Impact of Doppler-derived left ventricular diastolic performance on exercise capacity in normal individuals

Impact of Doppler-d&rived performance on exercise individuals Hiroyuki Kiyoshi

Ok&, Yoshida,

MD,a I-Iiroo Inoue, MD,b Miyo Tomon, MD,” Shoji Nishiyama, MD,= and Junichi Yoshikawa, MDd Kobe and Osaka, Japan

Background in patients

with

independent

diseases

To clarify

All underwent

Bruce was

assessed

left ventricular

as well

of noncardiac

equivalent was

er d erived

Doppl heart

Methods

left ventricular diastolic capacity in normal

individuals.

indexes

have

However,

been

shown

it is uncertain

Yoshikawa,

to correlate

whether

they

with predict

MD,a

exercise

capacity

exercise

capacity

factors. th e impact

protocol

of the LV diastolic

treadmill

calculated by Doppler

(LV) diastolic

as heolthy

MD,= Tadashi

from

stress

exercise

transmitral

testing

time flow

index and

capacity,

2-dimension01

(metabolic

velocity

on exercise

and

equivalent

pattern.

160

Doppler

function

individuals

were

echocardiography.

= 1.1 1 + 0.0

Pulmonary

healthy

16

tests

exercise

x

and

investigated.

Estimated time).

complete

metabolic

Diastolic

blood

cell

performance count

were

(A):

r = -0.5

also

performed.

Results

LV diastolic

P C .OOOl;

ratio

correlation

between

by multivariate younger

age

cardiac

and

LV systolic

analysis

were

(P = .OOSO),

ConchJsion of other

indexes

of early

c&d

extracardiac

well

transmitrol

indexes higher

Dopplerderived and

correlated late

and E/A

higher

with

filling metabolic

(P < ,000

factors.

concentration

index (Am

equivolent (E/A):

equivalent. 1 ), higher

hemoglobin

IV diastolic

metabolic

velocities

may

Heort

help J 2000;

Previous studies have suggested that measurements of left ventricular systolic indexes do not predict maximal exercise time in normal individuals or in patients with impaired left ventricular Cunction.l-‘2 Some authors have shown that echocardiographic Doppler indexes of left ventricular diastolic function are associated with exercise capacity in normal individuakl~* However, these previous reports have observed relatively small numbers of individuals and have not included other data that might affect exercise capacity, such as body mass index, pulmonary fkction, and hematologic data. Because of these limitations in previous reports, it is not clear whether left ventricular dia.+ tolic function is the strongest predictor of exercise capacity independent of other noncardiac factors. Therefore this From the aDepariment of Internal Medicine, Kobe Rehabilitation Hospital; the bDe poriment of Internal Medicine, Maikodd Hospital, Kobe; the ~Division of Cordial. ogy, Kobe General Hospital, and the %t Deportment of Internal Medicine, Osaka City University Medical School. Submitted May 3, 1999; accepted October 7, 1999. Reprint requests: Hiroyuki Okura, MD, Center for Research in Cardiovascular Interventions, Stanford University School of Medicine, 300 Pasteur Drive, H3554, Stanford, CA 94305. E-mail: hokvraYeland.stanford.edu Copyright Q 2000 by Mosby, Inc. 0002.8703/2000/S 12.00 + 0 4/l/103551 doi: IO. 1067/mhj.2000. IO355 I

vitol

(peak

transmitral

filling

velocity

r = 0.58,

P < .OOOl

Independent

predictors

for o higher

(P = .OO 1 ), smaller

body

capacity

). However,

there

was

metabolic

mass

index

1,

no significant equivalent (P = .0003),

(P = .0026). in predicting

exercise

capacity

in normal

individuals

independent

139:716-22.)

study was undertaken to evaluate whether Dopplerderived left ventricular diastolic index is the independent predictor of exercise capacity in normal individuals.

Methods Normal individuals who received a medical checkup in the Kobe Rehabilitation Hospital between April 1995 and August 1996 were enrolled in this study. Exclusion criteria included a baseline rhythm of atrial fibrillation; long-term use of any medication; history of hypertension, diabetes mellitus, cardiovascular disease; and exercise-limiting musculoskeletal, hematologic, or pulmonary diseases. Individuals were also excluded if they had positive results for ischemic heart disease by treadmill exercise test or were diagnosed as having diabetes mellitus by oral glucose tolerance test. All individuals underwent M-mode, Zdimensional, and Doppler echocardiographic studies, the Bruce protocol treadmill exercise test, and a pulmonary function test. Complete blood count examinations, serum chemistry screenings (including total and HDL cholesterol), and oral glucose tolerance tesfs were also performed. All individuals gave informed consent according to a protocol approved by the Human Study Committee of the Kobe Rehabilitation Hospital.

Exercise The Bruce tom-limited

test protocol maximal

for multistage exercise was

treadmill testing of symp used.13 This began with

Amerlcon Heart journal Volume I39 Number 4

Table

I. Clinical

Okura

characteristics

in 160

normal

individuals

Total Iv) Female (%) Body mass index (kg/m2) Echocardiagraphic parameters LVDd (cm) LVDs (cm) FS 1%) LAD (cm) AaD (cm) LVEDV (ml) LVESV [ml) EF (%) IVST (cm) PW T (cm) LV mass (g) Peak early transmitral filling velocity (m/s) Peak late transmitral filling velocity (m/s) E/A ratio Deceleration time of the early transmitral filling velocity Pulmonary function

(1) during

the first second

(n = 160)

54.5

Age

vc (Ll Forced VC (1) Forced expiratory volume Forced expiratory volume Hematologic data RBC (xl 04/mm2) Hemoglobin (g/dl) Hemotocrit (%)

et 01 717

f 8.0

Male

(n = 101)

Female

(n = 59)

53.9

+ 8.3

55.5

+ 7.5

38

(ms)

(%)

24.6

+ 2.9

24.8

i

2.6

24.2

-+3.4

4.7 2.8 39.9 3.2 2.9 103.8 3 1.3 70.0

* 0.4 f 0.4 zlc 5.7 f 0.4 k 0.3 f 20.3

4.8 3.0 38.9 3.2 3.0

f f f f f

0.4 013 5.9 0.4 0.2

A.5 2.6 41.4

f 0.4 + 3.5 + 5.3

f 9.5

f 6.9

l.O?O.l 0.9kO.l 158.2 f 32.6 0.69f0.14 0.60+0.15 1.2 1 f 0.37 201.9 f 27.3

3.5 3.3 2.9 88.8 457.7 14.0 42.1

f f f f

0.9 0.8 0.7 6.7

k 42.7 f 1.4 ? 3.9

110.1

34.4 68.7

+ 19.3

+ 9.0 f 7.0

l.Of0.1 1.OIf:O.l

69.1 f 28.8 0.66f0.13 0.56f0.14 1.25 f 0.38

99.9

3~ 28.5

3.9 3.7 3.3 88.3

+ k k f

470.1 14.5

43.6

0.7 0.7 0.6 6.4

f 38.3 f 1.2 L!Y3.2

3.1 kO.3

2.7 f 0.3 93.3 k 17.6 26.3 + 8.2 72.0 + 6.2 0.9kO.l 0.9 f 0.1 139.6 + 30.5 0.73f0.15 0.67 z!z 0.13 1.15f0.34 205.4 f 25.9

2.7 2.6 2.3 89.8

f f f f

0.5 0.5 0.5 7.2

435.1 +41.3 12.9f 1.2 39.3 + 3.4

IVDd, Left ventricular diastolic dimension; LVDs, left ventricular systolic dimension; FS, fractional shortening; LAD, left otriol dimension; AoD, oortic dimension; LVEDV, left ventrice lor end-diastolic volume; LVESV, left ventliculor end-systolic volume; MT, interventricular septum thickness; PWT, posterior wall thickness; LV, left ventricular; REC. red blood cell.

walking slowly for 3 minutes at 1.7 m/h at a 10% grade; speed and gnde then increased every 3 minutes until exhaustion. As an index of exercise capacity, estimated metabolic equivalent of workload was calculated from the exercise time as metabolic equivalent = 1 .l 1 + 0.016 x (exercise time in seconds).1.i-16 Echocardiographic study All individuals underwent echocardiographic examination within 24 hours after treadmill exercise test. Echocardiographic examination was performed with a commercially available echocardiographic machine (SSHl60A, Toshiba Medical Co, Tokyo, Japan) equipped with 2.5- and 3.75-MHz phased-array transducers. M-mode and 2dimensional examinations were performed from the standard parastemal and apical approaches with the individual in the left lateral decubitus position. Left ventricular end-diastolic and end-systolic dimensions and fractional shortening were measured according to the recommendations of the American Society of Echocardiography.L7 Left ventricular end-diastolic and endsystolic volumes and left ventricular ejection fraction (LVEF) were calculated by the previously reported formula.18 Left ventricular mass was also calculated as previously reported.‘” Transmitral pulsed-wave Doppler signals were recorded to assess left ventricular diastolic performance from apical 4chamber view.z0’2 The sample volume was positioned at the tips of the mitral leaflets. Measurements included peak early

transmitral filling velocity (E), peak late transmitral filling velocity (A), the ratio of early and late transmitral filling velocities (E/A), and deceleration time of the early transmitral filling velocity (DcT; time from peak early transmitral velocity to baseline). Individuals with E/A ratio 21.0 were defined as the normal diastolic pattern group (group N), and those with E/A ratio c 1 .O were defined as the abnormal relaxation pattern group (group A). We analyzed correlation between exercise time and both cardiac and nancardiac parameters. To determine the difference of the exercise capacity in the same age groups, we compared exercise time between group N and group A in those who were in their sixth and seventh decades, respectively. Statistical analysis The baseline characteristics of the 2 groups were compared with the Wilcaxon test (for continuous and ordinal variables) or x2 test (for categoric variables). Analysis of variance was used with the Scheffe test far multiple comparisons of group mean values. Univariate linear regression was performed to determine predictors of exercise capacity with age, body mass index, vital capacity (VC), forced expiratary volume during the first second aver forced VC (FEV 1 .O%>, hemoglobin cancentration, left ventricular mass, E, A, E/A, DcT, left ventricular end-diastolic and end-systolic dimensions, LVEF, and

718

Okura

Amer~con Heart Journal Apd 2000

et al

.2

.3

.4

.5

.6

.7

.8

.9

1

l.lW=C)

I

JI

.S .75

I 1

1 I 4 1.25 1.5 1.75

A

between

Table

of correlation

metabolic

between

equivalent

II. Baseline

and

peak

and

ratio

metabolic of eorly

hemodynamic

equivalent and

and

late transmitrol

peak

late filling

transmitral velocities

filling

velocity

(A).

8, Scattergrom

of correlation

(E/A).

data

Rest Systolic blood pressure Diastolic blood pressure Heart rate (beats/min) Rate-pressure products Stage Exercise time (s) Metabolic equivalent

2.25 2.5 2.75

E/A

. A, Scattergram

2

(mm Hg) (mm Hg)

the following variables at rest and peak exercise: systolic blood pressure, diastolic blood pressure, heart rate, and rate-pressure products. Univariate variables with P < .l were entered in a stepwise multivariate linear regression to determine the independent predictors of exercise capacity. Statistical significance was established at P < .Ol. AI1 statistical analyses were performed with Statview version 4.5 (SAS Institute).

Results Of the 178 individuals recruited, 18 were excluded because of positive electrocardiographic changes or a positive oral glucose tolerance test result, which left 160 individuals in our study population. There were 101 men and 59 women. Age ranged from 34 to 76

years (55 f 8 years). Clinical characteristics and baseline echocardiographic parameters are shown in Table I. Table II shows the hemodynamic parameters before and after peak exercise treadmill test. Systolic blood pressure, heart rate, and rate-pressure products increased significantly (P < .Ol). Diastolic blood pressure did not change significantly.

136.7 + 17.9 82.4 f 1 1 .O 75.1 + 14.2 10272k2366

Effects of cardiac bolic equivalent

Peak

P value

exercise

183.3 84.5 146.7 2685 1 2.7 384.1 7.25

f f + + f f zk

24.9 14.4 1 1 .o 3980 0.6 97.4 1.56

and noncardiac

co 1 NS co 1 co 1

factors

on meta-

Univariate predictors for a higher metabolic equivalent were a higher E/A, younger age, higher VC, and lower A (Table III, Figure 1). On the other hand, LVEF, LV mass, FEV 1.O%did not significantly correlate with metabolic equivalent (Table III, Figure 2). Multivariate analysis was performed with all univariate variables (P c . 10). The multivariate independent predictors for a higher metabolic equivalent were a higher ratio of E/A, younger age, higher VC, higher body mass index, and higher hemoglobin concentration (Table IV). Cardiac function and metabolic the same age groups

equivalent

among

Among 76 individuals in their sixth decade, 56 had a normal diastolic pattern (group N) and 20 had an abnormal relaxation pattern (group A). Although age and ejection fraction were similar between the 2 groups, group N had a significantly higher metabolic equivalent compared with group A (P < .Ol). Among 32 individu-

American Heart Journal Volume 139, Number 4

Figure

Okuro

2

3

..’ .

r=-O.lO p=O.2274

‘I’,‘,.,.,.,.,. 50 55 60

65

70

75

80

85

9OW)

3

r=O.o3 p=o.7397

.I *,~,‘,~,-,.I. 80 100 120 140 160 180 200 220 24OW

EF A, Scattergram of correlation and left ventricular mass.

Table 111. Univariate metabolic equivalent

LV mass

between

analysis

metabolic

of factors

equivalent

that correlate

Correlation coefficient

and LVEF. B, Scattergram

of correlation

E/A ratio

filling

velocity

Sex Hemoglobin Hematocrit Heart rote Deceleration time Systolic blood pressure Body moss index Peak early transmitral filling Diastolic blood pressure LV end-diastolic volume REC tV end-systolic volume FEV 1 .O% LVEF LV mass

velocity

0.58 -0.55 0.53 0.5 1 0.40 0.34 0.33 -0.30 -0.30 -0.28 0.26 0.24 -0.22 0.19 0.19 0.18 0.13 -0.10 0.03

IV, Left ventricle; RBC, red blood cell; FN I .O%, forced expiratory the first second over forced VC.

their seventh (Table v>.

als in

decade,

analysis

Regression coefficient

P value c.000 <.ooo

between

Table IV. Multiple regression with metabolic equivalent

with

(95%

Age vc Peak lote tronsmitral

et al

1 1

<.OOOl -coo0 1 <.OOOl

coo0 1 <.OOOl .OOOl

.0002 .0003 .0016 .0024 .0054 .0172 .0216 .0238 .1073 .2274 .7397 volume during

the results were the same

Discussion Our results show that of the parameters measured, left ventricular diastolic index as assessedby Doppler tmnsmitral flow velocity pattern was one of the strongest correlates of the exercise capacity in normal individuals independent of other cardiac and extracardiac factors.

E/A rotio vc Body moss index Age Hemoglobin

1.385 0.422 -0.1 16 -0.041 0.228

Cl)

(0,796-l ,975) (0.173-0.671) (-0.179-0.054) (-0.070-0.013) (0.081-0.375)

metabolic

equivalent

of factors

hat

Standardized regresrion coefficient 0.34 0.24 -0.22 -0.21 0.20

correlate

P value <.ooo 1 .OOlO .0003 .0050 .0026

Metabolic equivalent - 1.385 x (E/A ratio) + 0.422 x (VC) -0.1 16 x (body moss index) -0.041 x [age) + 0.228 x (hemoglobin) + 0.228. Multiple Rz value for model - 0.553; F = 34.878; P < ,000 1.

Although exercise capacity in patients with left ventricular dysfunction is limited, measures of left vemricular systolic function are poor predictors of exercise capacity.3.11 Echocardiographic Doppler indexes of left ventricular diastolic function have been reported to related to exercise capacity in patients with left ventricular systolic dysfunction.sl* Lewis et aI9 reported that exercise capacity after myocardial infarction did not correlate with LV systolic function but did with diastolic function. In their study, exercise capacity was inversely related to transmitral A velocity and directly to the VA. Recently several clinical observations have provided data on the significance of left ventricular diastolic dysfunction. About 30% to 40% of patients with congestive heart failure have been reported to have normal systolic function.*3-25 Left ventricular diastolic dysfunction in the absence of systolic dysfunction is the underlying cause of congestive heart failure in such patients. Since the introduction of the Doppler transmitral flow

719

American Heart Journal April 2C00

720 Okura et al

50-59 Group (n-54

Age (~1

Exercise time (5) Metabolic equivalent LVEF (%) E h/s) A (m/s) ’ E/A ratio Deceleration time (ms)

55.1 392.2 7.39 68.4 0.72 0.57 1.30 196.0

y (n - 76)

N

+ 2.9 f 85.8 f 1.37 f 4.9 fO.l 1 * 0.1 1 f 0.22 f 22.5

6049y(n=32) Group D (n = 20)

Group N (n = 14)

Group D (n = 18)

55.0 + 2.9 330.6 f 93.8” 6.40 a 1.50* 69.0 + 5.1 0.58 k 0.09* 0.69kO.12’ 0.85 f 0.08. 208.9 + 28.0

43.4 f 1.7 380.1 f 73.3 7.20 f 1.22 71.1 k7.4 0.68 + 0.10 0.56 f 0.10 1.23zk0.13 194.2 f 27.9

63.2 f 3.0 302.4 k 77.0 5.95* 1.21* 71.7 + 6.5 0.54f0.13 0.72kO.15’ 0.76 + 0.11 212.9f31.0

IV, left venlricl.. l Pc.Ol vrgroupN.

pattern analysii, noninvasive routine assessment of left ventricular diastolic function has become available.2~~ In normal young individuals, E/A is usually more than 1.O. With advancing age or myocudial diseases,E velocity is deaeased and A velocity is increased, reflecting impaired left ventricular mlaxation.31* Some investigators ha&reported on the association of left ventricular diastolic function and exetcise capacity in normal individualst~a Vanoverschelde et all studied 66 healthy individuals and found that the E/A was the strongest independent predictor of exercise capacity. Genovesi-Ebert et ala studied 20 healthy individuals and 34 patients with hypertension and showed that echocardiographic Doppler indexes of left ventricular filling were associated with exercise capacity. because these previous studies did not include extracardiac factors that might affect exercise capacity, it has been not clarified whether left ventricular diastolic function is a predictor of exercise capacity independent of pulmonary function,3s-37 body mass index,38 or hematologic conditions.3943

Although our study indicates that the echocardiographic Doppler-derived left ventricular diastolic index is highly predictive of the exercise capacity in normal individuals, its pathophysiology is still unclear. Several previous authors have reported some possible reasons for the exercise intolerance associated with diastolic dysfunction. Cuocolo et ala3 studied patients with essential hypertension and left ventricular hypertrophy and reported that an abnormal LVEF response during exercise in patients with impaired early diastolic f3ling was related to their decreased exercise capacity. They and other investigator9 found a significant correlation between left ventricular mass and diastolic indexes in patients with hypertension. Therefore left ventricular mass was suspected as one possible determinant of exercise capacity in patients with hypertension. However, Vanoverschelde et all and our data show no signifi-

cant correlation between left ventricular mass and exercise capacity in normal individuals. Thus we suppose the presence of diastolic dysfunction with or without increased left ventricular mass may limit left ventricular stroke volume to increase despite the elevated left ventricular filling pressure during exercise. In addition, compensatory tachycardia to increase cardiac output would cause a further deterioration in left ventricular filling. The direct relation between late peak velocity and pulmonary wedge pressure may be related to the poorer exercise performance as well. Our study has some limitations. First, peripheral muscular function, which can be another determinant of exercise capacity, was not evaluated in this study. Therefore, to minimize the influence of peripheral muscular function on the results, we excluded patients who exercised regularly. Second, although E/A ratio has been used as a simple and reproducible index of diastolic function, there are some known physiologic factors affecting transmitral flow pattern.** Therefore the ratio should not be interpreted as a measurement of all the complexities involved in diastolic function of the heart but as a representation of the overall diastolic filling characteristics of the heart.45 Third, smoking data were not available in our study. Smoking might affect exercise capacity by causing pulmonary dysfunction, hematologic abnormality (carbon monoxide toxicity), and autonomic dysfunction. Finally, although Bruce protocol treadmill testing has been widely used to assessexercise capacity, there may be some inaccuracy in estimating maximal exercise capacity or metabolic equivalent in patients with known cardiac diseases caused by relatively larger increments between stages compared to ramp protocol.*6 In healthy individuals such as our study population, the difference between Bruce and ramp protocol may be smaller.46 In addition, measurements of maximal oxygen consumption with direct gas exchange might be more accurate to evaluate

l

l

American Heart Journal Volume 139. Number 4

Okura

the exercise capacity. However, it was difficult to perform routinely in a large number of normal individuals, especially in a community hospital.47 In conclusion, our results suggest that even in apparently healthy individuals, exercise capacity is limited on the basis of diastolic dysfunction. Further investigation is necessary to clarify the impact of the abnormal diastolic indexes on future cardiac events and mortality rate. We thank MS Yasuko Yabuta, a sonographer, for her technical assistance.

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I, Shino T, Kondo

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