Effects of Exercise on Left Ventricular Volume and Output Changes in Severe Mitral Regurgitation

Effects of Exercise on Left Ventricular Volume and Output Changes in Severe Mitral Regurgitation* A Radionuclide Angiographic Study Carl] Laoie, M.D.;t James B. Lam, M.D.; and Raymond] Gibbons, M.D.

Symptom-limited supine bicycle exercise with radionuclide angiography was performed on II patients with severe mitral regurgitation (who were not receiving vasodilators), to assess changes in left ventricular volume, regurgitant fraction, forward Rowand regurgitant Rowduring exercise. All patients were in normal sinus rhythm with a normal resting ejection fraction (>0.50). During exercise, the enddiastolic volume index, end-systolic volume index, ejection fraction, and regurgitant fraction of the left ventricle did not change signi6cantly. The forward cardiac index increased by 86 percent (p
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patients with severe mitral or aortic regurM anygitation have symptoms of dyspnea with exer-

rate and decrease in regurgitant fraction leads to an increase in forward cardiac index, which helps preserve exercise capacity in patients with aortic regurgitation. Compared to aortic regurgitation, data on the effects of exercise on left ventricular volume and forward and regurgitant output changes in patients with severe mitral regurgitation (MR) are sparse. In one study of 53 patients with chronic, hemodynamically severe mitral regurgitation, there were no significant exercise changes in left ventricular ejection fraction. II However, no volume measurements were performed in this study. In a small study of seven patients with severe mitral regurgitation, the left ventricular ejection fraction and regurgitant fraction decreased significantly with exercise," Three of the seven patients in this study, however, had significant resting left ventricular dysfunction, and two patients had mild mitral stenosis. In the present study, we utilized radionuclide angiography to determine left ventricular volumes, regurgitant fraction, and forward and regurgitant Howat rest and during exercise in 11 consecutive patients with isolated severe mitral regurgitation.

·From the Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota. tPresentlyat the Ochsner Clinic, New Orleans. Presented in part at the 53rd Annual Scientific Assembly, American College of Chest Physicians, Atlanta, October 26-30, 1987, and at the 69th Annual Session, American College of Physicians (Associate's Program), New York, March 1988. Manuscript received March 17; revision accepted July 10. Reprint requests: Dr. Gibbons, Mayo Clinic, Rochester; Minnesota 55905

Study Population

cise. Numerous studies have demonstrated the accuracy of gated equilibrium radionuclide ventriculography for measuring the severity of valvular regurgitation.!" and radionuclide ventriculography has frequently been used to assess the exercise changes in left ventricular volume, ejection fraction, and regurgitant fraction in patients with aortic regurgitation.>" In general, patients with severe aortic regurgitation have dilated left ventricles (as determined by elevated end-diastolic and end-systolic volumes); in those patients with normal left ventricular ejection fraction at rest, there is usually no significant change in end-diastolic volume, stroke volume, or ejection fraction during maximal dynamic exercise, but the regurgitant fraction decreases significantly. Shortening the diastolic filling period due to tachycardia appears to be an important mechanism for the reduction in regurgitant fraction with high levels of supine bicycle exercise." In fact, tachycardia-induced reduction in regurgitant fraction in response to rapid atrial pacing has been demonstrated in patients with aortic regurgitation. 10 Therefore, an increase in heart

METHODS

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The study population consisted of 11 consecutive patients with severe chronic mitral regurgitation by clinical criteria who underwent supine rest and exercise radionuclide angiography for clinical indications at the Mayo Clinic over a two-year period. There were seven men and four women, ages 43-81 (mean 58± 11). Eight patients had mitral valve prolapse, two had rheumatic heart disease, and in one patient the severe MR resulted from subacute bacterial LVVolumeand Output in SevereMitral Regurgitation (Levie, Lam, Gibbons)

endocarditis. All had mild-to-moderate symptoms by clinical criteria (four were considered New YorkHeart Assocation class 1, four were in class 2, and three were in class 3). The following were grounds for exclusion: 1) other valvular heart disease; 2) known coronary artery disease (prior myocardial infarction or definite angina pectoris); 3) congenital heart disease; 4) significant conduction system disease (bundle branch block or pacemaker dependency); 5) atrial or ventricular dysrhythmias; 6) resting left ventricular ejection fraction sO.50; and 7) resting regional wall motion abnormalities. Most importantly, none of these patients was receiving vasodilators at the time of the study or during the month prior to the study, although four patients were receiving digitalis preparations, four diuretics, two anti-dysrhythmic therapy, and one was taking a very low dose of propranolol (20 mg daily).

Exercise Protocol The patients were exercised by supine bicycle ergometry (Quinton Instruments). Three ECG leads were monitored continuously and a standard IS-lead ECG was recorded every minute to monitor ST-segment changes. The blood pressure in the right arm was measured by cuff every three minutes. The standard exercise began at a workload of 300 kg-m/min and was increased every three minutes in increments of 300 kg-m1min. The protocol was modified occasionally at the discretion of the monitoring physician. Symptomlimited exercise tests were performed with exercise terminated at one of the following end-points: 1) moderate angina; 2) serious dysrhythmias; 3) marked dyspnea or fatigue; or 4) 2:2 mm STsegment depression.

Radionuclkle Angiography Erythrocytes were labeled with 30 mCi of technetium-99m (88IIifc) by using the in vivolJ or modified in vioo procedure." Acquisition was gated to the R-wave of the ECG and collected at 16 frames per cardiac cycle. Anterior, left lateral, and left anterior oblique (LAO) radionuclide angiograms were performed at rest; the LAO view which allowed maximum separation of left and right ventricles was used. Resting and exercise LAO views were performed with a parallel hole collimator with a caudal tilt of 15° and repeat LAO views were obtained during the last two minutes of each threeminute exercise stage. Radionuclide data were processed by using a commercially available computer system and software (Medical Data Systems) and previously reported teehniques.v-" A second derivative technique was employed to identify the left ventricular region of interest in each frame. A background was chosen 5 pixels lateral to the left ventricular region of interest. Ejection fraction (EF) was calculated at rest and at maximal exercise from a background-corrected left ventricle counts vs time curve using a variable region of interest. Wall motion was accessed at rest in the anterior, left lateral and LAO positions. Wall motion at rest and maximal exercise was accessed subjectively in the LAO projection as the consensus of two experienced observers (one staff cardiologist and one staff nuclear medicine physician). An exercise regional wall motion abnormality was considered present if wall motion in any segment worsened significantly from rest to exercise. End-diastolic and end-systolic volumes of the left ventricle were determined using a count-based method." A blood sample (10 ml) was obtained immediately after exercise for cardiac volume determination. The count activity in the blood pool was accessed directly on the gamma camera for two minutes. In order to determine left ventricular volume, left ventricular count activities were corrected for blood pool activity and time. A regression equation has been developed comparing the volume units determined in this fashion with volumes determined by contrast ventriculography. Correlation coefficients for end-diastolic and end-systolic volume determined in this fashion compared with those determined by contrast ventriculography were previously reported to be 0.85 and 0.94

respectively, with standard errors of 28 and 18 ml, respectively. 11 End-diastolic volume index (EDVI) and end-systolic volume index (ESVI) were determined by dividing the end-diastolic volume and end-systolic volume by the body surface area. These volumes are used to calculate the stroke volume index (SVI) and cardiac index (CI) for the left ventricle by the following equations: SVI (total) = EDVI - ESVI CI (total) = SVI (total) x Heart Rate

Eq 1 Eq 2

Regurgitant fraction (RF) was obtained at rest and after maximal exercise. The raw clinical data were filtered using a 9-point temporal and 9-point smoothing algorithm. Standard computer software was then employed to produce phase and amplitude images. The amplitude image was visually inspected, and the left ventricle (LV) and right ventricle (RV) are outlined to best separate the ventricles from the atria. These outlines are visually compared with the first frame of the smoothed raw data, and obvious discrepancies are corrected manually by using a joystick. The fixed LVand RVregions of interest are than applied to the raw data. The maximum and minimum counts are obtained for both the RV and LV and are used to calculate the stroke counts for each ventricle. The following equations were used: RF LV stroke counts - RVstroke counts Eq3 LV stroke counts SVI (reg) = SVI (total) x RF Eq 4 SVI (for) = SVI (total) x (1- RF) Eq 5 Regurgitant ftow = SVI (reg) X heart rate Eq 6 In our laboratory, regurgitant fraction of 25 percent represents the upper limit of normal (approximately two standard deviations above the mean); values between 25-30 percent are considered "borderline," 31-40 percent are consistent with mild mitral regurgitation, 41-50 percent are consistent with moderate MR, and values exceeding 50 percent are considered severe MR. The interobserver variability for determination of RF using these methods is less than 5 percent when performed by experienced physicians (Hauser M, Gibbons R, unpublished data). Statistical Analysis Comparison of the hemodynamics and volume and output changes at rest and during exercise were analyzed using a paired t-test. Univariate correlations were performed for the exercise-induced changes in forward and regurgitant ftows. RESULTS

The resting and exercise data of our patients are shown in Table 1. All patients had normal sinus rhythm and a resting left ventricular ejection fraction >0.55. Only one patient (No 6) has a regurgitant fraction <50 percent (46 percent). In general, these patients exercised to a reasonable workload (mean 664 ± 273 kg-m/ min). Three patients, however, achieved peak workloads less than 600 kg-m/min (200, 300, and 400 kgm/min, respectively). Only one patient (No 5) developed regional wall motion abnormalities with exercise, consisting of only mild hypokinesis in the inferoapical area. In this patient, the EF dropped from 0.71 at rest to 0.63 with exercise, but the RF also dropped from 53 percent at rest to 39 percent with exercise. Three additional patients had significant falls (>.05) in EF with exercise, but none had regional wall motion abnormalities. The exercise EF dropped below 0.50 in only one patient (No 2), from 0.59 at rest to 0.48 CHEST I 96 I 5 I NOVEMBER, 1989

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In patients with severe chronic mitral regurgitation, predominant early symptoms frequently include lassitude, fatigue, generalized weakness, and exerciseinduced dyspnea, which are felt to reflect a low cardiac output as a result of a large regurgitant volume of blood ejected into an enlarged left atrium." In contrast to the data available for aortic regurgitation, there are few data on left ventricular volume or forward and regurgitant flowat rest and during exercise in patients with severe mitral regurgitation. The patients in our study all had severe mitral regurgitation, without other valvular heart disease or suspected coronary artery disease. In addition, patients in the present study had "normal" resting systolic function, as determined by resting ejection fraction measurements. Due to favorable loading conditions in MR, however, patients with a normal resting LVVolume and Output In sew... Mitral Regurgitation (Lavle, Lam, Gibbons)

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ejection fraction may have significantly reduced overall contractility, when measured by a preload independent indicator such as the end-systolic stress/endsystolic volume index.!" Despite a resting regurgitant fraction that averaged 63 percent, resting forward cardiac index was reasonably maintained (mean of2.9 Umin/m2) via marked left ventricular dilatation (mean EDVI of 155 ml/m" with 65 ± 13 rnl/m"being the mean value in our laboratory) and hyperdynamic resting left ventricular function (mean resting ejection fraction of 0.69). Although there was considerable variability in ejection fraction changes with exercise, mean resting and exercise ejection fraction did not differ significantly in our patients, which is in agreement with a prior large study. 11 In normal individuals, systemic vascular resistance

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(SVR) usually falls markedly by 60-80 percent during maximal dynamic exercise.P' A significant fall in SVR during exercise in patients with severe mitral regurgitation could be expected to produce an effect similar to that produced by vasodilators-a fall in SVR should result in a decrease in regurgitant fraction with an associated increase in forward cardiac flow. A prior small study demonstrated that regurgitant fraction declined with exercise in patients with MR.8 Unlike our study, this prior report included patients with low resting ejection fraction (three of seven patients) and other cardiac diseases (two of seven had mitral stenosis with uncertain coronary status). Our study did not demonstrate any significant change in regurgitant fraction with exercise. Similar to the ejection fraction and regurgitant

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CHEST I 96 I 5 I NOVEMBER, 1989

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fraction response, left ventricular end-diastolic volume index and end-systolic volume index did not change significantly with exercise. In a recent study of normal patients in our laboratory, stroke volume index increased by 10 percent in both males and females during maximal supine bicycle exercise." In contrast to these normal patients, total stroke volume index declined by 8 percent with exercise in our study patients, and forward stroke volume index did not change. Therefore, our patients with severe MR were totally dependent on their heart rate response to increase forward cardiac index during dynamic exercise. Although the regurgitant stroke volume index declined by 12 percent with exercise, the 87 percent increase in the heart rate accounted for a marked, 64 percent increase in the regurgitant How (mean of 8.2 L'min/m''), which probably contributes to the dyspnea experienced during exercise in many patients with severe mitral regurgitation. There are several limitations of the present study First, a parallel hole, rather than a slant hole, collimator was used in the present study; and the regions of interest on the left and right ventricles were fixed. Using this technique, it is sometimes difficult to completely separate the left ventricle from an enlarged left atrium. This should not cause a significant problem, however, when comparing the rest and exercise studies of an individual patient, although the effects of exercise on left atrial size and volume are not well known. In addition, left atrial overlap should cause underestimation, rather than overestimation, of the regurgitant fraction. Second, there is often substantial right atrial-right ventricle overlap in the LAO position. As a result, equilibrium radionuclide angiography generally underestimates right ventricular ejection fraction and right ventricular stroke counts, resulting in a systematic error and a non-zero regurgitant fraction in normal Individuals.P Third, although none of our patients had evidence of other valvular heart disease, undetected significant regurgitation of the aortic or right sided valves could decrease the validity of these radionuclide measurements. Finally, there may be some degree of selection bias, since the physicians caring for these patients felt that they were well enough to undergo an exercise radionuclide angiographic study for clinical reasons. Despite these limitations, we feel that the present study suggests that there are no significant changes in left ventricular ejection fraction, regurgitant fraction or end-diastolic or end-systolic volumes with maximal supine bicycle exercise in patients with isolated chronic severe mitral regurgitation. In order to increase forward How during supine dynamic exercise, these patients with severe MR are totally dependent on an increase in heart rate, with no change in the forward stroke volume index. This suggests that any 1090

blunting of the heart rate response, due to beta-or calcium-entry blocking agents or sinus node dysfunction, could lead to severe incapacitation in this group of patients. In addition, our data indicate that there is a marked increase in regurgitant How during exercise, which presumably contributes to dyspnea. Although the techniques that we used did not allow for reliable measurement of right ventricular ejection fraction, recent data indicate that right ventricular resting and exercise ejection fractions are considerably depressed in patients with severe mitral regurgitation, even when left ventricular function remains relatively normal.P Long-term studies assessing right and left ventricular function at rest and during exercise by radionuclide angiography, including the response to vasodilators, may help further define the natural history of patients with severe mitral regurgitation. REFERENCES

1 Sorenson SG, O'Rourke RA, Chaudhari TIC Noninvasive quantitation of valvular regurgitation by gated equilibrium radionuclide angiography. Circulation 1980; 62:1089-98 2 Lam ~ Pavel 0, Byrom E, Sheikh A, Best 0, Rosen K. Radionuclide regurgitant index: value and limitations. Am J Cardioll981; 47:292-98 3 Urquhart J, Patterson RE, Packer M, Goldsmith SJ, Horowitz SF, Litwalc R, et al: Quanti6cation of valve regurgitation by radionuclide angiography before and after valve replacement surgery. Am J Cardioll981; 47:287-91 4 Nicod ~ Corbett JR, Firth BG, Dehmer GJ, Izquierdo C, Markham R~ et al. Radionuclide techniques for valvular regurgitant index: comparison in patients with normal and depressed ventricular function. J Nucl Med 1982; 23:763-69 5 Steingart RM, Vee C, Weinstein L, Scheuer J. Radionuclide ventriculographic study of adaptations to exercise in aortic regurgitation. Am J Cardioll983; 51:483-88 6 Dehmer GJ, Firth BG, Hillis LD, Corbett JR, Lewis SE, Parkey 1M; et al. Alterations in left ventricular volumes and ejection fraction at rest and during exercise in patients with aortic regurgitation. Am J Cardioll981; 48:17-27 7 Peter CA, Jones RH. Cardiac response to exercise in patients with chronic aortic regurgitation. Am Heart J 1981; 104:85-91 8 Henze E, Schelbert HR, Wisenberg G, Ratib 0, Schon H. Assessment of regurgitant fraction and right and left ventricular function at rest and during exercise. A new technique for determination of right ventricular stroke counts from gated equilibrium blood pool studies. Am Heart J 1982; 104:953-62 9 Gerson MC, Engel PJ, Mantil JC, Bucher PO, Hertzberg VS, Adolph RJ. Effects of dynamic and isometric exercise on the radionuclide-determined regurgitant fraction in aortic insufficiency. J Am Coll Cardioll984; 3:98-106 10 Firth BG, Dehmer GJ, Nicod ~ Willerson}T, Hillis LD. Effect of increasing heart rate in patients with aortic regurgitation. Effect of incremental atrial pacing on scintigraphic, hemodynamic and thermodilution measurements. Am J Cardiol 1982; 49:1860-67 11 Hochreiter C, Niles N, Devereux RB, Kligfield ~ Borer JS. Mitral regurgitation: relationship of noninvasive descriptors of right and left ventricular performance to clinical and hemodynamic findings and to prognosis in medially and surgically treated patients. Circulation 1986; 73:900-12 12 Pavel DG, Zimmer AM, Patterson VN. In vivo labeling of red blood cells with Tc-99m: a new approach to blood pool visualiLVVolume and Outputin Severe Mitral Regurgitation (Lavie, Lam, Gibbons)

zatioa., J Nucl Med 1977; 18:305-08 13 Callahan RJ, Froelich H~ McKusick KA, Leppo J, Strauss HW A modified method for the in vivo labeling of red blood cells with Tc-99m: concise communication. J Nucl Med 1982; 23:31518 14 Federman J, Brown ML, Tancredi RG, Smith HC, Wilson DB, Becker GE Multiple-gated acquisition cardiac blood-pool isotope imaging. Mayo Clio Proc 1978; 53:625-33 15 Gibbons RJ, Fyke FE III, Clements I~ Lapeyre AC III, Zinsmeister AR, Brown ML: Noninvasive identification of severe coronary artery disease using exercise radionuclide angiography. J Am CoD Cardioll988; 11:28-34 16 Dehmer GJ, Lewis SE, Hillis LD, Twieg D, Falkoff M, Parkey ~ et ale Nongeometric determination of left ventricular volume from equilibrium blood pool scans. Am J Cardiol 1980; 45:293-300 17 Clements I~ Brown ML, Smith HC: Radionuclide measurement of left ventricular volume. Mayo Clio Proc 1981; 56:733-37 18 Fuster ~ McGoon MD, Callahan JA, McGoon DC: Acquired valvular heart disease. Mitral valve incompetence. In: Braden-

burg R~ Fuster ~ Giuliani ER, McGoon DC, eds, Cardiology fundamentals and practice. Chicago Year Book, 1987; 1322-48 19 Wisenbaugb T, Spann JF, Carabello BA. Differences in myocardial performance and load between patients with similar amounts of chronic aortic versus chronic mitral regurgitation. J Am Coil Cardioll984; 3:916-23 20 Hossack KF, Bruce R, Kusumi F, Kannagi T: Predictions of normal cardiac output in preoperative patients with coronary artery disease. Am J Cardioll983; 52:721-26 21 Hanley PC, Zinsmeister AR, Clements I~ Bove AA, Brown ML. Gibbons K. Gender-related differences in cardiac response to supine exercise assessed by radionuclide angiography J Am Coil Cardioll989; 13:624-29 22 Zaret BL, Wacker F]: Measurement of right ventricular function. In: Gerson MC, ed. New York: Cardiac nuclear medicine. McGraw-Hill 1987; 161-72. 23 Horowitz SF, Matza D, Machac J, Alexopoulos D, McGoon MD, Gibbons R], et ale Right and left ventricular functional response to supine exercise in patients with asymptomatic mitral regurgitation, abstracted. 1 Am CoD Cardioll988; 11:229A.

Thoracic Imaging '90 The Society of Thoracic Radiology will present this program January 7-11 at the Ritz Carlton Resort Hotel, Naples, Florida. For information, contact Dawne Ryals, Ryals and Associates, PO Box 1925, Roswell, Georgia 30077-1925 (404:641-9773).

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