Response of Left Ventricular Volume to Exercise

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in Response of Left Ventricular Volume to Exercise Man Assessed by Radionuclide Equilibrium Angiography ROBERT SLUTSKY, M.D., JOEL KARLINER, M.D., DONALD RICCI, M.D., GERHARD SCHULER, M.D., MATTHIAS PFISTERER, M.

1 in Response of Left Ventricular Volume to Exercise Man Assessed by Radionuclide Equilibrium Angiography ROBERT SLUTSKY, M.D., JOEL KARLINER, M.D., DONALD RICCI, M.D., GERHARD SCHULER, M.D., MATTHIAS PFISTERER, M.D., KIRK PETERSON, M.D., AND WILLIAM ASHBURN, M.D. SUMMARY To assess the effects of exercise on left ventricular volumes we studied normal men, patients with coronary disease who developed angina pectoris during exercise, and patients with known coronary disease who did not develop angina during exercise. Each subject performed supine bicycle exercise under a mobile, single-crystal scintillation camera until angina or fatigue occurred. Technetium-m bound to human serum albumin was the imaging agent. Data were collected at rest and during the last minutes of each -minute stage of exercise and for minutes after exercise. Volumes were calculated by a new radionuclide technique that correlates well with cineangiography and is expressed in nondimensional units. In normal subjects, the end-diastolic volume (EDV) at rest was not different from that at peak exercise:. ±. (SD) vs. ± (NS). The end-systolic volume (ESV) decreased from 5. ±. to. ±. at peak exercise (p <.). ESV decreased progressively in all but two of exercise periods. Angina patients had a larger EDV (p <.) at rest and during chest pain (p <.) than normals. Angina patients increased their ESV from. ±. to. ±.5 during chest pain (p <.), resulting in a decreased ejection fraction (EF) (.5 ±. to.5 ±., p <.). All angina patients had a higher ESV during chest pain than during the exercise stage before chest pain. As a group, patients who did not develop angina had a lower EDV at rest and peak exercise than those who did develop angina:. vs.5 (p <.) and. vs.5 (p <.), respectively. The ESV went from. ±. at rest to. ± 5. at peak exercise, and the EF from.5 ±. to.5 ±. (all NS). We conclude: that the EF increases during exercise due to a decrease in ESV; that the EF in patients with angina decreases because of an increase in ESV; and that the EF in coronary disease patients without angina shows no change because there is no significant change in the ESV. Radionuclide equilibrium angiography may prove useful for assessing EF and volume changes in patients with coronary artery disease. Downloaded from by on January, RECENT DATA SUGGEST that assessment of left ventricular function during exercise may be a useful method of evaluating patients with coronary artery disease (CAD).- The response to exercise of left ventricular chamber size both in normal subjects and in patients with heart disease is of considerable physiologic interest. However, few reliable nontraumatic methods of assessing this response are available. Therefore, we compared the volumetric response to exercise in normals, patients with CAD who develop angina and patients with coronary disease who do not develop angina with exercise. To do this we used graded supine bicycle exercise and a newly described method for assessing left ventricular volume by radionuclide equilibrium angiography that does not require geometric assumptions of left ventricular shape. Subjects Group consisted of normal male volunteers who had no known illnesses and were taking no From the Divisions of Nuclear Medicine and Cardiology, University of California, San Diego, School of Medicine, San Diego, California. Supported by SCOR in Ischemic Heart Disease research grant HL-, awarded by the NHLBI, NIH. Address for reprints: Robert Slutsky, M.D., University of California Medical Center, 5 West Dickinson Street, San Diego, California. Received August, ; revision accepted March,. Circulation, No.,. 55 medications. These subjects ranged in age from - years (mean years). All of these subjects had normal resting and stress ECGs, as well as a normal clinical examination. None underwent contrast angiography. Group consisted of patients who were studied in the cardiac catheterization laboratory before angiography. All had obstructive CAD (at least one stenotic lesion > % of the diameter in a major coronary artery) and all developed classic angina pectoris during supine bicycle exercise. Seven had onevessel; four had two-vessel and four had three-vessel CAD. Seven patients had contraction abnormalities at rest. Four had one or more resting hypokinetic areas and three had one or more akinetic areas. In six patients, propranolol was stopped at least hours before exercise. Six patients were taking digoxin and diuretics. There were three women and men, ranging in age from - years (mean 5 ± years). Group consisted of patients with known CAD who did not develop angina pectoris during supine exercise. They were attending a rehabilitation or research clinic for patients who had suffered a welldocumented myocardial infarction. Four patients were taking propranolol, which was discontinued at least hours before the study. Five patients were taking digoxin and diuretics, and four patients had used nitroglycerin for rare angina in the past. Six patients had not had angina since suffering a myocardial infarction. All were men, ranging in age from -5 years (mean 5 ± years). No patient in this group

5 CIRCULATION VOL, No, SEPTEMBER Downloaded from http://ahajournals.org by on January, had undergone contrast ventriculography within year of the radionuclide study.

2 5 CIRCULATION VOL, No, SEPTEMBER Downloaded from by on January, had undergone contrast ventriculography within year of the radionuclide study. However all had undergone contrast angiography previously (mean. ±. years before the study). Seven patients had threevessel CAD and three had two-vessel CAD at the time of the study. All patients had at least one akinetic segment by ventriculography (see table for angiographic data from groups and ). Methods All subjects were studied in the nuclear medicine laboratory except those in group, who were studied in the cardiac catheterization laboratory immediately before contrast angiography. Each patient had an intravenous catheter placed in a forearm vein for the injection of -5 mci mtc bound to human serum albumin. Studies were performed with the patient in the supine position under a mobile, single-crystal scintillation camera in the left anterior oblique position. All patients in each group were studied within TABLE. Contrast Angiography Results Site of coronary Wall motion abnormalities Patient artery lesions Location Severity Group RCA Inferior LAD Anterior LAD Anterior RCA None 5 LAD None LAD None LAD None S LAD, RCA Anterior LAD, RCA Anterior LAD, LCX None LAD, LCX None LAD, LCX, RCA None LAD, LCX, RCA Inferior LAD, LCX, RCA Anterior LAD, LCX, RCA None Group LAD, RCA Inferior LAD, RCA Anterior LAD, RCA Inferior LAD, LCX, RCA Anterior, inferior, 5 LAD, LCX, RCA Anterior LAD, LCX, RCA Anterior LAD, LCX, RCA Inferior LAD, LCX, RCA Anterior, inferior LAD, LCX, RCA Inferior LAD, LCX, RCA Anterior Abbreviations: RCA = right coronary artery; LAD - left anterior descending artery; LCX = left circumflex artery; = no contraction abnormality; = hypokinetic contraction; akinetic contraction; = dyskinetic contraction. minutes of injection to minimize count rate decay and yet allow mixing throughout the blood pool. Ten minutes of ECG gated scintillation camera data were collected at rest; additional data were collected in all subjects during the last minutes of each subsequent -minute stage of progressively more strenuous supine bicycle exercise. After each -minute stage was completed, an additional workload was added until fatigue or pain resulted. Data were also collected for minutes after exercise. Thus, scintillation camera data were collected at the following times: ) rest (5 minutes); ) minutes and of exercise; ) minutes 5 and of exercise; ) maximal exercise ( minutes) or angina; 5) minutes and after exercise; ) minutes and 5 after exercise; and ) minutes and after exercise Exercise was discontinued if the patient complained of angina, severe fatigue or if marked electrocardiographic abnormalities (ST depression > mm) occurred. A modified V5 lead was used to monitor the ECG. The heart rate and blood pressure were also recorded at rest, at maximal exercise and during recovery. No patient had more than three ectopic beats/min at rest or peak exercise, and only one patient had more than one ectopic beat/min at rest or peak exercise. Data were stored on videotape (in a digital format) in real-time and transferred to a dedicated computer (Medical Data Systems), and a multiple image program (MUGE) summed the information into one time-activity (volume) curve, which was divided into - equal time frames (depending on the heart rate) for analysis. The EF was then determined and enddiastolic and end-systolic volumes (EDVs and ESVs, respectively) were calculated, as previously described x LJ C z D ui LUI C) D rr) 5 V * io lc_ * o * : * o S.n r y r r =. =x +. =.5 (EDV) =. (ESV) * = EDV - ESV 5 5 ML CONTRAST ANGIOGRAPHY VOLUME FIGURE. Left ventricular volumes derived from contrast ventriculography are compared with ventricular volumes derived by a radionuclide method (in nondimensional units). Using the regression equation, the SEE for end-diastolic volume (EDV) is ±. ml andfor ESVis. ml. See text for discussion of the method.

3 RESPONSE OF LV VOLUME TO EXERCISE/Sluisky et al. 5 Downloaded from by on January, in detail.' Briefly, end-diastolic and end-systolic counts were determined from the "volume curve." These counts were divided by the total number of processed heart beats and then corrected for the administered dose and the time of each frame. Volumes were expressed as nondimentional units and a regression analysis was developed in which the following equation was used to calculate EDV or ESV units: EDV or ESV = counts X mic/m X. heart beats actual dose/m time/frame When the EDV and ESV units derived by means of this radionuclide method were compared with left ventricular volumes calculated from contrast ventriculography, the correlation coefficients using the above equation were: EDV =.5 (n = 5); ESV =. (n = 5); all volumes =. (n = ). The regression equation was y =.x +. (fig. ). All patients gave informed written consent for this protocol, which was approved by the Committee on Investigations Involving Human Subjects/Volunteers, University of California Medical Center, San Diego. All statistics were calculated by repeated measures analysis of variance or paired t test. Results Group : Normal Subjects Each patient in the group was able to exercise for at least minutes. The EDV was not significantly different when resting and maximal exercise values were compared (. ±. vs. i units). During exercise, the ESV decreased from 5. ±. to.. (p <.5), and the EF increased from. +. to..5 (p <.). Individual results are given in tables and. In general, the EDV remained relatively constant during exercise, while the ESV de- TABLE. Normal Subjects Patient Rest / Ex 5/ Ex M Ex / PEx /5 PEx / PEx End-diastolic volume Mean = SD. =t. End-systolic volume Mean = SD Ejection fraction Mean SD. = i i i ' = i i Abbreviations: / Ex = minutes and of exercise; 5/ Ex = minutes 5 and of exercise; M Ex = maximal exercise; / PEx = minutes and after exercise; /5 PEx = minutes and 5 after exercise; / PEx = minutes and after exercise.

5 CIRCULATION VOL, No, SEPTEMBER Downloaded from http://ahajournals.org by on January, TABLE. Normal Subjects Heart rate Systolic BP Diastolic BP Time (beats/min) (mm Hg) (mm Hg) Rest 5.

4 5 CIRCULATION VOL, No, SEPTEMBER Downloaded from by on January, TABLE. Normal Subjects Heart rate Systolic BP Diastolic BP Time (beats/min) (mm Hg) (mm Hg) Rest 5. - = / Ex - 5/ Ex - M Ex = = i / PEx - /5 PEx - / PEx Values are - SD. Abbreviations: BP = blood pressure; / Ex = minutes and of exercise; 5/ Ex = minutes 5 and of exercise; M Ex = maximal exercise; / PEx = minutes and after exercise; /5 PEx = minutes and a after exercise; / PEx = minutes and after exercise. clined markedly, thus accounting for the increase in EF. These values returned to normal by minutes after exercise. Group : Patients Who Developed Angina During Exercise The patients in this group exercised to various levels, but all, by design, were limited by angina. The EDV in group patients was larger at rest than in the normal subjects (.5 ±. vs. ±. units, p <.5), and was not significantly different from the EDV at angina (.5 ± ). The ESV in group patients at angina increased by an average of % (. ±. vs. ±. at rest, p <.). Additionally, the ESV in all patients increased during the -minute exercise stage before angina compared with control values (% increase, p <.). The EF decreased from.5 ±. at rest to.5 ±. (p <.) at angina; this decrease was due to the rise in ESV and the decrease in stroke volume. In table, the heart rate and blood pressure measurements are given at the respective exercise stages. Because duration of exercise varied, the stages preceding angina were not included. Table 5 shows the volume and EF changes in all angina patients. The ESV was greater at angina than TABLE. Heart Rate and Blood Pressure in Angina Patients Heart rate (beats/min) Systolic BP (mm Hg) Diastolic BP (mm Hg) Rest.5 =. - Angina... - / PEx /5 PEx = / PEx = - Values are - SD. Blood pressures were assessed with cuff sphygmomanometers. Abbreviations: / PEx = minutes and after exercise; /5 PEx = minutes and 5 after exercise; / PEx = minutes and after exercise; BP = blood pressure. at rest in of patients (.%). The remaining patient had isolated right coronary artery disease. She had an initial decrease in ESV, but showed an increase in ESV when the value at angina and the value minutes before angina were compared. The ESV increased in all patients during the exercise stage minutes before angina. There was a rebound increase in EF after angina, which was associated with a decrease in EDV and an even more precipitous decline in ESV. Group : CAD Patients Who Did Not Develop Angina The work load and duration of exercise varied in group patients. In all patients, exercise was stopped because of fatigue. The blood pressure and heart rate results are shown in table. As shown in table, there was no change in either the average EDV (. +. at rest vs. ± units at maximal exercise (NS), or the average EF (. at rest vs.5 at maximal exercise (NS). However, in four of these patients, the EF increased at least %, and three had a decrease in ESV. Again, a postexercise early rebound in EF was seen, associated with a greater proportional reduction in ESV than in EDV (see figure for comparative results). Discussion Studies of exercise have indicated that within certain limits, stroke volume remains relatively constant,5- although in severe exercise this may not be the case. By use of silver-tantalum markers, decreases in both the end-diastolic and end-systolic dimension during exercise have been observed.- These studies were performed in patients who required cardiac surgery for either congestive heart failure or valvular lesions, thereby limiting patient selection. Using a thermodilution technique in a series of patients with cardiac disease, Bristow et al. reported no consistent changes in EDV with exercise." Similarly, Gorlin et al. found little change in EDV by angiography during supine exercise, while ESV decreased. Recently, Crawford et al.' examined left ventricular internal dimensions by echocardiography in exercising normal subjects and found results similar to those of Gorlin et al. Few studies have been designed to assess the change in left ventricular volume in response to ischemia. Sharma et al. reported an increase in both EDV and ESV with a decrease in EF during angina with contrast ventriculography. His results for normals and patients without angina are similar to ours. He found an increase in EDV with angina, which may be due in small part to the volume load of two contrast injections and the added depressant effect of the dye. Jones et al. also describe a large increase in both EDV and ESV in patients who develop angina pectoris.' They show much more impressive changes in patients with more severe coronary disease. Their patients exercised erect, which might explain why their volume response results differed from ours, which were obtained during supine exercise. Additionally, our angina patients tended to have fewer coronary lesions (with respect to

5 RESPONSE OF LV VOLUME TO EXERCISE/Slutsky et al. 5 Downloaded from by on January, TABLE 5. Angina Patients Patient Rest PTA A PEx / PEx /5 PEx / End-diastolic volume Mean SD.5 =.. = -.5, End-systolic volume Mean - SD. i. Ejection fraction 5 Mean - SD. %o rest i = i All volumes are given in nondimensional radionucide units (see text). Abbreviations: PTA = exercise stage preceding anginal exercise stage; A = exercise stage during which angina occurred; PEx / = minutes and after exercise; PEx /5 = minutes and 5 after exercise; PEx / = minutes and after exercise i = absolute number of lesions) than did either Sharma's or Jones's patients. The method used in our study was count-dependent and uncorrected for radiotracer decay. Thus, we might underestimate volumes with longer studies. Variable individual count attenuation and error estimates between the radionuclide and angiographic methods might also enhance the differences between our study and those of the previously mentioned investigators. Borer and his co-workers have suggested that gated equilibrium radionuclide

5 CIRCULATION VOL, No, SEPTEMBER Downloaded from http://ahajournals.org by on January, TABLE.

6 5 CIRCULATION VOL, No, SEPTEMBER Downloaded from by on January, TABLE. Coronary Disease Patients Without Angina Heart rate Systolic BP Diastolic BP (beats/min) (mm Hg) (mm Hg) Rest - MEx 5 / PEx 5 /5 PEx / PEx All blood pressures were assessed with cuff sphygmomanometers. All values are - SD. Abbreviations: BP = blood pressure; MEx = maximal exercise; / PEx = minutes and after exercise; /5 PEx = minutes and after exercise; / PEx = minutes and after exercise. angiography can be used to separate patients with ischemic heart disease from normal subjects.' They have already shown that EF declines with the onset of anginal symptoms. In the present study we used the gated radionuclide approach to assess left ventricular volumes during and after supine bicycle exercise. We have previously validated this method relative to standard contrast angiography. In normal subjects, the EDV does not change significantly with exercise, while the ESV declines by an average of 5%, thereby accounting for the rise in EF. In patients who develop angina, the EF decreases because of an increase in the ESV, while the EDV remains unchanged. In patients with coronary disease who do not develop angina, the changes in volume tend to vary considerably, but the mean values for this group show little change in EDV, ESV or EF. In this group of patients with infarcts and akinetic segments there may be perfusion of fibrotic zones of myocardium rather than reversibly ischemic muscle. Thus, exercise-induced perfusion deficits might have little direct effect on fibrotic zones, but may depress more normal muscle. However, we cannot ascertain this from our data. In conclusion, the response of left ventricular volume to supine bicycle exercise shows significant variation between normal subjects and patients with various manifestations of ischemic heart disease. This method may be useful in determining the origin of atypical forms of chest pain and the response of the ischemic myocardium to various interventions. References. Borer JS, Bachrach SL, Green MV: Real-time radionuclide cineangiography in the noninvasive evaluation of global and regional left ventricular function at rest and during exercise in patients with coronary artery disease. N Engl J Med :,. Sharma B, Goodwin JF, Raphael MJ, Steiner RE, Rainbow RG, Taylor SH: Left ventricular angiography on exercise: a new method of assessing left ventricular function in ischaemic heart disease. Br Heart J : 5,. Pfisterer M, Schuler G, Ricci D, Swanson S, Gordon D, Slutsky R, Peterson K, Ashburn W: Profiles of left ventricular TABLE. Coronary Artery Disease Patients Without Angina PEx PEx PEx Patient Rest ME / /5 / End-diastolic volume Mean.. SD -. - End-systolic volume 5 Mean = SD Ejection fraction i i Mean = SD =±. i Mean % All ventricular volumes are expressed in nondimensional radionuclide units. Abbreviations: MEx = maximal exercise; PEx / = minutes and after exercise; PEx /5 = minutes and 5 after exercise; PEx / = minutes and after exercise. ejection fraction during exercise and the recovery period in normals and patients with CAD. (abstr) J Nucl Med :,. Slutsky R, Karliner J, Ricci D, Pfisterer M, Kaiser R, Gordon D, Peterson K, Ashburn W: Left ventricular volumes calculated by gated radionuclide angiography. (abstr) Circulation 5 (suppl II): -, 5. Rushmer RF: Constancy of stroke volume in ventricular response to exercise. Am J Physiol : 5,. Chapman CB, Fisher JN, Sprouse BJ: Behavior of stroke volume at rest and during exercise in human beings. J Clin Invest :,. Ross J Jr, Linhart JW, Braunwald E: Effects of changing heart

7 RESPONSE OF LV VOLUME TO EXERCISE/Slutsky et al. 5 I I CD *LL ca- CD LUJ - LUJ NORMAL (N=) CAD AND ANGINA (N= ) CAD WITHOUT ANGINA (N-=) z : I. i -J C-, Downloaded from by on January, =CD -C,, C,, LUJ LU -J C) gi- j C LU Ili u 5 ;I; i REST M Ex / I 5/ / REST ANGINA / I 5/ / I REST I M Ex / I 5/ I / vj REST M Ex / 5/ / REST ANGINA / 5/ / REST M Ex / 5/ / P Ex P Ex P Ex P Ex P Ex P Ex P Ex P Ex P Ex FIGURE. Ejection fraction, end-diastolic volume and end-systolic volumeare plottedforall threegroups. Volumes are expressed in nondimensional units. M Ex = point of maximal exercise; Angina = the point at which angina developed; / P Ex = minutes and after exercise; 5/ P Ex = minutes 5 and after exercise; / P Ex = = minutes and after exercise; CAD coronary artery disease. Angina was accompanied by new ST-segment depression >. m V. rate in man by electrical stimulation of the right atrium: studies at rest during exercise and with isoproterenol. Circulation : 5, 5. Vatner S, Franklin D, Higgins C, Patrick T, Braunwald E: Left ventricular response to severe exertion in the untethered dog. J Clin Invest 5: 5,. Harrison D, Goldblatt A, Glick G, Mason D, Braunwald E: Studies on cardiac dimensions in intact, unanesthetized man. Circ Res :,. Braunwald E, Sonnenblick E, Ross J, Glick G, Epstein S: An analysis of the cardiac response to exercise. Circ Res (suppl ) :, I I.L.-. ""A - -JL JL. Bristow J, Kloster F, Farrehl C, Brodheur M, Lewis R, Griswold H: The effects of supine exercise on left ventricular volume in heart disease. Am Heart J :,. Gorlin R, Cohen L, Elliott W, Klein M, Lang F: Effect of supine exercise on left ventricular volume and oxygen consumption in man. Circulation :, 5. Crawford M, Amon W: Echocardiographic evaluation of left ventricular performance during supine and bicycle exercise. (abstr) Am J Cardiol : 5,. Rerych S, Scholz P, Newman G, Sabiston D, Jones R: Cardiac function at rest and during exercise in normals and in patients with coronary artery disease. Ann Surg :,

Left ventricular response to exercise in coronary artery disease: relation to myocardial ischaemia and effects of nifedipine

European Heart Journal (1985) 6, 1025-1031 Left ventricular response to exercise in coronary artery disease: relation to myocardial ischaemia and effects of nifedipine W. F. SHEN*, G. S. ROUBIN*, C. Y.-P.