Cardiac response to exercise in patients with chronic aortic regurgitation

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25. Holt JM, Lambert EH: Heart disease as the presenting feature in myotonia atrophica. Br Heart J 26:433, 1964. 26. Black WC, Ravin A: Studies in dystrophia myotonica. VII. Autopsy observations in five cases. Arch Path01 44:176, 1947. 27. Kennel AJ, Titus JL, Merideth S: Pathologic findings in the atrioventricular conduction system in myotonia dystrophy. Mayo Clin Proc 49:838, 1974. 28. Thompson AMP: Dystrophic cordis myotonica studied by serial histology of the pacemaker and conducting system. Pathology 96:285, 1968. 29. Venco A, Savioti M, Begana D, Finardi G, Lanzi G: Noninvasive assessment of left ventricular function in myotonic muscular dystrophy. Br Heart J 40:1262, 1978. 30. Gottdiener JS, Hawley RJ, Maron BJ, Bertorini TF, Engel WK: Characteristics of the cardiac hypertrophy in Friedreich’s ataxia. AM HEART J 103:525, 1982. 31. Kovick RB, Fogelman AM, Abbasi AS, Peter JB, Peance ML: Echocardiographic evaluation of posterior left ventricular wall motion in muscular dystrophy. Circulation 52:447, 1975.

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32. Markiewicz W, Stoner S, London E, et al: Mitral valve prolapse in one hundred presumably normal females. Circulation 53:464, 1976. 33. Gottdiener JS, Sherber HS, Hawley RJ, Engel WK: Cardiac manifestations in polymyositis. Am J Cardiol 41:1141, 1978. 34. Isner JM, Hawley RJ, Weintraub AM: Cardiac findings in Charcot-Marie-Tooth disease. A perspective study of 68 patients. Arch Intern Med 139:1161, 1979. 35. Darsee JR, Miklozek CL, Heymsfield SB, Hopkins LC Jr, Wenger NK: Mitral valve prolapse and ophthalmoplegia: A progressive cardioneurologic syndrome. Ann Intern Med 92~735, 1980. 36. Gulotta SP, Gulco L, Padmanabhan V, Miller S: The syndrome of systolic click, murmur and mitral valve prolapse-a cardiomyopathy? Circulation 49:717, 1974. 37. Scampardonis G, Yang SS, Maranhao V, Goldberg H, Gooch AS: Left ventricular abnormalities in prolapsed mitral valve syndrome. Circulation 46:287, 1973.

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Rest and exercise measurements of left ventricular (LV) ejection fraction (EF) and volumes were obtained by radionuclide angiocardiography (RNV) in 30 patients with severe aortic regurgitation (AR). The ratio of peak systolic pressure to end-systolic volume was used as an index of contractility. Volumetric cardiac output (CO) averaged 11.7 + 3.8 L/min at rest and 18.4 & 5.6 L/min during exercise. Much individual variation occurred in LVEF and end-diastolic volume (EDV) responses to exercise, and there was no consistent change in these measurements. Resting hemodynamic parameters and clinical history correlated poorly with changes observed during exercise. An increase in heart rate was one mechanism used by all 30 patients to increase CO during exercise. An inverse relationship was defined between the change in myocardial contractility and the change in EDV during exercise. Patients with the greatest increase in contractility during exercise showed the greatest decrease in EDV. Less use of an exercise increase in contractility was associated with an exercise increase in EDV to meet the demand for greater CO. Therefore, exercise measurements of LV function provide unique information regarding the degree of impairment of the LV myocardium in these patients with chronic AR. (AM HEART J 104:85, 1982.)

Claude A. Peter, M.D., and Robert H. Jones, M.D. Durham, N.C.

Normal individuals can respond to increased cardiac output (CO) demand by an increase in heart rate (HR), left ventricular (LV) filling, and myocardial contractility or a decrease in afterload to the LV. From the Department of Surgery, Duke University Medical Center. This work was supported in part by National Institutes of Health Grant No. 20677. Received for publication July 10, 1981; accepted July 2.4, 1981. Reprint requests: Robert H. Jones, M.D., P.O. Box 2986, Duke University Medical Center, Durham, NC 27710.

0002.8703/82/070085

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Chronic aortic regurgitation (AR) results in an increased resting end-diastolic volume (EDV) that may impose a higher LV preload. Consequently, resting total LV output is increased. Adequate increase in forward CO during exercise in these individuals is suggested by the fact that they frequently remain very active and relatively asymptomatic for a long period of time.’ Whether a large resting LVEDV in these patients alters use of the other mechanisms to increase CO and how these alterations relate to clinical history have not been

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documented. The purpose of this investigation was to document the hemodynamic changes during exercise and to examine the mechanisms used to increase CO in patients with AR. METHODS Patient population. The study group consisted of 30 patients with AR demonstrated by cardiac catheterization who underwent radionuclide angiocardiography (RNV) during the period from July 1, 1977, to March 1, 1980. There were 19 men with a mean age of 45 f 17 years (range, 8 to 68) and 11 womenwith a mean ageof 40 -t 16 years (range, 12 to 62); p = NS. The etiology of AR included syphilis in two patients, rheumatic fever in seven and bacterial endocarditis in two. One patient had congenital AR, and AR was the complication of aortic valvulotomy for stenosisin another patient. History did not suggest any etiology in 17 patients. Two patients were asymptomatic (NYHA Class I). Among the 28 patients who were symptomatic, 12 had angina and 16 did not. Twenty-six patients presented with a history of past or present congestive heart failure (CHF). ECG showedLV hypertrophy in every patient, and normal sinus rhythm was present in all but one patient who was in atria1 fibrillation. Every patient had cardiomegaly on chest radiograph. At the time of cardiac catheterization peakto-peak aortic valvular systolic gradient was lessthan 20 mm Hg in all patients. All patients had severe AR according to previously justified criteria presently used at this institution.* Three patients had trace mitral regurgitation and none had mitral stenosis.Coronary arteriography wasperformed in all patients with a history of angina pectoris or an age greater than 25 years. Eight patients had hemodynamicaly insignificant coronary artery disease (CAD) with a stenosis less than 25% of the luminal diameter of the artery, and the remaining patients had normal coronary arteries. Patient subgroups. Because resting hemodynamic conditions might have beenpredictors of the magnitude of changeselicited by exercise in LV function, we examined the effect of resting HR, ejection fraction (EF), and EDV on subsequent change in these three variables during exercise. The entire population was divided into subgroups to assessthe influence of duration of symptoms, severity of symptoms, character of symptoms, and age on the LV responseto exercise. The subgroup reflecting the shorter duration of symptoms was comprised of 16 patients with a mean age of 37 + 17 years. Two of these patients were asymptomatic, and 14 had beensymptomatic for less than 2 years. The subgroup with a longer duration of symptoms wascomprisedof 14patients with a mean ageof 50 + 12 years (p < 0.02) who were all symptomatic for more than 2 years. The subgroup with the less severe symptoms was comprised of 12 patients with a mean age of 35 + 17 years who had NYHA class I or II angina or CHF. The subgroup with greater severity of symptomswascomposedof 18patients with a meanageof 49 + 13 years (p < 0.05) who had NYHA classIII to IV

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angina or CHF. To evaluate the influence of a history of angina on exercise LV function, the 12 patients with angina were comparedto the 18 patients who were free of chest pain. Finally two groupswere separatedby age into a subgroupof 15 patients who were younger than 40 years old (mean, 30 +- 10 years) and a subgroup of 15 patients who were 40 years or older (mean, 57 * 8 years). Data acquisition. After informed consentwas obtained from eachpatient, a 20-gaugeTeflon catheter wasinserted into the external jugular vein. An eight-lead ECG (I, II, III, aV,, aVL, aV,, Vg,V,) wascontinuously observedon an oscilloscope display, and representative tracings were recorded each minute throughout the study. Systemic arterial pressure(BP) wasmonitored by sphygmomanometry. All RNVs were performed using a computerized multicrystal gamma camera (Baird Corporation System Seventy-Seven) equipped with a l-inch parallel hole collimator. A 15 mCi technetium-99m pertechnetate injection was made for each measurementwith patients seated in the erect position. Counts were recorded from an anterior position of the detector of a framing interval of 25 msecfor 1 minute. After completion of a rest study, dynamic exercise tests were performed using an isokinetic bicycle ergometer (Fitron). HR, BP, and ECG were monitored during the erect exerciseand subsequentrecovery period until both returned to baselinevalues. Exercise wasbegun at a 200 kpm/min workload, and the workload was increasedby 100 kpm/min every minute until a study end point wasachieved. End points usedto time the injection for the exercise study included achievement of target HR for age (85% of maximal predicted HR for age), onset of severefatigue or angina, and occurrence of arrhythmia. Data processing. The RNVs were analyzed as previously described.3-5Observed counts were corrected for variation in detector efficiency and electronic dead time lossof the instrument. Data obtained during exercisewere also corrected for background activity which was determined by a 15-secondmeasurementobtained just prior to the study. Data recorded over the LV region of interest defined a high frequency time-activity curve that had sufficient time resolution to reflect count changeswhich occur within individual cardiac cycles.An averagecardiac cycle was obtained by summing counts from several contractions recorded at the time when the radioactivity was maximal within the chamber. Background counts were subtracted by defining the spatial distribution of radioactivity just before the tracer filled the LV and multiplying this image by an intensity factor derived to describe the average change in counts outside the LV during the levophase. LVEF was determined from the background corrected representative cycle as (ED counts - ES counts)/ED counts where ED = end-diastole and ES = end-systole. The 21% isocount contour of the ED image was used to calculate the EDV in milliliters5 The area of the ED image was obtained by planimetry, and the length of the major axis was measuredusing a sonic digitizing device (Graph-Pen) coupled to a PDP 11/45 computer. The EDV calculated by the area-length method of Sandler and Dodge6was multiplied by EF to

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provide the stroke volume (SV) which was multiplied by HR to give CO. Validity of RNV technique. The radionuclide measurementsusedin this study have previously been validated in our laboratory.5,7Becausepatients with AR have a larger EDV than individuals without left-sided valvular regurgitation, radionuclide volume measurementmight be inaccurate in these patients. Radionuclide studies were obtained within 48 hours of the time of cardiac catheterization in 19 patients of the study population. The RNV EDV was compared to that measuredby biplane contrast angiography. Individual variations in EDV measuredby the two techniques can be related to the fact that these patients were not controlled for positioning or HR. Despite these differences, data obtained by both techniques compared quite satisfactorily (r = 0.79) (Fig. 1). Index of contractility. Because EF is dependent on preload and afterload, we used the ratio of peak systolic pressure to end-systolic volume (ESV) to describe the contractile state of the myocardium. Previous studies in experimental animalss,9and in patients’O~l’have shown that this index is relatively independent of preload and afterload of the LV. Systemic BP was measured each minute during the exercise period, and showeda consistent increase during the entire exercise period. BP recorded immediately after radionuclide injection was used to derive the exercise contractility index and mean BP by adding one third of the pulse pressure to diastolic pressure. Statistical analysis. Individual changes from rest to exercise were analyzed using Student’s paired t test. Group comparisonswere made by analysis of variance. Resting hemodynamicscompared to subsequenthemodynamic changesduring exercisewere computed as continuousvariables using a linear least-squareregressionanalysis. P values lessthan 0.05 were consideredsignificant. RESULTS LV response to exercise in all 30 AR patients. Mean arterial BP was 86 * 14 mm Hg (range, 60 to 120) at rest and 102 f 16 mm Hg (range, 67 to 137) during

exercise (p < 10m4). HR averaged 84 f 16 bpm (range 68 to 124) at rest and 148 t- 19 bpm (range 110 to 180) during exercise (p < 10e4). An inverse relationship was identified between resting HR and maximum HR achieved during exercise (r = -0.59). No correlation was found between resting HR and changes in EF (r = 0.12) or changes in EDV (P = 0.13) during exercise. LVEF averaged 0.51 + 0.15 (range 0.19 to 0.88) at rest and 0.51 + 0.18 (range, 0.22 to 0.79) during exercise (Fig. 2). Resting EF could not be used to predict any rest to exercise changes. The EDV for the group was 308 k 149 ml (range, 99 to 773) at rest and 281 +- 127 ml (range, 114 to 605) during exercise (Fig. 2). Resting EDV was unrelated to HR response (r = -0.09) or change in EF (r = -0.01) during exercise. A poor inverse

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1. Comparisonof end-diastolic volume (EDV) measured by contrast (C) and radionuclide CR) angiocardiography in 19 patients with severeaortic regurgitation. Fig.

relationship existed between resting EDV and its change during exercise (r = -0.53). ESV averaged 164 * 118 ml at rest and 153 f 111 ml during

exercise (Fig. 2). SV was 144 +- 56 ml at rest and decreased to 128 k 44 ml with exercise (p < 0.05) (Fig. 2). Volumetric CO was 11.7 f 3.8 L/min (6.723.1) at rest and averaged 18.4 f 5.6 L/min (range, 9.2 to 30.4) during exercise (p < 10m4). Relation of LV function to clinical history. The study population was divided into subgroups according to duration, severity, and nature of symptoms and age. Comparison of the pairs of each of the four subgroupings showed no difference in resting and exercise HR or change in HR during exercise. The 16 patients symptomatic for less than 2 years were younger than the 14 symptomatic for more than 2 years. Resting and exercise LV function measurements were comparable in the two groups, and there was no difference in the changes observed from rest to exercise. The 12 patients having symptoms NYHA class I to II were younger than those having symptoms NYHA class III to IV. However, analysis of LV function did not show any difference at rest and exercise in EF, volumes, and in CO or any difference in rest to exercise changes. The 12 patients with a history of angina had a resting EDV averaging 218 +- 50 ml that remained unchanged during exercise. The patients without angina had a higher resting EDV (369 +- 163 ml) (p < 10e2) which decreased to 317 f 139 ml during exercise (p < 0.05). Resting ESV (98 -+ 31 ml), SV (119 k 32 ml), and volumetric CO (9.3 f. 2.5 L/min) were also lower in the patients with angina when compared to ESV (208 k 135 ml) (p < lo-*), SV (160 + 63 ml) (p < 0.05), and CO (13.4 -t 3.7 L/min)

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2. Cardiac responseto exercise in 30 patients with severe aortic regurgitation.

(p < lo-*) in the nonanginal group. A decrease in ESV to 1’78 -t 125 ml during exercise @ < 0.05) and a higher exercise CO (20.7 t- 5.5 L/min) was achieved by the patients without angina (p < 0.05), whereas ESV in patients with angina did not change, and exercise CO increased only to 15.7 + 4.7 L/min. However, no difference in rest and exercise EF or change in EF was noted between these two patient groups. Examination of exercise response in two additional subgrou@s,identified according to magnitude of CHF symptoms, revealed that patients classified CHF III to IV had higher resting EDV than those with classI to II. However, the difference was not statistically significant (p = 0.07). The rest EF was lower in those with CHF class III to IV, but agAin this was not significant (p = 0.07). Comparison of the El? response to exercise between these two subgroups also showed no statistical difference (p = 0.06). The 15 patients younger than 40 years did not

differ from those 40 years or older in rest or exercise ESV, SV, or CO. Resting EF was also similar. However, younger patients achieved a higher EF at exercise (0.58 -+-0.17) than older patients (0.43 r 0.16) (p < O.OZ),and were able to decrease EDV by 52 ml (p < 0.02) despite a resting value similar to that of the older group. LV mechanisms used to increase CO. In order to examine the mechanisms used by the heart to increase CO, change HR, EDV, and contractility index were expressed in percent of the corresponding resting value. No relationship existed between HR increase during exercise and the change in contractility (r = -0.40) or change in EDV (r = -0.42). A definite inverse correlation existed between changes in contractility and change in EDV (F = -0.76). Because changes in HR, EDV, and contractility occur in combination with each other, a three-dimensional plot of these changes was constructed in order to provitka simultaneous view of

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the change in each of these three mechanisms for all 30 patients (Fig. 3). Patients with an increase in contractility during exercise consistently decreased their EDV. As use of contractility decreased, achievement of CO increase tended to be a result of greater EDV. Younger patients tended more to increase myocardial contractility and to decrease EDV during exercise, than did the older patients, but a large amount of overlap was observed between these two patient groups. Patients with a history of angina did not exhibit a specific combination of mechanisms to increase CO during exercise.

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DISCUSSION

In patients with AR, the LV responds by dilatation and hypertrophy. These two functional adaptive changes are reversible after removal of the volume overload if the disease is of short duration.12 However, with the passage of time and progressive structural changes within the myocardium,*3s l* insidious LV damage occurs which makes valve replacement for AR less likely to provide a good result.15* I6 The remarkable tolerance to the disease for a long period of time indicates that the heart activates adequate compensatory changes to maintain a normal CO at rest and to elicit an appropriate increase in forward output during exercise.‘, l7 Rest hemodynamics insensitive to early LV dysfunction in AR. Measurements of LV function at rest

describe mechanisms used by the heart to maintain CO while the ventricle functions at a high volume load.‘8-20 In many patients, LVEF remains normal, and an elevated EDV is the only abnormality present at rest. Therefore the heart in AR appears to respond to chronic volume overload by an enhanced use of the Starling mechanism at rest with little change in its resting contractility. Consequently, hemodynamics measured at rest are unlikely to provide a sensitive indicator of early LV dysfunction. By contrast, during exercise augmentation in contractility is an important mechanism used by the heart to increase CO. Chronic AR might cause myocardial damage and a progressive decrease in the capability to augment cardiac contractility during stress. Exercise hemodynamics provide assessment of LV function in AR. In this study we attempted to describe

mechanisms by which patients with severe, isolated AR increase CO during exercise. All patients came to cardiac catheterization to assist clinical management, and 28 out of 30 were symptomatic, so that the patient group could be characterized as representing an advanced stage of the disease. The technique used was first transit RNV, which provides

Fig. 3. Three-dimensional

representation of percent changes from rest to exercise in heart rate, end-diastolic volume, and index of contractility in 30 patients with aortic regurgitation. accurate and reproducible measurements of LV function.“vz2 The short time of data acquisition allows study of patients in a natural erect position at rest and during intense bicycle exercise.23 Ideally, one would like to measure regurgitant flow in order to examine the distribution of forward and regurgitant output at rest and during stress. Although previous investigators have devised approaches for quantitation of left-sided valvular regurgitationt4 we have not attained sufficient accuracy and reproducibility of radionuclide techniques to confidently measure regurgitant flow. Therefore, this study does not describe changes in regurgitant or forward flow as a result of exercise stress. However, measurements of EF and volumes at rest and during exercise represent the total workload of the LV and therefore provide useful information on the functional state of the myocardium. Rest LVEF inadequate predictor of AVR results in chronic AR. The large EDV and SV in the study

population typically describe the high preload state imposed on the LV by AR.18 Although all of the 30 patients in this study had severe AR defined by cardiac catheterization criteria, wide variation was observed in individual LVEF and volume measurements at rest and during exercise. Resting hemodynamics correlated poorly with changes observed during exercise. This finding corroborates and extends previous observations made on ejection phase indices that were found not to be significantly altered during chronic volume overload.25-28 Moreover, patients with mildly depressed resting EF are not prevented from achieving an appropriate exer-

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cise EF. In a series of 93 patients with aortic valve disease, O’Toole et a1.2s showed that a reduced preoperative resting EF did not markedly increase early or late mortality after aortic valve replacement (AVR). Clark et a1.3o observed that all 17 patients who survived AVR for isolated AR had either maintained or improved resting function after surgery despite a resting EF less than 0.50 before operation. Patient age better than symptomatology in predicting LV function in chronic AR. The fact that resting EF

alone is an inappropriate descriptor of LV reserve emphasizes the importance of exercise measurements. The most striking finding in this study is that exercise LV function related very poorly to clinical history. The discrepancy between symptoms and the degree of hemodynamic dysfunction has been documented by Goldschlager et a1.31 in 24 patients with AR studied preoperatively. These investigators observed at serial cardiac catheterizations that abnormally high pulmonary artery wedge pressure elicited by exercise preceded the onset of clinical symptoms. They also noted that patients below age 40 years tolerated AR remarkably well when compared to those older than 40 years. In the present study, age was a better predictor of LV function during exercise than any aspect of clinical history, a fact which suggests that age reflects the duration of myocardial insult more reliably than does clinical history. Angina unrelated to exercise LVEF in chronic AR. An unexpected finding in the present study is that a history of angina1 pain did not correlate with a decrease in LVEF during exercise. However, EDV in this group of patients was significantly lower than in patients without symptoms of angina, suggesting either a more recent disease or some more basic difference in the response of LV to AR. Subendocardial ischemia induced by an elevated end-diastolic pressure (EDP) may cause angina in these patients,32 rather than a decrease in the total transmural diastolic coronary artery flo~.~~ Therefore the changes in LV function commonly observed during exercise in patients with CAD might not be observed in patients with global subendocardial ischemia. However, LV pressure measurements were not obtained during exercise in this study, and there was no difference in the resting LVEDP measured at catheterization in the two patient groups. Conclusion. Afterload to the LV was not measured by the technique employed. Alteration of this factor during exercise may substantially influence LV performance and account for some of the individual variations in EF response. Therefore more detailed

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analysis of the mechanism of LV response to exercise in these patients needs to be presented. However, this study clearly demonstrates that patients with adequate myocardial reserve did not show a need for additional filling of the LV during exercise. Patients who lost the ability to increase myocardial contractility during exercise demonstrated an increase in LVEDV to meet increased CO demands. Previous studies have shown that failure to increase EF during exercise was a sensitive indicator of dysfunction of the LV in patients with AR.34 The present study corroborates these observations and, in addition, depicts a continum in LV dysfunction among these patients. Therefore assessment of the cardiac response to exercise is an important approach to describe the functional status of the LV myocardium in patients with chronic AR. REFERENCES

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25. Ross J Jr, McCullagh WH: Nature of enhanced performance of the dilated left ventricle in the dog during chronic volume overloading. Circ Res 30:549, 1972. 26. Taylor RR, Hopkins BE: Left ventricular response to experimentally induced chronic regurgitation. Cardiovasc Res 6:404, 1972. 27. Ross J Jr: Adaptations of the left ventricle to chronic volume overloading. Circ Res 35(suppl 11):64, 1974. 28. Rankin LS, Moos S, Grossman W: Alterations in preload and ejection phase indices of left ventricular performance. Circulation 51:910, 1975. 29. O’Toole JD, Geiser EA, Reddy PS, Curt& EI, Landfair RM: Effect of preoperative ejection fraction on survival and hemodynamic improvement following aortic valve replacement. Circulation 58:1175, 1978. 30. Clark DG, McAnulty JH, Rahimtoola SH: Valve replacement in aortic insufficiency with left ventricular dysfunction. Circulation 61:411, 1980. 31. Goldschlager N, Pfeifer J, Cohn K, Popper R, Selzer A: The natural history of aortic regurgitation. A clinical and hemodynamic study. Am J Med 54:577, 1973. 32. Buckberg GD, Fixler DE, Archie JP, Hoffman JIE: Experimental subendocardial ischemia in dogs with normal coronary arteries. Circ Res 30~67, 1972. 33. Wegria R, Muelheims G, Golub JR, Jerissaty R, Nakano J: Effect of aortic insufficiency on arterial blood pressure, coronary blood flow and cardiac oxygen consumption. J Clin Invest 37:471, 1958. 34. Borer JS, Bacharach SL, Green MV, Kent KM, Henry WL, Rosing DR, Seides SF, Johnston GS, Epstein SE, Mack B: Exercise-induced left ventricular dysfunction in symptomatic and asymptomatic patients with aortic regurgitation: Assessment with radionuclide cineangiography. Am J Cardiol 42:351, 1978.