transesophageal atrial pacing has obviated the need for invasive techniques to accomplish pacing-induced stress teting.92*33 Transesophageal atrial pacing, in conjunction with echocardiogra- phg3tS and other imaging modalities, has been used as a tool for the study of the cardiovascular system’s adaptation to physical and pharmacologic stresses.

2. Pharmacologic and metabolic stress testing. Various metabolic and pharmacologic interventions have been used to challenge the cardiovascular system in the attempt to assess ventricular contractile reserve. These include the following:

a. HYPOXIA TEST. This is one of the oldest means of inducing a metabolic change to stress the cardiovascular system.35-37 It is performed by having the subject breath varying mixtures of 0, and nitrogen. Most patients with obstructive coronary artery disease cannot compensate for a decrease in blood 0, supply by an appropriate increase in coronary blood flow. The predictive capacity of this test is based upon the resulting ECG changes of myocardial ischemia rather than upon the associated hemodynamic alterations. This test has been reported to have a significantly higher sensitivity and specificity for coronary artery disease than does dynamic exercise testing.% However, it carries an increased risk for central nervous system complications in patients with cerebral vascular disease.%

b. BIOACTIVEAMINESTRESSTRST. Isoproterenol,norepinephrine, dopamine, doubutamine, methoxamine, phenylephrine, and angiotensin have been used to pharmacologically stress the cardiovascular system in patients with coronary disease.sg-u Isoproter- enol induces an increase in blood pressure, heart rate, and velocity of LV fiber contraction. These cardiac effects, in conjunction with coronary and peripheral vasodilation, may cause myocardial ischemia in patients with coronary artery disease, due

to an increase in myocardial 0, demands, in conjunction with a disadvantageous redistribution of coronary flow. 45 In many ways, the metabolic effects of isoproterenol infusion are similar to those pro- duced by dynamic exercise testing.& Epinephrine and norepinephrine induce myocardial &hernia mainly by the abolition of the coronary vasodilator response to hypoxia, in conjunction with an increase in myocardial work. Dopamine and dobutamine can induce LV ischemia by the combination of peripheral vasoconstriction, tachycardia, and augmented LV contractility. Angiotensin, methoxamine, and phenylephrine cause peripheral vasoconstriction, leading to increased myocardial work with little change in LV contractile state. The subsequent hemodynamic alterations are somewhat comparable to those noted with isometric exercise.@

C. DIPYRIDAMOLE TEST. Oral or intravenously administered dipyridamole can elicit myocardial ischemia in patients with coronary artery disease by inducing coronary vasodilatation, and redistribution of coronary blood flow. Intravenously dipyridamole results in a dose-dependent 35% to 400% increase in coronary blood flow in association with a decrease in post-stenotic coronary artery pressure. The net result is a “coronary steal” phenomenon.“-” The combination of coronary and peripheral vasodilatation leads to an increase in heart rate and a decrease in systolic and diastolic blood pressure without a significant change in cardiac output.61,62 The major findings associated with the precipitation of myocardial ischemia are reversible perfusion defects seen with radioisotopic studies or regional wall motion abnormalities as detected by echocardiographic imaging. The dipyridamole test has been used mainly in patients who have difficulty perform- ing dynamic exercise.

COMMONLY USED NONINVASIVE PARAMETERS FOR ASSESSING STRESS-INDUCED CHANGES IN LEFT VENTRICULAR PERFORMANCE

The goal of an index of LV contractility is to be able to separate changes in contractile state from simultaneously occurring alterations in ventricular loading conditions and cardiac frequency. Unfortu- nately, all of the interventions described above induce a complex chain of hemodynamic events that can simultaneously alter contractility, preload, afterload, and heart rate. The following will address the utility and limitations of commonly used noninvasive parameters as measures of ventricular contractility in patients undergoing stress testing.

Heart rate. Heart rate is used primarily as a measure of the magnitude of work performed during

240 David, Lang, and Borow July 1066

American Heart Journ6l

Fig. 4. Breath-by-breath changes in oxygen uptake, ventilatory equivalent of oxygen (V,/VO,), ventilatory equivalent for carbon dioxide (V,JVCO,), end-tidal volume tension (P,,O,), end-tidal carbon dioxide tension (PET. CO,), and respiratory gas exchange ratio (R) during exercrse m a patient with congestive heart failure. The work rate of the cycle ergometer was increased continu- ously at a rate of 10 W/min after a period of rest and 3 minutes of unloaded pedaling (0 W). Each solid circle represents a single breath. Each number represents the

dynamic exercise. During the aerobic phase of upright dynamic exercise, heart rate is linearly related to workload and MVO, and is a clinically useful marker for cardiac performance.“~ 18, 63 How- ever, changes in heart rate alone cannot be used as an accurate measure of LV contractile state or reserve. For example, estimation of cardiac output and contractile reserve based on heart rate response to exercise is not the same in patients with mitral or aortic regurgitation as it is with age- and sex- matched normal individuals. Furthermore, isometric work, which may be part of isotonic exercise (e.g., the gripping of the bicycle handles), may introduce physiologic changes in peripheral resistance and venous return, thereby altering the normal heart rate-MV02 relationship. Similar reasoning applies when one considers other forms of stress testing such as supine exercise, atrial pacing, and pharmacologic interventions. In addition, it is well known that heart rate response to dynamic exercise may be blunted in patients with compromised cardiac function (i.e., “chronotropic incompetence”).17*5a-56

Systemic arterial pressure. Systemic arterial pressure measurements during dynamic exercise are diflicult to assess because of the problems encoun- tered in obtaining accurate noninvasive determina- tions. While the systolic blood pressure can be verified by palpation, there is no reliable method to noninvasively determine diastolic blood pressure under these conditions. Ellestadl’ and others have confirmed marked interobserver variations in diastolic blood pressure measurments during dynamic exercise testing. Invasive blood pressure measurements, although relatively accurate, depend on the location of the measuring catheter. Brachial and radial artery pressures are higher than central aortic pressures, and this difference is accentuated in patients with increased peripheral vascular tone (e.g., low cardiac output state). In addition, the magnitude of change in blood pressure is influenced by a multitude of parameters such as preload, afterload, contractility, and the rigidity of the vascu-

(Fig. 4-cont’d) mean value for the last 30 seconds of a l-minute interval. The vertical line denotes the anaerobic threshold, which is signified by an abrupt increase in R while VJVO, increases without an equivalent increase in v&,wm,. CsxGmitantly, P,,O, increases with a delayed decline in P,CO,. (Reproduced from Nemanich et al. Effects of long-term therapy with oral piroximone on resting hemoclynamics, peak aerobic capacity, and the anaerobic threshold in patients with heart failure. J Cardiovasc Pharmacol 1987;10:580-8.)

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Numbor 1, Part 1 Noninvasive determination of myocardial contractility 241

lar tree. Therefore, blood pressure cannot be regarded as an adequate parameter for the primary characterization of cardiac function.

Heart rate-pressure product. In normals, this noninvasively determined “double product” correlates fairly welI with 0, consumption during exercise.57 However, in various pathologic conditions in which left ventricular geometry is altered (e.g., hypertension, valvular heart disease, or myocardial ischemia), this relationship may be disturbed and therefore may not reflect the actual level of work performed by the heart.% Theoretically, the use of the “triple product” (rate, pressure, and ejection time)5g should enhance the specificity and sensitivity for the detection of abnormalities in LV performance. However, the addition of the systolic ejection time to the double product has inherent problems of its own. For example, the increase in heart rate that occurs with exercise will decrease the LV ejection time and possibly result in a fall in the triple product at the time when ventricular contractility and O2 consumption are progressively increasing.

ECG parameters. Several authors6op61 have suggest- ed the use of the R wave response to exercise as a means of assessing cardiac function. The theoretical basis for this ECG application was the mathematical model of Brody,61 showing that an increase in intracavitary blood volume should result in an increase in R wave vectors. It was postulated that patients with idiopathic dilated cardiomyopathy or ischemia- related cardiac dysfunction would show exercise- induced R wave increases due to an increase in LV end-diastolic volume.8o However, clinical reports that used this index to assess ventricular function have demonstrated conflicting results. Experimen- tal data from a canine model of acute myocardial ischemia have shown62*63 that changes in R wave amplitude are primarily related to the changes in the velocity of intramyocardial impulse conduction rather than to intracardiac volume changes. Recent studies conducted in human&-@ have shown that the increase in precordial R wave amplitude associated with LV chamber dilation is primarily a function of changes in the proximity of the LV lateral wall to the chest wall, rather than of an increase in LV blood volume.

Cardiopulmonary stress testing. The addition of the metabolic assessment of the cardiopulmonary system to standard stress testing techniques has been a major advance in the understanding of exercise physiology. Continuous “breath-by-breath” monitoring of 0, uptake, carbon dioxide (CO,) production, and mechanical ventilatory parameters allows for accurate monitoring of cardiopulmonary func-

tion under control conditions and throughout the stress test. Usually the goal of cardiopulmonary stress testing is to reach maximum oxygen consumption (VO,) (i.e., the stage where VO, remains steady despite a further increase in workload) (Fig. 4). V02,= permits more accurate classification of the degree of cardiopulmonary disability and has been used by several investigators to replace the New York Heart Association classification.6g VOZ, appears to’ be a more accurate measurement of aerobic capacity than the subjective index of the exercise duration.70 Use of cardiopulmonary stress testing to determine anaerobic threshold can be clinically useful in defining the relative contribution of cardiac and pulmonary abnormalities to the patient’s disability.

Ejection phase indices of global left VentriCUlar per-

formance. LV contrast angiocardiography, radionu- elide angiography, echocardiography, and other more sophisticated imaging modalities (e.g., rapid acquisition computed tomography and magnetic resonance imaging) allow the determination of the cyclic changes in intracardiac volume and wall motion characteristics. However, the resultant ejection phase indices (including such commonly used parameters as stroke volume, stroke work, cardiac output, ejection fraction, and velocity of fiber shortening) are highly load- and heart rate-dependent. It is known that patients with dilated cardiomyopathy can maintain near-normal LV stroke volume and ejectrion fraction by an increase in preload.71 On the other hand, an inappropriate increase in afterload can result in preload-afterload mismatch manifested by a decrease in stroke volume and ejection fraction without important impairment in LV contractility or reserve.71s72

It has been well established that load dependency in the resting state is a major confounding variable in a wide array of patients, including those with significant valvular lesions, systemic hypertension, and metabolic disorders.73-77 In an attempt. to cir- cumvent many of these issues, the LV ejection fraction response to dynamic exercise has been used as a measure of myocardial functional reserve. Inter- pretation of these data has been based upon the assumption that failure to augment ejection fraction during exercise is an early harbinger of ventricular dysfunction and diminished contractile reserve. However, in many cases, an abnormal LV ejection fraction response to exercise is of limited predictive value. This reflects the inability of the technique to distinguish between ejection fraction changes due to altered loading conditions and those due to LV contractile abnormalities. This limitation is further


American Heart Journal

compounded by the complexity of acute circulatory events that occur with dynamic exercise. These include (I) peripheral vasodilatation in exercising muscles, (2) increases in sympathetic tone to the heart, (3) release of catecholamines from the adrenal medulla, (4) alterations in systemic venous capaci- tance leading to maintenance of venous return and ventricular preload, and (5) augmentation of heart rate in association with a marked decreased in the length of the diastolic portion of the cardiac cycle. Derangements of any one of these mechanisms can result in failure to increase ejection fraction without implicating a depression in myocardial contractility*

NEWER APPROACHES TO THE NONINVASIVE ASSESSMENT OF STRESS-INDUCED CHANGES IN LEFT VENTRICULAR PERFORMANCE

End-systolic indices of global performance in the symmetrically contracting left ventricle. In contrast to all of the previously discussed load-dependent indices of cardiac performance, the end-systolic indices are measurements of LV contractility that incor- porate LV loading conditions into their analysis. Each relates a measure of LV fiber force at end systole (i.e., pressure or wall stress) to a measure of either (1) ventricular fiber length (i.e., end-systolic volume or dimension), (2) extent of ventricular fiber shortening (i.e., ejection fraction, percent fractional shortening, percent fractional thickening), or (3) velocity of ventricular fiber shortening (i.e., mean velocity of circumferential shortening). These indices have been used by numerous investigators as a means of assessing the ventricle’s response to dynamic exercise, atria1 pacing, and pharmacologic challenges. However, before they are accepted as being accurate measures of LV contractility during stress testing, critical appraisal of the uses and limitations of these indices is necessary.

1. Response to dynamic exercise. The slope of the end-systolic pressure-volume relation, which is usually generated from data acquired during an afterload or preload challenge, is independent of preload, incorporates afterload, and is a sensitive measure of contractility. Simplifications of this concept have been used to assess LV contractility during dynamic exercise in patients with suspected ischemic heart disease*lp 78 and in patients with chronic aortic regurgitation.7g-81 In general, these studies have shown LV contractile reserve to be diminished in both disease states. However, before accepting these conclusions, one should consider several limitations of the methods employed for data acquisition and analysis. First, all of these studies use radionuclide-deter-

mined LV end-systolic volumes. These volumetric measurements are subject to multiple variables, including estimations of background and attenua- tion.82 Compounding this concern is the fact that even small errors in end-systolic volume calculations can result in large variations in the end-systolic pressure-volume slope.

Second, LV peak systolic pressure (PSP) by cuff sphygmomanometer was used to approximate end- systolic pressure (ESP). This assumes that the relationship between these two pressures is the same under resting conditions and at peak dynamic exercise. However, this assumption is highly suspect, because dynamic exercise is associated with marked changes in (1) the timing and rate of development peak LV pressure, (2) peripheral arteriolator tone and vascular resistance, and (3) the velocity, as well as the amplitude, of reflected waves as they come back from the periphery to the central aorta and left ventricle. All of these factors may have a significant effect on the PSP-ESP relationship.

Third, in most cases, the ratio of PSP to end- systolic volume (ESV) was used as a simplified contractility index. This ratio, which is highly afterload-dependent, can be considered a pressure- volume slope generated from a single point, with its regression line always passing through the origin of the pressure and volume axes. This is rarely the case for true end-systolic pressure-volume regression lines.

Finally, the end-systolic pressure-volume relation can be thought of as a force-length relation. In a dilated or hypertrophied ventricle, the force variable is better measured as wall stress. This has the advantage of taking ventricular dimensions, shape, wall thickness, and pressure into account when quantifying the forces acting on the myocardium. It also allows more appropriate comparisons between ventricles of different size and wall thickness. Unfortunately, radionuclide techniques in use today are unable to quantitate wall stress because they cannot measure LV wall thickness.

2. Response to atria1 pacing. Several investigators have used the end-systolic indices as a means of assessing changes in LV contractility during atria1 pacing. The study by Iskandrian et a1.83 was performed in the cardiac catheterization laboratory with the use of right atria1 pacing in conjunction with radionuclide ventriculography. These investigators concldnrl thnt. the end-systolic pressure- volume relation could be used to quantitate pacing- induced changes in LV contractility in normal subjects, as well as in patients with coronary artery disease. Subsequent studies have been performed in

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Number 1, Parl 1 Noninvasive determination of myocardial contractility 243

EGG

BP

PCG

CPT

LVPW

PACED NON-PACED

Fig. 5. Example of the use of simultaneously recorded electrocardiogram (ECG), blood pressure (BP), phonocardiogram (PCG), carotid pulse tracing (CPT), and two-dimensional targeted M-mode echocardio- gram to assess left ventricular physiology during and after cessation of transesophageal atrial pacing. Note the differences in carotid pulse morphology, phonocardiogram, and left ventricular chamber size when heart rate abruptly drops from 136 to 71 beatslmin. IVS = interventricular septum; LVPW = left ventricular posterior wall; DN = dicrotic notch.

our laboratory84 with transesophageal left atrial pacing in conjunction with cardiac ultrasound imaging, calibrated carotid pulse tracings, and Doppler echocardiography (Fig. 5). Data were acquired over a heart rate range of 60 to 130 beats/min in each study subject. LV contractility was assessed by means of the relationship between the mean velocity of circumferential fiber shortening (Vcf,) and LV end- systolic wall stress (a,). This ues-Vcf, relation is preload-independent, incorporates afterload and heart rate in its analysis, and is highly sensitive to changes in LV contractile state. The use of Doppler and two-dimensional echocardiography allowed assessment of heart rate-related changes in LV stroke volume and cardiac output. Furthermore, when instantaneous ejection pressure (assessed by calibrated carotid pulse tracing) and instantaneous ejection flows (determined by Doppler echocardiography) were analyzed, it was possible to determine ventricular power (i.e., work per unit time) as well as the efficiency of the LV-central aortic coupling.@ These data can then be analyzed in conjunction with echocardiographic imaging to assess regional endocardial motion and transmural wall thickening

abnormalities. The net result is a totally noninvasive analysis of myocardial mechanics, wall dynamics, energetics, and central aortic blood flow during atrial pacing. Additional increases in myocardial workload can be obtained if an associated pharmacologic challenge is performed.

3. Response to pharmacologic challenges. One of the most extensive applications of the end-systolic indices has been to assess the inotropic response to pharmacologic agents that simultaneously alter contractility and ventricular loading conditions. Studies have been performed in normal subjects as well as in patients with dilated cardiomyopathy with the use of the end-systolic pressure-volume (or dimension), a,-volume (or dimension), a--percent fractional shortening, and a,-Vcf, relations. Specific cardioac- tive agents in which the contractile response has been assessed include dopamine, dobutamine, dopexamine, norepinephrine, calcium, amrinone, milrinone, and enoximone.72s73*86-v4 Use of the a,-Vcf, relation has been particularly advantageous because it is the only end-systolic index that readily allows quantitative separation of the inotropic and afterload-altering effects of a drug.72*73,W


American Heart Jwnal

End-systolic indices of regional left ventricular performance. The above discussion of global indices of myocardial function during stress testing leads nat- urally to the question of whether a similar analysis can be applied to individual regions of the myocardium. If such an analysis were possible, it might enable one to distinguish regional decreases in contractility from decreased localized performance due to regional loading differences. The description and quantification of local changes in myocardial function during stress testing appear to be essential to our understanding of the effects of various experimental and therapeutic approaches designed to improve myocardial performance and reduce tissue damage during myocardial ischemia.

In experimental and clinical settings, the two primary quantitative descriptors of regional function are wall motion (endocardial excursion) and wall thickening. Each of these approaches has major advantages and limitations.s5 Endocardial wall motion analysis is limited by the need to relate data to some reference point within or surrounding the heart (centroid-dependent), and is influenced by cardiac translation, rotation, respiratory motion, and ventricular shape changes. In contrast, assessment of regional wall thickening has the advantage of being independent of a center of reference and is unaffected by ventricular translation, rotation, or LV shape. Moreover, by combining regional wall thickening dynamics during systole with LV pressure, it is possible to define regional end-systolic measures of LV function. Osakada et al.% determined the relationship between regional end-systolic pressure and wall thickness to assess the effects of acute myocardial ischemia on regional contractile function. A wide range of LV loading conditions was generated by balloon occlusion of the inferior vena cava. Their results showed that the end-systolic pressure-wall thickness relation shifted leftward in the ischemic region due to a shift in the thickness- axis intercept without a change in the slope. No displacement of this relationship was observed in the control region. It was postulated that augmented load (reflected as increased pressure) contributed to the striking decreases in the extent of regional wall shortening and wall thickening in the ischemic zone. These studies characterized a phenomenon in which regional load was altered by ischemia, resulting in wall thinning; theoretically, this further increases regional afterload, which in turn leads to further mec!~nica! impsiriiiolli of local LV fiber function by way of the force-velocity-length relationship. This type of approach offers the possibility of a relatively load-independent measure of local myocardial con-

tractility during a variety of interventions in impaired as well as normal myocardium.

Clinical applications of end-systolic measures of regional fiber load and wall thickening should be feasible with currently available imaging techniques such as two-dimensional echocardiography, rapid acquisition cardiac computed tomography, and magnetic resonance imaging.

1. Two-dimensional echocardiography. Two- dimensional echocardiography is a tomographic technique. Since the endocardial and epicardial surfaces are visualized, wall thickness can usually be determined throughout the entire circumference of the ventricle. This technique is highly operator- interactive and therefore operator-dependent. Technically high quality recordings may be difficult to obtain in obese individuals, patients with chronic lung disease, and during dynamic exercise, because of the physical characteristics of ultrasonic trans- mission and reflection.

2. Rapid acquisition tine CT. Computed tomography provides cross-sectional (transaxial) images of the body. Farmer et alg7 assessed LV wall thickness and chamber dynamics in a canine model with the use of this device. Occlusion of the left anterior descending coronary artery resulted in regional systolic thinning demonstrable in tine CT, with no significant change in global LV function. An important contribution of the tine CT studies has been the finding of considerable heterogeneity of regional systolic wall thickening. Although studies that used this technique have been limited, the spatial and temporal resolution of tine CT makes this method a promising tool for the assessment of regional ventricular function. The major disadvantages of tine CT for cardiac imaging include the high initial cost of the equipment, the need for ionizing radiation, and the need for an infusion of iodinated contrast medium.

3. Magnetic resonance imaging. Magnetic resonance imaging (MRI) provides tomographic views of the heart that are generated without the need for infusion of iodinated contrast medium or the use of ionizing radiation. MRI exhibits excellent spatial resolution, allowing for accurate assessment of chamber dimensions and wall thickness. The different magnetic resonance characteristics of blood, myocardium, and lung permit delineation of endocardial and epicardial surfaces.s8 Another advantage of MRI is its three-dimensional reconstruction capabilities. ECG-gated tine MRI imaging has been used by Higgins et al.* in patients with chronic myocardial infarction and demonstrated abnormal postin- farction wall thinning, ventricular aneurysms, and

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mural thrombi. Eventually, MRI may also be helpful in identifying regional myocardial ischemia by direct evaluation of tissue properties.

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