Download Atrial Ejection Force in Systemic Autoimmune Diseases

Noninvasive and Diagnostic Cardiology
Cardiology 1999;92:269–274
Received: May 15, 1999
Accepted after revision: October 11, 1999
Atrial Ejection Force in Systemic
Autoimmune Diseases
Roland Jahns a Johji Naito b Hans-Peter Tony a Gerhard Inselmann a
a Department
b Osaka
of Internal Medicine, Medizinische Poliklinik, University of Würzburg, Germany;
National Hospital, Osaka, Japan
Key Words
Systemic autoimmune disease W Systemic lupus
erythematosus W Rheumatoid arthritis W Atrial ejection
force W Cardiac diastolic filling abnormalities
Abstract
Systemic autoimmune disorders may affect several organs, including the heart. We analyzed two-dimensional
and pulsed Doppler echocardiograms of patients (n = 37)
with systemic lupus erythematosus (SLE, n = 24) or rheumatoid arthritis (RA, n = 13) to determine whether atrial
ejection force (AEF) could represent a suitable parameter
for detecting left ventricular filling abnormalities in SLE
and RA. In both patient subgroups, AEF was significantly
higher than in healthy controls (n = 40) matched for gender and age (14.0 B 5.4 vs. 11.0 B 3.5 kdyn, p ! 0.01).
Because conventional echocardiographic parameters of
left ventricular function failed to detect such a difference,
AEF might serve as an additional sensitive parameter for
detecting left ventricular diastolic filling abnormalities
early in the course of a systemic autoimmune disease.
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Introduction
In a large number of patients suffering from connective
tissue disorders or rheumatoid arthritis (RA) the inflammatory process and/or antibody- and complement-mediated immune reactions may also affect the heart. In
patients with systemic lupus erythematosus (SLE), several
clinical and autopsy studies revealed a high incidence of
cardiovascular manifestations involving the peri-, myo-,
and endocardium, the coronary arteries, and, most notably, the cardiac valves [1–4]. The prevalence of valvular
lesions was strongly associated with the presence of anticardiolipin antibodies, suggesting a causal link between
high levels of such antibodies and cardiac damage [3, 4].
However, more recently a latent impairment in left ventricular function has been described in patients suffering
from early-stage connective tissue disorders without any
obvious signs of cardiac disease and independent of the
actual anticardiolipin antibody levels [5–7]. Thus, it has
been suggested that cardiovascular mortality in systemic
autoimmune disease might more often be related to congestive heart failure secondary to (chronic) autoimmuneinduced myocardial damage than to valvular heart disease, coronary artery disease, or hypertension [8, 9]. In a
majority of the patients, left ventricular diastolic filling
abnormalities have been found to precede the impairment in left ventricular systolic function [3, 5–7]. Hence,
precise determination of cardiac diastolic function (or
dysfunction, respectively) should allow for early detection
Dr. Gerhard Inselmann
Medizinische Poliklinik der Universität Würzburg
Klinikstrasse 6–8
D–97070 Würzburg (Germany)
Tel. +49 931 201 7080, Fax +49 931 201 3539
Table 1. Clinical characteristics and
conventional two-dimensional and Doppler
echocardiographic parameters of patients
and corresponding healthy controls
Parameters
SLE subgroup
RA subgroup
patients
(n = 24)
controls
(n = 25)
patients
(n = 13)
controls
(n = 15)
17/7
40B13
69B8
18/7
40B15
69B8
12/1
62B11
71B8
14/1
62B10
70B9
Two-dimensional echocardiography
Ao, mm
29B4
LA, mm
30B5
IVSth, mm
10B1
PWth, mm
9B1
LVDd, mm
49B4
LVDs, mm
33B3
FS, %
34B3
MOA, mm2
5.2B0.7
28B4
30B5
10B1
9B1
49B3
33B2
33B2
4.9B0.7
29B4
31B5
10B1
10B1
49B2
32B2
34B2
4.6B0.9
30B3
33B4
10B1
10B1
48B3
32B3
33B2
4.3B0.7
Pulsed Doppler echocardiography
E, cm W s –1
73B13
A, cm W s –1
69B12
E/A, ratio
1.08B0.21
DT, m
143B15
IVRT, ms
63B5
73B12
64B11
1.18B0.28
149B18
63B4
68B16
77B14
0.92B0.33
151B17
64B6
62B13
70B10
0.89B0.23
141B21
65B3
Clinical parameters
Gender, female/male
Age, years
Heart rate, b.p.m.
All values are given as means B SD. No significant differences were found for any of the
parameters analyzed. Ao = Aorta; LA = left atrium; IVSth = interventricular septum (wall
thickness); PWth = posterior wall (thickness); LVDd/s = left ventricular diameter at end
diastole/systole; FS = fractional shortening; MAO = mitral orifice area; E = peak early diastolic left ventricular inflow velocity; A = peak left ventricular inflow velocity at atrial contraction; E/A = ratio of (left ventricular) peak early diastolic inflow velocity to peak inflow velocity at atrial contraction.
of myocardial alteration in systemic autoimmune diseases, and thus be helpful in the well-timed treatment and
prevention of congestive heart failure in a large number of
patients.
A recent echocardiographic study on 29 patients who
successfully underwent cardioversion from atrial fibrillation has provided evidence that the determination of left
atrial systolic function by measuring atrial ejection force
(AEF) at left ventricular relaxation enables to assess atrial
contribution to the filling of the left ventricle [10]. Thus,
AEF serves equally as an indirect parameter of left ventricular diastolic function (i.e. to assess left ventricular
relaxation).
The purpose of our study was to analyze whether AEF
represents a sensitive and reliable parameter for the detection of cardiac alteration particularly in patients with SLE
or RA.
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Cardiology 1999;92:269–274
Patients and Methods
Patients and Healthy Control Groups
The study population consisted of 37 patients with systemic
autoimmune disorders (29 females and 8 males, mean age 48 B 16
years) and 40 healthy control subjects matched for gender and age
(32 females and 8 males, mean age 48 B 18 years). After informed
consent was obtained, the patients were divided into two subgroups
according to the type of the underlying autoimmune disease (table 1).
(i) Twenty-four patients had SLE (17 females and 7 males, mean age
40 B 13 years) with disease duration ranging from 10 months to 26
years (mean 7.2 B 6.6 years). Six patients (25%, 4 females and 2
males) had detectable anticardiolipin antibodies with low-to-moderate IgG levels (from 20 up to 80 ELISA units, mean value 49 B 29).
However, none of them had a clinically proven antiphospholipid syndrome, which is characterized by an elevated level of anticardiolipin
antibodies associated with recurrent venous and/or arterial thromboses, thrombocytopenia, and cutaneous vascular abnormalities.
Moreover, none of these patients had evidence of concomitant valvular lesions, which might generally serve as one of the most obvious
Jahns/Naito/Tony/Inselmann
clinical features of cardiac damage associated with high anticardiolipin IgG levels [3, 4]. Because of their restricted number and their
relatively low anticardiolipin levels, in the frame of the present study
these 6 patients were assigned to the SLE group without further subgroup analysis. (ii) The other subgroup included 13 patients with RA
(12 females and 1 male, mean age 62 B 11 years), and disease duration ranged from 6 months to 47 years (mean 6.5 B 12.7 years).
Because of clear differences in the clinical baseline characteristics
of our study population (mean age, gender, table 1) for each of the
two patient subgroups a corresponding control collective was selected: 25 healthy subjects (18 females and 7 males, mean age 40 B 15
years) were compared with the SLE patients, and another 15 healthy
individuals (14 females and 1 male, mean age 62 B 10 years) served
as controls for the RA subgroup.
All the SLE and RA patients were in clinical remission at the time
of our study. None of the patients or control subjects had evidence of
congenital heart disease, valvular heart disease, renal vascular disease, left ventricular hypertrophy (indicating concomitant hypertension), heart failure, or prior myocardial infarction in clinical history.
All individuals included in our study had normal blood pressure, and
none of them had a clinical history of hypertension and/or antihypertensive treatment. Moreover, no electrocardiographic abnormalities
were found at rest or during exercise stress test in any of the subjects
analyzed.
Echocardiographic Examinations
The study was performed utilizing a Hewlett-Packard Sonos 2500
with a 2.5-MHz transducer. Two-dimensional and pulsed Doppler
echocardiograms were obtained at rest with the patient placed in the
left lateral position. Left ventricular chamber size, wall thickness,
and wall motion were measured by two-dimensional and M-mode
echocardiography according to a standard procedure [11].
Pulsed Doppler (transmitral) left ventricular inflow velocities
were obtained from an apical four-chamber view, placing the Doppler sample volume exactly between the tips of the mitral leaflets. In
this position, peak left ventricular inflow velocities during early diastole and upon atrial contraction were measured and recorded at a
paper speed of 100 mm W s –1 for further analysis.
Deceleration time (DT) was calculated by computer-aided regression analysis of the transmitral inflow velocities from peak velocity
in early diastole [E, (m W s –1)] to the baseline (deceleration rate, fig. 1,
time interval E-DT). Isovolumetric relaxation time (IVRT) was
defined as the period between the closure of the aortic valve and the
onset of transmitral inflow (fig. 1, time interval AVCA-IVRT). On
the Doppler recordings, closure of the aortic valve is generally indicated by the typical ‘(aortic) valve closure artifact’ (fig. 1) [12].
Atrial Ejection Force
AEF was determined as previously described [10], using the equation
AEF = 0.5 ! Ú ! mitral orifice area ! (peak A velocity)2,
with Ú corresponding to the density of blood (Ú = 1.06 W g W cm –3), and
peak A velocity to the highest (in-)flow velocity recorded at atrial
contraction (A, [m W s –1]).
Mitral annulus diameter (d) was obtained from an apical fourchamber view, and mitral orifice area was calculated as  W d2/4,
assuming the shape of the annulus to be circular.
The unit of the force is dynes (or g W cm/s –2).
Cardiac Alterations in Autoimmune
Diseases
Fig. 1. Transmitral left ventricular inflow velocity pattern obtained
by pulsed Doppler echocardiography. Parameters derived are:
E = Peak early diastolic left ventricular inflow velocity; A = left ventricular inflow velocity at atrial contraction; DT = deceleration (by
extrapolation of E to the baseline); IVRT = isovolumetric relaxation
time; AVCA = aortic valve closure artifact.
Reproducibility of Measurements
To estimate the accuracy of our measurements, the intra- and
interobserver variability was calculated for all echocardiographic
parameters obtained from 15 randomly selected patients and 15
healthy control subjects (two-dimensional as well as pulsed Doppler
echocardiograms).
In our study, intraobserver variability was less than 4.5%, and
interobserver variability less than 7.5%.
Biochemical Analysis
Serum of the SLE patients was isolated from routinely obtained
venous blood samples (within 24 h before/after the echocardiographic study). Titers of IgG and IgM anticardiolipin antibodies were
measured by an enzyme-linked immunosorbent assay (ELISA) as
described elsewhere [13], and are expressed in arbitrary ELISA units
(normal mean values: 9 units for IgG, 8 units of IgM, normal range:
mean B 2 SD; increased IgG antibody levels: mild: 28–50 units,
moderate: 51–100 units, high: 1 100 units). Tests for the lupus anticoagulant or false-positive VDRL reactions were not routinely performed.
Statistical Analysis
All data are presented as means B SD. Values for patients and
controls were tested for significance by ANOVA, and for the subgroup analysis by Scheffé’s F test [14].
Cardiology 1999;92:269–274
271
trol groups (n = 25 or 15, respectively), a statistically significantly elevated AEF was obtained for these two types
of systemic autoimmune disease (SLE subgroup: AEF =
13.3 B 4.2 vs. 10.8 B 4.0 kdyn, p ! 0.05; RA subgroup:
AEF = 15.2 B 7.0 vs. 11.2 B 2.1 kdyn, p ! 0.05; fig. 2).
Only a minor fraction (25%, n = 6; 4 females and 2
males) of SLE patients had detectable low-to-moderate
levels of anticardiolipin IgG antibodies without clinical
signs of an antiphospholipid syndrome (APS) or evidence
for concomitant valvular lesions.
Discussion
Fig. 2. Mean values of echocardiographically determined AEF from
patients with systemic autoimmune diseases (hatched columns) and
the corresponding healthy controls, matched for gender and age
(open columns). Error bars indicate the SD of the respective mean
values. * p ! 0.05; ** p ! 0.01.
Results
Clinical Characteristics and Conventional Parameters
of Echocardiography
No significant differences were obtained between
healthy subjects and patients suffering from SLE or RA
with respect to heart rate, echocardiographically determined cardiac diameters, and/or the structure and function of the cardiac valves. None of the patients or healthy
controls presented left ventricular hypertrophy (suggesting concomitant hypertension), regional cardiac wall motion abnormalities or significant pericardial effusion. In
addition, there were virtually no differences between
patients and controls in the following (dynamic) echocardiographic parameters: fractional shortening, ratio of
peak early diastolic filling velocity to peak filling velocity
at atrial contraction (E/A ratio), DT and IVRT (table 1).
Atrial Ejection Force
Overall, AEF was significantly higher in the patients
with systemic autoimmune disorders than in the healthy
controls (AEF = 14.0 B 5.4 vs. 11.0 B 3.5 kdyn, p ! 0.01;
fig. 2). Even when comparing the SLE (n = 24) or RA subgroups (n = 13) separately with their corresponding con-
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Cardiology 1999;92:269–274
Assessment of Cardiac Alteration in Systemic
Autoimmune Disorders
Several morphological and/or functional studies have
demonstrated cardiac alterations in a substantial fraction
of patients suffering from systemic autoimmune disorders
[1–7]. From these studies it was concluded that abnormalities in the diastolic filling pattern of the left ventricle
represent one of the earliest indicators of cardiac involvement in systemic autoimmune disease: in most of the
patients analyzed, an alteration in left ventricular diastolic function was apparent before the onset of systolic dysfunction and/or the development of structural and morphological cardiac abnormalities [3, 5–7, 9]. Some earlier
echocardiographic studies utilized the pulsed Doppler
transmitral flow pattern to estimate the degree of left ventricular diastolic dysfunction in patients with systemic
autoimmune disorders. Parameters determined in the
frame of these studies included the peak left ventricular
inflow velocity in early diastole (E-wave), the left ventricular inflow velocity at atrial contraction (A-wave), and/or
IVRT [6, 7]. However, in our study, no significant differences could be detected between healthy subjects and
patients suffering from SLE or RA by using these parameters. By contrast, AEF differed significantly between patients and healthy control subjects. Thus, our results confirm the usefulness of echocardiographic determination of
left AEF to noninvasively assess atrial contribution to left
ventricular diastolic performance, as recently proposed
by Manning et al. [10]. In addition, our data demonstrate
that AEF represents a highly sensitive and suitable marker for early detection of left ventricular diastolic filling
abnormalities in patients with SLE or RA. It has been
commonly considered that cardiac involvement may be
clinically silent in a large number of patients suffering
from systemic autoimmune disorders, which contrasts
sharply to the high incidence of cardiac manifestations in
Jahns/Naito/Tony/Inselmann
autopsy studies [2, 15, 16]. From our data it seems advisable to routinely determine AEF in addition to the other
established echocardiographic parameters of left ventricular diastolic function in order to permit an earlier and
more sensitive detection of cardiac abnormalities in the
clinical course of patients suffering from SLE or RA.
APS or amyloidosis sometimes complicates SLE or
RA. These manifestations are frequently associated with
cardiac abnormalities [3, 4, 17, 18]. However, in our
study none of the patients suffered from amyloidosis, and
although 25% of the patients (n = 6) from the SLE subgroup had detectable low-to-moderate anticardiolipin
IgG levels, none of them had valvular lesions, pericardial
effusion, or a clinically proven APS. Thus, we assume that
the abnormal left ventricular diastolic filling pattern seen
in our patients was neither related to amyloidosis nor to
APS.
Usefulness and Limitations of AEF as an Indirect
Marker of Left Ventricular Diastolic Function
Some previous reports indicated that AEF should
allow for a correct assessment of atrial contractility,
because the peak velocity of transmitral (in-)flow at atrial
contraction has been shown to be virtually independent of
left ventricular pre- and afterload [10, 19], whereas the
loading conditions have a major impact on the early diastolic peak (in-)flow velocities at left ventricular relaxation [20–22]. The ventricular filling pattern at atrial contraction has now generally been accepted as a valid
parameter to estimate left ventricular diastolic function
[6, 7, 10, 12, 21]. Accordingly, in the present study we
focussed on measuring AEF, a parameter that has recently
been proposed as a physiological indicator of atrial systolic performance [10]. A separate analysis of either
(i) peak inflow velocity at atrial contraction, or (ii) the calculated mitral orifice area revealed no significant differences between healthy individuals and patients with SLE
or RA. Because AEF is solely influenced by these two
parameters of the equation, we believe that the square of
the peak inflow velocity at atrial contraction has produced
a significant difference in AEF between the subgroups
analyzed and thus, finally accounts for the high sensitivity
of this marker for detecting left ventricular diastolic filling
abnormalities in systemic autoimmune diseases.
However, some limitations of this method have to be
mentioned. First, mitral orifice is not a constant diameter
during the cardiac cycle; moreover, in men the orifice is
nearly elliptic, while it was considered to be circular for
calculating the AEF according to Manning et al. [10]. On
the other hand it has been reported that the mitral orifice
Cardiac Alterations in Autoimmune
Diseases
area does not significantly change during atrial systole
[23]. Since our measurements were obtained by the same
method for all of the individuals analyzed, this limitation
should not substantially affect our results.
Second, when left ventricular hypertrophy is evident
from two-dimensional echocardiography or expected
from clinical history (suggesting coincidence of systemic
autoimmune disease and hypertension, which was not the
case in our study), left ventricular diastolic filling abnormalities should be considered as (typical) indicators of
hypertensive heart disease rather than indicators of cardiac alteration in the course of a systemic autoimmune
disease. However, the diagnosis of left ventricular hypertrophy does not exclude concomitant systemic autoimmune disorders.
Finally, AEF cannot be correctly determined in patients with atrial arrhythmia, such as atrial fibrillation,
and/or in patients with conduction disturbances at the
sinuatrial or atrioventricular level [10], since the determination of AEF is based on the analysis of the peak left
ventricular inflow velocity at regular (physiological) atrial
contraction (A-wave). In such cases (arrhythmia, conduction disturbance) the loading conditions of the left ventricle may differ considerably, and the lack of a coordinated
contraction of the left ventricle and atrium [regularly
occurring after the early diastolic left ventricular filling
period (E-wave)] leads to a misinterpretation of AEF.
Conclusion and Perspectives
We explored whether AEF could represent an additional sensitive and suitable marker for noninvasively
diagnosing cardiac manifestation in the course of systemic autoimmune disorders. In autoimmune diseases,
impaired left ventricular diastolic function is now generally accepted as an early indicator of accompanying cardiac alteration [3, 5–7, 9]. Our data indicate that AEF
appears to be a more sensitive parameter for the detection
of left ventricular diastolic filling abnormalities in patients suffering from SLE or RA than other established
echocardiographic parameters of cardiac diastolic function. Therefore, a broad (additional) application of this
noninvasive and highly sensitive method might influence
early treatment and thereby contribute to prevent congestive heart failure in a number of patients suffering from
systemic autoimmune disorders. A longitudinal follow-up
study with this aim is currently under way.
Cardiology 1999;92:269–274
273
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