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Hemodynamic changes at rest and during exercise in patients with aortic stenosis of varying severity
Hemodynamic changes at rest and during in patients with aortic stenosis of varying Simon J. K. Lee, M.D., B. Jonsson, M.D. S. Bevegird, M.D. I. Karliilf, M.D. H. Astriim, M.D. Stockholm,p Sweden
F.R.C.P.(C.)
mhe effects of exercise on circulation in 1 patients with aortic stenosis have been reported previously,1-4 but attempts have not been made to correlate the hemodynamic abnormalities to the severity of the stenosis, nor were the left ventricular pressures studied during exercise. The purpose of this communication is to report the hemodynamic effects of exercise in relation to the severity of the disease in patients with “pure” aortic stenosis. Attempts were also made to measure the capacity for muscular work in a quantitative manner and to analyze the limiting factors of working capacity. Material
Thirty-four patients were selected for this study on the basis of a diagnosis of isolated aortic stenosis (rheumatic and congenital) following cardiac catheterization. Aortic root aortography* was also carried out in patients with the murmur of aortic regurgitation and only those with a slight regurgitation were included. All cases have valvular stenosis except one who has mem-
branous subvalvular stenosis. Cases of muscular subaortic or supravalvular stenosis were excluded. The material is classified into three groups according to the calculated aortic valve area index (AVAI) in square centimeters per square meter of body surface area. In Group I, AVAI is larger than 0.8, in Group II between 0.5 and 0.8, and in Group III less than 0.5 cm.2 per square meter. Clinically, Group I corresponds to mild stenosis, Group II to moderate stenosis, and Group III to severe stenosis. The age range is 10 to 59 years with the mean age being 34. The average age for Group I is 17 years, for Group II 25 years, and for Group III 46 years. Procedures
American Heart Journal
and
methods
Physical working capacity (PWC) was determined on an electrically braked constant load bicycle ergometer5 ’ using the method of Sjiistrand.6 The work load was successively increased every 6 minutes with an aim to achieve a steady pulse rate of 150 per minute to 170 per minute in 3
From the Laboratory of Clinical Physiology, Thoracic Clinic, Karolineka Received for publication April 28. 1969. Reprint requests to: Dr. Simon J. K. Lee, University of Alberta Hospital, *This was carried out by the department of Radiology.
318
exercise severity
March,
Sjukhuset, Edmonton,
1970
Stockholm, Alberta,
Vol. 79,
Sweden. Canada.
NO.
3, gp. 318-331
Volume
79
Number
3
Hemodynamic
319
changes in patients with aortic stenosis
in the left ventricle and the aorta in 29 patients and the withdrawal pressure tracings in the remaining 5 patients. A planimeter was used to calculate the area of the pressure gradient and the left ventricular mean systolic pressure (LVMSP). The left ventricular stroke work index (LVSWI) was calculated as follows: LVSWI (gmM. per beat per square meter) = 13.6 X (LVMSP - LVEDP) X SI, where LVEDP = left ventricular enddiastolic pressure (in millimeters of Hg) and SI = stroke index (in milliliters per square meter). The left ventricular work index (LVWI) was obtained by substituting the cardiac index for the stroke index in the above formula and expressing as Kg.-M. per minute per square meter. Pulmonary vascular resistance (PVR) is expressed as the ratio of the mean pressure gradient (mm. Hg) across the pulmonary vascular bed and the cardiac output (liters per minute). Systemic resistance was calculated by dividing the mean aortic pressure by cardiac output. The heart volume was calculated from simultaneously exposed biplane chest x-rays in prone position according to the method of Kjellberg and associates.rO Total hemoglobin was estimated using the carbon monoxide method of Sjiistrand.” The various parameters of these patients were compared to the normal values obtained in this laboratory using same methods.rJ2 The statistical analysis was carried out using the conventional methods,13 and the P value of less than 0.05 was defined as significant.
work loads. The electrocardiogram was monitored every minute and the heart rate was calculated from it. The exercise was continued until either a pulse rate of 150 to 170 per minute was achieved or the patient was unable to exercise due to symptoms. Because of the possible risk, exercise was stopped with the appearance of angina1 pain. The work intensity corresponding to the pulse rate of 170 per minute (PWC1rU) was calculated using the approximate linear relationship of the work intensity and the pulse rate. The methods of catheterization of the right side of the heart using a double lumen catheter and cardiac output determination using the Fick principle were described previously in detail.7 The left ventricle was also catheterized in all cases. In 25 patients, a transseptal puncture technique was used using a modified instrument as described previously.8 In 8 cases the left ventricle was catheterized from the aorta using a modified Seldinger technique. One patient was studied via transthoracic left ventricle puncture. Twenty-four patients were exercised in the supine position using the bicycle ergometer during cardiac catheterization. The electrocardiogram and pressures were continuously recorded on a photographic recorder (Mingograf) and the expired gas was collected in Douglas bags between the fourth and sixth minute of exercise with simultaneous collection of arterial and mixed venous blood. The methods of expired gas analysis and determination of oxygen uptake were the same as in a previous report.’ Aortic valve area (AVAI) was calculated using the method of Gorlin and Gorlin.9 The mean systolic gradient was calculated from the simultaneous pressure recordings
Results
The mean and standard deviations of the body surface area, total hemoglobin, blood volume, heart volume, and heart
Table I. Some anthropometric data with mean values, standard deviation Group
I 1::
Abbreviations:
1 :;;zf
1
7 10 17
B.S.A.
7.X;.
! Tg..fb.
1.58~ 1.78* 1.70*
0.28 0.14 0.20
= Body
surface
( Bloof;?
594 * 129 628 *+ 149 596 138
area;
Hb.
4.53 4.88 4.61
= hemoglobin;
1 Hea;;fme
* 0.85 *f 0.77 0.71
AVAI
= aortic
704 * 793 * 1147
valve
area
~zr~ry~me
162 192 550
index.
421 * 72 4.51* * 80 637 286
1
,SVA&
1.07 0.62 0.38
* *
0.43 0.07 0.09
320
Lee Et (11.
volume per square meter of body surface are listed in Table I. The total amount of hemoglobin per kilogram of body weight is 9.6 Gm. in Groups I and II and 9.4 Gm. in Group III, the difference being insignificant. The average blood volume per kilogram of body weight is 75.4 ml. in Groups I and II and 73.5 ml. in Group III. The blood volume and the total hemoglobin per kilogram of body weight are not different from the normal individuals.7t1z The heart volume (HV) in prone position was measured in 32 cases and compared to the normal individuals with respect to the total hemoglobin. 7,13 In all patients with severe stenosis (Group III), the heart volume is above one standard error of estimate, whereas in all patients with mild stenosis (Group I) it is within two standard errors of estimate. (Fig. 1). The mean heart volume index (milliliters per square meter) was 50 per cent larger in Group III compared to Groups I or II. A slight (7 per cent) but significant difference was also found between I and II.
volume,
All patients were exercised in attempts to estimate the work capacity at the pulse rate of 170 per minute (PWC,,,). No symptoms were experienced by the 9 patients with mild stenosis (Group I). The average highest pulse obtained in this group was 169 per minute. Two of the eight patients of (Group II developed symptoms during exercise: one complained of a slight chest pain and the other of general fatigue. The average highest pulse rate obtained in this group was 160 per minute. However, all patients except one in Group III developed symptoms during exercise (chest pain in 8 and dyspnea and/or fatigue in 5). The average peak pulse for this group was 133 per minute. Thus, in 13 patients of Group III, the PWCllo could not be estimated due to symptoms. In normal individuals7*13 and athletes14 a close correlation exists between the working capacity (PWC,,,) and the total hemoglobin or heart volume. Thus, using these normal regressions a “normal” work capacity can be predicted. In only 2 of the 14 pa-
ml A( 2600)
,’ 200
/ /’ LOO
THb, g 600
800
Fig. 1. Correlation between heart volume and total amount of hemoglobin cates the normal regression and the broken lines f one and two standard l = Group-II; A = Group III.
1000 line indi(T 2%). The continuous I, errors of estimate7Js 0 = Group
Volume Number
79 3
Hemodynamic
tients in Groups I and II, the PWClyo was below 70 per cent of the predicted value. Similarly in only 3 of the 14 patients, the PWC170 was below the two standard errors of estimate according to their heart volumes. Aortic valve area index (AVAI) varied from 1.64 to 0.21 cm.2 per square meter. The mean value and the standard deviation is listed in Table I. Basal oxygen consumption (v02) was measured using a Krogh spirometer a few days before cardiac catheterization. The predicted mean value according to Harris and Benedict is 212 ml. of STPD per minute and the actual value obtained is 226 ml. of STPD per minute. The difference is not significant. Resting VOZ during catheterization was 24 per cent higher than the basal VOZ obtained. The difference is similar to the results found in other patients in this laboratory. Cardiac output and other data obtained by cardiac catheterization are presented in Table II. Cardiac output was measured in
Cardiac 20 -
cha.nges in patients with aortic stenosis
all at rest and in 24 patients during exercise (Fig. 2). In comparison to the normal values established in this laboratory, the resting cardiac output is abnormally low for the \iO, in 3 patients of Group III but in no patient was abnormally high cardiac output found. The cardiac index is compared to the normal material in Table III. The mean cardiac index of Groups I and II is not different from the normal values, whereas it is significantly low in Group III (p
output I lmin
Oaygen 0’0
321
200
400
1000
2000
uptake
ml .StPO Imh
Fig. 2. Correlationbetweencardiacoutput and oxygenuptake at rest (left panel)and during exercise(right panel).Regression linesand symbolsasin Fig. 1. In cases with abnormallylow cardiacoutput during exercise, the valuesSt restand during exerciseareconnectedby continuouslines.Normalregression equation:Q = 6.24 + 0.0061 VO*, r = 0.96, S.E.E. = e1.33, n = 97.7J2
.‘Imrr. Heart J. Marc-h. 1970
Lee et al.
322
Table II. The data obtained by cardiac catheterization
Case NO.
Work load (kpm./min.)
1 2 3
Rest Rest Rest 250 500 Rest 600 Rest 400 Rest 400 800 Rest 600 Rest Rest 600 Rest 200 Rest 300 600 Rest 400 Rest 150 Rest Rest 300 600 Rest 600 Rest 400 800 Rest 200 Rest 200 Rest Rest Rest 137 Rest 400 Rest 200 Rest
7 8 9 10 11
12 13 14 15
16 17
18 19 20 21 22 23 24 25 Abbreviations:
Kpm..
kilopondmeters;
Pulse/n&
141 86 69 103 141 78 142 99 149 71 114 154 79 156 119 81 143 79 123 82 104 131 82 135 105 144 68 71 10.5 156 81 150 57 99 138 86 132 113 154 84 74 75 97 67 115 104 140 89 PA, pulmonary
’
Oxygen uptake (ml./min.)
A-V02 difference (ml/L.)
214 229 206 698 1084 325 1.518 253 1227 334 1091 1938 290 1481 191 313 1650 232 710 273 948 1391 288 1133 309 648 312 243 948 1632 311 1.546 351 1197 2207 240 810 208 585 263 308 248 576 252 1046 406 348 248 arterial;
at rest and during exercise
’
27 28 33 65 80 47 93 32 86 32 72 101 41 11 34 36 107 32 69 29 70 92 37 83 32 59 41 43 79 103 48 125 47 95 114 41 72 29 56 51 36 42 69 50 106 92 137 51 PCV,
pulmonary
Cardiac output (L./min.)
7.81 7.95 6.20 10.8 13.5 6.87 16.38 7.88 14.32 10.50 15.17 19.17 7.10 13.80 5.60 8.60 15.50 7.85 10.29 9.60 13.50 15.10 7.72 13.62 9.63 11.02 7.68 5.7 12.0 15.8 6.51 12.31 7.5 12.6 19.3 5.81 11.20 7.80 10.50 5.20 8.50 5.85 8.30 5.00 9.00 4.40 6.18 4.83 capillary
venous;
Stroke volume (ml. 1
55 88 90 104 96 88 11.5 79 96 143 133 125 90 89 47 106 108 100 82 114 130 115 94 101 92 77 113 80 114 101 80 82 132 126 140 68 85 69 68 62 115 79 86 75 86 42 44 54 LV, left ventricular;
Systolic period (Ill00 sec.)
24.6 28.6 26.4 22.0 32.0 27.0 21.2 30.9 26.7 30.7 25.1 27.6 23.9 31.2 30.0 27.0 21.8 29.6 24.6 31.1 37.1 37.0
31.3 34.5 26.0 31.9 26.2 26.1 22.5 33.5 30.9 29.5 35.9 30.25 28.9 22.4
LA, left atrial;
AVAI,
Volume Number
79 3
Hemodynamic
Pressures
aortic
27 20 31
13 10 1.5
20 15 20
26 37 24 40 22 28 42 23 36 17 26 47 17
11 1.5 10 14 9 8 9 12 16 13 10 16 7
16 24 17 21 16 18 23 17 26 15 17 29 13 23 14 22 23 20 33 14
21 30 30 27 49 18 4.5 31 18 30 44 26 44 22 53 56 22
8 1.5 17 15 18 9 25 16 8 10 10 16 30 1.5 34 33 11
20 34 33 28 3.5 41 26 49 80 110 43
6 16 11 14 17 28 16 24 43 59 16
valve
area
index;
20 13 19 23 21 19 4.5 44 17
1.5
11 15 10 11
12 14 11
9 1.5 16 14 11
9
11 14
14 21 20 26 34 19 59 8.5 31 S. systolic;
18
43
D, diastolic.
M.
(mm.
Hg)
117 90 91 12.5 123 107 141 118 121 103 114 120 117 130 111 111 117 113 120 89 107 116 135 143 94
84 60 66 63 82 67 83 73 79 70 80 88 73 76 79
103
77: 77 78 69 79 82 86 89 64
100
103 114 118 130 136 176 94 12 120 94
6.5 72 77 86 84 101 63 80 80 68
99 115 106 106 1.50 158 118 133 118 163 103
70 79 65 72 96 94
mean;
:; 75 95 60 ED,
323
changes in patients with aortic stenosis
end-diastolic.
98 83 107 97 80 92 101 94 100
92
99 109 113 67 86 84 91 108 103
100 103 79
84 117 117 87 107 93 12.5 7.5
134 117 117
13 9 12
120
14
0.85
141
11
0.88
127
12
1.41
136 159 151 203 244 182 210 160
1.5 18 10 17 22 10 1.5 1.5
0.87
185 224 200
18 21 16
197 164
22 12
178 212 173 193
14 18 28
192 245 190 242 175 216 200
14 14 12 17 25 26 24
172 227 182 252 235
21 33 36 47 30
17
12 9
1.64 1.38 1.46
10 11 13 8 13 10
0.70 0.66
13 16 12 20 17
0.74
0.62 0.55
0.59 0.51 0.61
10 19 12 25
0.59
9 9 10 13 17 17 17 19 16 27 35
0.39
0.31
20
0.27
0.60
0.48 0.42 0.47 0.49 0.45
324
Amev. Heart J. March, 1970
Lee et al.
Table II----Co&d. I
I I
Case No.
’
Work load (kpm./min.)
26 27 28
Rest Rest Rest 300 Rest 200 Rest 400 Rest Rest 400 Rest 300 Rest 300
29 30 31 32 33 34
Abbreviations:
Kpm.,
Oxygen uptake (ml./min.)
~ Pulse/m&z. ~
77 66 79 129 75 107 83 130 82 67 139 73 98 80 112
kilopondmeters;
A-V02 difference (ml./L.)
382 280 294 994 252 897 304 1085 280 267 838 245 885 378 1005
PA, pulmonary
arterial;
/
Cardiac output (L./w&.)
Stroke volume (ml.)
7.11 3.0 5.7 10.0 6.2 11.6 7.54 10.18 6.1 5.86 7.87 5.7 9.0 10.27 9.51
92 45 72 77 83 108 91 78 74 88 55 78 91 128 85
53 94 52 100 40 77 40 107 46 46 111 43 99 37 105
PCV,
pulmonary
capillary
venous;
LV.
left ventricular;
/
Systolic period (l/l00 sec.)
37.0 35.5 37.5 26.7 35.2 30.1
33.0 33.0 33.4 34.1 30.0
LA, left atrial;
Table II I. Cardiac index (L./rr~in./iW.~) Normal*
Group
Probability
*References
7 and
~ Mean
/ *S.D.
I n
~ Mean
4.19
0.76
28
4.89
Normal
I II III
p > p >
p <
/ :S.D. 1.06
0.1 0.2 0.001
/ n 7
~ Mean 4.55 I-II II-III I and II-III
/ 1l.D.
/ n
~ Mean
1 y1.D.
1 n
10
3.27
1.00
17
0.90 p >
p < p <
0.4 0.01 0.001
12.
between Groups I and II and the normal subjects is not significant. In normal individuals the mean stroke volume (SV) during exercise is about 2 per cent of the total blood volume.7J2 The average stroke volume at rest and during exercise in Group I is 2.3 per cent, in Group II 2.2 per cent, and in Group III 1.6 per cent of the blood volume. The difference between Group III and the other two groups is .significant. Similarly, the mean stroke index is significantly decreased in Group III (42 ml. per square meter) com-
pared to Groups I and II (60 ml. per square meter). During exercise, the stroke volume increased in 3 and decreased in 4 patients and it was unchanged in the remaining. In 28 patients, the aortic pressure tracings were satisfactory for the measurement of systolic period which is estimated from the beginning of the upstroke to the incisura (Table III). At rest, in 10 patients (3 in Group II and 7 in Group III), the systolic period is longer than two standard errors of estimate in relation to heart rate (Fig. 3). All in Group I are within the
AVAI,
Volume Number
79 3
Hemodynamic
Pressures
(mm.
325
changes in patients with aortic stenosis
Hg)
s ! p / IM()pr /1 s (*r / M1 s /r ED11 cct!.c% 56 96 47 82 38 58
24 43 23 48 16 27 13 22 17 11 40 10 19 11 19
2 47 28 63 29 56 3.5 53
aortic
valve
area
index;
39 62 34 65 26 44 17 35 29 17 52 16 39 23 34
S. systolic;
Systolic
12.5 124 106 168 119 132 112 138 106 148 185 118 134 153 154
iz
9 3.5 12 15 40 8 16
D, diastolic,
duration,
M, mean;
64 58 57 84 73 81 6.5 75 59 84 91 64 79 82 90
ED,
83 79 118 92 103 87 100 99 132 88 104 106 116
230 199 263 323 230 252 230
43 32 33 43 22 32 25
0.32
165 226
24 20
13
220 248 236
25 33 21
10 27 1.5 30
26 48 12 26
0.32 0.31
0.37 0.48 0.39 0.32
0.49
end-diastolic.
set
0.35
0.30
025
0.20 \ ‘\
. Heart
O.lS Fig. 3. Correlation between the systolic duration and the heart and symbols as in Fig. 1. Normal regression equation: systolic ~2.03, n = 62.rJ2
r8te
150 beattlmh rate at rest and during exercise. Regression lines duration = 37.8 - 0.106, heart rate S.E.E. =
326
.4mer. Heart 1. March, 1970
Lee et al.
LVEDP.
mmHg
Fig. 4. Correlation between the left ventricular end-diastolic pressure (LVEDP) and the left ventricular systolic pressure (LIr.52’). The continuous line indicates regression and the broken lines one standard error of estimate. Regression equation: LVEDP = 0.145 X LVSP - 6.95, S.E.E. = ~7.18, n = 43. The resting and exercise values are connected by continuous lines. Symbols as in Fig. 1.
normal range. In 15 the systolic duration was measured during exercise. Four of these show abnormally prolonged systolic period at rest while only one is prolonged during exercise. The systolic ejection period is measured from the simultaneous aortic and left ventricular pressure tracings as the period during which systolic gradient is present across the aortic valve. The mean ratio of systolic ejection period over the cardiac cycle in seconds is 37 per cent in Group I, 38 per cent in Group II, and 40 per cent in Group III at rest. The differences are not significant. The mean pulmonary capillary venous (PCV) pressure was 0.8 mm. Hg higher than the mean left atria1 pressure in 11 patients in whom both pressures were measured at rest. In 24 cases the left atria1 pressure was recorded, and in the remaining 10, the PCV mean pressure was used in the following calculation. The mean left
atria1 or PCV pressure is 11.4 mm. Hg in Group I, 10.7 mm. Hg in Group II, and 17.7 mm. Hg in Group III. The difference between Group III and Groups I or II is significant. During exercise, the left atria1 or PCV mean pressure was measured in 19 cases. The pressure increased in all except one. In 12 cases, the mean left atria1 or PCV pressure is 15 mm. Hg or higher at rest, and all these patients complained of either dyspnea or chest pain during the exercise test except one (No. 14). The mean left ventricular end-diastolic pressure (LVEDP) was 12 mm. Hg in Group I, 15 mm. Hg in Group II, and 2.5 mm. Hg in Group III. The difference between Group III and Groups I and II is highly significant. Of 15 cases with LVEDP above 20 mm. Hg at rest, all except one belong to Group III. In these with markedly elevated LVEDP, only one (No. 14) was able to perform the exercise test without having any
V&me Number
79 3
Hemodynamic
LVSWI,
changes in patients with aortic stenosis
327
g-M/beat/m2
LVEOP
lb Fig. 5. Correlation diastolic pressure in Fig. 1.
between (LVEDP).
i0 the left ventricular The resting and
%I stroke work exercise values
symptoms and in the remaining 14 either dyspnea or chest pain occurred during the exercise test. During rest and exercise, there is a close positive correlation between the left ventricular systolic pressure and the LVEDP (Fig. 4). In every case except one, the LVEDP increased during exercise. The LVEDP rises more during exercise in Group III than in the other groups. The resting mean pulmonary artery pressure was above 25 mm. Hg in 8 cases of Group III. During exercise, the mean pulmonary artery pressure increased further in all of these patients (Table II). The mean pulmonary vascular resistance index (unit per square meter) is 1.25 f 0.64 in normal individuals,7J2 1.22 f 0.21 in Group I, 1.36 f 0.88 in Group II, and 4.11 f 4.83 in Group III. It is significantly increased in Group III compared to the normal individuals. During exercise, the pulmonary vascular resistance either remained unchanged or increased slightly. The systemic vascular resistance at rest is within normal limits in all except one patient (No. 22) in comparison to the normal individuals. During exercise, the
index (LVSWI) are connected
40
mm Hg
and the left ventricular endby continuous lines. Symbols as
mean aortic pressure and the systemic resistance changed normally in relation to the cardiac output in all cases except 4 in whom these were abnormally high. In no case was the systemic resistance abnormally low in relation to cardiac output at rest or during exercise. The left ventricular stroke work varied from 39 to 130 with the mean of 86 gmM./ beat/M.2. At rest the average value in Group I is 71 f 13, in Group II 100 f 24, and in Group III 82 f 2.5gmM./beat/M.2. The difference between Groups I and II is significant, but the differences between Groups I and III or Groups II and I II are not significant. In many casesof Group III, the stroke work is considerably lower compared to the casesof Group I or II in spite of the marked elevation in the left ventricular end-diastolic pressure (Fig. 5). The mean left ventricular work in Group I is 6.2, in Group II 8.1, in Group III 6.6 Kg.-MJminJM.2, and the mean of the total material is 7.0 Kg.-M./min./M.2. Discussion
Cardiac index has been reported to be either decreased2J5or increased’s-is in pa-
328
Lee et al.
tients with aortic stenosis. Hancock and Fleming l7 found that cardiac output is above normal during investigation using a transthoracic puncture technique and they attributed this to the increased coronary blood flow. In the present study, no patient was found to have an abnormally increased cardiac output (in relation to the ir02) at rest or during exercise. In patients with mild to moderate aortic stenosis, cardiac output was normal, whereas it was significantly reduced in patients with severe stenosis. SimiIar observations were made by Wade and Bishoplg and others.4v5 The basal VO, is not increased from the predicted value. Although the myocardial blood flow and oxygen consumption is increased in these patients, it may not be sufficient to increase significantly the overall cardiac output or basal 00,. In order to analyze the factors which determine cardiac output and stroke volume in aortic stenosis, the hydraulic formula by Gorlin and Gorling may be expressed: SV = sep X AVA X 44.5 X -4 Ap where Ap is the mean systolic gradient. It is evident that with a progressively smaller AVA, either sep and/or the pressure gradient must increase in order to maintain the normal cardiac output. In patients with severe stenosis, the systolic period measured from the aortic pressure curves shows a general prolongation, as has been found in other studies,20-22 and the pressure gradient is markedly increased but these compensatory mechanisms appear to be insufficient to maintain a normal cardiac output. During exercise, the systolic period was found to decrease in patients with aortic stenosis as in normal individuals (Fig. 3). As the effective valve area is fixed in severely stenotic valve, the mean systolic pressure gradient must increase further during exercise to maintain the stroke volume of rest. However, as the flow is related to the square root of the pressure gradient and the peak systolic pressure that can be generated by the left ventricle is limited, a critical stenosis must result in diminished stroke volume. Thus, the stroke volume in patients with severe stenosis was significantly reduced compared to the
.lmrr.
Heart
March,
.I. 1970
normal group as well as in the patients with mild to moderate stenosis. A close correlation was found between the capacity to perform exercise and the degree of aortic stenosis. X’Iost patients with mild to moderate stenosis were able to perform exercise reaching a pulse rate of above 160 per minute without symptoms. However, in the patients with severe stenosis, the exercise tolerance was markedly reduced due to symptoms of angina1 pain and dyspnea or fatigue. In this group, the exercise had to be stopped due to these symptoms \vith pulse rate of only 126 per minute. Dyspnea during exercise tests occurred in patients with elevated left atria1 pressure. In these patients, the left atria1 pressure, the pulmonary capillary venous pressure, and the pulmonary artery systolic pressure increased further during exercise. Chest pain during exercise tests occurred in patients with severe stenosis and older age. In addition to the increased myocardial oxygen consumption due to the aortic stenosis,23t24 the coexisting coronary artery disease expected to be present in older patients may explain the high incidence of angina symptoms during exercise in these older patients. The work capacity corresponding to the heart rate of 170 per minute (PWC,,,) was possible to measure only in patients with mild to moderate stenosis. In the majority of these patients, the PWC170 was normal in relation to their total hemoglobin and the heart volume. This is in keeping with their normal stroke volume during exercise as the PWClyo depends on the oxygen pulse (ii0, per heart beat), which is the product of stroke volume and the arteriovenous 02 difference. The ejection fraction (SV/EDV) is an index of myocardial function. Therefore, it is reasonable to regard the ratio of stroke volume over the heart volume (SV/HV) as a function of myocardial efficiency. This index is found to correlate with left ventricular end-diastolic pressure (Fig. 6, r = -0.76), aortic valve area index (Fig. 7, r = 0.70), and age (r = -0.76). All these correlation coefficients are highly significant. The average SV/HV index is 14 per cent (8 to 20 per cent) in Groups I and II
Volume Number
79 3
Hemodynamic changesin patients with aortic stenosis
329
Stroke vol. I heart vol. 20 5% l
0
00.0 l
I5
0
0
0
0
.
.
0 .
*
0
ia
4
A
A
l
A .
0
A
A
l
4
A
. A A
LVEDP 10
15
Fig. 6. Correlation diastolic pressure
Stroke 20
20
between (LVEDP).
25
30
stroke volume in percentage of the heart y = -0.76. Symbols as in Fig. 1.
3s volume
and
the
40 mm Hg left
ventricular
end-
vol. I heart vol. to
15
0
0
00
0
l
l e
l
0 lr
.
la A .
.
.
.
.
0 0
. l
.
l d A
0
A A
Aortlc 0.5
Fig. 7. Correlation between Symbols as in Fig. 1.
stroke
volume
1.0 in percentage
of the heart
volume
valve area
cm*lm* and the aortic
valve
1.5 BSA area.
r = 0.70.
330
Lee et cd.
and 8 per cent (2 to 12 per cent) in Group III. Stroke volume during exercise was used for this calculation except in those who were not exercised during cardiac catheterization. During experimentally increased pressure load on the left ventricle, the enddiastolic pressure and systolic pressure shows a positive correlation in animals.25 A similar observation was made for human subjects as well. 26 A general positive correlation of LVEDP and LV systolic pressure was found in this study at rest and during exercise (Fig. 4). During exercise, the LVEDP increased in most patients, and the rise was more marked in patients with severe stenosis and of older age. This increase in LVEDP during exercise signifies the reduced myocardial compliance and the depressed myocardial functions in patients with aortic stenosis. In pulmonary stenosis, the positive correlation between the right ventricular systolic and the end-diastolic was also found.27 In most cases with increased LVEDP, the mean left atria1 or pulmonary capillary venous pressure remains considerably lower than the LVEDP. The importance of the left atria1 contraction in left ventricular diseasehas been pointed out by Braunwald and Frahm.28They found that the mean left atria1 pressure was 0.2 mm. Hg lower than the LVEDP in normal individuals, but a difference of 9 mm. Hg was found in patients with an abnormal left ventricle. The difference in these pressures was 1 mm. Hg in Group I, 4.4 mm. Hg in Group II, and 7.4 mm. Hg in Group III. The average resting left ventricular stroke work was higher (31 per cent) in patients with moderate stenosis than in those with mild stenosis. However, in patients with severe stenosis, the stroke work was lower (15 per cent) compared to the group of patients with moderate stenosis, in spite of the significantly higher LVEDP. Thus, the left ventricular function is depressed in patients with severe aortic stenosis compared to the milder group. Summary
Hemodynamic studies and estimations of heart volume and work capacity were carried out in 34 patients with “pure” aortic stenosis and the findings were cor-
related to the degree of stenosis estimated by the calculated valve area. In a majority of patients with mild stenosis (Group I) and moderate stenosis (Group II), cardiac output, stroke volume, heart volume, pulmonary vascular resistance, and work capacity were “normal.” However, in patients with severe stenosis (Group III), cardiac output and stroke volume were significantly decreased, heart volume and pulmonary vascular resistance were increased, and the left ventricular function assessedby the LVEDP and stroke work or the coefficient of the stroke volume and heart volume was depressed. The exercise tolerance was markedly decreased in Group III due to symptoms of angina1 pain or dyspnea. In those patients, the LVEDP was markedly elevated. The LVSP and LVEDP showed a positive correlation at rest and during exercise. The LVEDP and LVSP increased during exercise in most patients.
REFERENCES 1. Gorlin, R., McMillan, I. K. R., Medd, W. E., Matthews, M. B., and Daley, R.: Dynamics of the circulation in aortic valvular diseases, Amer. J. Med. 18:855, 1955. 2. Goldberg, H., Denton, C., Bender, S., and Uricchio, J.: The hemodynamic and clinical characteristic of rheumatic aortic stenosis, Dis. Chest 33:201, 1958. <. 1 Kleinman, J., and Sancetta, S. M.: Effect of mild steady state exercise on general and cerebral hemodynamics of patients with aortic stenosis, J. Clin. Invest. 35:717, 1956. 4. Cullhed, I.: Aortic stenosis, Stockholm, 1964. Almqvist and Wiksell, p. 39. 5. Holmeren. A.. and Mattson. K. H.: A new ergom\ter’with constant load ‘at varying pedalling rate in the supine and in the sitting position, S&d. J. Clin. Lab. Invest. 6:137, 1954. 6. Siostrand. T.: Functional canacitv and exercise tolerance in patients with’ impaired cardiovascular function. Clinical cardiopulmonary physiology, New York, 1960, Grune & Stratton, Inc., p. 201. 7. Bevegard, S., Holmgren, A., and Jonsson, B.: The effect of body position on the circulation at rest during exercise, with special reference to the influence of the stroke volume, Acta Physiol. Stand. 49:279, 1960. 8. Beveglrd, S., Jonsson, B., and Karlof. I.: A modified instrument for percutaneous transseptal catheterization of the left atrium, Stand. J. Clin. Lab. Invest. 15:436, 1963. 9. Gorlin, R., and Gorlin, S. G.: Hydraulic formula for calculation of the area of the stenotic mitral
Volume Number
10.
11.
12.
13. 14.
1.5.
79 3
Hemodynamic
valve, other cardiac valves and central circulatory shunt, AMER. HEART J. 41:1, 1951. Kjellberg, S. R., Rudhe, U., and Sjostrand, T.: The relation of the cardiac volume to the weieht and surface area of the body, the blood volume and the physical capacity of work, Acta Radiol. Stockholm 31:113, 1949. Sjostrand, T.: A method for determination of total hemoglobin content of the body, Acta Physiol. Stand. 16:20, 1948. Holmgren, A., Jonsson, B., and Sjostrand, T.: Circulatory data in normal subject at rest and during exercise in recumbent position with special reference to the stroke volume at different work load, Acta Physiol. Stand. 49:343, 1960. Snedecor, G. W.: Statistical methods, Ames, Iowa, 1959, Iowa State College Press. Bevegird, S., Holmgren, A., and Jonsson, B.: Circulatorv studv in well trained athletes at rest and during- heavy exercise, with special reference to stroke volume and the influence of body oositions. Acta Phvsiol. Stand. 49:279. 1960. . . Goldberg, H., Basket, A. A., and Bailey, C. P.: The dynamics of aortic valvular diseases, AMER.
HEART
J. 47:527,
changes in patients with aortic stenosis
W. H., Jr.: Relationship between left ventricular ejection time, stroke volume and heart rate in normal individuals and patients with cardiovascular disease, AMER. HEART J. 62:367, 1961. 21. Katz. L. N.. Rallis. E. P.. and Cheer. S. N.: The cardiodynamic’changes in the aorta and left ventricle due to stenosis of the aorta, J. Clin. Invest. 5:202, 1928. 22. Benchimol, A., Dimond, E. G., and Shen, Y.: Ejection time in aortic stenosis and mitral stenosis, comparison between the direct and indirect arterial tracings with special reference to pre and post-operative findings, Amer. J. Cardiol. 5:728, 1960. 23. Blumenthal, M. R., Wang, H. H., and Wang, S. C.: The effect of acute experimental aortic stenosis on coronary circulation, Circ. Res. 11:727, 24.
2s.
26.
1954.
16. Dexeter, L., Harken, D. E., Cobb, L. A., Novack, P., Schlant, R. C., Phinney, A. O., and Hayes, F. W.: Aortic stenosis, Arch. Intern. Med. 101:254, 1958. 17. Hancock, E. W., and Fleming, D. R.: Aortic stenosis, Quart. J. Med. 29:209, 1960. 18. Braunwald, E., Goldblatt, A., Aygaen, M. M., Rukoff, D., and Morrow, A. G.: Congenital aortic stenosis. I. Clinical and hemodynamic findings in 100 patients, Circulation 27:426, 1963. 19, Wade, 0. L., and Bishop, J. M.: Cardiac output and regional blood flow, Oxford, 1962, Blackwell Scientific Publications, p. 129. 20. Weissler, A. M., Peeler, R. G., and Roche,
331
27.
28.
1962.
Gren, H. D.: The coronary blood flow in aortic stenosis, in aortic insufficiency and in arteriovenous fistula, Amer. J. Physiol. 115:94, 1936. Goodyer, A. V. N., Goodkind, J. J., and Landry, A. B.: Ventricular response to a pressure load. Left ventricular function curve in intact animal, Circ. Res. 10:885, 1962. Braunwald, E., Frye, R. L., Aygaen, M. M., and Gilbert, J. W., Jr.: Studies on Starling’s law of the heart. III. Observation in patients with mitral stenosis and aortic stenosis on the relationship between left ventricular enddiastolic segment length, filling pressure and the characteristics of ventricular contraction, Clin. Invest. 39:1874, 1960. Ikkos, D., Jonsson, B., and Linderholm, H.: Physical working capacity and circulatory adaption to exercise in pulmonary stenosis with intact ventricular septum evaluated by heart catheterization, Brit. Heart J. In press. Braunwald, E., and Frahm, C. J.: Studies on Starling’s law of the heart. IV. Observation on the hemodynamic function of the left atrium in man, Circulation 24:633, 1961.
F.R.C.P.(C.)
mhe effects of exercise on circulation in 1 patients with aortic stenosis have been reported previously,1-4 but attempts have not been made to correlate the hemodynamic abnormalities to the severity of the stenosis, nor were the left ventricular pressures studied during exercise. The purpose of this communication is to report the hemodynamic effects of exercise in relation to the severity of the disease in patients with “pure” aortic stenosis. Attempts were also made to measure the capacity for muscular work in a quantitative manner and to analyze the limiting factors of working capacity. Material
Thirty-four patients were selected for this study on the basis of a diagnosis of isolated aortic stenosis (rheumatic and congenital) following cardiac catheterization. Aortic root aortography* was also carried out in patients with the murmur of aortic regurgitation and only those with a slight regurgitation were included. All cases have valvular stenosis except one who has mem-
branous subvalvular stenosis. Cases of muscular subaortic or supravalvular stenosis were excluded. The material is classified into three groups according to the calculated aortic valve area index (AVAI) in square centimeters per square meter of body surface area. In Group I, AVAI is larger than 0.8, in Group II between 0.5 and 0.8, and in Group III less than 0.5 cm.2 per square meter. Clinically, Group I corresponds to mild stenosis, Group II to moderate stenosis, and Group III to severe stenosis. The age range is 10 to 59 years with the mean age being 34. The average age for Group I is 17 years, for Group II 25 years, and for Group III 46 years. Procedures
American Heart Journal
and
methods
Physical working capacity (PWC) was determined on an electrically braked constant load bicycle ergometer5 ’ using the method of Sjiistrand.6 The work load was successively increased every 6 minutes with an aim to achieve a steady pulse rate of 150 per minute to 170 per minute in 3
From the Laboratory of Clinical Physiology, Thoracic Clinic, Karolineka Received for publication April 28. 1969. Reprint requests to: Dr. Simon J. K. Lee, University of Alberta Hospital, *This was carried out by the department of Radiology.
318
exercise severity
March,
Sjukhuset, Edmonton,
1970
Stockholm, Alberta,
Vol. 79,
Sweden. Canada.
NO.
3, gp. 318-331
Volume
79
Number
3
Hemodynamic
319
changes in patients with aortic stenosis
in the left ventricle and the aorta in 29 patients and the withdrawal pressure tracings in the remaining 5 patients. A planimeter was used to calculate the area of the pressure gradient and the left ventricular mean systolic pressure (LVMSP). The left ventricular stroke work index (LVSWI) was calculated as follows: LVSWI (gmM. per beat per square meter) = 13.6 X (LVMSP - LVEDP) X SI, where LVEDP = left ventricular enddiastolic pressure (in millimeters of Hg) and SI = stroke index (in milliliters per square meter). The left ventricular work index (LVWI) was obtained by substituting the cardiac index for the stroke index in the above formula and expressing as Kg.-M. per minute per square meter. Pulmonary vascular resistance (PVR) is expressed as the ratio of the mean pressure gradient (mm. Hg) across the pulmonary vascular bed and the cardiac output (liters per minute). Systemic resistance was calculated by dividing the mean aortic pressure by cardiac output. The heart volume was calculated from simultaneously exposed biplane chest x-rays in prone position according to the method of Kjellberg and associates.rO Total hemoglobin was estimated using the carbon monoxide method of Sjiistrand.” The various parameters of these patients were compared to the normal values obtained in this laboratory using same methods.rJ2 The statistical analysis was carried out using the conventional methods,13 and the P value of less than 0.05 was defined as significant.
work loads. The electrocardiogram was monitored every minute and the heart rate was calculated from it. The exercise was continued until either a pulse rate of 150 to 170 per minute was achieved or the patient was unable to exercise due to symptoms. Because of the possible risk, exercise was stopped with the appearance of angina1 pain. The work intensity corresponding to the pulse rate of 170 per minute (PWC1rU) was calculated using the approximate linear relationship of the work intensity and the pulse rate. The methods of catheterization of the right side of the heart using a double lumen catheter and cardiac output determination using the Fick principle were described previously in detail.7 The left ventricle was also catheterized in all cases. In 25 patients, a transseptal puncture technique was used using a modified instrument as described previously.8 In 8 cases the left ventricle was catheterized from the aorta using a modified Seldinger technique. One patient was studied via transthoracic left ventricle puncture. Twenty-four patients were exercised in the supine position using the bicycle ergometer during cardiac catheterization. The electrocardiogram and pressures were continuously recorded on a photographic recorder (Mingograf) and the expired gas was collected in Douglas bags between the fourth and sixth minute of exercise with simultaneous collection of arterial and mixed venous blood. The methods of expired gas analysis and determination of oxygen uptake were the same as in a previous report.’ Aortic valve area (AVAI) was calculated using the method of Gorlin and Gorlin.9 The mean systolic gradient was calculated from the simultaneous pressure recordings
Results
The mean and standard deviations of the body surface area, total hemoglobin, blood volume, heart volume, and heart
Table I. Some anthropometric data with mean values, standard deviation Group
I 1::
Abbreviations:
1 :;;zf
1
7 10 17
B.S.A.
7.X;.
! Tg..fb.
1.58~ 1.78* 1.70*
0.28 0.14 0.20
= Body
surface
( Bloof;?
594 * 129 628 *+ 149 596 138
area;
Hb.
4.53 4.88 4.61
= hemoglobin;
1 Hea;;fme
* 0.85 *f 0.77 0.71
AVAI
= aortic
704 * 793 * 1147
valve
area
~zr~ry~me
162 192 550
index.
421 * 72 4.51* * 80 637 286
1
,SVA&
1.07 0.62 0.38
* *
0.43 0.07 0.09
320
Lee Et (11.
volume per square meter of body surface are listed in Table I. The total amount of hemoglobin per kilogram of body weight is 9.6 Gm. in Groups I and II and 9.4 Gm. in Group III, the difference being insignificant. The average blood volume per kilogram of body weight is 75.4 ml. in Groups I and II and 73.5 ml. in Group III. The blood volume and the total hemoglobin per kilogram of body weight are not different from the normal individuals.7t1z The heart volume (HV) in prone position was measured in 32 cases and compared to the normal individuals with respect to the total hemoglobin. 7,13 In all patients with severe stenosis (Group III), the heart volume is above one standard error of estimate, whereas in all patients with mild stenosis (Group I) it is within two standard errors of estimate. (Fig. 1). The mean heart volume index (milliliters per square meter) was 50 per cent larger in Group III compared to Groups I or II. A slight (7 per cent) but significant difference was also found between I and II.
volume,
All patients were exercised in attempts to estimate the work capacity at the pulse rate of 170 per minute (PWC,,,). No symptoms were experienced by the 9 patients with mild stenosis (Group I). The average highest pulse obtained in this group was 169 per minute. Two of the eight patients of (Group II developed symptoms during exercise: one complained of a slight chest pain and the other of general fatigue. The average highest pulse rate obtained in this group was 160 per minute. However, all patients except one in Group III developed symptoms during exercise (chest pain in 8 and dyspnea and/or fatigue in 5). The average peak pulse for this group was 133 per minute. Thus, in 13 patients of Group III, the PWCllo could not be estimated due to symptoms. In normal individuals7*13 and athletes14 a close correlation exists between the working capacity (PWC,,,) and the total hemoglobin or heart volume. Thus, using these normal regressions a “normal” work capacity can be predicted. In only 2 of the 14 pa-
ml A( 2600)
,’ 200
/ /’ LOO
THb, g 600
800
Fig. 1. Correlation between heart volume and total amount of hemoglobin cates the normal regression and the broken lines f one and two standard l = Group-II; A = Group III.
1000 line indi(T 2%). The continuous I, errors of estimate7Js 0 = Group
Volume Number
79 3
Hemodynamic
tients in Groups I and II, the PWClyo was below 70 per cent of the predicted value. Similarly in only 3 of the 14 patients, the PWC170 was below the two standard errors of estimate according to their heart volumes. Aortic valve area index (AVAI) varied from 1.64 to 0.21 cm.2 per square meter. The mean value and the standard deviation is listed in Table I. Basal oxygen consumption (v02) was measured using a Krogh spirometer a few days before cardiac catheterization. The predicted mean value according to Harris and Benedict is 212 ml. of STPD per minute and the actual value obtained is 226 ml. of STPD per minute. The difference is not significant. Resting VOZ during catheterization was 24 per cent higher than the basal VOZ obtained. The difference is similar to the results found in other patients in this laboratory. Cardiac output and other data obtained by cardiac catheterization are presented in Table II. Cardiac output was measured in
Cardiac 20 -
cha.nges in patients with aortic stenosis
all at rest and in 24 patients during exercise (Fig. 2). In comparison to the normal values established in this laboratory, the resting cardiac output is abnormally low for the \iO, in 3 patients of Group III but in no patient was abnormally high cardiac output found. The cardiac index is compared to the normal material in Table III. The mean cardiac index of Groups I and II is not different from the normal values, whereas it is significantly low in Group III (p
output I lmin
Oaygen 0’0
321
200
400
1000
2000
uptake
ml .StPO Imh
Fig. 2. Correlationbetweencardiacoutput and oxygenuptake at rest (left panel)and during exercise(right panel).Regression linesand symbolsasin Fig. 1. In cases with abnormallylow cardiacoutput during exercise, the valuesSt restand during exerciseareconnectedby continuouslines.Normalregression equation:Q = 6.24 + 0.0061 VO*, r = 0.96, S.E.E. = e1.33, n = 97.7J2
.‘Imrr. Heart J. Marc-h. 1970
Lee et al.
322
Table II. The data obtained by cardiac catheterization
Case NO.
Work load (kpm./min.)
1 2 3
Rest Rest Rest 250 500 Rest 600 Rest 400 Rest 400 800 Rest 600 Rest Rest 600 Rest 200 Rest 300 600 Rest 400 Rest 150 Rest Rest 300 600 Rest 600 Rest 400 800 Rest 200 Rest 200 Rest Rest Rest 137 Rest 400 Rest 200 Rest
7 8 9 10 11
12 13 14 15
16 17
18 19 20 21 22 23 24 25 Abbreviations:
Kpm..
kilopondmeters;
Pulse/n&
141 86 69 103 141 78 142 99 149 71 114 154 79 156 119 81 143 79 123 82 104 131 82 135 105 144 68 71 10.5 156 81 150 57 99 138 86 132 113 154 84 74 75 97 67 115 104 140 89 PA, pulmonary
’
Oxygen uptake (ml./min.)
A-V02 difference (ml/L.)
214 229 206 698 1084 325 1.518 253 1227 334 1091 1938 290 1481 191 313 1650 232 710 273 948 1391 288 1133 309 648 312 243 948 1632 311 1.546 351 1197 2207 240 810 208 585 263 308 248 576 252 1046 406 348 248 arterial;
at rest and during exercise
’
27 28 33 65 80 47 93 32 86 32 72 101 41 11 34 36 107 32 69 29 70 92 37 83 32 59 41 43 79 103 48 125 47 95 114 41 72 29 56 51 36 42 69 50 106 92 137 51 PCV,
pulmonary
Cardiac output (L./min.)
7.81 7.95 6.20 10.8 13.5 6.87 16.38 7.88 14.32 10.50 15.17 19.17 7.10 13.80 5.60 8.60 15.50 7.85 10.29 9.60 13.50 15.10 7.72 13.62 9.63 11.02 7.68 5.7 12.0 15.8 6.51 12.31 7.5 12.6 19.3 5.81 11.20 7.80 10.50 5.20 8.50 5.85 8.30 5.00 9.00 4.40 6.18 4.83 capillary
venous;
Stroke volume (ml. 1
55 88 90 104 96 88 11.5 79 96 143 133 125 90 89 47 106 108 100 82 114 130 115 94 101 92 77 113 80 114 101 80 82 132 126 140 68 85 69 68 62 115 79 86 75 86 42 44 54 LV, left ventricular;
Systolic period (Ill00 sec.)
24.6 28.6 26.4 22.0 32.0 27.0 21.2 30.9 26.7 30.7 25.1 27.6 23.9 31.2 30.0 27.0 21.8 29.6 24.6 31.1 37.1 37.0
31.3 34.5 26.0 31.9 26.2 26.1 22.5 33.5 30.9 29.5 35.9 30.25 28.9 22.4
LA, left atrial;
AVAI,
Volume Number
79 3
Hemodynamic
Pressures
aortic
27 20 31
13 10 1.5
20 15 20
26 37 24 40 22 28 42 23 36 17 26 47 17
11 1.5 10 14 9 8 9 12 16 13 10 16 7
16 24 17 21 16 18 23 17 26 15 17 29 13 23 14 22 23 20 33 14
21 30 30 27 49 18 4.5 31 18 30 44 26 44 22 53 56 22
8 1.5 17 15 18 9 25 16 8 10 10 16 30 1.5 34 33 11
20 34 33 28 3.5 41 26 49 80 110 43
6 16 11 14 17 28 16 24 43 59 16
valve
area
index;
20 13 19 23 21 19 4.5 44 17
1.5
11 15 10 11
12 14 11
9 1.5 16 14 11
9
11 14
14 21 20 26 34 19 59 8.5 31 S. systolic;
18
43
D, diastolic.
M.
(mm.
Hg)
117 90 91 12.5 123 107 141 118 121 103 114 120 117 130 111 111 117 113 120 89 107 116 135 143 94
84 60 66 63 82 67 83 73 79 70 80 88 73 76 79
103
77: 77 78 69 79 82 86 89 64
100
103 114 118 130 136 176 94 12 120 94
6.5 72 77 86 84 101 63 80 80 68
99 115 106 106 1.50 158 118 133 118 163 103
70 79 65 72 96 94
mean;
:; 75 95 60 ED,
323
changes in patients with aortic stenosis
end-diastolic.
98 83 107 97 80 92 101 94 100
92
99 109 113 67 86 84 91 108 103
100 103 79
84 117 117 87 107 93 12.5 7.5
134 117 117
13 9 12
120
14
0.85
141
11
0.88
127
12
1.41
136 159 151 203 244 182 210 160
1.5 18 10 17 22 10 1.5 1.5
0.87
185 224 200
18 21 16
197 164
22 12
178 212 173 193
14 18 28
192 245 190 242 175 216 200
14 14 12 17 25 26 24
172 227 182 252 235
21 33 36 47 30
17
12 9
1.64 1.38 1.46
10 11 13 8 13 10
0.70 0.66
13 16 12 20 17
0.74
0.62 0.55
0.59 0.51 0.61
10 19 12 25
0.59
9 9 10 13 17 17 17 19 16 27 35
0.39
0.31
20
0.27
0.60
0.48 0.42 0.47 0.49 0.45
324
Amev. Heart J. March, 1970
Lee et al.
Table II----Co&d. I
I I
Case No.
’
Work load (kpm./min.)
26 27 28
Rest Rest Rest 300 Rest 200 Rest 400 Rest Rest 400 Rest 300 Rest 300
29 30 31 32 33 34
Abbreviations:
Kpm.,
Oxygen uptake (ml./min.)
~ Pulse/m&z. ~
77 66 79 129 75 107 83 130 82 67 139 73 98 80 112
kilopondmeters;
A-V02 difference (ml./L.)
382 280 294 994 252 897 304 1085 280 267 838 245 885 378 1005
PA, pulmonary
arterial;
/
Cardiac output (L./w&.)
Stroke volume (ml.)
7.11 3.0 5.7 10.0 6.2 11.6 7.54 10.18 6.1 5.86 7.87 5.7 9.0 10.27 9.51
92 45 72 77 83 108 91 78 74 88 55 78 91 128 85
53 94 52 100 40 77 40 107 46 46 111 43 99 37 105
PCV,
pulmonary
capillary
venous;
LV.
left ventricular;
/
Systolic period (l/l00 sec.)
37.0 35.5 37.5 26.7 35.2 30.1
33.0 33.0 33.4 34.1 30.0
LA, left atrial;
Table II I. Cardiac index (L./rr~in./iW.~) Normal*
Group
Probability
*References
7 and
~ Mean
/ *S.D.
I n
~ Mean
4.19
0.76
28
4.89
Normal
I II III
p > p >
p <
/ :S.D. 1.06
0.1 0.2 0.001
/ n 7
~ Mean 4.55 I-II II-III I and II-III
/ 1l.D.
/ n
~ Mean
1 y1.D.
1 n
10
3.27
1.00
17
0.90 p >
p < p <
0.4 0.01 0.001
12.
between Groups I and II and the normal subjects is not significant. In normal individuals the mean stroke volume (SV) during exercise is about 2 per cent of the total blood volume.7J2 The average stroke volume at rest and during exercise in Group I is 2.3 per cent, in Group II 2.2 per cent, and in Group III 1.6 per cent of the blood volume. The difference between Group III and the other two groups is .significant. Similarly, the mean stroke index is significantly decreased in Group III (42 ml. per square meter) com-
pared to Groups I and II (60 ml. per square meter). During exercise, the stroke volume increased in 3 and decreased in 4 patients and it was unchanged in the remaining. In 28 patients, the aortic pressure tracings were satisfactory for the measurement of systolic period which is estimated from the beginning of the upstroke to the incisura (Table III). At rest, in 10 patients (3 in Group II and 7 in Group III), the systolic period is longer than two standard errors of estimate in relation to heart rate (Fig. 3). All in Group I are within the
AVAI,
Volume Number
79 3
Hemodynamic
Pressures
(mm.
325
changes in patients with aortic stenosis
Hg)
s ! p / IM()pr /1 s (*r / M1 s /r ED11 cct!.c% 56 96 47 82 38 58
24 43 23 48 16 27 13 22 17 11 40 10 19 11 19
2 47 28 63 29 56 3.5 53
aortic
valve
area
index;
39 62 34 65 26 44 17 35 29 17 52 16 39 23 34
S. systolic;
Systolic
12.5 124 106 168 119 132 112 138 106 148 185 118 134 153 154
iz
9 3.5 12 15 40 8 16
D, diastolic,
duration,
M, mean;
64 58 57 84 73 81 6.5 75 59 84 91 64 79 82 90
ED,
83 79 118 92 103 87 100 99 132 88 104 106 116
230 199 263 323 230 252 230
43 32 33 43 22 32 25
0.32
165 226
24 20
13
220 248 236
25 33 21
10 27 1.5 30
26 48 12 26
0.32 0.31
0.37 0.48 0.39 0.32
0.49
end-diastolic.
set
0.35
0.30
025
0.20 \ ‘\
. Heart
O.lS Fig. 3. Correlation between the systolic duration and the heart and symbols as in Fig. 1. Normal regression equation: systolic ~2.03, n = 62.rJ2
r8te
150 beattlmh rate at rest and during exercise. Regression lines duration = 37.8 - 0.106, heart rate S.E.E. =
326
.4mer. Heart 1. March, 1970
Lee et al.
LVEDP.
mmHg
Fig. 4. Correlation between the left ventricular end-diastolic pressure (LVEDP) and the left ventricular systolic pressure (LIr.52’). The continuous line indicates regression and the broken lines one standard error of estimate. Regression equation: LVEDP = 0.145 X LVSP - 6.95, S.E.E. = ~7.18, n = 43. The resting and exercise values are connected by continuous lines. Symbols as in Fig. 1.
normal range. In 15 the systolic duration was measured during exercise. Four of these show abnormally prolonged systolic period at rest while only one is prolonged during exercise. The systolic ejection period is measured from the simultaneous aortic and left ventricular pressure tracings as the period during which systolic gradient is present across the aortic valve. The mean ratio of systolic ejection period over the cardiac cycle in seconds is 37 per cent in Group I, 38 per cent in Group II, and 40 per cent in Group III at rest. The differences are not significant. The mean pulmonary capillary venous (PCV) pressure was 0.8 mm. Hg higher than the mean left atria1 pressure in 11 patients in whom both pressures were measured at rest. In 24 cases the left atria1 pressure was recorded, and in the remaining 10, the PCV mean pressure was used in the following calculation. The mean left
atria1 or PCV pressure is 11.4 mm. Hg in Group I, 10.7 mm. Hg in Group II, and 17.7 mm. Hg in Group III. The difference between Group III and Groups I or II is significant. During exercise, the left atria1 or PCV mean pressure was measured in 19 cases. The pressure increased in all except one. In 12 cases, the mean left atria1 or PCV pressure is 15 mm. Hg or higher at rest, and all these patients complained of either dyspnea or chest pain during the exercise test except one (No. 14). The mean left ventricular end-diastolic pressure (LVEDP) was 12 mm. Hg in Group I, 15 mm. Hg in Group II, and 2.5 mm. Hg in Group III. The difference between Group III and Groups I and II is highly significant. Of 15 cases with LVEDP above 20 mm. Hg at rest, all except one belong to Group III. In these with markedly elevated LVEDP, only one (No. 14) was able to perform the exercise test without having any
V&me Number
79 3
Hemodynamic
LVSWI,
changes in patients with aortic stenosis
327
g-M/beat/m2
LVEOP
lb Fig. 5. Correlation diastolic pressure in Fig. 1.
between (LVEDP).
i0 the left ventricular The resting and
%I stroke work exercise values
symptoms and in the remaining 14 either dyspnea or chest pain occurred during the exercise test. During rest and exercise, there is a close positive correlation between the left ventricular systolic pressure and the LVEDP (Fig. 4). In every case except one, the LVEDP increased during exercise. The LVEDP rises more during exercise in Group III than in the other groups. The resting mean pulmonary artery pressure was above 25 mm. Hg in 8 cases of Group III. During exercise, the mean pulmonary artery pressure increased further in all of these patients (Table II). The mean pulmonary vascular resistance index (unit per square meter) is 1.25 f 0.64 in normal individuals,7J2 1.22 f 0.21 in Group I, 1.36 f 0.88 in Group II, and 4.11 f 4.83 in Group III. It is significantly increased in Group III compared to the normal individuals. During exercise, the pulmonary vascular resistance either remained unchanged or increased slightly. The systemic vascular resistance at rest is within normal limits in all except one patient (No. 22) in comparison to the normal individuals. During exercise, the
index (LVSWI) are connected
40
mm Hg
and the left ventricular endby continuous lines. Symbols as
mean aortic pressure and the systemic resistance changed normally in relation to the cardiac output in all cases except 4 in whom these were abnormally high. In no case was the systemic resistance abnormally low in relation to cardiac output at rest or during exercise. The left ventricular stroke work varied from 39 to 130 with the mean of 86 gmM./ beat/M.2. At rest the average value in Group I is 71 f 13, in Group II 100 f 24, and in Group III 82 f 2.5gmM./beat/M.2. The difference between Groups I and II is significant, but the differences between Groups I and III or Groups II and I II are not significant. In many casesof Group III, the stroke work is considerably lower compared to the casesof Group I or II in spite of the marked elevation in the left ventricular end-diastolic pressure (Fig. 5). The mean left ventricular work in Group I is 6.2, in Group II 8.1, in Group III 6.6 Kg.-MJminJM.2, and the mean of the total material is 7.0 Kg.-M./min./M.2. Discussion
Cardiac index has been reported to be either decreased2J5or increased’s-is in pa-
328
Lee et al.
tients with aortic stenosis. Hancock and Fleming l7 found that cardiac output is above normal during investigation using a transthoracic puncture technique and they attributed this to the increased coronary blood flow. In the present study, no patient was found to have an abnormally increased cardiac output (in relation to the ir02) at rest or during exercise. In patients with mild to moderate aortic stenosis, cardiac output was normal, whereas it was significantly reduced in patients with severe stenosis. SimiIar observations were made by Wade and Bishoplg and others.4v5 The basal VO, is not increased from the predicted value. Although the myocardial blood flow and oxygen consumption is increased in these patients, it may not be sufficient to increase significantly the overall cardiac output or basal 00,. In order to analyze the factors which determine cardiac output and stroke volume in aortic stenosis, the hydraulic formula by Gorlin and Gorling may be expressed: SV = sep X AVA X 44.5 X -4 Ap where Ap is the mean systolic gradient. It is evident that with a progressively smaller AVA, either sep and/or the pressure gradient must increase in order to maintain the normal cardiac output. In patients with severe stenosis, the systolic period measured from the aortic pressure curves shows a general prolongation, as has been found in other studies,20-22 and the pressure gradient is markedly increased but these compensatory mechanisms appear to be insufficient to maintain a normal cardiac output. During exercise, the systolic period was found to decrease in patients with aortic stenosis as in normal individuals (Fig. 3). As the effective valve area is fixed in severely stenotic valve, the mean systolic pressure gradient must increase further during exercise to maintain the stroke volume of rest. However, as the flow is related to the square root of the pressure gradient and the peak systolic pressure that can be generated by the left ventricle is limited, a critical stenosis must result in diminished stroke volume. Thus, the stroke volume in patients with severe stenosis was significantly reduced compared to the
.lmrr.
Heart
March,
.I. 1970
normal group as well as in the patients with mild to moderate stenosis. A close correlation was found between the capacity to perform exercise and the degree of aortic stenosis. X’Iost patients with mild to moderate stenosis were able to perform exercise reaching a pulse rate of above 160 per minute without symptoms. However, in the patients with severe stenosis, the exercise tolerance was markedly reduced due to symptoms of angina1 pain and dyspnea or fatigue. In this group, the exercise had to be stopped due to these symptoms \vith pulse rate of only 126 per minute. Dyspnea during exercise tests occurred in patients with elevated left atria1 pressure. In these patients, the left atria1 pressure, the pulmonary capillary venous pressure, and the pulmonary artery systolic pressure increased further during exercise. Chest pain during exercise tests occurred in patients with severe stenosis and older age. In addition to the increased myocardial oxygen consumption due to the aortic stenosis,23t24 the coexisting coronary artery disease expected to be present in older patients may explain the high incidence of angina symptoms during exercise in these older patients. The work capacity corresponding to the heart rate of 170 per minute (PWC,,,) was possible to measure only in patients with mild to moderate stenosis. In the majority of these patients, the PWC170 was normal in relation to their total hemoglobin and the heart volume. This is in keeping with their normal stroke volume during exercise as the PWClyo depends on the oxygen pulse (ii0, per heart beat), which is the product of stroke volume and the arteriovenous 02 difference. The ejection fraction (SV/EDV) is an index of myocardial function. Therefore, it is reasonable to regard the ratio of stroke volume over the heart volume (SV/HV) as a function of myocardial efficiency. This index is found to correlate with left ventricular end-diastolic pressure (Fig. 6, r = -0.76), aortic valve area index (Fig. 7, r = 0.70), and age (r = -0.76). All these correlation coefficients are highly significant. The average SV/HV index is 14 per cent (8 to 20 per cent) in Groups I and II
Volume Number
79 3
Hemodynamic changesin patients with aortic stenosis
329
Stroke vol. I heart vol. 20 5% l
0
00.0 l
I5
0
0
0
0
.
.
0 .
*
0
ia
4
A
A
l
A .
0
A
A
l
4
A
. A A
LVEDP 10
15
Fig. 6. Correlation diastolic pressure
Stroke 20
20
between (LVEDP).
25
30
stroke volume in percentage of the heart y = -0.76. Symbols as in Fig. 1.
3s volume
and
the
40 mm Hg left
ventricular
end-
vol. I heart vol. to
15
0
0
00
0
l
l e
l
0 lr
.
la A .
.
.
.
.
0 0
. l
.
l d A
0
A A
Aortlc 0.5
Fig. 7. Correlation between Symbols as in Fig. 1.
stroke
volume
1.0 in percentage
of the heart
volume
valve area
cm*lm* and the aortic
valve
1.5 BSA area.
r = 0.70.
330
Lee et cd.
and 8 per cent (2 to 12 per cent) in Group III. Stroke volume during exercise was used for this calculation except in those who were not exercised during cardiac catheterization. During experimentally increased pressure load on the left ventricle, the enddiastolic pressure and systolic pressure shows a positive correlation in animals.25 A similar observation was made for human subjects as well. 26 A general positive correlation of LVEDP and LV systolic pressure was found in this study at rest and during exercise (Fig. 4). During exercise, the LVEDP increased in most patients, and the rise was more marked in patients with severe stenosis and of older age. This increase in LVEDP during exercise signifies the reduced myocardial compliance and the depressed myocardial functions in patients with aortic stenosis. In pulmonary stenosis, the positive correlation between the right ventricular systolic and the end-diastolic was also found.27 In most cases with increased LVEDP, the mean left atria1 or pulmonary capillary venous pressure remains considerably lower than the LVEDP. The importance of the left atria1 contraction in left ventricular diseasehas been pointed out by Braunwald and Frahm.28They found that the mean left atria1 pressure was 0.2 mm. Hg lower than the LVEDP in normal individuals, but a difference of 9 mm. Hg was found in patients with an abnormal left ventricle. The difference in these pressures was 1 mm. Hg in Group I, 4.4 mm. Hg in Group II, and 7.4 mm. Hg in Group III. The average resting left ventricular stroke work was higher (31 per cent) in patients with moderate stenosis than in those with mild stenosis. However, in patients with severe stenosis, the stroke work was lower (15 per cent) compared to the group of patients with moderate stenosis, in spite of the significantly higher LVEDP. Thus, the left ventricular function is depressed in patients with severe aortic stenosis compared to the milder group. Summary
Hemodynamic studies and estimations of heart volume and work capacity were carried out in 34 patients with “pure” aortic stenosis and the findings were cor-
related to the degree of stenosis estimated by the calculated valve area. In a majority of patients with mild stenosis (Group I) and moderate stenosis (Group II), cardiac output, stroke volume, heart volume, pulmonary vascular resistance, and work capacity were “normal.” However, in patients with severe stenosis (Group III), cardiac output and stroke volume were significantly decreased, heart volume and pulmonary vascular resistance were increased, and the left ventricular function assessedby the LVEDP and stroke work or the coefficient of the stroke volume and heart volume was depressed. The exercise tolerance was markedly decreased in Group III due to symptoms of angina1 pain or dyspnea. In those patients, the LVEDP was markedly elevated. The LVSP and LVEDP showed a positive correlation at rest and during exercise. The LVEDP and LVSP increased during exercise in most patients.
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Volume Number
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11.
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79 3
Hemodynamic
valve, other cardiac valves and central circulatory shunt, AMER. HEART J. 41:1, 1951. Kjellberg, S. R., Rudhe, U., and Sjostrand, T.: The relation of the cardiac volume to the weieht and surface area of the body, the blood volume and the physical capacity of work, Acta Radiol. Stockholm 31:113, 1949. Sjostrand, T.: A method for determination of total hemoglobin content of the body, Acta Physiol. Stand. 16:20, 1948. Holmgren, A., Jonsson, B., and Sjostrand, T.: Circulatory data in normal subject at rest and during exercise in recumbent position with special reference to the stroke volume at different work load, Acta Physiol. Stand. 49:343, 1960. Snedecor, G. W.: Statistical methods, Ames, Iowa, 1959, Iowa State College Press. Bevegird, S., Holmgren, A., and Jonsson, B.: Circulatorv studv in well trained athletes at rest and during- heavy exercise, with special reference to stroke volume and the influence of body oositions. Acta Phvsiol. Stand. 49:279. 1960. . . Goldberg, H., Basket, A. A., and Bailey, C. P.: The dynamics of aortic valvular diseases, AMER.
HEART
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changes in patients with aortic stenosis
W. H., Jr.: Relationship between left ventricular ejection time, stroke volume and heart rate in normal individuals and patients with cardiovascular disease, AMER. HEART J. 62:367, 1961. 21. Katz. L. N.. Rallis. E. P.. and Cheer. S. N.: The cardiodynamic’changes in the aorta and left ventricle due to stenosis of the aorta, J. Clin. Invest. 5:202, 1928. 22. Benchimol, A., Dimond, E. G., and Shen, Y.: Ejection time in aortic stenosis and mitral stenosis, comparison between the direct and indirect arterial tracings with special reference to pre and post-operative findings, Amer. J. Cardiol. 5:728, 1960. 23. Blumenthal, M. R., Wang, H. H., and Wang, S. C.: The effect of acute experimental aortic stenosis on coronary circulation, Circ. Res. 11:727, 24.
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16. Dexeter, L., Harken, D. E., Cobb, L. A., Novack, P., Schlant, R. C., Phinney, A. O., and Hayes, F. W.: Aortic stenosis, Arch. Intern. Med. 101:254, 1958. 17. Hancock, E. W., and Fleming, D. R.: Aortic stenosis, Quart. J. Med. 29:209, 1960. 18. Braunwald, E., Goldblatt, A., Aygaen, M. M., Rukoff, D., and Morrow, A. G.: Congenital aortic stenosis. I. Clinical and hemodynamic findings in 100 patients, Circulation 27:426, 1963. 19, Wade, 0. L., and Bishop, J. M.: Cardiac output and regional blood flow, Oxford, 1962, Blackwell Scientific Publications, p. 129. 20. Weissler, A. M., Peeler, R. G., and Roche,
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Gren, H. D.: The coronary blood flow in aortic stenosis, in aortic insufficiency and in arteriovenous fistula, Amer. J. Physiol. 115:94, 1936. Goodyer, A. V. N., Goodkind, J. J., and Landry, A. B.: Ventricular response to a pressure load. Left ventricular function curve in intact animal, Circ. Res. 10:885, 1962. Braunwald, E., Frye, R. L., Aygaen, M. M., and Gilbert, J. W., Jr.: Studies on Starling’s law of the heart. III. Observation in patients with mitral stenosis and aortic stenosis on the relationship between left ventricular enddiastolic segment length, filling pressure and the characteristics of ventricular contraction, Clin. Invest. 39:1874, 1960. Ikkos, D., Jonsson, B., and Linderholm, H.: Physical working capacity and circulatory adaption to exercise in pulmonary stenosis with intact ventricular septum evaluated by heart catheterization, Brit. Heart J. In press. Braunwald, E., and Frahm, C. J.: Studies on Starling’s law of the heart. IV. Observation on the hemodynamic function of the left atrium in man, Circulation 24:633, 1961.