alterations in left ventricular volumes and ejection fraction at rest and during exercise in...

$: Alterations in left ventricular volumes and ejection fraction at rest and during exercise in patients with aortic regurgitation$
Alterations in Left Ventricular Volumes and Ejection Fraction at

Rest and During Exercise in Patients With Aortic Regurgitation

GREGORY J. DEHMER, MD BRIAN G. FIRTH, MD, D Phil L. DAVID HILLIS, MD, FACC JAMES R. CORBETT, MD SAMUEL E. LEWIS, MD ROBEPT W. PARKEY, MD, FACC JAMES T. WILLERSON, MD, FACC

Dallas, Texas

From the Departments of internal Medicine (Car- diology) and Radiology (Nuclear Medicine), the University of Texas Health Science Center and Parkland Memorial Hospital, Dallas, Texas. This work was supported by lschemic SCOR Grant HL-17669 from the National institutes of Health, Bethesda, Maryland and the Harry S. Moss Heart Fund, Dallas, Texas. Manuscript received August 25, 1980; revised manuscript received February 10, 1981, accepted February 13, 1981.

Address for reprints: Gregory J. Dehmer, MD, lschemic Heart Center, Room L5.134, University of Texas Health Science Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75235.

This study was performed (1) to determine the changes in left ventricular volumes durkg exercise in patients with aortk regurgltation, and (2) to evaluate the importance of these alterations in characterizing left ventricular function in these patients. In 15 normal subjects (Group I) and In 17 patients with aortk regurgttatkn (Group II), left ventrkular end-dlastolk volume index, end-systolic volume index, ejection fraction and the ratio of peak systolic blood pressure to end-systolic volume index were measured at rest and during supine exercise. The patients with aortk regurgitation were classified into two groups on the bask of symptoms and chest radiographs: Group IIA, minimal or no symptoms, no cardlomegaly or pulmonary venous congestion; Group IIB, definite symptoms, with cardiomegaly and pulmonary venous congestion. Patients with aortic regurgitation had greater left ventricular end-dlastolk and end-systolic volume indexes at rest and during exercise (p <O.OS) than did normal subjects. During exercise, lefl ventricular end-diastolic volume Index In- creased in normal subjects (53 f 13 ml/m2 [mean f standard deviation] at rest, 67 f 16 ml/m2 during exercise, p <O.Ol), demonstrated a heterogeneous response in patients in Group IIA and increased in patients in Group IIB (160 f 96 ml/m2 at rest, 209 f 102 ml/m2 during exercise, p <0.05). During exercise, left ventricular end-systolic volume Index decreased in normal subjects (16 f 5 ml/m2 at rest, 15 f 6 ml/m2 with exercise, p <O.Ol), increased in patients in Group IIB (62 f 60 ml/m2 at rest, 116 f 93 ml/m2 during exercise, p <0.05), and showed a variable response in those In Group IIA. At rest, left ventricular ejection fraction was similar in the three groups, but during exercise it increased in Group I (0.71 f 0.07 at rest, 0.62 f 0.07 with exercise, p <O.OOl), was unchanged In Group IIA and decreased In Group IIB (0.59 f 0.15 at rest, 0.50 f 0.16 during exercise, p <0.05). During exercise, there was an inverse relation between changes in left ventrkular ejection fraction and end- systolic volume, but no relation between changes in end-diastolic volume and ejection fraction. Changes in the systolic pressure-volume ratio provided no more information than changes in end-systdlc volume alone. Thus, abnormal alterations in left ventricular volumes occur during exercise in paiients with aortlc regurgitation and may be helpful in the further characterization of left ventricular performance In these patlents.

Although aortic regurgitation is easily recognized in most patients, an accurate assessment of left ventricular function in patients with the condition may be difficult. Previous studies demonstrated that some patients with aortic regurgitation have a protracted, asymptomatic clinical course1-4 despite marked hemodynamic derangements.5 Thus, impaired left ventricular performance may develop in patients with severe aortic regurgitation before symptoms of congestive heart failure appear. The serial evaluation of left ventricular function in these patients is important, because depressed preoperative ventricular function

July 1981 The American Journal of CARDIOLOGY Volume 48 17

VOLUME CHANGES IN AORTIC REGURGITATION--MHMER ET AL.

substantially worsens the chance for survival after aortic valve replacement.6

Several techniques are available for the evaluation of left ventricular function in such patients. First, invasive hemodynamic and angiographic measurements such as left ventricular end-diastolic pressure and volume or left ventricular ejection fraction can be made at the time of cardiac catheterization. However, these variables are affected by changes in preload and thus may be unreliable indicators of left ventricular performance in the patient with aortic regurgitation.6-10 In contrast, angiographic measurements of end-systolic volume appear promising as a useful predictor of operative outcome and subsequent left ventricular performance,” because end-systolic volume is relatively independent of alterations in preload.a12 Regardless of the variable measured with cardiac catheterization, serial invasive studies are impractical, especially in the asymptomatic patient. Second, echocardiography has been used to evaluate left ventricular performance in patients with aortic regurgitation. With this technique, left ventricular end-diastolic and end-systolic dimensions can be determined serially. Recent studies have suggested that changes in the end-systolic dimension may help to predict the optimal timing of surgical intervention.13-l5 However, echocardiography can be difficult to perform during exercise and has certain technical limitations, especially in patients with en- larged ventricles.16-lg

Finally, radionuclide ventriculography may be us&d to assess the patient with aortic regurgitation. Scinti- graphic methods exist for the quantitation of regurgitant fraction20921; however, this variable does not reflect actual left ventricular function in the patient with aortic regurgitation. Left ventricular ejection fraction may also

TABLE I

Findings In 17 Patlents With Aortlc Regurgitation

be determined both at rest and during exercise,22 but exercise-induced alterations in ejection fraction may occur for several reasons and thus may be difficult to interpret in these patients. Recently, we described and validated a scintigraphic method for the determination of left ventricular volumes,23324 and characterized the ‘exercise-induced changes in these volumes in normal subjects25 and in those with important coronary artery disease.26 We26 and other investigators8*27*28 also assessed the value of the systolic pressure-volume ratio as an index of ventricular function independent of the ejection fraction. This study was performed (1) to assess the alterations in left ventricular volumes, ejection fraction, and the systolic pressure-volume ratio at rest and during exercise in symptomatic and asymptomatic patients with aortic regurgitation, and (2) to determine if these measurements are useful in characterizing left ventricular function in these patients.

Methods

Study patients: For the purposes of this investigation three study groups were identified. Group I (normal subjects) consisted of 15 persons (11 men and 4 women with a mean age 33 years [range 24 to 511). Nine of the 15 were healthy volun- teers (age range 24 to 27 years), taking no medications, and with normal resting and exercise stress electrocardiograms. Cardiac catheterization was not performed in these subjects. The remaining six subjects in Group I had cardiac catheterization and coronary arteriography to evaluate atypical chest pain and were found to have normal intracardiac pressures and no angiographic evidence of coronary artery disease. All six subjects had normal resting and exercise stress electrocardiograms, although in four the exercise tolerance test was terminated because of fatigue before a maximal age-predicted heart rate was achieved. Two subjects had mild systemic arterial hypertension controlled with diuretic drugs.

Catheterization Findings

Case Age W

&Sex Symptoms LVH Cardiomegaly Severity of AR’

LVEDP (mm Hg)

Regurgitant Fraction l

Group IIA

:

3 :

6

: 9

10

59M None 29M Atypical chest pain 27M None 47F 34M DOE, None rare PND

28F Mild DOE

55M 20F DOE, DOE, fatigue fatigue 20M Atypical chest pain 83F DDE, chest pain

+ 3+ 8 0.62 + 3+ : 0 4-k 38

0.58 0.76

+ Borderline Borderline 3+ 3+ 20 12 0.47 0.41

! 0 : 0

1to2+ 0.38

3+ 2+ :03 9 0.66 0.28

: Borderline ito2+ 0.34 Borderline 3+ :: 0.45

Group IIB

:: 65F 63M CHF CHF LB+BB : 3to4+ 4+ 16 15 0.53 0.60 13 40F CHF + + 2+ 9 0.43

:: 47M 66M CHF CHF z : 3+ 4+ ;: 0.71 0.72

:; 24F CHF 65M Chest pain, CHF 1 :

4-k 0.78 2+ :o’ 0.40

l See text for definition. AR = aortic regurgitation; CHF = congestive heart failure; DDE = dyspnea on exertion; LBBB = left bundle branch block; LVEDP = left ventricular

enddiastolic pressure: LVH = left ventricular hypettrophy; PND = paroxysmal nocturnal dyspnea; + = present; 0 = negative.

18 July 1981 The American Journal of CARDIOLOGY Volume 48

VOLUME CHANGES IN AORTIC REGURGITATION-OEHMER ET AL.

Group II consisted of 17 patients with angiographically documented aortic regurgitation. Cardiac catheterization was performed in all patients and revealed no evidence of aortic stenosis, no additional valve disease and no associated coronary artery disease. These patients were classified into two subgroups on the basis of cardiac symptoms and radiographic findings (Table I). Group IIA consisted of 10 patients with minimal cardiac symptoms. Five patients demonstrated electrocardiographic evidence of left ventricular hypertrophy (Romhilt-Estes criteria),2g and four had borderline cardiac enlargement (cardiothoracic ratio = 0.50) on standard chest radiography. The average age of the patients in Group IIA was 38 years (range 20 to 63). Group IIB comprised seven patients with aortic regurgitation and definite symptoms of left ventricular failure. Six of the seven patients had electrocardiographic evidence of left ventricular hypertrophy and one had left bundle branch block. Each patient in this subgroup had symptoms, signs and radiographic evidence of congestive heart failure. Although therapy with digoxin and diuretic drugs produced a lessening of the symptoms before invasive and noninvasive testing, all seven patients continued to have radiographic evidence of cardiac enlargement (that is, a cardiothoracic ratio more than 0.50). The mean age of the patients in Group IIB was 53 years (range 24 to 66).

Cardiac catheterization: All patients in Groups IIA and IIB underwent right and left heart catheterization, left ventriculography, supravalve aortography and selective coronary arteriography. Left ventricular end-diastolic pressure and forward cardiac output (by the Fick method or indicator- dilution technique, or both) were measured before the ad- ministration of contrast material. Left ventricular volumes were determined with single plane ventriculography in the right anterior oblique projection using the area-length methodec and Kennedy regression equation.31 The regurgitant fraction was calculated as the difference between angiographic left ventricular output and forward output divided by the angiographic output. Aortic regurgitation visualized by supravalve contrast injection was graded on a scale of 0 to 4+, according to previously established criteria.32r33 Radionuclide ventriculography was performed at rest and during exercise within 1 month of cardiac catheterization in 14 of the 17 patients. No changes in medical therapy or clinical condition occurred in any patient between the time of catheterization and radionuclide study.

Resting and exercise radionuclide ventriculography: Multigated equilibrium blood pool imaging was performed after in vivo labeling of red blood cells with 30 millicuries (mCi) of technetium-99m sodium pertechnetate, according to the technique described previously.34p35 Data collection was performed with a portable gamma scintillation camera (Series 100, Ohio Nuclear, Solon, Ohio) equipped with an all-purpose parallel hole collimator and interfaced to a dedicated on-line computer system (VIP-450, Ohio Nuclear, Solon, Ohio). Gated blood pool scintigrams were obtained at rest and during supine exercise in a modified 35” left anterior oblique projection. Although this projection frequently separates the right and left ventricles, the angle of obliquity was always adjusted to allow the clearest separation between the ventricles while minimizing the interventricular septal thickness. Images at rest were acquired for (1) a predetermined number of cardiac cycles so that the total acquisition time was 5 to 8 minutes; (2) 32 frames/cardiac cycle; and (3) 100 percent of the cardiac cycle. This resulted in a minimum of 150,000 counts/frame of the study.

Each subject’s feet were elevated and attached to the bicycle pedals before the exercise study was started. After a 2 minute equilibration period, an additional scintigram at rest was obtained to assess the effect of leg elevation on the vari-

ables measured. These and subsequent exercise images were acquired for (1) a predetermined number of cardiac cycles so that the total acquisition time during exercise was 3 minutes; (2) 32 frames/cardiac cycle; and (3) 100 percent of the cardiac cycle. This provided a minimum of 100,000 counts/frame at peak exercise. Imaging was performed at each work load, beginning at an initial work load of 150 kilopond-meters (kpm)/min. At the beginning of the first and each subsequent work load, the subject exercised for 1 minute before the 3 minute imaging period began. Thus, the total duration of each work load was 4 minutes. This procedure allowed the heart rate to reach a new steady level and uninterrupted gating to occur. During the acquisition of scintigraphic data, the heart rate did not vary by more than 15 percent of the value recorded at the start of the acquisition period. An orthogonal lead system was used for electrocardiographic monitoring, and blood pressure was recorded with a programmed electro- sphygmomanometer (PE-300, E & M Instruments Co., Inc., Houston, Texas).

The left ventricular ejection fraction was determined from the time-activity curve of the left ventricle by constructing a region of interest over the left ventricle in the end-diastolic (ED) and end-systolic (ES) frames. After correcting for background activity, left ventricular ejection fraction (LVEF) was calculated using the formula:

LVEF = ED counts - ES counts

ED counts

This method has been shown to correlate well with results obtained with contrast angiography.23,36

Left ventricular volumes were estimated using a totally nongeometric technique recently developed and validated in our laboratorys3*24 and in others.37 In brief, the end-diastolic and end-systolic frames were isolated from the multiframe gated study and used for further processing. Background activity was subtracted using a linear interpolated subtraction technique.24 The number of radionuclide counts within the left ventricle at end-diastole and end-systole was then determined. Care was taken to exclude all left atrial activity and to adhere to consistent criteria for the definition of the left ventricular borders. The left ventricle was outlined twice for both images, and the average number of counts from these two determinations was used in the final calculation of volumes. Scintigraphic estimates of left ventricular volumes were calculated from the activity of the left ventricle normalized for the activity per milliliter of peripheral venous blood and corrected for the acquisition time per frame and decay of the radioisotope.

The following formula was used for the scintigraphic estimation of left ventricular volumes:

Background-corrected LV counts

Volume = Acquisition time per frame

Peripheral blood activity X esht,

where evxt is the general equation for isotope decay (h = 0.693Rsotope half-life). Left ventricular volumes determined with this technique are consistently smaller than those measured with contrast ventriculography, but a highly significant correlation exists between these two methods.23,24,37 Thus, a linear regression equation determined previously24 was used to convert the scintigraphic estimates of volume into actual volume expressed in milliliters. All volumes were then normalized for body surface area. To ensure consistency, analysis of the scintigraphic data was performed by the same observer throughout the study. The inter- and intraobserver variability of these volume measurements in our laboratory is 7.5 and 6 percent, respectively. 23*24 The reproducibility of these measurements over time has also been substantiated.3s


VOLUME CHANGES IN AORTIC REGURGITATION-DEHMER ET AL.

600 l End Diastolic Volumes

o End Systolic Volumes

/

y=O,93x +0.63

l l

SEE = 28ml

/ 0 0 0 0 r n=34 p< = 0.95 0.001

I i 1 I I I

100 200 300 400 500 600

ANGlOGRAPHIC VOLUME (ml)

FIGURE 1. Relation between scintigraphic and angiographic estimates of left ventricular volumes for the 17 patients with aortic regurgitation. Each closed circle represents the enddiastolic volume from one patient; each open circle represents the end-systolic volume from one subject. The correlation between scintigraphic and angiographic estimates is excellent.

In addition to the measurement of left ventricular volumes and ejection fraction, we evaluated noninvasively the ratio between cuff-determined peak systolic pressure (measured in millimeters of mercury) and scintigraphic end-systolic volume index.

Statistical analysis: Alterations in left ventricular volumes and ejection fractions for the two studies at rest (legs flat and legs elevated in the bicycle pedals) and during peak exercise within patient groups were compared with a single factor re-

peated measures analysis of variance.3g Intergroup differences were evaluated with an analysis of variance and an appropriate multiple range test using nonparametric methods whenever unequal variances between groups were present. All results are reported as mean f 1 standard deviation. A probability (p) value of 0.05 or less was considered significant.

Results

Correlation of scintigraphic and angiographic left ventricular volumes: Problems with the noninvasive estimation of left ventricular volumes in patients with aortic regurgitation have been emphasized by other investigators.lGlg To establish that scintigraphic volume estimates are valid even when marked ventricular enlargement is present, we evaluated the relation between scintigraphic and angiographic estimates of left ventricular volume in these patients and found the correlation to be excellent (r = 0.95, p <O.OOl) (Fig. 1). The standard error of estimation for this relation was 28 ml, which is considerably smaller than that reported for echocardiographic estimates of left ventricular volumes.16 Furthermore, the regression equation defines a slope and an intercept very close to the line of iden- tity.

Comparisons within patient groups: Within each patient group, changes in the variables were compared under three different conditions: (1) resting with legs flat, (2) resting with legs elevated in the bicycle pedals, and (3) peak exercise. Although scintigraphic data were acquired at the intermediate work loads, only the data acquired at peak exercise were analyzed. In each of the three patient groups, there were no significant differences between measurements of any variable (left ventricular volumes, ejection fraction, pressure/volume ratio, heart rate, systolic blood pressure or rate-pressure [double] product) at rest with legs flat and at rest with

TABLE II

Scintigraphlc Data in Group I (normal subjects)

LVEDVI (ml/m*) LVESVI (ml/m*)

Case Rest PEx Rest PEx

P/V Ratio LVEF

Rest PEx Rest PEx

;t 92 ;:

21 10 22 9 14.0 5.7 20.6 8.6 0.78 0.79 0.80 0.86 3‘ 70 26 22 5.2 8.6 0.7 1 0.84 4’ :f 63 13 12 6.9 15.8 0.72 0.86 5’

:; 12 8 10.5 27.5 0.73 0.91

;: :: :: 20 13 8.7 7.0 16.9 10.5 0.78 0.75 0.82 0.86

5; :: :: 18 15 17 4.0 7.8 15.3 9.1 0.73 0.69 0.80 0.83 lo+ :A :t ;z 27 4.8 6.7 0.54 0.62 11+ 1: :: 8 7.5 23.7 0.72 0.90 12+ 44 8.1 12.9 0.70 0.71 13+ 40 62 :z :: 8.8 18.5 0.75 0.85

:z* l 46 58 :: 21 :: 4.8 5.7 10.6 14.6 0.85 0.60 0.79 0.79 Mean 53 67 18 15 7.3 14.6 0.71 0.82 SD 13 18 5 6 2.6 6.1 0.07 0.07 p value <O.Ol <O.Ol <O.OOl <O.OOl

l Normal volunteer. + Normal at catheterization. LVEDVI = left ventricular end-diastolic volume index: LVEF = left ventricular ejection fraction; LVESVI = left ventricular end-systolic volume

index; p = probability; PEx = peak exercise: P/V ratio = systolic blood pressure/LVESVI (expressed in dimensionless units); SD = standard deviation.


VOLUME CHANGES IN AORTIC REGLRGITATION-DEHMER ET AL.

TABLE III TABLE V

Hemodynamic Data In Group I (normal subjects)

HR (beatslmin) SBP (mm Hg) Rate-Pressure Product X lo*

Case Rest PEx Rest PEx Rest PEx

1 66 175 120 190 61.6 332.5 3 :; 110 175 135 140 185 180 103.6 97.2 315.0 203.5

2 76 6 ;:

165 160 126 90 220 190 123.5 68.4 313.5 352.0 140 130 220 91.0 308.0

; t: 165 172 140 140 210 230 67.2 91.0 346.5 395.6 9

10 2: 148 95 155 50.4 229.4 125 120 180 96.0 225.0

:: t : 180 113 120 130 190 180 79.2 83.2 342.0 203.4 13 :: 122 140 240 71.4 292.8 14 165 110 170 71.5 280.5 15 Mean t;

168 120 190 72.7 319.2 152 124 195 83.0 284.0

SD 12 24 15 23 18 73 p value <O.OOl <O.OOl <O.OOl

HR = heart rate; SBP = systolic blood pressure. Other abbreviations as in Table II.

Hemodynamlc Data In Patients With Aortlc Regurgltatlon (Group IIA)

Rate-Pressure HR (beats/min) SBP (mm Hg) Product X lo*


: :5 123 102 110 100 170 150 46.0 71.5 209.1 153.0

: 100 145

: ;x 1:: 106

140 120 190 155 140.0 87.6 275.5 142.6

3 :: 190 125 230 150 114.0 62.5 269.1 159.0

9 ;:

121 80 140 150 200 185 115.5 81.2 242.0 148.0

115 130 180 84.5 207.0 10 Mean tt

100 175 240 119.0 240.0 110 138 185 92 205

SD 15 18 28 31 29 51 p value <O.Ol <O.Ol <O.Ol

Abbreviations as in Table III.

legs elevated. The resting measurements subsequently presented are those obtained with the legs flat.

Group I (15 normal subjects): The scintigraphic results for individual patients in this group are displayed in Table II. Mean left ventricular end-diastolic volume index was 53 f 13 ml/m2 at rest and increased to 67 f 18 ml/m2 (p <O.Ol) at peak exercise. Left ventricular end-systolic volume index decreased from a resting value of 18 f 5 to 15 f 6 ml/m2 during exercise (p <O.Ol). Left ventricular ejection fraction was 0.71 f 0.07 at rest and increased to 0.82 f 0.07 at peak exercise (p <O.OOl). The pressure-volume ratio in these subjects was 7.3 f 2.6 at rest, increasing to 14.6 f 6.1 (p <O.OOl) at peak exercise.

The hemodynamic data from Group I are displayed in Table III. Heart rate, systolic blood pressure and the rate-pressure product all increased from rest to peak exercise. The mean peak exercise work load in these patients was 810 f 366 kpm/min.

Group IIA (10 patients with aortic regurgitation and minimal symptoms): The scintigraphic and hemodynamic results from this group are listed in Tables IV and V, respectively. Mean left ventricular end-diastolic volume index did not change during exercise in these patients (106 f 24 ml/m2 at rest, 112 f 34 during exercise, difference not significant [NS]), but wide variation was noted: Left ventricular end-diastolic volume index at peak exercise increased in three, changed minimally (4 ml/m2 or less) in three and decreased in four. Similarly, mean left ventricular end- systolic volume index did not change with exercise (31 f 8 ml/m2 at rest, 33 f 14 at peak exercise, NS), but variation was again prominent: Left ventricular end- systolic volume index during exercise increased in three, changed minimally (4 ml/m2 or less) in five and decreased in two. During exercise, left ventricular ejection fraction decreased in two patients, increased in one patient and did not change by at least 0.05 in seven patients. Mean left ventricular ejection fraction did not change significantly with exercise (0.73 f 0.05 at rest, 0.72 f 0.09 at peak exercise, NS). The pressure-volume ratio averaged 4.8 f 1.5 at rest and increased to 6.4 f 2.3

TABLE IV

Bclntlgraphlc Data In Patients With Aortlc Regurgitation and Mlnlmal or No Symptoms (Group IIA)

LVEDVI (ml/m*) LVESVI (ml/m*) P/V Ratio


LVEF

Rest PEx

: 3 4

:

1:

1: Mean SD D value

126 92 97

104 100 92

149 66

137

1:: 24

129 117 92

104 126 74

152 96 96

1:; 34

NS

31 18

45 18

81 31

8

46

z:

:: 20 45 25 18

f i 14

3.6 3.7 0.77 0.66 5.5 7.1 0.84 0.84 5.2 7.2 0.76 0.77 3.5 4.1 0.69 0.66

K 3.8 0.67 0.54

3:1 7.5 0.71 0.81 4.1 0.72 0.72

8.3 8.0 0.76 0.77 3.9 10.0 0.72 0.75 5.5 8.6 0.70 0.67 4.8 6.4 0.73 0.72 1.5 2.3 0.05 0.09

<0.05 NS

NS = not significant: other abbreviations as in Table II.



TABLE VI

Scintigraphic Data in Patients Wlth Aortic Regurgitation and Definite Symptoms (Group 116)

LVEDVI (ml/m2) LVESVI (ml/m’) P/V Ratio LVEF

Case Rest PEx Rest PEx Rest PEx Rest PEx

:z :! Mean SD p value

153 240

1:; 300 210 119 180 96

170 258

89 176 402 233 135 209 102

<0.05

77 97 100 37 51

207

:z

168 37 70

302 92 48

118 93

<0.05

1.9 1.2 3.4 2.4 0.8 1.7 4.3 2.3 1.2

2.3 0.9 3.7 3.1 0.7 2.4 4.6 2.5 1.4

NS

0.51 0.44 0.59 0.35 0.65 0.63 0.66 0.61 0.31 0.25 0.62 0.58 0.77 0.66 0.59 0.50 0.15 0.16

<0.05

Abbreviations as in Tables II and IV.

during exercise (p <0.05). The mean peak work load achieved during exercise was 330 f 170 kpm/min. Heart rate, systolic blood pressure and rate-pressure product increased during exercise in patients in this group (Table V).

Group IIB (seven patients with aortic regurgitation and definite symptoms): The scintigraphic results in the patients in this group are displayed in Table VI. Mean left ventricular end-diastolic volume index was 180 f 96 ml/m2 at rest and increased to 209 f 102 ml/m2 at peak exercise (p <0.05). Left ventricular end-systolic volume index also increased during exercise (82 f 60 ml/m2 at rest, 118 f 93 at peak exercise, p <0.05). In contrast, left ventricular ejection fraction decreased during exercise (0.59 f 0.15 at rest, 0.50 f 0.16 at peak exercise, p <0.05). The pressure-volume ratio was unchanged during exercise (2.3 f 1.2 at rest, 2.5 f 1.4 at peak exercise, NS). The hemodynamic variables in this group are listed in Table VII. As in the other groups, heart rate, systolic blood pressure and rate-pressure product increased at peak exercise. The mean peak work load was 311 f 110 kpm/min.

Comparisons Among Patient Groups

Hemodynamic data: There was no significant difference in heart rate, systolic blood pressure or rate-

TABLE VII

Hemodynamic Data in Patients With Aortic Regurgitation (Group MB)

Rate-Pressure HR (beatsimin) SBP (mm Hg) Product X lo2


:: 90 124 150 220 135.il 272.8

z; 110 120 160 62.4 176.0

13 128 130 140 119.6 179.2

;z :: 122 120 220 108.0 268.4 110 170 200 137.7 220.0

:; 2; 150 130 220 119.6 330.0

1:: 130 220 65.0 198.0

Mean 78 136 197 107 235 SD 19 19 18 33 31 57 p value <O.Ol <O.Ol <O.Ol

Abbreviations as in Tables II and Ill.


pressure product among the three groups at rest. However, at peak exercise, heart rate and rate-pressure product were both higher in normal subjects than in either group with aortic regurgitation. Peak exercise systolic blood pressure was not different among the three groups. Peak exercise heart rate (110 f 18 beats/ min, Group IIA; 119 f 19 beats/min, Group IIB), systolic blood pressure (185 f 31 mm Hg, Group HA; 197 f 33 mm Hg, Group IIB), and rate-pressure product (205 f 51 X 102, Group IIA; 235 f 57 X 102, Group IIB) were not different in the two patient groups with aortic regurgitation. The mean peak work load was greater in normal subjects (810 f 367 kpm/min) than in either group with aortic regurgitation but did not differ in the two groups with aortic regurgitation (330 f 170 kpm/ min in Group IIA, 311 f 110 kpm/min in Group IIB).

Left ventricular volumes: The changes in left ventricular end-diastolic volume index during exercise in the three groups are displayed in Figure 2A. In contrast to the normal subjects (Group I), patients in the groups with aortic regurgitation (Groups IIA and IIB) had a higher left ventricular end-diastolic volume index both at rest and at peak exercise (p <0.05). Whereas the normal subjects and patients in Group IIB demonstrated an increase in left ventricular end-diastolic volume index with exercise, those in Group IIA showed a heterogeneous response with respect to this variable.

Changes in left ventricular end-systolic volume index during exercise are displayed in Figure 2B. Again, left ventricular end-systolic volume index both at rest and during exercise was higher in patients with aortic regurgitation than in normal subjects (p <0.05). During exercise, this index decreased 20 f 16 percent in normal subjects but increased 41 f 23 percent in patients in Group IIB. Patients with aortic regurgitation in Group IIA demonstrated heterogeneous changes in left ventricular end-systolic volume index.

Left ventricular ejection fraction: Alterations in left ventricular ejection fraction during exercise are displayed in Figure 2C. The mean left ventricular ejection fraction at rest was similar in the three patient groups. Six of the seven patients in Group IIB had an ejection fraction greater than 0.50 at rest. During ex-


C

250 -

I I I I I I

REST PEX REST PEX REST PEX

- - NORMALS GROUP IIA GROUP II 0

D

EJECTION FRACTION

N^ 250- E

i

2 200-

z

30-

25-

t: 20 -

s - 15- >

2 10 -

5-

- - NORMALS GROUP IIA GROUP I[0

P/V INDEX

_ p-coo1 - - PC.05 - c P-NS 7

L kk.001 -J - P-NS - - P-LO5 -

REiT PEX REST PEX RE’ST PEX

NORMALS GROUP IIA GROUP II B

REST PEX REST PEX REST PEX

NORMALS GROUP II A GROUP IIB

FIGURE 2. Values at rest and during peak exercise (PEX) in the three groups for left ventricular end-diastolic volume index (panel A), left ventricular end-systolic volume index (panel B), left ventricular ejection fraction (Panel C) and the pressure/volume ratio (P/V index) (panel D). Each line represents the data from one patient, and the mean f 1 standard deviation of the group is shown on either side of the individual lines. When the mean values at peak exercise are compared with those at rest within each goup, a p value is displayed. When mean values at rest or during exercise, respectively, in Groups IIA and IIB are compared with those in Group I, an asterisk is used to denote p KO.05. Panel A, during exercise, left ventricular enddiastolic volume index rises in normal subjects (Group I), remains unchanged in patients with aortic regurgitation and minimal symptoms (Group IIA), and increases modestly in those with aortic regwgitation and definite symptoms (Group MB). In comparison to normal subjects, left ventricular end-diastolic volume index both at rest and during exercise is significantly greater in Grwps IIA and IIB. Panel B, left ventricular end-systolic volume index decreases during exercise in normal subjects, increases in Group IIB and is unchanged in Group IIA. Left ventricular end-systolic volume index is larger both at rest and during exercise in both groups with aortic regurgitation compared with that in normal subjects. Panel C, with exercise, left ventricular ejection fraction increases in normal subjects, remains unchanged in Group IIA and decreases in Group IIB. Left ventricular ejection fraction at rest is not significantly different in the three groups, but during exercise it is significantly decreased in Group IIB. Panel D. the end-systolic pressure-volume ratio (P/V index) increases during exercise in Groups I and IIA but remains unchanged in Group IIB. The pressure-volume ratio both at rest and during exercise is lower in those with aortic regurgitation than in normal subjects.

July lg81 The American Journal oi CARDIOLOGY Volume 48 23

VOLUME CHANGES IN AORTIC REGURGITATION-DEHMER ET AL

ercise, the mean ejection fraction increased 15 f 9 percent in Group I and decreased 15 f 13 percent in Group IIB (p <0.05). Although the mean ejection fraction in Group IIA patients did not change during exercise, the response was again heterogeneous.

Individual patient alterations in left ventricular ejection fraction during exercise were assessed with particular attention to the changes in left ventricular end-diastolic and end-systolic volumes, There was no correlation between changes in left ventricular end- diastolic volume index and ejection fraction during exercise (Fig. 3A), but there was a significant inverse relation between exercise-induced changes in left ventricular end-systolic volume and ejection fraction (Fig. 3B). Thus, in the patients with aortic regurgitation, a decrease in left ventricular ejection fraction during exercise was related to an increase in end-systolic volume and, conversely, an increase in ejection fraction during exercise was associated with a decrease in end- systolic volume.

Pressure-volume ratio: Alterations in the pressure-volume ratio during exercise are presented in Figure 2D. The mean ratio in normal subjects was 7.3 f 2.6 at rest and increased to 14.6 f 6.1 at peak exercise (p <O.OOl). The patients with aortic regurgitation were different in several respects. First, the pressure-volume ratio at rest was lower in each patient group with aortic regurgitation (p <O.Q5); however, because systolic blood pressures were similar among the groups, this difference was due to alterations in left ventricular end-systolic volumes. Second, changes in the pressure-volume ratio during exercise were different in the patients with aortic regurgitation than in the normal subjects. In patients in Group IIA, the pressure-volume ratio increased during exercise from 4.8 f 1.5 to 6.4 f 2.3 (p <0.05), but the peak exercise value was lower than that seen in normal subjects (p <0.05). In patients in Group IIB, the

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pressure-volume ratio did not change during exercise (2.3 f 1.2 at rest, 2.5 f 1.4 at peak exercise, NS), and the peak exercise value was again lower than that seen in normal subjects (p <0.05). Because peak exercise systolic blood pressures were similar in the three groups, these differences were again the result of alterations in left ventricular end-systolic volumes.

Discussion

Exercise-induced changes in left ventricular ejection fraction: Previous studies have shown that patients with aortic regurgitation may have a normal left ventricular ejection fraction at rest despite symptomatic evidence of left ventricular decompensa- tion.5p6y40 Thus, although a depressed ejection fraction at rest implies diminished left ventricular performance and increased mortality,6 a “normal” ejection fraction does not necessarily imply normal left ventricular function. The patients in Group IIB exemplify this hypothesis, because most patients have a well preserved ejection fraction at rest despite evidence of congestive heart failure and substantial regurgitation. Because the resting ejection fraction may be misleading in assessing ventricular function in patients with aortic regurgitation, changes in ejection fraction during exercise were evaluated. Borer et al.22 showed that the resting ejection fraction in patients with symptomatic aortic regurgitation may be “normal” but declines during exercise. Their patients with asymptomatic aortic regurgitation demonstrated a variable response, whereas normal subjects had an increase in ejection fraction during exercise. Our findings agree with this earlier work.

However, in patients with aortic regurgitation, consideration must be given to the mechanism whereby changes in ejection fraction occur during exercise. With exercise, complex alterations occur in heart rate, blood pressure, venous return and circulating cate-

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FIGURE 3. Left, relation between exercise-induced changes in left ventricular end-diastolic volume index (LVEDVI) and left ventricular ejection fraction (LVEF). Rbht, relation between changes in left ventricular end-systolic volume index (LVESVI) and LVEF in response to exercise. Relative charges (% A) are displayed in the feft panels, and absolute chaqes (A) are shown in the rfgtht panels. There is a significant inverse relation between the charge in left ventricular ejection fraction and end-systolic volume Index but no relation between the change in left ventricular ejection fraction and end-diastolic volume index.


cholamines, any or all of which may contribute to alterations in ejection fraction during exercise. For ex- ample, an increase in heart rate (induced by atria1 pacing) causes left ventricular end-diastolic volume to decrease and end-systolic volume to remain unchanged, resulting in a decrease in ejection fraction.41 Thus, if the effects of tachycardia predominate during exercise, a decrease in ejection fraction may be the result of a change in end-diastolic volume and not a deterioration in left ventricular performance. Conversely, an increase in arterial pressure (induced by infusion of angiotensin) causes left ventricular end-diastolic volume to increase but ejection fraction to decrease or not change.42 Be- cause both heart rate and arterial pressure increase with exercise, concomitant changes in ejection fraction may be difficult to interpret, and an analysis of this variable may be further complicated by increases in inotropic state or venous return, or both, during exercise.

Relation between changes in left ventricular ejection fraction and volumes: Because alterations in left ventricular ejection fraction during exercise in these patients may be dependent on several variables, this study also assessed the changes in left ventricular volumes during exercise. Although end-diastolic volume increased or was unchanged during exercise in most patients with aortic regurgitation, three patients (Pa- tients 6,9 and 10, Group IIA) had a marked decrease in end-diastolic volume during exercise. However, in these patients, ejection fraction increased or was unchanged because of a concomitant decrease in end-systolic volume. Alterations in ejection fraction during exercise were not consistently related to changes in end-diastolic volume but, in contrast, generally showed an inverse relation to changes in end-systolic volume (Fig., 3).

The measureinent of end-systolic vblume (or dimension) may be superior to the ejection fraction in the assessment of patients with aortic regurgitation. Other investigators13J4 measured end-systolic dimension echocardiographically, suggesting it as a useful variable in the assessment of left ventricular function in patients with aortic regurgitation. However, the use of M mode echocardiography in patients with a dilated ventricle has certain technical problems,1619 and exercise-induced changes in dimension are difficult to assess with this technique. Alternatively, angiographi- tally determined end-systolic volume appears to be a valuable predictor of operative outcome and subsequent left ventricular performance in patients with aortic regurgitation, l1 but serial invasive measurements over a protracted period are impractical, particularly in patients with minimal or no symptoms.

Advantages of scintigraphic estimation of left ventricular volumes: The determination of left ventricular volumes with scintigraphy offers several advantages. First, it is noninvasive and therefore not ac- companied by the risks of contrast angiography. Second, it is independent of geometric assumptions regarding the shape of the ventricle; thus, errors in measurement due to distorted ventricular configurations are avoided. Third, it has no intrinsic effect on ventricular function or hemodynamics. Finally, because of these character-

VOLUME CHANGES IN AORTIC REGUf3GlTATION-DEHMER ET AL.

istics, repeated measurements can be made at rest and during exercise, and serial measurements over pro- longed intervals easily accomplished. Because the accuracy of other noninvasive volume measurements in patients with aortic regurgitation has been questioned, the correlation between scintigraphic and angiographic volumes was evaluated in this study and found satis- factory.

Exercise-indticed changes in left ventricular volumes: Previous studies have demonstrated the changes that occur in left ventricular volumes and ejection fraction during exercise in patients without aortic regurgitation. 25,4348 In contrast, patients with aortic regurgitation respond differently to exercise. In those with aortic regurgitation and congestive heart failure (Group IIB), both end-diastolic and end-systolic volumes increase during exercise. Because the increase in end-systolic volume is relatively greater than that in end-diastolic volume, the ejection fraction decreases. Patients with aortic regurgitation and minimal symptoms (Group IIA) have a variable response to exercise: Some have changes similar to those in Group IIB, whereas other patients demonstrate changes similar to those in normal subjects. An increase in end-systolic volume during exercise probably reflects a true deterioration in left ventricular performance; however, the mechanism for this remains unclear. Increases in end- systolic volume during exercise were most pronounced in ventricles with large end-systolic volumes at rest. This can be explained in part by the Laplace relation, because a given increase in systolic pressure during exercise will result in a greater increase in effective afterload in a larger ventricle. Whether resting or exercise-induced changes in.end-systolic volume and ejection fraction can reliably predict long-term left ventricular performance remains to be determined.

Noninvasive pl’essure-volume ratio: Previous studies8>49*50 suggested that the maximal slope of the instantaneous pressure-volume curve during systole (Emax) reflects the contractile state of the ventricle yet is independent of changes in preload. Other investiga- torpid have used the ratio of peak left ventricular systolic pressure to end-systolic volume as an estimate of this variable. Recently, we26 and other authors28 demonstrated that the ratio of peak cuff-determined systolic pressure to scintigraphically determined end-systolic volume is useful in assessing left ventricular performance in patients with coronary artery disease. As in patients with coronary artery disease, those with aortic regurgitation exhibit changes in the pressure-volume ratio that are different from those seen in normal subjects. However, because systolic pressure is similar both at rest and during exercise in the three patient groups, the pressure-volume ratio does not provide information in addition to that provided by end-systolic volume alone. Furthermore, there are many potential problems associated with the substitution of a cuff- determined systolic pressure for actual left ventricular pressure.

Clinical implications: Radionuclide ventriculography is useful in the evaluation of left ventricular

July 1981 The American Journal of CARDIOLOGY Vdume 48 25

VOLUME CHANGES IN AORTIC REGURGITATION-DEHMER ET AL

performance in patients with aortic regurgitation. The quantitation of left ventricular volumes at rest and during exercise provides a better understanding of the mechanism responsible for changes in ejection fraction. Because the ejection fraction is preload-dependent, the end-systolic volume may be a better predictor of left ventricular function in patients with aortic regurgitation. Whether the detection of exercise-induced changes in ejection fraction or end-systolic volume, or both, will

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help to define the optimal time for aortic valve replacement remains to be determined.

Acknowledgment We are indebted to Jean Cruz, Sarah Wern, Isabel Carrillo,

R. Scott Lyons, Norman Vance, Randy Christian and Carl Sorenson for their technical support in the performance of the scintigraphic and angiographic studies. In addition, the sec- retarial assistance to Juanita Alexander and Laurie Grey is gratefully acknowledged.

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